Contemporary Oral Medicine

Camile S.
Farah
Ramesh Balasubramaniam
Michael J. McCullough
Editors
Contemporary
Oral Medicine
A Comprehensive Approach to Clinical Practice
https://t.me/MBS_MedicalBooksStore
Contemporary Oral Medicine
Camile S. Farah
Editors
Contemporary Oral
Medicine
A Comprehensive Approach to
Clinical Practice
With 1623 Figures and 299 Tables
Editors
Camile S. Farah Ramesh Balasubramaniam
UWA Dental School and Oral Health UWA Dental School and Oral Health
Centre of Western Australia Centre of Western Australia
Faculty of Health and Medical Sciences Faculty of Health and Medical Sciences
University of Western Australia University of Western Australia
Perth, WA, Australia Perth, WA, Australia
Oral Anatomy, Medicine, and Surgery Section
Melbourne Dental School
Faculty of Medicine, Dentistry and Health Sciences
The University of Melbourne
Carlton, VIC, Australia
ISBN 978-3-319-72301-3 ISBN 978-3-319-72303-7 (eBook)

ISBN 978-3-319-72302-0 (print and electronic bundle)
https://doi.org/10.1007/978-3-319-72303-7
Library of Congress Control Number: 2018960941
# Springer Nature Switzerland AG 2019

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This book is dedicated to our families
Tess, Maya, Hannah, and Kayla
Davinia, Dhruva, and Mandira
Lindy, Meredith, Amelia, and Edward
in appreciation of our mentors, students, and patients.
Camile S. Farah
Foreword
The dominant pattern of education of oral health professionals and provision

of health care of oral and maxillofacial diseases throughout the world is
provided by a separate dental profession frequently leading to the unfortunate
separation of oral care from whole patient care.
In order to correct this deficiency, the specialty of oral medicine was
pioneered by dentists including Lester Burket, Sol Silverman, Thomas Lehner,
and David Mason, among others, who understood the growing importance of
teaching medicine to dental students and developing a dental specialty devoted
to the diagnosis and medical management of oral and maxillofacial disease as
well as dental treatment for patients with complex medical disorders. Their
vision and foresight resulted in the development of an international specialty
devoted to the expanding medical needs of patients with oral and maxillofacial
diseases.
Recent major medical progress has resulted in the development of new
drugs and procedures to more successfully treat cancer, infectious diseases,
and cardiovascular and neuromuscular diseases. These dramatic advances
have resulted in an aging population taking multiple drugs and who often
have undergone multiple surgical procedures to maintain their health. This has
resulted in increasing the complexity of diagnosis and management of oral and
maxillofacial diseases. In addition, the undergraduate medical education often
includes minimal training of management of oral diseases and complications,
broadening the scope of the disorders managed by oral medicine specialists.
There remains no doubt that all general and specialty dentists trained to care
for patients in the twenty-first century will require a solid foundation in
medicine and that proper care of complex medical problems of the maxillofa-
cial region will require an increasing number of highly trained specialists in
oral medicine to work closely with other medical, surgical, and dental
colleagues.
Drs. Farah, Balasubramaniam, and McCullough have made an important
contribution to oral medicine by organizing and writing a new, modern,
comprehensive textbook developed for the oral medicine specialist but
which also serves as an important reference for other dental and medical
practitioners. The editors should be congratulated for their efforts and their
choice of coauthors who are internationally recognized academics,
researchers, and clinicians in their fields who have authored comprehensive,
up-to-date, clearly written chapters.
vii
viii Foreword
The text starts with scholarly discussions of principles of diagnosis and

focused discussions of clinical immunology, neurophysiology, and neurosen-
sory disorders and then proceeds to detailed well-organized discussions of oral
mucosal, head and neck, pain, and neurosensory disorders.
The sections on orofacial pain are very welcome, as physicians including
headache specialists and those with a special interest in pain often have limited
knowledge in this area. We are pleased to note that the orofacial pain sections
are comprehensive and provide a welcome biopsychological approach to
management which will be valuable not just to specialists in oral medicine
but to a range of other health-care professionals.
It is encouraging to note the emphasis placed on a science-based approach
to temporomandibular disorders as recent large studies provide evidence that
they may be precursors of other chronic pain conditions requiring management
by multidisciplinary teams.
The three of us are delighted to have been asked to write this foreword. We
are based in three corners of the globe but all from English-speaking nations
with a common educational heritage. We realize the challenges of writing a
text devoted to providing the best oral and maxillofacial care to varied cultures,
economies, and societies with differing disease burdens.
We congratulate the editors and authors of this text for their accessible and
egalitarian approach and their major contribution to the progress of interna-
tional oral medicine.
Philadelphia, USA Martin S. Greenberg

Gold Coast, Australia Newell Johnson
London, UK Joanna Zakrzewska
Preface
Oral medicine is that specialist branch of dentistry concerned with the diag-
nosis, prevention, and predominantly nonsurgical management of medically
related disorders and conditions affecting the oral and maxillofacial region, in
particular oral mucosal disease and orofacial pain, as well as the oral health
care of medically complex patients. As such, it occupies a unique interface
between dentistry and medicine, bringing them together for the advancement
of both oral and systemic health. Progressive patient care in oral medicine
requires a thorough understanding of many disciplines of medicine and den-
tistry. Likewise, other cognate disciplines benefit from their understanding of
the art and science of oral medicine for overall patient management.
Contemporary Oral Medicine is the most comprehensive textbook in oral
medicine and includes 45 chapters arranged into 3 volumes. Volume 1 covers
foundation and diagnostic head and neck sciences in oral medicine; Vol.
2 covers oral and maxillofacial diseases and disorders; and Vol. 3 covers
orofacial pain and dental sleep medicine. It is a fresh holistic approach to
clinical practice.
This unique all-inclusive international textbook brings together 149 world-
renowned authors from 25 different countries, covering a wide variety of
disciplines including oral medicine, oral and maxillofacial pathology, dento-
maxillofacial radiology, head and neck radiology, oral and maxillofacial sur-
gery, head and neck surgery, dermatology, anatomy, pathology, immunology,
microbiology, physiology, general medicine, neurology, pain medicine, and
sleep medicine. The book is fully referenced and includes 1623 figures com-
posed of thousands of black and white and color images, in addition to
299 tables covering a spectrum of diagnostic algorithms, treatment regimes,
and photographs of all disease processes related to oral medicine.
In this book, we have focused our attention on the commonly accepted
designation of oral medicine and dedicated extensive parts of the book to its
content. We acknowledge that oral medicine clinicians may encounter more
common conditions of the oral cavity such as dental caries and periodontal
diseases, but these are only covered in brief as they sit better in the realm of
pediatric dentistry, restorative dentistry, endodontics, and periodontics. Our
focus was on diseases and conditions that are diagnosed and managed on a
regular basis by oral medicine specialists internationally. Each chapter is
authored by a group of international experts in their designated field, offering
the book a consensus approach to diagnosis and treatment of oral medicine
ix
x Preface
conditions without favoring one school of thought over another or one geo-
graphical area over another.
We have pitched this book at the level of a new graduate in oral medicine,
attempting to stay true to competencies of newly graduated specialists as
described in advanced training programs across the globe particularly
Australia, New Zealand, the United Kingdom, and the United States. We
acknowledge that the remit of practice of oral medicine in various countries
around the world differs based on local health system requirements, legisla-
tion, regulation, politics, disease distribution, interest, and workforce
demands. In compiling this book however, we have taken a comprehensive
all-encompassing approach, rather than limit the remit of practice, and hence
the designation of a subtitle, A Comprehensive Approach to Clinical Practice.
Another purposeful approach was the comprehensiveness of each of the
chapters with deliberate overlap of topics and conditions covered and the
general headings used in each chapter. Many of the diseases and disorders
outlined in the book can be covered under a myriad of headings and chapter
titles. We felt it was very important for the reader to encounter the material and
interact with the content from multiple points of view, taking into account the
many ways possible to classify and manage ailments of the head and neck
region. Importantly, we felt that each chapter should be self-contained, inde-
pendent but cross-referenced with other chapters, and also structured in a way
that provided consistency and purpose for the reader. Where we felt the topic
should be covered in detail we did, while in other instances we only briefly
mention the same condition in a different context for completeness. The
intention was that if a reader only read a chapter of particular interest, its
contents would suffice, but if the reader wished to explore the content in more
detail, then reading more of the book would provide an all-inclusive treatise.
We trust you will enjoy reading and using this text as much as we have
enjoyed writing and compiling it.
January 2019 Camile S. Farah

Acknowledgments
This book is a culmination of 4 years’ work. Our dream was to realize a

comprehensive textbook in oral medicine of international standing, and this
would not have been possible without the expert contributions and significant
input from luminary contributing authors, colleagues, mentors, and friends
from around the world. We thank the contributing authors for their dedication
and patience, while we worked through multiple versions of revised and edited
chapters to produce a product of the highest standard. We are grateful to those
who were willing to participate in such a massive undertaking, to give gener-
ously of their time and resources, and to join us in an international coming
together of knowledge, expertise, and collegiality in our chosen discipline. The
process has been both rewarding and instructive.
The comprehensiveness and clinical usefulness of this book are enhanced
by the many illustrations, clinical images, radiographs, and photomicrographs
generously supplied by many colleagues from all around the world. We are
indebted to our many colleagues who have shared their cases so generously in
an effort to improve the text, and they have been credited in the figure legends
for their contributions. In particular, we would like to thank Dr. Hala Al Janaby
for her original hand-drawn illustrations throughout the text and for the
stunning front cover, Dr. Andy Whyte for the many detailed radiographic
images he has provided, and Dr. Robert Anthonappa for the many cases related
to pediatric dentistry. Special thanks also to Drs. Rudolf Boeddinghaus, Marie
Matias, Kurt Gebauer, Mariana Villarroel Dorrego, Ajay Parihar, Tim
Hodgson, Chady Sader, Chris Van Vliet, Chris Dhepnorrarat, Amanda
Phoon Nguyen, Lalima Tiwari, and Qutaibah Alfadalah. We are also thankful
to all our patients who have allowed us to care for them but also allowed us to
document their cases for presentation in this book. Their contributions are a
reminder of why we do what we do.
We would like to thank our assistant staff Jane Burnell, Elai Justo, and
Maya Janik for their dedicated editing, referencing, and overall assistance and
Penny Comans for the provision of articles. We acknowledge the staff at
Springer Nature for their hard work, organization, and dedication to this
project including Karin Bartsch, Rebecca Urban, Tanja Maihoefer, Wilma
McHugh, Susanne Friedrichsen, Alison Wolf, Shruti Datt, and Sharmila
Thirumaniselvan.
Finally, we are eternally indebted to our families for their love, support, and
patience. Over the 4-year life-span of this book, we have spent significant
xi
xii Acknowledgments
portions of time away from them writing and editing this comprehensive text.
They have endured our neglect, while we simultaneously received their
encouragement. Their understanding of our passion for our specialty and
their tolerance for our desire to complete this project are equally appreciated.
Camile S. Farah
Contents
Volume 1
Normal Variation in the Anatomy, Biology, and Histology of

the Maxillofacial Region . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Rita Hardiman, Omar Kujan, and Nabil Kochaji
Interface Between Oral and Systemic Disease . . . . . . . . . . . . . . . . . 67
Michele D. Mignogna and Stefania Leuci
Clinical Evaluation of Oral Diseases . . . . . . . . . . . . . . . . . . . . . . . . 137
Chizobam N. Idahosa and A. Ross Kerr
Diagnostic Imaging Principles and Applications in Head and
Neck Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
Andy Whyte, Rudolf Boeddinghaus, and Marie Anne Teresa
J. Matias
Laboratory Medicine and Diagnostic Pathology . . . . . . . . . . . . . . . 255
Tim Hodgson, Barbara Carey, Emma Hayes, Richeal Ni Riordain,
Priya Thakrar, Sarah Viggor, and Paula Farthing
Clinical Immunology in Diagnoses of Maxillofacial Disease . . . . . . 315
Nathaniel Treister, Arturo Saavedra, and Alessandro Villa
Soft and Hard Tissue Operative Investigations in the Diagnosis
and Treatment of Oral Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
Marieke T. Brands, Ivan Alajbeg, Peter A. Brennan, and
Camile S. Farah
Pharmacotherapeutic Approaches in Oral Medicine . . . . . . . . . . . 401
Sandra Goncalves, Ray A. Dionne, Geraldine Moses, and
Marco Carrozzo
Odontogenic Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471
Takashi Takata, Mutsumi Miyauchi, Ikuko Ogawa, and Alan Mighell
Non-odontogenic Bone Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . 555
Hedley Coleman, Jos Hille, Willie van Heerden, Sonja Boy, and
Annabelle Mahar
xiii
xiv Contents
Head and Neck Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627

Moni A. Kuriakose, Swagnik Chakrabarti, Sok Ching Cheong,
Luiz P. Kowalski, Tiago Novaes Pinheiro, and Camile S. Farah
Cutaneous Pathology of the Head and Neck . . . . . . . . . . . . . . . . . . 763
Tami Yap, Johannes S. Kern, Benjamin Wood, and
Laura Scardamaglia
Volume 2
Odontogenic Bacterial Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . 819

Stuart G. Dashper, Alf Nastri, and Paul V. Abbott
Non-odontogenic Bacterial Infections . . . . . . . . . . . . . . . . . . . . . . . 871
Agnieszka M. Frydrych and Camile S. Farah
Oral and Maxillofacial Fungal Infections . . . . . . . . . . . . . . . . . . . . 935
Maddalena Manfredi, Luciano Polonelli, Laura Giovati,
Ali Alnuaimi, and Michael J. McCullough
Oral and Maxillofacial Viral Infections . . . . . . . . . . . . . . . . . . . . . . 983
Stephen Porter, Jair C. Leão, and Luiz Alcino Gueiros
Oral Ulcerative Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1009
Giovanni Lodi, Elena Varoni, Jairo Robledo-Sierra,
Alessandro Villa, and Mats Jontell
Oral Lichen Planus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1043
Michael J. McCullough, Mohammad S. Alrashdan, and
Nicola Cirillo
Oral Vesicular and Bullous Lesions . . . . . . . . . . . . . . . . . . . . . . . . . 1083
Stephen J. Challacombe and Jane F. Setterfield
Gingival Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1143
Anne Hegarty and Alison Rich
Pigmented Lesions of the Oral Mucosa . . . . . . . . . . . . . . . . . . . . . . 1175
Eric T. Stoopler and Faizan Alawi
White and Red Lesions of the Oral Mucosa . . . . . . . . . . . . . . . . . . 1207
Maryam Jessri, Hani Mawardi, Camile S. Farah, and
Sook-Bin Woo
Oral Mucosal Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1249
Camile S. Farah, Omar Kujan, Stephen Prime, and
Rosnah Binti Zain
Salivary Gland Disorders and Diseases . . . . . . . . . . . . . . . . . . . . . . 1437
Siri Beier Jensen, Arjan Vissink, and Norman Firth
Oral Manifestations of Systemic Diseases and Their Treatments . . . 1523
Sue-Ching Yeoh, Hong Hua, Juan Fernando Yepes, and
Douglas E. Peterson
Contents xv
Pediatric Oral Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1641

Anastasia Georgiou, Angus Cameron, and
Halitosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1719
Jaisri R. Thoppay, Andreas Filippi, Katharine Ciarrocca,
John Greenman, and Scott S. De Rossi
Volume 3
Neurophysiology of Orofacial Pain . . . . . . . . . . . . . . . . . . . . . . . . . 1749

Koichi Iwata, Mamoru Takeda, Seog Bae Oh, and
Masamichi Shinoda
Clinical Evaluation of Orofacial Pain . . . . . . . . . . . . . . . . . . . . . . . 1773
Jeffrey P. Okeson and Isabel Moreno Hay
Biopsychosocial Aspects of Orofacial Pain . . . . . . . . . . . . . . . . . . . 1797
Richard Ohrbach and Justin Durham
Classification of Orofacial Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1819
Gary D. Klasser, Jean-Paul Goulet, Antoon De Laat, and
Daniele Manfredini
Masticatory Muscle Pain and Disorders . . . . . . . . . . . . . . . . . . . . . 1843
Tommaso Castroflorio, Andrea Bargellini, Andrea Deregibus, and
Peter Svensson
Internal Derangements of the Temporomandibular Joint . . . . . . . 1881
James J. R. Huddleston Slater and Reny de Leeuw
Arthritic Conditions Affecting the Temporomandibular Joint . . . . 1919
L. G. Mercuri and S. Abramowicz
Headache . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1955
Steven J. Scrivani, Steven B. Graff-Radford, Shehryar N. Khawaja,
and Egilius L. H. Spierings
Neurovascular Orofacial Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1983
Yair Sharav, Yaron Haviv, Galit Almoznino, and Rafael Benoliel
Neuropathic Orofacial Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2005
Olga A. Korczeniewska, Eli Eliav, and Rafael Benoliel
Oral Dysesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2081
Giulio Fortuna, Joel Napenas, Nan Su, Miriam Gruskha, and
Gary D. Klasser
Neurosensory Disturbances Including Smell
and Taste . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2107
Saravanan Ram, Tomoko Wada, and Soma Sahai-Srivastava
Orofacial Pain in the Medically Complex Patient . . . . . . . . . . . . . . 2135
Martina K. Shephard and Gary Heir
xvi Contents
Orofacial Pain in Patients with Cancer and Mucosal Diseases . . . . 2187

Noam Yarom, Herve Sroussi, and Sharon Elad
Orofacial Pain and Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2213
Barry J. Sessle, Kazunori Adachi, Dongyuan Yao,
Yoshitaka Suzuki, and Gilles J. Lavigne
Sleep Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2241
David Hillman, Olivier Vanderveken, Atul Malhotra, and Peter
Eastwood
Sleep Bruxism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2267
Ramesh Balasubramaniam, Daniel Paesani, Kiyoshi Koyano,
Yoshihiro Tsukiyama, Maria Clotilde Carra, and Gilles J. Lavigne
Oral Appliance Therapy for Sleep-Disordered Breathing . . . . . . . 2303
Joachim Ngiam, Kate Sutherland, Ramesh Balasubramaniam,
Marie Marklund, Fernanda Almeida, and Peter Cistulli
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2333
About the Editors
Camile S. Farah BDSc, MDSc (OralMed, OralPath), PhD, GCEd (HE),

GCExLead, FRACDS (OralMed), FOMAA, FIAOO, FICD, FPFA
Professor of Oral Oncology
Dean and Head, UWA Dental School, University of Western Australia
Director, Oral Health Centre of Western Australia
Convenor, Oral Medicine Postgraduate Training Program, UWA Dental
School, University of Western Australia
Oral Medicine Consultant, Oral Health Centre of Western Australia
Oral Medicine Specialist, Perth Oral Medicine & Dental Sleep Centre
Consultant, Qscan Radiology Clinics
Camile is Professor of Oral Oncology, Dean and Head of the UWA Dental
School, and Director of the Oral Health Centre of Western Australia at the
University of Western Australia, Perth, Australia.
Camile is a Registered Specialist in both Oral Medicine and Oral Pathology
with subspecialty training in Oral Oncology. He is a Consultant in Oral
Medicine at the Oral Health Centre of WA and maintains a part-time private
practice in Oral Medicine at Perth Oral Medicine & Dental Sleep Centre
focused on oral mucosal diseases, salivary gland pathology, bone pathology,
xvii
xviii About the Editors
and orofacial pain. He is Convenor of the postgraduate training program in

Oral Medicine at the UWA Dental School, a Member of the Head & Neck
Cancer Multidisciplinary Team at Sir Charles Gairdner Hospital, Director of
the Australian Centre for Oral Oncology Research & Education, and Consul-
tant at Qscan Radiology Clinics.
Camile is a Fellow of the Royal Australasian College of Dental Surgeons
(Oral Medicine) by examination, the Oral Medicine Academy of Australasia,
the International Academy of Oral Oncology, the International College of
Dentists, and the Pierre Fauchard Academy. He is the Inaugural and Past
President of the Oral Medicine Academy of Australasia, Past President of
the Australian and New Zealand Division of the International Association for
Dental Research, President of the Asia Pacific Region of the International
Association for Dental Research, Chairman of the Australian Dental Research
Foundation, and Past Chairman of its Research Advisory Committee.
Camile has authored more than 160 peer-reviewed publications including
18 book chapters. He has personally attracted $7.5 million in competitive
research funding, has been involved in other successful collaborative grants
totaling nearly $10 million, and has mentored over 50 postgraduate students
and postdoctoral staff. Camile is Associate Editor of Journal of Oral Pathol-
ogy & Medicine and Oral Cancer and Reviewing Editor for Oral Diseases.
Camile is clinician-scientist with expertise in oral oncological translational
research. His clinical and laboratory research focuses on optical imaging
modalities, molecular genomics, clinical trials in early detection and oncolog-
ical surgery, and personalized patient care particularly related to oral cancer
and oral potentially malignant disorders. His laboratory has explored diagnos-
tic biomarker signatures for oral premalignant lesions, predictive biomarker
profiles for oral cancer progression, and a multigene discriminatory biomarker
panel for oral squamous cell carcinoma and epithelial dysplasia. He is a
supporter of patient and clinician education and professional development
and overall advocacy for patients with oral cancer.
Ramesh Balasubramaniam BSc, BDSc, MS, Cert Orofacial Pain, Cert Oral
Medicine, MRACDS (OralMed), ABOP, FOMAA, FADI, FPFA, FICD
About the Editors xix
Clinical Associate Professor, UWA Dental School, University of Western

Australia
Oral Medicine Consultant, Oral Health Centre of Western Australia
Oral Medicine Consultant, Perth Children’s Hospital
Oral Medicine Specialist, Perth Oral Medicine & Dental Sleep Centre
Ramesh graduated with a BDSc from the University of Western Australia in

2000 and subsequently practiced General Dentistry. In 2006, he completed a
certificate and Master of Science degree in Orofacial Pain at the University of
Kentucky. While at the University of Kentucky, Ramesh also underwent
training in the field of Dental Sleep Medicine. He is a Diplomate of the
American Board of Orofacial Pain. In addition, Ramesh completed a specialist
training in Oral Medicine as well as a Fellowship in Interdisciplinary Geriatrics
at the University of Pennsylvania in 2008.
Ramesh has numerous peer-reviewed publications, has contributed to sev-
eral chapters in various texts, and coedited the May 2008 Oral and Maxillo-
facial Surgery Clinics of North America on Orofacial Pain and Dysfunction. In
addition, he serves as a reviewer for a number of peer-reviewed journals.
Ramesh has an appointment as a Clinical Associate Professor at the UWA
Dental School, University of Western Australia, and is actively involved in
teaching and research. He also holds public appointments at the Oral Health
Centre of Western Australia and the Perth Children’s Hospital. He is President-
Elect of the Oral Medicine Academy of Australasia having served as its
Secretary. His Oral Medicine Specialist practice focuses on orofacial pain,
oral diseases and disorders, and dental sleep medicine.
Michael J. McCullough BDSc, MDSc (OralMed, OralPath), PhD, FRACDS

(OralMed), FOMAA, FPFA, FICD
Professor of Oral Medicine
Deputy Head, Melbourne Dental School, University of Melbourne
Convenor, Oral Medicine Postgraduate Training Program, Melbourne Dental
School, University of Melbourne
Oral Medicine Consultant, Melbourne Dental School, University of Mel-
bourne
Michael is Professor of Oral Medicine at the Melbourne Dental School, the

University of Melbourne. He is the Convenor of both the postgraduate and
xx About the Editors
graduate courses in Oral Medicine, has published 128 articles in peer-reviewed

scientific journals, and was on the Expert Panel for both editions of the
Therapeutic Guidelines book titled Oral and Dental. Michael is an Oral
Medicine Clinical Consultant to the Royal Dental Hospital of Melbourne,
the Royal Melbourne Hospital, and the University of Melbourne’s Dental
Clinic.
Michael gained a bachelor’s degree in Dental Science in 1982, a master’s
degree in Oral Medicine and Oral Pathology, and a PhD in 1995, all from the
University of Melbourne. He spent several years as a Postdoctoral Research
Fellow at Stanford University in California during 1996 and 1997, followed by
3 years as a Lecturer in Oral Medicine at the Eastman Dental Institute,
University College London. Michael has 27 years of experience in clinical
and academic Oral Medicine, was an Inaugural Fellow of the Royal Austral-
asian College of Dental Surgeons in Oral Medicine by examination, and is a
Fellow of the International College of Dentists, the Pierre Fauchard Academy,
and the Oral Medicine Academy of Australasia.
Michael has supervised to completion 18 research higher degree students,
and currently he is Principal Supervisor to 4 PhD students and co-supervisor to
3 PhD and 6 MPhil students. Michael has published 128 clinical and scientific
articles including 3 book chapters. His work is mostly published in ERA A*/A
ranked journals in the highest-ranking journals in his specialty.
Michael is the current President of the Oral Medicine Academy of Austral-
asia and the Inaugural Chair of the Australian and New Zealand Council of
Dental Specialists. He was the Chairperson of the Dental Therapeutics Com-
mittee of the Australian Dental Association from 2006 to 2012 and an active
member until 2016. He was on the Expert Panel of the Therapeutic Guidelines
book, Oral and Dental, whose first edition was in 2007 and the revised second
edition published in 2012. Michael has been a member of the Australian
Dental Research Foundation’s Research Advisory Committee since 2013
and served as its Chair from 2016 to 2018.
Contributors
Paul V. Abbott UWA Dental School and Oral Health Centre of Western
Australia, The University of Western Australia, Perth, Australia
S. Abramowicz Oral and Maxillofacial Surgery and Pediatrics, Emory

University and Children’s Healthcare of Atlanta, Atlanta, GA, USA
Kazunori Adachi Division of Pharmacology, Meikai University School of

Dentistry, Saitama, Japan
Ivan Alajbeg University of Zagreb School of Dental Medicine, Zagreb,

Croatia
Faizan Alawi Department of Pathology, University of Pennsylvania School

of Dental Medicine, Philadelphia, PA, USA
Fernanda Almeida Department of Oral Health Sciences, Faculty of

Dentistry, The University of British Columbia, Vancouver, BC, Canada
Galit Almoznino Department of Oral Medicine, Sedation and Maxillofacial

Imaging, School of Dental Medicine, Hebrew University-Hadassah, Jerusalem,
Israel
Department of Oral Medicine, Oral and Maxillofacial Center, Medical Corps,
Israel Defense Forces, Tel-Hashomer, Israel
Ali Alnuaimi Oral Anatomy, Medicine, and Surgery Section, Melbourne,

Dental School, Faculty of Medicine, Dentistry and Health, Sciences, The
University of Melbourne, Carlton, VIC, Australia
Mohammad S. Alrashdan Faculty of Dentistry, Department of Oral

Medicine and Oral Surgery, Jordan University of Science and Technology,
Irbid, Jordan
Ramesh Balasubramaniam UWA Dental School and Oral Health Centre of

Western Australia, Faculty of Health and Medical Sciences, University of
Western Australia, Perth, WA, Australia
xxi
xxii Contributors
Andrea Bargellini Gnathology Unit, Department of Surgical Sciences,

Lingotto Dental School, University of Torino, Torino, Italy
Specialization School of Orthodontics, Department of Surgical Sciences,
Dental School, University of Torino, Torino, Italy
Rafael Benoliel Department of Diagnostic Sciences, Rutgers School of

Dental Medicine, Rutgers State University of New Jersey, Newark, NJ, USA
Rudolf Boeddinghaus Perth Radiological Clinic, Subiaco, WA, Australia

University of Western Australia, Nedlands, WA, Australia
Sonja Boy Department of Oral Pathology, Sefako Makgatho Health Sciences

University, Pretoria, South Africa
Marieke T. Brands Department of Oral and Maxillofacial Surgery, Queen

Alexandra Hospital, Portsmouth, UK
Peter A. Brennan Department of Oral and Maxillofacial Surgery, Queen

Angus Cameron The University of Sydney, Sydney, NSW, Australia

University of Newcastle, Ourimbah, NSW, Australia
Charles Sturt University, Sydney, NSW, Australia
Barbara Carey Eastman Dental Hospital, London, UK
Maria Clotilde Carra Department of Periodontology, Service of Odontology,

Rothschild Hospital, AP-HP, Université Paris 7 – Denis Diderot, U.F.R. of
Odontology, Paris, France
Marco Carrozzo Center for Oral Health Research, Department of Oral

Medicine, School of Dental Sciences, Newcastle University, Newcastle upon
Tyne, UK
Tommaso Castroflorio Gnathology Unit, Department of Surgical Sciences,

Swagnik Chakrabarti Head and Neck Oncology Services, Tata Memorial

Hospital, Mumbai, India
Stephen J. Challacombe Department of Oral Medicine, King’s College

London, London, UK
Guys and St Thomas’ Hospital NHS Foundation Trust, London, UK
Sok Ching Cheong Cancer Research Malaysia, CARIF Oral Cancer

Research Team, Subang Jaya, Malaysia
Katharine Ciarrocca Dental College of Georgia, Augusta University,

Augusta, GA, USA
Contributors xxiii
Nicola Cirillo Melbourne Dental School and Oral Health CRC, Faculty of
Medicine, Dentistry and Health Sciences, The University of Melbourne,
Peter Cistulli Centre for Sleep Health and Research, Department of
Respiratory and Sleep Medicine, Royal North Shore Hospital, Northern
Sydney Local Health District, St Leonards, NSW, Australia
Charles Perkins Centre and Northern Clinical School, University of Sydney,
Sydney, NSW, Australia
Hedley Coleman Department of Tissue Pathology and Diagnostic Oncology,
Pathology West, Westmead Hospital, ICPMR, Sydney, NSW, Australia
Stuart G. Dashper Melbourne Dental School, Oral Health Cooperative
Research Centre, The University of Melbourne, Melbourne, Australia
Antoon De Laat Department of Oral Health Sciences, K.U. Leuven, Leuven,
Belgium
Department of Dentistry, University Hospitals Leuven, Leuven, Belgium
Reny de Leeuw Division of Orofacial Pain, College of Dentistry, University
of Kentucky, Lexington, KY, USA
Scott S. De Rossi UNC School of Dentistry, Chapel Hill, NC, USA
Andrea Deregibus Gnathology Unit, Department of Surgical Sciences,
Ray A. Dionne Department of Pharmacology and Toxicology, Brody School
of Medicine, and Department of Foundational Sciences, School of Dental
Medicine, East Carolina University, Greenville, NC, USA
Justin Durham School of Dental Sciences, Newcastle University, Newcastle-
Upon-Tyne, UK
Peter Eastwood Centre for Sleep Science, School of Human Sciences,
University of Western Australia, Perth, Australia
West Australian Sleep Disorders Research Institute, Sir Charles Gairdner
Hospital, Perth, Australia
Sharon Elad Department of Oral Medicine, Eastman Institute for Oral
Medicine, University of Rochester Medical Center, Rochester, NY, USA
Eli Eliav Eastman Institute for Oral Health, School of Medicine and
Dentistry, University of Rochester Medical Center, Rochester, NY, USA
Camile S. Farah UWA Dental School and Oral Health Centre of Western
Australia, Faculty of Health and Medical Sciences, University of Western
Australia, Perth, WA, Australia
Paula Farthing School of Clinical Dentistry, University of Sheffield,
Sheffield, UK
xxiv Contributors
Andreas Filippi Department for Oral Surgery, Oral Radiology and Oral
Medicine and Center of Salivary Diagnostics and Hyposalivation, University
Center for Dental Medicine Basel, University of Basel, Basel, Switzerland
Norman Firth UWA Dental School, University of Western Australia,
Nedlands, WA, Australia
Giulio Fortuna Department of Diagnostic Sciences, Louisiana State University
School of Dentistry, New Orleans, LA, USA
Agnieszka M. Frydrych UWA Dental School, University of Western
Australia, Perth, WA, Australia
Anastasia Georgiou Macquarie Oral and Maxillofacial Specialists, Sydney,
NSW, Australia
Sydney Skin, Sydney, NSW, Australia
Laura Giovati Dipartimento di Medicina e Chirurgia, University of Parma,
Parma, Italy
Sandra Goncalves Oral Medicine Department, Charles Clifford Dental
Hospital, Sheffield, UK
Jean-Paul Goulet Faculté de Médecine dentaire, Université Laval, Québec,
QC, Canada
Steven B. Graff-Radford Director, Division of Headache and Orofacial
Pain, Pain Center, Cedar Sinai Medical Center, Los Angeles, CA, USA
John Greenman Faculty of Health and Life Sciences, Bristol, UK
Miriam Gruskha Department of Dentistry, William Osler Hospital
(Etobicoke), Toronto, ON, Canada
Luiz Alcino Gueiros Oral Medicine Unit, Departamento de Clínica e
Odontologia Preventiva, Universidade Federal de Pernambuco, Recife, PE,
Brazil
Rita Hardiman Melbourne Dental School, The University of Melbourne,
Melbourne, VIC, Australia
Yaron Haviv Department of Oral Medicine, Sedation and Maxillofacial
Israel
Emma Hayes Eastman Dental Hospital, London, UK
Anne Hegarty Oral Medicine, Sheffield Teaching Hospitals, Sheffield, UK
Gary Heir Center for Temporomandibular Disorders and Orofacial Pain,
Rutgers School of Dental Medicine, Newark, NJ, USA
Jos Hille Department Oral and Maxillofacial Pathology, University of the
Western Cape/National Health Laboratory Service, Cape Town, South Africa
Oral/Head and Neck Pathology, University of the Western Cape, Cape Town,
South Africa
Contributors xxv
David Hillman Department of Pulmonary Physiology and Sleep Medicine,

West Australian Sleep Disorders Research Institute, Sir Charles Gairdner
Hospital, Perth, Australia
Centre for Sleep Science, School of Human Sciences, University of Western
Australia, Perth, Australia
Tim Hodgson Eastman Dental Hospital, London, UK
Hong Hua Department of Oral Medicine, Peking University, School of
Stomatology, Beijing, China
James J. R. Huddleston Slater Groningen, The Netherlands
Chizobam N. Idahosa Department of Oral and Maxillofacial Pathology,
Medicine and Surgery, Temple University Kornberg School of Dentistry,
Philadelphia, PA, USA
Koichi Iwata Department of Physiology, School of Dentistry, Nihon
University, Tokyo, Japan
Siri Beier Jensen Department of Dentistry and Oral Health, Aarhus
University, Aarhus C, Denmark
Maryam Jessri Division of Oral Medicine and Dentistry, Brigham and
Women’s Hospital, Boston, MA, USA
Department of Oral Medicine, Infection and Immunity, Harvard School of
Dental Medicine, Boston, MA, USA
UWA Dental School and Oral Health Centre of Western Australia, University
of Western Australia, Perth, WA, Australia
Mats Jontell Department of Oral Medicine and Pathology, Sahlgrenska
Academy, University of Gothenburg, Gothenburg, Sweden
Johannes S. Kern Department of Dermatology, Royal Melbourne Hospital,
Parkville, VIC, Australia
A. Ross Kerr Department of Oral and Maxillofacial Pathology, Radiology
and Medicine, New York University College of Dentistry, New York, NY,
USA
Shehryar N. Khawaja Resident, Orofacial Pain Program, Department of
Oral and Maxillofacial Surgery, Massachusetts General Hospital, Boston,
MA, USA
Gary D. Klasser Department of Diagnostic Sciences, School of Dentistry,
Louisiana State University Health Sciences Center, New Orleans, LA, USA
Nabil Kochaji Faculty of Dentistry, Damascus University, Damascus, Syrian
Arab Republic
Olga A. Korczeniewska Department of Diagnostic Sciences Rutgers School
of Dental Medicine, Rutgers The State University of New Jersey, Newark, NJ,
USA
xxvi Contributors
Luiz P. Kowalski Head and Neck Surgery and Otorhinolaryngology

Department, A.C. Camargo Cancer Center, São Paulo, Brazil
Kiyoshi Koyano Faculty of Dental Science, Kyushu University, Fukuoka,

Japan
Omar Kujan UWA Dental School, University of Western Australia, Perth,

WA, Australia
Moni A. Kuriakose Department of Head and Neck Surgery/Plastic and

Reconstructive Surgery, Roswell Park Cancer Institute, Buffalo, NY, USA
Gilles J. Lavigne Faculty of Dental Medicine, Univeristé de Montréal,

Montreal, QC, Canada
Centre for Advanced Research in Sleep Medicine and Trauma Unit, Surgery
Department, Hôpital du Sacré-Cœur de Montréal, Montreal, QC, Canada
Jair C. Leão Oral Medicine Unit, Departamento de Clínica e Odontologia

Preventiva, Universidade Federal de Pernambuco, Recife, PE, Brazil
Stefania Leuci Oral Medicine Complex Unit, Department of Neuroscience,

Reproductive and Odontostomatological Sciences, Federico II University of
Naples, Naples, Italy
Giovanni Lodi Dipartimento di Scienze Biomediche, Chirurgiche e

Odontoiatriche, Università degli Studi di Milano, Milan, Italy
Annabelle Mahar Department of Tissue Pathology and Diagnostic, Royal

Prince Alfred Hospital, Camperdown, NSW, Australia
Atul Malhotra Critical Care and Sleep Medicine, UC San Diego School of
Medicine, La Jolla, CA, USA
Maddalena Manfredi Dipartimento di Medicina e Chirurgia, Centro

Universitario di Odontoiatria, University of Parma, Parma, Italy
Daniele Manfredini School of Dentistry, University of Padova, Padova, Italy
Marie Marklund Department of Orthodontics, Umeå University, Umeå,

Sweden
Marie Anne Teresa J. Matias Perth Radiological Clinic, Subiaco, WA,

Australia
Qscan Radiology Clinics, Herston, QLD, Australia
Hani Mawardi Faculty of Dentistry, King Abdulaziz university, Jeddah,

Saudi Arabia
Division of Oral Medicine and Dentistry, Brigham and Women’s Hospital,
Boston, MA, USA
Michael J. McCullough Oral Anatomy, Medicine, and Surgery Section,

Melbourne Dental School, Faculty of Medicine, Dentistry and Health
Sciences, The University of Melbourne, Carlton, VIC, Australia
Contributors xxvii
L. G. Mercuri Department of Orthopedic Surgery, Rush University Medical

Center, Chicago, IL, USA
TMJ Concepts, Ventura, CA, USA
Alan Mighell Department of Oral Medicine, School of Dentistry, University

of Leeds, Leeds, UK
Michele D. Mignogna Oral Medicine Complex Unit, Department of

Neuroscience, Reproductive and Odontostomatological Sciences, Federico II
University of Naples, Naples, Italy
Mutsumi Miyauchi Department of Oral and Maxillofacial Pathobiology,

Graduate School of Biomedical and Health Sciences, Hiroshima University,
Hiroshima, Japan
Isabel Moreno Hay Orofacial Pain Program, College of Dentistry,

University of Kentucky, Lexington, KY, USA
Geraldine Moses Academic Practice Unit, Pharmacy Services, Mater Public

Hospital, South Brisbane, QLD, Australia
Joel Napenas Department of Oral Medicine, Carolinas Medical Center,

Charlotte, NC, USA
Alf Nastri Department of Maxillofacial Surgery, Royal Melbourne Hospital,

The University of Melbourne, Melbourne, Australia
Joachim Ngiam Centre for Sleep Health and Research, Department of

Richeal Ni Riordain Eastman Dental Hospital, London, UK

Tiago Novaes Pinheiro Anatomic Pathology Service, Amazonas State
University, Manaus, Brazil
Ikuko Ogawa Center of Oral Clinical Examination, Hiroshima University

Hospital, Hiroshima, Japan
Seog Bae Oh Department of Neurobiology and Physiology, School of

Dentistry, Seoul National University, Seoul, Republic of Korea
Richard Ohrbach Department of Oral Diagnostic Sciences, University at

Buffalo, Buffalo, NY, USA
Jeffrey P. Okeson Orofacial Pain Program, College of Dentistry, University

of Kentucky, Lexington, KY, USA
Daniel Paesani School of Odontology, University of Salvador/AOA, Buenos

Aires, Argentina
Douglas E. Peterson Department of Oral Health and Diagnostic Sciences,

School of Dental Medicine, Neag Comprehensive Cancer Center, UConn
Health, Farmington, CT, USA
xxviii Contributors
Luciano Polonelli Dipartimento di Medicina e Chirurgia, University of

Parma, Parma, Italy
Stephen Porter UCL Eastman Dental Institute, University College London,
London, UK
Stephen Prime School of Oral and Dental Sciences, University of Bristol,
Bristol, UK
Saravanan Ram Division of Diagnostic Sciences, Ostrow School of
Dentistry of USC, Los Angeles, CA, USA
Alison Rich The Department of Oral Diagnostic and Surgical Sciences,
University of Otago, Dunedin, Otago, New Zealand
Jairo Robledo-Sierra Department of Oral Medicine and Pathology,
Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Arturo Saavedra Department of Dermatology, Massachusetts General
Hospital, Harvard Medical School, Boston, MA, USA
Soma Sahai-Srivastava Headache and Neuralgia Center, Keck School of
Medicine of USC, Los Angeles, CA, USA
Laura Scardamaglia Department of Dermatology, Royal Melbourne Hos-
pital, Parkville, VIC, Australia
Steven J. Scrivani Chief, Division of Oral and Maxillofacial Pain,
Department of Oral and Maxillofacial Surgery, Massachusetts General
Hospital, Boston, MA, USA
Barry J. Sessle Faculty of Dentistry and Department of Physiology, Faculty
of Medicine, University of Toronto, Toronto, ON, Canada
Jane F. Setterfield Department of Oral Medicine, King’s College London,
London, UK
Department of Dermatology, King’s College London, London, UK
Guys and St Thomas’ Hospital NHS Foundation Trust, London, UK
Yair Sharav Department of Oral Medicine, Sedation and Maxillofacial
Israel
Martina K. Shephard Oral Medicine Unit, Eastman Dental Hospital,
University College London Hospitals NHS Trust, London, UK
Masamichi Shinoda Department of Physiology, School of Dentistry, Nihon
University, Tokyo, Japan
Egilius L. H. Spierings Craniofacial Pain Center, Tufts University School of
Dental Medicine, Headache and Facial Pain Program, Department of Neurol-
ogy, Tufts Medical Center and Tufts School of Medicine, Boston, MA, USA
Herve Sroussi Division of Oral Medicine and Dentistry, Brigham and
Contributors xxix
Eric T. Stoopler Department of Oral Medicine, University of Pennsylvania

School of Dental Medicine, Philadelphia, PA, USA
Nan Su Norman Bethune College of Medicine, Jilin, China
Kate Sutherland Centre for Sleep Health and Research, Department of
Charles Perkins Centre and Northern Clinical School, University of Sydney,
Sydney, NSW, Australia
Yoshitaka Suzuki Facultés de médecine dentaire et de médecine, Université
de Montréal, Montreal, QC, Canada
Department of Stomatognathic Function and Occlusal Reconstruction,
Tokushima University Graduate School, Tokushima, Japan
Peter Svensson Section of Orofacial Pain and Jaw Function, Department of
Dentistry and Oral Health, Aarhus University, Aarhus, Denmark
Department of Dental Medicine, Karolinska Institutet, Scandinavian Center
for Orofacial Neurosciences (SCON), Huddinge, Sweden
Takashi Takata Department of Oral and Maxillofacial Pathobiology,
Graduate School of Biomedical and Health Sciences, Hiroshima University,
Hiroshima, Japan
Mamoru Takeda Laboratory of Food and Physiological Sciences, Department
of Food and Life Sciences, School of Life and Environmental Sciences, Azabu
University, Sagamihara, Kanagawa, Japan
Priya Thakrar Eastman Dental Hospital, London, UK
Jaisri R. Thoppay Oral Medicine, Orofacial Pain and Geriatric Programs,
Orofacial Pain and Geriatric Oral Health Programs, Department of Oral and
Maxillofacial Surgery, VCU School of Dentistry and VCU Medical Center,
Virginia Commonwealth University, Richmond, VA, USA
Nathaniel Treister Department of Oral Medicine, Infection and Immunity,
Harvard School of Dental Medicine, Boston, MA, USA
Yoshihiro Tsukiyama Section of Dental Education, Faculty of Dental
Science, Kyushu University, Fukuoka, Japan
Willie van Heerden Department of Oral Pathology and Oral Biology,
University of Pretoria, Pretoria, South Africa
Olivier Vanderveken Faculty of Medicine and Health Sciences, University
of Antwerp, Antwerp, Belgium
Department of ENT, Head and Neck Surgery, Antwerp University Hospital,
Edegem, Belgium
Elena Varoni Dipartimento di Scienze Biomediche, Chirurgiche e
Odontoiatriche, Università degli Studi di Milano, Milan, Italy
Sarah Viggor Eastman Dental Hospital, London, UK
xxx Contributors
Alessandro Villa Department of Oral Medicine, Infection and Immunity,

Division of Oral Medicine and Dentistry, Brigham and Women’s Hospital,
Boston, MA, USA
Arjan Vissink Department of Oral and Maxillofacial Surgery,
University Medical Center Groningen, University of Groningen, Groningen,
The Netherlands
Tomoko Wada Orofacial Pain and Oral Medicine Center, Division of
Diagnostic Sciences, Ostrow School of Dentistry of USC, Los Angeles,
CA, USA
Andy Whyte University of Melbourne, Carlton, VIC, Australia
Perth Radiological Clinic, Subiaco, WA, Australia
Ear Science Institute, Subiaco, WA, Australia
Sook-Bin Woo Division of Oral Medicine and Dentistry, Brigham and
Department of Oral Medicine, Infection and Immunity, Harvard School of
Dental Medicine, Boston, MA, USA
Benjamin Wood QEII Medical Centre, Nedlands, WA, Australia
Dongyuan Yao Jiangxi Mental Hospital and School of Pharmaceutical
Science, Nanchang University, Nanchang, Jiangxi, China
Tami Yap Melbourne Dental School, University of Melbourne, Carlton, VIC,
Australia
Department of Dermatology, Royal Melbourne Hospital, Parkville, VIC,
Australia
Noam Yarom Oral Medicine Unit, Sheba Medical Center, Tel Hashomer,
Israel
Department of Oral Pathology and Oral Medicine, School of Dental Medicine,
Tel-Aviv University, Tel-Aviv, Israel
Sue-Ching Yeoh Sydney Oral Medicine, Baulkham Hills, NSW, Australia
Chris O’Brien Lifehouse, Camperdown, NSW, Australia
Juan Fernando Yepes Department of Pediatric Dentistry, James Whitcomb
Riley Hospital for Children, Indiana University School of Dentistry, Indianapolis,
IN, USA
Rosnah Binti Zain Department of Oral Pathology, MAHSA University,
Kuala Lumpur, Malaysia
Oral Cancer Research and Coordinating Centre, University of Malaya, Kuala
Lumpur, Malaysia
Normal Variation in the Anatomy,
Biology, and Histology of the
Maxillofacial Region
Rita Hardiman, Omar Kujan, and Nabil Kochaji
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Anatomy, Histology, Biology, and their Normal Variations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
The Link between Oral Structures and Other Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
The Role of Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Genetic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Development and Growth of the Craniofacial Region . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Early Embryogenesis, Germ Layers, and Neural Crest Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Development of the Jaws, Face, and Skull . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Odontogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Variations in the Dentition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Gross Anatomy, Histology, and Biology of the Maxillofacial Region . . . . . . . . . . . . . . . 13
Osteology of the Skull . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Anatomical Variations of the Skull . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Histology of Hard Tissues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Scalp and Facial Soft Tissues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Soft Tissue Structures in the Superficial Face . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Variation and Aging in Facial Soft Tissues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Histology of the Epidermis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
R. Hardiman (*)
Melbourne Dental School, The University of Melbourne,
Melbourne, VIC, Australia
e-mail: r.hardiman@unimelb.edu.au
O. Kujan
UWA Dental School, University of Western Australia,
Perth, WA, Australia
e-mail: Omar.Kujan@uwa.edu.au
N. Kochaji
Faculty of Dentistry, Damascus University, Damascus,
Syrian Arab Republic
e-mail: oralpathology@gmail.com
# Springer Nature Switzerland AG 2019 1

C. S. Farah et al. (eds.), Contemporary Oral Medicine,
https://doi.org/10.1007/978-3-319-72303-7_2
2 R. Hardiman et al.
Infratemporal Region and Pterygopalatine Fossa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

Trigeminal Nerve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
CNV1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
CNV2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
CNV3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Gross Anatomy of the Temporomandibular Joint . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Muscles of Mastication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Histology of the Temporomandibular Joint . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Nose and Paranasal Sinuses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Gross Anatomy of the Nose, Nasal Cavity, and Paranasal Sinuses . . . . . . . . . . . . . . . . . . . . . 34
Histology of Respiratory Epithelium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Oral Cavity and Tongue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
Dental Hard Tissues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Gross Anatomy of the Tongue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
Salivary Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
Major Salivary Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
Histology of Salivary Glands and Duct Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
Minor Salivary Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Histology of Oral Tissues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Dental Pulp . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Periodontal Ligament . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
Tongue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
Lips . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Tonsillar Tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Tissue Spaces of the Maxillofacial Region . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Fascial Layers and Spaces of the Head and Neck . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Submandibular Space . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Lateral Pharyngeal Space . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Retropharyngeal Spaces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Lymphatic Drainage of the Head and Oral Structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Retropharyngeal Nodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Submental Nodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Submandibular Nodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Upper Deep Cervical Nodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Lower Deep Cervical Nodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Pharynx and Larynx . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Waldeyer’s Ring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Gross Anatomy of the Pharynx and Larynx Including Anatomical Variations . . . . . . . . . 57
Histology of Pharyngeal Mucosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Histology of the Thyroid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Orbits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Gross Anatomy of the Orbits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Vascular Supply of the Maxillofacial Region . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
The Facial Artery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
The Lingual Artery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
The Maxillary Artery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
The Superficial Temporal Artery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Conclusions and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Normal Variation in the Anatomy, Biology, and Histology of the Maxillofacial Region 3
Abstract anatomical components exist in close proximity

This chapter discusses the normal anatomy of and are intimately located. In recent times, there
the maxillofacial region and variations thereof has been an increased reporting of occurrence of
when present and clinically relevant. Single or anatomical variations, particularly in the variabil-
rare cases of an anatomical variation are ity found in foramina, due to the use of high-
excluded, as are very minor variations, such resolution 3D imaging techniques such as com-
as deviations in the course of a nerve in the puterized tomography (CT) and cone beam CT
range of millimeters. Gross anatomy and his- (CBCT) scans (Eliades et al. 2016; Wolf et al.
tology of the most relevant structures in the 2016) or high-resolution magnetic resonance
maxillofacial region are described by anatom- imaging (MRI) (Jacobs et al. 2007). Conventional
ical region. radiographs may not be sensitive enough to show
small canals such as the incisive canal of the
Keywords mandible or accessory foramina (Jacobs et al.
Anatomy · Histology · Osteology · Variation · 2007). CBCT has been shown to detect a higher
Oral · Mucosa · Aging rate of anatomical variations in the maxillary
sinus compared with panoramic radiographs
(Kazunobu et al. 2014). These high-resolution
Introduction noninvasive techniques also enable investigators
to visualize structures in great detail without risk
Anatomy, Histology, Biology, and their of damaging or destroying the structures in ques-
Normal Variations tion (Stratmann et al. 1996).
The maxillofacial region is an intricate anatomical

region providing our main perceptual and com- The Link between Oral Structures
munication interface with the outside world, as and Other Systems
well as the first line of defense against inhaled or
ingested infectious or toxic agents. The special The oral cavity and associated structures are
senses of sight, smell, and taste have sensory unique. The mouth, lips, and other oral tissues
receptors in the maxillofacial region. are anatomically structured to complement other
This chapter begins with the scaffolding to body systems. The oral structures also share sim-
which all other structures in the maxillofacial ilar biological, molecular, and histological com-
region are attached, the skull. Subsequently, the positions and functions with other systems,
soft tissues of the maxillofacial region and super- mainly the upper digestive system, respiratory
ficial face are covered including their structure system, and skin. Therefore, several systemic dis-
and function. Regions of the deep face are then eases can manifest orally, and as a result, there is a
presented. Throughout, special attention is paid to need to view oral diseases in the context of other
the oral cavity, its regions, and tissues, including systems. Recognition of the fact that an oral med-
anatomical and regional variations and changes icine specialist is an oral physician, it is critical to
occurring throughout the human lifespan. Inner- have a profound understanding of oral diseases
vation is discussed within each region, as well as and their potential relevance to other systemic
vascular supply, drainage, and lymphatics. Com- diseases, and vice versa. For example, “a normal
ments on the embryological development are healthy dentition functioning in a healthy oral
made if these are pertinent to the structure in the cavity is critical to the patient’s nutritional well-
fully formed human, especially if the origin is being. Anything that interferes with mastication at
related to anatomical variations. Oftentimes it is the beginning of the digestive process only makes
easier to study the anatomy of the maxillofacial the functions of the patient’s other system more
region by compartmentalizing this by region or difficult” (Walker 1990). Diseases such as gastro-
system; however, it must be borne in mind that esophageal reflux disease, bulimia, or anorexia
may be associated with irreversible dental erosion Table 1 Examples of systemic diseases that may present
due to the exposure of tooth enamel to acidic in the oral and perioral region (Mays et al. 2012; Chi et al.
2010)
gastric contents. The oral manifestations of sys-
temic diseases will be discussed in other chapters Diseases of the heart and Congenital anomalies of
blood vessels the heart: Tetralogy of
of this textbook in far more detail. Fallot
The unique interrelationship between oral Rheumatoid endocarditis/
structures and other systems often results in dis- bacterial
eases of non-oral origin to manifest orally. More- endocarditis
Myocardial infarction
over, often at early stages of systemic diseases, Coronary insufficiency
oral signs and symptoms are early diagnostic fea- Thrombophlebitis
tures. The oral-related systemic changes should be Lymphangitis
distinguished from normal variations of oral struc- Diseases of the Tumor metastatic
tures and will be addressed in the context of the respiratory tract deposits
Tuberculosis
spectrum of the clinical presentations of these Lung infection
systemic diseases (Walker 1990). Table 1 lists Diseases of the Uremia
examples of systemic diseases that may have genitourinary system Tumor metastatic
manifestations in the oral and perioral region. deposits
Glomerulonephritis
Nephrotic syndrome
Diseases of the liver and Jaundice
The Role of Aging biliary tract Liver cirrhosis
Hepatitis
Aging is a complex process and reflects the changes Tumor metastatic
deposits
that occur over the lifespan (Rattan 2015). In some Neoplasms and cysts of
population groups worldwide, life expectancy has liver
increased remarkably during the latter half of the last Diseases of the Gastritis
century. The United Nations has projected that the gastrointestinal tract Peptic ulcer
number of persons aged 60 or above is expected to Chronic ulcerative
colitis
more than double and triple in 2050 and 2100, Inflammatory bowel
respectively, compared to that in 2017. The number disease
of persons aged 60 or above will rise from 962 mil- Plummer-Vinson
lion globally in 2017 to 2.1 billion in 2050 and 3.1 syndrome
Peutz-Jeghers
billion in 2100 (United Nations 2017). Recognizing syndrome
the manifestations of age changes in the oral and Osler-Rendu disease
dental tissues can help oral medicine specialists to Tumor metastatic
distinguish healthy aging changes from pathological deposits
conditions, even though the incidence and preva- Diseases of the Anemias
hematopoietic system Leukemias
lence of several oral disorders and conditions, such (blood and bone marrow) Thrombocytopenia
as oral lichen planus, oral ulceration, oral potentially Hemorrhagic disorders
malignant disorders, and oral cancer, frequently Diseases of the immune Behcet’s disease
increase with aging (Yap and McCullough 2015). system Chronic graft-versus-host
disease
Increasing evidence supports that osteoporosis
Sjögren’s syndrome
contributes to the loss of teeth (Merchant 2017; Lupus erythematosus
Kaye et al. 2017). Osteoporosis is associated with Diseases of the lymph Lymphadenopathies
decreased bone mineral density that may contrib- nodes and spleen Lymphomas
ute to the loss of alveolar bone and potentially Gaucher’s disease
Niemann-pick disease
basal bone (Merchant 2017; Kaye et al. 2017). It Malaria
can be difficult to distinguish aging changes from (continued)
those of osteoarthritis (Guiglia et al. 2013;
Table 1 (continued) anomalies, dysfunctions, and diseases of oral tis-

Diseases of the endocrine Diabetes mellitus sues and dentition. Many genetic dental/oral
system Thyroid gland diseases abnormalities represent more complex disorders
and tumors and are linked to inherited traits and defects or
Gigantism
Pituitary dwarfism result from spontaneous genetic mutations. Cleft
Acromegaly lip and palate, anodontia and hypodontia,
Addison’s disease amelogenesis imperfecta and dentinogenesis
Cushing’s syndrome imperfecta, supernumerary teeth, malocclusion,
Tumor metastatic
deposits and gingival fibromatosis are examples of these
Diseases of the skin Lichen planus genetic disorders (Madani et al. 2014). These are
Scleroderma discussed in more detail in relevant chapters such
Angioneurotic edema as ▶ “Odontogenic Pathology.”
Psoriasis
Vesiculobullous diseases
(pemphigus, erythema
multiforme) Development and Growth
Reiter’s syndrome of the Craniofacial Region
Bowen’s disease
Nevi and melanoma
Diseases of the Osteogenesis imperfecta
Early Embryogenesis, Germ Layers,
musculoskeletal system Scurvy and Neural Crest Cells
and joints Rickets
Osteomalacia Early embryogenesis involves cell proliferation,
Osteomyelitis
migration, and organization to establish the bulk
Osteoporosis
Paget’s disease of the embryo as well as define axes: cranio-
Giant cell lesions and caudal, mediolateral, and anteroposterior (dorso-
tumors ventral). A detailed discussion of every step in the
Osteoarthritis
process of embryogenesis is not within the scope
Myositis
Muscular dystrophy of this chapter, so only aspects of development
Myasthenia gravis pertinent to the establishment of the craniofacial
Tumors and dental complexes are included.
The early embryo consists of a mass of uniform
cells, before these organize into a bilayered disc,
Gulsahi 2015; McKenna and Burke 2010). The essentially endoderm and ectoderm. At this stage,
use of bisphosphonates to treat osteoporosis has the axes of the embryo are established. A depres-
been found to increase the incidence of sion forms along the cranio-caudal axis on the
osteonecrosis of the jaw (ONJ) in some cases. dorsal (ectoderm) surface of the embryonic disc,
This relationship has been established in different the primitive streak. At the point of establishment
populations throughout the world. of this depression is the primitive node. Here
With aging, an individual may lose some or all some ectodermal cells lose their orientation and
of their teeth. Teeth become worn, and muscles of begin to migrate into the primitive streak (Fig. 1).
mastication may be subject to atrophy. These These cells undergo a transformation from epithe-
changes lead to impairments in oral function, par- lial morphology and function to mesenchymal mor-
ticularly speech and mastication. phology and function (Morriss-Kay et al. 1993).
These cells form the intervening mass between
endoderm and ectoderm: the mesoderm. A tri-
Genetic Factors laminar embryo is now established, and all mature
tissues of the human body will be formed from one
Defective genes/genetic factors are responsible of the three germ layers (see Table 2 for adult
for the evolution of developmental mouth/dental craniofacial derivatives of the three germ layers).
Fig. 1 A diagram of the

embryonic disc as migration
of ectodermal cells to
become the mesoderm is
underway. (Original
drawing by Dr Hala Al
Janaby, Perth WA,
Australia)
Table 2 Adult derivatives of primary germ layers with a Table 3 Neural crest cell derivatives in the mature human
focus on the head and oral cavity being
Primary Anatomical
germ layer Tissue derivative region/system Neural crest cell derivatives
Ectoderm Nervous tissue, epidermis and Craniofacial Cartilage and bone (e.g.,
derivatives (hair, sebaceous and sweat region mesenchymal derivatives of the
glands), eye (cornea and lens), oral and frontal, parietal, squamous
nasal cavity epithelium (including temporal, nasal and vomer, palatine
epithelium of paranasal sinuses), bones, maxilla and mandible),
cranial nerve ganglia for cranial dentin, connective tissue of salivary
nerves V, VII, VIII (vestibulocochlear), and lacrimal glands
IX (glossopharyngeal), and X (vagus), Nervous system Neurons and glial cells of the
enamel organs peripheral nervous system
Mesoderm Skeletal and smooth muscle, cartilage Musculoskeletal Smooth muscle cells and tendons
and bone, blood, marrow, lymph, system
endothelial cells, synovial membranes
Integumentary Melanocytes
Endoderm Digestive tract epithelium (except oral system
cavity), respiratory epithelium
Endocrine Endocrine cells
(of tract), auditory tube and tonsillar
system
epithelium, thyroid, parathyroid and
thymus
1993), they migrate throughout the embryo con-
tributing to the formation of a number of tissues in
A rod of condensed tissue forms along the the human body. Neural crest cell derivatives are
cranio-caudal axis of the embryo, beneath the outlined in Table 3 and are particularly important
dorsal surface. This is the notochord, and it in the development of the craniofacial region.
induces the formation of the neural groove, later
to become the neural tube, and neural crest. Cells
from the neural crest sit within the ridge of cells Development of the Jaws, Face,
between the neuroepithelium and the epidermis. and Skull
Once they undergo epithelio-mesenchymal tran-
sition (Theveneau and Mayor 2012), similar to The first step in the development of the jaws,
that seen during gastrulation (Morriss-Kay et al. face, and skull following the establishment of
anatomical axes is the formation of the branchial the homeobox (HOX) gene family have been
(or pharyngeal) arches. These are six bilateral shown to be necessary for normal development
transverse bars of tissue bulging from the embryo. of the cranium, face, and jaws (Francis-West et al.
Externally they are lined with ectoderm, internally 1998). For example, Msx-I is directly linked to the
with endoderm, apart from the region of the future development of secondary palate and teeth
oral cavity, where the internal lining is also (Thesleff 1995). Animal studies have confirmed
formed by ectoderm (Table 2). Between each that altered msx genes are associated with severe
arch externally is a pharyngeal cleft. Internally, facial abnormalities. Further, retinoic acid
the equivalent furrow is called a pouch. The bulk (a metabolite of vitamin A) has a major role in
of each branchial arch consists of cartilage, mes- developing the lower part of the face and first arch
enchymal cells, nerves, and vessels. Specific structures. Animal studies show that retinoic acid
nerves, cartilage, and muscle groups are associ- interacts with HOX genes and that altered retinoic
ated with particular arches. Figure 2 shows a acid signaling pathways can lead to remarkable
diagram of the branchial arches in the embryo, facial abnormalities.
and Table 4 highlights the tissue associations Disturbances in development are beyond the
with each arch. Note that the fifth branchial arch scope of this chapter; however, these are
is taken over by adjacent arches and so disappears highlighted in the chapter on ▶ “Odontogenic
from descriptions of arch derivatives. Pathology,” ▶ “Pigmented Lesions of the Oral
Several genes, transcription factors, and Mucosa,” ▶ “Cutaneous Pathology of the Head
growth factors regulate the craniofacial develop- and Neck,” and ▶ “Pediatric Oral Medicine.”
ment (Francis-West et al. 1998). Several types of These are caused by changes in the fusion of
Fig. 2 A diagram showing the structure of the branchial (pharyngeal) arches in the embryo, with their associated nerves.
(Original drawing by Dr Hala Al Janaby, Perth WA, Australia)
Table 4 Branchial (pharyngeal) arch tissue associations

Arch Nerve Muscle Cartilage/bone
1 Trigeminal-mandibular Muscles of mastication, anterior belly of digastric Meckel’s cartilage,
division (CNV3) muscle, tensor veli palatini and tensor tympani malleus and incus
2 Facial (CN VII) Facial muscles, auricular muscles, occipitofrontalis, Lesser horn and superior
posterior belly of digastric muscle, and stylohyoid part of body of hyoid,
stapes
3 Glossopharyngeal Stylopharyngeus Greater horn and inferior
(CN IX) part of body of hyoid
4 Superior laryngeal Cricothyroid Thyroid cartilage
branch of the vagus
(CN X)
6 Recurrent laryngeal Intrinsic laryngeal muscles Arytenoid cartilage
branch of the vagus
(CN X)
different developmental processes (either prema- down and allows a continuity of stomodeum and
ture, delayed, or lack of fusion) or changes in pharynx. A week later, the nasal and optic
relative development of different components of placodes appear due to a localized thickening of
the face, jaws, or skull. Certain developmental ectoderm. These will later develop to form the
disturbances with consistent physical features nasal pits and eyes. A groove that reaches the
can indicate the presence of a developmental medial aspect of the developing eye separates
syndrome such as Crouzon’s syndrome or fetal the lateral nasal process from the maxillary pro-
alcohol syndrome. The causes may be genetic or cess. This groove closes over to form the
environmental and may point to any number of nasolacrimal duct. In some cases, the nasolacrimal
syndromes that have effects throughout the groove fails to close, leaving a nasolacrimal
body. These syndromes and developmental dis- fissure.
turbances are not within the scope of this chapter In the 6th week of embryonic life, the two
as they move beyond normal anatomical varia- mandibular processes merge at the midline to
tion, but have significant clinical relevance. construct the lower jaw. In very rare occasions,
Nevertheless, to understand the mechanism by the persistence of a midline groove in this region
which these developmental disturbances occur, can produce a mandibular cleft. The mandibular
it is essential to understand human craniofacial and maxillary processes fuse at the angles of the
development. mouth, thus defining its outline. Disturbances in
the development at this stage may cause micro-
Development of the Face stomia, macrostomia, or very rarely astomia
In a 4-week-old embryo, the primitive oral cavity (Berkovitz et al. 2016). The maxillary processes
(stomodeum), which is an ectoderm lined depres- continue from the corners of the mouth toward the
sion at the site of the future oral cavity, appears as medial nasal processes of the upper lip, thus con-
a result of the approximation of five facial pro- tributing to the formation of the upper lip. Distur-
cesses: the frontonasal prominence superiorly, the bance in the fusion of the maxillary process with
two maxillary swellings on either side laterally, the medial nasal process can disrupt upper lip
and the mandibular prominences inferiorly formation, leading to a cleft lip (often associated
(Berkovitz et al. 2016). The maxillary and man- with cleft palate). Clefts are usually unilateral,
dibular processes are derived from the first pha- rather than bilateral or central.
ryngeal arches. At this stage, the oropharyngeal
membrane separates the primitive oral cavity Development of the Palate
(ectoderm-lined) from the developing pharynx The palate develops between the sixth and eighth
(endoderm-lined). This membrane later breaks week of embryonic life. During the sixth week, an
intermaxillary segment appears anteromedially processes fuse at the midline marking the mid
due to the growth of the medial nasal process. palatine suture. Fusion begins at the junction
Later, the intermaxillary segment merges with between the premaxilla and two maxillary
the medial side of the maxillary processes to shelves. In the fully formed human, this point of
form the primary palate or premaxilla that bears initial fusion remains as the incisive foramen. Any
the maxillary central and lateral incisors. As the disturbance to palatal fusion presents as a type of
primary palate develops horizontally, it begins to cleft palate (Berkovitz et al. 2016).
separate the primitive oral and nasal cavities. Con-
currently, two lateral palatal shelves grow from Development of the Tongue
the maxillary processes posterior to the primary The first, second, and third branchial arches con-
palate. These shelves change growth orientation tribute to the development of the tongue. These
to a horizontal plane above the forming tongue at contributions form the floor of primitive mouth.
the 8th week. The processes merge during the Protrusions from these arches appear in weeks
9th–12th weeks of embryonic life to form the 4 and 5 of embryonic life. The tuberculum impar
secondary palate (Fig. 3). The lateral palatal (a central swelling in the floor of the mouth)
appears along with two lateral swellings. All of
these swellings merge to constitute the anterior
two thirds of the tongue. The hypobranchial emi-
nence (a midline swelling from the third arch)
NC
grows rapidly to form the posterior third of the
tongue. Given that the tongue develops from dif-
ferent branchial arches explains the complexity in
the tongue’s innervation (Berkovitz et al. 2016).
* The fusion of the anterior and posterior parts of
P the tongue is marked by the presence of a
V-shaped groove on the dorsum of the tongue:
OC the terminal sulcus. Posterior to this sulcus is the
foramen cecum, the point of thyroid gland migra-
B
tion initiation, from which it moves through the
T thyroglossal duct to its final position in the neck.
Ectopic thyroid gland tissue may be found at
MC points along the migratory path (Berkovitz et al.
2016).
Mb
Development of the Jaws
Both the mandible and maxilla develop
intramembranously as there is no cartilaginous
precursor to ossification. However, the mandible
Fig. 3 Hematoxylin and eosin stained histology slide undergoes subsequent growth at sites of second-
shows a coronal section through a developing face. On ary cartilage, the most long-lasting of which is
the right of the image, from superior to inferior, are the deep to the surface of the condyle.
nasal cavity (NC), the developing palate (P) – note the
The mandible develops around Meckel’s carti-
growth of the bony palatal shelf towards the midline of
the face (*), the oral cavity (OC), and tongue (T). On the lage (Fig. 3), a first branchial arch structure
left of the image are a maxillary and mandibular tooth bud appearing at the 6th week of embryonic life. The
(B), growing into the underlying mesenchyme towards the main function of this cartilage is to provide a
developing upper and lower jaws. The developing mandi-
framework around which the bone of the mandi-
ble (Mb) is seen, with its bony shelves surrounding the
tooth bud, and its position lateral to Meckel’s cartilage ble forms. The ossification site is at the point of
(MC) division of the inferior alveolar nerve into its
mental and incisive branches. The bone of the body primary tooth preceding the permanent, teeth
of the mandible develops lateral to Meckel’s carti- develop from the general lamina. Thus, the dental
lage and around the developing tooth buds (Fig. 3). lamina begins in the sixth week of embryonic life
Right and left halves of the mandible meet at the and ceases activity when the third molar develops,
midline and remain separated by fibrous tissue that at around 15 years of age. Developing teeth
forms a mandibular symphysis. Meckel’s cartilage undergo a number of recognizable stages: bud,
eventually undergoes resorption, but the posterior cap, and bell (named for the shape of the devel-
extremes ossify into two inner ear ossicles: the oping tooth) to form the crown before they begin
malleus and incus. The ramus of the mandible root development.
appears due to the posterior growth of mandibular A complex interaction between the dental lam-
body and the appearance of secondary cartilages ina (ectodermal in origin) and the underlying mes-
during the 10–14th weeks of embryonic life. These enchyme (with a contribution from neural crest
cartilages play a significant role in mandibular cells) must occur for odontogenesis to take place.
growth; the condylar cartilage is the largest and Primary and permanent dentitions undergo the
most important, the other two are the coronoid same odontogenic process, however differ in the
process and in the region of mandibular symphysis. number, morphology, and emergence timing
In the second year of life after birth, the mandibular (Arda et al. 2014; Berkovitz et al. 2016).
symphysis undergoes complete ossification that For the purposes of this text, a brief description
allows the two sides of the mandible to become a and defining features, both morphological and
single fused bone (Berkovitz et al. 2016). functional, are given for each stage of
The temporomandibular joint develops odontogenesis, before variations are discussed.
intramembranously from the mesenchyme
between the temporal bone superiorly and the Bud Stage
developing condylar cartilage inferiorly during Epithelial buds form from the dental lamina and
the 12th week of embryonic life. invade the undifferentiated mesenchymal tissue
Like the mandible, the maxilla develops that lies deep to the dental lamina at the sites of
intramembranously; a center of ossification future teeth, 20 buds for the primary dentition and
appears near the future site of the maxillary decid- between 28 and 32 for the permanent dentition
uous canine during the 8th week of embryonic (Fig. 4).
life. Bone formation extends from the ossification
center to form the palatine, zygomatic, frontal, Cap Stage
and alveolar processes. The incisor-bearing area As the epithelial bud enlarges, its morphology
is called premaxilla and is an extension of the changes to a concave cap shape. The epithelial
frontonasal process (Berkovitz et al. 2016). Bone cells are now ready to form the enamel organ, and
remodeling plays an important role in the subse- the mesenchyme directly adjacent to the concave
quent growth of both the mandible and maxilla part of the cap becomes the dental papilla. The
and helps to shape the terminal morphology of the surrounding mesenchyme becomes the dental fol-
jaw bones. licle (Fig. 5).
Bell Stage
Odontogenesis In the final soft tissue stage of odontogenesis, the
bell stage (Fig. 6), the cells that will produce the
Odontogenesis begins with the formation of a mineralized tissue of teeth, as well as their
“general dental lamina” (Nanci 2013) in the loca- supporting cells, undergo morpho- and histodiffer-
tion of the future dental arches. The general dental entiation. At the end of the bell stage, ameloblasts
lamina forms the 20 primary teeth. Succedaneous and odontoblasts are recognizable. The enamel
permanent teeth develop from a successional lam- organ now consists of a number of distinct cell
ina deep to the general lamina. Where there is no groupings: the inner enamel epithelium (IEE)
directly adjacent to the dental papilla, the outer

OC enamel epithelium (OEE) forming the outer bound-
ary of the enamel organ, the stellate reticulum
(SR) forming the bulk of the enamel organ, and a
layer of cells between the SR and IEE, the stratum
intermedium (SI). The shape of the future crown is
taken on by the IEE, and its cells differentiate into
ameloblasts (Robinson et al. 2017), starting at the
cusp tips or incisal edges of developing teeth. The
DL OEE serves as the covering and protecting layer for
SL
the enamel organ, and the SR and SI support the
function of ameloblasts. Bell stage is the last soft
tissue stage of tooth formation. Ameloblasts influ-
Mc ence the adjacent layer of cells in the dental papilla
to differentiate into odontoblasts that will start pro-
TB
ducing predentin, a mesh of collagen layer that
mineralizes within 24 hours, into dentin. As amelo-
B blasts are the initiators of odontoblast differentia-
tion, amelogenesis imperfecta affects both enamel
and dentin (Robinson et al. 2017)
The formation of dentin in turn influences the
Fig. 4 Hematoxylin and eosin stained section shows a ameloblasts to produce enamelin, a mesh of col-
tooth in the tooth “bud” stage (TB) including the dental lagen fibers but with 25% embedded hydroxyap-
lamina (DL) with surrounding mesenchymal cells (Mc). atite (Nanci 2013).
Inferior to the tooth bud is the developing bone of the jaw Predentin production continues throughout
(B) and deep to it is the successional lamina (SL) which
will become a permanent tooth. The immature oral cavity life, but the speed of apposition differs. Before
(OC) can be seen at the top of the image tooth eruption into the oral cavity, odontoblasts
DL
SL
OEE
SR
IEE SI
DP
DF
Fig. 5 Hematoxylin and eosin stained histology section and the successional lamina (SL) can be seen to the right of
shows a developing tooth in the “cap” stage. The inner and the image. The dental papilla, comprised of mesenchymal
outer enamel epithelia (IEE and OEE) are present and cells, is surrounded by the IEE, and the dental follicle
separated by the stellate reticulum (SR) and stratum (DF) surrounds the developing tooth structure
intermedium (SI). The dental lamina (DL) is still present,
Ab OM
D
OEE
Ob B
SI SR
BV
Fig. 6 Hematoxylin and eosin stained histology section blood vessels (BV) are infiltrating it. The outer enamel
shows a developing tooth at the “bell” stage. Dentin epithelium (OEE) can be seen and will soon fuse with the
(D) can be seen (in its greatest quantity at this stage at the stratum intermedium (SI) to become the reduced enamel
future cusp tip) being laid down by odontoblasts (Ob). epithelium. Bone (B) can be seen forming around the
Ameloblasts (Ab) are also present. The stellate reticulum developing tooth, and the oral mucosa (OM) is visible at
is still present (SR) as are parts of the stratum intermedium the top right corner of the image
(SI). The pulp is more developed at this stage too, and
deposit 4μm of well-structured predentin daily disturbances are thought to be genetic, develop-
(primary dentin). After eruption and functional mental, environmental, and evolutive. If the
occlusion, odontoblasts deposit 1.5μm of well- anomalies are present in the primary dentition,
structured predentin daily. Tertiary or reparative particularly if they are bilateral, it is more likely
dentin is produced by odontoblasts in response to that the anomaly will be present in the permanent
stimulation of odontoblasts from abrasion, attri- dentition (Gomes et al. 2014; Mukhopadhyay and
tion, or other causes. This is a dentin whose pro- Mitra 2014). Many variations have little effect on
duction is limited to areas of odontoblast the function of the dentition in humans.
stimulation. The speed at which it is produced As tooth formation has a defined and relatively
dictates its structure, from well-structured slow stable timeline throughout human populations,
production to disorganized fast production any effect on dental variation occurs within the
(Chiego 2014; Provenza 1988). timeframe of odontogenesis.
Failure of odontogenesis (tooth agenesis) leads
Root Formation to a decrease in the number of teeth in the dental
At the limits of the crown, IEE and OEE fuse to arch (hypodontia), usually the last tooth in a
form Hertwig’s epithelial root sheath. This sheath sequence (e.g., lateral incisor, second premolar,
directs the formation of the tooth’s root or roots and third molar). Hypodontia can affect either
(Nanci 2013). Odontoblasts differentiate and form arch. It can be uni- or bilateral, and if the primary
root dentin, and cells external to these differentiate teeth are affected, it is likely the condition will be
into cementoblasts and form cementum carried over to the permanent dentition. Hypo-
(Gonçalves et al. 2015) (Fig. 7). dontia can bring about a lack of alveolar bone
and malocclusion (Choi et al. 2017). The reported
incidence of hypodontia ranges from 2.7% to
Variations in the Dentition 12.2% in the permanent dentition (Al-Abdallah
et al. 2015). The third molars, however, are so
Variations in the dentitions encompass tooth num- commonly missing in modern times, that if they
ber, morphology (Mukhopadhyay and Mitra are missing, it is not considered hypodontia in the
2014), and/or structure. The causes of these scientific literature (Al-Abdallah et al. 2015).
REE
ES
B D
D
E
Ab P R
Sr
R ED
Ob B
PDL
B
Fig. 7 Hematoxylin and eosin stained demineralized sec- Developing periodontal ligament fibers (PDL) can be
tion showing a developing tooth at the root formation seen in the enlarged section, connecting the root (R) to
stage. Surrounding bone tissue (B) can now be seen close the adjacent bone (B). The enlarged section on the left
to the tooth’s root (R). The enamel space (ES) is caused by shows mature dentin (D) in addition to odontoblasts
the demineralization process, and the reduced enamel epi- (Ob). Ameloblasts (Ab) are present secreting enamel (E).
thelium (REE) has now created a protective layer around The stellate reticulum is still present (Sr). The pulp (P) is
the crown of the tooth. The epithelial root diaphragm more developed. Bone (B) can be seen forming around the
(ED) is visible in the enlarged section to the right. developing tooth root
The converse of hypodontia is hyperdontia, an tissue formation. Some of these are clinically sig-
increase in the number of teeth by one or more nificant, such as amelogenesis and dentinogenesis
supernumerary teeth. Causes of hyperdontia have imperfecta, and will not be discussed here but are
been proposed as a dichotomy of the tooth bud, an covered in the chapter on “Odontogenic Pathol-
overactive dental lamina, and genetic and cranio- ogy.” Environmental effects such as staining of
facial anomalies (Aslan and Akarslan 2013). teeth or disruptions in amelogenesis/dentino-
Other disturbances of odontogenesis can include genesis will appear as discolorations and morpho-
variations in the morphology of teeth. These can be logical defects in the crown of the tooth such as
considered variations because they are not often hypoplasia of enamel (Fig. 8).
diagnosed or noticed until a thorough examination
of the oral cavity is undertaken. Variations in tooth
morphology have a strong population affinity such Gross Anatomy, Histology,
as shovel-shaped incisors in Asian populations and and Biology of the Maxillofacial
Carabelli’s cusp in people with Mediterranean Region
ancestry. Morphological variations may also be
closely associated with hypodontia. Maxillary Osteology of the Skull
hypodontia, for example, has been found to have
a significant association with maxillary lateral inci- The skeleton of the head can be categorized in a
sor hypodontia (Al-Abdallah et al. 2015). number of different ways, depending on the focus
Variations in the structure of the teeth (enamel, of the discussion. The skull can be separated
cementum, and dentin) occur during the time of into the calvaria (skullcap) and cranial base or
Fig. 8 Close-up
photograph of the left lower
lateral incisor and canine.
The incisor and canine both
show broad horizontal
regions of linear enamel P
hypoplasia (H). In the
lateral incisor, the normal
external expression of
amelogenesis can be seen as
perikymata (P)
alternatively divided according to contents as the lighter and can be of great pathological impor-
neurocranium and viscerocranium. While the tance as the intraosseous lesions in the maxilla
adult skull may retain sutures separating individ- normally spread faster than that of the mandible
ual bones, some or all of these may become oblit- (Garant 2003).
erated over time. The synchondroses that are The flat bones of the calvaria are bilayered; there
present in the midline of the cranial base to is an inner layer of compact bone, the inner table,
allow for its growth in childhood and adolescence and an external layer, the outer table. The interven-
are all fused by the age of approximately 14 years. ing tissue is also bone, though less compact than
Premature obliteration of sutures or fusion of syn- either the inner or outer tables. The bones of the face
chondroses leads to dysfunctional growth of the are compact bone. The “pneumatic bones” are
skull to compensate for the inability of the fused hollowed out by sinuses or air cells. The presence
or obliterated growth surfaces to expand. of these warms and moistens inhaled air, resonates
The mature cranium is a single unit. It has the human voice, and may have a role in decreasing
articulations with the mandible and C1 vertebra the weight of the skull. Paranasal air sinuses are
(atlas). The cranium has many foramina to allow discussed in the relevant sections below.
the passage of nerves and vessels between the
cranial cavity and orofacial structures and the
rest of the body. The foramina transmitting nerves Anatomical Variations of the Skull
and vessels are discussed in the relevant craniofa-
cial regions below. The skeletal regions of the skull that have direct
The driving force of the early growth of the attachment of skeletal muscle are subject to varia-
neurocranium or cranial vault is the growth of the tions corresponding to each muscle’s cross-
brain and eyes. The remainder of the skull grows sectional size, with larger muscles leading to larger
at the somatic growth rate. Craniofacial growth is biomechanical forces and, consequently, thicker
subject to changes in relative size and proportions cortical bone at the site of muscle attachment
of individual elements. This leads to considerable (Iván and Daniela 2012). For example, if there is
variation in size and proportion of the adult cra- a preference for chewing on one side of the mouth,
niofacial complex (Wood 2015). The mandible is the attachment of masseter to the angle of the
constructed from both cortical bones as a liner and mandible on that side will be considerably larger
spongy bone in the center, while the maxilla has a than the contralateral angle and may even be
greater percentage of spongy bone making it everted slightly. This is because of the increased
force being applied by the larger masseter on the found fibers of the lingual nerve and mylohyoid
preferred chewing side. In other cases, the lack of nerve and branches of the lingual artery and sub-
balance between different structures can lead to lingual/submental artery branches entering the
changes in skeletal morphology. In children with superior and inferior genial spinal foramina, an
pharyngeal tonsil hypertrophy (adenoids), the important consideration when planning mandibu-
blocking of the nasopharynx necessitates mouth lar implants (Jacobs et al. 2007).
breathing. This leads individuals to retain an open The skull expresses sexual dimorphism in
mouth, and the tongue moves inferiorly. This in humans. The differences are established at
turn leaves the forces of buccinators on the upper puberty and are due to sex hormone expression.
arch unopposed. The resulting lateral compression In general, males have an overexpression of bony
leads to a short transverse axis in the upper arch and elevations in the skull compared with females; in
a high-set palate (Nishimura and Suzuki 2003). men, the size of ridges, tubercles, and processes is
Differences in skull morphology occur greater than in women. These effects are increased
between populations as a process of adaptation by the action of muscle forces on the bone. In
to environmental and subsistence patterns and general, the male skull is larger and more robust
drift as a factor of population size or isolation than the female skull, with bony features more
(Hanihara and Ishida 2001). prominent in the male. The forehead is steeper in
Where foramina exist in the skull for the pas- males. The body and ramus of the mandible are
sage of nerves and vessels, considerable variation greater in size in males compared with females.
in their form and position can be found. Foramina These differences are to be taken in general and
may be single or may consist of multiple smaller are certainly not universal determinants of gender
accessory foramina. Their position relative to in humans.
other anatomical landmarks may also vary. The The body of the mandible may be subject
position of the palatine foramen in the hard palate, to developing a mandibular torus, torus
for example, may be found opposite the third mandibularis (Fig. 10a), on the medial surface of
molar, distal to it, or between the third and second the body. This is not a pathological process and
molars (Fig. 9) (Chrcanovic and Custódio 2010). mostly does not interfere with function. These can
Recent three-dimensional studies have also occur on the palate, torus palatinus (Fig. 10a
improved the visualization capabilities of clini- and c). However, over time these can become very
cally important regions of the skull. One study large and may interfere with the construction of
Fig. 9 Palatine views of two skulls, showing the variable position of the greater palatine foramen (GPf.) relative to the
upper right third molar
Fig. 10 Tori can occur in the mandible, torus courtesy of Professor Michael McCullough, Melbourne
mandibularis (a) or the palate, torus palatinus (b and c), Dental School, University of Melbourne, Carton VIC and
be relatively small, not change over time and be of very images (b and c) courtesy of Professor Camile Farah, Perth
little consequence. However, they can increase with time Oral Medicine & Dental Sleep Centre, Perth WA,
and potentially be of concern, particularly to the fit of full Australia)
dentures and may require preprosthetic removal (Image a)
dentures should the patient require these (Fig. 10a,

b, and c).
The bony canal for the inferior alveolar nerve
and vessels in the mandible are subject to varia-
tions in their course and structure. Double and
bifid canals may be present, the location of the
mandibular foramen varies, and the location of the
canal in relation to the roots of mandibular teeth
can also vary (Fig. 11). Approximately 20% of
individuals have asymmetrically sized mental
foramina (Berge and Bergman 2001).
Age changes are an important consideration for
the study of landmarks. The bony tissue of the
skull is subject to remodeling as a result of muscle
and masticatory forces and as a result of changes Fig. 11 Inferior alveolar canal dissected on a dry mandi-
in the structure and number of teeth. The mandib- ble showing also the mental foramen
ular foramen, an important landmark for the
administration of local anesthetic to the mandibu- facilitates tissue turnover (Fig. 13), which is of
lar arch, changes its position relative to the occlu- great importance both physiologically for growth
sal plane, alveolar crest plane, anterior border of and maintenance of calcium homeostasis, and also
the ramus of the mandible, angle of the mandible, allows for orthodontic treatment (Hand and Frank
and the head of the mandible with increasing age 2014).
(Rodella et al. 2012). The mandibular foramen
moves superiorly relative to the occlusal plane
with increasing age (Hung-Huey 2004). Scalp and Facial Soft Tissues
There is considerable variation in the timing of
suture closure over the human lifespan. Sutures The scalp is a multilayer of soft tissues that
close on the endocranial surface first, followed by envelops the skull. It specifically covers the fron-
the external surface. tal, parietal, temporal, and occipital regions
(Fehrenbach and Herring 2012). It borders the
supraorbital margin anteriorly, the external occip-
Histology of Hard Tissues ital protuberance and superior nuchal line posteri-
orly, and the superior temporal line laterally. The
The skull consists of bone formed by either five layers of the scalp are the skin, connective
intramembranous ossification (flat bones of the tissue, aponeurosis, loose areolar connective tis-
cranial vault and mandible) or endochondral ossi- sue, and pericranium (conveniently forming the
fication (bones of the cranial base). Mature bone is acronym “SCALP”) (Norton and Netter 2012).
osteonal in nature and consists of an inorganic/ The skin is the thickest layer of the scalp; it con-
organic matrix. Osteons (Haversian systems) have tains hair follicles and other adnexal structures
concentric lamellae of matrix containing osteo- particularly oil-secreting sebaceous glands. The
cyte lacunae (Fig. 12). Similar to cementum subcutaneous layer of the scalp is formed by
(Fig. 13), the bone consists of 66% mineral, but dense fibrous tissue and firmly attaches the
the presence of both osteoblasts and osteoclasts overlying skin to the underlying epicranial
Fig. 12 Toluidine blue stained decalcified histological the diploё, which in this skull contains hematopoietic bone
slide shows two flat bones of the calvaria joined by a suture marrow (BM). Pericranium (periosteal tissue) lines the
(S) composed of fibrous tissue and fibroblasts. The inner external surface of the skull (P), just deep to the muscle
and outer tables of the skull are composed of osteonal bone which overlies the skull in some places (M). An osteon is
tissue (OB) and the inner and outer tables are separated by highlighted by a dotted line
Fig. 13 Hematoxylin and

eosin stained decalcified
section of the lower jaw
showing newly erupted
teeth embedded in alveolar
bone (A) by the periodontal
ligament (P). Teeth are
present on the left and right
of the image, with dentin
forming the visible bulk of
the tooth (D), and a thin
layer of cementum
(C) facing the periodontal
ligament. Rf resorption
front, Oc osteoclast, Ob
osteoblast
Fig. 14 Histological
sagittal section through a
developing rabbit head,
showing the layers of the
scalp (x 8.5). All layers of
the scalp are visible: skin
(S), connective tissue (C),
aponeurosis (A), loose
areolar tissue (L),
pericranium (P), and bone
(B). The immature
membranous bone of the
skull is also visible,
separating the scalp from
the cranial cavity. Hair
follicles (HF) and shafts
(Sh) can be seen embedded
in the connective tissue
aponeurosis (the fascia of the muscle occipito- to the posterior auricular (mastoid) and occipital
frontalis) (Snell 2012; Agur and Grant 2013). lymph nodes (Norton and Netter 2012; Snell
The scalp is highly vascular and vessels anas- 2012).
tomose freely. Combined with the tension pro- The skin of the scalp and face is innervated
duced anteroposteriorly by occipitofrontalis partly by cutaneous sensory branches of the cer-
muscle, this causes scalp wounds to gape and vical spinal nerves but mostly by the fifth cranial
bleed profusely. The principal arteries of the nerve: the trigeminal nerve (Norton and Netter
scalp, the superficial temporal, posterior auricular, 2012; Snell 2012) (Fig. 14). Note that C1 has no
and occipital arteries, are branches of the external cutaneous distribution.
carotid artery, while the supraorbital and supra-
trochlear arteries are branches of the ophthalmic
artery, a branch of the internal carotid artery (Nor- Soft Tissue Structures
ton and Netter 2012). Lymph from the part of the in the Superficial Face
scalp anterior to the auricles drains to the parotid,
submandibular, and deep cervical lymph nodes. Despite that much of the facial contour is dictated
Lymph from the posterior part of the scalp drains by underlying facial bone morphology, control of
facial sphincters and facial expressions is affected these muscles are associated with the second bran-
principally by the compartments of the facial soft chial arch, hence their common innervation. The
tissue. There are six groups of muscles that are facial nerve exits the skull through the
responsible: oral, nasal, orbital, auricular, scalp, stylomastoid foramen. It enters the face via the
and neck (Table 5). Superficial facial muscles substance of the parotid gland, which it does not
(Fig. 15) are difficult to identify with routine innervate (Gray et al. 1995). Two trunks are given
imaging methods as these muscles are closely off, the temporofacial and the cervicofacial. These
intertwined (Hutto and Vattoth 2015) and lack two trunks then give the five branches of the facial
bulk. Their common innervation derives from nerve with some branching variations. Table 6
their embryological origin in the mesoderm asso- outlines the innervation of individual facial mus-
ciated with the second branchial arch. The best cles as well as variations of the facial nerve
assessment for facial muscle, and therefore ipsi- branches.
lateral facial nerve function, is a visual assessment Several consistent ligaments that act to tether
of their function, asking the patient to raise their the facial skin to underlying structures have been
eyebrows, frown, puff out their cheeks, smile, identified; the zygomatic ligaments stabilize the
wrinkle their nose, and purse their lips. skin of the cheek by attaching them to the inferior
These facial muscles are all innervated by the border of the zygoma, mandibular ligament fibers
facial nerve (cranial nerve VII). Embryologically, tether the anterior mandible to overlying skin, and
Table 5 Facial muscles (Modified from Netter’s Head and Neck Anatomy for Dentistry; Norton and Netter 2012)
Group Muscle Actions
Oral Orbicularis oris Produces oral seal, protrusion of lips and pursing of lips
Depressor anguli oris Depresses the corners of the mouth
Levator anguli oris Elevates the angle of the mouth
Zygomaticus major Moves the angle of the mouth superiorly and laterally
Zygomaticus minor Helps elevate the upper lip
Levator labii superioris Elevates the upper lip
Levator labii superioris alaeque Elevates the upper lip and dilates the nostrils
nasi
Risorius Moves the angle of the mouth laterally
Depressor labii inferioris Depresses the lower lip
Mentalis Protrudes the lower lip
Buccinator Aids in mastication and helps to forcibly expel air or create a sucking
action
Nasal Nasalis compressor naris Compresses the nostril
Nasalis dilator naris Dilates the nostril
Depressor septi Draws nasal septum anteriorly to constrict nostril
Procerus Brings skin together producing transverse wrinkles on the bridge of
the nose
Orbital Orbicularis oculi orbital Forcible closure of the eye
Orbicularis oculi lacrimal Aids the flow of tears
Orbicularis oculi palpebral Closure of eyelids gently (blinking)
Corrugator supercilii Draws the eyebrows medially and inferiorly
Auricular Anterior Draws auricle anteriorly
Superior Draws auricle superiorly
Posterior Draws auricle posteriorly
Scalp Frontalis Elevates eyebrows and wrinkles forehead
Occipitalis Wrinkles the back of the head
Neck Platysma Wrinkles the skin of the neck
Fig. 15 Diagram showing locations of facial muscles. (Original drawing by Dr Hala Al Janaby, Perth WA, Australia)
the platysma-auricular ligament is a flat ligament structures arises from the facial branches of the
attaching the posterior border of the platysma to external carotid artery. The anterior part of the
the skin anterior to the auricle (Furnas 1989). forehead is supplied by branches from the internal
The arteries of the face anastomose freely carotid artery. The ophthalmic artery branches
(Norton and Netter 2012; Snell 2012). The prin- supply the dorsal surfaces of the external nose
cipal vascular supply of the facial soft tissue (Norton and Netter 2012).
Table 6 Branches of the facial nerve and observed variations

Division Branches Innervation Variations
Temporofacial Temporal Corrugator Procerus Six variations of facial nerve patterning have
supercilii Orbicularis been identified (Gataa and Faris 2016):
Anterior and oculi orbital Type I: No anastomosis between the two main
superior Orbicularis branches
auricular oculi Type II: Anastomosis only between branches of
Frontalis lacrimal the temporofacial division (second-most
Zygomatic Levator Orbicularis common variation)
anguli oris oculi Type III: One anastomotic incidence between
Zygomaticus palpebral the two divisions – Buccal and zygomatic
Buccal major Buccinator branches (most common variation)
Zygomaticus Nasalis Type IV: Combination of type II and III, with
minor compressor temporal, zygomatic, and buccal branch
Levator labii naris anastomoses
superioris Nasalis Type V: Double anastomosis between the two
Levator labii dilator naris divisions (least-common variation)
superioris Depressor Type VI: Complex anastomosis between the
alaeque nasi septi two divisions
Cervicofacial Marginal Depressor labii inferioris
mandibular Mentalis
Depressor anguli oris
Cervical Platysma
Posterior Occipitalis None to mention
auricular Posterior auricular muscle
Chorda Taste sensation to anterior two None to mention
tympani thirds of the tongue,
(intratemporal) parasympathetic fibers to
submandibular and sublingual
glands (Singh et al. 2015).
Postganglionic
parasympathetic fibers
hitchhike with branches of the
third division of the trigeminal
nerve to the submandibular
and sublingual glands. Taste
fibers hitchhike with the
lingual nerve (Baker et al.
2015)
The facial veins begin as small venules and facial expression (Fehrenbach and Herring 2012;
become larger as they join proximally Norton and Netter 2012). The three divisions of
(Fehrenbach and Herring 2012). These veins fol- the trigeminal nerve are responsible for supplying
low a similar distribution pattern to that of facial the sensory innervation for facial structures, and
arteries (Norton and Netter 2012). The facial vein the cervical plexus does similarly (Norton and
is the main drainage of the face and joins the Netter 2012).
internal jugular vein on its way to the heart
(Fehrenbach and Herring 2012; Snell 2012).
However, other areas of the face drain via the Variation and Aging in Facial Soft
retromandibular vein to the external jugular vein Tissues
(Fehrenbach and Herring 2012).
The face is innervated by motor and sensory Physical maturity is reached approximately in the
nerves. The facial nerve (Fig. 16) covers all motor early 20s, and subsequently human facial soft
nerves in the face and supplies the muscles of tissues begin to undergo changes not as a
Fig. 16 Diagram showing the course of the branches of the facial nerve (CNVII) over the face. (Original drawing by
Dr Hala Al Janaby, Perth WA, Australia)
consequence of growth but due to the onset of being thinnest over the tip and bridge of the nose
“aging.” The aging process involves gradual and infraorbital rim and thickest over the lips,
decrease in skin elasticity, reduction in subcuta- chin, cheek, and lower jaw (Stephan et al. 2013).
neous fatty tissue volumes, increase in muscle
tone, and the effects of gravity. These factors
lead to an increase in skin folds “wrinkles,” usu- Histology of the Epidermis
ally perpendicular to facial muscle fiber direction,
and a decrease in overall facial volume (Mydlová The epidermal covering of the head and neck
et al. 2015). Facial soft tissue thickness varies varies in thickness from the scalp to the skin
between different regions of the face, generally overlying the eyelids. Most of the epidermis
contains hair follicles, sweat, and sebaceous Infratemporal Region

glands. The epidermis overlies dermis, containing and Pterygopalatine Fossa
numerous blood vessels that anastomose freely,
especially over the face. The infratemporal region is located inferior to the
The epidermis of the head and face is a strati- horizontal shelf of the temporal bone, in a space
fied squamous keratinized epithelium. The epithe- referred to as the infratemporal fossa. It forms a
lial layers are avascular and receive their nutrition clinically important region because it contains
from the dermis and subcutaneous tissue that lie major muscles, nerves, vessels, glands, and joints
deep to the basement membrane of the epidermis of the head. The infratemporal fossa communi-
(Fig. 17). cates with the middle cranial fossa via the foramen
ovale and foramen spinosum that transmit the
mandibular division of the trigeminal nerve and
the middle meningeal artery, respectively. It com-
municates with the pterygopalatine fossa via the
pterygomaxillary fissure and inferiorly with the
parapharyngeal space, a potential fascial space
lateral to the pharynx (discussed elsewhere in
this chapter).
The main boundaries of the infratemporal fossa
are the zygomatic bone and infratemporal surface
of the greater wing of sphenoid bone superiorly,
with a small contribution from the squamous part
of the temporal bone, the ramus of the mandible
laterally, the styloid process posteriorly as well as
the carotid sheath and its contents, the
infratemporal surface of the maxilla anteriorly,
the lateral pterygoid plate and pyramidal process
of the palatine bone medially, and the level of a
transverse plane through the lower border of the
mandible inferiorly.
The bony borders of the infratemporal fossa are
incomplete (Fig. 18), and so there is much open
communication between structures within and
Fig. 17 Hematoxylin and eosin stained cross-section of
stratified squamous keratinized epithelium. The papillary
immediately adjacent to the fossa. The most clin-
layer of the dermis is seen beneath the epithelial layer (P). ically relevant of these is the pterygopalatine
A basement membrane (not visible in light microscopy) fossa, which communicates with the
supports the epithelial cells. The deepest layer is the stra- infratemporal fossa via the pterygomaxillary
tum basale (SB), a layer of undifferentiated epithelial cells.
The next superficial layer is the stratum germinativum
fissure.
(SGe). In this region of the epithelium, the cells have not The contents of the infratemporal fossa are the
yet changed their shape to a squamous morphology. The lateral and medial pterygoid muscles, the tendi-
stratum spinosum (SS) is the next superficial layer. Here, nous insertion of the temporalis muscle, the man-
the keratinocytes begin to flatten. They appear as having
small spiny processes projecting from the membrane. The
dibular division of the trigeminal nerve, the
next layer, present in keratinized epithelia, is the stratum posterior superior alveolar branch of the maxillary
granulosum (SGr), where the keratinocytes appear to have division of the trigeminal nerve, the otic ganglion,
granular cytoplasm. More superficial to this (stratum the lesser petrosal nerve, the chorda tympani, and
lucidum – SL and keratinized layer – K), the keratinocytes
begin to lose their nuclei and become flatter in the very
the maxillary artery and accompanying veins. The
thick keratin layer, eventually to be sloughed off from the temporomandibular joint is also placed just within
surface the infratemporal fossa (Mohl 1988).
structures. Within the fossa, the artery gives off five

branches: the infraorbital, sphenopalatine, poste-
rior superior alveolar, descending palatine
branches, and the artery of the pterygoid canal.
These are discussed in greater detail elsewhere.
The maxillary division of the trigeminal nerve
enters the pterygopalatine fossa via the foramen
rotundum.
Trigeminal Nerve
The trigeminal nerve (CNV) has a wide distribu-

tion in the craniofacial region. It supplies sensory
innervation to the face and scalp up to the vertex,
including most parts of the oral cavity. Being a
first pharyngeal arch structure, it is responsible for
motor innervation of the muscles of mastication.
The trigeminal nerve has three divisions, the
Fig. 18 Inferior view of the cranium outlining the bound- ophthalmic (CNV1), maxillary (CNV2), and man-
aries of the infratemporal fossa dibular (CNV3) whose territories roughly divide the
face into thirds: CNV1 from the vertex of the scalp
Clinically, the infratemporal fossa is accessed to the eyelid and a central strip of the nose, CNV2
in its anterior aspect to carry out a posterior supe- from the lower eyelid to the upper lip, and CNV3
rior alveolar nerve block. from the lower lip to the chin and angle of the jaw
The pterygopalatine fossa is a small inverse- (Fig. 19). Minor variations occur in branching.
pyramid-shaped fossa. Its roof is formed by the
greater wing of the sphenoid bone, its anterior
wall is formed by the infratemporal surface of CNV1
the maxilla, and its posterior wall by the root of
the pterygoid processes of the sphenoid. Laterally, The ophthalmic division of the trigeminal nerve
it communicates with the infratemporal fossa (Fig. 19a) is wholly sensory and is essentially the
via the pterygomaxillary fissure. Narrow nerve of the embryonic frontonasal process. The
pterygomaxillary fissures can be found in approx- nerve leaves the ganglion and passes by the cav-
imately 8% of individuals, hampering access to the ernous sinus, picking up sympathetic fibers for the
fossa for anesthesia (Stojčev Stajčić et al. 2010). An dilator pupillae muscles. After giving off a men-
enlarged sphenoidal spine may obstruct access to ingeal branch, the ophthalmic division splits into
the pterygomaxillary fissure in 15% of individuals three branches that leave the cranial cavity and
(Stojčev Stajčić et al. 2010). Inferiorly the fossa enter the orbit via the superior orbital fissure
communicates with the oral cavity via the greater (Fig. 19a). The three branches are the frontal,
palatine canal. The volume of the pterygopalatine lacrimal, and nasociliary nerves.
fossa (on dry skulls) has been measured at between The frontal nerve, which runs along the roof of
0.1cm3 and 1.0cm3, without significant bilateral the orbit, divides into the supraorbital and supra-
asymmetry (Stojčev Stajčić et al. 2010). trochlear branches. The supraorbital nerve sup-
The pterygopalatine fossa contains the plies the frontal sinus, upper eyelid, most of the
pterygopalatine part of the maxillary artery, one forehead, and scalp to the vertex. The supra-
of the terminal branches of the external carotid trochlear nerve supplies a small medial vertical
artery and one of the main arteries supplying facial strip of the forehead.
Fig. 19 The trigeminal nerve and its branches. The first the third, mandibular branch (V3) highlighted in blue.
branch, ophthalmic branch (V1) is highlighted in pink, the (Original drawing by Dr Hala Al Janaby, Perth WA,
second, maxillary branch (V2) highlighted in green, and Australia)
The lacrimal nerve courses along the lateral sensory innervation to the globe of the eye. It
wall of the orbit. Secretomotor fibers from the passes through the anterior ethmoidal foramen,
zygomatic nerve “hitchhike” with the lacrimal becomes the anterior ethmoidal nerve, and sup-
nerve to the lacrimal gland. It supplies a small plies the ethmoidal air cells. It then passes anteri-
part of the upper eyelid and associated orly into the roof of the nose, where it innervates
conjunctiva. the anterosuperior lateral nasal wall and septum.
The nasociliary nerve passes along the medial The nerve then supplies the external nose as the
wall of the orbit, carrying the “hitchhiking” sym- external nasal nerve. For variations, refer to
pathetic nerves to the dilator pupillae, and gives Table 7.
Table 7 Innervation of the face relevant to the maxillofacial region with variations
Nerve Branches Distribution Variations
Olfactory None Special sensation of smell via Occasional absence of olfactory
(CN I) olfactory bulbs in the roof of the nerve, bulbs, tracts, and lobes has
nasal cavity been reported
Trigeminal Lacrimal nerve Lacrimal gland and adjacent Sometimes receives a branch from
ophthalmic conjunctiva. Receives a branch the trochlear nerve (CN IV). The
division from the zygomaticotemporal lacrimal nerve is sometimes
(CNV1) branch of the maxillary nerve, absent, in which case the
which is thought to be zygomaticotemporal branch of the
secretomotor to the lacrimal gland maxillary nerve performs its
function. The reverse is also
sometimes true
Frontal nerve The supratrochlear branch supplies
(supratrochlear and a fiber to the nasociliary nerve. It
supraorbital branches) supplies the conjunctiva and skin
of the upper eyelid and the skin of
the inferior part of the forehead
close to the midline. The
supraorbital nerve passes through
the supraorbital fissure, divides
into medial and lateral branches,
and gives sensory supply to the
scalp to the vertex
Nasociliary nerve
Trigeminal Middle meningeal nerve Meninges of the middle cranial None to mention
maxillary fossa
division Zygomatic nerve Sensory to skin overlying the The two branches may emerge
(CNV2) (temporal and facial temple (temporal branch) and separately or via one foramen in
branches) upper lateral cheek (facial branch) the zygomatic bone. The
distribution may be taken over by
the infraorbital nerve (facial
branch) or lacrimal nerve
(temporal branch)
Posterior superior Sensory to upper molar teeth, *see entries for long buccal nerve
Alveolar nerve buccal mucosa, and gingivae and palatine nerve below
associated with these teeth; the
maxillary sinus
Infraorbital nerve Sensory to inferior lid of the eye There may be accessory
(middle and anterior including conjunctiva and infraorbital foramina (Rodella et al.
superior alveolar nerves) maxillary sinus (infraorbital), 2012). The middle superior
maxillary teeth (premolars – alveolar nerve may be absent
Middle superior alveolar, incisors, (Rodella et al. 2012). The nerve
and canines – Anterior superior may exist as a single trunk or
alveolar), associated gingiva and plexus (the single trunk being more
mucosa of the cheek (Leo et al. common) (Rodella et al. 2012)
1995)
Nasopalatine nerve Sensory to anterior hard palate and May give some branches to
inferior nasal septum maxillary incisors (Rodella et al.
2012)
Posterior superior nasal Sensory to posterior ethmoid air None to mention
nerve (lateral and medial cells and mucosa of the posterior
posterior superior nasal superior and middle conchae
nerves) (lateral posterior superior nasal
(continued)
Table 7 (continued)
nerve) and mucosa of the posterior
roof and septum (medial posterior
superior nasal nerve)
Palatine nerve (greater Sensory to hard palate mucosa, Branches from the palatine nerve
and lesser palatine gingivae and glands (greater), soft may innervate maxillary molars
nerves) palate, palatine tonsils, and uvula and premolars (Rodella et al. 2012)
(lesser)
Pharyngeal nerve Sensory to mucosa of nasopharynx None to mention
Trigeminal Recurrent meningeal Sensory to meninges of middle
mandibular cranial fossa
division Nerve to medial Motor to medial pterygoid and None to mention
(CNV3) pterygoid motor to tensor tympani and tensor
Anterior veli palatini
division Nerve to masseter Motor to masseter, sensory to None to mention
temporomandibular joint
Deep temporal nerves Motor to temporalis None to mention
Nerve to lateral Motor to lateral pterygoid None to mention
pterygoid
Long buccal nerve Sensory to cheek skin and mucosa The buccal nerve’s territory can be
and molar buccal gingivae covered by the posterior superior
alveolar nerve. The buccal nerve
may arise as a branch of the inferior
alveolar nerve (Bergman et al.
2006). The long buccal nerve may
be responsible for innervation of
the molars by entering through
retromolar foramina (Rodella et al.
2012)
Trigeminal Auriculotemporal nerve The Auriculotemporal nerve There may be some anastomosis of
mandibular supplies sensation to the innervation between the
division temporomandibular joint capsule, auriculotemporal nerve and
(CNV3) the skin over the ear and temple, as inferior alveolar nerve (Rodella
Posterior well as carrying postganglionic et al. 2012)
division parasympathetic fibers from the
otic ganglion
Lingual nerve Provides general sensory The lingual nerve may pierce the
innervation to the anterior two lateral pterygoid in its course and
thirds of the tongue, floor of may occasionally carry motor
mouth, and lingual gingiva. Carries branches to the pterygoids and
parasympathetic fibers to the palatoglossus (Bergman et al.
submandibular and sublingual 2006). The course of the lingual
salivary glands nerve varies in relation to the
alveolar crest, with the vertical
distance between the two ranging
from approximately 2 to 8 mm
(Rodella et al. 2012). The lingual
nerve may provide some fibers to
the inferior alveolar nerve (Rodella
et al. 2012). The lingual nerve may
also innervate the lingual gingiva
around the third molar region
(Rodella et al. 2012)
(continued)
Table 7 (continued)
Inferior alveolar nerve The inferior alveolar nerve is The inferior alveolar nerve may
(incisive and mental sensory to the mandibular molars give multiple extra-osseous
branches, nerve to and their associated gingiva. A branches before entering the
mylohyoid) branch to mylohyoid innervates mandibular foramen. These will
mylohyoid muscle and anterior enter via accessory canals (Wolf
belly of the digastric muscle; et al. 2016). Bifid inferior alveolar
mental nerve innervates the skin of canals show varying prevalence
the lower lip and chin and the (0.1%–65% of individuals)
inferior labial mucosa. The incisive depending on the study conducted
branch innervates the premolars, (Rodella et al. 2012). The inferior
canines, and incisors and their alveolar nerve may split into two
gingiva (Rodella et al. 2012) trunks intraosseously with one
trunk innervating the molars and
premolars and then becoming the
incisive nerve. The other trunk
becomes the mental nerve. The
nerve may also split into three
branches near the mandibular
foramen: One for the molars and
premolars, a second for canines and
incisors, and finally a mental branch
(Wolf et al. 2016). The inferior
alveolar nerve may have varying
associations with the maxillary
artery (Rodella et al. 2012). See also
the section on the auriculotemporal
nerve. The mental nerve may also
exit the mandible through more
than one foramen and may
innervate contralateral incisors
(Rodella et al. 2012). The nerve to
mylohyoid may give some
branches to the inferior alveolar
nerve (Rodella et al. 2012)
CNV2 supplies the skin of the cheek, lateral nose, lower

eyelid and associated conjunctiva, skin and mucosa
The maxillary division of the trigeminal nerve of the upper lip, as well as adjacent gingiva up to
(Fig. 19a) is, like the ophthalmic division, wholly the premolars. Before its emergence, when the
sensory. Its territory lies between the lower eye- nerve is within the infraorbital canal, it gives off
lids and the upper lip, excluding a midline strip of the middle superior alveolar nerve (when present –
skin along the nose and parts of the nasal cavity. see Table 7), responsible for innervating the upper
The maxillary nerve and its branches supply the premolars, and the mesiobuccal root of the first
palate, nasal mucosa, maxillary teeth, lacrimal molar, as well as some mucosa of the maxillary
gland, and skin. sinus (McMinn 1995). Next, the infraorbital nerve
The maxillary nerve leaves the cranial fossa via gives off the anterior superior alveolar nerve and
the foramen rotundum (after giving off a small supplies some of the maxillary sinus and the upper
meningeal branch) and passes anteriorly through incisors and canine, as well as the inferior lateral
the pterygopalatine fossa. It leaves the fossa nasal wall, nasolacrimal duct, and anterior floor of
through the inferior orbital fissure, becoming the the nose (McMinn 1995).
infraorbital nerve as it courses through the A zygomatic branch leaves the maxillary nerve
infraorbital groove, canal, and eventually emerging in the pterygopalatine fossa and enters the orbit
from the infraorbital foramen to the face, where it through the inferior orbital fissure. It carries
postganglionic secretomotor fibers for the lacri- CNV3

mal gland that it passes to the lacrimal nerve. The
zygomatic nerve eventually splits into the The mandibular division of the trigeminal nerve
zygomaticofacial nerve which innervates the (Fig. 19b) has a large sensory component and
skin over the zygomatic bone and the zygomati- small somatomotor component. It enters the
cotemporal nerve innervating the skin over the infratemporal fossa from the middle cranial fossa
temple. via the foramen ovale of the sphenoid bone. The
The posterior superior alveolar nerve is a single foramen ovale has shown bilateral asymmetry in
branch from the maxillary nerve in the its size, which may be of clinical relevance (Berge
pterygopalatine fossa. It divides into a number of and Bergman 2001). After entering the
branches that leave the fossa via the infratemporal fossa, it immediately gives off two
pterygomaxillary fissure. Two of these branches branches, a recurrent meningeal branch to supply
enter the posterior wall of the maxilla and inner- the dura that reenters the cranial cavity via the
vate some of the maxillary sinus and the upper adjacent foramen spinosum (or reenters through
molars except for the anterior mesiobuccal root of the foramen ovale) (McMinn 1995) to innervate
the first molar, which is innervated by the middle the cartilaginous auditory tube, dura mater, mas-
superior alveolar nerve when present. One branch toid antrum, and air cells. The second branch is
does not enter the maxilla, and it innervates the the nerve to the medial pterygoid innervating the
buccal gingiva of the molars. medial pterygoid and sending a branch to tensor
Ganglionic branches from the maxillary nerve veli palatini and tensor tympani.
join the maxillary nerve to the pterygopalatine The mandibular division of the trigeminal
ganglion within the fossa of the same name. nerve then divides into its anterior and posterior
These fibers pass through the ganglion without branches.
synapsing, but pick up postganglionic parasym-
pathetic fibers as they go through the ganglion.
Mandibular Division of the Trigeminal:
These become branches of the ganglion and are:
Anterior Branch
The anterior branch of CNV3 is predominantly
– The nasopalatine nerve innervating the post-
motor. The only sensory branch being the buccal
eroinferior nasal septum and then the palatal
(or long buccal) nerve, discussed in the section on
gingiva of the upper incisors after passing
the oral cavity. The motor branches supply the
through the incisive canal.
remaining muscles of mastication including the
– The posterior superior medial and lateral nasal
deep temporal nerves to temporalis, nerve to mas-
nerves supplying the corresponding nasal sep-
seter, and nerve to the lateral pterygoid.
tum and lateral wall.
– The greater palatine nerve, which enters the
palatine canal between the maxilla and palatine Mandibular Division of the Trigeminal:
bone and then exits to the hard palate through Posterior Branch
the greater palatine foramen (Fig. 9). It inner- The posterior branch of CNV3 is predominantly
vates some of the lateral nasal wall and adja- sensory with only one motor component. Its first
cent floor of the nose, some of the maxillary branch is the auriculotemporal nerve, which
sinus, and all of the hard palate except for the courses posterior to the temporomandibular joint
nasopalatine nerve territory. and through the parotid gland, giving sensory
– The lesser palatine nerves emerge from the supply to the temporomandibular joint’s capsule
lesser palatine foramina, posterior to the greater before dividing to pass around the middle menin-
palatine foramen, and innervate the mucosa of geal artery. Ultimately it supplies some skin over
the soft palate and palatine tonsil. the ear and temple. It also carries postganglionic
– A pharyngeal branch to supply the mucosa of parasympathetic fibers from the otic ganglion.
the nasopharynx to the level of the pharyngo- The lingual nerve provides sensory supply to
tympanic tube. mucosa of the oral cavity, discussed in a
subsequent section of this chapter. The inferior translation, hence function in speech, mastication,
alveolar nerve passes into the pterygomandibular respiration, and deglutition. It is one of the most
fossa and enters the mandibular canal after giving often used joints in the human body.
off the motor branch to the mylohyoid and the The bony articulation is between the condyle
anterior belly of the digastric muscle. After enter- of the mandible and the glenoid fossa of the tem-
ing the mandibular canal, it gives branches to the poral bone (Fig. 20), located directly anterior to
mandibular teeth before dividing into its terminal the external auditory meatus. The condyle of the
incisive and mental branches. The mental branch mandible at rest articulates with the articular fossa
exits the mandible via the mental foramen to sup- via its anterior surface. There is an intervening
ply the incisive labial gingiva and the skin of the biconcave articular disc constructed of dense
chin and lower lip. The incisive branch continues fibrocartilage. The lining of joint surfaces is not
in the mandibular canal to supply the anterior hyaline cartilage as in other synovial joints; rather,
mandibular teeth. Variations in the branching pat- it is fibrocartilage-like material to resist the con-
tern and course of the nerves supplying the struc- stant forces acting on the joint during mastication
tures of the upper and lower jaws can lead to and speech.
inadequate effectiveness of local anesthesia dur- The capsule of the joint follows the border of
ing dental procedures or injury to the nerves dur- the articular surfaces (Fig. 21) and is attached to
ing surgical procedures. For common variations in the anterior and posterior poles of the intra-
the course, distribution, and branching patterns of articular disc. The capsule is thickened laterally
nerves, see Table 7. to form the lateral capsular ligament of the joint,
preventing lateral excursion of the condyle.
The congruency of the joint is improved by an
Gross Anatomy intra-articular fibrocartilaginous disc. The disc is
of the Temporomandibular Joint concave and sits between the condyle of the man-
dible and articular eminence of the temporal bone.
The temporomandibular joints are specialized During movement of the temporomandibular joint,
synovial joints, called ginglymoarthrodial syno- the condyle rotates against the disc during the first
vial joints, providing articulation between the part of mandibular depression, but then the disc and
mandible and cranium. The joints function as condyle together slide anteriorly along the articular
modified hinge joints, enabling both rotation and eminence in the latter part of joint movement to
Fig. 20 Components of the

temporomandibular joint:
C condyle, AE articular
eminence, AT articular
tubercle, EAM external
auditory meatus, Cn
coronoid process, An
mandibular angle, R ramus
against the articular eminence. The muscles of

mastication are skeletal muscles which act mainly
to produce retraction and elevation of the mandi-
ble via the temporomandibular joints (Mohl
1988). The muscles must act bilaterally, as the
rami and body of the mandible join the two man-
dibular condyles to each other.
The largest of the muscles of mastication is the
temporalis muscle. Its belly is fan-shaped and
located in the shallow temporal fossa, overlying
the squamous part of the temporal bone. The
muscle fibers converge on a tendinous insertion
at the coronoid process of the mandible. The
coronoid process is a traction epiphysis, having
its growth directed by the tensional forces of the
Fig. 21 Left temporomandibular joint showing the out-
line of the attachment of the temporomandibular joint temporalis muscle. Because of the muscle’s
capsule fan-shaped structure, the temporalis produces ele-
vation and retraction of the mandible. The muscle
open the mouth. This part of the joint’s movement is covered with taut temporalis fascia that attaches
includes protrusion of the mandible. superiorly to the pericranium forming part of the
On closing the mouth, the disc and condyle are scalp. It is innervated by the deep temporal nerves
both retracted; elastic fibers attaching the poste- (mandibular division of the trigeminal nerve) and
rior aspect of the disc to the posterior border of the receives vascular supply from the deep temporal
glenoid fossa assist the disc in retracting with the arteries (from the maxillary artery). For attach-
condyle. An inferior inelastic set of fibers attach ments, actions, innervation, and variations of the
the disc to the posterior border of the condyle. muscles of mastication, refer to Table 8.
The capsule of the temporomandibular joint The muscles of mastication are innervated by
forms a collar around the neck of the mandible the anterior division or trunk of the trigeminal
and surrounds the articular surface of the glenoid nerve (CNV3). Their common embryological ori-
fossa. It is reinforced by capsular ligaments that gin as part of the first branchial arch dictates this
blend with the capsule and prevent lateral disloca- common innervation. The most powerful of this
tion of the joint. Anteriorly, the intra-articular disc group of muscles act to elevate and retract the
is attached to the smaller superior belly of the mandible (close the mouth) and secondarily to
lateral pterygoid muscle via its attachment to the stabilize the joints. Figures 22, 23, and 24 show
capsule. This attachment maintains the articulation bony attachments of these muscles on the
between the disc and condyle during protraction of mandible.
the mandible, which is performed by contraction of A decrease in muscle function has been
the lateral pterygoid muscle (Mohl 1988). reported with increasing age (Cecílio et al. 2010).
Muscles of Mastication Histology of the Temporomandibular

Joint
The muscles acting on the temporomandibular
joint are the muscles of mastication. They enable The histology of the temporomandibular joint
protrusion and retraction of the mandible as well demonstrates its adaptation to function. While
as opening and closing of the mouth via rotation other synovial joints in the human body have
of the condyle against the intra-articular disc and articular surfaces lined with hyaline cartilage, the
gliding of the condyle and intra-articular disc temporomandibular joint is lined with
Table 8 Muscles of mastication and variations

Muscle Attachments Actions Innervation Variations
Temporalis Temporalis attaches Vertical fibers elevate Deep temporal See the entry for
proximally to the floor of the mandible; horizontal nerves (CNV3) masseter muscle below
the temporal fossa and to fibers retract the
the overlying temporal mandible (Baker et al.
fascia. It inserts into the 2015)
coronoid process of the
mandible (Baker et al.
2015)
Masseter Zygomatic bone and Elevates and helps with Masseteric nerve Deeper fibers of
arch and mandibular mandibular protrusion (CNV3) masseter may contribute
ramus and angle (lateral and lateral movement of to temporalis (Bergman
surface) the mandible. Acting et al. 2006)
with medial pterygoid, it
provides a dynamic
stability sling for the
mandible
Medial Maxillary tuberosity and Elevation of the Nerve to medial None to mention
pterygoid palatine bone, medial mandible and protrusion pterygoid
surface of the lateral (working with lateral (CNV3)
pterygoid plate, and the pterygoid) (Baker et al.
medial surface of the 2015). Acting with
angle of the mandible masseter, it provides a
(Baker et al. 2015) dynamic stability sling
for the mandible
Lateral Upper head: Unilateral contraction: Nerve to lateral Opinion is mixed as to
pterygoid Infratemporal surface Lateral movement of pterygoid whether there is direct
and crest of greater wing mandible in contralateral (CNV3) attachment of the upper
of sphenoid. Lower direction. Bilateral: head to the articular disc
head: Lateral surface of Protrusion/anterior of the TMJ or indirect
lateral pterygoid plate. projection of mandible attachment via the
Upper head inserts into (Jorge et al. 2011). capsule (Tapia et al.
TMJ disc and capsule, Upper head is involved 2011). A third head,
lower head into in elevation of the attaching to the disc, has
pterygoid depression of mandible especially with been reported to exist in
mandible (Jorge et al. forceful closure 22% of individuals
2011) (Jorge et al. 2011)
Mylohyoid Mylohyoid line of the Elevates the floor of the Mylohyoid In some individuals (rate
mandible, a midline mouth and moves hyoid branch (CNV3) unknown), the muscle
raphe, and the body of bone and mandible may consist of anterior
the hyoid bone (Baker during mastication and and posterior portions.
et al. 2015) deglutition (Baker et al. The sublingual gland
2015) may protrude to some
extent through the gap
between the anterior and
posterior parts of the
muscle in these cases
(Malpas 1926)
Digastric Digastric fossa of the Elevates the hyoid bone Nerve to The posterior belly may
mandible, mastoid notch and can depress mylohyoid be fused to stylohyoid
of the temporal bone, mandible (anterior belly, (Bergman et al. 2006)
and to the body of the from CNV3),
hyoid bone via a facial nerve
tendinous loop (posterior belly,
CN VII)
(continued)
Table 8 (continued)
Muscle Attachments Actions Innervation Variations
Buccinator Pterygomandibular Produces negative (see Table 4) None to mention
raphe and molar alveolar pressure in the oral
processes. This muscle cavity and moves oral
inserts into the lips, contents from the
labial submucosa, and vestibule to the occlusal
cheeks, as well as plane. Unilaterally,
orbicularis oris buccinator draws the
mouth ipsilaterally
(Baker et al. 2015)
Fig. 22 Bony features

relevant to the muscles of
mastication and the
superficial muscles in situ.
(Original drawing by
Dr Hala Al Janaby, Perth
WA, Australia)
fibrocartilaginous-like material. Due to the high part of the capsule. Posteriorly the disc is attached
stress applied to these joints through mastication, to the posterior condyle by inelastic fibers of con-
and high frequency of movement, the articular nective tissue and to the anterior wall of the
surfaces have adapted to withstand effects of petrotympanic fissure via elastic connective tissue
these stresses. The joint is further augmented by fibers (Fig. 25). The intra-articular disc in healthy
way of a biconcave intra-articular disc. This disc individuals decreases in thickness with increasing
increases the articular surface of the joint, thereby age. The decrease is usually even across its
increasing congruence and stability (especially mediolateral dimension, however can show per-
dynamic stability). It further serves as a shock forations in the lateral and centro-lateral regions
absorber. The disc is indirectly attached to the as a consequence of physiological wear
superior fibers of lateral pterygoid via the anterior (Stratmann et al. 1996).
Fig. 23 Locations of
deeper muscles of
mastication and other
relevant landmarks.
(Original drawing by
Dr Hala Al Janaby, Perth
WA, Australia)
bone and the inferior concha, which is a small

Nose and Paranasal Sinuses
bony process attached to the maxilla. In almost
half of the population, the middle concha may
Gross Anatomy of the Nose, Nasal
itself be pneumatized containing an air cavity
Cavity, and Paranasal Sinuses
(Capelli and Gatti 2016). This variation is called
concha bullosa. The conchae create recesses: the
The external nose, nasal cavity, and paranasal air
sphenoethmoidal recess, superior to the superior
sinuses form part of the respiratory system. The
concha; the superior meatus, inferior to it; the
internal surfaces of the nose, nasal cavity, and
middle meatus, inferior to the middle concha;
paranasal air sinuses are lined by respiratory epi-
and, finally, the inferior meatus, inferior to the
thelium discussed separately below.
inferior concha. Each of these recesses has open-
The skeletal basis of the nasal cavity is formed
ings for communication with paranasal air sinuses
by the maxillary bones, nasal bones, ethmoid,
or ducts (Fig. 27).
concha, nasal septum, and palatine bones. The
The nasal cavity is surrounded by a number of
external nose is only partially based on skeletal
paranasal air sinuses, some of which are bilater-
tissue; the remainder of the scaffold being formed
ally symmetrical, others that are subject to quite
by elastic cartilage (Fig. 26).
large variation. The largest paranasal air sinuses
The lateral wall of the nasal cavity is formed by
are the maxillary sinuses. These lie on either side
the ethmoid superiorly and the maxilla and infe-
of the nasal cavity extending throughout the body
rior concha inferiorly. There are three bony
of the maxilla. They are pyramidal in shape, with
shelves projecting into the nasal cavity from the
the base lying anteriorly and the apex pointing
lateral wall. These are the superior and middle
posterosuperiorly. The maxillary ostium that
conchae formed by projections of the ethmoid
Fig. 24 The mandible

from the left, showing the
attachment sites of most
muscles of mastication:
M masseter, T temporalis,
LPt lateral pterygoid, and
MPt medial pterygoid
Fig. 25 Masson’s trichrome stained cross-section of a the secondary cartilaginous growth component for subse-
temporomandibular joint. The condyle (C), temporal quent remodelling of condylar morphology. This compo-
bone (T), and intra-articular disc (D) can be seen in artic- nent forms a larger region of the mandibular condyle in
ulation. To the right of the image (the anterior aspect of the infants and children. The capsule (Cp) is composed of
joint) is the joint capsule (Cp) and lateral pterygoid (LPt.). dense fibrous tissue, thicker in the regions that form cap-
To the left of the image (the posterior aspect of the joint) is sular ligaments. The intra-articular disc’s (D) biconcave
the external auditory meatus (EAM) in close proximity, as shape is indicated here in cross-section. With increased
well as the inelastic (Ie) and elastic (E) components of the age, the condyle may show a progressive, irregular
connective tissue joining the disc to the temporal bone and remodelled surface, however with cartilage of normal
posterior surface of the condyle, respectively. The condyle appearance
of the mature mandible (C) may contain some remnants of
drains the sinuses is found on the medial aspect, sinus (Capelli and Gatti 2016). Maxillary molar
opening into the nasal cavity just beneath the roots may project into the floor of the sinus, and
middle meatus. This relatively high point for the bony wall may be very thin inferiorly. Within
drainage can lead to a buildup of fluid and inflam- the maxillary sinus, in almost half of the popula-
matory or infectious material in the maxillary tion, there is a thin wall of cortical bone separating
sinus. In approximately 40% of individuals, the floor of the sinus into at least two separate
there is an accessory ostium of the maxillary basins (Kazunobu et al. 2014; Qian et al. 2016).
four types depending on its posterior wall’s rela-

tionship with the sella turcica. The extent of the
sinus can be limited to the body of the sphenoid,
but can extend into the greater wing and even into
the basi-occiput. This can be of clinical relevance
because any neurovascular structures passing
over the body of the sphenoid are then in close
contact with the sinus cavity and can be damaged
intraoperatively. These structures include the fora-
men rotundum and maxillary division of the tri-
geminal and the foramen ovale containing the
mandibular division of the trigeminal nerve
(Štoković et al. 2016). The courses of the optical
nerve and internal carotid artery are particularly
important to determine (Güldner et al. 2012).
Paranasal air sinuses are thought to warm and
Fig. 26 Anterior view of the face, highlighting skeletal humidify inhaled air before it reaches the deeper
components of the nasal cavity and external nose. NB nasal
bones, MC middle concha, IC inferior concha, and NS respiratory passages and ultimately the lungs, as
nasal septum well as decreasing the mass of skeletal tissue of
the face and adding to the resonance of the human
Most maxillary sinuses with septae contain only voice. Each of the paranasal air sinuses has an
one septum (approximately 84%). Two or three opening to the nasal cavity on its lateral wall.
septae are less common, approximately 14% and The sphenoidal sinus communicates with the
2%, respectively (Qian et al. 2016). Most septae nasal cavity via the sphenoethmoidal recess, the
are found in the anterior part of the sinus, in a posterior ethmoid air cells via the superior meatus,
buccopalatal orientation. The heights of the septae the frontal and maxillary sinuses via the middle
also vary, with the tallest found in the medial part meatus, and the nasolacrimal duct via the inferior
of the sinus (Qian et al. 2016). meatus.
Anteriorly, at the inferior aspect of the frontal The interior surfaces of all paranasal air sinuses
bones, are the frontal sinuses. These vary greatly are lined with respiratory epithelium, discussed in
in size and distribution in the population. Some detail below.
individuals have a thin intervening wall of the
bone in the midline, in others the wall deviates
to one side or the other, and in others there is an Histology of Respiratory Epithelium
uneven distribution of sinus volume bilaterally.
The morphology of the frontal sinuses is so Respiratory epithelium is the epithelium lining the
unique that they are considered useful in postmor- respiratory tract, characterized by the presence of
tem/antemortem comparisons for identification cilia at the apex of pseudostratified columnar
purposes (Beaini et al. 2015). cells. Goblet cells, so called because of their mor-
The ethmoidal air cells similarly vary in num- phology, are also present. These produce mucin
ber and relative size, but are numerous and large that is released to the surface by vesicles and
enough that the ethmoid bone is filled with air mixes with fluid to produce mucus. All paranasal
cells. In approximately 45% of individuals air sinuses, as well as the nasal cavity itself, are
(Capelli and Gatti 2016), there are extramural lined by respiratory epithelium (Fig. 28). In
ethmoidal air cells, extending into the infraorbital healthy individuals, the respiratory epithelium of
region. the maxillary sinus is less than 2 mm in thickness
The sphenoidal sinus is located primarily in the (Capelli and Gatti 2016). A gradual transition
body of the sphenoid bone and is classified into from respiratory epithelium to epidermal lining
Fig. 27 Lateral wall of the nasal cavity and the openings between the nasal cavity and the paranasal sinuses and air cells.
(Original drawing by Dr Hala Al Janaby, Perth WA, Australia)
is found at the nares, and a transition to the simple tract and to facilitate gas exchange in the lower
squamous epithelial lining of the alveoli is found parts of the tract (Gartner 2015; Young et al.
in the lungs. The surface area of respiratory epi- 2013). The epithelium of the middle concha
thelium in the nasal cavity, from the nares anteri- shows age-related changes, and other areas of
orly to the choanae posteriorly, is approximately respiratory epithelium most likely show age
120cm2 (Schrödter et al. 2003). The submucosa of changes as well but are not well investigated.
respiratory epithelium is highly vascularized to Ciliated epithelial cells decrease with age, but
warm the inspired air in the upper respiratory there is no correlation between goblet cell density
Fig. 28 A cross-section of
respiratory epithelium
showing the
pseudostratified ciliated
layer (Ep) with a number of
goblet cells (G) and the
glandular tissue (Gl) in the
underlying submucosa
and activity level with age (Schrödter et al. 2003). presentations. The early nutritional imbalance
With increased age, there is a thickening of the leads to malformations. It is important to note
basement membrane of the respiratory epithe- that nutritional imbalance in a very active period
lium, with a corresponding increase in thin, atro- of growth may cause greater damage (Scardina
phic epithelium and squamous metaplasia in and Messsina 2012; Moynihan and Petersen
individuals over the age of 40 years (Schrödter 2004). Vitamin and mineral deficiencies in the
et al. 2003). prenatal phase influence the development of the
embryo. It affects the odontogenesis, the growth
of the maxilla, oral mucosa genesis, and skull/
Oral Cavity and Tongue facial development (Scardina and Messina 2012;
Moynihan and Petersen 2004).
The oral cavity has unique structures to perform Neurological impairment increases with
functions necessary for life including speech, res- advanced age. Taste and smell sensitivities often
piration, mastication, special sensory functions decline with aging and maybe associated with a
(taste), digestion, and deglutition. Anatomical reduction of appetite as the food becomes tasteless
changes may have an impact on these functions (McKenna and Burke 2010). This decline is
(Waugh et al. 2014). thought to be due to apoptosis of cells in the
Healthy, well-functioning oral structures war- taste buds of the oral cavity. This may affect
rant a healthy balanced diet (Scardina and nutritional status, as individuals may add abun-
Messsina 2012). Nutritional disorders may have dant seasoning (particularly salt or sugar that have
a negative impact on oral structures. Specifically, potential harmful effects on some people), or they
poor diet is significantly associated with increased may prefer very hot foods, which may burn the
odds of oral disease and subsequently bad oral gingiva. At the same time, there are groups of
health (Scardina and Messsina 2012). Various elderly with certain disorders that affect their abil-
oral mucosal diseases can arise due to various ity to taste either as a response to the prolonged
nutritional deficiencies. For example, micronutri- use of medications or to the course of the disease
ent deficiencies of iron, folate, and vitamin B12 itself. Examples of these disorders include mouth,
may cause changes such as swelling of the tongue, nose, or sinus infections, gingivitis and periodon-
papillary atrophy, and surface ulceration (Thomas titis, cancer, and chronic kidney or liver disease.
and Mirowski 2010). Diet has a direct impact on Medications to manage hypertension (such as
the development of the oral structures. Early or captopril), hypercholesterolemia (such as the
late nutritional imbalances result in different statins), and depression may also affect the sense
of taste (Gueiros et al. 2009; McKenna and Burke Dentin forms the bulk of the tooth structure,
2010). 70% inorganic component by weight and 47% by
volume (Avery et al. 2002), and is formed by
odontoblasts that retreat as they form the dentin,
Dental Hard Tissues leaving a cell process within the dentinal tubule
they have formed (Fig. 29). Odontoblasts line
Teeth are composed of three distinct mineralized the internal surface of the dentin, adjacent to
tissues: enamel, dentin, and cementum. The com- the pulp, and produce dentin throughout life (Pro-
bination and apposition of these create a structure venza 1988). Odontoblasts are able to form sec-
resilient to masticatory forces. ondary dentin and reparative dentin in response to
Enamel is the highest mineralized tissue in the damage to the tooth. Secondary and reparative
human body, consisting mostly of an inorganic dentins differ in structure from initially formed
matrix, 96% by weight and 89% by volume, dentin.
(Avery et al. 2002) and arranged as enamel prisms Cementum lines the external surface of the root
(Fig. 29). It covers the anatomical crown of the of the tooth. Its structure is similar to that of the
teeth and protects them from masticatory forces bone, but contains less mineral than the bone and
(Berkovitz et al. 2016). Once enamel is formed dentin (Avery et al. 2002), and it is formed by cells
and the crown of the tooth is completed, the cells similar to osteocytes: cementocytes (Fig. 29). The
forming the enamel matrix, the ameloblasts, degen- cemental layer ends beneath the crown, at the
erate into the reduced enamel epithelium. This cemento-enamel junction. In 60% of individuals,
epithelium merges with the oral mucosa as the the cemental layer overlaps enamel, in 30% of indi-
tooth emerges into the oral cavity. Enamel has no viduals the cemental layer and enamel layer meet at
reparative and little resorptive abilities. If the tissue the cemento-enamel junction, and in 10% of indi-
is damaged, it cannot be regenerated. viduals, there is a small gap between the enamel and
Fig. 29 Hardground section of a tooth (left, also with (D, C, and PDL). Dentinal tubules are visible in both
inset) and a demineralized section of part of a tooth root images (DT). The dentino-enamel junction is seen in the
(right; hematoxylin and eosin stain). In the hard ground left image (DEJ) as well as the neonatal line (NNL) – a
section, dentin and enamel are seen in the crown (D and E, temporary cessation or slowing of enamel production at the
respectively), and in the demineralized section, dentin, time of birth
cementum and part of the periodontal ligament are visible
cementum (Avery et al. 2002). Cemental thickness The genioglossus, hyoglossus, styloglossus,
varies along the length of the root. It is thickest at the and palatoglossus muscles are the extrinsic
root tip, 150–200 μm, and thinnest near the crown, muscles that move the tongue in the oral cavity.
20–50 μm (Avery et al. 2002). The initially depos- However, the superior longitudinal, inferior
ited layer of cementum is acellular, and subsequent longitudinal, transverse, and vertical muscles
layers alternate, with some being cellular and others are intrinsic muscles and are responsible for
not (Avery et al. 2002). changing the shape of the tongue (Norton and
Netter 2012).
Five cranial nerves contribute to the complex
Gross Anatomy of the Tongue innervation of the tongue. The lingual nerve (one
of the terminal branches of CNV3) innervates the
The tongue contributes effectively to the primary anterior two thirds of the tongue for general
functions of the oral cavity and oropharynx sensation and by the chorda tympani (a branch
(Madani et al. 2014). Skeletal muscles represent of the facial nerve, CN VII) for taste. The
the bulk of the organ (Witt and Reuter 2015). glossopharyngeal nerve (CN IX) supplies the
The muscular structure of the tongue and its posterior third of the tongue for both general
position on the floor of the mouth, as well as its sensation and taste. The internal branch of the
muscular attachment to the hyoid bone, mandi- vagus (CN X) is responsible for general sensa-
ble, styloid processes, and pharynx allow it to tion and taste near the epiglottis. Thus, the nerves
perform the functions of deglutition, mastication, for taste are cranial nerves VII, IX, and X
speech, and accessory manual functions. The (Fehrenbach and Herring 2012; Norton and Net-
specialized mucosa that covers the dorsal surface ter 2012; Madani et al. 2014; O’Rahilly and
of the tongue has four types of papillae (epithe- Müller 1983).
lial specializations): circumvallate, foliate, fili- Motor innervation for all of the muscles of the
form, and fungiform. Apart from the filiform tongue comes from the hypoglossal nerve
papillae, lingual papillae contain taste buds that (CN XII), with the exception of the palatoglossus,
are responsible for the delivery of the sensory which is supplied by the pharyngeal plexus that
function of taste (Madani et al. 2014). The ven- are fibers from the cranial root of the spinal acces-
tral and lateral surfaces of the tongue have no sory nerve carried by the vagus nerve (CN X)
presence of lingual papillae. The lingual frenu- (Norton and Netter 2012). Palatoglossus is often
lum attaches the inferior surface of the tongue to considered to be a muscle of the palate, rather than
the floor of the mouth via a fold of mucosal the tongue.
tissue. The lingual artery, a branch from the external
The tongue has two parts, from developmen- carotid artery, is the main arterial supply of the
tally different origins. The movable anterior two tongue. The lingual artery passes into the tongue
thirds is termed the oral tongue and is separated deep to hyoglossus. It gives off dorsal lingual
from the non-movable posterior one third (pha- branches to supply the posterior tongue. The lin-
ryngeal part) by a V-shaped groove, the sulcus gual artery also supplies a branch to the sublingual
terminalis, which runs anterolaterally from a salivary gland as it passes toward the tip of the
small midline pit, the foramen cecum (O’Rahilly tongue. There is a midline fibrous septum along
and Müller 1983). the length of the tongue that prevents all
The anterior wall of the oropharynx is formed but minimal arterial anastomosis across the mid-
by the base of tongue and can be examined by line. Contrary to this, lymphatic drainage of the
depressing the tongue with a mirror or spatula. tongue is subject to a watershed overlying the
The submucosa has lymphatic follicles known midline, meaning that lymph can drain ipsi- or
as the lingual tonsil (O’Rahilly and Müller contralaterally from the tongue.
1983). The tongue has bilaterally symmetrical The lingual veins are prominently seen on the
muscles of two types, extrinsic and intrinsic. ventral surface of the tongue and ultimately drain
into the internal jugular vein (Madani et al. 2014; Lingual Thyroid
O’Rahilly and Müller 1983). Lingual thyroid is a rare developmental entity of
The lymphatic drainage of the tongue is impor- an ectopic thyroid gland that appears clinically as
tant in the locoregional spread of carcinoma of the a submucosal mass on the midposterior dorsum of
tongue to the submental, submandibular, and deep the tongue close to the foramen cecum (Canaan
cervical nodes. Extensive communications take and Meehan 2005; Madani and Kuperstein 2014).
place across the median plane (O’Rahilly and The pathogenesis of this entity is unclear. How-
Müller 1983). ever, some authors suggest that the failure of the
The appearance of the dorsal surface of the thyroid anlage migration during embryogenic
tongue is important clinically, as it may reflect development may lead to the evolution of this
an individual’s health status. However, there lesion. The size of the lesion may interact with
are wide variations in the normal appearance the functions of the mouth. The symptoms may
of the tongue that are discussed below and that range from mild dysphagia to severe upper airway
must be considered during an oral examination obstruction. Females are mostly affected than
when assessing the presence or absence of males, with a ratio ranging from 4:1 to 7:1 (Amr
pathology. and Monib 2011). The diagnosis is made by his-
tory, thyroid function tests, clinical examination,
Ankyloglossia and advanced imaging including computed
Commonly known as a “tongue-tie,” tomography and magnetic resonance imaging. A
ankyloglossia (Fig. 30a and b) is a condition in biopsy is preferably avoided because of the risks
which the tongue has limited mobility due the of the hemorrhage due to the vascular nature of
restriction of the lingual frenulum as a result of such lesions. Treatment options vary from
an increase in its size (Canaan and Meehan 2005). levothyroxine suppression therapy, radioactive
Clinically, individuals with tongue-tie may not iodine ablation, and lingual thyroidectomy (Amr
be able to protrude their tongue beyond the inci- and Monib 2011; Gallo et al. 2001).
sors or touch the palate. As this condition appears
since birth, it may interfere with breastfeeding. It Hairy Tongue
has also been proposed that the limited movement Hairy tongue is a relatively common temporary
of the tongue may interfere with the ability to clear lesion that is found in nearly 13% of the popula-
food debris and therefore enhance halitosis tion as a result of the elongation of the filiform
(Madani and Kuperstein 2014). In its most severe papillae on the dorsal surface of the tongue
form, this condition may cause a speech impedi- resulting in hairlike appearance (Fig. 31).
ment. Frenectomy is the treatment of choice if Smoking, poor oral hygiene, xerostomia, use
required. of antibiotics, immunosuppressive drugs,
Fig. 30 (a) Ankyloglossia, or tongue-tie, is present from Dr Angus Cameron, Sydney NSW, Australia, and image
birth and often observed in childhood (a) and is usually (b) courtesy of Professor Camile Farah, Perth Oral Medi-
treated before adulthood (b). (Image (a) courtesy of cine & Dental Sleep Centre, Perth WA, Australia)
Fig. 31 Hairy tongue caused by an elongation of the

filiform papillae on the dorsal surface. (Image courtesy of
Professor Camile Farah, Perth Oral Medicine & Dental
Sleep Centre, Perth WA, Australia) Fig. 32 Fissured tongue. (Image courtesy of Professor
Camile Farah, Perth Oral Medicine & Dental Sleep Centre,
Perth WA, Australia)
radiotherapy, excess use of mouthwashes
containing peroxidase, and oral candidosis are between geographic tongue and fissured tongue
the predisposing factors (Madani and Kuperstein has been observed. Interestingly, fissured tongue
2014). The lesion is primarily confined to the has been reported to be more frequent in individ-
posterior third of the dorsal surface of the tongue. uals with Down and Melkersson-Rosenthal syn-
The clinical color ranges from white, yellow, and dromes. As this lesion is part of the normal
brown to black due to the overgrowth of pigment- anatomical variation of the tongue, no treatment
producing bacteria or staining from food or is recommended. However, patients are encour-
tobacco. There is no need for a biopsy as the aged to brush the tongue regularly to prevent food
diagnosis is clinically based. Treatment requires debris from entrapping in the lingual grooves
enforcement of a high standard of oral hygiene, (Madani and Kuperstein 2014).
elimination of predisposing factors, and sparing
use of a toothbrush or tongue scraper to promote Geographic Tongue
the desquamation of the hyperkeratotic papillae Geographic tongue, also known as erythema
without inducing hyperkeratosis (Madani et al. migrans or benign migratory glossitis, is usually
2014). asymptomatic and mostly diagnosed incidentally
during routine oral examination (Madani and
Fissured Tongue Kuperstein 2014). Geographic tongue is fairly
Fissured tongue is characterized clinically by common with a prevalence of 1% to 3% of the
grooves on the dorsum of the tongue in varying population. Females are affected more than males
arrangements (Canaan and Meehan 2005). It is with a ratio of 2:1. The etiology of this lesion is
relatively common with a prevalence rate that unknown; however, hereditary and environmental
has been reported to range from 2% to 21% factors may play a role. Some evidence suggests a
among the general population (Canaan and link between geographic tongue and psoriasis
Meehan 2005). There are three well-recognized (Picciani et al. 2016), but this is not a commonly
presentations of fissured tongue: (1) a prominent accepted proposition. Geographic tongue and fis-
median groove as the sole presentation, (2) a sured tongue commonly occur together.
prominent groove with accessory grooves radiat- Geographic tongue has a distinctive clinical
ing laterally (Fig. 32), and (3) multiple grooves appearance of well-demarcated red zones sec-
arranged in an irregular, circinated pattern ondary to the atrophy of the filiform papillae
(Canaan and Meehan 2005). A strong link partially or entirely surrounded by a slightly
Fig. 33 Geographic tongue. (Image courtesy of Professor

Camile Farah, Perth Oral Medicine & Dental Sleep Centre, Fig. 34 Lingual tonsil. (Image courtesy of Professor
Perth WA, Australia) Camile Farah, Perth Oral Medicine & Dental Sleep Centre,
elevated white scalloped border (Fig. 33). This
lesion may appear on the dorsal, lateral, and
ventral surfaces of the tongue and other mucosal
surfaces such as labial and buccal mucosa. Treat-
ment is symptomatic as some patients may com-
plain from a burning sensation or sensitivity to
hot or spicy foods. The use of mouthwashes with
steroids or anesthetic agents may help the
patients with such symptoms.
Lateral Lingual Tonsil

The lymphoid tissue under stimulating conditions
undergoes hyperplasia. Hyperplastic lymphoid
tissue may present as non-tender, submucosal Fig. 35 Lingual veins
masses with a red-yellow color. Lymphoid hyper-
plasia appears more often asymptomatically as diagnosis is confirmed by the clinical examina-
bilateral swellings on the posterior-lateral tongue, tion, no treatment is required.
related to the foliate papillae, are known as lingual
tonsils (Fig. 34) (Madani and Kuperstein 2014). Crenation of Lateral Tongue
This lesion does not necessitate treatment unless it Tongue crenations (Fig. 36) are benign, relatively
has large asymmetrical presentation suggestive of common incidental findings on the tip and lateral
lymphoma, and then further evaluation and man- borders of the tongue as a result of stress-related
agement are warranted (Canaan and Meehan prolonged contact with adjacent teeth (Canaan
2005). and Meehan 2005). Tongue crenations may
appear in patients with either macroglossia, exces-
Lingual Varicosities sive lingual version of the teeth, tongue-sucking
Varices are abnormally dilated veins with habits, or complete dentures. Other systemic
unknown cause and may appear in the oral cavity factors can cause tongue crenations such as amy-
primarily on the ventral surfaces of the tongue loidosis, nervous disorders, or impaired lingual
(Fig. 35) (Canaan and Meehan 2005). They pre- lymphatic drainage secondary to malignancy. If
sent clinically as tortuous red-purple nodules with a local factor is identified, no treatment is
a remarkable transient blanching on pressure. required; however, crenations not attributed to
These lesions are seen in elderly adults. Once the local factors require further investigation.
Salivary Glands anteriorly from the gland along the floor of the
mouth and opens into the sublingual papilla lateral
Major Salivary Glands to the frenulum of the tongue.
The sublingual gland lies deep to the mucosa of
Three major paired salivary glands are located in the floor of the mouth. Its duct joins the subman-
the oro-maxillary region: the parotid glands, sub- dibular duct, opening into the sublingual papilla.
mandibular glands, and sublingual glands. With increasing age, saliva production may
The parotid gland is located anterior to the ear, decrease and some medications may have syner-
and it has an extensive fascial covering formed by gistic effects causing xerostomia. Xerostomia has
the superficial layer of investing fascia. Its duct several adverse reactions on oral structures and
leads anteriorly over the surface of the masseter eventually oral health as it exacerbates dental
and enters the oral cavity opposite the second caries, gingival disease, halitosis, and oral infec-
maxillary molar. tions such as candidiasis (Yap and McCullough
The submandibular gland can be found medial 2015). See Table 9 for anatomy and variations of
to the angle of the mandible at the posterior border the major salivary glands (Fig. 37).
of mylohyoid. The submandibular duct runs
Histology of Salivary Glands and Duct

Systems
Salivary glands are tubuloacinar structures that

secrete modified fluid into the oral and pharyngeal
spaces via a duct system. The saliva-producing
cells are simple cuboidal structures but appear
round to triangular in a stained histological sec-
tion. The saliva-producing elements (paren-
chyma) are supported by connective tissue septa
Fig. 36 Tongue crenations on lateral borders of the tongue
(stroma) that also contains the blood vessels and
as a result of stress-related prolonged contact with adjacent nerves of the salivary gland.
teeth. (Image courtesy of Professor Camile Farah, Perth Oral Acini are wholly mucous, wholly serous, or
Medicine & Dental Sleep Centre, Perth WA, Australia) mixed (Fig. 38). A mixed acinus appears to have
Table 9 Major salivary gland anatomy and variations

Saliva
Gland Type production Variations
Parotid Serous 25% of all The parotid gland can vary greatly in dimensions and volume
saliva between individuals. The horizontal length and depth can vary by
a factor of almost 3 and the vertical dimension by a factor of
approximately 2. The shape of the parotid gland is irregular
(Medbery et al. 2000). An accessory parotid gland of 5–10 mm
diameter can be found at an average length of 6 mm along the
parotid duct from the main gland. The incidence of accessory
parotid gland is between 21 and 56% in the population (Zhu et al.
2016)
Submandibular Predominantly 60% of all None to mention
serous saliva
Sublingual Predominantly 5% of all The duct may have a separate opening rather than joining the
mucous saliva submandibular duct. The sublingual duct may also join the
sublingual duct at its distal extreme, forming a common opening
into the oral cavity (Zhang et al. 2016)
Fig. 37 The major salivary glands of parotid, submandibular and sublingual glands. (Original drawing by Dr Hala Al
Janaby, Perth WA, Australia)
serous cells in a group outside mucous cells, in a collecting ducts. These ducts gradually change
serous “demilune” which is only an artifact of their epithelial morphology to stratified squa-
tissue processing (Fig. 39). mous epithelium as the ducts near the oral cavity
A salivary duct leaves the acinus as an inter- (Hellquist and Skalova 2014).
calated duct to lead saliva toward the oral/pha- Myoepithelial cells project cell processes over
ryngeal surface. The intercalated ducts are lined acini (Tamgadge et al. 2013). These cells are
with simple squamous epithelium and are longest epithelial cells with contractile properties that are
in the parotid gland. These join and lead to stri- thought to aid in the movement of saliva from
ated ducts. The epithelium of these ducts is sim- the acini to the ducts and have roles in salivary
ple cuboidal with a mid-placed nucleus. The gland architecture, histogenesis, and pathogenesis
basal cell membrane of these cells has many (Gartner and Hiatt 2013; Gudjonsson et al. 2005).
infoldings, giving it a striated appearance in a They are rarely seen in light microscopy because
good histological section. The salivary secretion of their morphology (squamous in shape, with a
is modified in this part of the ductal system. number of cell projections), but a nucleus is some-
Beyond the striated ducts, saliva enters the times visible adjacent to an acinus (Fig. 40).
Minor Salivary Glands located in the submucosa of lining oral mucosa

and in some locations underlying masticatory
There are numerous minor salivary glands that mucosa.
can be found in the oral cavity. These are usually
Functional Variations in Salivary Glands
Saliva has a significant role in the human body
generally, and the oral cavity in particular (Yap
and McCullough 2015; Tiwari 2011; Miletich
2010). The functions of saliva include lubricating
and maintaining the integrity of the oral mucous
membrane, soft tissue repair, balancing pH buff-
ering, maintenance of ecological equilibrium,
maintenance of tooth integrity, and physical and
immunological protection. There is supporting
evidence that the structure of the salivary paren-
chyma changes with age and is replaced with
adipose and fibrovascular tissues (Nagler 2004;
Gueiros et al. 2009). Measurement of salivary
flow is essential in diagnosing salivary gland
hypofunction. Stimulated and unstimulated
whole saliva flow rate measurements are the pri-
mary methods to quantify salivary secretion.
However, other specific tests can be undertaken
Fig. 38 This image shows a section of parotid gland (x5, and are discussed in the chapter on ▶ “Salivary
hematoxylin and eosin). The distinction between Gland Disorders and Diseases.” There is variabil-
supporting tissue, stroma (S), and the active producing
ity in the threshold of salivary production among
tissue, parenchyma (P) is clear. In one septum of the
stroma, a nerve – fibers grouped (N) is visible in various populations and age groupings. Nonethe-
crosssection less, hyposalivation is classically defined as an
Fig. 39 The image above shows a section of submandib- two (or possibly two parts of the same) striated duct (SD).
ular gland (x20, hematoxylin and eosin) in which can be Striations in the basal part of the duct lining cells can be
seen a mixed acinus (circled, MA) with a serous demilune seen in the left striated duct, at approximately the 5 o’clock
surrounding mucous cells, an intercalated duct (ID) and to 7 o’clock position
(Gueiros et al. 2009). Local and systemic diseases,

medications, head and neck radiation, and chemo-
therapy severely affect saliva production (Yap and
McCullough 2015). Recognizing the functional
variations of salivary glands helps to better under-
stand the health and disease of the oral cavity.
Histology of Oral Tissues
Oral mucosa consists of a specialized epithelium

lining the surfaces of the oral cavity. It is a stratified
squamous epithelium, either keratinized, non-
keratinized, or parakeratinized, and protects the
Fig. 40 Hematoxylin and eosin stained section of several oral cavity from mechanical, microbial, and chem-
mucous acini (MA). (Image courtesy of Professor Camile ical damage (Winning and Townsend 2000). Kera-
Farah, UWA Dental School, University of Western Austra-
lia, Perth WA, Australia) tinization of epithelium in the oral cavity protects
the mucosa from potential injury from food items
unstimulated whole saliva values below 0.1 ml/ (Ciano and Beatty 2015), both physical and ther-
min and a stimulated salivary flow below 0.5 ml/ mal injury. These regions are called masticatory
min, which corresponds to a 40–50% diminution mucosa, as opposed to the other regions that do
of salivary gland secretion (Flink et al. 2005; not come into direct first contact with food and are
Inoue et al. 2006). covered by nonkeratinized lining mucosa, which is
Although salivary flow is said to diminish as an less resistant to damage, but more distensible (Win-
age-related process, salivary production in ning and Townsend 2000). Parakeratinized epithe-
healthy elderly patients remains stable (Tiwari lium retains nuclei in the superficial layers. This
2011; Miletich 2010). Gender and weight can epithelium is common in gingival epithelium (Win-
influence salivary flow as these factors are corre- ning and Townsend 2000). The high turnover rate
lated with the size of salivary glands (Bergdahl of cells in the oral mucosa, although variable
2000). Male and overweight healthy subjects have between different parts of the oral cavity, is also a
larger major glands and subsequently have higher protective mechanism. Areas covered in mastica-
salivary flow (Miletich 2010; Inoue et al. 2006). tory mucosa include the hard palate, attached gin-
Increased body mass index is associated with giva, and the anterior two thirds of the dorsum of
larger salivary glands and increased salivary the tongue (excluding the fungiform papillae). Lin-
flow (Inoue et al. 2006). Gender-related salivary ing mucosa is nonkeratinized and has submucosa
flow variations become more obvious with aging deep to the lamina propria in most regions.
and beyond the age of 55 (Bergdahl 2000). Non-epithelial cells found in the mucosal epi-
It is important to note that hormonal changes in thelium include melanocytes, Langerhans cells,
postmenopausal females reduce unstimulated Merkel cells, and lymphocytes (Winning and
salivary flow remarkably. However, controversy Townsend 2000).
surrounds the impact of menopause on saliva pro- More broadly, the epithelial layer is arranged
duction (Inoue et al. 2006; Eliasson et al. 2003). into ridges and troughs against the underlying
Interestingly, the use of hormone replacement lamina propria. These papillae give mechanical
therapy in postmenopausal females results in strength to the oral mucosa by increasing the
recovery of salivary flow (Eliasson et al. 2003; surface in contact between the epithelium and
Laine and Leimola-Virtanen 1996). lamina propria. They are more numerous in mas-
The qualitative and/or quantitative changes in ticatory mucosa compared with lining mucosa
saliva have a direct impact on the quality of life (Table 10).
Table 10 Regional variations in oral mucosa and minor salivary glands (Berkovitz et al. 2016; Fehrenbach and
Popowics 2015; Roed-Petersen and Renstrup 1969; Hiatt and Gartner 2010)
Minor salivary
Region Mucosa type Lamina propria glands Submucosa
Alveolus Nonkeratinized lining, Short or absent Seromucous Mobile
thin mucosa
Hard Thick, keratinized, High number of Pure mucous Absent in midline –
palate masticatory mucosa: connective tissue papillae Lamina propria attaches
310 50 μm (Winning (Ciano and Beatty 2015) - to periosteum of hard
and Townsend 2000) 1.5 to 2.5 times more palate
connective tissue papillae (mucoperiosteum). Fat
per mm2 compared with present in the
lining mucosa (Winning posterolateral regions
and Townsend 2000) alters the color
(Winning and Townsend
2000)
Soft Nonkeratinized, lining Short papillae Pure mucous Presence of varying
palate amounts of fatty tissue
alters the color
2000)
Floor of Nonkeratinized, lining, Low number of short, Seromucous Loose submucosa
mouth thin mucosa: 190 40 μm broad connective tissue (Hand et al.
(Winning and Townsend papillae (seven times less 1999)
2000) per mm2 than in
masticatory mucosa)
2000)
Vermilion Keratinized, but thin None
zone
Buccal Nonkeratinized lining, High level of collagen Mixed Varying amounts of
mucosa thick mucosa: organization (Ciano and (predominantly fatty tissue alter the
580 90 μm (Winning Beatty 2015) mucous) color (Winning and
and Townsend 2000). Townsend 2000)
Ectopic sebaceous glands
may be found in 80% of
adults (Winning and
Townsend 2000)
Labial Nonkeratinized, lining. High number of rete Mixed Firm attachment to the
mucosa Upper labial mucosa may ridges in the region of (predominantly underlying muscle
contain ectopic sebaceous incisors (Ciano and mucous) tissue
glands found in 80% of Beatty 2015)
adults (Winning and
Townsend 2000)
Gingiva Keratinized, masticatory Low number of rete ridges None Indistinguishable in
epithelium – Gingiva in the region of the attached gingiva
facing oral surface. incisors in lingual gingiva
Crevicular gingiva is (Ciano and Beatty 2015).
nonkeratinized sulcular Attached gingiva has
gingiva (Winning and long, narrow papillae
Townsend 2000).
Attached gingiva appears
pitted because of collagen
fibers attaching the
gingiva to underlying
bone. The gingival sulcus
between 0.5 and 2 mm
(continued)
Table 10 (continued)
Minor salivary
Region Mucosa type Lamina propria glands Submucosa
deep in healthy
individuals and is mildly
inflamed due to the
presence of oral
microflora (Winning and
Townsend 2000)
Tongue Nonkeratinized, lining Short, numerous papillae Seromucous Indistinct. There is
(ventral) strong attachment to the
underlying muscle
Tongue Specialized, see section Long papillae Anterior: Indistinct. There is
(dorsal) on tongue Mixed – strong attachment to the
Predominantly underlying muscle
mucous
Posterior: Pure
mucous
Circumvallate
papillae: Pure
serous
Fig. 41 Mucosa of the hard palate and maxillary gingiva. Fig. 42 Mucosa of the floor of the mouth and gingiva,
Note the range of colors in the mucosa of the hard palate; with some labial mucosa visible. Note the delicate blood
presence of fatty tissue laterally gives a yellow appearance vessels in the thin mucosa of the floor of the mouth-lining
mucosa
A submucosa underlies the lamina propria in mucosa more susceptible to local trauma and oral
some regions of the oral cavity. diseases. Age-related hyposalivation may alter the
Healthy oral mucosa is pink because the epi- clinical appearance of oral mucosa substantially
thelium is semitransparent and the underlying (Yap and McCullough 2015; McKenna and Burke
connective tissue is well vascularized. Variations 2010).
in epithelial thickness, subepithelial edema, con-
nective tissue vascularization, and fiber thickness
can cause clinical color changes (Berkovitz et al. Dental Pulp
2016). Examples of healthy appearing oral
mucosa can be seen in Figs. 41 and 42. Histologically, dental pulp resembles connective
Changes to the oral mucosa with aging are tissue, but it has two unique features; the first
often unrecognizable; however aging makes the being that odontoblasts produce a layer between
Fig. 43 This high power hematoxylin and eosin stained adjacent to the predentinal layer is the odontogenic zone
decalcified section of the pulp cavity shows the dentin of (OgZ), comprised of odontoblasts. Deeper within the pulp
the tooth (D), including interglobular dentin (IgD) and tissue are fibroblasts (F), collagen fibrils (C), and blood
predentin (PD) which is yet to be mineralized. Immediately vessels (BV)
the pulp and dentin, and the second is that this thickness (Avery et al. 2002). This thickness
connective tissue is almost completely decreases with increasing age. The periodontal
surrounded by hard tissue (dentin), making the ligament is highly vascular and has a rich nerve
normal inflammatory process a cause of pulp supply. It consists of collagen fibers organized
necrosis due to lack of space for swelling and into thick fibrous bands, arranged into distin-
edema (Fehrenbach and Popowics 2015) guishable groups: oblique, apical, and horizontal
(Fig. 43). With increasing age, there is reduction fibers, alveolar crest fibers, and also interradicular
in the size of the pulp chamber due to the contin- fibers in multi-rooted teeth (Berkovitz et al. 1995).
ual production of dentin. This creates a change in Odontogenic epithelial rests of Malassez can
the arrangement of the odontoblasts to a pseudo- be found throughout the periodontal ligament,
stratified appearance, with histomorphometry forming a “fishnet stocking” structure around
changing from columnar cells to ovoid shorter the root. These cells, left after tooth formation,
cells (Daud et al. 2016). Pulp cell density also seem to prevent tooth ankylosis and certainly play
decreases with increasing age in both the crown a role in developing inflammatory odontogenic
and the root. The last cell population to decrease cysts.
in density are coronal odontoblasts. Their density
decreases after a decrease in fibroblast and sub-
odontoblast densities (Daud et al. 2016). Tongue
The epithelium of the tongue is multifunctional.

Periodontal Ligament This is reflected in its composition and arrange-
ment. The oral part (anterior two thirds) of the
The periodontal ligament is the connective tissue dorsum of the tongue is in contact with food and
found between the cementum of a tooth and the other items placed in the mouth. The mucosa on
alveolar bone of the tooth socket (Fig. 44). Its this part of the tongue forms a multitude of
function is partly to act as the periosteum of the keratinized filiform papillae that aid in this grip-
alveolar bone. Although of uniform thickness, the ping and protective function (Figs. 45 and 46).
periodontal ligament component of the tooth com- The keratinized layer helps to protect the tongue
plex ranges from 0.15 mm to 0.38 mm in from abrasion and to some extent extreme
Fig. 44 This high power

hematoxylin and eosin
stained decalcified section
shows the periodontal
ligament (P) attaching two
teeth (on either side of the
image) to alveolar bone (A).
Cementum (C) and
cementocyte lacunae can be
seen covering the dentin
(D) of the tooth on the left of
the image. Epithelial rests
(Er) can be seen within the
periodontal ligament
Fig. 45 Dorsal surface of

the tongue showing (a)
keratinized filiform
papillae; (b) slightly larger,
nonkeratinized fungiform
papillae; and (c) the
chevron-shaped row of
circumvallate papillae

eosin stained section of the
dorsal surface of the tongue
showing keratinized
filiform papillae (Fi) and
nonkeratinized fungiform
papillae (Fu) of the dorsum
of the oral part of the tongue
temperature. Interspersed among the filiform The dorsal surface of the posterior pharyngeal
papillae are slightly larger, nonkeratinized fungi- third of the tongue has glandular and lymphoid
form papillae (Figs. 45 and 46). These contain a tissue deep to its epithelial surface, giving it a
small number of taste buds. bumpy appearance.
Separating the anterior two thirds and posterior The final papilla type can be seen on the lateral
one third is the sulcus terminalis and foramen surface of the tongue, the foliate papillae. There
cecum – a remnant of the migratory path of the are a number of vertical grooves on the surface
thyroid gland. Immediately anterior to this is the of the tongue. Foliate papillae also contain
chevron-shaped row of circumvallate papillae taste buds.
(Figs. 45 and 47). There are approximately 12 to The ventral surface of the tongue is covered
14 of these, and they are large enough to be easily with thin nonkeratinized lining mucosa, beneath
distinguished with the naked eye. Histologically, which blood vessels are visible.
these papillae have quite a number of taste recep-
tor cells in their walls, as well as von Ebner
glands, to produce fluid that flushes molecules Lips
away from the papilla’s furrow so that new taste
molecules can enter. Taste perception is facilitated While the core of both lips is mainly formed from
by receptors (T2R for bitter taste, T1R for sweet skeletal muscle, the lip can be divided into three
and umami taste, and vanilloid receptor TRPV1 histological portions depending on their anatomi-
for salty taste), ion channels (PKD1L3 and cal location (Fig. 48). The outer surface is covered
PKD2L1 for sour taste), and epithelial sodium by hairy skin, and sweat glands can be found in
channels (for salty taste). Genetic variation in the dermis; the inner surface is covered by non-
these taste receptors (and therefore interindividual keratinized mucosa and minor salivary glands
variation in taste perception) may be linked to diet replace the sweat glands. Finally, the vermilion
and food choices, influencing nutritional and zone is located between the two surfaces, it being
health status (Garcia-Bailo et al. 2009). Previ- covered by keratinized stratified squamous epithe-
ously different regions of the dorsal surface of lium, rich in capillaries and free of both sweat and
the tongue have been ascribed to the different minor salivary glands (Kumar 2014).
tastes, sweet, bitter, sour, salty and umami. How-
ever, more recent evidence (Chandrashekar et al.
2006) supports the notion that taste buds consists Tonsillar Tissue
of a variety of taste receptors cells capable of
sensing all of the separate tastes, and this is not Tonsillar tissue forming Waldeyer’s ring has
region specific. an epithelial covering, folded into crypts or

eosin stained cross section
of the dorsum of the tongue
showing a circumvallate
papilla (CV) with taste buds
(Tb) in its lateral wall and a
Von Ebner’s gland duct
(VE) in the adjacent
epithelial wall. Numerous
serous acini are visible in
the lower third of the image
Tissue Spaces of the Maxillofacial

Region
Fascial Layers and Spaces of the Head

and Neck
The head and neck contain a number of fascial

layers that surround structures and lie at the inter-
face of movable components and so prevent friction
from affecting the components in question. Where
fascial layers lie adjacent to each other, they form
potential spaces. These fascial spaces are of clinical
relevance because they can both prevent and facil-
itate the spread of infections. Fascial compartments
are also prone to compression when fluids and
infectious substances accumulate within them.
These are important in the head and neck region
because of the respiratory passages that are present,
as well as the conductive fascial spaces that lead to
the middle and posterior mediastinum of the thorax.
Knowledge of the extent, contents, and communi-
cations between these fascial spaces can aid in
Fig. 48 Hematoxylin and eosin stained cross section of
the lip showing epithelial types: epidermis (Ep), vermilion differential diagnosis of infections and masses pal-
zone (Vz), and oral (lining) mucosa (Om). The muscle (M) pated in the head and neck region (Shrestha et al.
orbicularis oris is also shown, as well as a hair follicle (Hf) 2011; Warshafsky et al. 2012)
and glandular tissue (G)
The external-most layer of the neck fascia is the
investing layer. It has some bony attachments infe-
riorly and superiorly. The investing layer of fascia
grooves. Tonsils contain a number of cell types, can be imagined as a collar that surrounds the
including lymphocytes, plasma cells, macro- structures in the neck. It splits into a superficial
phages, and reticular cells, as well as extrava- and deep layer to surround the sternocleidomastoid,
sated erythrocytes and interdigitating cells (Perry parotid gland, and trapezius. All other fascial layers
1994; Avery et al. 2002). The crypt lumina con- are deep to this investing layer. The anterior-most of
tain desquamated epithelial cells, bacteria, as these is the pretracheal layer that contains the tra-
well as living and dead lymphocytes. Encapsula- chea and main bronchus more inferiorly, the esoph-
tion of the tonsil by a fibrous tissue capsule pre- agus, and the infrahyoid muscles. Note that the
vents the spread of any infection (Young et al. prefix “pre-” is used to denote fascia that surrounds
2013). The epithelium of the palatine tonsil is structures named in the suffix. Sometimes the layer
covered by a 15–20 cell layer of non- or para- surrounding the muscles is referred to separately as
keratinized mucosa (Perry 1994). The crypts of the muscular layer and the layer surrounding the
the palatine tonsil are lined with nonuniform tubes as the visceral layer. The posteriormost fascial
epithelium, with patches of stratified squamous compartment is the prevertebral fascia that sur-
and reticulated epithelium. Stratum spinosum rounds the pre- and post-vertebral muscles, the
cells are interspersed with non-epithelial cells, cervical spine, and the spinal cord. Components of
and the surface of the reticulated epithelium is these three fascial compartments combine to form
stratified squamous but is interrupted by areas the neurovascular compartment of the neck, the
where non-epithelial cells pass into the crypt carotid sheath itself considered to be a fascial com-
lumen. partment. The carotid sheath contains the common
carotid artery and its branches, the internal jugular Retropharyngeal Spaces
vein, and the vagus nerve. Note that the vein is in
the external-most orientation within the fascial layer The retropharyngeal space lies between the posterior
due to its need to expand considerably in volume. pretracheal fascial layer and the anterior prevertebral
The fascial spaces connected by these layers fascial layer. The deep cervical lymph nodes are
communicate with each other as well as distant located bilaterally in the retropharyngeal space.
anatomical compartments. These communica- Anteriorly, the prevertebral layer splits to create yet
tions are part of what makes these compartments another fascial space – the danger space. The danger
clinically important. Infections that are most com- space extends from the base of the skull through to
monly odontogenic in nature can spread by direct the posterior mediastinum to the level of the dia-
methods through these anatomical tissues and phragm. The prevertebral space encompasses the
structures or indirectly using fascial compart- musculature surrounding the cervical spine and ver-
ments as infection routes. Where these compart- tebral complex including the spinal cord.
ments communicate with organs essential to life The three spaces, although delineated by fas-
or are able to be constricted by products of infec- cia, readily communicate and allow for the spread
tion and thereby compress essential anatomical of infections beyond the head and neck. Infections
structures, infections can be immediately life- involving these spaces can lead to descending
threatening. Three of the spaces in the head and necrotizing mediastinitis (hence the term “dan-
neck region are considered to be particularly clin- ger” space given to the retropharyngeal spaces),
ically relevant: the submandibular, lateral pharyn- involvement of the pericardium and/or pleural
geal, and retropharyngeal-danger-prevertebral cavity, and even widespread retroperitoneal
spaces (Reynolds and Chow 2007). necrosis (Reynolds and Chow 2007).
Submandibular Space Lymphatic Drainage of the Head

and Oral Structures
The submandibular space is bounded by the body of
the mandible and subdivided into two compart- The immune system includes the lymphatic com-
ments separated by mylohyoid: the superior sublin- ponent, composed of a network of lymphatic ves-
gual compartment and the inferior submylohyoid sels and aggregates of lymphoid tissue known as
compartment. These two compartments communi- lymph nodes (Fehrenbach and Herring 2012)
cate with each other at the posterior free border of (Fig. 49). An oral health care practitioner should
mylohyoid. The submandibular space also commu- have the competency to examine carefully for
nicates posteriorly with the parapharyngeal space any palpable lymph nodes of the head and oral
through a gap created by the course of styloglossus structures. The lymph nodes have the primary
through the pharyngeal constrictors. function of filtering interstitial fluids. They also
produce lymphocytes that have a significant
role in combating infections. Lymph vessels are
Lateral Pharyngeal Space present in most tissues, including dental pulp.
Understanding the mechanical distribution of
The lateral pharyngeal space is found, as the name these vessels and the flow direction of lymph may
suggests, lateral to the pharynx, specifically the help in the diagnosis of oral infections and poten-
buccopharyngeal fascia overlying the superior tially can be used to slow cancer spread
constrictor. It is medial to the mandible and medial (Fehrenbach and Herring 2012). The lymph
pterygoid and parotid gland. The space is limited nodes have a particular arrangement, stellate in
inferiorly at the hyoid bone and by the sphenoid small, interconnected clusters (Fehrenbach and
bone superiorly. Posteriorly the space communi- Herring 2012). As each group of nodes drains
cates directly with the retropharyngeal space. fluids from designated anatomical locations,
Fig. 49 Locations and

relations of the cervical
lymph nodes. (Original
drawing by Dr Hala Al
Janaby, Perth WA,
Australia)
lymph nodes play a significant role in combating atlas, sitting in the buccopharyngeal fascia. They
infections in these sites of the body. In the node, receive drainage from the nasal cavities, the nasal
lymphocytes actively start fighting the infection. part of the pharynx, and the auditory tubes, and
As a consequence, lymph nodes enlarge and are subsequently these drain to the superior deep cer-
tender. In the case of strong control of the infection, vical nodes. These nodes are commonly involved
the node will eventually subside. The opposing in throat infections (Fehrenbach and Herring
scenario is that the node fails to confine the infec- 2012).
tion, and it spreads through that lymph node or
nodes to the next-proximal node or group of
nodes (Fehrenbach and Herring 2012; Snell 2012). Submental Nodes
The submental nodes are a small cluster of nodes

Retropharyngeal Nodes and found inferior to the border of the chin. These
nodes receive lymphatics from the mandibular inci-
Retropharyngeal nodes locate behind the upper sors, the tip of the tongue, and the midline of the
part of the pharynx and in front of the arch of the lower lip and chin. Tenderness and enlargement of
these nodes are associated with any infection from Lower Deep Cervical Nodes
the drained sites. These nodes tend to drain to the
submandibular nodes or directly to the lower deep The lower deep cervical nodes drain the upper
cervical nodes (Fehrenbach and Herring 2012; deep cervical nodes and many of the nodes of
Waugh et al. 2014). the posterior neck frequently referred to as
occipital nodes, as well as glands in the anterior
neck. This group of nodes is located on the
Submandibular Nodes lateral surface of the internal jugular vein and
deep to the anterior margin of the sternoclei-
The submandibular nodes are distributed around domastoid muscle. They are found superior to
the submandibular gland near the ramus of the the clavicle. The lymphatic fluid drains from
mandible and the commissures of the mouth. the lower deep cervical nodes to the junction
The easiest way to locate the gland and the of the subclavian and internal jugular veins
nodes is to place a finger on the inferior border (Fehrenbach and Herring 2012; Agur and
of the mandible near the angle. Run the finger Grant 2013).
back and forth until you feel the depression in
the inferior margin of the mandible. Just medial
to this depression is the submandibular gland, and Pharynx and Larynx
the submandibular lymph nodes are grouped
around it (Fehrenbach and Herring 2012). Waldeyer’s Ring
Lymphatics from all of the maxillary teeth and
the maxillary sinus, the mandibular canines and At the junction between the oral and nasal cav-
all mandibular posterior teeth, the floor of the ities and the oro- and nasopharynx are groups of
mouth and most of the tongue, the hard palate, lymphoid tissue, in the form of a circular band
the soft tissue of the buccal area, and the anterior (Waldeyer’s ring). Tonsils forming Waldeyer’s
nasal cavity are drained to this group of lymph ring are the lingual, palatine, pharyngeal, and
nodes. Further, the submental nodes may drain to tubal tonsils. The lingual tonsil is formed by
these nodes. Therefore, enlargement and tender- the lymphoid follicles in the mucosa of the pos-
ness of the submandibular nodes due to infections terior third of the tongue. The palatine tonsil
are relatively common as they receive lymph from is located between the palatoglossal and
many anatomical sites (Fehrenbach and Herring palatopharyngeal folds, the tonsillar fossa. The
2012; Waugh et al. 2014). floor of the fossa is formed by the superior con-
strictor of the pharynx. The fossa’s immune
activities are improved by the presence of
Upper Deep Cervical Nodes between 10 and 30 tonsillar crypts/infoldings
of the epithelium (Perry 1994).
The upper deep cervical nodes are a group of lymph The pharyngeal tonsil sits high on the posterior
nodes that receive lymphatics from other groups of wall of the nasopharynx. It is particularly promi-
lymph nodes including the submandibular nodes, nent in children and may affect breathing if hyper-
the retropharyngeal nodes, and the parotid nodes trophy is severe, leading to a characteristic facial
and from the third molar regions, the base of the expression (“adenoid face”) and altering the phys-
tongue, the tonsillar area, the soft palate, and the ical structure of the oral region (Nishimura and
posterior nasal cavity region. This important group Suzuki 2003).
of nodes is distributed on the lateral surface of the The tubal tonsil is located around the opening
internal jugular vein and lie just deep to the anterior of the auditory tube in the lateral wall of the
margin of the sternocleidomastoid muscle, about nasopharynx. It consists of lymphoid tissue in
2 inches below the ear (Fehrenbach and Herring the mucosa surrounding the cartilaginous audi-
2012; Agur and Grant 2013). tory tube.
Gross Anatomy of the Pharynx tube connects the mouth and the nose to the esoph-
and Larynx Including Anatomical agus and larynx. By doing so, it helps to regulate the
Variations passage of food and air (Norton and Netter 2012). It
extends from the skull base to the lower border of
The neck has unique structure and geometry as it the cricoid cartilage and is divided into three parts:
extends from the skull base and inferior mandib- the most superior, the nasopharynx, is involved only
ular margin to the superior thoracic aperture and in breathing and speech. The other two parts, the
includes relevant anatomical tissues and organs: oropharynx and the laryngopharynx, are used for
the pharynx, larynx, trachea, esophagus, thyroid both breathing and digestion. The pharynx is com-
gland, and parathyroid glands (Fehrenbach and posed of the following structures: three constrictor
Herring 2012; Agur and Grant 2013). Several muscles, three longitudinal muscles, cartilaginous
health problems can affect the neck including part of the pharyngotympanic tube, and soft palate
neck spasm and pain, whiplash, herniated disc, (Norton and Netter 2012; Agur and Grant 2013).
muscle sprain, laryngitis, airway obstruction, The wall of the pharynx has five layers
vocal cord polyps, primary and metastatic cancer, (inner to outer): mucous membrane, sub-
and other neoplasms. mucosa, pharyngobasilar fascia, muscular, and
The neck contains seven vertebrae called the buccopharyngeal fascia (Norton and Netter 2012;
cervical vertebrae. They are the smallest and Agur and Grant 2013; Waugh et al. 2014). The
uppermost vertebrae in the body. The first cervical pharynx is richly vascularized and receives the
vertebra (atlas) articulates with the skull. The sec- arterial supply from the ascending pharyngeal,
ond cervical vertebra (axis) has an odontoid pro- ascending palatine, tonsillar, pharyngeal arteries
cess that articulates anteriorly with the atlas and and superior and inferior thyroid arteries (Norton
inferiorly with the third cervical vertebra and Netter 2012). The pharyngeal plexus is respon-
(Fehrenbach and Herring 2012; Norton and Netter sible for the venous drainage of the pharynx. The
2012; Agur and Grant 2013). motor and sensory innervation of the pharynx is by
The neck also has striking external feature, the the pharyngeal branch of the glossopharyngeal
laryngeal prominence that is commonly known as nerve, the pharyngeal branch of the vagus nerve,
Adam’s apple. It is more evident in males than in and the cranial part of the spinal accessory nerve
females. At the level of the third cervical vertebra, (Norton and Netter 2012; Waugh et al. 2014).
there is mobile, disconnected bone known as The larynx has a significant role in connecting
hyoid bone that provides anatomical support to the pharynx to the trachea to prevent the entry of
other muscles and ligaments that function during foreign bodies to the airways. It is also called the
swallowing, mastication, and speech (Fehrenbach voice box as the larynx produces vocal sounds
and Herring 2012; Agur and Grant 2013). (phonation). Other functions of the larynx include
There are two cervical muscles: sternoclei- coughing, the Valsalva maneuver, control of ven-
domastoid and trapezius (Fehrenbach and Herring tilation, and acting as a sensory organ
2012; Agur and Grant 2013). The major arterial (Fehrenbach and Herring 2012; Norton and Netter
supply comes from the carotid and subclavian arter- 2012; Agur and Grant 2013). The larynx is shorter
ies. The venous drainage is inconsistent and mostly in women and children than males and adults.
to the internal, external, and anterior jugular vein Structurally the larynx has three large, unpaired
(Norton and Netter 2012). The neck is richly inner- cartilages (cricoid, thyroid, epiglottis), three pairs
vated with motor and sensory nerve branches. The of smaller cartilages (arytenoids, corniculate, cune-
large bones and muscles in the neck divide it into iform), extrinsic and intrinsic ligaments, and
anterior and posterior cervical triangles that can be muscles (cricothyroid, thyroarytenoid, posterior
subdivided into smaller triangles (Fehrenbach and cricoarytenoid, lateral cricoarytenoid, transverse
Herring 2012; Agur and Grant 2013). The pharynx arytenoid, oblique arytenoid, aryepiglottis,
(throat) has a principle contribution to the functions thyroepiglottis) (Norton and Netter 2012; Waugh
of digestion and respiration. This 5-inch muscular et al. 2014). Superior and inferior laryngeal arteries
and veins are responsible for the blood supply (Nor-

ton and Netter 2012; Waugh et al. 2014). The ana-
tomical structure of the larynx has four cavities
(laryngeal cavity, laryngeal ventricles and saccules,
rima vestibuli and rima glottidis, and piriform
recesses) that facilitate the functions of the larynx
(Norton and Netter 2012; Agur and Grant 2013).
The lymphatic vessels that drain above the vocal
folds drain to the deep cervical lymph nodes at the
bifurcation of the common carotid artery. However,
the lymphatic vessels that drain below the vocal
folds drain to the upper tracheal lymph nodes
(Agur and Grant 2013; O’Rahilly and Müller 1983).
Histology of Pharyngeal Mucosa
The pharyngeal mucosa is a stratified squamous Fig. 50 The right orbit showing skeletal components:
nonkeratinized epithelium that lines an elastic yellow – maxilla, pink – frontal bone, green – zygomatic
fibrous connective tissue; these elastic fibers are bone, red – ethmoid, purple – lacrimal bone. G– greater
oriented longitudinally (Gartner 2015) and allow orbital fissure, O – optic canal both within the sphenoid
bone, NC – nasal cavity
for distension of the pharynx when swallowing a
solid or liquid bolus and also enable recoil of the
tissue afterward to prevent obstruction of the gas- The extraocular muscles are responsible for
trointestinal or respiratory tracts. positioning the globes of the eye for functional
vision. There are six distinct muscles for each eye:
superior and inferior rectus muscles, medial and
Histology of the Thyroid lateral rectus muscles, and the superior and infe-
rior oblique muscles. These muscles are under
The thyroid, like other glands in the human body, somatic afferent control by cranial nerve IV (supe-
contains mainly cuboidal simple secreting epithe- rior oblique), cranial nerve VI (lateral rectus), and
lium forming a follicle, but no ducts. The hormone cranial nerve III for the rest. The muscles all
secreted is stored in cavities and then absorbed originate from a common tendon at the posterior
into luminal spaces as colloid (Gartner 2015; Witt aspect of the cone-shaped orbital cavity and then
and Reutter 2015). diverge to attach at various points around the
globe of the eye (Kels et al. 2015).
Orbits
Vascular Supply of the Maxillofacial
Gross Anatomy of the Orbits Region
The orbits form the containers for the eyes; extra- The head and neck are supplied by three main
ocular muscles; optic, oculomotor, trochlear, and branches of the brachiocephalic trunk of the
abducens nerves; lacrimal apparatus; and supporting aorta on the right and the vertebral and common
tissues (Fig. 50). Each of the orbits is formed by the carotid branches of the aorta on the left (Gray et al.
frontal bone, maxilla, lacrimal bone, zygomatic 1995).
bone, ethmoid bone, and the greater and lesser Orofacial structures are supplied by four main
wings of the sphenoid. branches of the external carotid artery: the facial,
lingual, maxillary, and superficial temporal The common carotids ascend in the neck to
branches (Fig. 51). There is extensive vascular the level of the superior border of the thyroid
anastomosis in the orofacial region, and supply cartilage, where they divide into the external and
to any particular tissue is not hampered by the internal carotids. At this level is the carotid
blockage or hemorrhage in just one vessel. sinus, a baroreceptor. On the internal wall of the
The right common carotid (shorter than the artery at its bifurcation is the carotid body, a
left) arises from the brachiocephalic trunk, chemoreceptor.
whereas the left originates directly from the The external carotid is one of the branches of
aorta. This difference in origin is a consequence the bifurcation of the common carotid and begins
of embryological development. its course at the level of L3/L4 intervertebral disc.
Fig. 51 The vascular supply of the maxillofacial region. (Original drawing by Dr Hala Al Janaby, Perth WA, Australia)
The external and internal carotids are located lingual artery have been found to enter the supe-
in the carotid sheath, deep to the sternoclei- rior genial spine foramen of the mandible (Jacobs
domastoid muscle. The external carotid ultimately et al. 2007), and this is an important consideration
passes posterior to the angle of the mandible and for implant surgery in the anterior mandible.
anterior to the mastoid process to reach the parotid
gland, within which it divides into its two terminal
branches: the maxillary and superficial temporal The Maxillary Artery
arteries. The branches of the external carotid
innervating orofacial structure are the facial The maxillary artery is one of the terminal branches
artery, the lingual artery, and the superficial tem- of the external carotid artery. It arises within the
poral artery. parotid gland and eventually courses medially over
lateral pterygoid before entering the pterygopalatine
fossa. Variations of this have the artery coursing
The Facial Artery either between the superior and inferior heads of
the lateral pterygoid or inferior to it. The course
The facial artery branches from the external through the lateral pterygoid is used to divide the
carotid artery at the greater horn of the hyoid artery into three artificial sections: the first prior to
bone. It courses anteriorly, crossing the border of lateral pterygoid, the second over lateral pterygoid,
the body of the mandible at the anterior border of and the third beyond the lateral pterygoid. There are
masseter to reach the face. The artery’s pulse can five branches from each of these three sections of
be felt as it crosses the border of the mandible. The the maxillary artery. These branches can be thought
artery then travels obliquely superiorly to reach of as an aid to memory; the first part gives off bony
the angle between the eye and external nose. Here branches, the second muscular branches, and the
it supplies the lacrimal gland and anastomoses third nervous branches (Fig. 52).
with the external nasal artery of the ophthalmic The largest branch of the first part is the middle
artery. It was once thought that the artery had a meningeal artery. This artery enters the cranial
torturous course, but this is probably due to its cavity via the foramen spinosum together with
appearance in cadaveric dissections. Occasionally the meningeal branch of the trunk of the mandib-
there is a more superior origin of the facial artery ular division of the trigeminal nerve. Other
(just inferior to the maxillary artery), and it then branches are the anterior tympanic artery, the
runs through the parotid gland to reach facial deep auricular artery, the accessory meningeal
tissues. Even less frequently it may branch artery, and the inferior alveolar artery, which
together with the lingual artery as the linguofacial enters the mandibular foramen with the inferior
trunk (Mangalgiri et al. 2015). alveolar nerve.
The facial artery’s branches supply structures Branches arising from the second part of the
in the pharynx as well as the lower lip and chin, maxillary artery are the three temporal branches,
soft palate, and external nose. medial pterygoid artery, masseteric artery, and
buccal artery.
The third part of the maxillary artery is within
The Lingual Artery the pterygopalatine fossa. It gives off the posterior
superior alveolar branch, infraorbital artery, greater
The lingual artery is the main supply to the tongue palatine artery, pharyngeal artery, and artery of the
and floor of the mouth. It enters the tongue at the pterygoid canal. All arteries branching from the
root and branches into superior and inferior lin- maxillary within the pterygopalatine fossa accom-
gual arteries, supplying tongue musculature and pany nerves. The final continuation of the maxil-
overlying mucosa. Small branches from the lary artery is the sphenopalatine artery that enters
Fig. 52 The maxillary artery and its branches. (Original drawing by Dr Hala Al Janaby, Perth WA, Australia)
the nasal cavity and divides into posterior medial The increasing average lifespan and average age
and lateral nasal branches to supply mucosa of the of the population in many communities throughout
nasal septum as well as the paranasal air sinuses the world should lead us to a better understanding
and conchae of the lateral nasal cavity. of the healthy range of aging processes. Longitu-
dinal studies of changes in oral and facial anatom-
ical features would help clinicians understand
normal variation compared with disease process
The Superficial Temporal Artery or risk of onset of a disease. Again, imaging tech-
niques that are noninvasive and repeatable over
This is the other terminal division of the external time will be crucial to revealing the variation of
carotid artery within the parotid gland. It courses normal age changes in the population.
superiorly through the parotid gland and runs as
two branches, over the temporal region. It sup-
plies the parotid gland, temporomandibular joint, Cross-References
and masseter. It gives off the transverse facial
artery within the parotid gland. ▶ Clinical Evaluation of Oral Diseases
▶ Clinical Evaluation of Orofacial Pain
▶ Cutaneous Pathology of the Head and Neck
Conclusions and Future Directions ▶ Head and Neck Tumors
▶ Neurophysiology of Orofacial Pain
The normal variation of anatomical features can go ▶ Neurosensory Disturbances Including Smell
unnoticed as the incidence of variations in the and Taste
population might be very low, the variation may ▶ Odontogenic Pathology
be located in a rarely imaged or investigated region, ▶ Pediatric Oral Medicine
imaging techniques might not be sensitive enough ▶ Pigmented Lesions of the Oral Mucosa
to show certain variations, and the variation itself ▶ Salivary Gland Disorders and Diseases
may not produce any symptoms or clinical ▶ Soft and Hard Tissue Operative Investigations
significance. in the Diagnosis and Treatment of Oral Disease
With increasing sophistication and availability
of treatments, the presence of variations may
become an important consideration for the clini- References
cian. The range of healthy gross and histomor-
phometries has to be taken into consideration Agur AMR, Grant JCB. Grant's atlas of anatomy. 13th
when making a decision about clinical interven- ed. Philadelphia: Wolters Kluwer Health/Lippincott
Williams & Wilkins; 2013. xiv, 871 p
tion. Surgical options must take into consideration Al-Abdallah M, AlHadidi A, Hammad M, Al-Ahmad H,
the underlying anatomical features whose pres- Saleh R. Original article: prevalence and distribution of
ence/absence/size might have an impact on dental anomalies: a comparison between maxillary
patient outcomes after surgery. and mandibular tooth agenesis. Am J Orthod Dentof
Orthoped. 2015. https://doi.org/10.1016/j.
Three-dimensional imaging technologies in ajodo.2015.05.024.
the oral and maxillofacial regions are beginning Amr B, Monib S. Lingual thyroid: a case report. Int J Surg
to enable better visualization of varying anatomi- Case Rep. 2011;2(8):313–5.
cal features. Techniques such as cone beam com- Arda O, Göksügür N, Tüzün Y. Basic histological structure
and functions of facial skin. Clin Dermatol. 2014;32
puted tomography can be used to make three- (1):3–13.
dimensional measurements and assessments of Aslan BI, Akarslan ZZ. Teeth number anomalies in perma-
anatomical features at high resolution and will nent dentition among non-syndromic dental patients.
hopefully draw attention to the range of anatom- Coll Antropol. 2013;37(1):115–20.
Avery J, Steele P, Avery N. Oral bevelopment and histol-
ical variations in a way that previous techniques ogy (Avery JK (ed); Steele PF; Avery N (asso ed)).
have not been able to do. Stuttgart/New York: Thieme; 2002, c2002.
Baker E, Schünke M, Schulte E, Schumacher U. Anatomy Eliasson L, Carlen A, Laine M, Birkhed D. Minor Gland
for dental medicine. New York: Thieme; 2015. and whole saliva in postmenopausal women using a
Beaini T, Duailibi-Neto E, Chilvarquer I, Melani R. Orig- low potency oestrogen (oestriol). Arch Oral Biol.
inal communication: human identification through 2003;48(7):511–7.
frontal sinus 3D superimposition: pilot study with Fehrenbach MJ, Herring SW. Illustrated anatomy of the
cone beam computer tomography. J Forensic Legal head and neck. 4th ed. St. Louis: Elsevier/Saunders;
Med. 2015;36:63–9. 2012. ix, 317 14 p
Bergdahl M. Salivary flow and oral complaints in adult Fehrenbach MJ, Popowics T.Illustrated dental embryology,
dental patients. Community Dent Oral Epidemiol. histology, and anatomy. Elsevier Health Sciences;
2000;28(1):59–66. 2015.
Berge JK, Bergman RA. Variations in size and in symmetry Flink H, Tegelberg A, Lagerlof F. Influence of the time of
of foramina of the human skull. Clin Anat. measurement of unstimulated human whole saliva on
2001;14:406–13. the diagnosis of hyposalivation. Arch Oral Biol.
Bergman RA, Afifi AK, Miyauchi R. Illustrated encyclo- 2005;50(6):553–9.
pedia of human anatomic variation, 2006. Francis-West P, Ladher R, Barlow A, Graveson A. Signal-
Anatomyatlases.org. Accessed 24 Apr 2017. ling interactions during facial development. Mech Dev.
Berkovitz BK, Holland GR, Moxham BJ. Oral anatomy, 1998;75:3–28.
histology and embryology. Elsevier; 2016. Frommer J. The human accessory parotid gland: its inci-
Berkovitz B, Moxham B, Newman H. The periodontal dence, nature, and significance. Oral Surg Oral Med
ligament in health and disease. London/Baltimore: Oral Pathol. 1977;43:671–6.
Mosby-Wolfe; 1995. Furnas DW. The retaining ligaments of the cheek. Plast
Canaan TJ, Meehan SC. Variations of structure and appear- Reconstr Surg. 1989;83(1):11–6.
ance of the oral mucosa. Dent Clin N Am. 2005;49 Gallo A, Leonetti F, Torri E, Manciocco V, Simonelli M,
(1):1–14. vii DeVincentiis M. Ectopic lingual thyroid as unusual
Capelli M, Gatti I. Radiological study of maxillary sinus cause of severe dysphagia. Dysphagia. 2001;16
using CBCT: relationship between mucosal thickening (3):220–3.
and common anatomic variants in chronic Garant PR. Oral cells and tissues. Chicago: Quintessence
rhinosinusitis. J Clin Diag Res. 2016;10(11):7–10. Pub. Co; 2003. c2003
Cecílio F, Regalo S, Palinkas M, Issa J, Siéssere S, Garcia-Bailo B, Toguri C, Eny K, El-Sohemy A. Genetic
Hallak J, Machado-de-Sousa J, Semprini M. Ageing variation in taste and its influence on food selection.
and surface EMG activity patterns of masticatory mus- OMICS. 2009;1:69.
cles. J Oral Rehabil. 2010;37(4):248–55. Gartner LP. Textbook of histology. Philadelphia: Elsevier;
Chandrashekar J, Hoon MA, Ryba NJP, Zucker CS. The 2015.
receptors and cells of the mammalian taste. Nature. Gartner L, Hiatt J. Color atlas and text of histology. Phil-
2006; 444:288–94. adelphia: Wolters Kluwer Health/Lippincott Williams
Chi AC, Neville BW, Krayer JW, Gonsalves WC. Oral & Wilkins; 2013. c2014
manifestations of systemic disease. Am Fam Physician. Gataa I, Faris B. Patterns and surgical significance of facial
2010;82(11):1381–8. nerve branching within the parotid gland in 43 cases.
Choi SJ, Lee JW, Song JH. Dental anomaly patterns asso- Oral Maxillofac Surg. 2016;2:161.
ciated with tooth agenesis. Acta Odontol Scand. Gomes RR, Fonseca JC, Paula LM, Acevedo AC,
2017;75(3):161–5. Mestrinho HD. Dental anomalies in primary dentition
Chiego DJ. Essentials of oral histology and embryology-e- and their corresponding permanent teeth. Clin Oral
book: a clinical approach. Elsevier Health Sciences; Investig. 2014;4:1361.
2014. Gonçalves PF, et al. Dental cementum reviewed: develop-
Chrcanovic B, Custódio A. Anatomical variation in the ment, structure, composition, regeneration and poten-
position of the greater palatine foramen. J Oral Sci. tial functions. Br J Oral Sci. 2015;4(12):651–8.
2010;52(1):109–13. Gray H, Williams PL, Bannister LH. Gray's anatomy : the
Ciano J, Beatty B. Regional quantitative histological vari- anatomical basis of medicine and surgery. New York:
ations in human oral mucosa. Anat Record. 2015;298 Churchill Livingstone; 1995. p. 1995.
(3):562–78. Gudjonsson T, et al. Myoepithelial cells: their origin and
Daud S, Nambiar P, Hossain M, Rahman M, Bakri M. function in breast morphogenesis and neoplasia. J
Changes in cell density and morphology of selected Mammary Gland Biol Neoplasia. 2005;10(3):261–72.
cells of the ageing human dental pulp. Gerodontology. Gueiros LA, Soares MS, Leao JC. Impact of ageing and
2016;3:315. drug consumption on oral health. Gerodontology.
Eliades A, Papadeli C, Tsirlis A. Mandibular canal, foram- 2009;26(4):297–301.
ina of the mandible and their variations: part II: the Guiglia R, Di Fede O, Lo Russo L, Sprini D, Rini G-B,
clinical relevance of the preoperative radiographic Campisi G. Osteoporosis, jawbones and periodontal
evaluation and report of five cases. Oral Surg. disease. Med Oral Patol Oral Cir Bucal. 2013;18:
2016;2:85. e93–9.
Güldner C, Pistorius S, Diogo I, Bien S, Sesterhenn A, Kumar GS. Orban's oral histology & embryology,
Werner J. Analysis of pneumatization and vol. 2014. London: Elsevier Health Sciences APAC;
neurovascular structures of the sphenoid sinus using 2014.
cone-beam tomography (CBT). Acta Radiol. 2012;53 Laine M, Leimola-Virtanen R. Effect of hormone replace-
(2):214–9. ment therapy on salivary flow rate, buffer effect and pH
Gulsahi A. Osteoporosis and jawbones in women. J Int Soc on perimenopausal and postmenopausal women. Arch
Prev Community Dent. 2015;5:263–7. Oral Biol. 1996;41(1):91–6.
Hand A, Pathmanathan D, Field R. Morphological features Leo J, Cassell M, Bergman R. Variation in human
of the minor salivary glands. Arch Oral Biol. 1999;44 infraorbital nerve, canal and foramen. Ann Anat.
(Suppl 1):S3–S10. 1995;1:93.
Hand AR, Frank ME. Fundamentals of oral histology and Madani M, Berardi T, Stoopler ET. Anatomic and exami-
physiology. Oxford: Wiley; 2014. nation considerations of the oral cavity. Med Clin North
Hanihara T, Ishida H. Frequency variations of discrete Am. 2014;98(6):1225–38.
cranial traits in major human populations. IV. Vessel Madani FM, Kuperstein AS. Normal variations of oral
and nerve related variations. J Anat. 2001;199 anatomy and common oral soft tissue lesions: evalua-
(Pt 3):273–87. tion and management. Med Clin North Am. 2014;98
Hellquist H, Skalova A. Histopathology of the salivary (6):1281–98.
glands, vol. 2014. Heidelberg: Springer; 2014. Malpas P. Anomalies of the Mylohyoid Muscle. J Anat.
Hiatt JL, Gartner LP. Textbook of head and neck anatomy. 1926; 61(Pt 1):64–67.
Philadelphia: Wolters Kluwer Health/Lippincott Wil- Mangalgiri A, Namdev LN, Mahore D, Kapre M. The
liam & Wilkins; 2010. study of higher origin of facial artery and its surgical
Hung-Huey T. Panoramic radiographic findings of significance. In J Otolaryngol Head Neck Surg.
the mandibular foramen from deciduous to early per- 2015;67(1):72–4.
manent dentition. J Clin Pediatr Dent. 2004;28(3): Merchant AT. Low bone mineral density based on meta-
215. carpal cortical bone area may predict tooth loss in older
Hutto J, Vattoth S. A practical review of the muscles of men. J Evid Based Dent Pract. 2017;17:298–9.
facial mimicry with special emphasis on the superficial Mays JW, Sarmadi M, Moutsopoulos NM. Oral
musculoaponeurotic system. Am J Roentgenol. manifestations of systemic autoimmune and inflam-
2015;204(1):W19–26. matory diseases: diagnosis and clinical manage-
Inoue H, Ono K, Masuda W, Morimoto Y, Tanaka T, ment. J Evid Based Dent Pract. 2012;12(3 Suppl):
Yokota M, et al. Gender difference in unstimulated 265–82.
whole saliva flow rate and salivary gland sizes. Arch McMinn RMH. Last’s anatomy, regional and applied. 9th
Oral Biol. 2006;51(12):1055–60. ed. London: Churchill Livingstone; 1995.
Iván S, Daniela Z. Age effect in the morphological traits McKenna G, Burke FM. Age-related oral changes. Dent
performance for sex determination in human skulls and Update. 2010;37(8):519–23.
mandibles. Int J Morphol. 2012;1:296. Medbery R, Yousem D, Needham M, Kligerman M.
Jacobs R, Lambrichts I, Liang X, Martens W, Mraiwa N, Variation in parotid gland size, configuration, and
Adriaensens P, Gelan J. Oral and maxillofacial radiol- anatomic relations. Radiother Oncol. 2000;54(1):
ogy: Neurovascularization of the anterior jaw bones 87–9.
revisited using high-resolution magnetic resonance Miletich I. Introduction to salivary glands: structure, func-
imaging. Oral Surg Oral Med Oral Pathol Oral Radiol tion and embryonic development. Front Oral Biol.
Endodontol. 2007;103:683–93. 2010;14:1–20.
Jorge T, Mario C, Daniela Z, Iván S. Percentage of lateral Mohl N. The temporomandibular joint. Textbook of occlu-
pterygoid muscle inserted in the disc of human tempo- sion. Chicago: Quintessence Publishing Co. Inc; 1988.
romandibular joint. Int J Morphol. 2011;3:965. p. 81–96.
Kazunobu S, Tatsurou T, Shinji K, Nao W, Shinobu M, Morriss-Kay G, Ruberte E, Fukiishi Y. Mammalian neural
Masafumi O, Shun N, Yasuhiro M. The significance crest and neural crest derivatives. Ann Anat. 1993;175
of cone beam computed tomography for the visuali- (6):501–7.
zation of anatomical variations and lesions in the Moynihan P, Petersen PE. Diet, nutrition and the preven-
maxillary sinus for patients hoping to have dental tion of dental diseases. Public Health Nutr. 2004;7
implant-supported maxillary restorations in a private (1A):201–26.
dental office in Japan. Head Face Med. 2014;10(1): Mukhopadhyay S, Mitra S. Anomalies in primary denti-
3–28. tion: their distribution and correlation with permanent
Kaye EK, Vokonas P, Garcia RI. Metacarpal cortical bone dentition. J Nat Sci Biol Med. 2014;5(1):139.
area predicts tooth loss in men. JDR Clin Transl Res. Mydlová M, Dupej J, Koudelová J, Velemínská J. Sexual
2017;2:179–86. dimorphism of facial appearance in ageing human
Kels BD, Grzybowski A, Grant-Kels JM. Human Ocular adults: a cross-sectional study. Forensic Sci Int.
Anatomy. Clin Dermatol. 2015;33:140–6. 2015;257:519.e1–9.
Nagler RM. Salivary glands and the aging process: mech- Snell RS. Clinical anatomy by regions. 9th ed. Baltimore:
anistic aspects, health-status and medicinal-efficacy Lippincott Williams & Wilkins; 2012. 754 p
monitoring. Biogerontology. 2004;5(4):223–33. Stephan C, Simpson E, Byrd J. Facial soft tissue depth
Nanci A. Ten Cate’s oral histology Development, Struc- statistics and enhanced point estimators for craniofacial
ture, and Function. St. Louis: Elsevier; 2013. identification: the debut of the Shorth and the
Nishimura T, Suzuki K. Anatomy of oral respiration: mor- 75-Shormax. J Forensic Sci. 2013;58(6):1439–57.
phology of the oral cavity and pharynx. Acta Stojčev Stajčić L, Gačić B, Popović N, Stajčić
Otolaryngol Suppl. 2003;123:25. Z. Research paper: anatomical study of the
Norton NS, Netter FH. Netter's head and neck anatomy for pterygopalatine fossa pertinent to the maxillary
dentistry. 2nd ed. Philadelphia: Elsevier/Saunders; nerve block at the foramen rotundum. Int J Oral
2012. xii, 659 p Maxillof Surg. 2010;39:493–6.
O'Rahilly R, Müller F. Basic human anatomy : a regional Štoković N, Trkulja V, Dumić-Čule I, Čuković-Bagić I,
study of human structure. Philadelphia: Saunders; Lauc T, Vukičević S, Grgurević L. Sphenoid sinus
1983. xi, 566 p types, dimensions and relationship with surrounding
Perry ME. The specialised structure of crypt epithelium in structures. Ann Anat. 2016;203:69–76.
the human palatine tonsil and its functional signifi- Stratmann U, Schaarschmidt K, Santamaria P. Morphomet-
cance. J Anat. 1994;185(Pt 1):111–27. ric investigation of condylar cartilage and disc thick-
Picciani BL, Domingos TA, Teixeira-Souza T, Santos ness in the human temporomandibular joint:
Vde C, Gonzaga HF, Cardoso-Oliveira J, et al. Geo- significance for the definition of osteoarthritic changes.
graphic tongue and psoriasis: clinical, histopathologi- J Oral Pathol Med. 1996;25(5):200–5.
cal, immunohistochemical and genetic correlation - a Tamgadge S, et al. Myoepithelial cell–a morphologic
literature review. An Bras Dermatol. 2016;91 diversity–a review. Res Rev J Dent. 2013;4(1):5–12.
(4):410–21. Tapia CJ, Cantín M, Zavando D, Suazo GI. Percentage of
Provenza DV. Fundamentals of oral histology and embry- lateral pterygoid muscle inserted in the human tempo-
ology. Philadelphia: Lea & Febiger; 1988. romandibular joint disc. Int J Morphol. 2011;29
Qian L, Tian X, Zeng L, Gong Y, Wei B. Dental implants: (3):965–70.
analysis of the morphology of maxillary sinus septa on Thesleff I. Homeobox genes and growth factors in regula-
reconstructed cone-beam computed tomography tion of craniofacial and tooth morphogenesis. Acta
images. J Oral Maxillofac Surg. 2016;74:729–37. Odontol Scand. 1995;53:129–34.
Rattan SI. Biology of ageing: principles, challenges and Theveneau E, Mayor R. Neural crest delamination and
perspectives. Romanian J Morphol Embryol. 2015;56 migration: from epithelium-to-mesenchyme transition
(4):1251–3. to collective cell migration. Dev Biol. 2012;366
Reynolds SC, Chow AW. Life-threatening infections of the (1):34–54.
peripharyngeal and deep fascial spaces of the head and Thomas DM, Mirowski GW. Nutrition and oral mucosal
neck. Infect Dis Clin NA. 2007;21:557–76. diseases. Clin Dermatol. 2010;28(4):426–31.
Robinson C, Kirkham J, Shore RC. Dental enamel forma- Tiwari M. Science behind human saliva. J Nat Sci Biol
tion to destruction. Boca Raton: CRC press; 2017. Med. 2011;2(1):53–8.
Rodella L, Buffoli B, Labanca M, Rezzani R. Review: a Walker WB. The oral cavity and associated structures. In:
review of the mandibular and maxillary nerve supplies Walker HK, Hall WD, Hurst JW, editors. Clinical
and their clinical relevance. Arch Oral Biol. methods: the history, physical, and laboratory exami-
2012;57:323–34. nations. 3rd ed. Boston: Butterworths; 1990.
Roed-Petersen B, Renstrup G. A topographical classifica- Warshafsky D, Goldenberg D, Kanekar SG. Imaging anat-
tion of the oral mucosa suitable for electronic data omy of deep neck spaces. Otolaryngol Clin NA.
processing its application to 560 leukoplakias. Acta 2012;45:1203–21.
Odontol Scand. 1969;27(6):681–95. Waugh A, Grant AW, Chambers G. Ross and Wilson
Scardina GA, Messina P. Good oral health and diet. J anatomy and physiology in health and illness. Edin-
Biomed Biotechnol. 2012;2012:720692. burgh: Elsevier; 2014.
Schrödter S, Biermann E, Halata Z. Histological evaluation Winning T, Townsend G. Oral mucosal embryology and
of age-related changes in human respiratory mucosa of histology. Clin Dermatol. 2000;18:499–511.
the middle turbinate. Anat Embryol (Berl). 2003;207 Witt M, Reutter K. Anatomy of the tongue and taste buds.
(1):19–27. In: Handbook of olfaction and gustation. 3rd
Shrestha MK, Ghartimagar D, Ghosh A. Diagnostic accu- ed. Hoboken: Wiley; 2015. p. 637–63.
racy of computed tomogram in the evaluation of a neck Wolf K, Brokaw E, Bell A, Joy A. Variant inferior alveolar
mass. J Nepal Med Assoc. 2011;51(184):164–70. nerves and implications for local Anesthesia. Anesth
Singh D, Hsu C, Kwan G, Bhuta S, Skalski M, Jones Prog. 2016;63(2):84–90.
R. High resolution CT study of the chorda tympani Wood C. The age-related emergence of cranial morpholog-
nerve and normal anatomical variation. Jpn J Radiol. ical variation. Forensic Sci Int. 2015;251:220.e1–220.
2015;5:279. e20.
Yap T, McCullough M. Oral medicine and the ageing Zhu W, Hu F, Liu X, Guo S, Tao Q. Role of the accessory
population. Aust Dent J. 2015;60(Suppl 1):44–53. parotid gland in the Etiology of Parotitis: statistical
Young B, Woodford P, O'Dowd G. Wheater's functional analysis of Sialographic features. PLoS One. 2016;11
histology: a text and colour atlas. Saint Louis: Elsevier (2):1–6.
Health Sciences; 2013. United Nations. Department of Economic and
Zhang B, Yang Z, Zhang R, Liu L, Zhang F, Chen J, Zhang K. Social Affairs, Population Division. World popula-
Are the patients with anatomic variation of the sublingual/ tion prospects: the 2017 revision, key findings
Wharton's duct system predisposed to ranula formation? and advance tables. Working Paper No. ESA/P/WP/
Int J Pediatr Otorhinolaryngol. 2016;83:69–73. 248.
Interface Between Oral and Systemic
Disease
Michele D. Mignogna and Stefania Leuci
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Cardiovascular Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Ischemic Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Congenital Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Hypertensive Vascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Disorders of Rhythm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Valvular Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
Infective Endocarditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
Anticoagulant Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Cardiac Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
Oral Manifestations of Cardiovascular Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Respiratory Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Chronic Obstructive Pulmonary Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
Oral Manifestations of Respiratory Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Endocrine Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
Diseases of the Adrenal Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Diseases of Parathyroid Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Gonadal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Thyroid Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Oral Manifestations of Endocrine Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
Gastrointestinal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
Dysphagia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
Gastroesophageal Reflux Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Inflammatory Bowel Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Hepatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
Alcoholic Liver Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
M. D. Mignogna (*) · S. Leuci

Oral Medicine Complex Unit, Department of
Neuroscience, Reproductive and Odontostomatological
Sciences, Federico II University of Naples, Naples, Italy
e-mail: mignogna@unina.it; ste.leuci@gmail.com

https://doi.org/10.1007/978-3-319-72303-7_9
68 M. D. Mignogna and S. Leuci
Oral Manifestations of Gastrointestinal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

Musculoskeletal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
Osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
Osteoarthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
Fibromyalgia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
Oral Manifestations of Musculoskeletal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
Hematological Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
Leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
Lymphomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
Oral Manifestations of Hematological Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
Renal Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
Oral Manifestations of Kidney Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
Neurological Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
Amyotrophic Lateral Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
Dementia/Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
Oral Manifestations of Neurological Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
Psychiatric Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
Anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
Eating Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
Substance-Related Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
Oral Manifestations of Psychiatric Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
Conclusions and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
Abstract systems and “think systemically”. After all, oral

Oral medicine is a specialty of dentistry health is part of general health. Careful exam-
concerned with the oral health care of patients ination of the oral cavity may reveal findings
with chronic, recurrent and medically related indicative of underlying systemic diseases.
disorders of the orofacial region and with their Further, local diseases may result from treat-
diagnosis and nonsurgical management. For ments and drugs with a profound impact on the
these reasons, familiarity with medical condi- patient’s health. This strong relationship
tions that correlate with the most common oral between internal medicine and oral medicine
diseases is absolutely essential for specialists mandates a comprehensive understanding of
in oral medicine, as well as for all health care medicine for all oral medicine specialists.
practitioners, to provide their patients with the This chapter focuses on systemic diseases
best possible care. within an oral medicine context, specifically
In internal medicine, medical professionals presenting diseases of cardiovascular, respira-
usually take a whole of person approach to tory, endocrine, gastrointestinal, musculoskel-
diagnosis and treatment of systemic diseases. etal, hematologic, renal, neurologic, and
Similarly, oral medicine specialists should con- psychiatric disorders. This chapter is intended
sider the orofacial region as a mirror to body to offer a pathway for guidance of in depth
Interface Between Oral and Systemic Disease 69
medical information critical in contemporary Cardiovascular Diseases

oral medicine practice.
Ischemic Heart Disease
Keywords
Systemic evaluation · Systemic diseases · Ischemic heart disease, also known as coronary
Systemic pathology · Internal medicine · artery disease, is a disease characterized by
Disseminated diseases · Localized diseases · reduced blood supply to the heart. It is the most
Cardiovascular diseases · Respiratory common cause of death worldwide (Murray et al.
diseases · Endocrine disorders · 2012); however, many patients survive acute
Gastrointestinal disorders · Musculoskeletal myocardial infarction (MI), and many adults live
disorders · Hematological disorders · Renal with disabling symptoms of stable angina pectoris
diseases · Neurological disorders · Psychiatric or ischemic heart failure. Ischemia is a condition
disorders in which the blood flow, and thus oxygen, is
restricted or reduced to a part of the body, in this
case the heart muscle and arteries. Myocardial
Introduction ischemia is a consequence of reduced blood flow
in coronary arteries due to a combination of fixed
This chapter addresses the complex, multifaceted vessel narrowing and abnormal vascular tone as a
relationship between oral and systemic health, and result of atherosclerosis and endothelial dysfunc-
the deep link with medicine, as the oral cavity can tion (Fig. 1). Other nonatherosclerotic causes of
be thought of as an expression of the homeostasis ischemia include (a) decreased coronary perfusion
of the whole body. The focus is on the major pressure due to hypotension, such as hyper-
systems, providing data on a selection of diseases volemia and septic shock; (b) decreased blood
and conditions regarding the definition, etiology, oxygen content, such as in marked anemia or
pathogenesis, and their management useful in oral pulmonary disease; (c) significant increase in
medicine practice. This cannot substitute dedicated myocardial oxygen demand, such as caused by
textbooks in internal medicine and does not include rapid tachycardia, acute hypertension, or severe
a complete and detailed description of all systemic aortic stenosis; (d) unusual coronary abnormali-
diseases, as it is beyond the scope of this text. The ties; (e) coronary emboli caused by endocarditis
major objective of this comprehensive chapter is to or artificial heart valves; (f) inflammation of the
provide oral medicine specialists an overview with coronary arteries; (g) severe transient coronary
consistent information on the most frequent sys- spasm resulting from cocaine abuse; and
temic diseases related to oral health and to review (h) congenital abnormalities, trauma, or aneurysm
important aspects of systems pathology. The oral of the coronary arteries (Davies 2000). Traditional
medicine clinician should be well versed in general and Framingham risk factors, such as hyperten-
and systemic pathology, systems pathology, and sion, hyperlipidemia, diabetes, tobacco use, life-
general and internal medicine, and should use this style, and diet, are modifiable both for women and
chapter as a starting point for further reading and men (Mahmood et al. 2014). Over the last decade
exploration of systemic diseases and not as an the increased research focus of women at risk for
exhaustive list of conditions. While this chapter ischemic heart disease has helped define and
highlights the oral manifestations of systemic con- delineate some of the gender-specific factors at
ditions, it includes them for completeness, and not play, such as metabolic syndrome, pregnancy
to delve into them in any great detail. A sole ded- related disorders, autoimmune disorders, sleep
icated chapter titled ▶ “Oral Manifestations of apnea, chronic kidney disease, psychosocial fac-
Systemic Diseases and Their Treatments” explores tors such as depression, anxiety, low socioeco-
these in much greater detail and is designed to nomic status, and work and marital stress (Mehta
complement the contents of this chapter. et al. 2015). The severity and duration of ischemia
Table 1 Heart failure risk factors. (Adapted from Bui

et al. 2011)
Major clinical risk factors: Age, male gender,
hypertension, LV hypertrophy, myocardial infarction,
valvular heart disease, obesity, diabetes
Minor clinical risk factors: Smoking, dyslipidemia,
chronic kidney disease, albuminuria, sleep-disordered
breathing, anemia, increased heart rate, dietary risk
factors, sedentary lifestyle, low socioeconomic status,
psychological stress
Immune-mediated: Peripartum cardiomyopathy,
hypersensitivity
Infectious: Viral, parasitic (Chagas disease), bacterial
Toxic risk precipitants: Chemotherapy (anthracyclines,
cyclophosphamide, 5-FU), targeted cancer therapy
(trastuzumab, tyrosine kinase inhibitors), cocaine,
NSAIDs, thiazolidinediones, doxazosin, alcohol
Genetic risk predictors: SNP (e.g., α2CDel322–325,
β1Arg389), family history, congenital heart disease
Morphological risk predictors: Increased LV internal
dimension, mass, asymptomatic LV dysfunction
Biomarker risk predictors: Immune activation (e.g.,
IGF1, TNF, IL-6, CRP), natriuretic peptides (e.g., BNP
and NT-BNP), high sensitivity cardiac troponin
BNP brain natriuretic peptide, CRP C-reactive protein,
5-FU 5-fluorouracil, HF heart failure, IGF insulin-like
growth factor, IL interleukin, LV left ventricular, NSAIDs
nonsteroidal anti-inflammatory drugs, NT-BNP N-terminal
BNP, SNP single-nucleotide polymorphism, TNF tumor
Fig. 1 Pathological specimen of advanced atherosclerosis necrosis factor
with extensive thrombus (white arrows) and an aortic rup-
ture (black arrow) at the base of the plaques. (Image cour-
tesy of the Harry Brookes Allen Museum of Anatomy and
Pathology, The University of Melbourne, Carlton VIC, per 1000 person-years in patients >65 years of age
Australia) (Lloyd-Jones et al. 2002). The increasing incidence
of HF in the elderly is consistent with trends in
determines a spectrum of myocardial dysfunction, hypertension and ischemic heart disease. Although
from stable angina to heart failure. current therapeutic approaches have improved prog-
nosis, HF mortality remains high, comparable to
Heart Failure that of the most common cancers, with <50%
Heart failure (HF) is a major public health issue with 4-year survival (Henkel et al. 2008). Many patients
a prevalence of over 5.8 million in the USA and over die because of progressive pump failure and con-
37.7 million worldwide and rising. HF represents a gestion, although about one half die from sudden
considerable burden to the health-care system, cardiac death. Some patients die from end-organ
responsible for costs of more than $39 billion annu- failure resulting from inadequate systemic organ
ally in the USA alone, and high rates of hospitaliza- perfusion, particularly to the kidneys. Multiple fac-
tion, readmission, and outpatient visits. It affects tors are implicated in the increased risk for develop-
more men than women, and its prevalence greatly ment of HF (Table 1).
increases with advancing age and seems to be about HF is not a single entity, but a complex clinical
2–3% (Lloyd-Jones et al. 2010). Depending on the syndrome that may have different characteristics
different groups of patients included in epidemio- depending on age, sex, race or ethnicity, and HF
logical studies, the incidence shows a great variation etiology. It can result from any structural or func-
from 2–5 per 1000 person-years in USA to 10–19.3 tional cardiac disorder that impairs the ability of the
ventricle to fill or eject blood (Jessup et al. 2009). Table 2 Signs of heart failure. (Adapted from McMurray
The global Myocardial Infarction Task Force et al. 2012)
defines myocardial infarction as cardiac myocyte More specific Less Specific
necrosis with an increase and/or decrease in plasma Elevated jugular Peripheral edema (ankle,
of cardiac troponin (cTn). At least one cTn mea- venous pressure scrotal, sacral)
surement should be greater than the 99th percentile Hepatojugular reflux Pulmonary crepitations
Third heart sound Reduced air entry and dullness
normal reference limit during: (1) symptoms of
(gallop rhythm) to percussion at lung bases
myocardial ischemia; (2) new (or presumably (pleural effusion)
new) significant electrocardiographic (ECG) Laterally displaced Tachycardia
ST-segment/T-wave changes or left bundle branch apical impulse
block; (3) the development of pathological ECG Q Cardiac murmur Irregular pulse
waves; (4) new loss of viable myocardium or Tachypnea (>16 breaths/min)
regional wall motion abnormality identified by an Hepatomegaly
imaging procedure; or (5) identification of Ascites
intracoronary thrombus by angiography or autopsy Tissue wasting (cachexia)
(Thygesen et al. 2012). The pathogenesis of HF is a
complex mechanism due to activation of various
Table 3 Symptoms of heart failure. (Adapted from
immunologic and neuro-humoral mechanisms that McMurray et al. 2012)
induce ischemic, pro-arrhythmic, vascular, and
Typical Less Typical
structural changes in the myocardium. There are
Breathlessness Nocturnal cough
several compensatory mechanisms involved from
Orthopnea Wheezing
subcellular to organ-to-organ interactions. The Paroxysmal nocturnal Weight gain (>2 kg/
most important of these are: (a) neuro-hormonal dyspnea week)
activation (sympathetic nervous system, Renin- Reduced exercise tolerance Weight loss
Angiotensin-Aldosterone System, Vasopressin) to (in advanced heart
increase circulating blood volume; (b) the Frank failure)
Starling mechanism by which the heart is able to Fatigue, tiredness, increased Bloated feeling
time to recover after exercise, Loss of appetite
change its force of contraction, and therefore stroke ankle swelling Confusion (especially
volume, in response to changes in venous return; in the elderly)
(c) ventricular remodeling. Depression
The signs (Table 2) and symptoms (Table 3) of Palpitations
HF are due in part to compensatory mechanisms Syncope
utilized by the body in an attempt to adjust for a
primary deficit in cardiac output. There is a wide
spectrum of potential clinical manifestations of the Angina Pectoris
disease. The goal of treatment for all stages of HF “Angina” is a term used to describe clinical symp-
includes a number of: (a) nonpharmacologic strate- toms such as discomfort in the chest, jaw, shoul-
gies, such as dietary sodium and fluid restriction, der, back, or arms that are induced by physical
appropriate physical activity, cessation to smoking, exertion or emotional stress and subside with rest
attention to weight gain; (b) pharmacologic, such as or treatment with nitroglycerin. Angina pectoris
diuretics, vasodilators, inotropic agents, anticoagu- (AP) is an important common condition with
lants, beta-blockers, and digoxin; (c) invasive strat- appreciable morbidity and mortality, caused by
egies with electrophysiological intervention to limit rapid, transient myocardial ischemia and hypoxia.
and reverse the manifestations of HF, through life- Coronary artery disease is still highly prevalent
style changes as well as the treatment of the under- worldwide, and stable angina pectoris is one of its
lying cause (i.e., coronary heart disease, more common presentations. An average of 3.4
hypertension, diabetes); (d) reduction of symptoms; million US adults older than 40 years of age
and (e) surgical procedures. experience angina each year. Among US adults,
Fig. 2 Photomicrograph of a histopathology specimen of and eosin stain. (Images courtesy of Professor Camile
a recent myocardial infarct (a; 20) showing the affected Farah, UWA Dental School, University of Western
areas across the whole of the cardiac wall, and (b; 100) Australia, Perth WA, Australia)
showing areas of necrosis (black arrows). Hematoxylin
Fig. 3 Photomicrograph of a histopathology specimen of (Images courtesy of Professor Camile Farah, UWA Dental
an old myocardial infarct (a; 20) showing the affected School, University of Western Australia, Perth WA,
areas becoming organized, and (b; 100) showing areas of Australia)
fibrosis (black arrows). Hematoxylin and eosin stain.
the age-adjusted prevalence of AP is higher disease. Stable angina is a clinical expression of

among women than among men, while in those MI associated with fixed atherosclerotic coro-
aged 60–79 years, it is higher in men than nary stenosis, which prevents the adaptation of
women (Mozaffarian et al. 2015). Community- coronary perfusion to an increased oxygen
based studies suggest that people with diagnosed requirement. MI manifested by angina pectoris
angina have a better 5-year survival than patients can be either acute or chronic. In addition, angina
affected by myocardial infarction (MI; hazard can occur in patients with a recent MI and termed
ratios 3.5 and 6.8, respectively) (Figs. 2 and 3), postinfarction angina. Myocardial ischemia is
compared with people without manifest ische- the result of an imbalance between myocardial
mic heart disease (Lampe et al. 2000). The prog- oxygen supply and myocardial oxygen demand.
nosis of each patient is related to individual The inability of the coronary arteries to increase
factors and is strictly linked to the underlying blood flow in response to increased cardiac
Table 4 Clinical classification of chest pain. (Adapted Table 5 Canadian Cardiovascular Society grading of
from Fox et al. 2006) angina pectoris. (Adapted from Campeau 2002)
Typical angina Meets three of the following Grade Description
(definite) characteristics Grade 1 Ordinary physical activity does no cause
Substernal chest discomfort (may angina, such as walking and climbing stairs.
be felt anywhere from the Angina with strenuous or rapid or prolonged
epigastrium to the lower jaw or exertion at work or recreation
teeth) with brief duration Grade 2 Slight limitation of ordinary activity.
(< 10 min) Walking or climbing stairs rapidly, walking
Provoked by exertion or emotional uphill, walking or stair climbing after meals,
stress or in cold, in wind or under emotional stress,
Relieved by rest and/or or only during the few hours after
nitroglycerin awakening. Walking more than two blocks
Atypical angina Meets two of the above on the level and climbing more than one
(probable) characteristics flight of ordinary stairs at a normal pace and
in normal conditions
Noncardiac Meets one or none of the above
chest pain characteristics Grade 3 Marked limitation of ordinary physical
activity. Walking one or two blocks on the
level and climbing one flight of stairs in
normal conditions and at normal pace
metabolic demands is the baseline dysfunction Grade 4 Inability to carry out any physical activity
instable angina. The majority of patients are without discomfort; angina may be present at
rest
symptomatic, but a certain percentage (25%) There are four subgroups in CCS Grade
can be asymptomatic, with the clinical manifes- 4. Groups A to D:
tations of myocardial ischemia being general (A) Admitted to hospital, becomes
chest discomfort (angina pectoris), arrhythmias, relatively asymptomatic with aggressive
medical therapy, and may be managed on an
and left ventricular dysfunction (Conti 2007). outpatient basis
The characteristics of discomfort related to myo- (B) Admitted to hospital, continues to
cardial ischemia have been extensively have angina despite aggressive medical
described and may be divided into four catego- therapy, and cannot be safely discharged
home, but does not require IV nitroglycerin
ries: location, character, duration, and relation to (C) Admitted to hospital and maximal
exertion, and other exacerbating or relieving fac- medical therapy, including IV nitroglycerin,
tors (Table 4). For patients with stable angina, fails to control symptoms
the Canadian Cardiovascular Society Classifica- (D) Patient in shock
tion divides the severity of symptoms using a
grading system (Table 5). Initial diagnostic man-
agement of patients with suspected AP is elec- Cor Pulmonale
trocardiography, biochemistry exams, Cor pulmonale is defined by the World Health
echocardiography, and chest x-ray. Treatments Organization as “hypertrophy of the right ventri-
for AP include lifestyle changes, medicines, cle resulting from diseases affecting the function
medical procedures, and cardiac rehabilitation. and/or structure of the lungs, except when these
Different modalities of regimens with various pulmonary alterations are the result of diseases
drugs are described in the literature based on that primarily affect the left side of the heart, as
the needs of a heterogeneous patient population. in congenital heart disease” (WHO 1963) (Fig. 4).
Patients with recurrent angina pectoris most It is characterized by the presence of pulmo-
likely will require multidrug protocols, includ- nary hypertension (PH) resulting from diseases
ing beta-blockers, calcium channel blockers, affecting the structure and/or the function of the
nitrates, and new antianginal class molecules lungs. PH results in right ventricular enlargement
such as ranolazine, where different mechanisms and may lead with time to right HF (Weitzenblum
may complement each other and result in a more and Chaouat 2009). The development of cor
efficacious strategy. pulmonale is generally associated with poor
Table 6 Classification of pulmonary hypertension.

(Adapted from Simonneau et al. 2004)
1. Pulmonary arterial hypertension
1.1. Idiopathic
1.2. Familial
1.3. Associated with:
1.3.1. Collagen vascular disease
1.3.2. Congenital systemic-to-pulmonary shunts
1.3.3. Portal hypertension
1.3.4. HIV infection
1.3.5. Drugs and toxins
1.3.6. Other (thyroid disorders, glycogen storage
disease, Gaucher’s disease, hereditary hemorrhagic
telangiectasia, hemoglobinopathies, chronic
myeloproliferative disorders, splenectomy)
1.4. Associated with significant venous or capillary
involvement
1.4.1. Pulmonary veno-occlusive disease
1.4.2. Pulmonary capillary hemangiomatosis
1.5. Persistent pulmonary hypertension of the newborn
Fig. 4 Pathological specimen of right ventricular
(RV) wall hypertrophy (black arrows) and dilation in a 2. Pulmonary hypertension with left heart disease
man of 59 years with a 15 year history of asthma and 2.1. Left-sided atrial or ventricular heart disease
emphysema, diagnosed with Cor pulmonale and cardiac 2.2. Left-sided valvular heart disease
dysfunction. (Image courtesy of the Harry Brookes Allen 3. Pulmonary hypertension associated with lung
Museum of Anatomy and Pathology, The University of diseases and/or hypoxemia
Melbourne, Carlton VIC, Australia)
3.1. Chronic obstructive pulmonary disease
3.2. Interstitial lung disease
prognosis and increased death (Fig. 4). Cor 3.3. Sleep-disordered breathing
pulmonale encompasses 6–7% of all types of 3.4. Alveolar hypoventilation disorders
adult heart disease in the United States where 3.5. Chronic exposure to high altitude
chronic obstructive pulmonary disease (COPD) 3.6. Developmental abnormalities
is the major cause. Mortality in patients 4. Pulmonary hypertension due to chronic thrombotic
and/or embolic disease
with concurrent COPD and cor pulmonale is
4.1. Thromboembolic obstruction of proximal
higher than that in patients with COPD alone pulmonary arteries
(Han et al. 2007). The global incidence is related 4.2. Thromboembolic obstruction of distal pulmonary
to the geographic area depending on the preva- arteries
lence of cigarette smoking, air pollution, and other 4.3. Nonthrombotic pulmonary embolism (tumor,
risk factors for various lung diseases. Lung parasites, foreign material)
disorders cause PH by several mechanisms: 5. Miscellaneous
Sarcoidosis, histiocytosis X, lymphangiomatosis,
(a) vasoconstriction caused by hypoxia;
compression of pulmonary vessels (adenopathy, tumor,
(b) hypercapnia, or both; (c) loss of capillary fibrozing mediastinitis)
beds; (d) increased alveolar pressure; and
(e) medial hypertrophy in arterioles. The causes
of PH are copious and a classification is shown in the 2nd heart sound (S2), and murmurs of func-
Table 6. Dyspnea is the most common symptom; tional tricuspid and pulmonic insufficiency. Later,
the development of additional symptoms such as an RV gallop rhythm (3rd [S3] and 4th [S4] heart
chest pain, light-headedness, syncope, and lower sounds) augmented during inspiration, distended
extremity edema may prompt further evaluation. jugular veins (with a dominant a wave unless
Physical findings commonly include a left para- tricuspid regurgitation is present), hepatomegaly,
sternal systolic lift, a loud pulmonic component of and lower-extremity edema may occur.
Many treatment options are available of the aorta) and left-to-right shunt lesions (atrial
depending on the medical conditions that cause septal defect, ventricular septal defect, patent
PH, involving diuretics and oxygen therapy. Dig- ductus arteriosus). The cyanotic defects, by defi-
italis is used only in the case of an associated left nition, affect right-to-left shunt (Tetralogy of
HF or in the case of arrhythmia. Long-term oxy- Fallot, Transposition of the great arteries, Tricus-
gen therapy is at present the best treatment for PH pid atresia). One fifth of these patients undergo
in chronic respiratory failure. Future treatment cardiac surgical procedures, 40% of whom have
may combine oxygen therapy and specific vaso- reoperations. Perioperative mortality varies
dilators (Weitzenblum and Chaouat 2009). according to basic anatomic diagnosis, age, pres-
ence of cyanosis, type of surgical procedure, and
lastly reoperation. Not all patients require treat-
Congenital Heart Disease ment; in some cases, surgery or cardiac catheter-
ization may be needed to reduce the effects of
Congenital heart disease (CHD) is “a gross struc- and/or to repair the defect.
tural abnormality of the heart or intrathoracic
great vessels that is actually or potentially of func-
tional significance” (Mitchell et al. 1971). It is a Hypertensive Vascular Disease
general term for a range of birth defects that affect
the normal workings of the heart. The term “con- Clinical hypertensive vascular disease is the result
genital” means the condition is present at birth. of complex alterations in the cellular components
CHD affects nearly 1% of – or about 40,000 – of the arterial wall. Changes in the endothelium,
births per year in the United States (Reller et al. smooth muscle cell, extracellular matrix, and pos-
2008). The most common type of heart defect is a sibly the adventitia, contribute to complications of
ventricular septal defect. About 25% of babies hypertension. An inflammatory state in the arterial
with a CHD have a critical CHD and generally wall mediated by reactive oxygen species is the
need surgery or other procedures in their first year main cause of damage through mechanical and
of life. Certain chromosomal abnormalities, such humoral signaling pathways. Mechanical stimuli
as trisomy 21, trisomy 18, trisomy 13, and mono- have three basic components: shear stress
somy X (Turner syndrome), are strongly associ- imposed by the flow of blood, wall stress as a
ated with CHD. However, these abnormalities result of pressure-induced wall deformation, and
account for only about 5% of patients with subsequent strain and the direct effects of pressure
CHD. Many other cases involve microscopic itself. The renin angiotensin system has been used
deletions on chromosomes or single-gene muta- as a prototypical model of altered humoral factors
tions. The prevalence of CHD in adults is 3–6 per in hypertension.
1000 adults (Webb et al. 2015). Approximately
8–12% of CHD is attributed to environmental Hypertension
factors during pregnancy, such as alcohol con- The National Heart Lung and Blood Institute
sumption, rubella infection, hydantoin and thalid- (NHLBI) defines hypertension (high blood pres-
omide intake, phenylketonuria, and poorly sure) as a systolic pressure of 140 mmHg or
controlled insulin-dependent diabetes (Bernier greater, diastolic pressure of 90 mmHg or greater,
et al. 2010). Common complications of CHD are or taking antihypertensive medication. Consensus
heart failure, arrhythmias, endocarditis, pulmo- recommendations for the management of hyper-
nary arterial hypertension, and thrombotic events. tension in adults have recommended a systolic
CHD may be classified into acyanotic and cya- pressure threshold 150 mm Hg for initiation
notic depending upon whether the patient clini- of drug therapy and a therapeutic target of
cally exhibits cyanosis. The acyanotic defects <150/90 mm Hg in patients 60 years of age
may further be subdivided into obstructive lesions (James et al. 2014; Whelton et al. 2017). Hyper-
(pulmonary stenosis, aortic stenosis, coarctation tension has been termed an epidemic affecting one
billion people and is the most common risk factor stimulation, and vagal nerve stimulation. New
for death throughout the world with an estimated pharmacological approaches are emerging with
prevalence of 29.2% in males and 24.8% in new targeted therapies, in Phase 1/2 clinical trials
females (Chobanian et al. 2003). There are a num- (Lobo et al. 2017).
ber of important factors that lead to high incidence
of hypertension, including obesity, excess sodium Atherosclerosis
intake in food, reduced physical activity, inade- Atherosclerosis is a multifactorial pathological
quate intake of fruits, vegetables, and potassium, condition affecting small and large sized arteries,
and excess alcohol intake. characterized by accumulation of cholesterol-
Hypertension is the most common risk factor containing lipoproteins, particularly low-density
for death throughout the world, associated with a lipoprotein, and fibrous elements formed within
significant increase in the risk of coronary artery the intimal layer of vessels (Fig. 5). Inflammation
disease, stroke, and chronic kidney disease. Mor- is an integrative factor and can operate in all
bidity and mortality associated with hypertension stages of the disease from initiation through pro-
are a major health challenge in the twenty-first gression and thrombotic complications at the final
century. Most patients with hypertension have stage. Endothelial cell dysfunction is an initial
essential hypertension or well-known forms of step in atherosclerotic lesion formation and is
secondary hypertension, such as renal disease, more likely to occur at arterial curves and
renal artery stenosis, obstructive sleep apnea, or branches that are subjected to low shear stress
common endocrine diseases (hyperaldosteronism and disturbed blood flow (Fig. 6). Activated endo-
or pheochromocytoma). Different and multiple thelial cells increase their expression of various
drug modalities and strategies are available for leukocyte adhesion molecules, through which
patients with hypertension. One of the major monocytes penetrate into the inner layer of arter-
problems is the non-adherence to antihyperten- ies and initiate an atherosclerotic lesion. Macro-
sive drug therapy, which is caused in part by phages then induce a cascade of events that cause
drug intolerance due to side effects. For these foam cell formation. Foam cells contain choles-
patients, a novel class of interventional proce- terol and characterize the first step of atheroscle-
dures to manage hypertension has emerged with rotic lesions. Macrophages secrete many growth
new technologies, such as renal sympathetic factors and activate cytokines involved in lesion
denervation, Baroreflex activation or amplifica- progression (Libby et al. 2013). Moreover, self-
tion therapy, central iliac arterio-venous anasto- and non-self-antigens, such as apolipoprotein
mosis, carotid body ablation, deep brain B-100 and heat shock proteins, can contribute to
Fig. 5 Pathological
specimen comprising open
bifurcations of both
common carotid arteries
with mild irregular
elevations of the artery
lining and severe narrowing
and ulceration (black
arrows) of one internal
carotid artery. (Image
courtesy of the Harry
Brookes Allen Museum of
Anatomy and Pathology,
The University of
Melbourne, Carlton VIC,
Australia)
Table 7 Criteria to define metabolic syndrome. (Adapted

from Grundy 2005)
At least three of the following:
Waist circumference 102 cm (men), 88 cm (women)
or diagnosed type 2 diabetes
Triglycerides 1.7 mmol/L or specific treatment for
hypertriglyceridemia
High density lipoprotein cholesterol <1.03 mmol/L in
men, < 1.3 mmol/L in women or specific treatment
Systolic blood pressure 130 mmHg or diastolic blood
pressure 85 mmHg or drug treatment for hypertension
Fasting plasma glucose 5.6 mmol/L
Fig. 6 Photomicrograph of a histopathology specimen of problem with no differences noted between males
thrombosis of the heart wall (black arrows) showing a
characteristic inflammatory reaction. Hematoxylin and and females: one fourth of the adult European
eosin stain. (Image courtesy of Professor Camile Farah, population is estimated to have it, with a similar
UWA Dental School, University of Western Australia, prevalence in Latin America (Padwal 2014). It is
Perth WA, Australia) also considered an emerging problem in develop-
ing East Asian countries. Table 7 summarizes the
vascular inflammation by triggering the response most recent criteria to define MS, and it is diag-
of T and B cells, locally. This process can influ- nosed when a patient has at least 3 of the 5 condi-
ence the initiation, progression, and stability of tions described. Risk factors for metabolic
plaques. Major clinical manifestations of athero- syndrome include family history, diet, and life-
sclerosis include ischemic heart disease, ischemic style. MS is associated with fatty liver, resulting
stroke, and peripheral arterial disease. The major in inflammation and potential cirrhosis, kidney
risk factors for atherosclerosis include smoking, damage, and sleep apnea. The goal of treatment
hypertension, dyslipidemia, diabetes mellitus, is to reduce the risk of coronary heart disease,
chronic kidney disease, obesity, physical inactiv- lowering low density lipoprotein cholesterol and
ity, and poor diet. Changes to lifestyle and appro- hypertension, and managing diabetes (if these
priate antihyperlipidemia treatment are conditions are present). It is imperative to add
responsible for dramatic declines in vascular mor- lifestyle changes, including healthy diet, optimal
tality rates in high-income countries over the last weight, physical activity, and smoking cessation.
60 years.
Disorders of Rhythm
Metabolic Syndrome
A rhythm disorder or arrhythmia is an abnormal
Metabolic syndrome (MS), also called insulin variation of the normal heartbeat; it can involve
resistance syndrome, is an important risk factor abnormalities of heart rate, irregularity of beats,
for the development of cardiovascular diseases sites where electrical impulses originate, or
and type II diabetes; it is established as the com- sequence of activation of heartbeats. To under-
bination of obesity (especially on the abdomen) stand arrhythmias, it is imperative to understand
and different metabolic disturbances, such as the heart’s internal electrical system, but this is
insulin resistance, hypertension, dyslipidemia, beyond the scope of this chapter. Blood circula-
and endothelial dysfunction (Padwal 2014). tion is the result of the beating of the heart, which
Cross-sectional surveys indicate that in the USA, provides the mechanical force to pump oxygen-
one-third of adults and an alarming proportion of ated blood to, and deoxygenated blood away
children have MS (Padwal 2014). It is a global from, peripheral tissues. This depends critically
on the preceding electrical activation. Disruptions lightheadedness, rapid heartbeat, shortness of

in the orderly pattern of this propagating cardiac breath, neck fullness, chest discomfort/pain, nau-
excitation wave can lead to arrhythmias. Arrhyth- sea, diaphoresis, syncope, collapse, and sudden
mias may be completely harmless or life threaten- cardiac arrest. Diagnosis is based on medical and
ing. There are hundreds of different types of family histories, a physical examination (listening
cardiac arrhythmias. Even if benign cardiac of heart rate, rhythm, murmur, check legs/feet
arrhythmias are common, statistics from the Cen- swelling or signs of other related-diseases like thy-
ters for Disease Control and Prevention have esti- roid disease, etc.) and the results from tests and
mated sudden cardiac death rates at more than procedures (electrocardiogram, holter monitor
600,000 per year; up to 50% of patients suffer records, echocardiography, blood tests, chest
sudden death as the first manifestation of cardiac X-ray). In selected cases, specialists request an
disease (Zheng et al. 2002). Congenital heart electrophysiology study where they electrically
defects, lifestyle (tobacco, alcohol, diet, excessive stimulate the heart and trigger an arrhythmia.
caffeine), drugs (cocaine or amphetamines), and The management of arrhythmias is very com-
strong emotional stress, can lead to arrhythmias. plex and is focused on preventing blood clots to
Sometimes the cause of arrhythmias is unknown. reduce stroke risk, control heart rate, restore a nor-
In line with the guidelines of the American Heart mal heart rhythm, treat heart disease/condition that
Association, in general terms, a fast heart rate may be causing arrhythmia, and reduce other risk
(in adults, more than 100 beats per minute) is factors for heart disease and stroke. It can include
called tachycardia, while a slow heart rate (less the use of medications (antiarrhythmic drugs, cal-
than 60 beats per minute) is referred to as brady- cium channel blockers, beta blockers, anticoagu-
cardia. Specifically, the four main types of lants), vagal maneuvers, cardioversion, catheter
arrhythmia are premature (extra) beats, supraven- ablation, implantable devices such as pacemaker,
tricular arrhythmias (atrial fibrillation, atrial flut- cardioverter defibrillator, and surgical treatments.
ter, paroxysmal supraventricular tachycardia, and The artificial pacemaker is an electronic implant-
Wolff-Parkinson-White syndrome), ventricular able device, temporary or permanent, placed under
arrhythmias (ventricular tachycardia and ventric- the skin near the collarbone in a minor surgical
ular fibrillation), and bradyarrhythmias, further procedure, with wires that connect electrodes at
divided in sinus node dysfunction (sinus brady- their tips. Pacemakers can be used both in selected
cardia, sinus pauses or arrest) and atrioventricular patients affected by bradycardia and tachycardia
conduction disturbances or blocks (first-, second- and also coordinate electrical signaling between
type I and II, or third-degree) (Fig. 7). A peculiar the upper and lower chambers of the heart.
disorder of rhythm is the sinus node dysfunction,
characterized by dysfunction of the sino-atrial
node, the “natural” pacemaker that sends electri- Valvular Heart Disease
cal impulses to the heart in order to set the heart
rhythm. This alteration leads to the inability of the Valvular heart disease (VHD) encompasses a
sino-atrial node to generate a heart rate commen- number of common cardiovascular conditions
surate with the physiologic needs of an individual. that account for 10–20% of all cardiac surgical
Sinus node dysfunction can include sinus brady- procedures in the United States with a prevalence
cardia, alternating bradycardia and atrial tachyar- estimated to be approximately 2.5% in the 1990s,
rhythmias (bradycardia-tachycardia syndrome), but currently it is thought to be increasing because
sinus pause or arrest, sinoatrial block (Epstein of more accurate diagnostic methods and aging
et al. 2013). Many arrhythmias cause no signs of the population (Maganti et al. 2010). It is
or symptoms, and when they are present, there characterized by damage to, or a defect in, one
is a broad range of variation from simple of the four heart valves: the mitral, aortic, tricus-
palpitation to sudden cardiac death. The more seri- pid, or pulmonary (Maganti et al. 2010) that can
ous signs and symptoms are: fatigue, dizziness, lead to valvular stenosis and valvular
Fig. 7 ECG rhythm stripes. (From https://ecg-educator.blogspot.it/2016/11/ecg-rhythm-strips.html)
insufficiency (regurgitation). Valvular stenosis is syndrome; (c) myocardial dysfunction-ischemic

characterized by different degrees of narrowing of cardiomyopathy; (d) diseases and disorders of
the valvular orifice that prevents adequate outflow other organs as causes of VHD, such as chronic
of blood; when the stenosis is mild, general func- renal failure; (e) aging related calcification;
tioning of the heart may not be reduced, but when (f) following surgical interventions such as
it is severe, heart function is reduced leading to valvuloplasty, valve reconstructive surgery and
valvular insufficiency. Classification of VHD can valve replacement; (g) related to drugs and phys-
be categorized based upon the etiology: ical agents, such as chronic ergotamine use, radi-
(a) heritable-congenital causes (e.g., atresia, ste- ation therapy, and trauma. In clinical practice, the
nosis, malposition, abnormalities of valve most common causes of mitral regurgitation are
structure-bicuspid valves, the Marfan syndrome); floppy mitral valve with mitral valve prolapse,
(b) inflammatory-immunologic causes, such as ischemic heart disease, dilated cardiomyopathy,
rheumatic fever, acquired immune deficiency and mitral annular calcification, while the most
Fig. 8 Photomicrograph of a histopathology specimen Hematoxylin and eosin stain. (Images courtesy of Profes-
of bacterial endocarditis (a; 20) showing whole of the sor Camile Farah, UWA Dental School, University of
cardiac wall and (b; 100) showing bacterial colonies Western Australia, Perth WA, Australia)
(black arrows) on the endocardium with inflammation.
common cause of mitral stenosis is rheumatic indwelling cardiac device with an annual inci-
fever. The most common valvular lesions in clin- dence ranging from 3 to 7 per 100,000 person-
ical settings are mitral stenosis and aortic stenosis years in the most contemporary population sur-
(Herrera 2018). veys (Murdoch et al. 2009). Staphylococcus
Some patients with VHD may not experience aureus is now the most common causative organ-
symptoms for many years; the most common ism in most of the industrialized world (Fig. 8).
symptoms include fatigue, shortness of breath, Characteristics of IE patients have changed over
edema of lower extremities, dizziness, fainting, time and now there is an increased mean patient
and irregular heartbeat. The final diagnosis is age, with a higher proportion of prosthetic valves
made by a combination of physical examination and other cardiac devices, and a decreasing pro-
(heart murmur), echocardiography, electrocardio- portion of rheumatic heart disease. Though there
gram, chest x-ray, and in special situations cardiac have been no randomized controlled trials that
MRI, stress tests, and cardiac catheterization to prove the effectiveness of IE prophylaxis at the
obtain more detailed diagnostic information. time of dental, gastrointestinal, or genito-urinary
Aside from antibiotic prophylaxis in patients procedures, it has been common practice since the
with infective endocarditis and the use of direct 1950s. The most recent practice guidelines from
oral anticoagulants in patients with atrial fibrilla- the National Institute for Health and Care Excel-
tion and heart valve disease, very little medical lence (National Institute of Clinical Excellence
therapy is available for patients with VHD. Sur- 2008) and its next amendment in 2016 (Thornhill
gery is the treatment for most symptomatic lesions et al. 2016) and the task force for the management
or for lesions causing left ventricular dysfunction of IE of the European Society of Cardiology
even in the absence of symptoms, such as trans- (ESC) (Habib et al. 2015), published in 2015,
catheter aortic valve replacement. represent the outcome of major reviews of the
prevention, diagnosis, and management of
IE. They represent the most up-to-date interna-
Infective Endocarditis tional guidance on antibiotic prophylaxis to pre-
vent infective endocarditis. In line with these
Infective endocarditis (IE) occurs worldwide and recommendations, antibiotic prophylaxis is
is defined by infection of a native or prosthetic recommended for patients at highest risk of IE
heart valve, the endocardial surface, or an undergoing a high risk procedure but not
“routinely” for people undergoing dental Anticoagulant Therapies

(or other) procedures, indicating that antibiotic
prophylaxis may be appropriate in individual Anticoagulants are broadly divided into 2 groups:
cases. (a) drugs with rapid activity, parenteral (heparin,
High-risk patients are considered those with: indirect factor Xa Inhibitors); and (b) drugs with
(a) acquired valvular heart disease with stenosis or slow activity, oral (coumarine derivatives, warfa-
regurgitation; (b) valve replacement; (c) structural rin, indandione derivatives, direct thrombin inhib-
congenital heart disease, including surgically itors). In emergency or for long-term therapies,
corrected or palliated structural conditions, but anticoagulants are prescribed in the following
excluding isolated atrial septal defect, fully conditions: atrial fibrillation, deep vein thrombo-
repaired ventricular septal defect or fully repaired sis, cerebral venous thrombosis, stroke, pulmo-
patent ductus arteriosus, and closure devices that nary thromboembolism, unstable angina, and
are judged to be endothelialized; (d) previous myocardial infarction. Where there is no urgency,
infective endocarditis; and (e) hypertrophic treatment is often started with an oral anticoagu-
cardiomyopathy. lant alone for patients with prosthetic valves.
High-risk procedures for which antibiotic pro- When anticoagulation is needed for brief periods,
phylaxis should be considered are dental proce- heparin alone is used such as in cases of cardiac
dures requiring manipulation of the gingival or bypass surgery or hemodialysis. Warfarin acts by
periapical region of the teeth or perforation of preventing maturation of vitamin K dependent
the oral mucosa (including scaling and root canal clotting factors (VII, IX, X, and prothrombin),
procedures). Antibiotic prophylaxis is not while heparin potentiates action of antithrombin-
recommended for local anesthetic injections in III. Laboratory tests to monitor anticoagulant
noninfected tissues, treatment of superficial car- activity are: (a) Partial Thromboblastin Time
ies, removal of sutures, dental x-rays, placement (PTT) in heparin therapy that is maintained at
or adjustment of removable prosthodontic or 1.5–2 times the normal value (normal value:
orthodontic appliances or braces or following the 33–45 s); (b) Prothrombin Time (PT) in Warfarin,
shedding of deciduous teeth or trauma to the lips that is maintained at 1.5–3 times the control value
and oral mucosa. In respiratory (including bron- (12–14 s). The INR (international normalized
choscopy or laryngoscopy, or transnasal or endo- ratio) was introduced in 1983 by the World Health
tracheal intubation), gastrointestinal or urogenital Organization (WHO) and has resulted in greater
(including gastroscopy, colonoscopy, cystoscopy, safety and effectiveness of oral anticoagulant
vaginal or caesarean delivery, or transesophageal treatment with warfarin and related drugs (normal
echocardiography) and skin procedures, antibiotic range two to three). Both PT and INR are assays
prophylaxis is not recommended. that evaluate the extrinsic pathway of coagulation,
The recommended antibiotic prophylaxis reg- while PTT measures the intrinsic and common
imen (for those not allergic to penicillin) is pathway. An INR check 72 h prior to dental sur-
amoxicillin 2 g (50 mg/kg in children) orally or gery is recommended in order to change the dose
i.v. 30–60 min before the procedure; alterna- and ensure a safe INR on the day surgery. Dental
tively, cephalexin 2 g i.v. for adults or 50 mg/ procedures with high or significant risk of bleed-
kg i.v. for children, cefazolin or ceftriaxone 1 g ing include extractions, local anesthesia by infe-
i.v. for adults or 50 mg/kg i.v. for children. In rior alveolar, or other regional nerve blocks or
case of allergy to penicillin or ampicillin, the first lingual/floor of mouth infiltrations, subgingival
choice is clindamycin 600 mg (20 mg/kg in scaling and root surface instrumentation, minor
children) orally or i.v. 30–60 min before the oral surgery (biopsies), periodontal surgery, and
procedure. Cephalosporins should not be used surgical endodontics. Surgery is strictly
in patients with anaphylaxis, angioedema, or contraindicated in patients with INR > 4, liver
urticaria after intake of penicillin or ampicillin impairment and/or chronic alcoholism, renal fail-
due to cross-sensitivity. ure, thrombocytopenia, and common inherited
bleeding disorders (hemophilia A, B, von evidence supports that the removal of the antico-
Willebrand Disease). agulant a few hours before the procedure appears
Unfractionated heparin and low molecular to be an adequate approach for decreasing
weight heparin are both administered parenterally bleeding associated with dental procedures and
with problems related to low compliance in that this does not increase the risk of thrombo-
patients unwilling or unable to self-administer, embolic events (Lanau et al. 2017). However,
and they are expensive for long-term use. Vitamin these authors also recommend that when dental
K antagonists, even if oral drugs, have a narrow procedures are performed without withdrawal
therapeutic window, an unpredictable pharmacol- of the drug, the bleeding is manageable with
ogy, and numerous food and drug interactions that conventional hemostasis measurements (Lanau
necessitate frequent, inconvenient, and costly et al. 2017). Finally, they consider that in patients
monitoring and dose adjustment to ensure their with complex issues, such as clinical character-
effect. Patients can remain under-anticoagulated istics predisposing to bleeding and complex
or over-anticoagulated, which places them and invasive dental procedures, an individual-
at increased risk for experiencing thromboem- ized approach with the consensus between
bolic events or bleeding, respectively (Ansell the dentist and the patient’s responsible
et al. 2004). physician should be undertaken (Lanau et al.
A new class of direct oral anticoagulant 2017) (Table 8).
(DOAC) drugs (dabigatran, rivaroxaban,
apixaban, and edoxaban) have emerged in the
last decade to overcome some of the drawbacks Cardiac Transplantation
of existing medications. These are nonpeptidic
small-molecules, orally bioavailable, that selec- Heart transplantation is the procedure by which
tively and specifically inhibit individual serine the failing heart is replaced with another heart
proteases within the coagulation cascade. from a suitable donor. The 1-year survival rate
Dabigatran acts on the thrombin inhibitor, while after cardiac transplantation is as high as 81.8%,
rivaroxaban, apixaban, and edoxaban act on the with a 5-year survival rate of 69.8%. A significant
factor Xa inhibitor. Due to this specific action and number of recipients survive more than 10 years
their short biological half-life, DOAC drugs show after the procedure.
different advantages compared to old anticoagu- Independent of the cause, heart transplant can-
lants namely: (a) predictability of response; (b) no didates are patients with advanced end-stage heart
need for constant monitoring of coagulation; failure when all organ conserving medical and
(c) administration at fixed doses with higher com- surgical treatment options have failed and they
pliance; (d) minimal drug interaction and no food are estimated to have less than 1 year to live
interaction; and (e) wide therapeutic margin (Lip without the transplant (Griepp and Ergin 1984).
et al. 2016). To date, data in the published litera- There are selection inclusion and exclusion
ture do not include clinical guidelines about the criteria with meticulous guidelines both for the
protocol to follow in patients on DOACs who donor and the recipient, but the complex group
need dental treatments. General agreement of details is beyond the scope of this chapter.
among cardiologists exists relating to minimum Evaluation of the heart transplant candidate
knowledge of the type of DOAC the patient is on, includes laboratory tests, imaging studies, and
the difficulty of dental procedures to be other tests as appropriate, such as biopsy. Post-
undertaken, and the risk of bleeding, embolism, transplant complications can include bleeding,
in addition to the patient’s renal function. rejection, infection, and allograft vascular disease.
The systematic review undertaken by Lanau Immunosuppression, started soon after surgery,
in 2017 concluded that DOACs are relatively has significantly reduced the incidence of cellular
safe drugs in terms of dental bleeding, and rejection and improved patient outcomes with
although there are no definitive guidelines, the routine use of calcineurin inhibitors.
Table 8 Comparison of newer direct oral anticoagulants with warfarin
Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban Fondaparinux
Administration Oral Oral Oral Oral Oral Subcutaneous
Dosing Individualized Fixed dose Fixed dose Fixed dose Fixed dose Fixed dose
– highly
variable
Onset of action 36–72 h 2–4 h 2–4 h 3–4 h 1–2 h 2h
Duration of 48–96 h 24–36 h 24 h 24–48 h 24 h
action
Elimination 20–60 h 14–17 h 5–13 h 9–13 h 10–14 h 17–20 h
Interface Between Oral and Systemic Disease
half-life
Interactions Many foods Possible interaction with drugs Systemic azole Systemic azole Verapamil Possible
and drugs that impair renal function antifungals antifungals (except Quinidine interaction with
systemic azole antifungals (except fluconazole) Dronedarone drugs that impair
(except fluconazole), fluconazole) HIV protease inhibitors Ketoconazole renal function
cyclosporin, dronedarone, HIV protease Erythromycin
tacrolimus, simultaneous inhibitors Protease inhibitors
initiation with verapamil Cyclosporine
Rifampin
Clearance / Hepatic Renal excretion Metabolic Metabolites with fecal Renal excretion (50%) Renal excretion
metabolism metabolism degradation clearance renal excretion Metabolic degradation (unmetabolized)
Fecal clearance biliary and intestinal Biliary and intestinal
Renal clearance clearance
excretion
Bleeding risk Significant Significant – not worse than warfarin or enoxaparin
Monitoring INR, usually Not required
fortnightly –
monthly once
stable
(continued)
83
84
Table 8 (continued)
Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban Fondaparinux
Tests to INR aPTT, ECT, TT, dTT PT, anti-FXa aPTT, anti-FXa activity Dilute Russell viper venom aPTT, anti-FXa
consider if activity time, thrombin generation activity
hemorrhage assay, PT, aPTT, anti-FXa
activity
Bridging Required due Not required
anticoagulation to initial
procoagulant
effect
Reversibility Fresh frozen Idarucizumab Cannot dialyze Aripazine
plasma Partial reversal with Cessation of drug
Prothrombin hemodialysis (60% after 2 h) Modified recombinant FXa (andexanet-alfa)
complex Cessation of drug Aripazine
concentrates Prothrombin complex Prothrombin concentrate complex?
Vitamin K concentrates? Recombinant FVIIa?
Recombinant FVIIa?
Anticoagulant Clinical trials – similar to warfarin at INR 2.0–3.0
equivalence Clinical trials – similar to warfarin at INR 2.0–3.0
Table courtesy of Dr Jacinta Vu, UWA Dental School, The University of Western Australia, Perth WA, Australia
References: AusDI (2018), Costantinides et al. (2016), Parasrampuria and Truitt (2016), Raimondi et al. (2017), Rose and Bar (2018), Stacy et al. (2016), Tornkvist et al. (2018),
and Tran et al. (2014)
M. D. Mignogna and S. Leuci
Several regimens can be used, including pre- fibrotic diseases, connective-tissue diseases,
transplantation induction therapy and simple post- drug-induced lung disease, sarcoidosis) and
operative maintenance therapy. extrinsic (neuromuscular disorders,
non-muscular diseases of the chest wall); and
(c) perfusion (i.e., pulmonary thromboembolism,
Oral Manifestations of Cardiovascular pulmonary hypertension).
Diseases
Pain in the orofacial region can occur during MI Asthma

and is described as “pressure” and/or a “burning”
sensation. This pain can occur in the throat, jaw, Asthma is one of the most common disorders in
temporomandibular joint, ear, and mandibular both children and adults. The number of people
molar teeth. Although this is classically described with asthma globally may be as high as 334 mil-
to occur on the left side, it can also occur on the lion, of which 14% are children (aged 10–14) and
right side. On occasion, this pain can be the only 8.6% young adults (aged 18–45) (Guy et al.
prodromal manifestation of MI. During the infarc- 2014). Asthma is a multifactorial disease process
tion, the patient’s lips, tongue, and mucous mem- that comprises a range of heterogeneous pheno-
branes can acquire a blue color due to central types that differ in presentation, etiology, and
cyanosis during cor pulmonale associated with pathophysiology, with genetic, allergic, environ-
increased jugular venous pressure. mental, infectious, emotional, and nutritional
Anticoagulant and antiplatelet therapy only components. Asthma is currently considered to
rarely cause oral manifestations occasionally be a group of different disorders characterized by
observed with minor trauma to the oral mucosa three major features: (1) intermittent and revers-
causing hemorrhagic lesions, such as petechiae, ible airway obstruction leading to recurrent epi-
purpura, ecchymosis, hemorrhagic bullae, and sodes of wheezing, breathlessness, chest
even hematoma formation. These are outlined in tightness, and cough; (2) broncho-hyper-respon-
separate chapter on ▶ “Oral Manifestations of siveness, which is defined as an increased sensi-
Systemic Diseases and Their Treatments.” tivity to bronchoconstrictors such as histamine or
Finally, patients who have undergone cardiac cholinergic agonists; and (3) airway inflamma-
transplantation have an increased risk of develop- tion. Inflammation plays a major role in the path-
ing orofacial diseases such as mucositis, peri- ogenesis with an abnormal or inadequately
odontal diseases, dental caries, angiogranuloma, regulated CD4 Th2 immune response to otherwise
drug-induced gingival overgrowth, hairy leuko- harmless environmental antigens. This aberrant
plakia, MALT lymphoma, and oral graft versus immunological response produces a series of
host disease. These oral manifestations are further pro-inflammatory cytokines that stimulate the
discussed in several chapters in this text, including growth, differentiation, and recruitment of mast
▶ “Oral Manifestations of Systemic Diseases and cells, basophils, eosinophils, and B-cells, all of
Their Treatments” and ▶ “Pharmacotherapeutic which are involved in humoral immunity and the
Approaches in Oral Medicine.” allergic response. In addition, antigens cross-link
with IgE on mast cells, with subsequent release of
histamine and leukotrienes that amplify the
Respiratory Diseases inflammatory response by damaging local tissue
and attracting other lymphocytes. Prenatal
A simple classification of diseases of the respi- risk factors include maternal lifestyle (tobacco,
ratory system encompasses three types: nutrition, stress, drugs) and delivery by cesarean
(a) obstructive (i.e., asthma, chronic obstructive section; childhood risk factors include allergic
pulmonary disease, bronchiectasis); sensitization, exposure to tobacco and animals,
(b) restrictive, divided into intrinsic (idiopathic lack of breastfeeding, decreased lung function,
Symptoms consistent with Asthma
Spirometry before and after bronchodilator

(if unavailable: peak flow monitoring, trial of therapy)
Spirometry results normal Spirometry results consistent with asthma

• Consider an alternative diagnosis and/or • Administer short-acting beta-agonist as
• Peak flow monitoring and/or needed to relieve symptoms.
• Bronchoprovocation challenge testing. • Commence anti-inflammatory therapy
• Introduction of treatment (appropriate only for (usually low-dose inhaled corticosteroids).
those with high likelihood of asthma; diagnostic • Look for triggers by history and occupational
confirmation should occur at some later date). exposure and consider allergy testing (skin
prick or radioallergosorbent testing.
• Consider comorbidities such as rhinitis and
gastroesophageal reflux disease.
Arrange follow-up to reassess diagnosis, control and treatment.
Fig. 9 Diagnostic algorithm of asthma. (Adapted from Kaplan et al. 2009)
family size and structure, socio-economic status, persistent respiratory symptoms and airflow limi-
antibiotics, infections, and gender. Asthma in tation that is due to airway and/or alveolar abnor-
adults may be derived from childhood or may be malities usually caused by significant exposure to
true adult-onset. In this case, the disease may have noxious particles or gases. The chronic airflow
environmental (especially occupational) causes or limitation is caused by a mixture of small airways
may develop in relation to specific drug treat- disease (e.g., obstructive bronchiolitis) and paren-
ments such as β-blockers, nonsteroidal anti- chymal destruction (emphysema) (Fig. 10), the
inflammatory drugs, or hormone replacement relative contributions of which vary from person
therapy (Wenzel 2006). Diagnosis of asthma is to person” (Global Strategy for Diagnosis 2017).
based on the combined presence of typical symp- COPD is common in the older population and is
toms and objective tests of lung function (Fig. 9). highly prevalent in those aged more than 75 years;
the global prevalence in adults aged 40 years is
approximately 9–10% (Halbert et al. 2006). The
Chronic Obstructive Pulmonary development of COPD is multifactorial and the
Disease risk factors of COPD include genetic (alpha1-
antitrypsin deficiency and different loci associated
Globally, chronic obstructive pulmonary disease with COPD susceptibility) and environmental fac-
(COPD) is a major cause of significant morbidity tors (tobacco, outdoor air pollution, occupational
and mortality and is now the third leading cause of exposure to dust and fumes, biomass smoke inha-
death in the United States. The Global Initiative lation, exposure to second-hand smoke and previ-
for Chronic Obstructive Lung Disease (GOLD) ous tuberculosis). Pathologic changes occur in the
recently defined COPD as “a common, prevent- large (central) airways, the small (peripheral)
able and treatable disease characterized by bronchioles, and the lung parenchyma with
Fig. 10 Photomicrograph of a histopathology specimen matter (black arrows) interspersed throughout. Hematoxy-
of emphysema (a; 20) showing the loss of normal struc- lin and eosin stain. (Images courtesy of Professor Camile
ture of the lung and (b; 100) showing individual alveoli Farah, UWA Dental School, University of Western
filled with edema, inflammation and foreign particulate Australia, Perth WA, Australia)
associated abnormal inflammatory response in the ‘wheezing’ on lung auscultation), spirometry, and
lungs, which may result in mucous hypersecretion additional lung function assessment can be help-
(chronic bronchitis), tissue destruction (emphy- ful in the diagnostic work-up for COPD. Cough,
sema), and disruption of normal repair and wheeze, phlegm, and shortness of breath on exer-
defense mechanisms causing small airway inflam- tion have diagnostic value as major and common
mation and fibrosis (bronchiolitis). These patho- symptoms for COPD, especially if chronic (longer
logical changes result in progressive airflow than 3 months) or recurrent. Clinical features that
obstruction. Two other processes are involved in should be considered in the differential diagnosis
the pathogenesis of COPD – an imbalance between asthma and COPD are described in
between proteases and antiproteases and an Table 9.
imbalance between oxidants and antioxidants
(oxidative stress) in the lungs. Oxidative metabo-
lism is over-activated in COPD (Rahman et al. Oral Manifestations of Respiratory
2006), where the major source of oxidants is Diseases
represented by cigarette smoke and the major
antioxidants are represented by the glutathione The association of asthma with oral conditions
system and the hemoxygenase (HO)-1 pathway. such as dental caries, dental erosion, periodontal
Gas exchange abnormalities and pulmonary diseases, and oral candidosis has been the subject
hypertension occur in advanced disease; structural of debate for a considerable time. The role of an
changes in the pulmonary arterioles result in per- oral acidic environment, either related to asthma
sistent pulmonary hypertension and right ventric- medication, associated gastroesophageal reflux,
ular hypertrophy or enlargement and dysfunction or salivary hypofunction, in the development of
(cor pulmonale). Patients with severe COPD can these oral manifestations is thought to be key and
show systemic signs as skeletal muscle atrophy, has been reviewed with the suggestion that simply
normochromic normocytic anemia, osteoporosis, prophylactic measures can diminish these effects
cardiovascular disease, and depression. The sum (Thomas et al. 2010).
of history taking (tobacco, low birth weight, In a recent study assessing 100 patients with
asthma, respiratory tract infections including COPD, 61% reported the perception of oral dry-
tuberculosis and a family history of COPD), phys- ness, while only 16% had measureable
ical examination (diminished breath sounds and unstimulated salivary hypofunction and 9%
Table 9 Clinical differences in the differential diagnosis reproductive organs (ovaries and testes). The pan-
between asthma and COPD. (Adapted from Pinnock 2004) creas is also part of this system; it has a role in
Feature COPD Asthma hormone production as well as in digestion. These
Smoker or ex-smoker Nearly all Possibly glands produce different types of hormones that
Symptoms before Rare Often evoke a specific response in other cells, tissues,
35 years and/or organs located throughout the body. This
Chronic productive Common Uncommon
complex group of glands communicates through
cough
Breathlessness Persistent Variable
many feedback mechanisms that ensure correct
and hormonal balance in the body. Common endo-
progressive crine disorders include diabetes mellitus,
Nighttime walking with Uncommon Common acromegaly (overproduction of growth hormone),
breathlessness and/or Addison’s disease (decreased production of
wheeze
hormones by the adrenal glands), Cushing’s syn-
Substantial diurnal or Uncommon Common
day-to-day variability of drome (high cortisol levels for extended periods
symptoms of time), Graves’ disease (excessive thyroid
hormone production), Hashimoto’s thyroiditis
(autoimmune disease resulting in hypothyroid-
measurable stimulated salivary hypofunction ism), hyperthyroidism (overactive thyroid),
(Saltnes et al. 2014). Further, although the major- hypothyroidism (underactive thyroid), and hyper-
ity (68%) attended the dentist regularly, and 72% prolactinemia (overproduction of prolactin by the
had seen a dentist in the previous year, 39% still pituitary gland). These disorders often have
reported oral health problems such as pain, widespread symptoms, affect multiple parts of
chewing difficulties or esthetic problems (Saltnes the body, and can range in severity from mild to
et al. 2014). very severe.
Finally, treatment of sleep apnea with the use
of an oral appliance usually can have only minor
side effects with most being transient. As Diabetes
discussed in the chapter ▶ “Oral Appliance Ther-
apy for Sleep-Disordered Breathing,” problematic Worldwide the most common endocrine disorder
side effects such as jaw pain and occlusal alter- is diabetes mellitus (DM), a group of disorders
ations require close attention, but usually can be associated with an elevation of glucose concen-
managed, especially if identified early. Unfortu- tration in the blood (hyperglycemia). The global
nately, there is no one single reliable method to prevalence of diabetes is increasing due to factors
predict who will definitely succeed with oral such as population growth, aging, urbanization,
appliance therapy for sleep apnea. and increased prevalence of obesity and physical
inactivity. It is associated with several micro- and
macrovascular complications and is also a leading
Endocrine Disorders cause of morbidity and mortality, including
nephropathy (leading to end-stage renal disease),
The endocrine system is a network of glands that retinopathy (leading to blindness), heart disease
produce and release hormones that help control (leading to MI and stroke), various neurological
many important body functions: growth and disorders, and poor wound healing. In brief, it
development, metabolism (digestion, elimination, results from a reduction in the production of the
breathing, blood circulation, and maintaining major anabolic peptide hormone insulin by the β
body temperature), sexual function reproduction, cells of the pancreas, or a decrease in the respon-
and mood. The major glands of the endocrine siveness of the insulin receptors on cell surfaces to
system are the hypothalamus, pituitary, thyroid, the action of insulin (Maritim et al. 2003). The
parathyroids, adrenals, pineal body, and the balance between insulin action and the effects of
the counter-regulatory hormones (glucagon, cor- T2DM is characterized by multiple defects in

tisol, epinephrine, and norepinephrine) ensures both insulin action and insulin secretion. Both
normal glucose homeostasis. insulin’s inhibitory effect on liver glucose produc-
DM can be classified in different ways, but one tion and its stimulatory effect on peripheral glu-
form of classification is according to the American cose uptake are diminished. Most T2DM patients
Diabetes Association (2004): are obese, which lead to the finding that obesity is
associated with diminished insulin action both in
• Type I diabetes (T1DM, insulin dependent) is the liver and in the periphery. This association is
due to immune mediated B-cell destruction, probably the result of multiple mechanisms,
leading to insulin deficiency (about 10% of including elevation in plasma free fatty acids and
all diabetes patients). tumor necrosis factor released from adipocytes
• Idiopathic diabetes is type 1 diabetes with no (Coope et al. 2016).
known etiology and is strongly inherited. The World Health Organization (WHO) clas-
• Type II diabetes (T2DM, non-insulin depen- sifies hyperglycemia first identified in pregnancy
dent) is due to insulin secretory defect and as: (1) diabetes mellitus in pregnancy and
insulin resistance (about 80% of all diabetes (2) GDM (WHO 2013). GDM generally refers to
patients). milder hyperglycemia and lesser degree of glu-
• Gestational diabetes mellitus (GDM) is any cose intolerance occurring in the latter half of
form of intolerance to glucose with onset or pregnancy, which usually does not persist after
first recognition of pregnancy. delivery in most patients. Women with DM who
become pregnant have more severe complications
Both T1DM and T2DM show familial predis- compared to pregnant women with GDM. GDM
position, which is a strong indication for the carries a small but potentially important risk of
involvement of genes in susceptibility to the adverse perinatal outcomes (such as preeclamp-
disease. However, the etiology underlying sia, premature rupture of membranes, and caesar-
types 1 and 2 is different, and different genes ean section) and a longer-term risk of obesity and
are likely to be involved in each type of DM. In glucose intolerance in offspring. Mothers with
general, the major classic findings of hypergly- GDM have an excess of hypertensive disorders
cemia are polyuria, polydipsia, polyphagia, during pregnancy and a high risk of diabetes
weight loss, and fatigue. Ketoacidosis may mellitus thereafter. Hyperglycemia tends to
develop rapidly and lower the pH of blood, lead- develop in the second trimester and is seen in
ing to coma and death. 5–10% of women who have not had a previous
T1DM is an autoimmune disorder, where diagnosis of DM (Veeraswamy et al. 2012). The
autoantibodies progressively destroy pancreatic following tests can be used for diagnosis: A1C
β cells creating insulin deficiency in the body. test, also called the hemoglobin A1c, HbA1c, or
The exact etiology of T1DM is currently glycohemoglobin test, fasting plasma glucose
unknown; however, several factors may be (FPG) test, and oral glucose tolerance test
responsible such as genes (e.g., human leukocyte (OGTT) (Table 10). The goals in caring for
antigen class II alleles, PTPN22, IL2RA, and patients with DM are to eliminate symptoms and
CTLA-4), viruses (e.g., Coxsackie B virus, to prevent, or at least slow, the development of
Rubella virus, Epstein-Barr Virus, and cytomeg- complications, through medications and dietary
alovirus), and environmental factors (e.g., zinc and exercise modifications.
and magnesium). An increased risk of T1DM
seems due to cow’s milk in genetically suscepti-
ble individuals (Haller et al. 2005). The onset of Diseases of the Adrenal Glands
signs and symptoms of T1DM is relatively
abrupt and usually occurs at a young age, Located at the top of each kidney, the adrenal
although it may occur at any age. glands produce hormones that help the body
control blood sugar, burn protein and fat, react to trigger the “fight or flight” response increasing
stressors like a major illness or injury, and regulate heart rate and blood flow to the muscles; aldo-
blood pressure. The adrenal glands are vital in sterone acts on the kidneys regulating the Na+
the body’s response to environmental stress. and K+ balance and extracellular fluid volume, to
Each gland consists of two functionally distinct maintain blood pressure; and adrenal androgens
portions: the cortex and the medulla. The adrenal promote the development of secondary male
cortex consists of three concentric zones that sexual characteristics. Glucocorticoids and min-
secrete mineralocorticoids such as aldosterone, eralocorticoids are essential for survival, but the
glucocorticoids such as cortisol, and androgens adrenal androgens play only a minor role in
chiefly dehydroepiandrosterone (DHEA). The reproductive function.
adrenal medulla is part of the sympathetic nervous The main disorders of the adrenal cortex
system and produces the catecholamine, epineph- encompass: primary hyperaldosteronism, primary
rine (Fig. 11). hypoaldosteronism, hypercortisolism (Cushing’s
Adrenal disorders can be caused by increased Syndrome), congenital adrenal hyperplasia, adre-
or decreased hormones. Cortisol helps the body nal insufficiency (Addison’s disease), and
to adapt to physical and emotional stress by adrenogenital syndrome (androgen excess).
boosting blood glucose level and helps to regu- Pathology within the adrenal medulla and the
late protein and fat metabolism; epinephrine autonomic nervous system is primarily a result of
(adrenaline) and norepinephrine (noradrenaline) neoplasms. The most common tumor is pheochro-
mocytoma located in the adrenal medulla, origi-
Table 10 Blood test levels for diagnosis of diabetes and nating from chromaffin cells and excretes
prediabetes. (Adapted from American Diabetes Associa- catecholamines, but when located in extra-adrenal
tion 2016) chromaffin cells is known as paraganglioma.
Fasting
glucose Oral glucose Cushing’s Syndrome
A1C plasma tolerance test Endogenous Cushing’s syndrome is a rare disor-
(%) mg/dl mg/dl
der that results from prolonged and pathological
Diabetes 6.5 or 126 or 200 or above
above above exposure to excess glucocorticoids. The incidence
Prediabetes 5.7–6.4 100 to 25 140–199 varies depending on the population studied from
Normal About 5 99 or below 139 or below 1 to 2 cases per million population per year
For all three tests, within the prediabetes range, the higher (Lindholm et al. 2001). Iatrogenic (exogenous)
the test result, the greater the risk of diabetes Cushing’s syndrome caused by the administration
Tissue Area Hormones released Examples

Zona glomerulosa Mineralocorticoids
Connective Aldosterone
(adrenal complex) (regulate mineral balance)
Cortex Tissue capsule
Medulla • Cortisol
Zona fasciculata Glucocorticoids
• Corticosterone
(adrenal complex) (regulate glucose metabolism)
Superior surface • Cortisone
of kidney
Zona reticularis Androgens Dehydroepian-

(adrenal complex) (stimulate masculinization) drosterone
Stress hormones • Epinephrine

Adrenal medulla
(stimulate sympathetic ANS) • Norepinephrine
Fig. 11 Adrenal gland hormone secretion

of supra-physiologic doses of glucocorticoids is Table 11 Signs and symptoms of Cushing’s syndrome

much more common (although under-reported) Hypertension
than endogenous causes. Adipose
Endogenous Cushing’s syndrome can be Weight gain
divided into adrenocorticotropin (ACTH)- Increased centripetal, supraclavicular, temporal,
and/or dorsocervical fat
dependent and independent forms. ACTH-
Skin
independent Cushing’s syndrome (15%) results Hirsutism
from increased autonomous production of Striae (especially >1 cm diameter and purple)
cortisol from adrenal tumors (adenoma or Easy bruising
Plethora
carcinoma) or hyperplasia. The ACTH-
Reproductive system
dependent form of the disease includes ACTH Menstrual irregularity
production from pituitary adenoma (70%) or Amenorrhea
other tumors (ectopic 15%) and rarely, cortico- Decreased libido
tropin-releasing hormone (CRH)-producing Psychiatric and cognitive
tumors such as medullary thyroid carcinoma Depression
Emotional lability
and neuroendocrine pancreatic tumor (Nieman Irritability
and Ilias 2005). Decreased memory
The normal hypothalamic-pituitary-adrenal Decreased concentration
(HPA) axis exhibits a circadian rhythm. Clinical Skeleton and muscle
manifestations of hypercortisolism are the Proximal muscle weakness
Reduced bone mineral density
result of an altered rhythm (quality) and excess Fractures
cortisol load (quantum). Cushing’s syndrome Metabolism
is associated with severe morbidities and an Impaired glucose tolerance
increased mortality. The major systemic Diabetes
complications and the main cause of death are
represented by cardiovascular disease. Hyper-
cortisolism has a broad spectrum of manifesta- Diseases of Parathyroid Glands
tions (Table 11); these are variably present in any
given patient and can differ in a cyclic way, Parathyroid glands are four small endocrine
causing diagnostic difficulty (Sharma and glands located behind the thyroid and control
Nieman 2011). the homeostasis and balance of calcium and
Initial diagnosis is performed using 24-h uri- phosphorous in blood and bones through the
nary free cortisol, low-dose dexamethasone production of parathyroid hormone (PTH) and
tests, salivary cortisol, or night-time plasma cor- calcitonin (produced by the thyroid gland).
tisol values. Biochemical investigations cannot PTH is a polypeptide containing 84 amino
absolutely distinguish pituitary from ectopic acids that is a prohormone; effective hormone-
sources of ACTH, and therefore, body CT scan- receptor interaction requires solely the 34-N-ter-
ning and percatheter venous sampling are essen- minal amino acids. The major target end organs
tial diagnostic investigations. The treatment of for PTH action are the kidneys, skeletal system,
the disease remains a considerable challenge. and intestine in general. Secretion of PTH serves
Tumor localization may result in resection and to increase blood calcium and decrease phosphate
complete cure, although even small tumors may concentrations, which varies inversely with blood
have malignant potential or recurrences. Medical calcium concentration. PTH action on the bones
therapy with steroidogenesis inhibitors such as can have a rapid or slow effect; in the first case, it
metyrapone or ketoconazole, in association or acts on osteocytes to rapidly release exchangeable
with radiotherapy, may be indicated in patients bone salts increasing extracellular calcium and
with severe hypercortisolism or if surgery is not phosphate levels within minutes, in the second
possible. case it activates osteoclasts and promotes
Decreased serum
calcium
Increased serum calcium
Parathyroid
glands
Bone
Increased bone resorption

Parathyroid hormone
Kidney
Increased calcium reabsorption
Increased calcium
absorption in the
gastrointestinal tract.
Negative feedback/
decreased activity
Positive feedback/
Intestine stimulation
Fig. 12 Parathyroid hormone (PTH) is secreted form the bones, increase absorption of Ca2+ in the intestines, and
parathyroid glands in response to low blood serum calcium increase reabsorption of Ca2+ from the kidneys
levels. PTH will act to increase resorption of Ca2+ from the
development of new osteoclasts to resorb evaluation of serum electrolyte levels. This alter-
hydroxyapatite and release calcium and phos- ation can be derived from an intrinsic abnormal
phate into the extracellular fluid within days to change altering excretion of PTH (primary or
months. The effects of PTH on kidneys are real- tertiary hyperparathyroidism) or from an extrinsic
ized through its action on the late distal tubule and abnormal change affecting calcium homoeostasis
collecting ducts to enhance resorption of tubular stimulating production of PTH (secondary hyper-
calcium and to increase urinary excretion of phos- parathyroidism). Primary hyperparathyroidism is
phate. Finally, PTH indirectly induces higher a relatively common endocrine disorder, with
Vitamin D levels and biosynthesis (Fig. 12). prevalence estimates of 1–7 cases per 1000 adults
Parathyroid disorders are usually classified (Adami et al. 2002). Secondary hyperparathyroid-
into three groups: (i) hyperparathyroidism, ism is most commonly associated with chronic
(ii) hypoparathyroidism, and (iii) parathyroid can- kidney disease or vitamin D deficiency (which
cer, commonly presenting with serum calcium may arise from malabsorption syndromes or
abnormalities. chronic lack of exposure to sunlight); estimates
report that as many as 90% of patients with kidney
Hyperparathyroidism disease develop secondary hyperparathyroidism
Hyperparathyroidism is due to increased activity by the time hemodialysis is initiated (Memmos
of the parathyroid glands with an unregulated et al. 1982). Tertiary hyperparathyroidism occurs
overproduction of PTH resulting in hypercalce- most commonly in the setting of renal transplan-
mia, often discovered incidentally during tation where up to 30% of patients with secondary
disease continue to have elevated PTH levels after Ovaries are located on both sides of the uterus
receiving a renal allograft. below the opening of the fallopian tubes. They
Exceptionally in symptomatic patients, a diag- produce estrogen and progesterone, the two major
nosis can be established on the basis of clinical hormones that affect many of the female charac-
data. Normal calcium level is 2.3–2.7 mmol/l; teristics and reproductive functions. Testes are
mild hypercalcemia (calcium 3 < mmol/l) is egg-shaped organs located in the scrotum outside
asymptomatic, but severe hypercalcemia can the male body. They produce testosterone, which
show different signs and symptoms including affects many of the male characteristics and sperm
(a) general such as tiredness, malaise, dehydra- production. Women synthesize most of their
tion, and depression; (b) renal such as renal colic estrogen in their ovaries and other reproductive
from stones, polyurea, hematuria, and hyperten- tissues. Since men lack this female anatomy, they
sion; (c) bone such as pain, cyst, Brown tumors need to produce estrogen through a process
(due to osteoclastic activity); and (d) abdominal involving an enzyme called aromatase that trans-
pain, chondrocalcinosis and atopic calcification, forms testosterone into estradiol. In women, tes-
and corneal calcification. tosterone is produced in various locations:
Hyperparathyroidism must always be evalu- ovaries, adrenal glands, and peripheral tissues
ated in patients with a clinical history of from the various precursors produced in the ova-
nephrolithiasis, nephrocalcinosis, osseous pain, ries and adrenal glands. Gonadal function is deter-
subperiosteal resorption, and pathologic frac- mined by the activity of testes and ovaries through
tures, as well as in those with osteoporosis- the regulation of the hypothalamic-pituitary-
osteopenia, a personal history of neck irradia- gonadal axis. One of the multiple functions of
tion, or a family history of multiple endocrine the hypothalamus is the control of the pituitary
neoplasia syndrome (types 1 or 2). The diagnos- gland (or hypophysis), which in turn, by releasing
tic work-up is made with laboratory studies different kinds of hormones, influences the major-
(such as total serum or ionized calcium, 24-h ity of the endocrine glands in the body – such as
urine calcium, albumin level, PTH levels) and thyroid, adrenal, and gonads – as well as regulates
imaging studies. growth, milk production, and water balance. It is a
Treatment options are variable depending on multilevel hormonal system involving the brain
the final diagnosis and clinical data; surgery is first and pituitary regulated by a complex network of
line therapy to remove an overactive parathyroid excitatory and inhibitory factors including gonad-
gland in primary hyperparathyroidism. Patients otropin-releasing hormone (GnRH), luteinizing
who have mild primary hyperparathyroidism hormone (LH), and follicle stimulating hormone
may not need immediate care or any surgery and (FSH). This axis is active in the embryonic and
can be safely monitored. Different classes of early postnatal stages of life and is subsequently
drugs namely calcimimetics, bisphosphonates, restrained during childhood. Its reactivation cul-
and hormone replacement therapy can be used in minates in puberty initiation. Female and male
some cases if surgery is unsuccessful or not an gonads produce sex hormones in different
option. amounts: estrogen, progesterone, testosterone,
androstenedione, and inhibin.
The two major classes of gonadal diseases
Gonadal Disorders can be divided into hypogonadism and hyper-
gonadism. Inadequate gonadal function is called
Gonadal development is a complex process, hypogonadism, in which the hypothalamic-
which involves the tightly regulated differentia- pituitary-gonadal axis is interrupted at any level
tion of a bipotential embryonic gonad into either and may result in a reduction of sex hormone
testes or ovaries. Once this has occurred, the phe- biosynthesis before and after the onset of puberty,
notypic and gonadal sex of an individual is genet- both in males and females. Hypogonadism is
ically determined. increasingly common in the aging male
population with a decrease in either of the two three stages: premenopause (transition between
major functions of the testes: sperm and testoster- fertility and the last menstrual period), meno-
one production (Wang et al. 2009). Hypo- pause, and postmenopause (the years after the
gonadism is divided into primary and secondary end of menstruation). Menopause is characterized
hypogonadism. Primary hypogonadism is gener- by a dramatic decline in primordial follicle and
ally related to defects inherent within the gonad increased levels of follicle stimulating hormone
such as chromosomal abnormalities (Noonan (FSH) and luteinizing hormone (LH) until com-
Syndrome, Turner Syndrome, Klinefelter syn- plete anovulation. When there is a rapid decrease
drome, XY females with SRY gene-immunity), of estrogens, menstruation stops and symptoms of
orchitis, varicocele, trauma, drugs including menopause start, even if the ovarian stroma con-
chemo-radiotherapy, and autoimmune damage. tinues to produce small amounts of androstenedi-
Secondary hypogonadism is caused by various one and testosterone. Ovarian hormones are
lesions and/or diseases involving either the hypo- necessary for the maintenance and health of
thalamus or the pituitary (i.e., isolated idiopathic most tissues in women. Alterations in these hor-
hypogonadotropic hypogonadism, Kallmann’s mones can lead to osteoporosis, atrophy and
syndrome, sella or suprasellar tumors, trauma, inflammation of estrogen-deprived tissues (e.g.,
surgery, radiation, meningitis, sarcoidosis, atrophic vaginitis), atherogenesis and alterations
hemochromatosis). in cardiovascular compliance, and an increased
Signs and symptoms suggestive of male hypo- risk of some forms of cancer (e.g., endometrial
gonadism are related to androgen deficiency and carcinoma as a consequence of estrogen excess).
involve musculoskeletal system (reduction of Symptoms of menopause encompass hot flushes,
muscle strength, vigor and physical energy), sex- psychological changes, and nocturia. Vaginal
uality (impotence, infertility, loss of libido), vaso- mucosa experiences atrophic changes, with reduc-
motor and nervous system (hot flushes, sweating), tion of pH and lubrication; uterus, ovaries, and
mood disorder and cognitive function (depres- breasts are reduced in size and sometimes there is
sion, insomnia, difficulty with short-term mem- a prolapse of the pelvic floor. Diagnosis includes a
ory). Often patients show gynecomastia, complete serological assessment of estrogen, FSH,
abdominal obesity, loss of body hair, infantile and LH levels. Some women can have benefits
genitalia; they also have a wide spectrum of sys- from estrogen therapy, especially those with pre-
temic complications because a low level of testos- mature ovarian failure; but a risk of breast cancer
terone seems to be a risk factor for diabetes, and heart disease when combined hormone therapy
metabolic syndrome, inflammation, dyslipidemia, (estrogen plus progestin) is used for a long-term is
and osteoporosis (Maggio and Basaria 2009). described (Chlebowski and Anderson 2015).
Diagnosis is based on the evaluation of the Hypergonadism is a rare condition where there
complete panel of hormone levels in blood is a hyperfunction of the gonads. The imbalance
and an MRI of the brain. Treatment includes of the hormones can lead to puberty at an early
testosterone replacement and the management of stage, later in life or in the newborn. It can occur in
underlying disease. both males and females, but is more common in
Diseases associated with the ovaries include males. In hypergonadism, the level of reproduc-
ovarian cysts, ovarian cancer, menstrual cycle tive hormones increases and causes infertility in
disorders, polycystic ovarian syndrome, and oste- males and females. While there can be a multitude
oporosis. Menopause is a form of hypogonadism of causes for the development of hypergonadism
that occurs naturally; the term derived from the (genetics, autoimmune disorders, anabolic ste-
Greek Meno (months) and Pause (cessation); the roids), tumors affecting the adrenal glands are a
word means cessation of menstruation. Climac- leading cause of this hormonal abnormality. It can
teric consists of physical and emotional change manifest as precocious puberty, rapid growth in
that precedes and accompanies menopause. These adolescents, high libido, acne, excessive hairi-
changes usually occur gradually and consist of ness, increased muscle mass, and mood swings.
Thyroid Disease chromosome 6 and associations with other dis-

eases that are characterized by markers of autoim-
The thyroid gland consists of two lobes lying munity (pernicious anemia, Sjogren’s syndrome,
on either side of the ventral aspect of the Addison’s disease, type 1 diabetes mellitus, and
trachea connected together by a thin band of primary biliary cirrhosis). Graves’ disease is char-
connective tissue called the isthmus. It performs acterized by periods of remission and exacerba-
a vital function producing hormones that tion; 10–15% of patients will progress to
regulate metabolism. The understanding of thy- hypothyroidism or to Hashimoto’s thyroiditis
roid disease requires an understanding of hypo- (deBruin et al. 1988). Classical symptoms include
thalamic–pituitary–thyroid feedback control; the weight loss despite increased appetite, heat intol-
hypothalamic hormone, thyrotropin releasing hor- erance, irritability, insomnia, sweatiness, diarrhea,
mone (TRH), all of which modulate the release of palpitations, muscular weakness, and menstrual
pituitary thyroid stimulating hormone (TSH). irregularity; clinical signs include diffuse goiter,
TSH interacts with specific receptors on thyroid fine resting tremor, tachycardia, hyperreflexia,
follicular cells to stimulate thyroid hormone pro- eyelid lag, warm and smooth skin, and proximal
duction, 80% of thyroxine (T4) and 20% of triio- myopathy and less commonly atrial fibrillation. A
dothyronine (T3). T4 and T3 are transported low serological level of TSH indicates likely sup-
blood bound to serum proteins. The 80% of T3 pression of the hypothalamic–pituitary axis and
production comes from the conversion of T4 in should be followed by the measurement of free
peripheral tissues. The effects of thyroid hor- thyroxine (T4) and free triiodothyronine (T3),
mones on virtually every cell in the body are both of which are usually elevated in Grave’s
manifest in the widespread clinical effects of hyperthyroidism. Technetium-labeled thyroid
their lack or excess. scintigraphy may aid diagnosis when the cause
All forms of thyroid diseases are much more of hyperthyroidism remains uncertain. Treatment
frequently observed in women than in men, strategies for Grave’s hyperthyroidism include the
although the reasons for this are not completely use of thionamides (antithyroid drugs), radioac-
elucidated, and their manifestations are deter- tive iodine therapy, or surgery.
mined by dietary iodine availability. Thyroid dis- On the other hand, the most common causes of
eases can be broadly classified as euthyroidism, hypothyroidism are autoimmunity (Hashimoto’s
hyperthyroidism, and hypothyroidism, clinical thyroiditis), iodine deficiency, or following sur-
states reflecting normal, excessive, or defective gery or radioiodine therapy (Gessl et al. 2012).
levels of thyroid hormones respectively. Hormone Hashimoto’s thyroiditis, also known as chronic
levels can reflect a primary biosynthetic problem lymphocytic thyroiditis, was first described by
of the thyroid gland, or a destruction of thyroid Hashimoto in 1912. It is characterized by gradual
cells with release of thyroid hormones, or iatro- destruction of the thyroid gland, through autoim-
genic causes, or changes resulting from target mune processes, due to a combination of genetic
tissue abnormalities (Table 12). and environmental factors. Genes for human leu-
The most frequent causes of hyperthyroidism kocyte antigen, cytotoxic T lymphocyte antigen-
are various forms of thyroid dysfunction in elderly 4, protein tyrosine phosphatase nonreceptor-type
women or Graves’ disease, which occurs mostly 22, thyroglobulin, vitamin D receptor, and cyto-
in younger women. The causes of Graves’ disease kines are considered to be of utmost importance
include autoimmune stimulation to TSH receptor (Zalatel and Gaberscek 2011). Environmental fac-
(80%), toxic multinodular goiter (15%), toxic ade- tors include iodine intake, drugs, infections, and
noma (2%), thyroiditis (1%), and tumors (2%) different chemicals.
(TSH secreting pituitary tumor, trophoblastic Biochemical markers of the disease are thyroid
tumors, thyroid follicular carcinoma). It seems peroxidase and/or serum thyroglobulin autoanti-
there exists a genetic background with a linkage bodies which are present with a higher prevalence
to certain histocompatibility complex genes on in females than in males and increase with age.
Table 12 Classification of thyroid diseases. (Adapted from Monaco 2003)

I. Diseases characterized by (tissue) euthyroidism
A. Euthyroid goiter (chronic)
1. Diffuse
a. Sporadic
b. Endemic (iodine deficiency)
2. Nodular
a. Uninodular
1. Sporadic
2. Endemic (iodine deficiency)
b. Multinodular
1. Sporadic
2. Endemic (iodine deficiency)
3. Euthyroid diffuse goiter (transient)
a. Menarche, pregnancy, menopause (in iodine-deficient environments)
b. Iatrogenic (antithyroid substances), iodide (deficiency/excess), environmental/diet (goitrogens, drugs, etc.)
B. Tumors
1. Benign (single nodule)
a. Adenoma
b. Unusual tumors (teratoma, lymphoma, etc.)
2. Malignant
a. Differentiated
1. Papillary
2. Follicular
b. Undifferentiated (anaplastic)
1. Small cell
2. Giant cell
c. Medullary
d. Other malignant (lymphoma, sarcoma, metastatic tumors)
C. Thyroiditis
1. Acute thyroiditis
2. Subacute thyroiditis (De Quervain’s) (in the euthyroid phase: polar disease)
3. Chronic autoimmune thyroiditis or Hashimoto’s disease (in the euthyroid phase: polar disease)
4. Postpartum and silent thyroiditis (in the euthyroid phase: polar disease)
5. Riedel’s thyroiditis
II. Diseases characterized by (tissue) hyperthyroidism
A. With thyroid gland hyperfunction
1. Diffuse hyperthyroid goiter with thyroid associated ophthalmopathy or Basedow-Graves’ disease
2. Multinodular hyperthyroid goiter or Plummer’s disease
3. Autonomous nodule (hyperthyroid)
4. Rare forms: excessive exogenous iodine, chronic autoimmune (i.e., Hashitoxicosis) and postpartum thyroiditis
(in the hyperthyroid phase, polar diseases), pituitary resistance to thyroid hormones, TSH-secreting pituitary adenoma,
chorionic gonadotrophin-secreting tumors (choriocarcinoma, hydatiform mole, embryonal carcinoma of the testis),
follicular adenoma or carcinoma of the thyroid
B. Thyrotoxicosis (without thyroid gland hyperfunction)
1. Excessive, exogenous thyroid hormones (thyrotoxicosis factitia, iatrogenic thyrotoxicosis) (see also transient
hyperthyroidism)
2. Postinflammatory (subacute thyroiditis) or from destruction of the thyroid (see also transient hyperthyroidism)
3. Amiodarone induced
(continued)
C. Transient hyperthyroidism
1. Adult forms (excessive exogenous iodine intake, excess of thyroid hormone intake, post-I therapy, hyperthyroid
phase of polar diseases = postpartum, silent, and subacute thyroiditis)
2. Neonatal forms (maternal antibodies)
III. Diseases characterized by (tissue) hypothyroidism
A. With hypothyroidism
1. Primary hypothyroidism:
a. Adult
1. Chronic autoimmune thyroiditis (with or without goiter)
2. Iatrogenic (surgery, I-therapy)
3. Diffuse and nodular goiter
4. Severe iodine deficiency
b. Neonatal congenital (ectopia, agenesis, dyshormonogenesis (iodine metabolism, thyroglobulin biosynthesis,
enzymatic defects))
2. Pituitary (or secondary) hypothyroidism (tumor, inflammation, infiltration, trauma, TSH deficiency, isolated or
panhypopituitarism)
3. Hypothalamic (or tertiary) hypothyroidism (tumor, inflammation, infiltration, trauma)
B. Without hypothyroidism
1. Generalized and peripheral resistance to thyroid hormones (receptor and postreceptor defects)
C. Transient hypothyroidism
1. Adult forms [iodine deficiency/excess, drug induced, environmental/diet, postpartum, and subacute thyroiditis
(hypothyroid phase)]
2. Neonatal forms (iodine deficiency/excess, maternal goitrogen ingestion/antithyroid substances, maternal
antibodies)
IV. Thyroid associated ophthalmopathy
1. Only signs
2. Soft tissue involvement with signs and symptoms
3. Proptosis (exophthalmos)
4. Extraocular muscle involvement
5. Corneal involvement
6. Sight loss
V. Abnormal thyroid parameters without thyroid diseases (non-thyroidal illness, deficit of TBG, etc.)
Autoantibodies (IgG) are directed against the two and symptoms can vary from person to person and
major thyroid antigens: thyroid peroxidase (TPO) may include fatigue, weight gain, puffy face, cold
and thyroglobulin (Tg); their action is the primary intolerance, joint and muscle pain, constipation,
cause of the modification of the parenchyma, dry skin and hair, decreased sweating, menstrual
which is diffusely replaced by a lymphocytic infil- disorders/infertility, and depression. Diagnosis
trate and a fibrotic reaction. Patients with relies on the demonstration of circulating autoan-
Hashimoto’s thyroiditis are usually asymptom- tibodies to thyroid antigens and reduced
atic, and some patients develop goiters with or echogenicity on thyroid sonogram in a patient
without hypothyroidism. Clinically patients pre- with clinical features. Treatment remains symp-
sent gradual enlargement of the thyroid gland tomatic and based on the administration of syn-
(goiter) and gradual development of hypothyroid- thetic thyroid hormones to correct the
ism; sometimes the thyroid gland may enlarge hypothyroidism as required.
rapidly; rarely, it is associated with dyspnea or Hashimoto’s thyroiditis is often associated
dysphagia from pressure on structures in the with other organ specific diseases (e.g., pernicious
neck or mild pain and tenderness. Classical signs anemia, vitiligo, celiac disease, type 1 diabetes
mellitus, autoimmune liver disease, primary bili- Menopause has been associated with diminished
ary cirrhosis, myasthenia gravis, alopecia areata, salivation, mucosal atrophy, oral dysesthesia, and
sclerosis multiplex, Addison’s disease), and non- dysgeusia, while patients who are pregnant have
specific diseases (e.g., rheumatoid arthritis, sys- an increased incidence of oral peripheral giant cell
temic lupus erythematosus, Sjögren’s syndrome, granuloma, angiogranuloma, and periodontal dis-
systemic sclerosis, mixed connective tissue disease. Oral lichenoid lesions can be seen in patients
ease). Both Hashimoto’s thyroiditis and Grave’s with Hashimoto’s thyroiditis, and patients with
disease have been associated with diabetes diabetes, particularly poorly controlled diabetes,
mellitus: about 11% of patients affected by diabe- can present with mucosal atrophy and oral
tes show thyroid dysfunction (Kadiyala et al. candidosis. These conditions are discussed in
2010). Thyroid hormones directly control insulin other chapters within this text, such as ▶ “Oral
secretion; conversely type 1 and type 2 diabetes Manifestations of Systemic Diseases and Their
may induce a “low T3 state” characterized by low Treatments,” ▶ “Oral Lichen Planus,” ▶ “Oral
serum total and free T3 levels, but near normal and Maxillofacial Fungal Infections,”
serum T4 and TSH concentrations. Diabetes and ▶ “Pigmented Lesions of the Oral Mucosa,” and
thyroid disorders have been shown to mutually ▶ “Gingival Pathology.”
influence each other. In hypothyroidism, there is
a reduction in glucose-induced insulin secretion
by β cells, and the response of β cells to glucose or Gastrointestinal Disorders
catecholamine is increased in hyperthyroidism
due to increased β cell mass. Insulin resistance Gastrointestinal disorders (GD) may affect any sec-
states may increase thyroid gland nodularity and tion of the gastrointestinal tract, from the esophagus
coexisting diabetes may increase risk of vision to the rectum, and the accessory digestive organs
loss in patients with Grave’s disease. Hypothy- (liver, gall bladder, and pancreas). The term encom-
roidism can cause significant changes in blood passes acute, chronic, recurrent, or functional dis-
glucose control and reduce the clearance of insu- orders and covers a wide range of diseases,
lin from the bloodstream, so the dose of insulin including inflammatory bowel disease and func-
may be reduced. Hyperthyroidism is typically tional dyspepsia. From the mouth to the anus, the
associated with worsening blood glucose control gastrointestinal tract allows for the digestion of
and increased insulin requirements. The excessive food, through the action of muscles with the release
thyroid hormone causes increased glucose proof hormones and enzymes. It is conventionally
duction in the liver, rapid absorption of glucose divided into the upper (mouth to ileum) and lower
through the intestines, and increased insulin resis- (cecum to anus) gastrointestinal tracts. The global
tance. Moreover, thyroid hormones may further spectrum and classification of GD is very wide; and
alter carbohydrate metabolism through the inter- it is possible to divide diseases into (a) functional
action with leptin, adiponectin, and gut hormones, disorders (i.e., globus, functional dysphagia, and
namely, ghrelin. irritable bowel diseases); (b) motility disorders
(i.e., gastroesophageal reflux disease, diarrhea,
and achalasia); (c) other diseases (i.e., inflamma-
Oral Manifestations of Endocrine tory bowel diseases, celiac disease, malabsorption,
Disorders and diverticulosis).
Oral and peri-oral melanotic pigmentation can

occur in Addison’s disease and although this Dysphagia
may be the first sign of the disease, it can also be
seen later during the course of the disease. Hyper- The term dysphagia is commonly used to describe
parathyroidism can cause central and peripheral a symptom that manifests as (a) subjective aware-
giant cell tumors, also known as “Brown tumors.” ness of swallowing difficulty during the passage
of a liquid or solid bolus from the mouth to with dysphagia may experience the sensation of
the stomach, or (b) the perception of obstruction food getting stuck in the throat or chest, coughing
during swallowing (Domenech Kelly 1999). It is or choking with swallowing, delayed or absent
included in the WHO’s classification of diseases; trigger to swallow discomfort, or the ability to
it can cause severe complications such as malnu- “sense” the act of swallowing. In addition,
trition, dehydration, respiratory infections, aspira- patients with dysphagia may experience voice
tion pneumonia, increased readmissions, changes or wet voice, frequent throat clearing,
institutionalization, and morbidity. Swallowing otalgia, weight loss, abnormal lip closure and
occurs in 3 phases: oral, pharyngeal, and esopha- tongue movement, lingual dis-coordination,
geal, and it is possible to identify an oropharyn- delayed oral and pharyngeal transit time, incom-
geal dysphagia (OD) typically as a result of plete oral clearance, nasal regurgitation, pharyn-
neuromuscular disorders or hyposcialia caused geal pooling, dehydration, and/or pneumonia
by drugs or therapies and an esophageal dyspha- (Fig. 13). Patients reporting “swallowing prob-
gia commonly caused by anatomic defects of the lems” may be experiencing dysphagia,
esophagus, motility disorders, or intrinsic or odynophagia, globus sensation, and/or heartburn
extrinsic obstructive lesions. More generally neu- (Perry and Love 2001). If oropharyngeal dyspha-
rogenic causes of dysphagia include stroke, mul- gia is suspected, the patient should undergo initial
tiple sclerosis, amyotrophic lateral sclerosis, testing with a water or semisolid bolus swallow
diabetic neuropathy, cerebral palsy, Guillain- test. If results are positive, the diagnosis can be
Barrè syndrome, dementia, and head trauma, confirmed with a videofluoroscopic swallowing
while myogenic causes refer to muscular dystro- study. If esophageal dysphagia is suspected,
phy, myasthenia gravis, and gastrointestinal resec- patients typically undergo endoscopic esophago-
tion. Other conditions that could represent gastroduodenoscopy; if obstruction or gastro-
potential causes of dysphagia encompass connec- esophageal reflux disease is suspected, biopsies
tive tissue disorders, rheumatologic (rheumatoid can confirm the presence of esophagitis and
arthritis) and other connective tissue disorders provide specific pathologic identification of the
(scleroderma, systemic lupus erythematous) obstructive lesion. In addition, therapeutic dilata-
(Ney et al. 2009). Pathologic conditions of the tion of a stricture and removal of foreign bodies
oral cavity, pharynx, esophagus, and proximal can be accomplished as part of the evaluation
stomach can manifest with dysphagia. Patients procedure.
Fig. 13 Photomicrograph of a histopathology specimen showing the infected portion of the lung. Hematoxylin
of pneumonia of the lung (a; 20) showing a clear demar- and eosin stain. (Images courtesy of Professor Camile
cation between the infected area on the top right with Farah, UWA Dental School, University of Western
congestion of almost all the alveolar, and (b; 100) Australia, Perth WA, Australia)
Fig. 14 Photomicrograph of a histopathology specimen neoplasm attempting to form glandular structures. Hema-
of colon adenocarcinoma (a; 20) showing extensive toxylin and eosin stain. (Images courtesy of Professor
infiltration of the adenocarcinoma across the colon (black Camile Farah, UWA Dental School, University of Western
arrows) and (b; 100) showing nuclear atypia, pseudo- Australia, Perth WA, Australia)
stratification, and hyperchromasia (yellow arrows) with the
Gastroesophageal Reflux Disease motility disturbances, fibrogenesis, and carcino-

genesis (Fig. 15). The mechanisms of esophageal
Gastroesophageal reflux disease (GERD) is one of carcinogenesis associated with prolonged GERD
the most common problems encountered in clini- remain obscure. Recent attention has focused
cal practice today, particularly in the Western on the role of nitrosating species and nitric
world (about 10–20% in Western countries and oxide at the gastroesophageal junction (McColl
under 5% in Asia) (Dent et al. 2005). 2005). Among the environmental factors,
The pathophysiology of GERD is complex and lifestyle factors, in particular being overweight/
multifactorial involving gastric acid secretion, obese, poor dietary habits, the lack of regular
dysfunction of the antireflux barrier, gastric emp- physical activity, and smoking, have frequently
tying disturbances, and abnormalities in esopha- been suggested to be possible GERD risk
geal defense mechanisms. How these different factors (Kaltenbach et al. 2006). The falling
factors cause GERD is incompletely understood, prevalence of Helicobacter pylori infection
but they all share one common initiating process: and related diseases in developed countries
increased exposure of the esophageal squamous during the twentieth century has been paralleled
epithelium to gastric contents, namely, acid, by an increase in GERD and its complications;
pepsin, trypsin, and bile acids. Acid breakdown there is circumstantial evidence that infection
of the tissue defenses is what ultimately leads to with H. pylori is relatively protective for the
symptom production, ulceration, strictures, occurrence of GERD (Delaney and McKoll
columnar metaplasia (Barrett’s esophagus), and 2005). Heartburn and acid regurgitation are
adenocarcinoma (Fig. 14) (Dodds et al. 1982). the most common symptoms of GERD,
The pathogenesis of GERD is complex; essen- although pathologic reflux can result in a wide
tially all nonimmune cell types of the esophagus, variety of clinical atypical presentations such as
such as resident epithelial, mesenchymal, and retrosternal chest pain without evidence of
endothelial cells, actively contribute to the initia- coronary artery disease, asthma, chronic cough,
tion and perpetuation of the inflammatory and hoarseness. Up to 70% of patients with com-
response with the involvement of inflammatory plaints of GERD symptoms have been noted to
cytokines, platelet activating factor, and reactive have nonerosive reflux disease (NERD). Thus,
oxygen species. Once the inflammatory cascade NERD is the most common presentation of
with its inflammatory infiltrate described above GERD. NERD patients are often considered to
fully unfolds, complications induced by be afflicted with psychological comorbidity
pro-inflammatory mediators can occur, such as (Fass 2007).
Pepsin Trypsin Acid Bacteria
Epithelial cells
Inflammatory mediators
Muscle cells
Fibroblasts Endothelial cells
Immune cells
Chronic Inflammation
Motility dysfunction Fibrosis Carcinogenesis
Fig. 15 Interactions between immune and nonimmune cells in gastroesophageal reflex disease
The diagnosis of typical GERD begins with a to find a treatment that is safe and effective for
detailed clinical history to identify the character- long-term use. Surgical intervention is often nec-
istic symptom and define the intensity, duration, essary in patients who fail medical therapy, are
and frequency, uncover the triggering and reliev- noncompliant or wish to discontinue long-term
ing factors, and determine the pattern of evolution medical therapy, have complications secondary
of the disorder over time, as well as its impact on to GERD, or present with extra-esophageal
the quality of the patient’s life. In this context, it is symptoms.
important to consider the patient’s age and the
presence or absence of alarm manifestations,
which include dysphagia, odynophagia, weight Inflammatory Bowel Diseases
loss, GI bleeding, nausea and/or vomiting, and a
family history of cancer. Confirmation is achieved Inflammatory bowel diseases (IBDs) represent a
using various preoperative evaluations including: family of clinically diverse conditions that are
ambulatory pH monitoring, esophageal manome- characterized by chronic, primarily cell-mediated
try, upper endoscopy (esophagogastroduo- inflammation that leads to the damage of the gas-
denoscopy), and barium swallow. Currently, the trointestinal tract (Neuman and Nanau 2012).
main aim in the management of most patients with IBDs encompass ulcerative colitis (UC) (Fig. 16)
reflux symptoms is to achieve effective control of and Crohn’s disease (CD) (Fig. 17), two chronic
symptoms, which would be expected in turn to inflammatory diseases of uncertain etiology
improve health-related quality of life. Because of affecting the gut, characterized by alternating
the chronic evolution of the disease, the priority is recurrence and alleviation periods (Fig. 18). In
Fig. 16 Photomicrograph of a histopathology specimen Hematoxylin and eosin stain. (Images courtesy of Profes-
of ulcerative colitis (a; 20) showing central area of ulcer- sor Camile Farah, UWA Dental School, University of
ation and inflammation of mucosa and submucosa (dashed Western Australia, Perth WA, Australia)
oval) and (b; 100) showing a highly inflamed region.
Fig. 17 Photomicrograph of a histopathology specimen cells (black arrows). Hematoxylin and eosin stain. (Images
of Crohn’s disease (a; 20) showing inflammation of courtesy of Dr Anitha Thomas, PathWest, Perth WA,
mucosa and submucosa and (b; 80) showing a highly Australia)
inflamed region with obvious granulomas including giant
North America and Northern Europe (areas with an immunological response that promotes intesti-
highest IBD occurrence), the incidence of UC and nal inflammation. An imbalanced intestinal
CD is much higher than Southern Europe. IBD immune defense and intestinal immune tolerance
was traditionally thought to be of low occurrence is one of the risk factors for developing IBD.
in Eastern Europe, Asia, and Africa till recently Alterations in gut microbiota, and specifically
(Molodecky et al. 2012). The development and reduced intestinal microbial diversity, have been
course of IBDs is probably the result of the found to be associated with chronic gut inflamma-
complex interactions between genetic susceptibil- tion in these disorders. Specific bacterial patho-
ity, environmental triggers (breast feeding, gens, such as virulent Escherichia coli strains,
diet, smoking, drugs), and bacterial provocation, Bacteroides spp., and Mycobacterium avium sub-
producing sustained inflammation supported by species paratuberculosis, have been linked to the
altered mucosal barrier and immune pathogenesis of IBDs (Nitzan et al. 2016). The
dysregulation. A defective mucosal barrier may immunology of IBDs represents an imbalance
result in increased intestinal permeability that pro- between two types of T cell populations: regula-
motes the exposure to luminal content and triggers tory T cells and pro-inflammatory T cells. Key
Muscle hypertrophy
Crohn’s disease
Characterized by
Cobblestone appearance chronic inflammation
that affects any part of
the gastrointestinal
tract. Inflammation
extends all the way
through the intestinal
wall from mucosa to
Fissures serosa.
Ulcerative colitis
Characterized by
inflammation in the
large intestine. Only
the innermost layer of
the intestinal wall is
Ulceration within affected.
the mucosa
Fig. 18 Different anatomical locations affected by Irritable Bowel Disease
events that lead to the initiation of inflammatory abdominal pain and diarrhea. In CD, the most
changes include upregulation of various inflam- common complication is blockage of the intestine
matory pathways and persistent activation of due to swelling, which results in thickening of the
mitogen-activation protein kinase and NF-kB sig- bowel wall. Patients affected by UC tend to expe-
naling (Neuman and Nanau 2012). The subse- rience pain in the lower left part of the abdomen as
quent release of proinflammatory cytokines leads well as diarrhea. As a result, they may experience
to activation of T cells and other immune cells. weight loss and blood on rectal examination. In
TNF-α is a proinflammatory cytokine that plays a contrast, patients with CD experience pain in the
major role in the inflammation caused by IBDs. lower right abdomen, and bleeding from the rec-
Levels of TNF-α are significantly increased in tum is less frequent than in UC.
response to intestinal inflammation (Thomson The European evidence-based consensus on
et al. 2012). Although CD and UC share similar the diagnosis and management of IBDs states
characteristics, they differ in terms of the location that diagnosis should rely on physicians taking
and nature of the inflammatory changes. The dis- into account a number of factors including clinical
tinction between these two diseases is that in CD, and endoscopic evaluation as well as histologic,
inflammation can affect any part of the gastroin- serologic, and radiologic assessment. There is no
testinal tract, while UC is characterized by inflam- gold standard diagnostic tool (Dignass et al.
mation localized to the large intestine. 2012). Biopsies of the colon can be taken to
Malnutrition affects 20–25% of individuals with confirm the diagnosis. In CD, mucosal damage
IBDs with a major prevalence in CD. Oral and is characterized by focal infiltration of leukocytes
perioral lesions associated with CD can cause into the epithelium; granulomas and aggregates of
difficulty in eating and drinking; moreover, macrophages are also found. The pathology in UC
patients may reduce dietary intake due to fear of typically involves hemorrhage or inflammatory
Fig. 19 Photomicrograph of a histopathology specimen arrows) and the ductal cells presenting with more eosino-
of biliary cirrhosis (a; 20) showing the damage and philic cytoplasm. Hematoxylin and eosin stain. (Images
inflammation across many bile ducts throughout the liver courtesy of Professor Camile Farah, UWA Dental School,
and (b; 100) showing the presence of plasma cells and University of Western Australia, Perth WA, Australia)
intraepithelial lymphocytes within the bile duct (black
cells in the lamina propria and distortion of crypt parenteral infection. These 5 types are of greatest
architecture. Treatment of the disease involves use concern because of the burden of illness and death
of immunosuppressive drugs that can signifi- they cause and the potential for outbreaks and
cantly reduce the symptoms of the disease and epidemic spread (Table 13). The clinical features
help maintain its remission. IBD has no cure, of viral hepatitis at the onset are similar regardless
and patients commonly require a lifetime of care; of the specific hepatotrophic virus involved. The
thus, effective management to reduce morbidity, symptoms may include fever, malaise, anorexia,
hospitalization, and surgery are critical to improv- arthralgia, vomiting, abdominal pain, headache,
ing disease-free remission and quality of life. and possibly jaundice. Extrahepatic manifesta-
tions and complications may differ quantitatively,
but qualitatively they are also common.
Hepatitis The hepatitis A virus (Hep A) is a common
cause of hepatitis worldwide where spread of
Hepatitis is an inflammatory condition of the liver, infection is generally person to person or by oral
an organ which performs many critical functions intake after fecal contamination of skin or mucous
that affect metabolism including bile production membranes; less commonly, there is fecal con-
essential to digestion, filtering of toxins from the tamination of food or water. Although it is rare,
body, excretion of bilirubin, cholesterol, hor- parenteral transmission of Hep A is possible due
mones, and drugs, metabolism of carbohydrates, to use of contaminated blood products or needles
fats, and proteins, activation of enzymes, storage of during blood transfusion. Hepatitis A is endemic
glycogen, minerals, and vitamins (A, D, E, and K), in developing countries, and most residents are
synthesis of plasma proteins, such as albumin, exposed in childhood. Hep A infection stimulates
and synthesis of clotting factors. Hepatitis can be both humoral immune response with production
self-limiting or can progress to fibrosis (scarring), of antibodies and subsequent development of cir-
cirrhosis (Fig. 19), or liver cancer (hepatocellular culating immunocomplexes that are associated
carcinoma). Hepatitis viruses are the most com- with signs and symptoms of the disease and cel-
mon cause of hepatitis, but other infections, toxic lular immune response, the major factor of the
substances (e.g., alcohol, drugs), and autoimmune process of clearance of viral infection. Immuno-
diseases can also cause hepatitis. There are 5 main globulin M (IgM), IgG, and IgA antibodies
hepatitis viruses (Fig. 20), referred to as types A directed against conformational surface epitopes
and E for enteric infection and B, C, and D for on the Hep A particle are induced and can usually
Fig. 20 Photomicrograph of a histopathology specimen glass hepatocytes (black arrows) indicative of hepatitis
of viral hepatitis (a; 20) showing extensive damage B. Hematoxylin and eosin stain. (Images courtesy of Pro-
across widespread areas of the liver and (b; 100) showing fessor Camile Farah, UWA Dental School, University of
the presence of lobular inflammation, hepatocyte necrosis Western Australia, Perth WA, Australia)
with rounded apoptotic bodies and importantly ground
Table 13 The major hepatitis viruses

Virus Classification Genome Envelope Spread
HAV Picornaviridae, genus Hepatovirus RNA Nonenveloped Fecal-oral
HBV Hepadnaviridae DNA Lipid enveloped Parental
HCV Flaviviridae, genus Hepacivirus RNA Lipid enveloped Parental
HDV Unclassified RNA Lipid enveloped Parental (from HBV)
HEV Caliciviridae, genus proposed RNA Nonenveloped Fecal-oral
be detected by the onset of clinical illness liver is usually detected. Serum alanine amino-
(Stapleton 1995). Although the disease is usually transferase (ALT) and aspartate aminotransferase
self-limiting, the severity of illness is (AST) levels usually both rise rapidly during the
age-dependent; in children, Hep A is usually prodromal period, reach peak levels, and then
asymptomatic, while in adults, symptomatic decrease by approximately 75% per week. Several
infection is characteristic, in which jaundice may unusual clinical manifestations of Hep A are cho-
(icteric in 70% of patients) or may not (anicteric) lestatic hepatitis, relapsing hepatitis, and fulmi-
be present. Asymptomatic infection can be classi- nant and subfulminant hepatitis (Lemon 1985).
fied into two categories: subclinical and The hepatitis E virus (Hep E) infection is a
unapparent infection. In subclinical infections, worldwide disease, often under-diagnosed in part
only the biochemical features of hepatitis can be due to the use of serological assays with low
detected. Unapparent infection can be identified sensitivity. In developing countries, Hep E is
only by serological studies (Hadler and transmitted between humans by the fecal-oral
McFarland 1986). Fulminant hepatitis A is rare. route, usually via contaminated water, while in
The course of disease shows three phases: incu- developed countries, it is transmitted zoonotically
bation (fecal Hep A excretion), symptomatic from animal reservoirs (Kamar et al. 2012). Hep E
infection (presence of anti-Hep A IgM, main sero- infection is usually an acute self-limiting disease,
logical marker for diagnosis), and convalescence. with symptomatic and biochemical recovery
The onset of Hep A is often abrupt and character- within 4 to 6 weeks, but in developed countries
istic prodromal symptoms are followed, within a it causes chronic infection with rapidly progres-
few days to a week, by dark urine and jaundice. sive cirrhosis in organ transplant recipients,
Mild to moderate tenderness over an enlarged patients with hematological malignancy requiring
chemotherapy, and individuals with human B virus (Hep B)-specific antigens and antibodies.
immunodeficiency virus (HIV). Jaundice occurs Different serologic markers or combinations of
in about 75% of patients; the ALT level is usually markers are used to identify different phases of
1000–3000 IU/liter, but the range is wide. There Hep B infection and to determine whether a
are two subgroup high risk patients in which the patient has acute or chronic Hep B infection, is
course of the infection and the prognosis are dif- immune to Hep B as a result of prior infection or
ferent: patients with preexisting chronic liver dis- vaccination, or is susceptible to infection
ease and immunocompromised individuals. A (Table 14).
minority of patients develop extrahepatic mani- The hepatitis C virus (Hep C) infection still
festations: (1) neurological symptoms such as represents a major public health threat, with a
Guillain-Barré syndrome, Bell’s palsy, neuralgic global diffusion, characterized by its propensity
amyotrophy, acute transverse myelitis, and acute to chronicity. The most recent data of disease
meningoencephalitis (Cheung et al. 2012); (2) kid- burden show an increase in seroprevalence over
ney injury; (3) pancreatitis; and (4) thrombocyto- the last 15 years to 2.8% with an estimation of
penia and aplastic anemia. Hep E infection can be 130–170 million people chronically infected,
diagnosed either indirectly by detecting serum equating to >185 million infections worldwide
anti-Hep E antibodies or directly by detecting (Messina et al. 2015). Hep C is a member of the
the Hep E genome in blood or other bodily fluids; Flaviviridae family, naturally infecting only
the presence of anti-Hep E IgM is a marker of humans and chimpanzees, characterized by
acute infection. 7 major genotypes, further classified into 67 con-
The hepatitis B virus (Hep B) infection is firmed and 20 provisional subtypes. Studies sug-
caused by a double-stranded DNA virus of the gest that specific genotypes, such as genotype
hepadnaviridae family. More than 400 million 1, can be more cytopathic or can induce more
people worldwide are chronically infected with rapid progression of the disease than do other
Hep B; 82% of the world’s 530,000 cases of genotypes (Smith et al. 2014). Hep C is primarily
liver cancer per year are caused by viral hepatitis transmitted via the parentral route which includes
infection, with 316,000 cases associated with hep- injection drug use, blood transfusion, unsafe
atitis B and 118,000 with hepatitis C (Lai et al. injection practices, other healthcare-related pro-
2003). The virus is transmitted via percutaneous cedures, tattooing, perinatal and sexual transmis-
or permucosal exposure to infected blood or body sion. Hep C is not directly cytopathic and liver
fluids and has an incubation period ranging from lesions are mainly related to immune-mediated
40 to 160 days. In low prevalence areas such as mechanisms, which are characterized by a pre-
Northern Europe and North America, Hep B dominant type 1 helper cell response. Co-factors
infection is primarily acquired in adulthood influencing the outcome of the disease including
through sexual contact or injecting drug use, age, gender, smoking, alcohol consumption,
whereas in high prevalence areas, Hep B infection endovenous acquisition of Hep C coinfection
is most commonly acquired perinatally or in early with other viruses such as HIV, Hep B, and
childhood (Alter 2003). There are seven major human T-cell lymphotropic virus are poorly
Hep B genotypes (A to H) prevailing in different understood, and other factors such as immuno-
parts of the world. The distribution of various logic and genetic factors may play an important
genotypes is as follows: A is pandemic, B and C role. Hep C enters the liver cell and undergoes
are found in Asia, D in Southern Europe, E in replication simultaneously causing cell necrosis
Africa, F in the USA, G in the USA and France, H by several mechanisms including immune-
in Central America. The majority of acute Hep B mediated cytolysis in addition to various other
infections are asymptomatic; in adults, 30% will phenomena such as hepatic steatosis, oxidative
present with jaundice and 0.1–0.5% develop ful- stress, and insulin resistance (Irshad and Dhar
minant liver failure (Kao 2008). Hep B serologic 2006). Whereas both innate and adaptive immu-
testing involves measurement of several hepatitis nity are involved in the pathogenic action of
Table 14 Possible interpretations of some common patterns of results in HBV infection

Initial tests Follow-up tests
Hep B Hep B Core Hep B
Hep B surface antibody core
surface antibody Total (anti- antibody Hep B e Hep B e Hep B e Possible
antigen (anti- HBc (anti-HBc antigen antigen antigen interpretation/stage
(HBsAg) HBs) IgG + IgM) IgM) (HBeAg) (HBeAg) (HBeAg) of infection
Negative Negative Negative Not Not Not Not No active or prior
performed performed performed performed infection; not
immune – may be
good candidate for
vaccine; possibly in
the incubation stage
Negative Positive Negative Not Not Not Not Immunity due to
performed performed performed performed vaccination
Negative Positive Positive Not Not Not Not Infection resolved
performed performed performed performed (recovery), virus
cleared; immunity
due to natural
infection. However,
if
immunosuppressed,
virus can reactivate
Positive Negative Positive/or Positive/ Negative Negative Detected Infection resolved
negative or or none (recovery), virus
negative detected cleared; immunity
due to natural
infection. However,
if
immunosuppressed,
virus can reactivate
Negative Negative Positive Positive Positive Positive None Acute infection is
detected resolving
(convalescent)
Positive Positive Positive Negative Negative Negative Detected Acute infection is
resolving
(convalescent)
Positive Negative Positive Negative Negative Positive None Chronic infection
detected but low risk of liver
or damage – carrier
detected state
at very
low level
Hep C, cytotoxic lymphocytes are crucial in deter- cause of death in HIV-positive patients on highly
mining eradication or persistence of viral parti- active antiretroviral therapy. Hep C can also
cles. Approximately 25% of patients exposed to directly infect the lymphatic tissues, and its stim-
Hep C surmount the infection naturally, but the ulation can lead to the development of B-cell
remaining 75% face persistent or life-long Hep C lymphomas (Ferri et al. 1994).
infection. In most cases, acute infection is asymp- The WHO recommends offering the Hep C
tomatic, until the disease reaches a late stage, with serology test to individuals from populations
the development of liver cirrhosis, hepatocellular with high Hep C prevalence or those with a his-
carcinoma, liver failure (leading to liver transplan- tory of Hep C risk exposure/behavior (WHO
tation), and death. Hep C is the most common 2015a) such as people who have received blood
or blood components (red cells, platelets, fresh Alcoholic Liver Disease

frozen plasma), injection drug users (past or pre-
sent), people with associated HIV infection, Alcoholic liver disease (ALD) is a broad term that
hemophilia, on hemodialysis, with unexplained encompasses a spectrum of phenotypes ranging
abnormal aminotransferase levels, children born from simple steatosis (fatty liver) (Fig. 21) in
to Hep C-infected mothers, healthcare workers patients who consume over 80 mg of alcohol/
after a needle stick injury or mucosal exposure day to steatohepatitis (that can occur at any stage
to Hep C-positive blood, and current sexual part- of the disease), progressive fibrosis in about 40%
ners of Hep C-infected persons. Diagnostic tests of cases, cirrhosis in approximately 15% of
for Hep C can be divided into two broad catego- patients, and hepatocellular carcinoma in 1–2%
ries: serologic assays that detect antibodies to Hep of cases. One of the most important causative
C and molecular assays that detect or quantify factors is represented by the amount and duration
HCV Hep C RNA. The diagnostic tests used, of alcohol consumption, the leading cause of the
including the presence of anti-Hep C antibodies morbidity and mortality of liver disease. Alcohol
in serum, cannot differentiate between acute and is responsible for over 2.5 million deaths every
chronic Hep C infection because anti-Hep C IgM, year; in 2010, alcoholic cirrhosis caused half a
used as a marker of acute infection, is variable million deaths worldwide, accounting for 50% of
in acute infectious disease and is also detected all cirrhosis-related mortality. An additional
at high rates in patients with chronic Hep C 80,000 deaths resulted from alcohol-related hepa-
infection. For this reason, reverse transcription tocellular carcinoma (Cojocariu et al. 2014).
polymerase chain reaction (RT-PCR) for the Because the liver is the major organ responsible
detection of Hep C RNA is necessary to confirm for alcohol metabolism, it is vulnerable to alcohol-
the diagnosis. Other investigations such as related injury. While fatty liver is usually revers-
genotype testing, serum fibrosis panels, and liver ible upon cessation of alcohol use, other forms of
biopsy may help to predict the response to treat- ALD tend to progress despite abstinence. Several
ment and prognosis. The serum fibrosis panel risk factors for ALD have been identified: female
represents a pool of markers, divided into Class I gender, obesity, drinking patterns, dietary factors,
(direct) and Class II (indirect), useful to identify non-sex-linked genetic factors, and cigarette
different liver fibrosis stages related to Hep C smoking while comorbidities encompass: viral
virus (Valva et al. 2016). hepatitis, hemochromatosis, and HIV. The
Fig. 21 Photomicrograph of a histopathology specimen of visible adipose tissue (b). Hematoxylin and eosin stain.
of fatty changes in the liver with early changes and only (Images courtesy of Professor Camile Farah, UWA Dental
small amounts of adipose tissue interspersed throughout School, University of Western Australia, Perth WA,
the liver (a), and marked fatty changes with a large amount Australia)
pathogenesis of ALD can be broadly divided into recurrent aphthous stomatitis, cobblestoning of
3 steps, each of which with a multitude cascade of the buccal oral mucosa, mucosal hypertrophy
processes: (1) ethanol mediated liver injury, and swelling of the gingiva, labial mucosa, muco-
(2) inflammatory immune response, and (3) intes- sal tags, angular cheilitis, perioral erythema, and
tinal permeability and microbiome changes. oral candidosis. Yellow oral mucosal pigmenta-
The early step starts with the metabolism of tion can be seen in patients suffering from hepati-
ethanol to acetaldehyde with toxic effects on tis, and they can also present with oral mucosal
hepatocytes; these damaged cells in turn release atrophy, lichenoid lesions, hyposalivation, and
damage-associated molecular patterns with the parotid gland swellings. These lesions are exten-
recruitment of innate and adaptive immune cells sively discussed in other chapters of this text, such
that perpetuate liver disease. Alcohol also has as ▶ “Oral Lichen Planus,” ▶ “Salivary Gland
direct effects on intestinal microbiome and gut Disorders and Diseases,” ▶ “Oral Ulcerative
permeability through the action of bacterial prod- Lesions,” ▶ “Oral and Maxillofacial Viral Infec-
ucts that reach the liver and stimulate an immune tions,” ▶ “Oral and Maxillofacial Fungal Infec-
response and damage (Dunn and Shah 2016). The tions,” in addition to ▶ “Oral Manifestations of
presence of symptoms and signs depends on the Systemic Diseases and Their Treatments.”
stage of the liver disease; fatty liver is often
asymptomatic, and patients with alcoholic hepati-
tis may also be asymptomatic. Some patients Musculoskeletal Disorders
show only hepatomegaly, or in association jaun-
dice, fever, ascites and in the last stage hepatic Musculoskeletal disorders (MSDs) are injuries
encephalopathy, anorexia, and fatigue. There is no and disorders that affect the body’s movement or
single laboratory or imaging study that can con- musculoskeletal system (muscles, tendons, liga-
firm the diagnosis, which is made by a combina- ments, joints, nerves, discs, blood vessels). Mus-
tion of positive anamnesis of habitual alcohol cle diseases can be classified into: regional
intake in terms of duration and quantity, physical syndrome (myofascial pain syndrome, tension-
signs and laboratory evidence of liver disease neck syndrome, rotator cuff syndrome, compart-
(abnormal serum transaminases, particularly if ment syndrome), local muscle diseases (muscular
the level of AST is greater than that of ALT and rheumatism, fibrositis, myositis, myalgia, tender
elevated levels of gamma-glutamyl transpeptidase point, trigger point), and general syndromes
(GGT)); in uncertain situations, it can be (fibrositis syndrome, fibromyalgia syndrome
supported by imaging and liver biopsy results. related to chronic or psychopathologic diseases,
Corticosteroids are the first-line therapy for severe idiopathic fibromyalgia, polymyalgia, polymyosi-
alcoholic hepatitis; pentoxifylline is an alternative tis). Bone and joint diseases include osteopenia,
therapy, liver transplantation is the ultimate ther- osteoporosis, osteoarthritis, scoliosis, spondylo-
apy for severe ALD, but generally requires listhesis, ruptured or prolapsed disc, degenerative
6 months of proven abstinence for eligibility. disc disease, and spinal stenosis (Bernard 2018).
MSDs have many terms, such as repetitive
motion injuries, repetitive strain injuries, cumula-
Oral Manifestations of Gastrointestinal tive trauma disorders, occupational
Disorders cervicobrachial disorders, overuse syndrome,
regional musculoskeletal disorders, and soft tissue
Patients suffering from dysphagia or gastroesoph- disorders. MSDs can arise from the interaction of
ageal reflux disease can complain of oro-pharyn- physical factors with ergonomic, psychological,
geal burning, erythematous lesions of the social, and occupational factors. Typical symp-
oropharyngeal region, hypersalivation, dysgeusia, toms can be acute or chronic and include pain,
and dental erosion. Inflammatory bowel disease fatigue, inflammation, weakness, joint noises,
can result in persistent oral ulceration, increase in stiffness, limited range of motion, lack of
coordination, and sleep disturbances. The pain removed by osteoclasts and subsequently
may be dull, sharp, radiating, or local and may replaced by new bone, formed by osteoblasts in
be mild or severe. The causes of pain are multiple a series of coordinated or coupled actions. During
including trauma, postural strain, repetitive move- middle age and in older adults, above all during
ments, overuse, and prolonged immobilization. menopause, there is an increase in bone turnover
Changes in posture or poor body mechanics may and a decrease in bone formation, the result of
bring about spinal alignment problems and mus- which is a progressive loss of bone mineral from
cle shortening, therefore causing other muscles to osteopenia to osteoporosis. During menopause,
be misused and become painful. Diagnosis is the this complex mechanism is caused mostly by the
result of the evaluation of symptoms and physical reduction of sex hormones (estrogen and testos-
examination. Laboratory tests (i.e., erythrocyte terone) with subsequent loss of suppression of
sedimentation rate, creatinine kinase, rheumatoid bone resorption. Estrogen deficiency induces a
factor, anticyclic citrullinated peptide antibody, prolonged resorption phase with a reduction of
antinuclear antibodies), imaging tests (radio- osteoclast apoptosis and a shortened formation
graphs, arthrography, dual-energy x-ray absorpti- phase with an increase of osteoblast apoptosis
ometry, computed tomography, magnetic (Manolagas 2000). A similar effect is caused by
resonance imaging, bone scan), and other diag- testosterone through different pathways. Osteopo-
nostic procedures (electromyography, arthros- rosis can also develop as a consequence of dis-
copy, joint aspiration) are sometimes necessary eases or pathological processes, and this is labeled
to help the clinician establish or confirm a diag- secondary osteoporosis. However, regardless of
nosis (Gatchel and Kishino 2011). the etiology, the initiating event in the process of
osteoclastic activation is not yet completely
understood. Common sites for osteoporotic frac-
Osteoporosis ture are the spine, hip, distal forearm, and proxi-
mal humerus. The presence of osteoporosis
Osteoporosis is a skeletal condition characterized should be ascertained in all women aged
by a decline in bone mineral density (mass/vol- 65 years. Men 65 years or women aged
ume) of normally mineralized bone. The reduced 65 years should be screened for the presence
bone density leads to decreased mechanical of risk factors such as early menopause (
strength, thus making the skeleton more likely to 45 years), anorexia, smoking or alcohol abuse,
fracture. Bone strength is considered to be primar- chronic use of certain drugs, or diseases associ-
ily due to bone density and quality (NIH 2001). ated with an increased risk for osteoporosis (Coo-
Osteoporosis is responsible for more than 1.5 per et al. 2011). Diagnosis is commonly based on
million fractures annually, including 300,000 hip the evaluation of bone mineral density (BMD)
fractures, approximately 700,000 vertebral frac- measurements, which provide prognostic infor-
tures, 250,000 wrist fractures, and more than mation on the probability of future fractures and
300,000 fractures at other sites (Masi 2008). Mor- also on the evaluation of serological exams (eryth-
tality associated with osteoporotic fractures rocyte sedimentation rate, blood cell count, pro-
ranges from 15% to 30%, a rate similar to breast tein electrophoresis, calcium/phosphorus,
cancer and stroke. The decline in bone mineral alkaline phosphatase, creatinine). There are a vari-
content and the structural deterioration in osteo- ety of procedures to assess BMD including dual
porosis are evident microscopically and upon energy x-ray absorptiometry, quantitative ultra-
bone imaging. The cortical layer becomes thin sound, quantitative computed tomography, digital
and the normally dense network of calcified tra- x-ray radiogrammetry, radiographic absorptiome-
beculae is disconnected. The bone appears porous try, and other radiographic techniques.
and fragile. During adult life, the mechanical Comprehensive treatment includes both a
integrity of the skeleton is maintained by the pro- pharmacologic and non-pharmacologic approach.
cess of bone remodeling, in which old bone is Current FDA-approved pharmacologic options
include bisphosphonates, calcitonin, estrogen Symptomatic OA is generally defined by the

agonist/antagonist (raloxifene), estrogens and/or presence of pain, aching, stiffness, and locomotor
hormone therapy, tissue-selective estrogen com- restriction in a joint with radiographic evidence of
plex (conjugated estrogens/bazedoxifene), para- OA. Signs of OA include coarse crepitus, bone
thyroid hormone (teriparatide), and receptor enlargement (caused by bone remodeling, exces-
activator of nuclear factor kappa-B ligand inhibi- sive osteophytosis, or joint subluxation), reduced
tor (denosumab). Nonpharmacologic approaches range of movement, and joint-line tenderness.
encompass limiting the risk of falls; maintaining Muscle wasting and joint deformity occur with
adequate intake of calcium, vitamin D, and pro- severe OA. Pain can derive from inflammatory
tein; performing adequate weight-bearing physi- processes with the stimulation of nociceptive
cal activity and exercise to maintain or improve fibers and mechanoreceptors in the synovium,
balance and posture; and making appropriate life- subchondral bone, periosteum, capsule, tendons,
style changes, such as smoking cessation and or ligaments. Pain generally progresses through
moderating alcohol intake. three stages: (a) early, with predictable sharp pain
induced by mechanical insult and mild limitation
of function; (b) mild/moderate where pain
Osteoarthritis becomes regular with severe limitation of function
during daily activities; and (c) advanced, where
Osteoarthritis (OA), the commonest arthropathy, pain is constant and intense (Abhishek and
also called osteoarthrosis or degenerative joint dis- Doherty 2013). Diagnosis is based on a history
ease, is a progressive disorder of the joints caused of joint pain worsened by movement; plain radi-
by gradual loss of cartilage of one or more joints ography may help in the diagnosis, but laboratory
(usually knees, hips, and hands) typically with testing usually does not.
onset during middle or older age and resulting in Treatment strategies usually start with the use of
the development of overgrowth of adjacent bone. nonsteroidal anti-inflammatory drugs associated
The prevalence of OA varies depending on the with exercise, useful to reduce pain and disability,
specific joint(s) under study and the characteristics and glucosamine and chondroitin in combination.
of the study population (i.e., 19.2% in knee OA in Other drug options include the use of corticosteroid
patients aged 45, 27.2% in hand OA, and 7% in and hyaluronic acid injections. Total joint replace-
hip OA) (Lawrence et al. 2008). ment is recommended for symptomatic patients
OA is a multifactorial disease with systemic despite maximal medical therapy.
and local factors. Systemic factors are the cause of
the onset of susceptibility of patients to have OA
and include age, gender, ethnicity, bone density, Fibromyalgia
congenital/developmental conditions, estrogen
replacement therapy in postmenopausal women, Fibromyalgia (FM) is a chronic pain syndrome
nutritional factors, and genetics. Local factors characterized by dysregulation of pain-processing
include obesity, joint injury/surgery or deformity, mechanisms and by widespread pain at multiple
occupation, muscle weakness, local biomechani- tender points, joint stiffness, and systemic symp-
cal factors due to physical activity/sports or laxity toms (i.e., fatigue, sleep disturbances, mood dis-
or alignment. Although OA has been classified as orders, and cognitive dysfunction). It affects
a noninflammatory arthritis, increasing data on its 2–8% of the population; up to 85% of patients
pathogenesis show that multiple processes of with FM are female, typically of childbearing age
inflammation occur, where different cytokines or older (Vincent et al. 2013). FM may arise de
(i.e., interleukin-17) and metalloproteinases are novo or evolve following nervous system sensiti-
released into the joint. These agents are involved zation after an identifiable triggering event or
in excessive matrix degradation that characterizes related to a peripheral pain generator such as
cartilage degeneration. osteoarthritis. The cause of fibromyalgia is not
known; symptoms sometimes begin after physical Oral Manifestations of Musculoskeletal

trauma, surgery, infection, or significant psycho- Disorders
logical stress. In other cases, symptoms gradually
accumulate over time with no single triggering Medications for the treatment of patients suffering
event. However, many factors are known to from osteoarthritis may result in the development
aggravate existing symptoms. Cold, damp of oral lichenoid lesions. There can be a complex
weather, mental health disturbance, physical or interplay between patients suffering fibromyalgia
psychological stress, and also physical inactivity and the development of orofacial pain, particu-
have all been associated with fibromyalgia. Famil- larly temporomandibular disorders, persistent idi-
ial studies have suggested an underlying genetic opathic facial pain, and oral dysesthesia. These
susceptibility on which environmental factors are discussed in detail in multiple chapters
trigger the expression of symptoms (Buskila throughout this text, including ▶ “Arthritic Con-
et al. 2007). Polymorphisms of serotonin trans- ditions Affecting the Temporomandibular Joint,”
porters and dopamine receptors have also been ▶ “Classification of Orofacial Pain,” ▶ “Diagnos-
evaluated in patients with FM; all these polymor- tic Imaging Principles and Applications in Head
phisms affect the metabolism or transport of and Neck Pathology,” ▶ “Oral Dysesthesia,” and
monoamines, compounds that have a critical role ▶ “Oral Manifestations of Systemic Diseases and
in both sensory processing and the human stress Their Treatments.”
response (Gürsoy et al. 2001; Buskila et al. 2004).
Different studies confirm changes in neuroendo-
crine transmitters such as serotonin, substance P, Hematological Disorders
growth hormone, and cortisol that suggest that the
pathophysiology of the syndrome may be associ- Blood diseases are collectively referred to as hema-
ated with autonomic and neuroendocrine regula- tological disorders (HD) including a wide group of
tion. Moreover, in FM the stress–adaptation diseases, classified into four distinct categories:
response, modulated mostly by the hypotha- (i) hemoglobinopathy, (ii) anemia, (iii) hemato-
lamic-pituitary axis is disrupted, leading to logical malignancies, and (iv) coagulopathies.
stress-induced symptoms (Jahan et al. 2012). Hemoglobinopathies are inherited disorders of
FM is a challenging diagnosis for many health globin, the protein component of hemoglobin
care providers given the breadth of symptoms (Hb); they are the most common genetic defect
patients have on presentation and the paucity of worldwide with an estimated 269 million carriers
specific objective findings. FM is often mis- particularly in certain populations (South East
diagnosed because its symptoms are similar to Asia, sub-Saharan Africa and West Pacific region)
other conditions like rheumatoid arthritis. There (Angastiniotis and Modell 1998). Hemoglobinop-
is no specific diagnostic laboratory test or bio- athies are primarily grouped into thalassemia syn-
marker available for the diagnosis of FM and dromes (α and β thalassemias) and structural
diagnosis is made largely by clinical judgment. hemoglobin variants (abnormal hemoglobins).
Medical care of FM and its comorbidities are quite They are caused by mutations affecting the pro-
difficult, time consuming, and costly; and this duction of α-globin chains and β-globin chains of
disorder also tends to be intractable. There is the Hb molecule. The severity of the anemia and
no reliable tool to predict treatment response in its consequences depend on the molecular defects
individual patients. There are currently no defini- that are involved in each affected individual.
tive treatments, but a combination of some med- There are a number of clinically significant hemo-
ications (such as antidepressants, antiepileptic, globins that do not alter the overall charge of the
anti-inflammatory agents), cognitive behavioral protein so are detected by other methods other
therapies/counseling, and lifestyle changes help than electrophoresis, e.g., isoelectric focusing,
relieve some of the symptoms and make the high-performance liquid chromatography, and
condition easier to live with. immunologic techniques.
Contact Phase Activation

(Intrinsic Pathway) Tissue Factor Pathway
(Extrinsic Pathway)
PKa PK
HK Tissue factor
TFPI F Xa
F XII F XIIa
F VIIa F VII
F XI F XIa
Ca2+
C1 Inhibitor
F IX F IXa
Ca2+
F VIII F VIIIa
FX
Ca2+ F Xa Antithrombin III
FV F Va Ca2+
prothrombin Fibrinolysis
thrombin
Protein S Protein C
fibrinogen
Fibrin monomer plasminogen
PAI-1
Fibrin ploymer uPA, tPA
F XIIIa plasmin
Ca2+
TAFI Fibrin clot
α2-antiplasmin
Clot lysis
Fig. 22 The blood coagulation cascade. (Adapted from Tapper and Herwald 2000)
The term “sickle-cell disease” includes all the vessel wall (i.e., Scurvy and Ehlers-Danlos
manifestations of abnormal Hb levels; these syndrome, Henoch-Schonlein purpura, peri-
include homozygous sickle-cell disease and a vascular amyloidosis) or qualitative/quantitative
range of mixed heterozygous hemoglobinopa- defects of platelets that may cause bleeding in
thies. It is a life-threatening genetic disorder char- varying severity. A decreased platelet function
acterized by chronic hemolytic anemia, vascular can be inherited (Bernard-Soulier syndrome,
injury, and multiorgan dysfunction. The diagnosis Glanzmann thrombasthenia) or acquired (uremia,
of hemoglobinopathies in routine practice massive blood transfusion, drug-related); a
involves a red blood cell count with erythrocyte reduced platelet number or thrombocytopenia
indices, and a hemoglobin test (hemoglobin elec- can be caused by decreased production (common
trophoresis and/or chromatography). sign in hematological malignancies) or decreased
Coagulophathies include various abnormali- survival (common in autoimmune diseases, in
ties of the coagulation system (Fig. 22), classified drug reactions, infections or hypersplenism).
as: (1) disorders that affect primary hemostasis; The normal coagulation pathway represents
(2) the coagulation pathways; and (3) the fibrino- a balance between the pro-coagulant pathway that
lytic system. Hemostasis is a complex physiolog- is responsible for clot formation and the mecha-
ical process, maintaining the fluidity of blood, and nisms that inhibit the same beyond the injury site.
is regulated by the delicate balance existing Hence, coagulopathies can be categorized into
between thrombogenic and antithrombogenic disorders that lead to abnormal bleeding and those
mechanisms present in the body. Defects of pri- that lead to abnormal clotting (thrombophilia),
mary hemostasis may be due to abnormalities of in both cases acquired and hereditary (Table 15).
Table 15 Classification of coagulopathies the number of red blood cells. According to the
Thrombotic disorders WHO, anemia is present if the blood concentra-
Bleeding disorders (thrombophilia) tion of hemoglobin (Hb) falls below 130 g/L in
Hereditary Hereditary men or 120 g/L in women, except for infants,
Von Willebrand Hereditary thrombophilia children, and pregnant women, who have their
disease own lower limits of Hb concentration (WHO
Hemophilia A Antithrombin III deficiency
1968). The WHO definition has not been adopted
Hemophilia B Protein C deficiency
universally because Hb concentration in blood
Hemophilia C Protein S
may vary depending on the population analyzed,
Factor V deficiency Factor V Leiden (factor V
mutation) age, gender, environmental conditions, and food
Factor X deficiency Prothrombin mutation habits (Beutler and Waalen 2006). For these rea-
Factor VII deficiency Factor II mutation (gene sons, epidemiological data can be largely different
Factor XIII deficiency 20210 mutation) depending on the cut-off values of hemoglobin
Prothrombin considered; definitive data towards differences
deficiency
Afribrinogenemia
between races need to be addressed. In line with
Acquired Acquired the WHO definition and parameters, prevalence of
Consumptive Antiphospholipid antibody anemia ranges from 9.2% to 23.9% in men, while
Coagulopathies syndrome in women the range is 8.1–24.7%. Anemia repre-
Disseminated Increased levels of factors sents the first cause of medical visits in children
intravascular VIII, IX, XI or fibrinogen
and elderly people, where it is usually associated
coagulation Fibrinolysis defects
Microangiopathic Homozygous homocystinuria with nutritional deficiencies; on the other hand,
Hemolytic anemias anemia can be the first manifestation of a variety
Vitamin K deficiency of systemic diseases.
Liver disease
Anemia causes hypoxia and induces different
compensating mechanisms. Signs and symptoms
include fatigue, weakness, pale or yellowish skin,
An excess of activation of the fibrinolytic system irregular heartbeats, shortness of breath, dizziness
is associated with increased tendency to bleed, or lightheadedness, chest pain, cold hands and
while deficiency of the same predisposes to throm- feet, and headache. Anemia can be classified
boembolism. Excessive activation of fibrinolysis from three points of view: pathogenesis, red cell
may be observed during cardiopulmonary bypass; morphology, and clinical presentation (Chulilla
hence, antifibrinolytics have a beneficial role in et al. 2009). In a diagnostic approach to the dis-
the prevention of same. Acquired hyperfibrinolysis ease, it is mandatory firstly to distinguish if ane-
may be seen in trauma, liver cirrhosis, amniotic mia is due to decreased red blood cell (RBC)
fluid embolism, multiple myeloma, snake bite, production or to an increased RBC loss through
and conditions associated with massive activation the reticulocyte count. Reticulocytes are young
of tissue plasminogen activator, which can lead RBC, usually present in the form of anemia due
to disseminated intravascular coagulation (DIC) to hemolysis or bleeding. The reticulocyte count
and hemorrhage. is used to assess the appropriateness of the bone
marrow response to anemia. Anemia can be
microcytic, macrocytic, and normocytic based
Anemia on RBC size that can be small, large, or normal,
respectively. RBCs are analyzed not only for size
Anemia (from the ancient Greek, anaimia, mean- but also for morphology that in the normal state is
ing “lack of blood”) is a common, multifactorial characterized by a donut shape with the center
condition among older adults associated with a third of the red cell being pale or without hemo-
variety of adverse outcomes. It is defined by a globin. Moreover, it is possible to recognize a
decrease in the total amount of hemoglobin or hypochromic (decreased Hb per RBC) or
normochromic (normal Hb per RBC) form of the for children up to 18 years (Antony 2003). Diets
disease. A complete blood cell count, Hb and free of animal products or patients affected by
hematocrit values, RBC indices, and peripheral pernicious anemia (i.e., malabsorption) are the
blood smear constitute a baseline panel useful in common causes of development of vitamin B12
the first step of diagnosis. The common causes of deficiency. This causes a wide range of hemato-
anemia are described in Table 16. logical, gastrointestinal, psychiatric, and in some
Iron deficiency anemia is the most common cases permanent neurological disorders. Perni-
subtype of anemia; it is a public health burden cious anemia is characterized by an increase of
characterized by microcytic and hypochromic RBC mean corpuscular volume (MCV) and neu-
RBCs and reduction of iron stores, usually seen trophil hypersegmentation.
with low serum ferritin and low serum iron levels Management of anemia is established based
with high serum total binding capacity. Moreover, on the etiology of the disease; drugs, nutritional
iron deficiency is associated with growth failure, supplementation (iron, vitamins, folates), chemo-
immune system dysfunction, learning difficulties, therapy, surgery (splenectomy, bone marrow
and behavioral problems (Hurrell and Egli 2010). transplant), or blood transfusion are all potential
Generally, physiological iron levels are equal to strategies to treat the disease.
4–5 g with a complex balance and control of its
absorption, mobilization, storage, and recycling,
of which 25–30 mg daily are necessary for Hb Leukemia
synthesis. Iron recycling is carried out by spleen
macrophages (90%) and about 10% is derived The term leukemia, from the greek leukos “clear,
from diet (Zhang et al. 2014). Different causes white” and haima “blood,” encompasses a wide
may contribute to iron deficiency anemia such as group of neoplasms involving the body’s
genetic defects (Fanconi anemia), or increased blood-forming tissues, including the bone marrow
iron demand not balanced by a correct supply and the lymphatic system with a final result of
(childhood, pregnancy, elderly). Another com- formation of abnormal white blood cells called
mon cause of nutrition related anemia is the defi- “blasts.” The excessive number of abnormal
ciency of vitamin B12 or cobalamin (less than cells can also interfere with the level of other
150 pmol/L). A correct daily dosage is 2.4 μg for cells, causing further harmful imbalance in the
men and nonpregnant women, 2.6 μg for pregnant blood count. Leukemia represents 3.6% of all
women, 2.8 μg for lactating women, and 1.5–2 μg new cancer cases in the USA, most frequently
diagnosed among people aged 65–74; the number
Table 16 Common causes of anemia of new cases is 13.5 per 100,000 men and
Microcytic, hypochromic Iron deficiency women per year, while the number of deaths is
Thalassemia syndromes 6.9 per 100,000 men and women per year
Sideroblastic anemia (NIH-SEER 2016a).
Transferrin deficiency Didactically, leukemia is classified into four
Macrocytic Megaloblastic anemias
major categories: acute lymphoblastic leukemia
Liver diseases
Reticulocytosis (ALL) in adults and children, acute myelogenous
Bone marrow failure leukemia (AML), chronic lymphocytic leukemia
Drugs (CLL), and chronic myelogenous leukemia
Normocytic, normal Chronic diseases (CML). In 2008, WHO in collaboration with the
morphology Infections
Hemorrhage
European Association for Haematopathology and
Normocytic, abnormal Hemoglobinopathies the Society for Hematopathology revised and
morphology Hereditary updated the classification based on genetics, mor-
Spherocytosis phologic, cytochemical, immunophenotypic, and
Autoimmune hemolytic clinical features of the disease (Vardiman et al.
anemia
2009). Common and general signs include
enlarged lymph nodes, hypertrophic gingivitis, Lymphoma represents many different cancers of
enlarged liver and spleen, fever, bleeding, bruis- lymphocytes, about 35–60 different subtypes
ing, fatigue, persistent mild or life-threatening described in the WHO classification (Campo
infections, cutaneous rash (petechiae), headache, et al. 2011). Lymphomas fall into one of two
weight loss. Leukemic infiltration of the gingivae major categories: Hodgkin’s lymphoma (HL or
has been associated with monocytic variants of Hodgkin’s disease) (Fig. 23) and all other lym-
AML (M4) (Mani et al. 2008). phomas (non-Hodgkin’s lymphomas or NHLs).
Diagnosis involves a baseline blood test show- The two groups show similarities such as location
ing an abnormal white cell count and a consequent of onset, symptoms, and often similar appearance
bone marrow biopsy may confirm and identify the on physical examination (e.g., swollen lymph
specific type of leukemia (leukemic cells, DNA nodes). They are identifiable only with micro-
markers, and chromosome changes). The treat- scopic examination of a tissue biopsy; HL is
ment and prognosis for leukemia depend on the marked by the presence of a type of cell known
type of blood cell affected and whether the leuke- as Reed-Sternberg cells; abnormal B lymphocyte
mia is acute or chronic. In some patients, blood lineage. NHL can derive from either B-cells or
tests may not show variations, especially in the T-cells with aggressive development and can be
early stages of the disease or during remission. slow-growing. HL represents 0.5% of all new
Anti-leukemic therapy in the acute forms of the cancer cases in the USA, in comparison to 4.3%
disease is divided into 3 phases: (1) induction of of NHL; HL is mostly diagnosed in young
complete remission with the use of different che-
motherapies for reducing the leukemia mass in Table 17 Chemotherapy approaches with specific infor-
the shortest possible time and allowing growth mation on drugs in AML and ALL
of a normal bone marrow after aplasia; (2) consol- Acute Lymphoblastic Leukemia (ALL)
idation of remission with the administration of 1. Induction of remission
drugs sequentially or alternatively, to eliminate • Remission – Blasts <5% in the marrow and no
leukemic cells resistant to the drugs used in induc- leukemic cells in peripheral blood
• Vincristine, anthracyclines, corticosteroids
tion and to reduce the risk of chemoresistance; and
• Central nervous system protection with prophylactic
(3) maintenance phase (2–3 years), in which dif- treatment: intrathecal injection of methotrexate
ferent drugs are used, either continuously or alter- 2. Post-induction therapy (consolidation)
nately, to eliminate residual leukemic cells in the • Recurrence prevention (risk assessment)
• Autologous or heterologous transplant (young)
cellular quiescent phase.
• Chemotherapy Antiblastics: methotrexate,
Chemotherapy approaches with specific infor- cyclophosphamide, cytosine arabinoside
mation on drugs and regimes for AML and ALL • Goal ! induction of complete remission and
are described in Table 17. Allogenic heterologous recurrence prevention
transplantation is indicated in case of high risk of Acute Mylegenous Leukemia (AML)
recurrence in patients <55 years with an associ- 1. Induction of remission
• Remission – Blasts <5% in the marrow and no
ated mortality of 5–15%. The related complica- leukemic cells in peripheral blood
tions are linked to immunosuppression • Daunomycin, cytosine arabinoside, idarubicin,
(infections, cancer) and graft versus host disease. etoposide
2. Postinduction therapy (consolidation)
• Recurrence prevention (risk assessment)
• Autologous or heterologous transplant (young)
Lymphomas • Chemotherapy Antiblastics: daunomycin, cytosine
arabinoside, idarubicin, etoposide, mitoxantrone
The term lymphoma, from the latin lympha • Goal ! induction of complete remission and
recurrence prevention
“water” and oma “disease, morbidity” refers to a
Courtesy of Professor AM Risitano and Professor
group of malignancies that develop from lympho- Francesco Grimaldi, Department of Hematology and
cytes localized in lymph nodes, spleen, thymus, Transplant Unit, University Federico II of Naples, Naples,
bone marrow, and other parts of the body. Italy
Fig. 23 Photomicrograph of a histopathology specimen background of lymphocytes, plasma cells, eosinophils,

of mixed cellular Hodgkin lymphoma, (a; 20) showing neutrophils, and histiocytes. Hematoxylin and eosin stain.
gross changes across the whole of a lymph node and (b; (Images courtesy of Professor Camile Farah, UWA Dental
100) showing several Reed-Sternberg cells (black School, University of Western Australia, Perth WA,
arrows) with large binucleated cell with well-defined cell Australia)
border and abundant cytoplasm in a mixed cellular
patients (20–34 years old), while NHL involves These oral manifestations are discussed further
patients aged 65–74. For both subgroups, the in chapters within this text, including ▶ “Oral
5-year survival rate is relatively high, 86.2% in Lichen Planus,” ▶ “Gingival Pathology,”
HL and 70.7% in NHL (NIH-SEER 2016b). ▶ “Oral Mucosal Malignancies,” ▶ “Salivary
Signs and symptoms are similar to leukemia. Gland Disorders and Diseases,” and ▶ “Oral
The definitive diagnosis is made through exci- Manifestations of Systemic Diseases and Their
sional biopsy of lymph nodes, because fine needle Treatments.”
aspiration has a high likelihood of false negative
results, in addition to a complete clinical evalua-
tion that includes a careful history and physical Renal Diseases
examination, recording disease-related symp-
toms, and measuring nodes and spleen size The kidneys are two bean-shaped organs located
(Hehn et al. 2004). at the bottom of the rib cage. They are mainly
responsible for filtering waste products (from
blood, muscle activity, medications), for
Oral Manifestations of Hematological maintaining a correct hydro-electrolytic balance,
Disorders for acid-base balance, for producing renin, a crit-
ical enzyme for the regulation of blood pressure,
Patients with anemia can present with oral muco- and erythropoietin, which stimulates red blood
sal atrophy and increased risk of developing oral production. Moreover, they are responsible for
candidosis. Gingival enlargement, ulceration, the activation of vitamin D, a key step for calcium
spontaneous oral bleeding, and the presence of homeostasis. Therefore, renal dysfunction can
hemorrhagic blisters can be seen in patients with result from, or cause, a variety of pathologies.
leukemia. Lymphoma can present in the oral cav- Epidemiological data show that about four million
ity as isolated or multiple proliferative lesions adults (>18 years) suffer from kidney disease in
with or without necrosis and ulcerations and can the United States, approximately 2% of the adult
occur in either bone or soft tissues. Graft versus population (Schiller et al. 2012).
host disease is often a complication of bone mar- Renal diseases, also known as nephropathies,
row transplantation with the oral appearance of arise when kidneys become damaged and cannot
lichenoid lesions, hyperkeratotic plaques, muco- perform their function; it is possible to distinguish
sal ulceration, and salivary gland dysfunction. “nephritis,” an inflammatory kidney disease
(Fig. 24) and “nephrosis,” a noninflammatory

nephropathy, both of which in absence of prompt
and adequate treatment can evolve to kidney fail-
ure. Renal diseases can be divided into two large
groups: acute kidney disease (AKD) and chronic
kidney disease (CKD). Both subtypes,
irrespective of the initiating cause, have inflam-
mation and immune system activation as a com-
mon underlying mechanism. Multiple
components of innate immunity have been impli-
cated in the progression of renal disease, including
the complement system, toll-like receptors, den-
dritic cells, macrophages, natural killer cells, and
inflammatory cytokines. The humoral-mediated
immunological system is implicated in renal dis-
eases in patients affected by systemic lupus
erythematosus, Goodpasture’s syndrome, and
immunoglobulin A nephropathy. Cytotoxic T Fig. 24 Pathological specimen of the kidney showing
cells can be activated by specific renal auto- areas of infarction and necrosis (black arrows) characteris-
antigens causing local damage and contributing tic of suppurative pyelonephritis. (Image courtesy of the
Harry Brookes Allen Museum of Anatomy and Pathology,
to renal disease and inflammation; in particular
The University of Melbourne, Carlton VIC, Australia)
CD8+ T cells have a complex role in chronic
renal diseases like lupus nephritis.
AKD is defined as a rapid decline in the glo- nephropathy. It can cause end-stage renal disease
merular filtration rate (GFR) resulting in retention directly and increase the risk of developing CKD.
of nitrogenous wastes, primarily creatinine and CKD, in turn, is an important risk factor for the
blood urea nitrogen (Thadhani et al. 1996). development of AKD. After episodes of injury
AKD accounts for approximately two million from different causes, kidneys may be susceptible
deaths annually worldwide (Ali et al. 2007), to progression to CKD, which is similarly inde-
increasingly common in critically hospitalized pendent of the initial cause of AKD. The patho-
patients and those requiring renal replacement genic mechanisms start with an initial impairment
therapy. AKD is diagnosed if there is an increase of oxygen balance, causing renal tissue hypoxia
in serum creatinine 0.3 mg/dl (26.5 umol/l) that in turn induces systemic and intrarenal hyper-
within 48 h, or an increase in serum creatinine to tension and hyperfiltration, tubular hypertrophy,
1.5 times baseline, which is known or presumed hypertension resulting in arteriosclerosis,
to have occurred within the preceding 7 days, or a tubulointerstitial fibrosis, glomerulosclerosis,
urine volume < 0.5 ml/kg/h for 6 h (KIDGO and endocrine dysfunction (Hostetter 1995). An
2012). It can be classified clinically based on the underlying feature is a rapid decline in glomerular
genesis of the disorder as prerenal, renal, or post- filtration rate (GFR) usually associated with
renal; bacterial infection, sepsis, or ischemia- decreases in renal blood flow. The most common
reperfusion injury being the most common sign is oliguria; creatinine and urea concentrations
causes. AKD arises when kidneys suddenly lose are the most widely used parameters. It is impor-
their function due to a reduction/lack of blood, tant to note the increase of creatinine can be the
direct damage, or an interruption of urine flow result of different kidney diseases; AKD, CKD, or
caused by different etiologies such as acute tubu- secondary kidney involvement during a chronic
lar necrosis, prerenal azotemia, acute interstitial disease. The evaluation of risk factors (hyperten-
nephritis, acute glomerular and vasculitic renal sion, diabetes, obesity), or positive abnormal sero-
diseases, and acute post-renal obstructive logical exam prior to presentation, or a slow
progress of the renal disease with normocytic More generally the most common symptoms
anemia suggest the diagnosis of CKD. Renal of kidney disorders are nonspecific; they can be
ultrasonography may provide evidence of chronic early warnings such as fatigue, trouble sleeping,
disease with small kidneys (Bellomo et al. 2012). poor appetite, muscle cramping, swollen feet/
CKD is one of the most prevalent chronic ankles, puffiness around the eyes in the morning,
conditions and is a frequent complication of dia- dry skin, frequent urination, especially late at
betes, cardiovascular disease, obesity, autoim- night or they can represent an evolution to kidney
munity, exposure to certain drugs (acyclovir, failure such as nausea, vomiting, changes in urine
aminoglycosides, amphotericin B, lithium, nonste- output, fluid retention, anemia, hyperkalemia, or
roidal anti-inflammatory drugs, sulfonamides, van- inflammation of the pericardium (Fig. 25). Man-
comycin, zoledronic acid), family history positive agement and treatment may vary depending on the
for CKD, nephrolithiasis, and neoplasms (https:// stage and cause of kidney disease, from medica-
www.niddk.nih.gov). It affects about 27 million tion to dialysis and kidney transplant.
adults in the United States, with an increasing
trend partly explained by the increasing prevalence
of diabetes mellitus and hypertension, the leading Oral Manifestations of Kidney
risk factors for CKD (https://www.usrds.org). Disorders
The criteria to define CKD are: (a) kidney dam-
age for 3 months, as defined by structural or Patients with acute kidney disease can present
functional abnormalities of the kidney manifest with autoimmune oral ulcerative manifestations
by either pathologic abnormalities or positive and uremic stomatitis. Chronic kidney disease
markers of kidney damage (blood, urine, imaging can result in an increased likelihood of developing
tests), (b) GFR <60 mL/min/1.73 m2 for 3 oral candidosis, oral mucosal atrophy, hypo-
months, with or without kidney damage (National salivation, and increased incidence of oral
Kidney Foundation 2002). A possible clinical dysesthesia. These oral manifestations are
classification is shown in Table 18. After the discussed further in chapters within this text,
diagnosis is made, staging based on estimated including ▶ “Oral and Maxillofacial Fungal
GFR determines prognosis, evaluation, and Infections,” ▶ “Oral Ulcerative Lesions,”
management.
Table 18 Classification of chronic kidney disease. (Adapted from Levey et al. 2005)
Classification by severity
GFR
mL/min/ Classification by
Stage Description 1.73 m2 Related terms treatment
1 Kidney damage with 90 Albuminuria, proteinuria,
normal or " GFR hematuria
2 Kidney damage with 60–89 Albuminuria, proteinuria,
mild # GFR hematuria
3 Moderate # GFR 30–59 Chronic renal insufficiency, early T if kidney transplant
renal insufficiency recipient
4 Severe # GFR 15–29 Chronic renal insufficiency, late
renal insufficiency, pre-ESRD
5 Kidney failure <15 Renal failure, uremia, end-stage
(or dialysis) renal disease
D if dialysis
(hemodialysis,
peritoneal dialysis)
GFR glomerular filtration rate, ESRD end-stage renal disease, “T” for Transplant, “D” for Dialysis
Related terms for CKD stages 3–5 do not have specific definitions, except ESRD
Fig. 25 Photomicrograph of a histopathology specimen damage to structure of the kidney (black arrows). Hema-
of a recent infarct of the kidney (a; 20) showing the toxylin and eosin stain. (Images courtesy of Professor
central portion with a large amount of hemorrhage and Camile Farah, UWA Dental School, University of Western
loss of normal renal architecture, and (b; 100) showing Australia, Perth WA, Australia)
▶ “Salivary Gland Disorders and Diseases,” and broadest division is between central nervous dis-
▶ “Oral Manifestations of Systemic Diseases and orders and peripheral nervous disorders and
Their Treatments.” includes epilepsy, Alzheimer’s disease and other
dementias, cerebrovascular diseases including
stroke, migraine and other headache disorders,
Neurological Disorders multiple sclerosis, Parkinson’s disease, neuro-
infections, brain tumors, traumatic disorders, and
Neurological disorders are diseases caused by a malnutrition.
dysfunction that affects the central and peripheral
nervous system; brain, spinal cord, cranial and
peripheral nerves, nerve roots, autonomic nervous Multiple Sclerosis
system, neuromuscular junctions, and muscles
can be involved in structural, biochemical, or Multiple sclerosis (MS) is a chronic inflammatory
electrical abnormalities, resulting in physical disease of the central nervous system and a com-
and/or psychological symptoms. Epidemiologists mon cause of nontraumatic neurological disability
estimate that neurological disorders represent 3% in young adults. MS is idiopathic in nature, but
of the worldwide burden of disease. Although this increasing correlative evidence supports a strong
value seems small overall, dementia, epilepsy, association between genetic background, environ-
migraine, and stroke rank in the top 50 causes of ment (nicotine, exposure to the Epstein-Barr
disability-adjusted life years (Murray et al. 2012). virus, low exposure to sunlight, presumed to be
Neurologic disorders are wide ranging and may mediated through vitamin D insufficiency), and
have various causes, complications, and out- the immune system. The prevalence of MS has
comes. They can be congenital (gene and chro- been recorded as >200/100,000 in restricted
mosome abnormalities, metabolic disorders, pre-/ populations; there is a global latitude gradient,
perinatal causes), acquired (immune-mediated, so disease appears to be more common in the
infections, traumatic, neoplastic), or idiopathic. northern hemisphere with lower prevalence seen
There are over 600 neurological disorders that nearer the equator (Simpson et al. 2011). Gener-
can be categorized according to the primary loca- ally, MS is of lower prevalence in Asian countries
tion affected, the primary type of dysfunction and is more common within populations as socio-
involved, or the primary type of etiology. The economic status increases. MS affects more
women than men, Caucasians, is associated with Trigeminal neuralgia is present in 6.3% of cases
other autoimmune diseases (e.g., type 1 diabetes (Putzki et al. 2009). Another common presenting
and autoimmune thyroiditis), and has a clear sign of MS is optic neuritis, highlighted by com-
genetic predisposition associated with variations plete or partial loss of vision (Hauser and
of class II Major Histocompatibility Complex Goodwin 2008).
(MHC) and non-MHC variants which are Diagnosis is established if: (1) there is evi-
involved in T-cell activation/regulation dence of damage in at least two separate areas of
(Compston and Coles 2008). The pathogenesis is the central nervous system; (2) damaged areas
characterized by inflammation and develop at least 1 month apart; (3) there are pos-
neurodegeneration mediated by the adaptive and itive MRI findings; and (4) all potential different
innate arms of an unregulated immune response. diseases are excluded. To date, no definitive treat-
There are patches of inflammation within the cen- ments are available.
tral nervous system (plaques) with demyelination
of axons and oligodendrocyte loss, as shown on
magnetic resonance imaging (MRI), caused by an Amyotrophic Lateral Sclerosis
immune attack against central nervous system
antigens mediated through activated CD4+ and Amyotrophic lateral sclerosis (ALS) is a term
CD8+ myelin-reactive T cells, activated macro- used to cover the spectrum of neurodegenerative
phages/microglia, and plasma cells with a possi- syndromes characterized by progressive degener-
ble contribution by B cells (O’Connor et al. 2001). ation and death of motor neurons. “Amyotrophy”
MS plaques can be further classified histologi- refers to the atrophy of muscle fibers, while “lat-
cally as active, chronic, and demyelinated. Corti- eral sclerosis” refers to hardening of the anterior
cal involvement can occur in MS with three and lateral corticospinal tracts as motor neurons in
distinct lesion types: subpial, intracortical, and these areas degenerate and are replaced by gliosis
leukocortical (Bogdan et al. 2013) that correlate (Rowland and Shneider 2001). This terminology
with cognitive impairment. is usually used in the most common form of the
MS can be classified into: (1) a clinical isolated disease, classical (Charcot’s) ALS. Other related
syndrome, characterized by acute or subacute syndromes include progressive bulbar palsy, pro-
onset of monophasic episode suggestive of MS, gressive muscular atrophy, primary lateral sclero-
where the episode usually affects the optic nerve, sis, flail arm syndrome (Vulpian-Bernhardt
brain stem, and spinal cord; (2) a relapsing-remit- syndrome), flail leg syndrome (pseudo-
ting MS, characterized by relapses over days to polyneuritic form) and ALS with multisystem
weeks, followed by complete or partial remissions involvement (e.g., ALS-Dementia). Motor neu-
over months or years; and (3) a progressive MS rons are nerve cells located in the brain, brain
characterized by progressive accumulation of dis- stem, and spinal cord that serve as controlling
ability after an initial relapsing course of the dis- units and vital communication links between the
ease. Symptoms of MS are variable and may nervous system and the voluntary muscles of the
result from involvement of sensory, motor, visual, body. In ALS, both the upper and lower motor
and brainstem pathways. Initial clinical findings neurons degenerate or die and stop sending mes-
are paresthesias (numbness and tingling), sages to muscles. Unable to function, the muscles
dysesthesias (burning and “pins and needles”), gradually show atrophy and fasciculation. The
diplopia, ataxia, vertigo, and bladder (urinary prevalence of the disease is 3–5 cases/100,000
sphincter) disturbances (Lublin et al. 2014). A persons, even if some areas in the Western Pacific
common manifestation of MS is unilateral numb- present prevalence around 50 times higher;
ness affecting one leg that spreads to involve the median survival is 2–4 years from onset; only
other leg and rises to the pelvis, abdomen, or 5–10% of patients survive beyond 10 years
thorax. Sensory disturbances usually resolve but (Chio et al. 2009). Etiology is still unknown and
sometimes evolve into chronic neuropathic pain. there is no consensus; genetics (superoxide
dismutase 1 mutation), environmental and occu- (locally), generalized (bilaterally), and unclassi-
pational factors (tobacco, pesticides, drugs, fied. Partial seizures can be complex or simple
heavy-metal intoxication), viral infection and based on the presence or absence of impairment
physical activity are the most commonly postu- of consciousness; generalized seizures are further
lated risk factors. In the pathogenesis of the dis- divided into: (a) absence (true absence or “petit
ease, mitochondrial dysfunction seems to be a mal”); (b) myoclonic; (c) clonic; (d) tonic;
crucial step both for the onset and progression of (e) tonic-clonic; and (f) atonic.
the disease; other implicated altered mechanisms Etiology of the disease is not completely clar-
include the action of free radicals, inflammation ified; potentiation of excitatory synapses and
and apoptosis, and glutamate-induced depression of inhibitory synapses are probable
excitotoxicity (Naganska and Matyja 2011). critical events in epileptogenesis. Ion channel
Signs and symptoms are variable, characterized gene mutations have been identified in some
by progressive muscle weakness, fasciculation, type of epilepsies such as generalized forms with
and cramps leading to death, usually from respi- febrile seizures, autosomal dominant nocturnal
ratory failure; at the onset symptoms are often frontal lobe epilepsy, benign familial neonatal
unilateral and focal, patients show foot drop, dif- convulsions, and episodic ataxia type 1 with par-
ficulty walking, loss of hand dexterity, or weak- tial seizures. For all other types, there are probably
ness when lifting the arms. Moreover, patients alterations of synaptic functions with an imbal-
may have dysarthria followed by dysphagia, ance between glutamate and gamma-
which may progress to sialorrhea, malnutrition, aminobutyric acid neurotransmitter systems on
and anarthria; an atrophied fasciculating tongue one hand, and catecholaminergic neurotransmitter
is diagnostic of bulbar ALS (Chio et al. 2009). systems and opioid peptides on the other side.
The diagnostic process is based on clinical data, These imbalances after complex processes can
neuroimaging, evoked potential studies, and in lead to hyperexcitability of neuronal circuits
selected cases by cerebrospinal fluid analysis. (Engelborghs et al. 2000). Classification of epi-
Management of ALS is complex, encompassing lepsy may be established based on 5 etiologic
pharmacologic and nonpharmacologic treatments categories: (1) idiopathic genetic or presumed
based on individual symptoms with the involve- genetic origin); (2) symptomatic (acquired or
ment of a large group of health professionals. genetic cause with anatomic or pathologic abnor-
malities or conditions); (3) provoked (when a
specific systemic or environmental factor is iden-
Epilepsy tified); and (4) cryptogenic (idiopathic probably
non-genetic).
Epilepsy was defined conceptually as a disorder of At the onset of the disease, differential diagno-
the brain characterized by an enduring predispo- sis should be established between an epileptic
sition to generate epileptic recurrent seizures (two seizure and a series of paroxysmal phenomena,
or more), and the neurobiologic, cognitive, psy- such as syncope, pseudo-seizure, or aura related to
chological, and social consequences of this con- migraine, which may manifest with similar symp-
dition. A seizure is a transient manifestation of an toms. The diagnostic process encompasses medi-
abnormal, hypersynchronous activity of a popula- cal history, electroencephalogram (EEG), and
tion of cortical neurons (Fisher et al. 2005). It is magnetic resonance imaging. EEG remains the
estimated that 50 million individuals worldwide most commonly used technique for the evaluation
have a diagnosis of epilepsy, but available data on of patients with epilepsy, demonstrating the phys-
incidence and prevalence are not homogeneous iological manifestations of abnormal cortical
depending on study methodology and character- excitability that underlie epilepsy. Routine EEG
istics of population (genetics, socioeconomic sta- helps in diagnosis, classification of seizure, iden-
tus, access to health care) (WHO 2001). Seizures tification of treatment, and monitoring the efficacy
are commonly clinically classified into partial of therapy. A lumbar puncture may be helpful in
specific clinical circumstances such as in patients 2009). The duration and reversibility of brain
who are otherwise febrile. Medications, implant- ischemia are variable with signs and symptoms
able devices, and surgery represent the main treat- that may be clinically transient with evidence of
ment modalities. Because of more frequent brain infarction. Risk factors are divided into non-
comorbidities, physiologic changes, and a higher modifiable (age, sex, race, ethnicity, geography,
sensitivity to drugs, the management with anti- heredity) and modifiable (infections, renal dis-
epilepsy drugs is not unique because of acute ease, inflammation, diet). The major risk factors
and chronic related side effects. The goal of treat- for intracerebral hemorrhage are hypertension,
ment is seizure freedom in order to reduce injury age, current smoking, diabetes mellitus, and
and mortality and improve quality of life. high/moderate alcohol intake.
Ischemic stroke can be thrombotic (large and
small vessel type), embolic, caused by systemic
Stroke hypoperfusion or venous thrombosis. The final
result is a compromised vascular supply to the
Stroke or brain attack represents the leading cause brain. Pathogenesis at the cellular level encom-
of chronic disability worldwide, the second lead- passes different excitotoxicity mechanisms,
ing cause of dementia and the fourth leading cause inflammatory pathways, nitric oxide production,
of death in USA; it is the typical result of the two free radical oxidative damage, ionic imbalances,
common diseases atherosclerosis and hyperten- and apoptosis.
sion. The incidence of stroke rapidly increases Hemorrhagic stroke can be intracerebral (more
with age, doubling for each decade after age common, due to hypertension, trauma, bleeding
55 (Roger et al. 2011). disorders, drug related, malformations) and sub-
The trends in stroke incidence and mortality arachnoid (caused by the rupture of aneurysm
rates have decreased in recent decades for high- from the base of the brain). In this type of stroke,
income countries such as the USA, the United the results are hypoxia, direct inflammation of
Kingdom, and Canada (Carandang et al. 2006) bleeding on brain parenchyma, and increased
due to the prevention measures of the major risk intracranial pressure.
factors and higher standard of care. Common and reliable symptoms include sub-
Stroke is classically defined as a neurological jective arm/leg/facial weakness, speech distur-
deficit attributed to an acute focal injury of the bance, arm/leg paresthesia, headache, and
central nervous system by a vascular cause, dizziness. Signs include arm/leg/facial paresis,
including cerebral infarction, intracerebral hemor- dysphasia or dysarthria, eye movement abnormal-
rhage, and subarachnoid hemorrhage, and is a ity, and visual defect. The most important histor-
major cause of disability and death worldwide. ical feature of stroke in the first steps of the
In 1970, WHO defined stroke as “rapidly devel- diagnostic process is the suddenness of the onset
oping clinical signs of focal (or global) distur- of the neurological symptoms. Brain and
bance of cerebral function, lasting more than neurovascular imaging is required for diagnosis;
24 hours or leading to death, with no apparent noncontrast computed tomography is the current
cause other than that of vascular origin” (Aho standard, while MRI has greater spatial resolution
et al. 1980). With more research, evidence, and to detect brain ischemia in TIA or minor ischemic
advances of technologies, it has been clear that stroke. Computed tomography angiography is
this WHO definition is obsolete because the “24- recommended immediately following
hour” inclusion criterion for cerebral infarction is non-contrast head CT for the identification of
inexact, since permanent damage can occur much vascular damage. In cases of hemorrhagic stroke,
sooner. Transient ischemic attack (TIA) is defined intracranial CT angiography will identify intracra-
as a transient episode of neurological dysfunction nial aneurysm. The most common conditions that
caused by focal brain, spinal cord, or retinal ische- can mimic a stroke are seizure, conversion or
mia without acute infarction (Higashida et al. somatoform disorder, migraine, hypoglycemia,
systemic infections, hypotension/syncope, tumor, dysfunction, cognitive/neurobehavioral abnor-

vertigo, and dementia. malities, sleep disorders, and sensory abnormali-
The management of stroke in the context of an ties such as anosmia, paresthesias, and pain).
acute setting follows the paradigm, “Time is Diagnosis is still largely a clinical one; physicians
brain”; every passing minute reduces the chance should consider other causes besides PD, includ-
of neurological recovery and worsens prognosis. ing medication side effects, vascular parkinson-
With this view, the focus is manifold to reduce ism, and dementia with Lewy bodies. Drug-
time to symptom recognition, patient transport, induced Parkinsonism is most important to diag-
and neurological evaluation and intervention. nose, given that it can be reversed. Genetic tests,
MRI, and dopamine-transporter single-photon-
emission computed tomography imaging can
Parkinson’s Disease help with clinical diagnostic decisions (Tolosa
et al. 2006).
Parkinson’s disease (PD) is a chronic, progressive Levodopa in association with carbidopa, a
neurodegenerative disease characterized by both peripheral decarboxylase inhibitor, remain the
motor and nonmotor features, resulting from the gold standard of symptomatic treatment for
death of the dopamine containing cells of the PD. This association is important because
substantia nigra. Dopamine is a chemical messen- carbidopa inhibits the decarboxylation of levo-
ger that transmits signals between two regions of dopa to dopamine in the systemic circulation,
the brain to coordinate activity. PD affects 1–2 per allowing for greater levodopa distribution into
1000 of the population at any time; the prevalence the central nervous system. Other strategies of
increases with age, affecting 1% of the population medication include the association of carbidopa/
above 60 years (Tysnes and Storstein 2017). Eti- levodopa/entacapone, dopamine-receptor ago-
ology is still unknown in most cases; genetic risk nists (bromocriptine, ropinirole, pramipexole,
factors have been identified in 5–10% of patients apomorphine), rotigotine transdermal system,
related to mutations on chromosome 4. Several catechol-O-methyltransferase inhibitors, selective
environmental factors like exposure to herbicides monoamine oxidase-B inhibitors, and anticholin-
and pesticides are associated with increased risk ergic agents (muscarinic receptor antagonists).
of PD (Zhou et al. 2008). Pathologically con- Treatment should be individualized.
firmed PD encompasses a spectrum of micro-
scopic findings with respect to mitochondrial
dysfunction, calcium homestasis dysregulation, Dementia/Alzheimer’s Disease
the extent and distribution of Lewy body
(intracytoplasmic inclusions) deposition, and Dementia is a progressive group of disorders of
spreading to neocortical and cortical regions. memory loss and impaired cognitive ability. It is
Lewy bodies consist of eosinophilic inclusions an acquired clinical syndrome characterized by
containing a loosely compact core of aggregated deterioration of mental functioning in its cognitive,
α-synuclein and other proteins. The extension of affective, and conative aspects. The Diagnostic and
their localization may reflect the clinical pheno- Statistical Manual of Mental Disorders (American
types observed during life. Psychiatric Association. DSM-5 2013) has
Clinically, PD is characterized by four cardinal changed some definitions from the previous one
signs: resting tremor, bradykinesia or slowness, (DMS-IV); the term dementia has been replaced
rigidity, and postural instability. Other clinical by “major neurocognitive disorder” with four main
features include secondary motor symptoms characteristics: (1) evidence of significant cognitive
(e.g., hypomimia, dysarthria, dysphagia, decline from a previous level of performance in one
sialorrhea, micrographia, shuffling gait, or more cognitive domains (learning and memory,
festination, freezing, dystonia, glabellar reflexes), language, executive function, complex attention,
and nonmotor symptoms (e.g., autonomic perceptual-motor, social cognition); (2) the
cognitive deficits interfere with independence in Early diagnosis of dementia can be difficult
everyday activities (at a minimum, assistance due to its insidious onset, symptoms resembling
should be required with complex instrumental “normal aging” memory loss; this often requires
activities of daily living, such as paying bills or more than one visit before confirming the diagno-
managing medications); (3) the cognitive deficits sis. Additionally, a family member should be
do not occur exclusively in the context of a delir- interviewed with the patient. Diagnosis of subtype
ium; and (4) the cognitive deficits are not better is important given differences in management,
explained by another mental disorder (e.g., major disease course, and outcomes for different demen-
depressive disorder, schizophrenia) (American tias. A complete neurological examination is
Psychiatric Association. DSM-5 2013). The most requested and brain imaging (MRI or CT) is
common type of dementia is Alzheimer’s disease recommended. Serological tests should be consid-
(AD) in 50–70% of cases; other common types ered to identify reversible conditions that may
include vascular dementia (25%), Lewy body mimic dementia.
dementia (15%), and frontotemporal dementia. Currently, there is no US FDA-approved ther-
Less common causes are hydrocephalus, apy to delay onset or progression of dementia;
Parkinson’s disease, neuro-infections (i.e., syphilis, agents with possible neuroprotective characteris-
Creutzfeldt-Jakob disease), metabolic central ner- tics are vitamins and dietary supplements
vous system disorders, demyelinating disease (mul- (vitamin E, vitamin B6, folate, ginkgo biloba,
tiple sclerosis), head trauma, neuropsychiatric curcumin spice, docosahexaenoic acid), hor-
disorders, and effects of medication. Different sub- mones (testosterone, estrogens), and medications
types of dementia can coexist in the same patient (selegiline, nonsteroidal anti-inflammatory drugs,
(WHO 2014). More than 25 million individuals and lipid-lowering agents (statins and fibrates)).
suffered from dementia in 2000; by 2030, that is
expected to rise to 63 million, 65% of whom from
less developed countries (Launer 2005). Non- Oral Manifestations of Neurological
modifiable risk factors are age, family history, Disorders
Down Syndrome, mild cognitive impairment that
means difficulty with memory without loss of daily Patients suffering from multiple sclerosis can pre-
function. Modifiable risk factors include heavy sent with chronic orofacial pain, trigeminal neu-
alcohol use, cardiovascular disease, depression, ralgia, oral paresthesia, and taste disturbances.
diabetes, smoking, and sleep apnea. There are Progressive paralysis of orofacial and pharyngeal
four main causes of reversible dementia including functions can be observed in patients suffering
hypothyroidism, vitamin B12 deficiency, Lyme with amyotrophic lateral sclerosis and an
disease, and neurosyphilis. Based on ICD-10, AD atrophied fasciculating tongue is reportedly diag-
clinically is different from typical senile dementia nostic of bulbar ALS. Patients who have suffered
because of insidious onset with slow deterioration, a stroke can present with difficult to diagnose
absence of indication of other systemic or brain chronic orofacial pain, oral dysesthesia, and taste
disease that can induce a dementia, and absence disturbances, while those patients with dementia
of apoplectic onset or focal neurological signs early can have significant difficulty with drooling and
in the disease (WHO 2016). Neurodegenerative sialorrhea. These oral manifestations are
dementia is age related, with prevalence estimated discussed further in separate chapters within this
at 20% in individuals older than 85 years; it is text, including ▶ “Salivary Gland Disorders and
characterized by the deposition of abnormal pro- Diseases,” ▶ “Oral and Maxillofacial Fungal
teins in the brain: beta amyloid in AD, Tau in Infections,” ▶ “Neurovascular Orofacial Pain,”
frontotemporal lobar degeneration, TDP-43 in ▶ “Neuropathic Orofacial Pain,” ▶ “Oral
ALS, alpha-synuclein in PD, polyglutamine- Dysesthesia,” ▶ “Neurosensory Disturbances
expanded proteins in Huntington’s disease, and Including Smell and Taste,” and ▶ “Orofacial
prion protein in Creutzfeldt-Jakob disease. Pain in the Medically Complex Patient.”
Psychiatric Disorders Table 19 Classification of mental disorders. (Adapted

from DSM 5, fifth edition) (American Psychiatric Associ-
ation. DSM-5 2013)
Psychiatric disorders are defined as behavioral or
psychological syndromes or patterns that occur in Neurodevelopmental disorders
an individual, the consequences of which are clin- Schizophrenia Spectrum and other psychotic disorders
Bipolar and related disorders
ically significant distress (e.g., a painful symp-
Depressive disorders
tom) or disability (i.e., impairment in one or
Anxiety disorders
more important areas of functioning). This must
Obsessive-compulsive and related disorders
not be merely an expectable response to common
Trauma- and stressor-related disorders
stressors and losses, or a culturally sanctioned Dissociative disorders
response to a particular event, or a result of social Symptom and related disorders
deviance, or conflicts with society that reflects an Feeding and eating disorders
underlying psychobiological dysfunction (Stein Elimination disorders
et al. 2010). In this group, a wide range of mental Sleep-wake disorders
health conditions are included that combine a Sexual dysfunctions
variety of symptoms with a substantial change of Gender dysphoria
mood, thinking, and behavior. Statistics show on Disruptive, impulse-control, and conduct disorders
average that one in five adults (17.6%) experience Substance-related and addictive disorders
a common mental disorder within a 12-month Neurocognitive disorders
period and 29.2% across their lifetime with a Personality disorders
major prevalence among females. North and Paraphilic disorders
South East Asia are the only regions where there Other mental disorders
is a lower prevalence estimation in comparison to Medication-induced movement disorders and other
adverse effects of medications
other areas of the world (Steel et al. 2014).
Worldwide, mental illnesses are some of the
and sleep, thinking or talking about suicide,
most common causes of hospitalizations, disabil-
excessive anger, or violent behavior.
ities with related reduction of productivity, and
The diagnosis is based on the evaluation of
elevated risks of suicide. They are generally
symptoms and not on a quantitative medical test.
referred to as “disorders” (illnesses that disrupt
For this purpose, the American Psychiatric Associ-
normal function) and only a few as “diseases”
ation publishes the Diagnostic and Statistical Man-
(disorders with known pathophysiology or struc-
ual of Mental Disorders; currently in its fifth
tural pathology). Over 300 psychiatric disorders
edition) (American Psychiatric Association.
have been described, and Table 19 lists a sche-
DSM-5 (2013)) which was recently updated, to
matic classification, according to the Diagnostic
diagnose specific mental illness. The manual pro-
and Statistical Manual of Mental Disorders
vides important information on the description of
(American Psychiatric Association. DSM-5
disorders and a list of typical symptoms.
2013). Etiological factors include a combination
of biological, psychological, and environmental
factors (such as injury, poor nutrition, and expo- Anxiety
sure to toxins). Research has focused attention on
the potential role of neurotransmission and related Anxiety is a feeling of unease characterized by
problems between neurons in the brain. transient fear, a persistent sense of apprehension,
From a clinical perspective, each psychiatric uncertainty, and it can range from mild to severe
disorder is marked by a specific pattern of signs (Barlow 2004). The terminology of anxiety disor-
and symptoms, but there are common signs that ders includes different diseases such as generalized
combine the majority of patients such as marked anxiety disorder, panic disorder, phobias, and
personality change, excessive anxiety, prolonged others. Anxiety is often associated with:
depression or capacity, marked changes in eating (a) physical symptoms such as sweating,
Table 20 Classification of anxiety disorders. (Adapted Table 21 Classification of depression disorders. (Adapted
from DSM 5, fifth edition) (American Psychiatric Associ- from DSM 5, fifth edition) (American Psychiatric Associa-
ation. DSM-5 2013) tion. DSM-5 2013)
Generalized anxiety disorders Disruptive mood dysregulation disorder
Selective mutism Major depressive disorder
Separation anxiety disorders Persistent depressive disorder (dysthymia)
Social anxiety disorders Premenstrual dysphoric disorder
Specific phobia Substance/medication-induced depressive disorder
Agoraphobia Depressive disorder due to another medical condition
Panic attack Other specified depressive disorder
Panic disorders Unspecified depressive disorder
Substance-induced anxiety disorders
Anxiety disorder due to another medical condition
pharmacodynamic properties, and potential inter-
actions with co-administered medications and
palpitations, shortness of breath, and muscle ten- co-morbidities.
sion; (b) behavioral symptoms such as compul-
sions and nervous habits; and (c) cognitive
symptoms such as worries, obsessions, and racing Depression
thoughts. Patients usually report restlessness, a
sense of impending doom, fear of dying, fear of Depression is a common mental disorder, charac-
embarrassment or humiliation, or fear of something terized by sadness, loss of interest or pleasure,
terrible happening. According to epidemiological feelings of guilt or low self-worth, disturbed
surveys, about 34% of the population are affected sleep or appetite, feelings of tiredness, and poor
by an anxiety disorder during their lifetime; they concentration. Depression disorders include a
affect mainly women, usually during midlife large group of diseases (Table 21), which symp-
(Bandelow and Michaelis 2015). The different sub- toms must be present for at least 2 weeks to make
types that belong to the group of anxiety disorders a proper diagnosis of “depression.” WHO has
are specified in Table 20, of which the most com- ranked depression as the fourth leading cause of
mon is social phobia that typically develops in disability worldwide. Data of prevalence differ in
young patients. The diagnosis is made only when a wide range from 3% in Japan to 17% in USA,
clinicians exclude other medical conditions or with a major prevalence in females. Major depres-
effects derived from drugs compatible with the sive disorders (MDD) are the most common
same symptoms. Management includes clinical among the group, with severe and persistent
intervention with effective treatments including symptoms (Kessler et al. 2003). There is varying
cognitive-behavior therapy, behavior therapy, and evidence that confirm MDD as a multifactorial
relaxation training, in addition to antianxiety med- disease where multiple causes (psychological,
ication. Different and multiple neurotransmitters biological, genetic, and social) may act at different
play a role in normal states and in pathologic levels. Genetic studies show different gene poly-
anxiety states. Each of these systems is a potential morphisms in the glucocorticoid receptor gene
target for pharmacologic intervention, but rela- NR3C1, the monoamine oxidase A gene, the
tively few classes of medications are used in gene for glycogen synthase kinase-3β, the seroto-
clinical practice for the treatment of anxiety. nin transporter gene (SLC6A4) (Kupfer et al.
These agents are represented by selective serotonin 2012). Molecular studies underline at least three
reuptake inhibitors (SSRIs), serotonin- main categories of peripheral hormone-type
norepinephrine reuptake inhibitors (SNRIs), ben- factors implicated in the pathophysiology of
zodiazepines, antiseizure medications, and tricyclic MMD: (1) neurotrophic factors and other growth
antidepressants. The choice of medication is based factors; (2) proinflammatory cytokines; and
on the side-effect profile, pharmacokinetic and (3) impaired regulation of the hypothalamic-
pituitary-adrenocortical axis (Brunoni et al. and social features. They represent an important
2008). Moreover, magnetic resonance images of cause of physical and psychosocial morbidity in
the brains of patients with depression have iden- adolescent girls and young adult women and less
tified differences in both structure and function frequently in men. Eating disorders are divided
compared to nondepressed subjects, providing into three diagnostic categories: anorexia nervosa,
evidence for specific functional abnormalities in bulimia nervosa, and binge eating disorder
these neural systems in adults (Videbech and (DSM-V). The average prevalence rates for
Ravnkilde 2004). Diagnosis is based on clinical anorexia nervosa and bulimia nervosa are 0.3%
symptoms of at least 2 weeks’ duration (although and 1% among adolescence and young people in
most episodes last considerably longer) involving western countries, respectively (Hudson et al.
clear-cut changes in affect, cognition, and 2007). Anorexia nervosa has the highest mortality
neurovegetative functions. rate, and in about 10% of cases, patients die within
Many people with depression also suffer from 10 years of the onset of the disorder for medical
anxiety symptoms and medically unexplained complications of suicide. In surviving patients, on
somatic symptoms. Somatization is a pattern of average, only 46.9% of patients make a full recov-
behaviors in which an individual presents with a ery, while 33.5% improve, and 20.8% have a
set of somatic symptoms. The term “somatic” chronic course of disease (Sullivan 2002). In the
means different bodily sensations that a depressed development of ED, a pivotal role is represented
individual perceives as unpleasant or worrisome. by sociocultural factors (media and peer influ-
These dysesthesias are very often localized, may ences), family factors (enmeshment and criti-
affect the whole body with fatigue or loss of cism), negative affect, low self-esteem,
energy. Other symptoms such as disturbances of personality trait, and body dissatisfaction. Cogni-
sleep, appetite, or digestion, are also to be tive factors such as obsessive thoughts, inaccurate
included in the term “somatic.” These symptoms judgments, perfectionism, and rigid thinking pat-
are also considered as typical variants of terns are also important. But ED are also consid-
somatoform disorders and termed according to ered as neuroendocrine dysfunctions that could be
the diagnostic standards of the various medical primary (i.e., a hormonal aberration triggers the
disciplines, such as fibromyalgia, chronic fatigue disorder or central dysfunction of the hypothala-
syndrome, and irritable bowel syndrome. mus) or mediational (i.e., stress or some other
Management of depression is the result of a environmental factor disrupts hormonal function-
combination of medication and non- ing, which in turn affects eating). DSM-V
pharmacological strategies (psychoeducation, describes diagnostic criteria for ED in detail.
psychotherapeutic interventions such as cognitive Anorexia nervosa, divided into the two main
behavioral therapy). There is no gold standard for subtypes “restricting” and “binge/purging,” has
the best choice of antidepressants; the medication 3 main features: (a) reduction of food intake leading
should be prescribed depending on patient factors to a significantly low body weight (defined as less
(preference, previous history of response/tolera- than minimally normal or, for children and adoles-
bility, past side effects, age, drug interactions, cents, less than that minimally expected);
comorbidities, sexual dysfunction), cost, dosing (b) intense fear of gaining weight or of becoming
strategy, and type of formulation. In general, fat, or persistent behavior that interferes with
selective serotonin reuptake inhibitors (SSRI) are weight gain, even though at a significantly low
considered to be first line antidepressants. weight; and (c) disturbance in the way in which
one’s body weight or shape is experienced. The
severity of the disease is classified in mild, moder-
Eating Disorders ate, severe, extreme following BMI measures that,
respectively, are 17 Kg/m2, between 16 and 16.99
Eating disorders (ED) comprise a range of syn- Kg/m2, between 15 and 15.99 Kg/m2, and < 15
dromes encompassing physical, psychological, Kg/m2. Serological exams typically reveal
underlying leukopenia, anemia, high levels of urea anorexia nervosa, the combination of medical
nitrogen (dehydration) and hepatic enzymes, management, behavioral therapy, cognitive ther-
hypercholesterolemia, metabolic alkalosis in case apy, and family therapy represents the best choice,
of self-vomiting, low T3, T4 and estrogen levels while drugs are second-line therapy. In bulimia
(amenorrhea is a common finding). Sinus brady- nervosa, the treatment is cognitive-behavioral
cardia and low bone mineral density are common. therapy in association with antidepressants. In
Typical signs include emaciation, hypotension, binge eating disorder, cognitive-behavioral ther-
hypothermia, peripheral edema, petechie, or ecchy- apy and interpersonal therapy produce substantial
moses (bleeding diathesis). and long-lasting changes and pharmacologic
Bulimia nervosa has four main characteristics: treatment often has a useful role (Halmi 2005).
(a) recurrent episodes of binge eating; (b) fear of
weight gain, reason to assume self-induced
vomiting, misuse of laxatives, diuretics, or other Substance-Related Disorders
medications, fasting, excessive exercise; (c) these
compensatory behaviors occur at least once a Substance related disorders (SRD) are disorders
week for 3 months; and (d) body shape and weight of intoxication, dependence, abuse, and substance
become parameters for self-evaluation. withdrawal caused by various substances, both
The severity of the disease is classified as mild, legal and illegal, that activate the reward system
moderate, severe, and extreme following the num- in the brain, which produce feelings of pleasure in
ber of episodes/week of compensatory behaviors the user. According to DSM-V, SRD encompass
that, respectively, is between 1 and 3, 4 and 7, 8 10 separate classes of drugs: (1) alcohol; (2) caf-
and 13, and greater than 14. Patients with bulimia feine; (3) cannabis; (4) hallucinogens; (5) inhal-
nervosa typically are within the normal weight or ants; (6) opioids; (7) sedatives, hypnotics, and
overweight range. Typical signs are menstrual anxiolytics; (8) stimulants (amphetamine-type
irregularity or amenorrhea, electrolyte imbalance, substances, cocaine, and other stimulants);
metabolic alkalosis (vomiting) and acidosis (diar- (9) tobacco; and (10) other (or unknown) sub-
rhea), esophageal tears, gastric rupture, cardiac stances. SRD are usually divided into two groups:
arrhythmia, and rectal prolapse. substance-induced disorders (caused by the direct
Binge eating disorder has five main characteris- effects of a drug) and substance use disorders
tics: (a) recurrent episodes of binge eating; (b) it is (when patients continue to use a substance despite
associated with 3 or more of the following features: having problems caused by its use).
eating quickly, until feeling uncomfortably full, Patients affected by substance use disorder
eating large amounts of food without a real need, have persistent desire or unsuccessful attempts
eating alone, feeling disgusted afterward; (c) binge to cut down or control use of the substance, failing
eating is associated to marked distress; (d) binge to fulfill major roles (work, school, home), with
eating episode occurs at least once a week for persistent social or interpersonal problems
3 months; and (e) binge eating is not associated caused by the substance abuse. They use drugs
with the recurrent use of inappropriate compensa- in physically hazardous situations and despite
tory behavior. The severity of the disease is classi- physical or psychological problems caused by
fied as mild, moderate, severe, and extreme their use.
following the frequency of episodes of binge eating Patients affected by substance-induced disor-
per week and, respectively, is between 1 and 3, 4 ders show the following features: intoxication,
and 7, 8 and 13, and greater than 14. withdrawal, psychotic/bipolar disorder, major
Bipolar, depressive, and anxiety disorders depression, anxiety/sleep disorders, delirium,
commonly co-occur in all the three diseases. The and sexual dysfunction. Intoxication is a revers-
treatment strategy is not unique and is deeply ible substance-specific syndrome due to recent
influenced by the severity of diseases and the ingestion of a substance; this can lead to direct
presence of comorbidities. For the treatment of effects on the central nervous system with
disturbances of perception, attention, and wake- otolaryngology, psychiatry, and medical oncology
fulness. It is not related to tobacco. The severity of would doubtlessly increase the quality of oral
the intoxication depends on the type, dose, and medicine practice. An increase in
route of administration of the substance, individ- interprofessional knowledge and cooperation
ual degree of tolerance, and time since last dose. will improve clinical outcomes and provide
Withdrawal is a substance-specific syndrome patients with better care.
problematic behavioral change due to stopping Understanding of systemic diseases and their
or reducing prolonged use of the substance. oral manifestations is a cornerstone of contempo-
Treatment strategies for both inpatients rary oral medicine practice. The oral medicine
and outpatients are the combination of psycho- specialist should keep abreast of advances in mod-
dynamic, behavioral, cognitive-behavioral, ern day medical innovations, techniques, and
and biological approaches, along with several practices, as they have direct effects on patient
sociocultural therapies. The biological approach care and safety.
consists of programs of detoxification, use of
antagonist drugs when possible (i.e., disulfiram
for alcohol), and drug maintenance therapy.
Cross-References
Oral Manifestations of Psychiatric ▶ Arthritic Conditions Affecting the Temporo-

Disorders mandibular Joint
▶ Biopsychosocial Aspects of Orofacial Pain
Oral dysesthesia and persistent idiopathic facial ▶ Classification of Orofacial Pain
pain are often seen in patients with a variety of ▶ Clinical Evaluation of Oral Diseases
psychiatric disorders. Psychosocial factors are ▶ Diagnostic Imaging Principles and Applica-
also known to aggravate and perpetuate chronic tions in Head and Neck Pathology
orofacial pain. Patient’s suffering from eating dis- ▶ Gingival Pathology
orders can present with oral mucosal atrophy, oral ▶ Laboratory Medicine and Diagnostic
candidosis, salivary gland enlargement, and den- Pathology
tal enamel erosions that occur typically on the ▶ Neuropathic Orofacial Pain
lingual surfaces of the teeth. These oral manifes- ▶ Neurosensory Disturbances Including Smell
tations are discussed further in chapters within this and Taste
text, including ▶ “Salivary Gland Disorders and ▶ Neurovascular Orofacial Pain
Diseases,” ▶ “Oral and Maxillofacial Fungal ▶ Oral and Maxillofacial Fungal Infections
Infections,” ▶ “Odontogenic Pathology,” ▶ Oral and Maxillofacial Viral Infections
▶ “Neurovascular Orofacial Pain,” ▶ “Neuro- ▶ Oral Appliance Therapy for Sleep-Disordered
pathic Orofacial Pain,” ▶ “Oral Dysesthesia,” Breathing
▶ “Neurosensory Disturbances Including Smell ▶ Oral Dysesthesia
and Taste,” ▶ “Orofacial Pain in the Medically ▶ Oral Lichen Planus
Complex Patient,” and ▶ “Biopsychosocial ▶ Oral Manifestations of Systemic Diseases and
Aspects of Orofacial Pain.” Their Treatments
▶ Oral Ulcerative Lesions
▶ Orofacial Pain in the Medically Complex
Conclusions and Future Directions Patient
▶ Pharmacotherapeutic Approaches in Oral
Sound comprehensive training in internal Medicine
medicine together with in depth clinical experi- ▶ Pigmented Lesions of the Oral Mucosa
ences in medical specialties such as dermatology, ▶ Salivary Gland Disorders and Diseases
References Bogdan FP, Pirko I, Lucchinetti FC. Pathology of multiple

sclerosis: where do we stand? Cont Lifelong Learn
Abhishek A, Doherty M. Diagnosis and clinical presenta- Neurol. 2013;19:901–21.
tion of osteoarthritis. Rheum Dis Clin Am. Brunoni AR, Lopes M, Fregni F. A systematic review and
2013;39:45–66. meta-analysis of clinical studies on major depression
Adami S, Marcocci C, Gatti D. Epidemiology of primary and BDNF levels: implications for the role of
hyperparathyroidism in Europe. J Bone Miner Res. neuroplasticity in depression. Int J Neuropsycho-
2002;17:N18–23. pharmacol. 2008;11:1169–80.
Aho K, Harmsen P, Hatano S, Marquardsen J, Smirnov Bui AL, Horwich TB, Fonarow GC. Epidemiology and
VE, Strasser T. Cerebrovascular disease in the commu- risk profile of heart failure. Nat Rev Cardiol.
nity: results of a WHO collaborative study. Bull World 2011;8(1):30–41.
Health Organ. 1980;58:113–30. Buskila D, Cohen H, Neumann L, Ebstein RP. An associ-
Alter MJ. Epidemiology of hepatitis B in Europe and ation between fibromyalgia and the dopamine D4
worldwide. J Hepatol. 2003;39:S64–9. receptor exon III repeat polymorphism and relationship
American Diabetes Association. Diagnosis and classifi- to novelty seeking personality traits. Mol Psychiatry.
cation of diabetes. Diabetes Care. 2004;27(1): 2004;9:730–1.
S5–S10. Buskila D, Sarzi-Puttini P, Ablin JN. The genetics of
American Diabetes Association. 2. Classification and diag- fibromyalgia syndrome. Pharmacogenomics.
nosis of diabetes. Diabetes Care. 2016;39(Suppl 1): 2007;8:67–74.
S13–22. Campeau L. The Canadian Cardiovascular Society grading
American Psychiatric Association. Diagnostic and statisti- of angina pectoris revisited 30 years later. Can J
cal manual of mental disorders. 5th ed. Arlington: Cardiol. 2002;18(4):371–9.
American Psychiatric Association; 2013. Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe
Angastiniotis M, Modell B. Global epidemiology of hemo- ES. The 2008 WHO classification of lymphoid neo-
globin disorders. Ann N YAcad Sci. 1998;850:251–69. plasms and beyond: evolving concepts and practical
Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek applications. Blood. 2011;117(19):5019–32.
E. The pharmacology and management of the vitamin Carandang R, Seshadri S, Beiser A, et al. Trends in incidence,
K antagonists: the seventh ACCP conference on anti- lifetime risk, severity, and 30-day mortality of stroke over
thrombotic and thrombolytic therapy. Chest. 2004;126 the past 50 years. JAMA. 2006;296:2939–46.
(3 Suppl):204S–33S. Cheung MC, Maguire J, Carey I, Wendon J, Agarwal
Antony AC. Vegetarianism and vitamin B-12 (cobalamin) K. Review of the neurological manifestations of hepa-
deficiency. Am J Clin Nutr. 2003;78:3–6. titis E infection. Ann Hepatol. 2012;11:618–22.
AusDI. ausdi.hcn.com.au. 2018. [online] https://ausdi.hcn. Chio A, Logroscino G, Hardiman O, Swingler R, Mitchell D,
com.au/productInformation.hcn?file=p01084. Accessed Beghi E, Traynor BG. Prognostic factors in ALS: a crit-
21 May 2018. ical review. Amyotroph Lateral Scler. 2009;10:310–23.
Bandelow B, Michaelis S. Epidemiology of anxiety disor- Chlebowski RT, Anderson GL. Menopausal hormone ther-
ders in the 21stcentury. Dialogues Clin Neurosci. apy and breast cancer mortality: clinical implications.
2015;17(3):327–35. Ther Adv Drug Saf. 2015;6(2):45–56.
Barlow DH. Anxiety and its disorders: the nature and Chobanian AV, Bakris GL, Black HR, Cushman WC, Green
treatment of anxiety and panic. New York: Guilford LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright
Press; 2004. JT Jr, Roccella EJ, National Heart, Lung, and Blood
Bellomo R, Kellum JA, Ronco C. Acute kidney injury. Institute Joint National Committee on Prevention, Detec-
Lancet. 2012;380(9843):756–66. tion, Evaluation, and Treatment of High Blood Pressure,
Bernard BP, editor. Centers for Disease Control and Pre- National High Blood Pressure Education Program Coor-
vention National Institute for Occupational Safety and dinating Committee. The seventh report of the Joint
Health. A critical review of epidemiologic evidence for National Committee on Prevention, Detection, Evalua-
work-related musculoskeletal disorders of the neck, tion, and Treatment of High Blood Pressure: the JNC
upper extremity, and low back. 2018. www.cdc.gov/ 7 report. JAMA. 2003; 289(19):2560–72.
niosh/docs/97-141/pdfs/97-141.pdf. Accessed 8 May Chulilla JAM, Colás MSR, Martín MG. Classification of
2018. anemia for gastroenterologists. World J Gastroenterol.
Bernier PL, Stefanescu A, Samoukovic G, Tchervenkov 2009;15(37):4627–37.
CI. The challenge of congenital heart disease world- Cojocariu CE, Trifan AV, Gîrleanu I, Stanciu C. Alcoholic
wide: epidemiologic and demographic facts. Semin liver disease – epidemiology and risk factors. Rev Med
Thorac Cardiovasc Surg Pediatr Card Surg Annu. Chir Soc Med Nat Iasi. 2014;118(4):910–7.
2010;13(1):26–34. Compston A, Coles A. Multiple sclerosis. Lancet.
Beutler E, Waalen J. The definition of anemia: what is the 2008;372:1502–17.
lower limit of normal of the blood hemoglobin concen- Conti CR. Re-thinking angina. Clin Cardiol. 2007;
tration? Blood. 2006;107:1747–50. 30(2 Suppl 1):I1–3.
Coope A, Torsoni AS, Velloso LA. Mechanism in endo- Fox K, et al. Task force on the management of stable
crinology: metabolic and inflammatory pathways on angina pectoris of the European Society of Cardiology;
the pathogenesis of type 2 diabetes. Eur J Endocrinol. ESC Committee for Practice Guidelines (CPG). Guide-
2016;174(5):R175–87. lines on the management of stable angina pectoris:
Cooper C, Cole ZA, Holroyd CR, et al. Secular trends in executive summary: the task force on the management
the incidence of hip and other osteoporotic fractures. of stable angina pectoris of the European Society of
Osteoporos Int. 2011;22:1277–88. Cardiology. Eur Heart J. 2006;27(11):1341–81.
Costantinides F, Rizzo R, Pascazio L, Maglione Gatchel RJ, Kishino N. Pain, musculoskeletal injuries, and
M. Managing patients taking novel oral anticoagulants return to work. In: Quick JC, Tetrick LE, editors. Hand-
(NOAs) in dentistry: a discussion paper on clinical book of occupational health psychology. 2nd ed. -
implications. BMC Oral Health. 2016;16(1):5. Washington, DC: American Psychological
Davies MJ. The pathophysiology of acute coronary syn- Association; 2011.
dromes. Heart. 2000;83(3):361–6. Gessl A, Lemmens-Gruber R, Kautzky-Willer A. Thyroid
deBruin TWA, Bolk JH, Bussemaker JK, Stijnen T, disorders. Handb Exp Pharmacol. 2012;214:361–86.
Schreuder GM, deBries RRP, van der Heide Global Strategy for the Diagnosis, Management and Pre-
D. Graves’ disease: immunological and immunoge- vention of COPD (2017) Global initiative for Chronic
netic indications of relapse. Br Med J. Obstructive Lung Disease (GOLD) [internet]. http://
1988;296:1292–5. goldcopd.org/gold-2017-global-strategy-diagnosis-man
Delaney B, McColl K. Review article: Helicobacter pylori agement-prevention-copd/
and gastro-oesophageal reflux disease. Aliment Griepp RB, Ergin MA. The history of experimental heart
Pharmacol Ther. 2005;22(Suppl 1):32–40. transplantation. J Heart Transplant. 1984;3:145.
Dent J, El-Serag HB, Wallander MA, Johansson Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel
S. Epidemiology of gastro-oesophageal reflux disease: RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ,
a systematic review. Gut. 2005;54:710–7. Smith SC Jr, Spertus JA, Costa F. Diagnosis and man-
Dignass A, Eliakim R, Magro F, Maaser C, Chowers Y, agement of the metabolic syndrome. An American
Geboes K, Mantzaris G, Reinisch W, Colombel JF, Heart Association/National Heart, Lung, and Blood
Vermeire S, et al. Second European evidence-based Institute Scientific Statement. Executive Summary. Cir-
consensus on the diagnosis and management of ulcer- culation. 2005.
ative colitis part 1: definitions and diagnosis. J Crohns Gürsoy S, Erdal E, Herken H, Madenci E, Alasehirli B.
Colitis. 2012;6:965–90. Association of T102C polymorphism of the 5-HT2A
Dodds WJ, Dent J, Hogan WJ, Helm JF, Hauser R, Patel receptor gene with psychiatric status in fibromyalgia
GK, Egide MS. Mechanisms of gastroesophageal syndrome. Rheumatol Int. 2001;21:58–61.
reflux in patients with reflux esophagitis. N Engl J Guy M, Neil P, David S, Innes A. The global asthma report.
Med. 1982;307:1547–52. 2014 [Internet]. http://www.globalasthmareport.org/
Domenech E, Kelly J. Swallowing disorders. Med Clin burden/burden.php
North Am. 1999;83(1):97–113. Habib G, Lancellotti P, Antunes MJ, Bongiorni MG,
Dunn W, Shah VH. Pathogenesis of alcoholic liver disease. Casalta JP, Del Zotti F, et al. 2015 ESC guidelines for
Clin Liver Dis. 2016;20(3):445–56. the management of infective endocarditis: The Task
Engelborghs S, D’Hooge R, De Deyn PP. Pathophysiology Force for the Management of Infective Endocarditis
of epilepsy. Acta Neurol Belg. 2000;100(4):201–13. of the European Society of Cardiology (ESC) Endorsed
Epstein AE, DiMarco JP, Ellenbogen KA, et al. For the by: European Association for Cardio-Thoracic Surgery
American College of Cardiology Foundation, Ameri- (EACTS), the European Association of Nuclear Medi-
can Heart Association Task Force on Practice Guide- cine (EANM). Eur Heart J. 2015;36:3075–128.
lines, et al. 2012 ACCF/AHA/HRS focused update Hadler SC, McFarland L. Hepatitis in day care centers:
incorporated into the ACCF/AHA/HRS 2008 guide- epidemiology and prevention. Rev Infect Dis. 1986;8
lines for device-based therapy of cardiac rhythm abnor- (4):548–57.
malities: a report of the American College of Halbert RJ, Natoli JL, Gano A, Badamgarav E, Buist AS,
Cardiology Foundation/American Heart Association Mannino DM. Global burden of COPD: systematic
Task Force on Practice Guidelines and the Heart review and meta-analysis. Eur Respir J. 2006;28
Rhythm Society. J Am Coll Cardiol. 2013;61(3):e6–75. (3):523–32.
Fass R. Erosive esophagitis and non-erosive reflux disease Haller MJ, Atkinson MA, Schatz D. Type 1 diabetes
(NERD) – comparison of epidemiological, physiolog- mellitus: etiology, presentation, and management.
ical and therapeutic characteristics. J Clin Pediatr Clin N Am. 2005;52:1553–78.
Gastroenterol. 2007;41:131–7. Halmi KA. The multimodal treatment of eating disorders.
Ferri C, et al. Hepatitis C virus infection and B-cell lym- World Psychiatry. 2005;4(2):69–73.
phomas. Eur J Can. 1994;30:1591–2. Han MK, McLaughlin VV, Criner GJ, Martinez
Fisher RS, van Emde BW, Blume W, et al. Epileptic sei- FJ. Pulmonary diseases and the heart. Circulation.
zures and epilepsy: definitions proposed by the Inter- 2007;116(25):2992–3005.
national League Against Epilepsy (ILAE) and the Hauser SL, Goodwin DS. Multiple sclerosis and other
International Bureau for Epilepsy (IBE). Epilepsia. demyelinating diseases. In: Fauci AS, Braunwald E,
2005;46:470–2. Kasper DL, Hauser SL, editors. Harrison’s principles
of internal medicine, vol. II. 17th ed. New York: Kamar N, Bendall R, Legrand-Abravanel F, Xia NS, Ijaz S,
McGraw-Hill Medical; 2008. pp. 2611–2621. Izopet J, Dalton HR. Hepatitis E. Lancet.
Hehn ST, Grogan TM, Miller TP. Utility of fine-needle 2012;379:2477–88.
aspiration as a diagnostic technique in lymphoma. J Kao HJ. Diagnosis of hepatitis B virus infection through
Clin Oncol. 2004;22:3046–52. serological and virological markers. Expert Rev
Henkel M, Redfield M, Weston SA, Gerber Y, Roger Gastroenterol Hepatol. 2008;2:553–62.
VL. Death in heart failure. A community perspective. Kaplan AG, Balter MS, Bell AD, Kim H, McIvor
Circ Heart Fail. 2008;1:91–7. RA. Diagnosis of asthma in adults. CMAJ. 2009;181
Herrera A. Valvular heart disease. In: Steolting’s anesthe- (10):E210–20.
sia and co-existing disease. 7th ed. Philadelphia: Kessler RC, Berglund P, Demler O, Jin R, Koretz D,
Elsevier; 2018. p. 128. Merikangas KR, Rush AJ, Walters EE, Wang PS,
Higashida RT, Johnston SC, Kidwell CS, Lutsep HL, National Comorbidity Survey Replication. The epide-
Miller E, Sacco RL. Definition and evaluation of tran- miology of major depressive disorder: results from the
sient ischemic attack: a scientific statement for National Comorbidity Survey Replication (NCS-R).
healthcare professionals from the American Heart JAMA. 2003;289(23):3095–105.
Association/American Stroke Association Stroke KIDGO. The Kidney Disease Improving Global Outcomes
Council; Council on Cardiovascular Surgery and Anes- Working Group. Definition and classification of acute
thesia; Council on Cardiovascular Radiology and Inter- kidney injury. Kidney Int Suppl. 2012;2:19–36.
vention; Council on Cardiovascular Nursing; and the Kupfer DJ, Frank E, Phillips ML. Major depressive disor-
Interdisciplinary Council on Peripheral Vascular Dis- der: new clinical, neurobiological, and treatment per-
ease. Stroke. 2009;40:2276–93. spectives. Lancet. 2012;379(9820):1045–55.
Hostetter TH. Progression of renal disease and renal hyper- Lai CL, Ratziu V, Yuen MF, Poynard T. Viral hepatitis
trophy. Annu Rev Physiol. 1995;57:263–78. B. Lancet 2003;20;362(9401):2089–2094.
Hudson JI, Hiripi E, Pope HG, et al. The prevalence and Lampe FC, Whincup PH, Wanamethee SG, Shaper AG,
correlates of eating disorders in the National Comor- Walker M, Ebrahim S. The natural history of prevalent
bidity Survey Replication. Biol Psychiatry. ischaemic heart disease in middle aged men. Eur Heart
2007;61:348–58. J. 2000;21:1052–62.
Hurrell R, Egli I. Iron bioavailability and dietary reference Lanau N, Maresque J, Gilner L, Zabalza M. Direct oral
values. Am J Clin Nutr. 2010;91(5):1461S–7S. anticoagulants and its implications in dentistry. A review
Irshad M, Dhar I. Hepatitis C virus core protein: an update of literature. J Clin Exp Dent. 2017;9(11):e1346–54.
on its molecular biology, cellular functions and clinical Launer LJ. The epidemiologic study of dementia: a life-
implications. Med Princ Pract. 2006;15:405–16. long quest? Neurobiol Aging. 2005;26:335–40.
Jahan F, Nanji K, Qidwai W, Qasim R. Fibromyalgia syn- Lawrence RC, Felson DT, Helmick CG, et al. Estimates of
drome: an overview of pathophysiology, diagnosis and the prevalence of arthritis and other rheumatic condi-
management. Oman Med J. 2012;27(3):192–5. tions in the United States. Part II. Arthritis Rheum.
James PA, Oparil S, Carter BL, et al. 2014 Evidence-based 2008;58(1):26–35.
guideline for the management of high blood pressure in Lemon SM. Type A viral hepatitis. New developments in
adults: report from the panel members appointed to the an old disease. N Engl J Med. 1985;313(17):1059–67.
Eighth Joint National Committee (JNC-8). JAMA. Levey AS, Eckardt KU, Tsukamoto Y, Levin A, Coresh J,
2014;311:507–20. Rossert J, De Zeeuw D, Hostetter TH, Lameire N,
Jessup M, Abraham WT, Casey DE, Feldman AM, Eknoyan G. Definition and classification of chronic
Francis GS, Ganiats TG, Konstam MA, Mancini kidney disease: a position statement from Kidney Dis-
DM, Rahko PS, Silver MA, Stevenson LW, Yancy ease: Improving Global Outcomes (KDIGO). Kidney
CW. 2009 focused update: ACCF/AHA guidelines Int. 2005;67(6):2089–100.
for the diagnosis and Management of Heart Failure Libby P, Lichtman AH, Hansson GK. Immune effector
in adults: a report of the American College of Cardi- mechanisms implicated in atherosclerosis: from mice
ology Foundation/American Heart Association Task to humans. Immunity. 2013;38(6):1092–104.
Force on Practice Guidelines: developed in collabo- Lindholm J, Juul S, Jorgenson JO, et al. Incidence and late
ration with the International Society for Heart and prognosis of Cushing’s syndrome: a population based
Lung Transplantation. Circulation. 2009;119 study. J Clin Endocrinol Metab. 2001;86:117–23.
(14):1977–2016. Lip GY, Mitchell SA, Liu X, Liu LZ, Phatak H, Kachroo S,
Jin J. Inflammatory bowel disease. JAMA. 2014; et al. Relative efficacy and safety of non-vitamin K oral
311(19):2034. anticoagulants for non-valvular atrial fibrillation: net-
Kadiyala R, Peter R, Okosieme OE. Thyroid dysfunction work meta-analysis comparing apixaban, dabigatran,
in patients with diabetes: clinical implications and rivaroxaban and edoxaban in three patient subgroups.
screening strategies. Int J Clin Pract. Int J Cardiol. 2016;204:88–94.
2010;64(8):1130–9. Lloyd-Jones DM, Larson MG, Leip EP, Beiser A,
Kaltenbach T, Crockett S, Gerson LB. Are lifestyle mea- D’Agostino RB, Kannel WB, Murabito JM, Vasan
sures effective in patients with gastroesophageal reflux RS, Benjamin EJ, Levy D. Lifetime risk for developing
disease? An evidence-based approach. Arch Intern congestive heart failure: the Framingham Heart Study.
Med. 2006;166:965–71. Circulation. 2002;106(24):3068–72.
Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Memmos D, Williams G, Eastwood J, et al. The role of
Dai S, De Simone G, Ferguson TB, Ford E, Furie K, parathyroidectomy in the management of hyperpara-
Gillespie C, Go A, Greenlund K, Haase N, Hailpern S, thyroidism in patients on maintenance haemodialysis
Ho PM, Howard V, Kissela B, Kittner S, Lackland D, and after renal transplantation. Nephron. 1982;30:143.
Lisabeth L, Marelli A, MM MD, Meigs J, Messina JP, Humphreys I, Flaxman A, Brown A, Cooke
Mozaffarian D, Mussolino M, Nichol G, Roger VL, GS, Pybus OG, Barnes E. Global distribution and prev-
Rosamond W, Sacco R, Sorlie P, Roger VL, Thom T, alence of hepatitis C virus genotypes. Hepatology.
Wasserthiel-Smoller S, Wong ND, Wylie-Rosett J, 2015;61(1):77–87.
American Heart Association Statistics Committee and Mitchell SC, Korones SB, Berendes HW. Congenital heart
Stroke Statistics Subcommittee. Heart disease and disease in 56,109 births. Incidence and natural history.
stroke statistics – 2010 update: a report from the Amer- Circulation. 1971;43:323.
ican Heart Association. Circulation. 2010;121(7): Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M,
e46–e215. Chernoff G, Benchimol EI, Panaccione R, Ghosh S,
Lobo MD, Sobotka PA, Pathak A. Interventional proce- Barkema HW, et al. Increasing incidence and preva-
dures and future drug therapy for hypertension. Eur lence of the inflammatory bowel diseases with time,
Heart J. 2017;38(15):1101–11. based on systematic review. Gastroenterology.
Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sorensen 2012;142:46–54.
PS, Thompson AJ, Wolinsky JS, Balcer LJ, Banwell Monaco F. Classification of thyroid diseases: suggestions
B, Barkhof F, Bebo B Jr, Calabresi PA, Clanet M, for a revision. JCEM. 2003;88(4):1428–32.
Comi G, Fox RJ, Freedman MS, Goodman AD, Mozaffarian D, Benjamin EJ, Go AS, et al. For the Amer-
Inglese M, Kappos L, Kieseier BC, Lincoln JA, ican Heart Association Statistics Committee and
Lubetzki C, Miller AE, Montalban X, O’Connor Stroke Statistics Subcommittee. Heart disease and
PW, Petkau J, Pozzilli C, Rudick RA, Sormani MP, stroke statistics-2015 update: a report from the ameri-
Stuve O, Waubant E, Polman CH. Defining the clini- can heart association. Circulation. 2015;131(4):
cal course of multiple sclerosis: the 2013 revisions. e29–e322.
Neurology. 2014;83:278–86. Murdoch DR, Corey GR, Hoen B, The International Col-
Maganti K, Rigolin VH, Sarano ME, Bonow RO. Valvular laboration on Endocarditis-Prospective Cohort Study
heart disease: diagnosis and management. Mayo Clin (ICE-PCS) Investigators. Clinical presentation, etiol-
Proc. 2010;85(5):483–500. ogy, and outcome of infective endocarditis in the 21st
Maggio M, Basaria S. Welcoming low testosterone as a century: the International Collaboration on
cardiovascular risk factor. Int J Impot Res. 2009; Endocarditis-Prospective Cohort Study. Arch Intern
21(4):261–4. Med. 2009;169:463–73.
Mahmood SS, Levy D, Vasan RS, Wang TJ. The Framing- Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, et
ham Heart Study and the epidemiology of cardiovas- al. Disability-adjusted life years (DALYs) for 291 dis-
cular disease: a historical perspective. Lancet. eases and injuries in 21 regions, 1990–2010: a system-
2014;383(9921):999–1008. atic analysis for the Global Burden of Disease Study
Mani A, Lee DA. Images in clinical medicine. Leukemic 2010. Lancet. 2012;380(9859):2197–223. https://doi.
gingival infiltration. N Engl J Med. 2008;358(3):274. org/10.1016/S0140-6736(12)61689-4.
Manolagas SC. Birth and death of bone cells: basic regu- Naganska E, Matyja E. Amyotrophic lateral sclerosis-
latory mechanisms and implications for the pathogen- looking for pathogenesis and effective therapy. Folia
esis and treatment of osteoporosis. Endocr Rev. Neuropathol. 2011;49(1):1–13.
2000;21:1132–6. National Institute of Clinical Excellence. Prophylaxis
Maritim AC, Sanders RA, Watkins JB. Diabetes, oxidative against infective endocarditis: antimicrobial prophy-
stress, and antioxidants: a review. J Biochem Mol laxis against infective endocarditis in adults and chil-
Toxicol. 2003;17(1):24–38. dren undergoing interventional procedures. Clinical
Masi L. Epidemiology of osteoporosis. Clin Cases Miner guideline. 2008. www.nice.org.uk/guidance/cg64
Bone Metab. 2008;5(1):11–3. National Kidney Foundation. Clinical practice guidelines
McColl KE. When saliva meets acid: chemical warfare at for chronic kidney disease: evaluation, classification
the oesophagogastric junction. Gut. 2005;54:1–3. and stratification. Am J Kidney Dis. 2002;39:S1–S266.
McMurray JJ, et al. ESC guidelines for the diagnosis and Neuman MG, Nanau RM. Inflammatory bowel disease:
treatment of acute and chronic heart failure 2012: the role of diet, microbiota, life style. Transl Res.
task force for the diagnosis and treatment of acute and 2012;160(1):29–44.
chronic heart failure 2012 of the European Society of Ney DM, Weiss JM, Kind AJ, Robbins J. Senescent
Cardiology. Developed in collaboration with the Heart swallowing: impact, strategies, and interventions.
Failure Association (HFA) of the ESC. Eur Heart Nutr Clin Pract. 2009;24(3):395–413.
J. 2012;33(14):1787–847. Nieman LK, Ilias I. Evaluation and treatment of Cushing’s
Mehta PK, Wei J, Wenger NK. Ischemic heart disease in syndrome. Am J Med. 2005;118:134–46.
women: a focus on risk factors. Trends Cardiovasc NIH Consensus Development Panel on Osteoporosis Pre-
Med. 2015;25(2):140–51. vention, Diagnosis, and Therapy. Osteoporosis
prevention, diagnosis, and therapy. JAMA. 2001;285 Simonneau G, et al. Clinical classification of pulmonary
(6):785–95. hypertension. J Am Coll Cardiol. 2004;43:5S–12S.
NIH-Surveillance, Epidemiology, and End Result Program. Simpson S Jr, Blizzard L, Otahal P, van der Mei I, Taylor B.
https://seer.cancer.gov/statfacts/html/leuks.html. 2016a. Latitude is significantly associated with the prevalence
NIH-Surveillance, Epidemiology, and End Result Pro- of multiple sclerosis: a meta-analysis. J Neurol
gram. https://seer.cancer.gov/statfacts/html/hodg.html; Neurosurg Psychiatry. 2011;82:1132–41.
https://seer.cancer.gov/statfacts/html/nhl.html. 2016b. Smith DB, Bukh J, Kuiken C, Muerhoff AS, Rice CM,
Nitzan O, Elias M, Peretz A, Saliba W. Role of antibiotics Stapleton JT, Simmonds P. Expanded classification of
for treatment of inflammatory bowel disease. World J hepatitis C virus into 7 genotypes and 67 subtypes:
Gastroenterol. 2016;22(3):1078–87. updated criteria and genotype assignment web
O’Connor KC, Bar-Or A, Hafler DA. The resource. Hepatology. 2014;59:318–27.
neuroimmunology of multiple sclerosis: possible roles Stacy ZA, Call WB, Hartmann AP, Peters GL, Richter
of T and B lymphocytes in immunopathogenesis. J Clin SK. Edoxaban: a comprehensive review of the pharma-
Immunol. 2001;21:81–92. cology and clinical data for the management of atrial
Padwal RS. Obesity, diabetes, and the metabolic syn- fibrillation and venous thromboembolism. Cardiology
drome: the global scourge. Can J Cardiol. 2014; and therapy. 2016;5(1):1–18.
30(5):467–72. Stapleton JT. Host immune response to hepatitis A virus.
Parasrampuria DA, Truitt KE. Pharmacokinetics and phar- J Infect Dis. 1995;171:S9–S14.
macodynamics of edoxaban, a non-vitamin K antago- Steel Z, Marnane C, Iranpour C, Chey T, Jackson JW, Patel
nist oral anticoagulant that inhibits clotting factor V, Silove D. The global prevalence of common mental
Xa. Clin Pharmacokinet. 2016;55(6):641–55. disorders: a systematic review and meta-analysis
Perry L, Love CP. Screening for dysphagia and aspiration 1980–2013. Int J Epidemiol. 2014;43(2):476–93.
in acute stroke: a systematic review. Dysphagia. Stein DJ, Phillips KA, Bolton D, Fulford KW, Sadler JZ,
2001;16(1):7–18. Kendler KS. What is a mental/psychiatric disorder?
Pinnock H. Respiratory medicine. Br J Gen Pract. 2004; From DSM-IV to DSM-V. Psychol Med. 2010;40
54(504):539–47. (11):1759–65.
Putzki N, Pfriem A, Limmroth V, Yaldizli O, Tettenborn B, Sullivan P. Course and outcome of anorexia nervosa and
Diener HC, Katsarava Z. Prevalence of migraine, bulimia nervosa. In: Eating disorders and obesity, vol.
tension-type headache and trigeminal neuralgia in mul- 6. 2002, p. 226–32.
tiple sclerosis. Eur J Neurol. 2009;16(2):262–7. Tapper H, Herwald H. Modulation of hemostatic mecha-
Rahman I, Biswas SK, Kode A. Oxidant and antioxidant nism in bacterial infectious diseases. Blood.
balance in the airways and airway diseases. Eur J 2000;96:2329–37.
Pharmacol. 2006;533:222–39. Thadhani R, Pascual M, Bonventre JV. Acute Renal Fail-
Raimondi P, Hylek EM, Aronis KN. Reversal agents for ure. N Engl J Med. 1996;334:1448–60.
oral antiplatelet and anticoagulant treatment during Thomas MS, Parolia A, Kundabala M, Vikram
bleeding events: current strategies. Curr Pharm Des. M. Asthma and oral health: a review. Aust Dent
2017;23(9):1406–23. J. 2010;55:128–33.
Reller MD, Strickland MJ, Riehle-Colarusso T, Mahle WT, Thomson A, Gupta M, Freeman H. Use of the tumor
Correa A. Prevalence of congenital heart defects in necrosis factor-blockers for Crohn’s disease. World J
Atlanta, 1998–2005. J Pediatr. 2008;153:807–13. Gastroenterol. 2012;18:4823–54.
Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease Thornhill MH, Dayer M, Lockhart PB, McGurk M,
and stroke statistics – 2011 update: a report from the Shanson D, Prendergast B, et al. A change in the
American Psychiatric Association DSM 5 2013. Circu- NICE guidelines on antibiotic prophylaxis. Br Dent
lation. 2011;123:e18–e209. J. 2016;221:112–4.
Rose DK, Bar B. Direct oral anticoagulant agents: phar- Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman
macologic profile, indications, coagulation monitoring, BR, White HD. Third universal definition of myocar-
and reversal agents. J Stroke Cerebrovasc Dis. 2018; dial infarction. Nat Rev Cardiol. 2012;9:620–33.
Rowland LP, Shneider NA. Amyotrophic lateral sclerosis. Tolosa E, Wenning G, Poewe W. The diagnosis of
N Engl J Med. 2001;344:1688–700. Parkinson’s disease. Lancet Neurol. 2006;5(1):75–86.
Saltnes SS, Storhaug K, Borge CR, Enmarker I, Willumsen Tornkvist M, Smith JG, Labaf A. Current evidence of oral
T. Oral health-related quality-of-life and mental health anticoagulant reversal: a systematic review. Thromb
in individuals with chronic obstructive pulmonary dis- Res. 2018;162:22–31.
ease (COPD). Acta Odontol Scand. 2014;73(1):14–20. Tran H, Joseph J, Young L, McRae S, Curnow J,
Schiller JS, Lucas JW, Ward BW, Peregoy JA. Summary Nandurkar H, McLintock C. New oral anticoagulants:
health statistics for U.S. adults: National Health Inter- a practical guide on prescription, laboratory testing and
view Survey, 2010. Vital Health Stat. 2012;10:1–207. peri-procedural/bleeding management. Intern Med J.
Sharma ST, Nieman LK. Cushing’s syndrome: all variants, 2014;44(6):525–36.
detection and treatments. Endocrinol Metab Clin North Tysnes OB, Storstein A. Epidemiology of Parkinson’s
Am. 2011;40(2):379–91. disease. J Neural Transm. 2017;124(8):901–5.
Valva P, Ríos DA, De Matteo E, Preciado MV. Chronic of high blood pressure in adults: a report of the Amer-
hepatitis C virus infection: serum biomarkers in pre- ican College of Cardiology/American Heart Associa-
dicting liver damage. World J Gastroenterol. 2016; tion Task Force on Clinical Practice Guidelines. J Am
22(4):1367–81. Coll Cardiol. 2017;(17):735–1097.
Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz WHO. World Health Organization. Chronic cor
MJ, Porwit A, Harris NL, Le Beau MM, Hellström- pulmonale: a report of the expert committee. Circula-
Lindberg E, Tefferi A, Bloomfield CD. The 2008 revi- tion. 1963;27:594–8.
sion of the World Health Organization (WHO) classifi- WHO. World Health Organization. Report of a WHO
cation of myeloid neoplasms and acute leukemia: scientific group. Nutritional anaemias. World Health
rationale and important changes. Blood. 2009;114 Organ Tech Rep Ser. 1968;405:5–37.
(5):937–51. World Health Organization. Epilepsy: epidemiology,
Veeraswamy S, Vijayam B, Gupta VK, Kapur aetiology and prognosis. WHO Factsheet 2001.
A. Gestational diabetes: the public health relevance WHO. World Health Organization. Diagnostic criteria and
and approach. Diabetes Res Clin Pract. 2012; classification of hyperglycaemia first detected in preg-
97(3):350–8. nancy. Geneva: WHO Press; 2013.
Videbech P, Ravnkilde B. Hippocampal volume and World Health Organization. Dementia Fact sheet N 362.
depression: a meta-analysis of MRI studies. Am J Psy- Archived from the original on 18 March 2015.
chiatry. 2004;161(11):1957–66. Retrieved 28 Nov 2014.
Vincent A, Lahr BD, Wolfe F, Clauw DJ, Whipple MO, Oh WHO. World Health Organization. Fact sheet. 164.
TH, et al. Prevalence of fibromyalgia: a population- Geneva: World Health Organization; 2015a [internet].
based study in Olmsted County, Minnesota, Utilizing Hepatitis C. http://www.who.int/mediacentre/
the Rochester Epidemiology Project. Arthritis Care Res factsheets/fs164/en/
(Hoboken). 2013;65:786–92. WHO. World Health Organization. International statistical
Wang C, Nieschlag E, Swerdloff RS, Behre H, Hellstrom classification of diseases and related health problems
WJ, Gooren LJ, Kaufman JM, Legros JJ, Lunenfeld B, 10th revision. Geneva: World Health Organization;
Morales A, Morley JE, Schulman C, Thompson IM, 2015b. http://apps.who.int/classifications/icd10/
Weidner W, Wu FC, ISA ISSAM. EAU, EAA and ASA browse/2015/en/
recommendations: investigation, treatment and moni- World Health Organization. http://apps.who.int/classifica
toring of late-onset hypogonadism in males. Aging tions/icd10/browse/2016/en
Male. 2009;12(1):5–12. Zalatel K, Gaberscek S. Hashomoto’s thyroiditis: from
Webb G, Mulder BJ, Aboulhosn J, et al. The care of adults genes to the disease. Curr Genomics. 2011;
with congenital heart disease across the globe: current 12(8):576–88.
assessment and future perspective: a position statement Zhang DL, Ghosh MC, Rouault TA. The physiological
from the International Society for Adult Congenital functions of iron regulatory proteins in iron homeosta-
Heart Disease (ISACHD). Int J Cardiol. sis – an update. Front Pharmacol. 2014;5:130.
2015;195:326–33. Zheng ZJ, Croft JB, Giles WH. State specific mortality
Weitzenblum E, Chaouat A. Cor pulmonale. Chron Respir from sudden cardiac death – United States, 1999.
Dis. 2009;6(3):177–85. MMWR Morb Mortal Wkly Rep. 2002;51:123–6.
Wenzel SE. Asthma: defining of the persistent adult phe- Zhou C, Huang Y, Przedborski S. Oxidative stress in
notypes. Lancet. 2006;368(9537):804–13. Parkinson’s disease: a mechanism of pathogenic and
Whelton PK, Carey RM, Aronow WS, et al. Guideline for therapeutic significance. Ann N Y Acad Sci.
the prevention, detection, evaluation, and management 2008;1147:93–104.
Clinical Evaluation of Oral Diseases
Chizobam N. Idahosa and A. Ross Kerr
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
The Medical Record . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
The Patient History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
The Patient Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
Referral/Consultation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
Documentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
Abstract region, as well as the oral health management of

Oral medicine is concerned with the diagnosis medically compromised patients. Oral diseases
and nonsurgical management of medically have a wide range of clinical presentations and
related disorders of the oral and maxillofacial can manifest either as a local oral disease or as
a sign of an underlying systemic condition.
Therefore, oral health is a vital component of
overall systemic health, and an oral lesion may
C. N. Idahosa in certain situations be the initial presentation
Department of Oral and Maxillofacial Pathology, Medicine of a systemic disorder. Consequently, it is
and Surgery, Temple University Kornberg School of imperative that oral healthcare providers and
Dentistry, Philadelphia, PA, USA
e-mail: cidahosa@temple.edu
physicians are adequately trained to accurately
diagnose and manage diseases affecting the
A. R. Kerr (*)
Department of Oral and Maxillofacial Pathology,
oral and maxillofacial region. This chapter
Radiology and Medicine, New York University College of addresses the systematic approach required
Dentistry, New York, NY, USA for the evaluation of patients who present with
e-mail: ark3@nyu.edu

https://doi.org/10.1007/978-3-319-72303-7_3
138 C. N. Idahosa and A. R. Kerr
oral diseases. This includes the process of scope of oral medicine and provide safe dental
obtaining a thorough history, performing a com- treatment to those patients with underlying sys-
prehensive clinical examination, performing temic disorders (Miller et al. 2001). This chapter
vital signs, and ordering appropriate investiga- addresses the necessary steps involved in the
tions that provide the clinician with key infor- evaluation of patients who present with such
mation vital to establishing a final diagnosis. diseases, both soft and hard tissue diseases.
The categories and classification systems of This includes the process of obtaining a thorough
oral diseases as well as the indications for history, performing a comprehensive clinical
referrals and consultations with other health- examination, performing vital signs, and order-
care providers and guidelines for documenta- ing appropriate investigations such as laboratory
tion are reviewed. tests and imaging, that provide the clinician with
key information vital to establishing a final diag-
Keywords nosis. The categories and classification systems
Medical history · Physical examination · of oral diseases, a general overview of the diag-
Extraoral examination · Intraoral examination · nostic process, the indications for referrals and
Differential diagnosis · Definitive diagnosis · consultations with other healthcare providers,
Documentation as well as guidelines for documentation are
reviewed.
Introduction
The Medical Record
Oral medicine is a specialty at the interface of
medicine and dentistry, focused on the diagnosis The patient’s medical information obtained from
and nonsurgical management of medically related a clinical evaluation is considered confidential
disorders of the oral and maxillofacial region and must be carefully documented and stored
(Scully et al. 2016; Stoopler et al. 2011). The for future reference, in a safe and protected man-
scope of practice of an oral medicine specialist ner. The medical record is collected either as a
involves the evaluation of patients with a wide paper-based health record or as an electronic
range of maxillofacial conditions including “oral health record (EHR). Transmission of informa-
mucosal disorders, orofacial pain, temporoman- tion between multiple providers caring for the
dibular disorders, salivary gland disorders, same patient is often inefficient, prone to errors,
chemosensory disorders, sleep disorders, oral and slow with the use of paper-based health
manifestations of systemic disorders, as well as records. As clinical management of patients
the dental treatment of medically compromised often requires input from multiple health-care
patients” (Sollecito et al. 2013). The oral cavity providers, there has been a move by many coun-
is the gateway to the body; therefore, oral health is tries to implement the use of EHR as a means
an essential component of overall systemic health. of improving safety, efficiency, and accessibility
Many systemic disorders have oral manifesta- of records across multiple sites (Ludwick and
tions; conversely, the oral management of patients Doucette 2009). Irrespective of the type of
may be impacted by the presence of systemic record used, it is the responsibility of the oral
disorders (Stoopler and Sollecito 2016). There- health-care provider to obtain and record all
fore, it is important that oral healthcare providers information relevant to the patient’s treatment
are trained, not only to diagnose and manage including all aspects of the history, examination
patients with odontogenic diseases (i.e., dental findings, vital signs, and investigational reports
caries/odontogenic infections, periodontal dis- such as clinical photographs, radiographs/medi-
eases, and malpositioned teeth/jaws) but also to cal imaging studies, laboratory tests, and histo-
effectively diagnose other oral diseases within the pathological findings.
Clinical Evaluation of Oral Diseases 139
The Patient History will maximize the opportunity to capture all rele-
vant information and minimize the risk of missing
The history is the information relevant to the vital data. The master clinician with years of
patient’s health obtained by careful interview of experience can often quickly and efficiently nav-
the patient or a reliable source. For new patients, igate the history, whereas the novice may be less
the initial goal of the history is to help reach a final efficient and take longer. The road to mastery is
diagnosis and formulate a treatment plan. For an built on a disciplined systematic approach where
established patient, the goal is to elicit new infor- there is no room for shortcuts. Table 1 provides
mation to facilitate ongoing care. The patient’s the elements for taking both a new and established
history alone often reveals key elements of the patient history.
information needed to reach a definitive diagno- Biographical data: The biographical data are
sis, and the importance of a thorough and system- important for identification and administrative
atic approach to collect this information cannot be purposes as well as to ensure that the patient’s
underestimated. The history also aids in the risk contact information is accurate and available for
assessment of patients prior to the provision of use when needed. This includes the patient’s
oral care as medical conditions that may increase name, contact information, date of birth, gender,
the risk of adverse events and complications in the race/ethnicity, primary language, occupation, and
dental setting are identified. Likewise, through the primary care physician’s name and contact infor-
history, symptoms that may indicate the presence mation (and other pertinent specialists).
of undiagnosed health conditions may be recog- Chief concern: The chief concern states why
nized. The process of history-taking provides an the patient is in your office. It is a brief description
opportunity for the clinician to develop a rapport of the primary reason for the patient’s consultation
with the patient, which is necessary for effective and evaluation recorded in the patient’s own
communication during the interview and subse- words. Examples of chief concerns include oral
quent encounters. It is important for the clinician lesions, pain, altered sensations (e.g., numbness,
to make the patient comfortable bearing in mind taste alterations), dry mouth or excessive saliva,
that patients come from diverse social and cultural halitosis, slow healing of a surgical wound, facial
backgrounds with differing attitudes and beliefs to or oral/neck swelling, abnormal bleeding, an alter-
health care. The clinician should therefore encour- ation in oral function (e.g., chewing, swallowing),
age the participation of the patient in decision- or tooth abnormalities.
making and should listen to the patient’s percep- History of presenting concern: The history of
tions and concerns regarding their clinical prob- presenting concern is an exhaustive chronological
lems respectfully and without bias. It is also account of all aspects of the chief concern
important that the clinician greets the patient in a obtained by carefully interviewing the patient.
culturally appropriate manner, ensures that the The following information should be documented
interview location is private, and pays attention as part of the history of presenting concern, and
to the patient during the interview. The use of the reader is alerted to Table 2 where examples of
open-ended questions is preferred to direct specific questions for selected categories of chief
questioning and clarification of the patient’s complaints are provided.
understanding should be sought when appropri-
ate. Language barriers can be a major issue, and (i) Onset of symptoms: Determine when the
interpreters should be on hand to facilitate com- symptoms started and if the onset was sud-
munication. In addition, parents or legal guardians den or gradual.
must accompany minors and those with disabil- (ii) Anatomic site(s): Determine the anatomic
ities that limit communication. An exhaustive site affected and ascertain whether the
systematic approach should be followed for symptoms involve a single anatomic loca-
every patient, whether new or established. This tion or multiple sites.
Table 1 Elements of the new patient encounter Table 1 (continued)

Chief concern Lips
History of presenting concern Labial mucosae
Onset of symptoms Buccal mucosae
Anatomic site(s) Gingivae
Description of symptom(s) Tongue
Precipitating factors Hard palate
Aggravating/relieving factors Oropharynx
Secondary signs or symptoms Floor of mouth
History of past investigations and treatments Dentition
Medical history Saliva
Current medical diagnoses Cranial nerves (I–XII)
Past medical history Vital signs
Current medications Blood pressure
Allergies Heart rate and rhythm
Review of systems Respiration
Family medical history Temperature
Sexual history Imaging
Social history Photography/videography
Relationship status Plain films
Children Computed tomography (CT)
Occupation Magnetic resonance imaging (MRI)
Cultural and religious beliefs Sialography
Tobacco use Diagnosis
Alcohol use Differential diagnosis/working diagnosis
Illicit drug use Definitive diagnosis
Recent travel history Treatment
Dental history
Current dental symptoms
Last dental visit and reason for seeking dental care
Frequency of dental visits (iii) Description of symptoms: This includes a
Previous dental treatments description of the course of symptoms and
History of maxillofacial trauma their characteristics considering both qualita-
Home care tive and quantitative descriptors. Establish
Oral habits whether the symptoms are occurring for the
TMJ history first time or recurring. Determine whether the
Exposure to fluoride and type of fluoride
symptoms are constant or episodic. Also,
Presence of dental phobia
find out whether symptoms are stable, wors-
Nutritional history
ening, or improving. Ask the patient to
Extraoral examination
describe the characteristics of the symptoms,
General inspection
Skin/hair
in their own words, using qualitative descrip-
Eyes tors such as dull, sharp, throbbing, aching,
TMJs stabbing, electric shock-like, burning, dry,
Muscles of mastication itchy, thick, rough, bumpy, swollen. Pain or
Salivary glands discomfort should be rated quantitatively
Midline neck structures using a scale such as visual analog/numerical
Lymph nodes rating scale from 1 (minimal) to 10 (unbear-
Intraoral examination able) or a Wong-Baker Faces scale (Fig. 1)
(continued) (Wong-Baker FACES Foundation 2016).
Table 2 History of presenting concern (v) Aggravating/relieving factors: Determine

Questions for patients with ulcerative lesions what makes the symptoms better or worse.
When did it start? (vi) Secondary signs or symptoms: These are
How did it start? separate from the primary symptom(s) and
Any history of trauma? often the patient may be unaware they may
Is this the first episode or is it recurrent? be correlated with the underlying problem
How many? Single or multiple? (e.g., primary herpetic gingivostomatitis can
Do the old ones heal before new ones come up? be associated with fever and malaise, or
Any pain, sensitivity to spicy foods, difficulty eating or sleep issues may lead to an increase in
swallowing?
orofacial pain).
Any extraoral sites involved? Skin, genital, scalp, ocular
(vii) History of past investigations and treat-
Did you start a new medication or oral hygiene product?
ments: Prior diagnoses, investigations, and
Any associated systemic symptoms such as fever and
malaise? treatment modalities for the chief concern
Does anyone in your family have similar problems? should be noted including pertinent negative
Do you have any gastrointestinal symptoms such as results and failed treatments such as medi-
diarrhea and bleeding? cation regimens.
Any joint pain?
Questions for patients with salivary gland disorders Medical history: Although a self-
When did the problem start? administered health history form is routinely uti-
Any swelling? Where is the swelling? Is it associated lized for obtaining medical history information
with meals?
from patients, it is not equivalent to an exhaustive
Any pain? Where is the pain? Is it associated with meals?
history. It is imperative that the oral healthcare
Is your mouth dry?
provider verbally reviews all entries on the health-
Has the texture of your saliva changed?
history form with all patients and supplements
Any pus draining?
Are your eyes dry?
the history with additional questions as deemed
Any joint pain?
necessary.
Any associated systemic symptoms such as fever and
malaise? (i) Current medical diagnoses: A thorough
Does anyone in your family have similar problems? medical history should be elicited to
Questions for patients with temporomandibular joint include details of the patient’s current med-
disorders ical diagnosis as well as treatment modali-
When did the symptoms start? ties. The oral health-care provider should
Any precipitating factors such as trauma or prolonged determine if the patient has been diagnosed
mouth opening?
with any of the medical conditions listed in
Any joint sounds in the past or currently?
Table 3. Information relevant to the onset of
Is your mouth opening restricted?
diagnosis, course of disease, associated
Has your jaw ever locked in the past?
complications, and level of control should
Do you clench or grind your teeth?
Has your occlusion changed?
be documented. This will facilitate risk
Do you have joint/muscle pain affecting other parts of assessment and the identification of condi-
your body? tions that may necessitate modifications to
Any altered sensation? treatment. In addition, it is important to
include information on routine health main-
tenance, the type of medical specialist man-
Enquire about the impact of the symptoms on aging the patient, as well as the frequency
the patient’s quality of life. of office visits. For example, the medical
(iv) Precipitating factors: Enquire about any fac- history on a 57-year-old diabetic female
tors that triggered the onset or that exacer- patient would include information on date
bated the symptoms. of diagnosis, frequency of office visits to
®
Fig. 1 Wong-Baker FACES Pain Rating Scale. After choose the face that best depicts the pain they are
explaining to the patient that each face represents a person experiencing
with no pain, some, or a lot of pain, the patient is asked to
Table 3 Pertinent medical history

Cardiovascular Hypertension, congestive heart failure, angina, myocardial infarction, arrhythmia, infective
endocarditis, rheumatic heart disease
Pulmonary Asthma, emphysema, tuberculosis, seasonal and environmental allergies
Endocrine Diabetes, thyroid disease, Addison’s disease, Cushing syndrome
Hematologic Sickle cell anemia, other forms of anemia, leukemia, lymphoma, multiple myeloma, other
hematologic disorders
Genitourinary Kidney disease
Gastrointestinal Peptic ulcer, GERD, Crohn’s disease, ulcerative colitis, hepatitis, cirrhosis
Neurologic Epilepsy/seizures, CVA, headaches, multiple sclerosis
Psychiatric/ Anxiety, depression, eating disorders, drug abuse and dependence, bipolar, schizophrenia
emotional
Musculoskeletal Osteoarthritis, osteoporosis, rheumatoid arthritis
Infectious HIV/AIDS
diseases
Skin Rashes, ulcers
Malignancy
AIDS acquired immunodeficiency syndrome, CVA cerebrovascular accident, GERD gastroesophageal reflux disease, HIV
human immunodeficiency virus
her endocrinologist and/or primary care problems in the past. The history should
physician, home blood glucose test results, include previous major illnesses, consulta-
HbA1c, and target organ damage. The med- tions and referrals to specialists and their
ical history should also include all relevant outcomes, hospitalizations, surgeries, major
details of treatment modalities, which can trauma, and blood transfusions.
potentially alter the delivery of care, such (iii) Current medications: Document all current
as implanted defibrillators in patients with medications and supplements taken by the
cardiovascular disorders, chemotherapy patient. These include prescription medica-
scheduling in oncology patients, dialysis tions, over-the-counter medications, vita-
scheduling in patients with end-stage renal mins, herbal supplements, and traditional
disease, and a chronicle of total joint home remedies. The name, dosage, route,
replacements. frequency, start date, and reason why the
(ii) Past medical history: Patients should be patient is taking each medication should
asked if they have had any relevant medical be noted. Online medication references
have evolved rapidly and are indispensable episode should be noted (e.g., contact der-
tools that should be utilized for checking the matitis, anaphylactic reaction). It is impor-
category, mechanism of action, dosing and tant to make a distinction between adverse
administration details, adverse reactions, reactions to medications and true allergy.
and interactions. When possible, the generic For example, gastrointestinal side effects
medication name should be used for the such as nausea, vomiting, and constipation
purposes of recording the medications in may not be related to an allergic reaction.
the patient’s record. When patients are (v) Review of systems: The review of systems
unsure of the medications they are taking, is a careful and systematic review of rele-
it is important to seek clarification from their vant signs and symptoms related to differ-
physician or pharmacist. Clinicians should ent body systems that the patient may be
be alerted to specific medications that have experiencing or has experienced in the
increased potential for adverse events and recent past (see Table 4). As an integral
that can influence treatment decisions, such part of the medical history, the review of
as antiresorptive agents (e.g., bisphospho- systems is helpful in identifying other med-
nates), anticoagulants, immunosuppressants ical problems that have not yet been
(e.g., corticosteroids), immunomodulators, diagnosed (e.g., polydipsia, polyphagia,
and medications for treating cancer (e.g., polyuria in a patient who has not been diag-
chemotherapy and immune therapies). nosed with diabetes mellitus). Review of
(iv) Allergies: History of drug, food, and envi- systems is also helpful in assessing the
ronmental allergies should be carefully severity of diagnosed medical problems.
documented. The type of allergic reaction An example would be dyspnea with mild
experienced as well as the severity of the activity versus strenuous exercise in a
Table 4 Review of systems

General Recent weight change, fatigue, malaise, fever, chills, night sweats
Dermatologic Rashes, lumps, ulcers, dryness, pruritus, finger clubbing, nail changes
Head Headaches, dizziness, head trauma
Eyes Changes in vision and visual fields, spots, floaters, diplopia, blurriness, dryness, tearing, itching
Ears Hearing loss, pain, discharge, tinnitus, vertigo
Nose, sinuses Stuffiness, sneezing, rhinorrhea, itching, epistaxis, changes in sense of smell
Mouth, throat, Bleeding or painful gums, lesions, dental pain, halitosis, altered taste, hoarseness, sore throat,
neck dysphagia, neck swelling
Respiratory Dyspnea, chest pain, wheezing, cough, sputum, hemoptysis
Cardiovascular Chest pain, palpitations, orthopnea, dyspnea on exertion, paroxysmal nocturnal dyspnea,
peripheral edema
Gastrointestinal Appetite changes, abdominal pain, nausea, vomiting, diarrhea, constipation, heart burn, belching,
bloating, flatulence, dysphagia, bleeding (hematemesis, hemorrhoids, melena, hematochezia),
jaundice, ascites
Genitourinary Frequency, hesitancy, urgency, incontinence, nocturia, dysuria, hematuria, abnormal genital
discharge, genital lesions, changes in libido
Endocrine Polydipsia, polyuria, polyphagia, heat and cold intolerance, weight gain or loss, excessive
sweating, thyroid enlargement or pain
Hematologic Anemia, easy bruising or bleeding, lymphadenopathy
Musculoskeletal Arthritis, arthralgia, pain, swelling, redness, limitations in range of motion, muscle weakness,
trauma
Neurologic Seizures, memory loss, loss of consciousness, paresthesia, anesthesia, muscle weakness, paralysis
Gynecologic Menopause, menstrual changes, dysmenorrhea
Psychiatric/ Mood, anxiety, depression, changes in sleep pattern, decreased ability to concentrate
emotional
patient diagnosed with congestive heart Patients who appear to have undiagnosed
failure. Finally, the review of systems can mental illness should be referred to a pri-
uncover pertinent details relevant to the mary care provider.
chief concern/history of presenting con-
cern, which will aid in reaching a dia- Social history: The patient’s social history will
gnosis (e.g., skin and genital lesions in a reveal information about the following domains:
patient with oral ulcers secondary to
Behcet’s disease). Both positive and nega- (i) Relationship status: This will provide
tive responses should be documented. All insight on the level of support available to
positive responses should be followed up the patient. Find out whether the patient is
with more in-depth and focused questions single, married, divorced, in a domestic
and these patients should be referred to partnership, or in a long-term relationship.
their physicians for further evaluation and (ii) Children: Find out if the patient has chil-
management as indicated. dren and their level of dependency. Alter-
(vi) Family medical history: This should natively, if they are older, can they provide
include information on hereditary diseases additional support as needed by the patient?
(e.g., hemophilia), familial illnesses (e.g., (iii) Occupation: It is helpful to know the type
recurrent aphthous stomatitis, hyperten- of work the patient does (e.g., outdoors
sion, diabetes mellitus, cancers, psychiatric vs. indoors).
disorders, alcohol, and drug addiction), (iv) Cultural and religious beliefs: With the
contagious infections (e.g., tuberculosis), growing trend in immigration and popula-
and illnesses arising from environmental tion migration, oral health-care providers
exposure to toxins. The relationship of the should be cognizant of the fact that patients
patient to the affected relative, current sta- come from different backgrounds with var-
tus of the relative (alive or deceased), and ious cultural and religious beliefs, which
cause of death if deceased should be noted. can impact provision of care. Patients
(vii) Sexual history: Information related to the from certain ethnicities may decline oral
patient’s sexual history (sexual relation- medications and opt for herbal and tradi-
ships, practices, and number of partners) tional remedies while others may be
relevant to their chief concern or examina- unable to comply with instructions during
tion findings should be documented. This is periods of fasting. Based on their religious
particularly relevant to infectious diseases doctrine that blood is sacred, Jehovah’s
with the potential to have oral manifesta- Witnesses do not accept transfusion of
tions including human immunodeficiency whole blood and its four major derivatives
virus (HIV) infection, syphilis, gonorrhea, (red cells, white cells, plasma, and plate-
human papilloma virus (HPV) infections, lets) but may accept transfusion of blood
herpes simplex virus (HSV) infection, products such as clotting factors, erythro-
infectious mononucleosis, and hepatitis poietin, and immunoglobulins (Sarteschi
B or C. 2004).
(viii) Psychological history: The psychological (v) Tobacco use: Tobacco use is a leading
history is an important element of the med- cause of preventable death. According to
ical history that may be overlooked. the World Health Organization (WHO),
Patients suffering from depression, anxiety, there are one billion smokers worldwide
or other mental illnesses require careful and tobacco use is a public health threat
evaluation, and a comprehensive history leading to the death of approximately six
of their clinical course and treatments, million people a year (WHO 2016).
including medications, must be elicited. Tobacco products adversely affect nearly
every human organ system. Exposure leads 20 cigarette-packs per day multiplied by
to the development of a wide range of dis- the number of years smoked).
orders including systemic diseases (e.g., (vi) Alcohol use: Alcohol use disorder is com-
cardiovascular diseases, respiratory dis- mon in society and alcohol use can lead to
eases, and cancers) and oral diseases (e.g., multiorgan consequences, some of which
periodontal disease, oral potentially malig- carry significant morbidity and mortality
nant disorders, and oral cancer) resulting in (e.g., liver cirrhosis). Studies have shown
reduced quality of life and life expectancy. an association between the consumption of
Oral health-care providers can make a sig- alcohol and the risk of oral cancer (Ogden
nificant impact by asking every patient 2005). Alcohol potentiates the carcinogenic
about tobacco use and providing applicable effect of tobacco in a synergistic manner,
tobacco cessation educational resources. thereby multiplying the risk of oral cancer
They should be aware of the different (Petersen 2009; Reidy et al. 2011). Oral
types of tobacco products available, such health-care providers can and should elicit
as smoked tobacco products (cigarettes, a history of alcohol use, and collect infor-
cigars, and pipe), clove cigarettes known mation about current or past use, types of
as kreteks, bidis (coarse tobacco rolled in alcoholic beverages consumed, current
a tree leaf from South Asia), hookah (the drinking patterns (i.e., how many days a
smoking of flavored tobacco with a form month or week, the time of day when the
of water-pipe (Waziry et al. 2016)), and patient consumes alcohol), and quantity
smokeless tobacco formulations including (number of units of alcohol/week). It is
snuff, snus (Swedish-style tobacco), and important to appreciate the dose equiva-
paan/betel quid (areca nut and tobacco lents for alcoholic beverages [i.e., a 12 oz.
wrapped in a betel leaf and chewed), and beer (5% alcohol) is equivalent to a 5 oz.
gutkha (an areca nut tobacco mixture sold glass of table wine (12% alcohol) or a
in single use sachets and chewed) (Couch 1.5 oz. distilled alcoholic drink (40% alco-
et al. 2016). E-cigarettes are relatively new hol)]. Low risk use is defined as either
handheld nicotine delivery systems that fewer than three units of alcohol at a sitting
produce a vaporized flavored liquid by or seven or less units of alcohol/week for
pressing a button. The long-term oral and women, and either fewer than four units at a
systemic health risks of e-cigarettes are sitting or 14 or less units of alcohol/week
currently unknown (Couch et al. 2016). for men. Higher rates carry significantly
The risk of oral and pharyngeal cancers higher risk for alcohol use disorder
increases the longer a person smokes. The (NIAAA (National Institute on Alcohol
use of paan, betel quid and related products, Abuse and Alcoholism) 2005). It is also
which are usually placed in the oral vesti- important to assess the impact of alcohol,
bules, increases the risk of submucous if any, on the patient’s quality of life by
fibrosis, a precancerous condition charac- finding out if alcohol has adversely affected
terized by oral burning and limited their mood, behavior, diet, occupation, and
mouth opening (Tilakaratne et al. 2016). relationships in which case referral to a
The tobacco history, therefore, should medical professional may be indicated.
include information on current and past This can be done using the Diagnostic and
use, the type of tobacco products, duration Statistical Manual of Mental Disorders
and frequency of use, and details about available from the National Institute on
cessation attempts, if any. A cumulative Alcohol Abuse and Alcoholism (Table 5)
cigarette smoking history should be (NIAAA 2016), (DSM–5) diagnostic criteria
documented in pack-years (number of for abuse and dependence.
Table 5 Assessment for alcohol use disorder

In the past year have you?
1. Had times when you ended up drinking more, or longer than you intended?
2. More than once wanted to cut down or stop drinking, or tried to, but could not?
3. Spent a lot of time drinking? Or being sick or getting over the aftereffects?
4. Experienced craving, a strong need, or urge to drink?
5. Found that drinking, or being sick from drinking, often interfered with taking care of your home or family? Or caused
job troubles? Or school problems?
6. Continued to drink even though it was causing trouble with your family or friends?
7. Given up or cut back on activities that were important or interesting to you, or gave you pleasure, in order to drink?
8. More than once gotten into situations while or after drinking that increased your chances of getting hurt (such as
driving, swimming, using machinery, walking in a dangerous area, or having unsafe sex)?
9. Continued to drink even though it was making you feel depressed or anxious or adding to another health problem? Or
after having had a memory blackout?
10. Had to drink much more than you once did to get the effect you want? Or found that your usual number of drinks had
much less effect than before?
11. Found that when the effects of alcohol were wearing off, you had withdrawal symptoms, such as trouble sleeping,
shakiness, irritability, anxiety, depression, restlessness, nausea, or sweating? Or sensed things that were not there?
(vii) Illicit drug use: This encompasses the non- services, and risk/susceptibility for dental disease.
medical use of prescription drugs (e.g., opi- The following should be documented as part of
oids, barbiturates, and amphetamines) and the dental history:
illicit drugs (such as cocaine and heroin)
(Degenhardt and Hall 2012). Marijuana is (i) Current dental symptoms: Pain, swelling,
considered an illicit drug in most countries. halitosis, bleeding, mobile, or fractured
Enquire about current and past history of teeth.
drug use, the type(s) used, the route of (ii) Last dental visit and reason for seeking
administration (i.e., intravenous, inhaled, dental care: Emergency or routine dental
smoked, or consumed by mouth), and any care.
treatment for addiction. It is important to (iii) Frequency of dental visits.
consider prescribing medications without (iv) Previous dental treatments: Recall visits/
increased potential for addiction to patients dental prophylaxis, restorative dentistry,
with a history of drug abuse and depen- oral surgery, implants, orthodontics, peri-
dence. Also, current use of some illicit odontics, endodontics, and fixed and
drugs may potentially interact with local removable prosthodontics.
anesthesia or medications prescribed by (v) History of maxillofacial trauma.
oral physicians (e.g., cocaine). (vi) Home care: Brushing and flossing/inter-
(viii) Recent travel history: This has become proximal habits (i.e., frequency, timing in
more important with respect to recent travel the context of meals, and technique). Oral
to geographic regions with endemic dis- hygiene products such as dentifrices,
eases such as tuberculosis, Ebola, leish- flosses, and mouth rinses should be
maniasis, or Zika virus. recorded as they can sometimes cause
mucosal reactions.
Dental history: The dental history can provide (vii) Oral habits: Clenching, bruxism, cheek bit-
additional information related to the chief concern ing, nail biting.
that is valuable in reaching a diagnosis. It is also (viii) History of temporomandibular joint (TMJ)
important for evaluating the patient’s level of den- pain, clicking or locking, and the use of
tal awareness, motivation, utilization of dental orthotic devices or night guards.
(ix) Exposure to fluoride and type of fluoride. The Patient Examination

(x) Presence of dental phobia and anxiety.
The history is followed by a comprehensive
Nutritional history: Nutritional factors are visual/tactile head and neck examination. Medical
associated with the development and progression providers (i.e., primary care physicians) rarely
of various oral and systemic diseases. Therefore, it perform a detailed intraoral examination, which
is necessary to evaluate the nutritional and dietary underscores the important role of oral health-care
habits of patients in relation to their chief concern providers in this regard. Yet, the patient examina-
and presenting symptoms. Oral health-care pro- tion performed by oral health-care providers goes
viders may also play a role in the interception and far beyond the evaluation of dental and periodon-
management of obesity and eating disorders (e.g., tal structures. Clinicians should have detailed
bulimia and anorexia nervosa). The following knowledge of how to evaluate both oral and non-
points may be considered when taking the nutri- oral structures of the head and neck and perform a
tional history: cranial nerve examination. An understanding of
normal anatomy and function facilitates the detec-
(i) Dental caries: There are multiple risk tion of abnormalities during the examination. The
factors for dental caries, a number of interplay between the history and the examination
which are modifiable, including diet. deepens as the clinician explores new avenues of
Therefore, the nutritional history should questioning based upon the detection of such
include information on frequency of meals abnormalities. This section emphasizes the impor-
and snacks, and a detailed history of the tance of performing a consistent and comprehen-
consumption of sugared beverages (Mar- sive examination, a skill that is vastly undervalued
shall 2009). and yet, when performed correctly, can yield
(ii) Periodontal diseases: Severe vitamin C defi- important clues to the diagnostic process. With
ciency (i.e., scurvy) is associated with peri- practice, this examination should not take longer
odontal disease. than a few minutes on average. Table 1 summa-
(iii) Dental erosion: Repeated exposure to rizes the steps.
acidic beverages (e.g., carbonated soda and Extraoral examination: This part of the
sports drinks) can promote the initiation examination has been broken into eight sections
and progression of dental erosion. Patients and requires the patient to loosen/remove any
who suffer from eating disorders such as clothing to allow visualization of the head and
anorexia nervosa and bulimia may practice neck structures:
self-induced vomiting leading to dental ero-
sion on the lingual and palatal surfaces of (i) General inspection: During the history tak-
teeth. ing an astute clinician has already begun the
(iv) Oral cancer: A diet rich in fruits and vegeta- examination process by performing a visual
bles is protective against oral cancer. inspection of the patient. Height and
(v) Oral mucosal disorders and neuropathies: weight; dress and personal hygiene; posture
Vitamin B12 deficiency may occur in strict and gait; dexterity and body movements;
vegetarians and is associated with glossitis eye movements and facial expression;
and stomatitis. Chronic undernutrition and speech, mood, and cognitive ability; and
other vitamin deficiencies (B2, B6, folic others may be gauged over the first few
acid) may predispose patients to angular minutes of the patient encounter. Height
cheilitis, stomatitis, oral ulcerations, and and weight may be combined to assess a
burning mouth symptoms. patient’s body mass index (BMI), calculated
(vi) Major salivary gland enlargement: May be as the weight in kilograms (kg) divided by
seen in patients with chronic malnutrition. the height in meters squared (m2).
(ii) Skin/hair: Clinicians should evaluate the distance with a ruler (Fig. 2b) or vernier
head, face, and neck, or any other visible calipers, or crudely by the number of fin-
areas of skin (i.e., hands, arms, legs, or feet) gers one is able to insert between the teeth.
noting the texture, turgor, color, and obvi- Three fingers (measuring approximately
ous asymmetry, growths, or lesions (e.g., 47 mm) is a reliable surrogate for normal
pigmented or ulcerated skin lesions). Fin- opening (Zawawi et al. 2003). Observing
gernails and hair distribution should also be excursive jaw movements (i.e., protrusion,
evaluated (e.g., hair loss or fingernail or lateral excursions of approximately
pathology such as onychomycosis). 7 mm) reveal limitations in range, allow
(iii) Eyes: Observe general features such as eye comparison between sides (i.e., asymme-
position, eyelids, lashes, and structures of try), and show which movements, if any
the eyeball (cornea, sclera, iris, pupils, tear cause pain or other signs.
production, noting any asymmetry). (v) Muscles of mastication and other head and
Assessment of visual acuity and ocular neck musculature: There are four main
function is covered in the cranial nerve pairs of masticatory muscles: masseters,
assessment. temporalis, medial pterygoids, and lateral
(iv) Temporomandibular joints (TMJs): The pterygoids. All are innervated by the man-
TMJs may be examined by placing the dibular branch of the trigeminal nerve (V3),
index fingers anterior to the tragus of and therefore V3 nerve function may be
the ears and asking the patient to open and assessed when examining these muscles.
close their jaws (Fig. 2a). This will allow The examination of the muscles of mastica-
the clinician to locate the lateral poles of the tion begins with a visual inspection for any
condyles, palpate any TMJ swelling or asymmetry or gross enlargement of the mas-
pain, assess the rotation and translation of seters and temporalis muscles at rest. Then
the condyles, and detect joint sounds (i.e., the patient is asked to clench their teeth in
crepitus, clicks, or pops), or deviations/ order to visualize and palpate muscle con-
limitations in the normal range of jaw move- traction and assess strength, symmetry, and
ment. Subtle joint sounds may be appreci- size of the muscles. At a minimum, digital
ated more easily by using a stethoscope. palpation of the masseters and temporalis
The range of motion is an easily reproduc- muscles should be performed (the predictive
ible measure of jaw movement. The normal value of palpating the pterygoids is low) and
range for maximum opening is variable may reveal muscle tenderness or pain, or
(approximately 40–60 mm) and obtained indicate sites of referred pain. It is impor-
by precisely measuring the interincisal tant to assess each muscle in turn using
Fig. 2 (a) Location of lateral pole of right TMJ. (b) Measurement of interincisal opening
consistent pressure (approximately 1 kg), and levator scapulae), and strap muscles
palpating at multiple points, for approxi- of the neck may be similarly palpated and
mately 2 s each, along the length of the also evaluated for range of motion by turn-
muscles, comparing right to left. Identified ing the head all the way to the left, then to
painful trigger points may be palpated for the right, then lifting the chin up, and then
up to 5 s to appreciate referral patterns tilting the head left and right.
(Schiffman et al. 2014). The use of an (vi) Salivary glands: There are three paired
algometer may assist in providing consis- major salivary glands (parotid, submandib-
tent pressure. The anterior (Fig. 3a) and ular, and sublingual glands) along with
more posteriorly the middle and posterior greater than 300 minor salivary glands dis-
aspects of the temporalis muscles may be tributed throughout the mouth. Assessment
examined in turn, followed by the masseter begins with a visual inspection of the
muscles (Fig. 3b). The tendon of the parotid and submandibular glands for
temporalis at the coronoid process of the swelling or asymmetry. There are a number
mandible may be palpated intraorally. Ask of chronic disease processes (e.g., diabetes
patients to provide a rating of any tender- or liver disease) that can manifest with
ness or pain (0 for no tenderness, 1 for bilateral salivary gland enlargement. In
uncomfortable tenderness, 2 for definite health, palpation of the salivary glands
tenderness or pain, or 3 for significant will reveal a soft consistency without
pain that causes the patient to pull away to tenderness.
avoid further pain). The lateral and medial (vii) Midline neck structures (trachea and thy-
pterygoids are difficult to reliably palpate roid gland): Examination of the trachea is
but may be assessed functionally. Pain warranted to rule out displacement or
elicited when protruding the jaw with resis- change in axial mobility, possibly due to
tance from the examiner may indicate the the encroachment of neck neoplasms. The
inferior lateral pterygoid muscles as a pos- trachea extends inferiorly from the larynx,
sible source. The power stroke of biting and half of the trachea is within the neck.
down on an object may result in pain from Tracheal displacement from its midline
the superior lateral pterygoid muscles. position may be verified by both inspection
Neck muscles, such as the sternocleido- and palpation of the trachea in relation to
mastoids, posterior cervical muscles the suprasternal notch. By gently grasping
(i.e., trapezius, longissimus (capitis and the tracheal rings, the trachea can be moved
cervicis), splenius (capitis and cervicis), laterally and a grating is appreciated
Fig. 3 (a) Palpation of right anterior temporalis muscle. (b) Palpation of right masseter muscle
because of the movement of the cartilagi- inferior to this is the location of the isthmus.
nous rings. Equal movement and grating is Pushing the sternocleidomastoid muscles
a normal finding. The thyroid is a bilobed laterally and posteriorly, it is possible to
gland found in the midline of the lower palpate the lobes in turn by applying light
neck. The lobes are joined by an isthmus, pressure, comparing the right and left sides
which crosses in front of the trachea inferior for asymmetry (Fig. 4b).
to the level of the cricoid cartilage. The (viii) Lymph nodes: An understanding of the
lobes extend laterally with the most lateral lymphatic drainage of the head and neck is
aspects of the gland found deep to the a prerequisite for this step of the extraoral
sternocleidomastoid muscles (Fig. 4a). examination. There is a collar of lymph
The first step to examining the thyroid is nodes of the head that drain into the deeper
the inspection (both from in front and from neck lymph nodes, which ultimately drain
the side of the patient) for any obvious into the thorax (Fig. 5a, b). The head and
asymmetry or swelling (e.g., a goiter or neck lymph node system is divided into
thyroid neoplasm). Since the thyroid gland levels (I–VI) from superior to inferior.
moves with the trachea during swallowing, Superficially located lymph nodes are pal-
the patient can be asked to swallow a sip of pable in health, and they are soft, moveable,
water, facilitating visualization as the thy- and nontender. Deeper nodes may become
roid tissue moves superiorly. This is palpable when enlarged (lymphadenopa-
followed by palpation, performed either thy). Most commonly, lymphadenopathy
from behind (i.e., the posterior approach) is due to an inflammatory etiology (e.g.,
or in front of the patient to detect any dis- an odontogenic infection) and involved
crete nodules within the gland or its associ- lymph nodes become enlarged and tender,
ated lymph nodes. The prominence of the although they typically remain soft and
thyroid cartilage (Adam’s apple) is an easy moveable. Lymphadenopathy can occur in
first landmark to detect manually. The next association with cancer metastasis (e.g.,
ring inferior is the cricoid cartilage, and just squamous cell carcinoma) and are typically
Fig. 4 (a) Position of the thyroid gland and its isthmus (i) in relation to thyroid cartilage (tc), cricoid cartilage (cc), and
sternocleidomastoid muscle (scm). (b) Palpation of the thyroid gland
Fig. 5 (a) Collar of lymph

nodes draining head and
face. (b) Descending
system of lymph nodes
enlarged, firm to palpation, nontender and, examination of the thyroid gland, it makes
if there is extracapsular spread, they may sense to begin the lymph node examination
become nonmovable or fixed. Level I nodes in the anterior triangle, then move into the
are detected in the submandibular and sub- posterior triangle, and end with the sub-
mental triangles of the neck. Level II, III, mandibular and submental triangles. The
and IV lymph nodes may be detected boundaries of the anterior triangle of the
within the anterior triangle of the neck, neck are the midline of the neck anteriorly,
and level V nodes in the posterior triangle the sternocleidomastoid muscle posteriorly,
of the neck. Level VI nodes are found and the inferior border of the mandible
below the hyoid bone in the anterior superiorly (Fig. 6a). The level II, III, and
central aspect of the neck. Following the IV deep lateral cervical nodes follow the
path of the internal jugular vein deep to the and submental triangles comprise the most
sternocleidomastoid muscle. Look for the superior aspect of the anterior triangle of
outline of the sternocleidomastoid muscles, the neck and contain level I nodes which
and asking the patient to lift and turn their receive drainage from most oral structures
head away from the side being examined is (Fig. 8a). Submandibular nodes are gener-
often helpful to identify this muscle. With ally superficial and therefore palpable in
the neck relaxed, it is possible to palpate health, allowing the examiner to feel the
anterior and deep to the muscle from supe- characteristics of healthy nodes. Have the
rior to inferior, and compare findings from patient lower their chin and then gently pull
both sides (Fig. 6b). The boundaries of the soft tissues laterally across the inferior
the posterior triangle are the sternoclei- border of the mandible (Fig. 8b). In this
domastoid muscle anteriorly, the trapezius way, it is possible to “capture” the node
muscle posteriorly, and the clavicle inferi- between the examiner’s finger and the infe-
orly (Fig. 7a). Palpate along the posterior rior border, and then feel the node “pop”
border of the sternocleidomastoid muscle back into place. Similarly, submental nodes
from the supraclavicular nodes inferiorly may be palpated by moving the submental
to the postauricular and occipital nodes soft tissues anteriorly (Fig. 8c). Lymph
superiorly (Fig. 7b). The submandibular nodes draining facial structures, such as
Fig. 6 (a) Boundaries of

the anterior triangle of the
neck. (b) Palpation of the
deep cervical nodes
Fig. 7 (a) Boundaries of

the posterior triangle of the
neck. (b) Palpation of the
posterior triangle
the preauricular and buccal nodes may also concept of self-examination may also be broached
be palpated. with the patient, along with instructions of the
steps they can perform at home. This exam is
Intraoral examination: This part of the exam- both visual and tactile (i.e., with palpation), and
ination is rarely performed in a comprehensive patients should be asked to remove removable
manner by health-care providers outside of den- dental appliances and to rinse out food particles.
tistry, and as such, it is critical to perform it when Develop a consistent examination sequence, the
the opportunity arises, certainly for all new order of which is not that important, as long as all
patients, for all recall visits, and during emer- elements are completed. An adequate light source
gency/urgent care visits regardless of the type of is critical to the intraoral examination. A standard
emergency/urgency. Patients should be informed overhead halogen dental light or, preferably, a
that they are receiving an oral examination to portable light-emitting diode (LED) white head-
detect not only dental and periodontal problems light affixed to loupes should be used in order to
but also to detect mucosal and other abnormali- keep both hands free. Other adjuncts include an
ties, such as the rare instance of oral cancer. The air syringe, mouth mirrors, and gauze.
Fig. 8 (a) Boundaries of submandibular/submental triangles. (b) Palpation of the superficial submandibular lymph
nodes. (c) Palpation of the submental nodes
(i) Lips: The lips’ vermillion border with the The oral tongue is comprised of the dorsal,
skin is normally sharply demarcated and lateral, and ventral surfaces, which are ame-
homogenous in color and texture. Inspect nable to inspection and palpation. A piece
and bimanually palpate the lip for surface of gauze may be wrapped around the tongue
changes or color irregularities (Fig. 9a). to allow access to the posterior aspects of
(ii) Labial mucosae: Reflect the lips to visualize the dorsum and posterolateral border of the
the labial vestibule, and inspect/palpate for tongue where the foliate papillae and lym-
any surface or submucosal abnormalities phoid tissues may be inspected/palpated and
(Fig. 9b–d). compared bilaterally (Fig. 9g–i). The dorsal
(iii) Gingivae: Inspect and palpate all gingival tongue harbors a number of specialized
structures. Healthy gingivae should be papillae, namely a row of round, pink, mildly
pink, stippled, nonedematous, and have elevated circumvallate papillae dotted in a
knife-edged interdental papillae (Fig. 9e). V-distribution at the posterior border of
(iv) Buccal mucosae: Retract this tissue digi- the oral tongue; small red fungiform papil-
tally or with a mouth mirror to inspect/pal- lae distributed throughout the dorsal sur-
pate all aspects of the buccal mucosae, face (and often concentrated at the tip of
including the posterior aspects of the buccal the tongue); and most commonly the tiny
vestibules. Palpate the parotid extraorally fingerlike keratinized filiform papillae. The
to evaluate salivary flow through the foliate, circumvallate, and fungiform papil-
Stenson’s duct orifice (Fig. 9f). lae house taste buds. The ventral tongue has
(v) Tongue: The tongue is divided into the a thin mucosal lining contiguous with the
“oral tongue” (the anterior two-third) and floor of mouth, contains a midline frenum,
the base of tongue (the posterior one-third). plica frimbriata lateral to the frenum, and
Fig. 9 Soft tissue examination: (a) Lips, (b) lower labial (j) ventral surface of tongue, (k) floor of mouth, (l) palpa-
mucosa/vestibule, (c) palpation of lower lip, (d) upper tion of hard palate, (m) oropharynx, (n) indirect inspection
labial mucosa/vestibule, (e) gingivae, (f) buccal mucosa, of base of tongue, (o) palpation of base of tongue,
(g) dorsal tongue, (h) lateral border of tongue, (i) postero- (p) bimanual palpation of the floor of mouth
lateral tongue showing foliate papillae/lymphoid tissue,
one may observe the deep lingual veins (ix) Dentition: A detailed description of the
(Fig. 9j). The posterior one-third of the examination of the teeth and supporting
tongue is more difficult to visualize structures to detect common dental diseases
directly; however, it should be palpated (i.e., caries and periodontal disease) is
and/or visualized indirectly by mirror or beyond the scope of this book. However,
endoscopy, gag reflex permitting (Fig. 9n, o). the state of the dentition can provide
(vi) Floor of mouth: Since abnormal surface insights about the overall health of the
changes may be subtle, air-drying this patient, and a careful examination of the den-
region facilitates examination. The sublin- tition to detect dental abnormalities beyond
gual caruncles or sublingual papillae are caries, periodontitis, odontogenic infec-
two small round structures found either tions, and occlusal/jaw discrepancies (i.e.,
side of the frenum, and these house that might typically be managed orthodon-
Wharton’s duct openings. Fanning out lat- tically) is warranted. Examples are dental
erally from these papillae are elevated sub- erosion, disorders of enamel or dentin
lingual folds containing the openings from formation, and intrinsic or extrinsic discol-
the sublingual glands (Fig. 9k). Bimanual oration (e.g., secondary to tetracycline use).
palpation of the floor of mouth should be Deviations from the normal tooth number,
performed by gently moving two opposing shape, color, eruption patterns, and occlu-
fingers, one extraorally and the other sion offer the initial clues. The involvement
intraorally, from posterior to anterior, softly may be restricted to a single tooth, multiple
palpating the interposing soft tissue teeth, or be generalized to the entire
(Fig. 9p). dentition. These clues provide the basis
(vii) Hard palate: Inspection and palpation of the for further probing of the patient’s history,
hard palate is important. Small mucosal including family history (e.g., where a
swellings are easy to miss when the exam- hereditary disease, such as amelogenesis
iner relies on inspection alone (Fig. 9l). imperfecta, might be suspected). The
(viii) Oropharynx: The oropharynx comprises clinical examination may need to be
the soft palate, the uvula, anterior and pos- supplemented with radiographs (or other
terior pillars (or fauces), the posterior pha- diagnostic testing) to further characterize
ryngeal wall, the palatine tonsils, and base the abnormalities. Clinicians should also
of tongue (Fig. 9m). These structures, along assess the relationship of teeth to the sur-
with the nasopharyngeal and lingual rounding mucosae. Broken and sharp teeth,
tonsils comprise Waldeyer’s ring, part of restorations, or dentures can lead to fric-
the mucosal immune system. A tongue tional keratosis or traumatic ulcers. Large
blade or mouth mirror may be used to amalgam restorations can cause local
depress the tongue. This is the opportunity lichenoid reactions of the adjacent mucosa.
to assess cranial nerves IX and X by pro- (x) Saliva: Salivary gland function may be
voking a gag reflex and having the patient crudely assessed by identifying the gland
say “aahh” and watch the even elevation of openings intraorally (Stenson’s ducts from
the soft palate. The retromolar trigone is the the parotid glands open on the buccal
area distal to the mandibular retromolar pad mucosae near the maxillary second molar,
and this should be part of the examination. and Wharton’s ducts emanate from the sub-
The palatine tonsils sit in the tonsillar fos- lingual caruncles in the floor of mouth), and
sae between the pillars. It is important to then “milking” each gland and observing
record their presence (many patients have saliva secretion. The presence, consistency/
had them surgically removed), color, and viscosity (normal viscosity versus thick/
symmetry. The base of tongue contains the stringy, or bubbly), and color of the saliva
lingual tonsils. (clear vs. turbid) may be recorded, although
a reduction or absence of saliva may not base, paraffin wax, or a sugarless lemon
necessarily be associated with true salivary drop for 5 min, expectorating every 30 s
gland hypofunction (e.g., dehydration). during collection. The mean normal stimu-
Other signs of normal salivary flow may lated flow rate is 1–2 mL/min. In patients
include a glistening of mucosal surfaces suspected to have dental erosion, salivary
commensurate with adequate saliva and pH and buffering capacity can also be
the presence of salivary pooling in the undertaken using commercially available
floor of the mouth. Clinicians should also kits (e.g., GC Saliva Check, GC Corpora-
look for signs of salivary dysfunction (see tion, Japan).
chapter ▶ “Salivary Gland Disorders and Sialometry to measure individual gland
Diseases”). secretions, to detect salivary pH, buffering
The gold standard for the assessment of capacity, and composition is also possible,
normal salivary gland function is by although not routinely performed outside of
sialometry, measuring the quantity and a research setting.
quality of saliva generated by the glands (xi) Screening adjunctive techniques: These are
in both the basal (unstimulated) state and defined as techniques that are applied to
during stimulation, either by measuring the patients during an examination to provide
collective secretions from all the glands additional information about the patient or
(i.e., whole saliva) or by measuring saliva a specific abnormality detected (e.g., the
from each gland individually. Ideally, use of light-based visualization techniques
sialometry should be performed during a such as tissue autofluorescence devices to
morning appointment with the patient screen for malignant and potentially malig-
instructed not to eat or drink (except water nant disorders). This is covered in more
as needed) for 90 min before the appoint- detail in the chapter ▶ “Oral Mucosal
ment. With the patient in a relaxed state and Malignancies.”
in a quiet environment, the procedures
of saliva collection should be clearly Cranial nerve examination: There are 12 cra-
explained to the patient. Sitting in an nial nerves (CN), although routine assessment of
upright position, the patient should be every cranial nerve is not typically indicated. Oral
instructed to swallow their saliva, tilt their health-care providers will routinely test cranial
head forward, and place a preweighed nerves V, VII, IX, X, and XII during a routine
collecting tube next to their mouth examination. The others may be tested when there
(Navazesh et al. 2008). Setting the timer is an indication.
for 5 min or more, they should allow saliva
to drool out of their mouth into the tube. At (i) Olfactory nerve (CN I): The sense of smell
the end of the time, they should expectorate may be tested using familiar inoffensive
all residual saliva into the tube. The tube odors, such as soap. First assess the patency
should be weighed to calculate the weight of each nasal passage by asking the patient
of saliva and the value divided by the num- to occlude one side and then breathe
ber of minutes collected to generate a flow through the open passage of the other side.
rate. One gram is equivalent to 1 mL of If both are patent, ask the patient to close
saliva and mean normal unstimulated flow their eyes, occlude one nostril at a time and
rates are 0.3–0.4 mL/min. Stimulated sali- sniff the smell of the selected substance.
vary flow rates are performed if a patient Ask them to name the substance and test
has an abnormally low unstimulated flow both sides.
rate (i.e., <0.2 mL/min) and may be mea- (ii) Optic nerve (CN II): Visual acuity may be
sured by a number of techniques including tested using a Snellen chart. Patients
asking the patient to chew a flavorless gum are positioned 20 ft from the chart
(alternatively, a miniature hand chart may mandibular). The sensory nerves may be
be used) and asked to cover one eye and assessed by having the patient close their
then read the smallest line of print possible. eyes and then lightly touching the facial
Visual acuity is expressed as two numbers skin distribution, on both sides, of the
(e.g., 20/40). The first is the distance from three sensory branches. Then, perform the
the patient to the chart, and the second is the same steps with a pin or sharp object. Ask
distance at which the patient’s eye can read the patient to tell you where they feel the
the line of the smallest numbers. Visual sensation, and the type of sensation (soft
fields may also be assessed via confronta- touch or sharp prick), comparing sides.
tion testing, usually by the static finger The corneal reflex (V1) may be assessed
wiggle test and the kinetic red target test. by touching the cornea with a wisp of cot-
Pupillary reactions are mediated by CNs II ton and observing a blink. Motor branches
and III (see below). to the muscles of mastication may be
(iii) Oculomotor nerve (CN III): The pupillary assessed by asking the patient to clench
reflex (also mediated by CN II) may be their jaws and observing bilateral contrac-
assessed through two reactions: the light tion of the masseters and temporalis mus-
reaction and the near reaction. The light cles. The patient’s ability to perform
reaction is assessed by shining a light into symmetric jaw movements (opening, clos-
one eye which should lead to pupillary con- ing, lateral, and protrusive jaw movements)
striction in both eyes (the light is sensed by may be assessed too.
the retina, which stimulates the optic nerve, (vi) Abducens nerve (CN VI): This nerve pro-
and then impulses are sent from the brain vides motor innervation to the lateral rectus
back via CN III to cause the pupil to con- ocular muscle, and assessment is similar to
strict (i.e., iris muscle dilation)). The near that of CNs II and IV.
reaction is when the patient is asked to (vii) Facial nerve (CN VII): This nerve provides
focus their gaze on an object, such as a motor innervation to the muscles of facial
finger placed equidistant from both eyes, expression and also carries taste and other
that is brought closer and leads to pupillary sensory neurons. The motor portion may be
constriction (i.e., accommodation). CN III assessed by asking patients to perform a
also provides motor innervation to most of number of facial grimaces, such as wrin-
the extraocular muscles (i.e., all except the kling their forehead (contracting the
lateral rectus and superior oblique mus- frontalis muscles), tightly contracting the
cles), along with the levator palpebrae eyelids (orbicularis oculi), or smiling and
superioris muscles (to elevate the upper showing the teeth (orbicularis oris). Look
eyelid). for symmetry.
(iv) Trochlear nerve (CN IV): This nerve pro- (viii) Vestibulocochlear nerve (CN VIII): Audi-
vides motor innervation to the superior tory acuity may be simply assessed by
oblique muscle and is assessed along with the whispered voice test. Standing behind
CNs III and VI by instructing the patient to the patient so they cannot see the lips of the
follow the six extraocular movements (i.e., examiner, simultaneously occlude the non-
an “H” shape made by a finger or pencil): test ear and gently rub the external meatus,
all the way to one side, then up and down, then exhale completely and then whisper
then all the way to the other side, then up three random numbers from 6 in. away.
and down. Ask the patient to repeat the numbers and
(v) Trigeminal nerve (CN V): This nerve has repeat on the other ear. For patients who fail
three divisions, two of which are sensory this test, a tuning fork may be used to assess
(V1: ophthalmic and V2: maxillary) and neurosensory and conductive hearing loss
one which is both sensory and motor (V3: (i.e., the Rinne test for air and bone
conduction, and the Weber test for laterali- their head against the force of your hand,
zation). Assessment of the vestibular sys- and the trapezius muscles may be assessed
tem is rarely performed as part of the by shrugging the shoulders against force.
routine cranial nerve examination. Look for symmetrical strength.
(ix) Glossopharyngeal nerve (CN IX): Visceral (xii) Hypoglossal nerve (CN XII): This nerve
functions aside, this nerve provides motor provides motor innervation to the intrinsic
innervation to the stylopharyngeus muscle and extrinsic tongue muscles. Look for
which helps elevate the pharynx and lar- symmetry at rest and then ask the patient
ynx, and provides sensation to the posterior to protrude their tongue. Fasciculation of
oral cavity including taste sensation from the the tongue or deviation may indicate an
posterior third of the tongue. It is usually ipsilateral CN XII palsy.
assessed by testing the gag reflex, by placing
a tongue depressor onto the posterior aspect Vital signs: Oral health-care providers should
of the tongue; however, absence of a gag be able to perform vital signs on all patients; this
reflex does not assure a glossopharyngeal includes blood pressure, heart rate and rhythm,
nerve palsy. respiration, temperature, and others.
(x) Vagus nerve (CN X): The vagus provides
motor innervation to other pharyngeal and (i) Blood pressure: Blood pressure is typically
laryngeal muscles, along with fibers to the measured chairside using a sphygmoma-
heart, thoracic, and abdominal viscera. It nometer and stethoscope and is technique
may be assessed in conjunction with CN sensitive. Either arm may be selected (unless
IX by asking the patient to say “ah” and one arm has an A-V shunt for dialysis or has
watching the symmetric elevation of the lymphedema secondary to a breast mastec-
soft palate and uvula. tomy), but the arm should be free of any
(xi) Spinal accessory nerve (CN XI): This is a clothing. The brachial artery should be pal-
motor nerve to the sternocleidomastoid pated for a pulse (Fig. 10a) and the arm lifted
(SCM) and trapezius muscles. The SCMs so that the antecubital crease is at heart
may be assessed asking the patient to turn height, then the inflatable cuff is centered
Fig. 10 (a) Palpation to identify brachial artery. (b) Placement of cuff and bell of stethoscope. (c) Palpation to identify
radial artery
over the artery, positioned above the crease. Irregular rhythm, tachycardia, or bradycar-
Inflate the cuff until the radial pulse is elim- dia typically will indicate further cardiac
inated and check the blood pressure reading. testing (e.g., electrocardiography) to identify
Deflate the cuff, place the bell-side of the the underlying etiology.
stethoscope over the brachial artery, and (iii) Respiration: The rate, rhythm, and depth of
reinflate to a pressure 30 mg Hg above the breathing may be observed over a 60-s
previous inflation value, and slowly deflate period. A regular rhythm of approximately
the cuff listening for two sets of sounds 20 breaths is normal.
(Fig. 10b): the pressure at which the sounds (iv) Temperature: An average normal oral tem-
are initially heard is the systolic pressure, perature is 37 C (98.6 F), yet it can fluctu-
and the pressure when the sounds are ate to as low as 35.8 C (96.4 F) in the early
completely lost is the diastolic pressure. morning or to as high as 37.3 C (99.1 F) in
Blood pressure is calculated from the aver- the evening. The oral temperature is
age of two readings (one on each arm). A performed preferably by an electronic ther-
threshold blood pressure reading of 90 mg mometer with the tip placed under the tongue
Hg diastolic in an adult aged 30–59 years or and with the lips closed.
readings of either 150 mg Hg systolic or (v) Other vital signs: Pain assessment is consid-
90 mg Hg diastolic in adults >60 years is ered a vital sign in most medical settings.
indicative of hypertension and a strong rec- There are a number of validated pain assess-
ommendation for initiation of pharmacother- ment tools available (see the chapter
apy (Grade A evidence) (James et al. 2014). ▶ “Clinical Evaluation of Orofacial Pain”).
There are a number of scenarios leading to Pulse oximetry is also considered a vital
false positive (e.g., white coat hypertension, sign. It is a surrogate measure for arterial
or recent coffee intake) or false negative blood oxygen saturation and normal values
(e.g., orthostatic hypotension) blood pres- are >90%.
sures in a clinical setting. Serial ambulatory
or home blood pressure testing will provide
more predictable readings. Blood pressure
readings in excess of 180 mg Hg systolic Imaging
or 110 mg Hg diastolic are suggestive of a
hypertensive urgency, regardless of the pres- Imaging studies, discussed in greater detail in the
ence of associated signs and symptoms such chapter ▶ “Diagnostic Imaging Principles and
as headache, nosebleeds, severe anxiety, or Applications in Head and Neck Pathology,” are
shortness of breath. Such patients require a important diagnostic tools. In addition to radio-
more detailed examination to rule out under- graphic and other imaging modalities (i.e., mag-
lying systemic diseases (e.g., renal disease). netic resonance imaging (MRI)), this section will
(ii) Heart rate and rhythm: The radial artery is include digital photography and videography.
typically chosen to assess this, and the clini- Because most radiographs utilized by oral
cian should place the pads of both the middle health-care providers carry the risk of radiation
and index fingers just proximal to the wrist exposure, they should be carefully selected (Far-
with sufficient pressure to detect the pulse man 2005). The choice of an imaging modality
(Fig. 10c). Assess the rhythm first, and if should therefore be based upon its ability to con-
regular, count the pulse for 30 s then multiply tribute to diagnosis and management and not on
the value by 2. The normal range is its availability. In addition to dental disease, radio-
50–90 beats/min and if the rate is abnormally graphs should be ordered to visualize the bone
high (tachycardia) or low (bradycardia), underlying soft tissue lesions, for intraosseous
measure again for a full 60 s. If the rhythm pathology, trauma and suspected fractures, salivary
is irregular, attempt to detect a pattern. gland disorders, TMJ pain, and dysfunction and to
rule out intracranial lesions in specific patients. It If this is not feasible, images should be labeled
is important for radiographs to show the full with the date, and patient’s name and chart num-
extent of all lesions captured. Key findings that ber on an encrypted computer or other storage
should be put into consideration when inter- device.
preting jaw lesions include: location, number of Plain films: Traditional dental radiographs
lesions, shape, border characteristics, dimension, include bitewings, periapicals, occlusal, and pan-
internal structure, cortical expansion, and effect oramic radiographs. Bitewing radiographs are
on adjacent structures/teeth. Imaging modalities particularly useful for visualizing interproximal
utilized in the head and neck region include the caries. Intraoral periapical radiographs are useful
following: for imaging the dentition and supporting struc-
Photography and videography in oral med- tures, while occlusal radiographs of the maxilla
icine: The documentation of examination abnor- and mandible are utilized for visualizing the palate
malities, typically by digital photography, serves a and floor of the mouth, respectively. Panoramic
number of important functions. Firstly, images radiographs are useful for gross evaluation of
serve as a baseline record of the initial presenta- intraosseous lesions of the maxilla and mandible
tion of an abnormality that may be used for diag- and the TMJ. Other maxillofacial radiographs
nosis, to communicate with colleagues who are may also be prescribed depending on the specific
part of the patient’s care, as part of a scientific needs of the patient such as the occipitomental
publication, or for the purpose of comparison over (Waters) skull projection used for visualization
a number of follow-up visits (e.g., to gauge of the maxillary sinuses.
response to treatment). Secondly, images can be Computed tomography (CT): CTs are asso-
used for patient education and may be sent to ciated with a higher radiation dose compared with
patients for their own records. Thirdly, images plain films but provide better anatomic details of
serve as part of the patient’s record. They “speak the hard tissues. With the utilization of contrast
a thousand words” and can be useful from a med- media, soft tissue structures can also be visual-
icolegal standpoint. Videography may also be ized. In the maxillofacial region, they are useful
useful to convey abnormal examination findings, for evaluating the extent of maxillary and man-
such as a cranial nerve palsy or recording a pro- dibular cysts and tumors, salivary gland pathol-
cedure. There is a dizzying array of digital camera ogy, fascial space infections of the head and neck,
systems available to clinicians that range in cost and cervical lymph node involvement in head and
and image output. Smart phones have become neck cancer patients. Cone beam CT (CBCT) pro-
popular in medical photography for their simplic- vides reduced radiation exposure compared with
ity, good image resolution, and ease of sharing CT and is the imaging modality of choice for
images. Sophisticated digital cameras with macro- visualizing hard tissue structures when a limited
lenses and ring flash systems are expensive, field of the head and neck is to be evaluated.
although they produce images suitable for publi- Magnetic resonance imaging (MRI):
cation quality, with excellent resolution and the Although expensive, MRIs have no associated
ability to capture focused images of intraoral radiation exposure and are excellent for visualiza-
abnormalities with variable depth of field. Before tion of soft tissues. In the maxillofacial region,
taking images, the patient should provide written they are indicated for evaluation of the articular
consent that covers all issues related to patient disc and other soft tissue components of the TMJ,
privacy, although these requirements may vary neoplasms, and salivary glands and to rule out
depending on local regulations. Patient position- intracranial lesions in specific subsets of orofacial
ing and the use of oral retractors will greatly pain patients such as those presenting with cranial
facilitate the capture of quality images. The stor- nerve abnormalities or trigeminal neuralgia.
age of images is also an important issue. If an Other imaging modalities utilized in the maxil-
electronic health record is being used, images lofacial region include ultrasonography and
should be uploaded as part of the patient’s record. sialography for evaluation of salivary glands as
well as positron emission tomography (PET) uti- fever, malaise, burning, sensitivity to acidic or
lized for detection and monitoring of malignancies. spicy foods or beverages, taste changes, numb-
ness, oral dryness, inability to chew, tooth mobil-
ity, bleeding, and others. Signs such as color,
Diagnosis shape, number, location/distribution, symmetry,
surface topographical features, margin definition,
Abnormal findings: Abnormal clinical features size, and tactile consistency of oral soft tissue
(i.e., symptoms and signs) should be accurately lesions as well as the presence or absence of
described and recorded. This disciplined process regional lymph nodes should be recorded.
of accurately describing clinical features will Table 6 provides a list of physical descriptors
greatly facilitate the diagnostic process and commonly applied to oral mucosal lesions. Simi-
allow effective communication of findings with larly, for bone diseases/jaw lesions, the following
colleagues. It is helpful to develop a vocabulary of nonradiographic features should be described and
descriptors for the myriad of signs and symptoms noted: asymmetry/bony expansion, palpation of
patients may present with. As an example, oral cortex (bony hard, soft, egg shell), presence of
lesions may be described by symptoms such as the bruit, tooth mobility, and displacement. Radio-
sensation of a surface change or a growth, pain, graphic features include size, number, both single
Table 6 Descriptive terminology for oral lesions

Term Definition
Abscess Localized collection of purulent exudate
Atrophy Loss of tissue resulting in thinning of the epithelium and usually associated with erythema
Bulla Fluid filled elevated lesion >5 mm in diameter
Ecchymosis Red/purple macular area of submucosal hemorrhage/extravasated blood
Endophytic A lesion that is growing inwards into the underlying tissue
Erosion Partial loss of the surface epithelium not extending through the full thickness
Erythema Redness of the mucosa usually caused by inflammation, atrophy of capillary dilatation
Exophytic A lesion that grows outwards from the surface epithelium
Fissure Linear slit or groove in the skin or mucosa
Fistula Abnormal tract connecting two body cavities
Fixed A lesion that is firmly attached to the overlying or underlying structures
Hematoma A localized swelling filled with blood
Indurated Hardening of soft tissue usually due to chronic inflammation or malignancy
Macule Circumscribed discolored flat lesion not raised above level of surrounding mucosa
Mobile A lesion that is freely movable and not attached to the overlying or underlying structures
Nodule Circumscribed elevated solid lesion >5 mm in diameter
Papillary A lesion that has numerous surface projections
Papule Circumscribed elevated solid lesion <5 mm in diameter
Pedunculated Exophytic lesion attached to the underlying tissue by a stalk
Petechiae Pin-point red or purple spots caused by submucosal hemorrhage
Plaque Slightly elevated area of mucosa with a flat surface
Pustule Circumscribed raised lesion containing pus
Reticular Resembling a net
Sessile Exophytic lesion attached to the underlying tissue by a broad base
Ulcer Break in continuity of the oral mucosa due to loss of full thickness of oral epithelium resulting in
exposure of underlying connective tissue which is usually coated by a white or yellow membrane
Verrucous An exophytic lesion with rough wartlike projections
Vesicle Fluid filled elevated lesion <5 mm in diameter
versus multifocal and localized versus generalized; typically classified by their radiographic features,
position in the jaws; characteristics of lesion bor- such as radiolucent (Table 11) versus radio-
der/periphery such as well-defined versus poorly opaque or mixed lesions (Table 12).
defined, punched-out, corticated, sclerotic; shape Differential diagnosis: Effective management
(e.g., circular, scalloped); internal structures such of patients with oral and maxillofacial diseases
as radiolucent, radio-opaque, mixed radiolucent/ hinges on the ability of the oral health-care pro-
radio-opaque, multilocular with or without septae; vider to arrive at an accurate diagnosis. For some
and changes in trabecular patterns or the presence diseases, a clinical diagnosis that can be made
of dystrophic calcifications and tooth-like based on the pathognomonic appearance of a
structures. lesion (e.g., fluid-filled vesicles of recurrent her-
Categories/classification systems of oral dis- pes labialis) is equivalent to the definitive diagno-
eases: Oral and maxillofacial diseases encompass sis. However, other diagnoses are more elusive,
a wide variety of disorders with different etiolo- and the clinician may not be able to single out a
gies and pathogenesis. It is always a challenge to diagnosis, but is able to generate a “shortlist” of
adequately fit diseases into classification systems, possible diagnoses, known as the differential diag-
and overlap is inevitable. Oral and maxillofacial nosis. This list of possible diagnoses is based on the
diseases are initially grouped by their primary patient’s history and physical examination findings
clinical features, such as soft tissue versus hard and is ranked in order from most likely to least
tissue/bone diseases, orofacial pain, temporoman- likely. The diagnosis placed at the top of a differ-
dibular disorders, salivary gland dysfunction ential list is known as the working diagnosis. For
(hypofunction vs. sialorrhea), neurosensory disor- novices, the initial differential diagnosis may be
ders (halitosis, taste changes, dysesthesias), fairly broad in scope incorporating many different
movement disorders, dental anomalies, and sub- entities. In contrast, the experienced master clini-
sequently each group branches into classification cian may have only two or three entities listed.
trees based on a myriad of different features. Thorough knowledge of human anatomy, patho-
As an example, the group of soft tissue dis- physiology, and clinical behavior of oral and max-
eases may be classified based on underlying dis- illofacial diseases is critical to ascertaining the
ease process (Table 7), clinical appearance correct diagnosis while avoiding dangerous medical
(Table 8), location (Table 9), or clinical behavior errors. Figures 11–15 outline differential diagnosis
(Table 10). These classification systems can facil- algorithms for ulcerative, pigmented, white, red,
itate the process of narrowing down a list of pos- and exophytic soft tissue lesions.
sible diseases while formulating a differential Definitive diagnosis: The definitive diagnosis
diagnosis. Hard tissue diseases/jaw lesions are is based on the result of a gold standard test for
Table 7 Differential diagnosis of oral mucosal diseases based on etiology

Infectious diseases Candidosis, herpes simplex virus infection, varicella zoster virus infection,
coxsackie virus infections, measles, oral hairy leukoplakia, tuberculosis,
syphilis, human papillomavirus associated oral lesions, infectious
mononucleosis
Allergic, immune-mediated, and Pemphigus vulgaris, mucous membrane pemphigoid, linear IgA disease,
autoimmune diseases aphthous stomatitis, Behçet syndrome, erythema multiforme, oral lichen
planus, lupus erythematosus, graft-versus-host disease, orofacial
granulomatosis
Malignant and potentially malignant Actinic cheilitis, leukoplakia, erythroplakia, erythroleukoplakia, oral
disorders submucous fibrosis, salivary gland malignancies, oral melanoma, verrucous
carcinoma, and oral squamous cell carcinoma
Reactive lesions Traumatic ulcerations, frictional keratosis, linear alba, nicotinic stomatitis, focal
fibrous hyperplasia, chemical and thermal burns
Hereditary conditions White sponge nevus, epidermolysis bullosa
Table 8 Differential diagnosis of oral mucosal diseases based on clinical appearance

White lesions that can be Pseudomembranous candidosis, chemical and thermal burns
wiped off
White lesions that cannot be Linear alba, morsicatio buccarum, leukoedema, white sponge nevus, oral hairy
wiped off leukoplakia, leukoplakia, oral lichen planus, lupus erythematosus, hyperplastic
candidosis, frictional keratosis, smoker’s keratosis, submucous fibrosis
Red lesions Erythematous candidosis, denture associated erythematous stomatitis, irritational
erythema from trauma and burns, submucosal hemorrhage, erythroplakia, linear
gingivitis, plasma cell gingivitis, Kaposi sarcoma
Mixed white/red lesions Candidosis, erosive lichen planus, geographic tongue/erythema migrans, systemic
lupus erythematosus, contact and systemic allergic reactions, erythroleukoplakia
Vesicular and ulcerated Aphthous stomatitis, ulcerative lichen planus, mucous membrane pemphigoid, pemphigus
lesions vulgaris, erythema multiforme, linear IgA disease, epidermolysis bullosa, traumatic ulcers,
herpes simplex virus infections, varicella zoster virus infections, coxsackie virus
infections, tuberculosis, deep fungal infections, necrotizing sialometaplasia, syphilis,
squamous cell carcinoma, traumatic ulcerative granuloma with stomal eosinophilia
Submucosal bumps and Focal fibrous hyperplasia, mucocele, lipoma, angiogranuloma, peripheral ossifying
lumps fibroma, peripheral giant cell granuloma, epulis fissuratum, parulis, sialolith, granular
cell tumor, hemangioma, neurofibroma, other mesenchymal tumors, salivary gland
neoplasms, squamous cell carcinoma
Papillary and verrucous Squamous papilloma, verruca vulgaris, condyloma acuminatum, focal epithelial
lesions hyperplasia, proliferative verrucous leukoplakia, verrucous carcinoma, verruciform
xanthoma, verrucous leukoplakia, verrucous hyperplasia
Pigmented lesions Physiologic pigmentation, amalgam tattoo, smoker’s melanosis, melanotic macule,
melanocytic nevus, melanoacanthoma, Peutz Jeghers syndrome, Addison’s disease,
oral melanoma
Table 9 Differential diagnosis of oral mucosal diseases based on location

Lip Fordyce granules, recurrent herpes labialis, actinic cheilitis, angular cheilitis, squamous cell
carcinoma
Labial mucosa Mucocele, epulis fissuratum, focal fibrous hyperplasia, salivary gland neoplasms, aphthous
ulcers, other mesenchymal tumors
Buccal mucosa Linear alba, leukoedema, pseudomembranous candidosis, Fordyce granules, aphthous ulcers,
focal fibrous hyperplasia, lipoma, morsicatio buccarum, oral lichen planus, mucous
membrane pemphigoid, pemphigus vulgaris, leukoplakia
Hard palate Denture associated erythematous stomatitis, nicotinic stomatitis, thermal burn, inflammatory
papillary hyperplasia, palatal abscess, recurrent intraoral herpes simplex infection,
melanocytic nevus, necrotizing sialometaplasia, salivary gland neoplasm, lymphoma, Kaposi
sarcoma, melanoma
Soft palate Petechiae, viral papilloma, pseudomembranous candidosis
Tonsils/oropharynx Tonsillitis, tonsiloliths, bifid uvula, viral papilloma, lymphoepithelial cyst, squamous cell
carcinoma
Tongue Hairy tongue, fissured tongue, hairy leukoplakia, erythema migrans, oral lichen planus,
mucous membrane pemphigoid, pemphigus vulgaris, granular cell tumor, focal fibrous
hyperplasia, neurofibroma, neurilemmoma, median rhomboid glossitis, atrophic glossitis,
angiogranuloma, hemangioma, lymphangioma, proliferative verrucous leukoplakia,
squamous cell carcinoma
Floor of mouth Ranula, sialolith, dermoid cyst, lymphoepithelial cyst, salivary gland neoplasm, squamous
cell carcinoma
Gingiva and alveolar Gingivitis, oral lichen planus, recurrent intraoral herpes simplex infection, herpes zoster,
process mucous membrane pemphigoid, pemphigus vulgaris, gingival overgrowth, parulis, acute
necrotizing ulcerative gingivitis, primary herpetic gingivostomatitis, angiogranuloma,
peripheral giant cell granuloma, peripheral ossifying fibroma, pericoronitis, epulis fissuratum,
leukemic infiltrates, Kaposi sarcoma, metastatic tumors
Table 10 Differential diagnosis of ulcerative mucosal diseases based on clinical behavior

Localized acute vesicular and/or Aphthous ulcer, traumatic ulcer, necrotizing sialometaplasia, recurrent herpes
ulcerative lesions labialis, recurrent intraoral herpes, syphilitic chancre, anesthetic necrosis
Localized chronic vesicular and/or Traumatic ulcerative granuloma with stromal eosinophilia, squamous cell
ulcerative lesions carcinoma, deep fungal infections, tuberculous ulcers
Multiple acute vesicular and/or Erythema multiforme, primary herpetic gingivostomatitis, allergic reactions,
ulcerative lesions varicella zoster infections (chicken pox and shingles), coxsackie virus infections
Multiple chronic vesicular and/or Oral lichen planus, mucous membrane pemphigoid, pemphigus vulgaris, linear
ulcerative lesions IgA disease, Behçet syndrome, lupus erythematosus, epidermolysis bullosa,
graft-versus-host disease, Wegener’s granulomatosis
Table 11 Differential diagnosis of radiolucent jaw lesions

Single unilocular Apical abscess, periapical granuloma, periapical cyst, periapical scar, focal cemento-osseous
periapical dysplasia (early stage), cementoblastoma (early stage)
Single unilocular Hyperplastic follicle, eruption cyst, dentigerous cyst, unicystic ameloblastoma, odontogenic
pericoronal keratocyst, ameloblastic fibroma, adenomatoid odontogenic tumor, calcifying odontogenic cyst
Multilocular Odontogenic myxoma, ameloblastoma, central giant cell granuloma, hemangioma,
odontogenic keratocyst, cherubism, brown tumor of hyperparathyroidism, ameloblastic
fibroma
Irregular or ill-defined Rarefying osteitis, osteomyelitis, MRONJ, ARONJ, osteoradionecrosis, osteosarcoma,
chondrosarcoma, other primary malignancies, metastasis
Multifocal Florid cemento-osseous dysplasia (early stage), multiple myeloma, Gorlin syndrome,
Langerhans cell disease, cherubism, hyperparathyroidism
MRONJ medication-related osteonecrosis of the jaw
ARONJ anti-resorptive drug-related osteonecrosis of the jaw
Table 12 Differential diagnosis of radiopaque and mixed jaw lesions

Well-defined apical lesions Retained roots, condensing osteitis, idiopathic osteosclerosis, cementoblastoma, focal
cemento-osseous dysplasia, periapical cemento-osseous dysplasia
Well-defined lesions: other Torus, exostosis, idiopathic osteosclerosis, odontoma, osteoma, central ossifying
locations fibroma, calcifying odontogenic cyst, calcifying epithelial odontogenic tumor,
adenomatoid odontogenic tumor, ameloblastic fibro-odontoma
Irregular or ill-defined Osteomyelitis, MRONJ, ARONJ, osteoradionecrosis, cemento-osseous dysplasia, fibrous
dysplasia, osteosarcoma, chondrosarcoma, squamous cell carcinoma, metastatic carcinoma
Multifocal Craniofacial fibrous dysplasia, florid cemento-osseous dysplasia, MRONJ, ARONJ,
Paget’s disease, Gardner’s syndrome, osteopetrosis
MRONJ medication-related osteonecrosis of the jaw
ARONJ anti-resorptive drug-related osteonecrosis of the jaw
diagnosing a particular disease such as histopa- laboratory studies, and biopsy/histopathological

thology to diagnose a squamous cell carcinoma. studies. Data from the investigations are then cor-
In many situations, arriving at an accurate defini- related with the clinical findings before the final
tive diagnosis from the differential diagnosis will diagnosis is rendered. The management of the
necessitate an analytic process involving gather- patient is based on the definitive diagnosis; there-
ing additional clinical information from tests and fore, it is imperative that the correct diagnosis is
investigations. The choice of diagnostic tests is made.
based on the items in the differential diagnosis and
the most appropriate tests should be chosen based (i) Diagnostic adjuncts: Diagnostic adjuncts are
on test accuracy. Types of investigations neces- applied to an identified lesion or lesions to
sary to determine a diagnosis may be in the form provide additional information about the
of imaging studies, chairside diagnostic adjuncts, nature of the lesion. A number of diagnostic
Ulcerative lesions Ulcerative lesion(s)
Persistent
(> 2 weeks)
No Yes
Acute traumatic Aphthous ulcer(s) Viral etiology Erythema

• mechanical • recurrent aphthous stomatitis • HSV multiforme
• thermal (minor/herpetiform)
• VZV
• chemical • hematinic deficiencies • CMV
• celiac disease • Coxsackie
• Behcet’s
• PFAPA
Chronic traumatic Aphthous-like ulcer(s) Vesiculobullous disorders Neoplastic

• TUG/TUGSE • Crohn’s disease •pemphigus • SCC
• ulcerative colitis •pemphigoid • lymphoma
• orofacial granulomatosis •linear IgA disease • salivary gland
• neutropenia •epidermolysis bullosa
Aphthous ulcer(s) Bacterial or Lichen planus

• major fungal etiology or allergic reaction
HSV: Herpes Simplex Virus

VZV: Varicella Zoster Virus
CMV: Cytomegalovirus
SCC: Squamous cell carcinoma
PFAPA: Periodic fever, aphthous stomatitis, pharyngitis, adenitis syndrome
TUGSE: Traumatic ulcerative granuloma with stromal eosinophilia
Fig. 11 Algorithm for ulcerative lesions
adjuncts may have utility in the characteriza- a mucosal smear), plated on a glass slide,
tion of potentially malignant disorders (e.g., immediately fixed, and sent to a pathology
light-based adjuncts, vital staining with tolu- laboratory for staining and microscopic anal-
idine blue, cytopathogical platforms, and ysis. Lesions that are suspected to be caused
salivary techniques) and a more detailed by or associated with candidiasis, yet not
description about these adjuncts, their indi- overtly obvious based on clinical features
cations, and accuracy will be covered in the alone (e.g., erythematous candidosis), are
chapter ▶ “Oral Mucosal Malignancies.” indicated for a mucosal smear and candidal
The process of procuring cells from a lesion, hyphae may be confirmed by periodic acid-
typically from the lesion surface, is known as Schiff staining, or in the office by a potas-
exfoliative cytology. Conditions amenable to sium hydroxide float.
exfoliative cytology are candidosis and pos- (ii) Laboratory investigations: These include
sibly herpes simplex infections. Identified microbiological testing (i.e., standard culture
lesions may be sampled by scraping the sur- techniques, or by detecting microbial
face with a metal spatula or cotton swab (i.e., antigens, antibodies and other immune
Pigmented lesions
Pigmented lesions
Generalized
Yes No
Racial Reactive Syndromes/

• tobacco (smoking) Systemic Diseases
• post-inflammatory • Peutz-Jeghers
• drugs • Laugier-Hunziker
• hormonal • Addison Disease
Amalgam Melanotic Intraoral Melanoacanthoma Malignant

tattoo macule nevus • melanoma
Fig. 12 Algorithm for pigmented lesions
White Lesions or lesions with predominant white component
White lesions
Does the lesion rub away
Yes No
Infectious Reactive
• pseudomembranous • thermal or chemical
candidosis • allergy
• mechanical trauma
Infectious No apparent cause

Keratosis
• hereditary • hairy leukoplakia Striae
eg white • HPV-related
sponge • hyperplastic candidosis Leukoplakia: rule out
nevus
dysplasia or carcinoma
• frictional
• hyperkeratosis or
• tobacco hyperplasia
Classic reticular striae Atypical striae
• ilchen planus • Lupus erythematosus • dysplasia
• ilchenoid mucositis • Graft versus host disease • carcinoma in situ
• squamous cell carcinoma
Fig. 13 Algorithm for white lesions or lesions with a predominant white component
Red Lesions or lesions with a predominant red component
Red lesions
Widespread
Yes No
Vesiculobullous Fungal Nutritional Other

• pemphigus • erythematous deficiency • erythema migrans
• pemphigoid candidosis • iron • vascular lesions
Immune-mediated • folate
• lichen planus • vitamin B12
Center of tongue Bilateral corners of mouth Other

• median rhomboid • angular cheilitis • vascular lesion (s)
glossitis No apparent cause
Erythroplakia: rule out

Palate Gingival dysplasia or carcinoma
• erythematous candidosis • plaque-associated gingivitis • dysplasia
(denture stomatitis) • desquamative gingivitis • carcinoma in situ
• allergy to denture material • plasma cell gingivitis • squamous cell carcinoma
Fig. 14 Algorithm for red lesions or lesions with a predominant red component
reactions, or by newer molecular techniques taken. The tissue sample should be immedi-
(e.g., 15s ribosomal RNA)), and bloodwork ately placed into a bottle containing formalin
(e.g., complete blood counts, metabolic or other appropriate solutions depending on
panels, serological analyses). These investi- the investigation required and transported to
gations are covered in the chapters the pathology laboratory along with a requi-
▶ “Laboratory Medicine and Diagnostic sition form that describes the patient demo-
Pathology” and ▶ “Clinical Immunology in graphics, history, and physical findings
Diagnoses of Maxillofacial Disease.” including the site of biopsy, and a presump-
(iii) Biopsy and histopathological investigation: tive/differential diagnosis. These techniques
The definitive diagnosis of many oral and are covered in the chapter ▶ “Soft and Hard
maxillofacial diseases is based on a histo- Tissue Operative Investigations in the Diag-
pathologic diagnosis. Performing a biopsy nosis and Treatment of Oral Disease.”
of soft tissue lesions requires minimal surgi-
cal expertise; however, selecting the biopsy
site that will optimally provide representa- Referral/Consultation
tive tissue requires careful consideration
because different diseases dictate different It is imperative that oral health-care providers are
sampling techniques. Excisional biopsy is competent in their ability to communicate and
performed when the intent is to remove an collaborate with other members of the health-
entire lesion, while incisional biopsy is indi- care team to facilitate the provision of health
cated when a representative part of a lesion is care. Medical consultation may be initiated with
Exophytic Lesions
Exophytic soft tissue lesion (s)
Multiple
No
Yes
HPV-related
• viral papilloma
Traumatic Reactive Gingival • condyloma
• traumatic fibroma • angiogranuloma • verruca vulgaris
• fibrous hyperplasia • peripheral giant cell fibroma
• mucocele • peripheral ossifying fibroma
• neuroma
Developmental Malignant
Benign Neoplasm • lymphoepithelial cyst •salivary
• neurogenic •lymphoma
• lipoma •SCC
• muscle-derived •sarcoma
• vascular
• minor salivary gland
HPV-related Others
Neurogenic
• HIV-associated • gingival overgrowth
• neurofibromatosis
• Heck's disease • AML
• MEN 2b
• Cowden’s syndrome
• Tuberous sclerosis
MEN 2b: Multiple endocrine neoplasia 2b

SCC: Squamous cell carcinoma
AML: Acute myelogenous leukemia
Fig. 15 Algorithm for exophytic soft tissue lesions
a patient’s physician or other health-care profes- (1) patients with extraoral lesions; (2) patients
sionals in the following scenarios: (1) the patient with oral and maxillofacial signs and symptoms
is a poor historian and the medical history is suggestive of a systemic disease; and (3) patients
unclear or incomplete; (2) the patient has a severe requiring specialized interventions such as sur-
medical condition which increases the risk of an gery. It is preferable that referral and consultation
adverse event (e.g., recent myocardial infarction); requests be made in writing in the form of a report.
(3) the patient has an abnormal review of systems However, in certain situations, a phone call or text
or physical examination/vital signs finding that message may be more practical when it is neces-
needs further evaluation (e.g., shortness of breath, sary to obtain information immediately. In such
pallor, or elevated blood pressure); or (4) when it circumstances, the phone conversation and mes-
is necessary to obtain reports of laboratory tests sages must be documented afterward. Table 13
and other investigations required for diagnosis lists the information for referral and consultation
and management. At other times, it may be nec- requests.
essary to refer a patient for evaluation and man- When medical consultation with a patient’s
agement of specific clinical problems when the physician is required prior to dental treatment or
patient’s treatment needs fall outside the treating surgery, it is important to communicate the details
doctor’s scope of practice. Examples include: of the planned procedure, anticipated amount of
Table 13 Information for referral and consultation Patients with chronic oral diseases will return
requests for follow-up evaluation and care. An abbreviated
Patient’s full name, date of birth, address, phone number, history is sufficient and the SOAP format is help-
and email ful to update the patient’s history and examination
Referring doctor’s full name, title, address, phone findings since the last visit (subjective, objective,
number, fax, and email
assessment, and plan). “Subjective” refers to the
Description of the problem
Relevant history and physical examination findings
history, “objective” refers to examination find-
Differential diagnosis/definitive diagnosis if available ings, “assessment” is the diagnosis along with
Radiographs, laboratory tests, and investigations already the disposition of the patient relative to the diag-
performed nosis (e.g., lichen planus, significant improve-
All treatment modalities that have been initiated or are ment on topical steroids), and “plan” is the new
anticipated management plan.
blood loss if applicable and level of stress to the Conclusions and Future Directions
patient. These medical consultations are made to
request additional information concerning the The goal of clinically evaluating oral diseases is to
patient that will aid in risk assessment and poten- arrive at a definitive diagnosis and provide effec-
tial modifications to treatment. Therefore, the final tive and safe treatment to patients. A careful and
responsibility regarding the risk of treatment lies systematic approach must be applied to gathering
with the oral health-care provider who must care- and interpreting the information collected during
fully make the final treatment decisions and not the medical history and physical examination.
the physician (Gary and Glick 2012). Thorough knowledge of the anatomy, physiology,
and clinical behavior of oral diseases is essential to
make the correct diagnosis. It is extremely impor-
Documentation tant that oral health-care providers are appropri-
ately trained in the diagnosis and management of
Medical records provide information regarding the diseases affecting the oral and maxillofacial region.
history of patients’ evaluation and treatment and
can serve as useful evidence during lawsuits.
Therefore, it is important to maintain accurate Cross-References
well-organized and complete records in a chrono-
logical order. In settings where paper-based health ▶ Clinical Evaluation of Orofacial Pain
records are utilized, it is important to ensure that all ▶ Clinical Immunology in Diagnoses of Maxillo-
pages of the health record contain the patient’s facial Disease
name and identification number. All entries should ▶ Diagnostic Imaging Principles and Applica-
be legible, dated, and contain the author’s name tions in Head and Neck Pathology
and identification. Although there is no generally ▶ Head and Neck Tumors
accepted format for documentation of clinical data, ▶ Interface Between Oral and Systemic Disease
it is imperative to carefully record all aspects of the ▶ Laboratory Medicine and Diagnostic Pathology
clinical history, physical examination, diagnosis, ▶ Odontogenic Pathology
and treatment plan at every patient encounter ▶ Oral Mucosal Malignancies
(Table 1). Other important components of the med- ▶ Oral Ulcerative Lesions
ical record, which should be filed in the chart, ▶ Oral Vesicular and Bullous Lesions
include laboratory and imaging reports, referral ▶ Salivary Gland Disorders and Diseases
and consultation requests, informed consent, oper- ▶ Soft and Hard Tissue Operative Investigations
ative notes, postoperative orders, email, text mes- in the Diagnosis and Treatment of Oral Disease
sages, and telephone conversations. ▶ White and Red Lesions of the Oral Mucosa
References Petersen PE. Oral cancer prevention and control – the

approach of the World Health Organization. Oral
Couch ET, Chaffee BW, Gansky SA, Walsh MM. Oncol. 2009;45(4–5):454–60.
The changing tobacco landscape: what dental profes- Reidy J, McHugh E, Stassen LF. A review of the relation-
sionals need to know. J Am Dent Assoc. 2016; ship between alcohol and oral cancer. Surgeon. 2011;
147(7):561–9. 9(5):278–83.
Degenhardt L, Hall W. Extent of illicit drug use and depen- Sarteschi LM. Jehovah’s witnesses, blood transfusions and
dence, and their contribution to the global burden of transplantations. Transplant Proc. 2004;36(3):499–501.
disease. Lancet. 2012;379(9810):55–70. Schiffman E, Ohrbach R, Truelove E, Look J, Anderson G,
Farman AG. ALARA still applies. Oral Surg Oral Med Goulet JP, et al. Diagnostic criteria for temporomandib-
Oral Pathol Oral Radiol Endod. 2005;100(4):395–7. ular disorders (DC/TMD) for clinical and research
Gary CJ, Glick M. Medical clearance: an issue of profes- applications: recommendations of the international
sional autonomy, not a crutch. J Am Dent Assoc. RDC/TMD consortium network* and orofacial pain
2012;143(11):1180–1. special interest Group†. J Oral Facial Pain Headache.
James PA, Oparil S, Carter BL, Cushman WC, Dennison- 2014;28(1):6–27.
Himmelfarb C, Handler J, et al. 2014 evidence-based Scully C, Miller CS, Aguirre Urizar JM, Alajbeg I, Almeida
guideline for the management of high blood pressure in OP, Bagan JV, et al. Oral medicine (stomatology) across
adults: report from the panel members appointed to the the globe: birth, growth, and future. Oral Surg Oral Med
Eighth Joint National Committee (JNC 8). JAMA. Oral Pathol Oral Radiol. 2016;121(2):149–157.e5.
2014;311(5):507–20. Sollecito TP, Rogers H, Prescott-Clements L, Felix DH,
Ludwick DA, Doucette J. Adopting electronic medical Kerr AR, Wray D, et al. Oral medicine: defining an
records in primary care: lessons learned from emerging specialty in the United States. J Dent Educ.
health information systems implementation experi- 2013;77(4):392–4.
ence in seven countries. Int J Med Inform. 2009; Stoopler ET, Sollecito TP. Focusing on the medicine in
78(1):22–31. dental medicine. Spec Care Dentist. 2016;36(2):59.
Marshall TA. Chairside diet assessment of caries risk. J Am Stoopler ET, Shirlaw P, Arvind M, Lo Russo L, Bez C, De
Dent Assoc. 2009;140(6):670–4. Rossi S, et al. An international survey of oral medicine
Miller CS, Epstein JB, Hall EH, Sirois D. Changing oral practice: proceedings from the 5th world workshop in
care needs in the United States: the continuing need for oral medicine. Oral Dis. 2011;17(Suppl 1):99–104.
oral medicine. Oral Surg Oral Med Oral Pathol Oral Tilakaratne WM, Ekanayaka RP, Warnakulasuriya S. Oral
Radiol Endod. 2001;91(1):34–44. submucous fibrosis: a historical perspective and a
Navazesh M, Kumar SK, University of Southern Califor- review on etiology and pathogenesis. Oral Surg Oral
nia School of Dentistry. Measuring salivary flow: chal- Med Oral Pathol Oral Radiol. 2016;122(2):178–91.
lenges and opportunities. J Am Dent Assoc. 2008;139 Waziry R, Jawad M, Ballout RA, Al Akel M, Akl EA. The
(Suppl):35S–40S. effects of waterpipe tobacco smoking on health outcomes:
NIAAA (National Institute on Alcohol Abuse and Alco- an updated systematic review and meta-analysis. Int J
holism). Helping patients who drink too much: a clini- Epidemiol. 2017 Feb 1;46(1):32–43. https://doi.org/
cian’s guide. 2005. http://pubs.niaaa.nih.gov/ 10.1093/ije/dyw021.
publications/Practitioner/CliniciansGuide2005/clini WHO. World Health Organization tobacco fact sheet.
cians_guide.htm. Accessed 20 Aug 2016. 2016. http://www.who.int/mediacentre/factsheets/
NIAAA (National Institute on Alcohol Abuse and fs339/en/. Accessed 1 July 2016.
®
Alcoholism). Alcohol use disorder. A comparison Wong-Baker FACES Foundation. Wong-Baker FACES
between DSM-IV and DSM-5. 2016. https://pubs. Pain Rating Scale. 2016. http://www.wongbakerfaces.
niaaa.nih.gov/publications/dsmfactsheet/dsmfact.htm. org/. Accessed 04 2017.
Accessed 10 July 2017. Zawawi KH, Al-Badawi EA, Lobo SL, Melis M, Mehta
Ogden GR. Alcohol and oral cancer. Alcohol. 2005;35(3): NR. An index for the measurement of normal maxi-
169–73. mum mouth opening. J Can Dent Assoc. 2003;69(11):
737–41.
Diagnostic Imaging Principles and
Applications in Head and Neck Pathology
Andy Whyte, Rudolf Boeddinghaus, and

Marie Anne Teresa J. Matias
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
Imaging Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
Anatomical Techniques Using Ionizing
Radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
Anatomical Techniques Without Ionizing
Radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
Functional Imaging Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
Principal Applications of Advanced Imaging in
Oral Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
Imaging of Mass Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
Imaging of Salivary Gland Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
Imaging of Malignancy of the Oral Cavity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
Imaging of Osteomyelitis and Osteonecrosis of the Jaws . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
Imaging of Temporomandibular Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
Imaging of Orofacial Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
Imaging of Sleep-Disordered Breathing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
Imaging of Headache . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
A. Whyte (*)
University of Melbourne, Carlton, VIC, Australia
Ear Science Institute, Subiaco, WA, Australia
e-mail: Andy.Whyte@perthradclinic.com.au
R. Boeddinghaus
e-mail: Rudolf.Boeddinghaus@perthradclinic.com.au
M. A. T. J. Matias
Qscan Radiology Clinics, Herston, QLD, Australia
e-mail: Tess.Matias@perthradclinic.com.au

https://doi.org/10.1007/978-3-319-72303-7_6
174 A. Whyte et al.

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
Abstract Osteonecrosis of jaws · Temporomandibular

Head and neck pathology encompasses mul- disorders · Obstructive sleep apnea · Headache
tiple, diverse conditions and disease pro-
cesses, many of which are complex and
require imaging as adjunct to clinical exami- Introduction
nation. Imaging techniques can provide ana-
tomical or functional information, some using Imaging is an adjunct to, and not a substitute for,
ionizing radiation while others do not. Plain an optimal clinical examination. Intraoral radio-
radiographs provide a two-dimensional over- graphs, extraoral radiographs, and dental pano-
view of the region of interest, and cross- ramic tomography (DPT) (also known as
sectional imaging modalities such as com- orthopantomograph, OPG) provide an overview
puted tomography (CT), cone beam computed of the mandible and maxillofacial skeleton and
tomography (CBCT), and magnetic resonance allow more detailed analysis of the dentition and
imaging (MRI) provide multiplanar evalua- alveolar process.
tion of osseous structures of the oral and max- Cross-sectional imaging modalities such as
illofacial region. CT and MRI have the computed tomography (CT) and magnetic reso-
additional advantage of providing high- nance imaging (MRI) provide high-resolution,
resolution imaging of soft tissues. Initial eval- multiplanar evaluation of the osseous structures
uation of superficially located head and neck and soft tissue of the oral and maxillofacial region,
soft tissue lesions frequently utilize ultra- respectively. These modalities, in addition to cone
sound. Nuclear medicine techniques provide beam computed tomography (CBCT), provide
functional information, evaluating metabolic detailed analysis of the dentition and of cortical
turnover of tissue and differentiating patho- and medullary bone free of the superimposition
logical from normal tissue. The applications inherent in radiographs. CBCT can visualize the
of these imaging techniques are discussed in outline of skin and also the mucosal outline of the
several clinical scenarios under the headings pharynx and oral cavity but lacks soft tissue con-
of mass lesions, salivary gland disease, oral trast resolution. Ultrasound is frequently used as
cavity malignancy, osteonecrosis of the jaws, the initial diagnostic imaging modality in head
temporomandibular joint disorders, orofacial and neck imaging, especially for evaluating soft
pain, obstructive sleep apnea, and headaches. tissue lesions and guiding biopsy.
This chapter provides the most current data Nuclear medicine techniques involving radio-
regarding the advantages and disadvantages isotopes evaluate metabolic turnover of tissue,
of imaging techniques as they relate to head differentiating pathological from normal tissue,
and neck pathology. and are primarily used in the evaluation of malig-
nancy and infection.
Keywords The applications of these various imaging tech-
Maxillofacial imaging · Cross-sectional niques are discussed in various clinical scenarios,
imaging · Cone beam computed tomography · including mass lesions, salivary gland disease, oral
Magnetic resonance imaging · Ultrasound · cavity malignancy, osteonecrosis of the jaws, tem-
Dental panoramic tomography · Nuclear poromandibular joint disorders, orofacial pain,
medicine · Computed tomography · obstructive sleep apnea, and headaches.
Diagnostic Imaging Principles and Applications in Head and Neck Pathology 175
Imaging Techniques rocks and soil, radon gas that seeps from the
ground, and cosmic sources. This therefore varies
Imaging techniques can provide anatomical or from place to place: it is estimated at 2.4 milli-
functional information. Techniques can also be sieverts (mSv) per annum worldwide (Australian
divided into those using ionizing radiation and Radiation Protection and Nuclear Safety Agency
those that do not use ionizing radiation. 2015), equating to about 6.6 microsieverts (μSv)
per day, but ranges from less than 1 mSv per
annum to over 10 mSv (and exceptionally over
Anatomical Techniques Using Ionizing 70 mSv) per annum. Radiation doses from differ-
Radiation ent imaging modalities can be expressed in terms
of multiples of the daily background dose (Back-
An imaging technique should only be used if the ground Radiation Equivalent Time: BRET, also
potential diagnostic benefit exceeds the estimated known as BERT) a more meaningful concept for
risk from ionizing radiation. There is substantial most patients than comparing absolute dose.
evidence for a dose-related stochastic response to Different tissues in the body have different
high levels of ionizing radiation in the form of cancer risk from the same radiation dose, and
cancer developing years after initial exposure this concept is incorporated when calculating the
(Hendee and O’Connor 2012). Although there is Effective Dose (E) of an imaging examination and
debate as to the level of risk associated with the low to which region of the body it is applied. In addi-
radiation doses employed in diagnostic radiology, tion to the brain and thyroid, the mucosa of the
including dental and maxillofacial radiology oral cavity, pharynx, and upper respiratory tract
(DMFR), a linear non-threshold (LNT) model is and the salivary glands have relatively high tissue
assumed for purposes of radiation protection. This weighting when calculating the potential deleteri-
LNT model implies that even very low doses of ous effects of imaging of the dental and maxillo-
ionizing radiation have the potential to result in a facial region (Ludlow and Ivanovic 2008).
small increased incidence of cancer. This stochastic
carcinogenic effect has been very difficult to dem- i) Radiographs: Intraoral radiographs are read-
onstrate directly because of the high background ily available and provide a low cost, low radi-
prevalence of malignancy, the fact that radiation- ation dose, and high spatial resolution
induced malignancy has no features which can modality for evaluating the dentoalveolar
distinguish it from any other malignancy, and the structures and specifically for detecting caries,
long lead time between radiation exposure and a periapical pathology, and periodontal disease.
clinically apparent cancer. However, there is now For each radiograph, the field of view is lim-
direct epidemiological evidence of a small increase ited and a full-mouth evaluation may require
in cancer incidence after CT scanning in children up to 18 radiographs resulting in a radiation
and young adults (Pearce et al. 2012; Mathews dose of up to 150 μSv, equivalent to 23 days of
et al. 2013). Children are considered more sensitive background radiation (BERT).
to radiation-induced carcinogenesis due to imma- In contrast, the DPT is a curved panoramic
turity of developing tissues, their smaller size, and tomogram that provides an overview of the den-
proximity or inclusion of more radiosensitive tition, mandible, temporomandibular joints
organs such as the brain, thyroid, salivary glands, (TMJ), and maxilla and maxillary sinuses. It is
and mucosa of the maxillofacial region, as well as also a readily available, low-cost, and low-
the longer life expectancy in which a radiation- radiation-dose imaging modality but is of
induced malignancy may manifest. much lower resolution than intraoral radio-
Background radiation is an important concept graphs and is prone to artefacts inherent in the
when considering total radiation dose. It is pre- technique and also dependent on the patient and
dominantly comprised of terrestrial radiation in technical errors.
176 A. Whyte et al.
The lateral cephalogram provides a stan- an effective dose of 200–300μSV for a

dardized assessment of the dental and medium field of view scan in the oral and
skeletal relationship of the jaws as well as maxillofacial region, equivalent to between
two-dimensional (2D) evaluation of the airway. 30 and 45 days of BERT.
Digital rather than traditional film-screen Intravenous iodinated contrast medium is
techniques have numerous advantages includ- used to increase the difference in attenuation
ing significantly lower radiation dose, image (density) between pathological lesions and
processing, fewer repeat examinations, digital adjacent normal tissue, either inflammatory
storage, and potentially higher resolution. The or neoplastic. Hypervascularity within or at
average effective dose of a digital DPT is the margin of the lesion leads to accumulation
15 μSv (2.5 days of BERT) and that of a lateral of radiodense iodine, and it becomes “whiter”
cephalogram is 3 μSv (less than half a day on a gray-scale image and more conspicuous.
of BERT). On the other hand, central necrosis or pus
ii) Computed tomography (CT): The invention within a tumor or abscess does not enhance
of CT in 1972 allowed true cross-sectional and is more clearly visualized than on
imaging for the first time, initially of the non-contrast scans. In patients with kidney
brain. All CT scanners utilize a thin, disease and those with diabetes on metformin
fan-shaped X-ray beam which passes through treatment, the risks of contrast medium-
the area being scanned, with the variable induced renal failure and lactic acidosis,
attenuation of the beam being detected by a respectively, are significantly increased.
detector array. In the late 1980s, slip-ring tech- iii) Cone Beam Computed Tomography (CBCT):
nology was developed allowing continuous This imaging technique was initially devel-
rotation of the ring-shaped gantry containing oped for use with clinical applications
the X-ray tube and detector array around the in angiography, nuclear medicine, and
patient, the table, and the patient travelling at a imaging-guided radiotherapy. Initial devel-
constant speed through the gantry. The X-ray opment of CBCT for maxillofacial use
beam described a helical path around the occurred in the late 1990s with rapid evolu-
patient: helical CT (also known as spiral CT). tion into scanners with decreased scanning
Multidetector or multislice CT (MDCT or times, a range of scanning options, and less
MSCT) was a critical technological develop- predisposition to artefacts.
ment in 1998 replacing the single long detec- CBCT uses a cone-shaped X-ray beam cen-
tor (up to 20 mm in the longitudinal axis) used tered on a flat panel 2D detector. The source
in single slice scanners with multiple small detector performs a single 360-degree rotation
detectors. This enables large volumes of tissue around the head producing a series of 2D
to be scanned rapidly with the simultaneous images from which a volumetric data set is
generation of thick and thin slices. The thin reconstructed using algorithms similar to
slices contain isotropic voxels (i.e., volume those used in MDCT. Multiplanar 2D recon-
elements which are of equal length in all structions in the axial, coronal, sagittal, and
three dimensions of space) allowing for multi- curved planes are produced from the volume
planar 2D reconstructions of equivalent reso- data set, and, using dedicated software, three-
lution to the acquired axial slices. Currently, dimensional (3D) reconstructions of the skin
64- to 320-slice MDCT represents state-of- surface, airway, or maxillofacial bony skele-
the-art technology. ton can be obtained. Scan times are greater
Additional hardware and software devel- than those of MDCT (9–27 s, compared to
opments have contributed to significant reduc- 2–4 s for MDCT) with patients generally
tion in radiation dose without deleterious being scanned in the erect or sitting position
increase in image noise or loss of diagnostic (a single supine CBCT scanner is currently
efficacy. Current MDCT scanners will result in available).
The main advantages of CBCT (over MDCT) “window” that is unimpeded by bone or air,
are higher resolution (0.075–0.15 mm voxel limiting the type of examination it can provide
lengths as compared with 0.5–0.625 mm for when compared to CT or MRI.
MDCT) and lower radiation dose: 60–250 μSv For evaluation of the neck and maxillofacial
for state-of-the-art equipment (Ludlow and region, high-frequency transducers are used,
Ivanovic 2008; De Vos et al. 2009; Casselman using sound waves between 7.5 and 15 MHz:
et al. 2013), (equivalent to 9–38 days of BERT). compared with conventional transducers used
Streak artefacts resulting from beam hardening for abdominal and pelvic imaging; these result
by metallic restorations are less pronounced and in higher spatial resolution but are unable to
more localized with CBCT. In addition, a CBCT penetrate as deeply into the soft tissues.
scanner is smaller and is generally lower in cost Sound waves are reflected back from every
than MDCT. anatomical interface in the tissue being exam-
Significant disadvantages include the ined. Echogenicity is the degree to which the
absence of soft tissue contrast which is princi- interface reflects sound and returns a signal to
pally related to the lower radiation dose but the transducer, which also acts as receiver.
also the detector design and inability to accu- Hyperechoic structures appear whiter on a
rately measure tissue density (in Hounsfield gray-scale image and include bone or calculi.
units) as compared with the high accuracy of All sound is reflected and an acoustic shadow
conventional CT (Table 1). is created. If sound is poorly reflected or not
reflected at all and passes easily through the
structure, it appears darker or black and is
Anatomical Techniques Without described as hypoechoic or anechoic, respec-
Ionizing Radiation tively. Acoustic enhancement occurs deep to
these structures as the easily propagated sound
There are no known significant side effects waves are reflected at the next tissue interface,
resulting from the use of ultrasound or magnetic examples being cysts and some tumors such as
resonance imaging, the principal imaging tech- pleomorphic adenomas. Isoechoic structures
niques which do not use ionizing radiation. have the same echogenicity as their surround-
ings, for example, muscle.
i) Ultrasound (US): This is widely available, Color Doppler US is an additional ultra-
inexpensive, noninvasive, and highly accurate sound technique which supplements the gray-
in the evaluation of superficial structures of the scale examination and can be used to deter-
head and neck, including the oral cavity. Ultra- mine the presence, distribution, and type of
sound, especially in the head and neck, does blood vessels in a lesion, often increasing the
have some limitations. The accuracy relies on specificity of diagnosis.
the experience and knowledge of the operator In the maxillofacial region and neck, US is
and also the habitus and cooperation of the an excellent initial examination for the salivary
patient. In addition, ultrasound requires a glands, thyroid, lymph nodes, congenital
Table 1 Comparison of intra-oral radiographs, DPT, CBCT, and CT

Modality Intra-Oral Radiographs DPT CBCT CT
Volumetric data set No No Yes Yes
Spatial resolution +++ + ++ +
Soft tissue contrast No No No Yes
Effective dose of 150 μSv (full mouth) 15 μSv 60–250 μSv 200–300 μSv
radiation
Scan time (seconds) very short (<<1s); multiple 10s: 9–27 s: long 2–4 s: short
exposures long (less motion artefact)
178 A. Whyte et al.
lesions, and miscellaneous mass lesions. Eval- of radiofrequency excitations and readouts) and
uations of complications of infection or post- reflects the different magnetic spin properties of
surgical sequelae, with or without CT or MRI, hydrogen according to how it is chemically
are further potential uses. US can also be used bound within different tissues. Fat and water
to guide an imaging procedure such as fine are the standards used to describe a T1- or
needle aspiration cytology (FNAC), core T2-weighted image: fat is bright and water
biopsy, aspiration or drainage of collections, dark on a T1-weighted image while water is
and also placement of a needle into the TMJ bright on a T2-weighted image. Fat is classically
for therapeutic injection of steroids and local described as dark on T2, but this is not the case
anesthetic. The use of a small footplate, very on most currently used fast T2 sequences.
high-frequency probe used intraorally is an T1-weighted images are optimal for assessing
established, fast, and accurate method of deter- anatomy and T2 (often used with a technique for
mining the depth of submucosal invasion suppressing the signal from fat) for differentiat-
of squamous cell carcinoma (Yesuratnam ing pathology from normal tissue (Fig. 1). Most
et al. 2014). inflammatory and neoplastic lesions are water-
ii) Magnetic resonance imaging (MRI): This rich and therefore are of higher signal than
imaging modality is based on the principles surrounding tissue on a T2-weighted image.
that atoms with an odd number of neutrons or Because air and cortical bone have no mobile
protons have spin and that a moving electrical protons, they have no signal on any MRI
charge produces a magnetic field. Hydrogen is sequence. The presence of signal within cortical
the atom most commonly imaged in MRI bone is always pathological apart from normal
because of its abundance in the body. Hydro- neurovascular canals and sutures.
gen nuclei in tissue spin randomly until placed Intravenous contrast agents can also be
in the strong magnetic field of an MRI scan- used to increase the signal intensity difference
ner, which causes the protons to align with the between a pathological lesion and normal
external magnetic field, analogous to minia- tissue. The most commonly used MRI contrast
ture compass needles. If the protons are then agent is gadolinium (a trivalent rare earth
exposed to a short burst of electromagnetic element) bound to a chelate. Gadolinium
energy in the form of a radiofrequency pulse, increases the signal intensity of enhancing tis-
they will momentarily flip from their axis. sues on T1-weighted imaging: this greater con-
In the process of returning to their original spicuity can be further improved by using a
orientation, they emit a characteristic radio- fat-suppression sequence to remove the normal
frequency signal which is detected by a high signal from fat. Patterns of enhancement
receiver coil adjacent to the region of interest. can increase the specificity of diagnosis, and this
The intensity of this emission reflects a is of value in differentiating cystic from solid
combination of the density of protons and lesions and differentiating between common
the chemical qualities of the surrounding types of tumors. Gadolinium is contraindicated
tissues. in patients with impaired kidney function in
MRI scanners used in current clinical prac- whom it may rarely result in nephrogenic sys-
tice generally have magnetic field strengths of temic fibrosis, a debilitating and occasionally
1.5 or 3 Tesla (T). Higher field strength (3 T) fatal condition. Although gadolinium chelate is
magnets generate more signal and improved almost completely excreted in urine within 24 h
image quality, especially of small structures of injection, there is recent evidence that traces
such as cranial nerves or small joints such as of unbound gadolinium accumulate and remain
the TMJ. in the brain, probably indefinitely (Kanda et al.
The contrast of a routine MRI image is 2014; McDonald et al. 2015). Although this has
dependent on whether the image is T1- or not been shown to have clinical effects, gado-
T2-weighted (determined by the specific timing linium should not be used indiscriminately but
Fig. 1 Basic MRI sequences: (a) T1 – fat is hyperintense; cortical bone have no signal on any sequence. The dashed
simple fluid (globe – g) is hypointense. (b) T2 – fat is white arrow indicates hyperintense proteinaceous fluid in
slightly less hyperintense; simple fluid is hyperintense. the left posterior ethmoid air cells on the T1 sequence
(c) Fat saturation T2 – fat is hypointense (the signal is which then loses signal on the T2 sequences mimicking
suppressed); simple fluid remains hyperintense. Air and clear air cells
reserved for cases where its use is likely to region. It can determine if there is arterial sup-
improve diagnostic accuracy. ply to a suspected vascular malformation.
Compared with other anatomical imaging MRA can be performed either using gadolin-
modalities, MRI has excellent contrast resolu- ium contrast or without contrast, using special
tion, allowing optimal delineation of normal techniques relying on higher signal from
from abnormal tissue. Like MDCT and flowing protons.
CBCT, MRI is now capable of submillimeter One in three patients experiences anxiety
imaging which is essential for evaluation of the and one in six patients becomes claustrophobic
trigeminal and the lower cranial nerves in the in an MRI scanner (Enders et al. 2011). Most
evaluation of orofacial pain and optimal for can complete the examination with encourage-
the assessment of soft tissue and bone. High- ment and simple measures but some may
spatial-resolution MRI of the oral and maxillo- require sedation. The development of shorter
facial region requires high field strength (3 T) and wider bores in current MRI scanners has
and optimal receiver coils to maintain adequate also improved patient acceptance.
signal. Most cardiac pacemakers and a variety of
The technique of magnetic resonance metallic implants and coils may contraindicate
angiography (MRA) can be used to study arte- MRI; safety is paramount and all implanted
rial anatomy and flow in the maxillofacial devices require rigorous evaluation.
180 A. Whyte et al.
Functional Imaging Techniques reconstructed in axial, coronal, and sagittal

planes.
Functional methods of imaging usually involve When sepsis is thought to be the likely
radioisotopes and therefore ionizing radiation. cause of increased osteogenesis on a bone
They assess metabolic turnover and can be com- scan, a specific diagnosis of infection can be
bined with anatomical imaging (MDCT or MRI). provided by an additional nuclear medicine
MRI can also be used to assess function, primarily scan using white cells labeled with the isot-
of the brain but also in the oral and maxillofacial ope (indium-111 or technetium-99 m) or a
region. gallium scan, the latter having increased sen-
sitivity for the detection of chronic infections
i) Conventional Nuclear Medicine: A minute such as osteomyelitis.
amount of a radioactive isotope is bound to a ii) Positron emission tomography (PET): The
carrier molecule, and this combination (called main tracer used is F18 -fluorodeoxyglucose
a tracer) is injected intravenously to study a (18F–FDG); fluorine-18 is the isotope and is
particular body function by evaluating the produced in a cyclotron with a half-life of just
spatial and temporal distribution of the tracer less than 2 h. As the carrier molecule is a
within the body. The isotope decays by emit- glucose analogue, 18F–FDG is taken up by
ting gamma rays (photon of a specific energy) tissues within 1–2 h according to metabolic
which are measured by a gamma camera activity, producing a “glucose map” with
which maps the detected gamma rays. physiological activity in the brain and heart
The most frequently used radioisotope is as well as (in the head and neck region) the
technetium-99 m (99mTc) which is commonly salivary glands, tonsils, and larynx. Diseased
bound to a diphosphonate carrier molecule. metabolically active tissues, in particular
It emits a gamma ray of an energy which is malignant tumors, exhibit a high rate of glu-
optimal for detection by the scintillation cose metabolism.
detector of the gamma camera and loses The decay of F-18 produces a positron
50% of its radioactivity in 6 h making it which travels a short distance before annihi-
ideal for medical imaging. Radiolabeled lating with an electron, producing two pho-
diphosphonates bind to hydroxyapatite at tons propagating in opposite directions
sites of active osteogenesis which is a non- which are detected simultaneously by a ring
specific response of bone to a range of stimuli, detector. PET is usually combined with
including injury, infection, or tumor. low-dose CT on the same scanning platform
Bone scans are of low sensitivity for (PET-CT) producing co-registered images to
tumors confined to the marrow (such as mye- improve anatomical localization as well as
loma) and those that are osteolytic with little correction of the PET emission data for atten-
or no osteogenic reaction (such as myeloma uation by the tissues of the body (Fig. 2). A
and renal cell carcinoma). The effective radi- PET scan covering the brain to the thighs
ation dose (about 6 mSv, BERT of about takes 20 min with 30 s for the CT of the
2.5 years) is relatively high when compared same region and a combined radiation dose
to maxillofacial CBCT or MDCT. of 14 mSv (equivalent to a BERT of nearly
Bone scans can be either conventional (pla- 6 years).
nar 2D) or tomographic (single photon emis- The principal use of PET-CT in oral and
sion computed tomography, SPECT). SPECT maxillofacial region is in the assessment of
can also be combined with low-dose CT to head and neck cancer. A large field of view
provide a fused SPECT/CT image providing means that metastatic disease and second pri-
optimal anatomical localization of abnormal mary tumors can be detected, and PET may
bone scan activity. Images can be detect malignancy in structures which appear
Fig. 2 PET-CT of a left retromolar trigone squamous cell the intense metabolic activity in the small primary (white
carcinoma with metastatic left level 2 nodes. The superior arrow) and nodes (dashed white arrow) are shown in
axial scans (a, b, and c) correspond to the primary tumor. orange. Scans c and f are post-contrast CT scans; the site
Inferior scans: d, e, and f demonstrate the metastases. of the primary is difficult to appreciate and is indicated by a
Scans a and d are the non-contrast CT component of the white arrow and the metastatic nodes by a dashed white
PET-CT scan used for localization and attenuation correc- arrow
tion. Scans b and e are the fused CT and metabolic images;
normal or are difficult to assess on CT and an abscess or a keratocystic odontogenic

MRI, such as small volume lymph node tumor of the jaw restrict the random motion
metastases. A large multicenter study of of water molecules and lower diffusion, mea-
patients with head and neck cancer has sured as a diffusion coefficient (Sumi et al.
shown that PET was able to detect additional 2008). DWI is a rapid means of tumor
sites of disease in 39.4% of patients and characterization and assessing response of
resulted in management change in 33.8% of malignant tumors to treatment in the oral and
patients. PET therefore has a vital role in opti- maxillofacial region (Thoeny et al. 2012;
mal staging, treatment planning, and follow- Payne et al. 2015).
up post-therapy for head and neck cancer Diffusion tensor imaging (DTI) visualizes
(Castaldi et al. 2013; Purohit et al. 2014). the location, orientation, and microstructure of
iii) Functional MRI techniques: white matter tracts as well as the root-entry
Diffusion weighted imaging (DWI) is a zone of the cisternal segment of the trigeminal
form of MRI which quantifies diffusion of nerve to the pons. It has been applied to the
water occurring naturally at a molecular level study of the pathophysiology of neuropathic
(Brownian movement). The dense cellular tis- pain and the response to treatment.
sue of tumors, cellular edema of recent cere- Magnetic resonance spectroscopy (MRS)
bral infarcts, and the proteinaceous contents of supplements anatomical MRI and allows the
182 A. Whyte et al.
presence and concentration of key metabolites Imaging of Mass Lesions

to be measured within lesions, aiding the dis-
tinction between inflammatory and neoplastic Mass lesions may arise from orofacial soft tis-
processes in the brain. sues, the maxillofacial skeleton, or odontogenic
Functional magnetic resonance imaging tissues:
(fMRI) is a technique that measures brain
activity. Cerebral blood flow and blood oxy- a. Orofacial soft tissues. Palpable lesions in the
genation are coupled to neuronal activity. The orofacial region may arise from skin, subcuta-
primary technique used in fMRI is blood-oxy- neous tissue, pilosebaceous glands, muscle,
gen-level-dependent (BOLD) contrast, which fat, fascia, nerves, blood vessels, lymph
is based on the different magnetic properties nodes, or embryonic remnants. The differential
of oxygenated and deoxygenated hemoglobin. diagnosis may be wide, and the majority of
fMRI provides a noninvasive means of map- these lesions will be benign. The location of
ping brain function. It can be used in assessing the lesion, the patient’s age, and medical his-
orofacial pain processing areas. It can be com- tory including a history of previous malig-
bined with spectroscopy (fMRS). At present, nancy are important factors in approaching a
this is primarily a research tool which has been diagnosis.
used in migraine and pain research to evaluate If imaging is required because the diagnosis
changes in metabolites in areas involved is not clear after clinical examination, US with
in pain. color Doppler should be the initial imaging
Voxel-based morphometry (VBM) is a modality, if necessary proceeding to
widely used and validated technique using ultrasound-guided fine needle aspiration cytol-
high-resolution 3D MRI data to evaluate ogy (FNAC) which provides a definitive diag-
brain structure. This technique has shown nosis in most cases. US can usually distinguish
reduction in gray matter volume in the pain between a simple cyst, a more complex lesion
processing areas of the brain in patients with containing debris or small solid components,
severe chronic facial pain and migraine. These and solid lesions of various types. CT or MRI
changes are reversible with successful treat- may be required if US suggests that the lesion
ment in a matter of weeks, a direct measure of contains fat or is hypervascular, if it cannot
neuroplasticity (May 2009). demonstrate the full extent of the lesion or
there is sonographic or cytological evidence
of malignancy.
Principal Applications of Advanced Cystic lesions in younger patients are usu-
Imaging in Oral Medicine ally congenital in nature, arising from embry-
onic remnants (Woo and Connor 2007; Mittal
The applications of advanced imaging techniques et al. 2012). Thyroglossal duct cysts (TGDC)
are discussed in various clinical scenarios below occur along the embryologic path of descent of
under the headings of imaging of (1) mass lesions, the thyroid gland from the foramen cecum at
(2) salivary gland disease, (3) malignancy of the the tongue base to the lower neck. They are the
oral cavity, (4) osteomyelitis and osteonecrosis of commonest congenital neck masses. Many pre-
the jaws, (5) temporomandibular joint disorders, sent in childhood but they may not present until
(6) orofacial pain, (7) obstructive sleep apnea, and later in life, often when the cyst becomes
(8) headaches. A comprehensive description of infected (Fig. 3). Most are located at or inferior
the radiologic features of all types of pathology to the level of the hyoid bone in the midline, but
is beyond the scope of this chapter. The reader is infrahyoid lesions may deviate away from the
referred to other chapters for descriptions of the midline. Rarely, thyroid neoplasms (usually
imaging features of the main conditions described papillary thyroid carcinoma) may arise within
in those chapters. a TGDC.
Fig. 3 Thyroglossal duct cyst, indicated by a white arrow. invaginates the left strap muscles (c). (a) Sagittal, midline
This small lesion is hypodense on CT consistent with fluid CT reconstruction. (b and c) Axial CT reconstructions. (d)
and is situated inferior to the hyoid bone (H). It extends Axial US scan showing a sonolucent lesion. Posterior
inferiorly into the superior thyroid notch (b) and then acoustic enhancement is indicated by the white dotted oval
Branchial cleft anomalies arise from incom- malformations (Guneyli et al. 2014; Gamss
plete obliteration of the embryonic branchial et al. 2015). Vascular tumors are true neoplasms
(pharyngeal) clefts or pouches, resulting in either which proliferate secondary to mitosis and
a cyst or, less frequently, a sinus or fistula. First include infantile hemangioma and congenital
branchial cleft anomalies are intra-parotid or peri- hemangioma. In contrast, vascular malformat-
auricular in location. Second branchial cleft cysts ions are structural abnormalities of the capillary,
comprise 95% of all branchial cleft lesions and venous, lymphatic, or arterial system that grow in
most commonly present in the 20–40 year age proportion to the child. Vascular tumors and vas-
group, often becoming evident after an upper cular malformations must be distinguished from
respiratory infection. They are most commonly hypervascular neoplasms derived from
positioned deep to sternomastoid, lateral to the non-vascular tissues arising in the maxillofacial
carotid space, and posterior to the submandibular region, such as juvenile angiofibromas and para-
salivary gland (Fig. 4). gangliomas (glomus tumors) (Fig. 5). Imaging,
The widely accepted International Society for especially MRI and US, plays a key role in the
the Study of Vascular Anomalies (ISSVA) clas- diagnosis and classification of vascular lesions.
sification divides vascular lesions into two cate- Hemangiomas are benign and divided into
gories: vascular tumors and vascular infantile and congenital subtypes. Infantile
184 A. Whyte et al.
Fig. 4 Second branchial cleft cyst: (a) axial post-contrast on US, usually indicative of inflammation. The deeply
CT scan and (b) color Doppler US. The lesion is of low situated common carotid artery (CCA) is indicated by a
density on CT (white arrow) and contains internal echoes dashed white arrow
hemangiomas arise 2–8 weeks after birth and triangle of the neck. They have an infiltrative
undergo a proliferative growth phase until they pattern of growth, extending freely between
reach their full size. In contrast, congenital adjacent fascial spaces. Unlike venous
hemangiomas are fully formed at birth and malformations, they do not enhance with con-
may be further subdivided into involuting hem- trast (Fig. 7).
angiomas, which regress completely within High-flow vascular malformations are rare;
2 years, and non-involuting hemangiomas, they usually present after a period of rapid
which show proportional growth without growth and include arterial malformations, arte-
regression. MRI optimally demonstrates the riovenous malformations, and arteriovenous fis-
typical imaging features. tulae. They are best demonstrated by MRI with
Low-flow vascular malformations include magnetic resonance angiography (MRA). Feed-
capillary, venous, lymphatic, and combined ing arteries, the malformation or fistula, large
venolymphatic malformations and are the draining veins, and possible osseous involve-
commonest vascular lesions. They demon- ment are the principal imaging features.
strate proportional growth and do not involute. Epidermoid cysts are thin-walled cystic
Venous malformations (still widely and incor- lesions that commonly occur in the floor of
rectly termed cavernous hemangiomas) have the mouth superior to mylohyoid and often
characteristic imaging features including mimic a simple ranula. Dermoid cysts are
strong contrast enhancement and often most common in the submandibular space
phleboliths (Fig. 6). Lymphatic malformations (i.e., inferior to mylohyoid); they mimic plung-
(still widely termed lymphangiomas) occur ing ranulas or lymphatic malformations and
most commonly in the head and neck in the often appear as a complex cyst due to the
first 2 years of life. They are subdivided into presence of debris, fat, or calcium produced
macrocystic (cysts > 20 mm, also known as by skin appendages in the lining of keratinized
cystic hygromas), microcystic (cysts < 20 mm), squamous epithelium (Fig. 8).
and mixed types. They are commonly situated Most apparently cystic lesions in patients
in the floor of the mouth or the posterior over the age of 40 years will be due to
Fig. 5 Carotid body tumor (a type of paraganglioma or Fat saturation T2 coronal MRI (dotted white arrows): the
glomus tumor). These uncommon tumors arise from tumor is hyperintense and contains multiple punctate and
neuroectodermal cells acting as chemoreceptors for major curvilinear low-signal vessels. (d) Color Doppler US: blood
arteries. (a) Post-contrast CT: enhancing mass in the right flow is color coded according to the direction of flow (white
carotid sheath (dotted white arrow). The separated internal arrows) – either blue or red. Multiple small vessels are shown
jugular vein (IJV) and internal carotid artery (ICA) are indi- either within or around the tumor (dotted white arrow)
cated. (b) Post-contrast MRI showing the same features. (c)
metastatic carcinoma to cervical lymph nodes, lymph nodes are the commonest mass lesion
most commonly human papillomavirus (HPV)- detected by clinical examination; normal-sized
related squamous cell carcinoma (SCC) of the or enlarged, reactive-appearing nodes are
oropharynx or papillary thyroid carcinoma ovoid with a vascular supply via the hilus
(Fig. 9). Nodal necrosis or abscess formation which commonly contains a small nidus of fat
can be due to various inflammatory and infec- (Fig. 10). Reactive cervical lymph nodes tend
tive conditions (Mittal et al. 2012). to be larger in children, the largest usually
The nature of solid lesions can usually be being the jugulodigastric node. Absolute
determined by imaging. The location, mor- nodal size is less important than change in
phology, margin, vascularity, and multiplicity nodal morphology when assessing for meta-
are the principal diagnostic features. Palpable static disease or lymphadenitis. Pathological
186 A. Whyte et al.
Fig. 6 Venous malformation with a lymphatic component by the lower-density lymphatic component. The dense,
in the left submandibular space (dotted oval). This lesion calcified foci represent phleboliths. Post-contrast, fat satu-
inferiorly displaces and compresses the submandibular ration T1-weighted MRI (b); the enhancement is more
salivary gland (SMG). Post-contrast CT in the axial (a) conspicuous than on CT, and the phleboliths are not seen.
and coronal (d) planes. There is central enhancement The fat saturation T2-weighted MRI (c) demonstrates uni-
(white arrow) within the venous component surrounded form hyperintensity in both components of the lesion
nodes tend to be round rather than oval, with Lipomas are common in the neck, including
loss of normal hilar fat and blood flow. US with the peri-parotid region. The appearance of fat
color Doppler demonstrates abnormal vascular within lipomas varies on US; US-guided
patterns in larger nodes. With CT and MRI, FNAC is rarely diagnostic, and confirmation
abnormal nodes are of heterogeneous attenua- of the nature of these lesions commonly
tion or signal, respectively, especially after requires CT or MRI (Fig. 12). Atypical
the administration of intravenous contrast lipomas which contain enhancing tissue or
(Fig. 11). Diffusion-weighted imaging (DWI) septa in addition to fat require excision to
is a rapid MRI technique that can be used exclude malignancy. Spindle cell lipomas,
to characterize enlarged lymph nodes by mea- characteristically occuring in the subcutaneous
suring the apparent diffusion coefficient fat of the posterior neck of middle-aged men,
(ADC) which help to distinguish between reac- although benign can contain enhancing soft
tive, lymphomatous, and metastatic causes tissue mimicking a liposarcoma (Choi
(Ali 2012). et al. 2013).
Fig. 7 Lymphatic malformation (L) deep to the right white arrows indicate mediolateral airway narrowing (the
sternomastoid muscle (sm) extending toward the posterior patient also has obstructive sleep apnea). Longitudinal US
triangle and supra-clavicular fossa (white arrows). Post- (c) showing the macrocystic structure and color Doppler
contrast CT in the coronal (a) and axial (b) planes. Open (d) confirms absence of internal blood flow
Fig. 8 Epidermoid/dermoid in the right submandibular enhancing wall, compressing the right submandibular
space. Axial (a) and coronal (b) CT reconstructions show- gland
ing a bilobulate cystic lesion containing debris with a thin
188 A. Whyte et al.
Fig. 9 (a) Enlarged left level 2 node (white arrow). CT. (c) Occult primary SCC in the left palatine tonsil
The mass has a peripheral enhancing margin with central which was only identified on PET-CT (dashed white
fluid attenuation representing nodal necrosis. (b) No oro- arrow). HPV-positive disease in a 42-year-old male
pharyngeal abnormality was seen on post-contrast
b. Maxillofacial skeleton. Lesions arising within contain normal-appearing bone and have a
the mandible or bones of the midface usually smooth surface (Fig. 13). The major differen-
present as a mass or facial asymmetry. These tial is an osteoma which presents as an
lesions may be tori, hamartomas, or neo- exophytic, pedunculated sclerotic lesion com-
plasms, either benign or malignant. Malignant monly arising from the ramus and inferior bor-
tumors of bone may be primary or secondary. der of the mandible or within the frontal or
An exostosis is a hyperplastic protuberance ethmoid sinuses.
of normal cortical and cancellous bone, the Fibrous dysplasia (FD) is a dysplastic con-
prevalence of which is higher in certain ethnic dition of bone leading to its replacement with
groups and increases with age. Those arising fibrous tissue. In its distribution, it can be
from the midline of the palate or the lingual monostotic or polyostotic, but in the craniofa-
cortex of the mandible are designated as tori cial region, it can involve contiguous bones
(torus palatinus and torus mandibularis, across sutures; hence craniofacial FD com-
respectively). Size varies, but all lesions prises a third subtype, with a mean age of
Fig. 10 Normal jugulodigastric lymph node. (a) Color the carotid sheath. It is of soft tissue density with a small
Doppler US: echogenic fat within the hilus surrounds a nidus of low-density fat representing the hilus. (c)
vascular core (orange) with a “branching tree” appearance T1-weighted MRI: fat in the hilus is hyperintense on this
of peripheral vessels. The remainder of the node is uni- MRI sequence as is subcutaneous fat. (d) Post-contrast, fat
formly hypoechoic. (b) Post-contrast CT: the node (dashed saturation T1 MRI: the node enhances uniformly apart
white oval) is situated anterior to the enhancing vessels of from the low signal fat in the hilus
diagnosis of 25 years, no sex predilection, and Ossifying fibromas (OF) can appear identical
with the maxilla being involved twice as often to active FD on histological examination but are
as the mandible (Menon et al. 2013). In the well defined and occur predominantly in the
mandible, posterior involvement predomi- posterior mandible. The mean age of presenta-
nates: superior displacement of the inferior tion is 31 years, and they predominate in
alveolar canal is virtually pathognomonic. females (Cure et al. 2012; MacDonald 2015).
Midface involvement may be confined to a Maxillary lesions tend to be larger, because they
single bone (i.e., monostotic) or be part of the can expand into the sinus without producing an
entity of craniofacial FD in which multiple obvious mass. The risk of recurrence of OF
contiguous facial bones and the skull base following excision is of the order of 20%. The
may be involved. The classic expansile, lesions are expansile and well defined with var-
ill-defined lesion exhibiting ground-glass scle- iable radiopacity of the contents dependent on
rosis is the commonest appearance on radio- the maturity of the lesion (Fig. 15).
graphs, MDCT, or CBCT. However, the Primary and metastatic malignant tumors of
patterns of radiolucency and radiopacity as the mandible and maxillofacial skeleton are
well as the signal of FD on MRI are variable uncommon. In addition to the rare central car-
(Fig. 14). cinomas which may arise in a preexisting
190 A. Whyte et al.
Fig. 11 Abnormal lymph nodes. Color Doppler US of Multiple metastatic cervical nodes (dotted white oval) are
metastatic papillary carcinoma of the thyroid gland to shown on post-contrast CT, axial reconstructions (c and d).
cervical nodes (a and b) in two different patients. Nodal There is also an enlarged node in the tail of the left parotid
blood flow is abnormal, being peripheral rather than central gland (white arrow) due to undifferentiated carcinoma,
(hilar) as in normal nodes. Nodes may be more echogenic probably from a skin primary. The nodes demonstrate
than usual, lucent, or mixed as in these examples. The node heterogeneous enhancement and several have ill-defined
in (a) is predominantly echogenic with small cystic foci margins with edema of surrounding fat consistent with
(short white arrows), and the node in (b) is predominantly extra-capsular invasion
cystic with micro-calcifications (white dotted arrows).
odontogenic lesion or glandular remnants, the or multiple ill-defined lucencies being the most
jaws may be the site of origin of sarcomas, common appearance on radiographs, CT, or
non-Hodgkin’s lymphoma (NHL), and mye- CBCT. However, virtually all metastases from
loma. Often the imaging appearance is non- prostate carcinoma and treated breast carci-
specific, but internal calcification, aggressive noma are sclerotic. MRI and isotope medicine
bone destruction, and periosteal new bone for- bone scans are more sensitive in detecting
mation suggest a sarcoma of bone or cartilage metastases to bone (Fig. 17).
origin (Fig. 16). c. Odontogenic tissues. Palpable mass lesions
Metastases to the jaws are rare, comprising arising from the dentition, supporting struc-
only 1–1.5% of all malignant oral neoplasms tures and alveolar bone, can be inflammatory,
(Dunfee et al. 2006). Breast carcinoma pre- developmental, or neoplastic. Several excellent
dominates in females and lung and prostate review articles, in addition to the chapter on
carcinoma in males. The posterior mandible is “▶ Odontogenic Pathology” in this textbook,
the most common location for metastases. discuss the wide spectrum of odontogenic cysts
Imaging appearances are variable with single and tumors and their specific clinical,
Fig. 12 Lipoma in the left submandibular space (white planes (b). Lipoma within the left parotid gland on T1 (c)
arrows) compressing the submandibular gland (SMG). and fat saturation T2-weighted MRI (d) (white arrows).
The density of the lesion is identical to that of subcutane- The signal intensity of the lesion is identical to that of
ous fat. Post-contrast CT in the coronal (a) and axial subcutaneous and deep fat on both sequences
demographic, imaging, and pathological fea- 50% of KCOTs being associated with an
tures (Dunfee et al. 2006; Devenney-Cakir unerupted tooth and mimicking a dentigerous
et al. 2011; Avril et al. 2014). The peak age of cyst. The keratin-rich debris in a KCOT gives
occurrence of odontogenic tumors and the characteristic imaging findings on MRI and
favored location varies widely according to CT (Fig. 18).
the histological subtype. The sequelae of acute or subacute dental
Lesions which present as a painless sepsis are normally evident clinically, but
mass are most commonly due to an apical chronic presentations such as an inflammatory
radicular cyst, dentigerous cyst, keratocystic mass in the submandibular triangle, a cutane-
odontogenic tumor (KCOT), or occasional- ous sinus, or facial pain may be of uncertain
ly other odontogenic tumors such as an etiology, especially to physicians or surgeons
ameloblastoma. Apical radicular cysts are without dental training (Fig. 19).
most common in middle-aged men and asso- d. Maxillary sinus. The differential diagnosis of
ciated with a non-vital tooth. Dentigerous opacification of a maxillary sinus on imaging is
cysts and KCOTs predominate in the second wide and depends on specific radiological find-
or third decade, and both lesions occur most ings, age of the patient, precipitating factors,
frequently in the posterior mandible, with and clinical features such as pain, swelling,
192 A. Whyte et al.
Fig. 13 Tori and exostoses. Reconstructions from CBCT and CT demonstrate midline palatal exostoses (a), lingual tori
in the mandible (b), buccal exostoses in the maxilla (c), and mandible (d)
discharge, or sensory changes (Whyte and demonstrate an irregular mass destroying the
Chapeikin 2005). sinus walls and invading adjacent structures
It has been estimated that 10–12% of max- such as the cheek, deep fascial spaces,
illary sinusitis is dental in origin, and this is nasal cavity, ethmoid labyrinth, and orbit
likely to be an underestimation as otolaryngol- (Fig. 22). Sinonasal malignancy tends to be
ogists performed these studies so subtle peri- advanced at presentation. MRI, in addition to
apical pathology may have been missed CT, is essential in treatment planning as it more
(Mehra and Jeong 2008). optimally demonstrates soft tissue invasion
Mucous retention cysts are common inci- and large nerve perineural tumor spread
dental findings on imaging and are estimated to (Baulch et al. 2015).
occur in 30% of the population. Most are
asymptomatic, and current clinical opinion is
that they are rarely of relevance (Fig. 20). Imaging of Salivary Gland Disease
Opportunistic colonization of the maxillary
sinus may lead to development of a a) Imaging indications and recommendations
fungal ball (aspergilloma) with characteristic Disease entities may arise within the major
increased density and calcification on CT and or, less commonly, minor salivary glands. The
occasionally CBCT (Fig. 21). Maxillary sinus high resolution of US provides excellent defi-
mucoceles are uncommon and invariably seen nition of the salivary glands to evaluate
following surgery involving the sinus walls suspected duct obstruction, inflammation, or a
and mucosa. mass. Duct dilatation and calculi 3 mm or
The most common malignant tumor of the larger in size can be reliably detected (Burke
maxillary sinus is squamous cell carcinoma et al. 2011). US-guided FNAC is reliable in the
(90% of cases). Cross-sectional imaging will preoperative diagnosis of mass as a primary
Fig. 14 Fibrous dysplasia (open white arrow) involving sclerosis. Longitudinal expansion of basal bone of the left
the frontal process of the right maxilla (a) and more exten- mandibular body (dotted white oval) shown on a cropped
sive involvement of the right maxilla and maxillary sinus panoramic radiograph (c) and axial CT (d). There is central
(b). Both lesions demonstrate diffuse ground-glass lucency surrounded by ground-glass sclerosis
salivary gland neoplasm; however, the cyto- the lesion and surrounding normal tissue.
logical distinction between different histologi- Detection can be improved by performing an
cal subtypes can be challenging. initial non-contrast CT scan. Pre-contrast CT is
CT (or CBCT) can demonstrate calculi that also performed for better detection of subtle
may not be seen on US due to very small size or small calculi (Burke et al. 2011; Abdullah
inaccessibility, and CT with contrast will also et al. 2013).
demonstrate duct dilatation, acute or chronic MRI provides optimal evaluation of tumors
sialadenitis, cellulitis, or a collection (Fig. 23). arising in the major and minor salivary glands,
MRI is preferable to CT for further assess- especially malignant lesions exhibiting extra-
ment of solid or cystic lesions that are incom- capsular spread or large nerve perineural tumor
pletely visualized on US and lesions that are involvement (Fig. 24). The advanced MRI
suspected to be malignant on clinical, sono- techniques of DWI and dynamic contrast
graphic, or cytological grounds. Tumors in enhancement (DCE) can improve distinction
the major salivary glands are usually more between benign and malignant parotid tumors
clearly visualized using US or MRI than as well as between the commoner benign
CT. Following iodinated contrast, tumors parotid tumors (Yabuuchi et al. 2003).
may enhance such that there is minimal Sialography is occasionally indicated for
difference in density (attenuation) between recurrent swelling and pain of the parotid or
194 A. Whyte et al.
Fig. 15 Ossifying fibroma in the right maxilla (a) and in dysplasia but they expand perpendicular to the long axis
the third molar region of the left mandible (b and c). These of the involved bone and have a more clearly defined
tumors have similar internal appearances to fibrous margin
submandibular glands where US and CT have gland or duct (Fig. 25). About 50% of calculi
not demonstrated a cause. Magnetic resonance occur distally in the duct and 31% at the hilus
sialography is a noninvasive alternative that or in the gland. Calculi are multiple in 25% of
does not require cannulation and relies on visu- cases (Lustmann et al. 1990; Abdullah et al.
alizing fluid in a dilated duct (Burke et al. 2013). Strictures account for 22% of salivary
2011). Sialography is also performed to guide duct obstruction; they involve the parotid in
interventional imaging techniques used for 75% of cases and are more common in
extraction of calculi or dilatation of duct females. The causes of strictures are calculi,
strictures. recurrent infection, autoimmune disease, and
b) Unilateral swelling and/or pain occasionally trauma (Ngu et al. 2007).
These signs and symptoms usually indicate The typical features of bacterial sialadenitis
obstruction of the duct of a major salivary include duct dilatation, calculi in about half of
gland by a calculus or a stricture with second- cases, and an enlarged gland which is hyper-
ary infection, glandular inflammation, and vascular and of heterogeneous texture.
enlargement. Enlarged intra-glandular lymph nodes occur
Sialolithiasis predominates in the 30–50 in the parotid gland, and enlarged reactive-
year age group and is more common in appearing lymph nodes occur in the subman-
males. The saliva of the submandibular gland dibular space adjacent to the inflamed salivary
is viscous with a high mucous content pre- gland. Occasionally an intra-glandular abscess
disposing to sialolithiasis. Approximately or pyocele of an obstructed duct may develop,
85% of calculi occur in the submandibular necessitating surgical drainage.
Fig. 16 Uncommon jaw tumors. (a and b) Non-Hodgkin rubbery soft tissue mass, confirmed as NHL. (c and d)
lymphoma (NHL) of the right maxilla: there is ill-defined Chondrogenic osteosarcoma of the left mandibular body.
bone destruction from 12 to 16 inclusive as seen on this Bizarre new bone formation overlying the buccal aspect of
bone window CT scan. Open biopsy demonstrated a the alveolar crest in the 36 region with medullary sclerosis
Obstruction of a sublingual or minor sali- (Fig. 27). Most commonly, the major salivary
vary gland may result in formation of glands are enlarged and infiltrated with fat.
a mucocele (Woo and Connor 2007; Mikulicz’s disease is a distinct pathologic
La’porte et al. 2011). If this is confined to the entity that is characterized by painless swelling
sublingual space of the floor of the mouth, it is of the parotid, submandibular, sublingual, and
known as a simple ranula and will be evident lacrimal glands. It is now considered to be one
clinically (Fig. 26). A plunging ranula results of the manifestations of IgG4-related disease, a
from extension to the submandibular space systemic disease that is characterized by abun-
around the posterior margin of mylohyoid or dant infiltration of IgG4-positive plasma cells
through a common developmental defect in and lymphocytes with associated fibrosis, lead-
mylohyoid (Kiesler et al. 2007). MRI is pre- ing to organ dysfunction. Involved glands are
ferred to CT to delineate the full extent of these enlarged and hypervascular on post-contrast
trans-spatial lesions (Fig. 26). CT (Fig. 28). Multi-organ involvement is com-
c) Bilateral swelling mon, and in the head and neck region, this
Sialosis refers to diffuse, non-inflammatory, includes inflammatory conditions involving
non-neoplastic recurrent enlargement of the the orbits, thyroid, sinonasal cavity and pitui-
major salivary glands. It is uncommon and tary gland in addition to the salivary and lacri-
has a variety of systemic associations includ- mal glands (Fujita et al. 2012). PET-CT
ing obesity, diabetes mellitus, and alcoholism optimally demonstrates IgG4-related disease
196 A. Whyte et al.
Fig. 17 Multiple osseous metastases. Initial presentation (c) with an isotope bone scan (d) demonstrates additional
with left TMJ pain. CT (a and b) showed permeative metastases in the articular eminence and central skull base
lucency and periosteal new bone formation of the posterior not visible on CT. The primary was a clinically occult
aspect of the junction of the condylar neck and ramus carcinoma of the kidney
(black arrows). SPECT CT (e) combining low-dose CT
outside of the head and neck, most frequently and lacrimal glands (but also other exocrine
in the abdomen, where autoimmune pancreati- glands) with a characteristic clinical presenta-
tis and sclerosing cholangitis are the most fre- tion of dry mouth, dry eyes, and parotid swell-
quent manifestations. ing. It is the second most common autoimmune
Juvenile recurrent parotitis (JRP) is an idi- disorder after rheumatoid arthritis and predom-
opathic recurrent inflammatory condition of inates in middle-aged females. In 40% of
the parotid, occurring in children (Gadodia cases, SS occurs in isolation, and in the
et al. 2010). Boys are more commonly remaining 60%, it is associated with several
affected. Symptoms are more commonly uni- other entities, the most common of which
lateral than bilateral. In most cases, the symp- are other connective tissue disorders and pul-
toms resolve spontaneously after puberty. monary diseases. In the early phase of the
Characteristic US features include a hyper- disease, the salivary and lacrimal glands are
vascular gland containing multiple small enlarged and hypervascular. With disease pro-
round hypoechoic foci representing sialectatic gression, the glands decrease in size and
cavities. Sialectasis can also be demonstrated become heterogeneous in texture: atrophy of
by MRI sialography and in the past by conven- the submandibular glands is pronounced
tional sialography. (Fig. 29). They contain small round hypo-
Sjögren’s syndrome (SS) is a chronic auto- echoic foci on US which are hypodense on
immune disorder involving mainly the salivary CT and hyperintense on T2-weighted MRI
Fig. 18 Keratocystic odontogenic tumor (KCOT). CT shows characteristic features: intermediate to low T2 signal
(oblique sagittal reconstruction) shows a large, uniloculate (b, white arrows), high central T1 signal (c, dotted white
lucent lesion in the right posterior mandible (a). MRI oval), and restricted diffusion (d, dashed white oval)
images. These reflect focal lymphocytic lymphoid tissue (MALT) lymphoma, a subset
sialadenitis and/or sialectatic cavities. Accu- of B-cell NHL. The involved glands are
mulation of fat in chronic SS also contributes enlarged, and US demonstrates multiple hypo-
to the heterogeneity of glandular tissue and is echoic foci which are usually hypervascular
best demonstrated on CT or T1-weighted MRI (Fig. 31).
sequences (Burke et al. 2011; Abdullah et al. d) Focal mass
2013). Sialography and MR sialography dem- Focal chronic sclerosing sialadenitis, also
onstrate typical findings of multiple small known as Kuttner’s pseudotumor, usually pre-
cavities communicating with the terminal sents as a painless, palpable mass in the sub-
duct-acinar unit (sialectasis), as well as dilata- mandibular gland and is a manifestation of
tion of the main duct and its proximal branches IgG4-related disease. It has characteristic US
(Fig. 30). The diagnosis of SS requires histo- features (Fig. 32), and FNAC may confirm the
logical demonstration of focal lymphocytic diagnosis, although cytological assessment
sialadenitis in minor salivary glands (typically can be challenging.
from a lip biopsy) plus a positive finding of Salivary gland neoplasms are uncommon,
either reduced salivary flow or positive imag- accounting for 6% of head and neck tumors.
ing features, US being the preferred modality Approximately 80% of tumors occur in the
(Vitali et al. 2013). In SS, there is a 5–10% risk parotid gland, 10% in the submandibular
of development of mucosal-associated- gland, and the remainder in the sublingual
198 A. Whyte et al.
Fig. 19 Chronic manifestations of periapical (PA) sepsis. white arrow), a buccal cortical plate fistula, and sinus
An oblique sagittal CT reconstruction (a) demonstrates a track extending to skin (dashed white arrows) on the soft
chronic PA abscess (dotted white arrow) associated with tissue window image (d). US (e) was the preliminary
36. On a coronal soft tissue window CT reconstruction (b), imaging requested for investigation of a discharging
there is a chronic inflammatory phlegmon in the left sub- sinus; the track is sonolucent (white dashed arrows), and
mandibular space (white arrows) manifesting as a firm, the cortical defect is clearly shown (dotted, double-head
painless swelling. An axial bone window CT scan (c) white arrow)
shows a chronic PA abscess associated with 34 (open
and minor salivary glands. The palate is the to be round with well-defined, smooth, or lob-
commonest site of minor salivary gland tumors ulated margins. Pleomorphic adenoma is
(Burke et al. 2011; Abdullah et al. 2013). hypoechoic on US with moderate vascularity
The chance of a salivary gland neoplasm and posterior acoustic enhancement. On
being malignant increases as the size of the T2-weighted MRI, it is characteristically
affected salivary gland decreases. Thus, hyperintense (Fig. 33). Rapid increase in size
about 80% of parotid tumors are benign, but of a previously stable lesion could indicate
almost half of all submandibular gland neo- malignant transformation which occurs in
plasms and most of those arising in the sub- 5–10% of pleomorphic adenomas.
lingual and minor salivary glands are Warthin’s tumor (adenolymphoma) is the
malignant. Malignant tumors are more com- second most common benign salivary gland
mon in children. neoplasm. It predominates in elderly male
Pleomorphic adenoma is the most common smokers and is usually situated in the inferior
benign tumor and is seen in all age groups but aspect of the parotid gland (parotid tail), with
predominates in the superficial lobe of the tumors being multiple in 30% of cases.
parotid gland in middle-aged females. It tends Warthin’s tumor tends to be ovoid in shape
Fig. 20 Mucous retention cyst. Coronal bone-window CT equivalent to fluid, on soft tissue windows (b). Axial
(a) shows a well-defined dome-shaped lesion in the right T2-weighted MRI (c) confirms the hyperintense fluid
maxillary sinus (white arrows) that is low density, within the cyst (black arrow)
Fig. 21 Aspergilloma (fungal ball) of the right maxillary fungal ball has no mobile protons and appears as a signal
sinus. The fungal ball is hyperdense on this soft tissue void (dotted white oval) on T2-weighted MRI (b). It is
window CT (a) due to desiccated contents containing surrounded by peripheral mucosal thickening which is
calcification and heavy metals (dotted black oval). The hyperintense
and well defined. Cystic components are seen The malignant tumors most commonly
in 30% of cases (Fig. 34). A mural nodule affecting the major salivary glands are
within the cystic components is a described mucoepidermoid carcinoma, acinic cell carci-
feature (Miao et al. 2015). noma, and adenoid cystic carcinoma.
200 A. Whyte et al.
Fig. 22 Squamous cell carcinoma of the left maxillary window axial CT reconstruction (b). Fat saturation T2 MRI
sinus. Coronal CT (a) demonstrates pan sinus opacification in the coronal (c) and axial (d) planes depict ill-defined
and destruction of the inferolateral wall of the left maxil- tumor of intermediate signal (open white arrows). The
lary sinus (open white arrow). Ill-defined soft tissue superior contrast resolution of MRI (as compared with
extends anteriorly into the cheek and posterolaterally into CT) allows distinction between tumor and the high-signal
the infratemporal fossa (white arrows) on this soft tissue inflammatory mucosal thickening
Mucoepidermoid carcinoma predominates in evaluation and predicting the necessity for

the parotid gland, and adenoid cystic carci- postoperative radiotherapy (Fig. 35).
noma is the most common subtype in the sub- Enlarged lymph nodes in the submandibular
mandibular, sublingual, and minor salivary triangle due to metastatic malignancy, infection,
glands. Small- or low-grade malignant tumors or other inflammation may not be distinguish-
may appear similar to benign lesions on imag- able from a submandibular salivary gland mass
ing. Larger and more aggressive lesions tend to on clinical grounds. US clarifies the diagnosis
have irregular-shaped, ill-defined margins, and can be used to guide FNAC (Fig. 36).
heterogeneous texture, and are hypervascular Accessory parotid tissue is present in
with a “chaotic” vascular pattern on Doppler 21–56% of the population. When unilateral,
US. Extracapsular spread and large nerve peri- this may be palpable. Salivary gland tumors
neural involvement of the facial and/or may also arise in this tissue. Symmetric
auriculotemporal nerves require dedicated benign masseteric hypertrophy may mimic
post-gadolinium MRI for optimal preoperative parotid gland enlargement, and asymmetric
Fig. 23 Submandibular calculi. CBCT (a) and CT (b) position of the right intraglandular duct (c) on a cropped
demonstrate multiple calculi in the submandibular duct panoramic tomogram are situated within a minimally
(white arrows). Several calculi within the expected dilated duct on US (d)
enlargement may occasionally be mistaken More than 90% of malignant lesions of the oral
for a parotid mass on clinical examination cavity are squamous cell carcinomas (OC-SCC).
(Fig. 37). Low-grade verrucous carcinomas and minor sali-
vary gland tumors constitute the remainder. The
mean age of occurrence of OC-SCC is 62 years. It
Imaging of Malignancy of the Oral is twice as common in men. There is a 20-fold
Cavity increased risk of having a second oral cancer, as
well as an increased risk of carcinoma elsewhere
Oral cancer is common, accounting for 270,000 in the upper aerodigestive tract. The oral tongue is
new cases annually. It has a relatively low survival the most common subsite of OC-SCC, accounting
rate, with fewer than 50% of patients surviving for 29%, followed by the lower lip (19%), the floor
more than 5 years (Arya et al. 2014). Etiological of mouth, and then other subsites (gingivae, buc-
factors include smoking, alcohol, areca (betel) nut cal mucosa, hard palate, and retromolar trigone).
chewing in India and elsewhere in Asia, a diet There has been a substantial decrease in the inci-
lacking in antioxidants, poor oral hygiene, and to dence of SCC of the lip, which has a relatively
a lesser extent human papillomavirus (HPV) high 5-year survival of 90% and unlike other oral
(Mirghani et al. 2015). HPV infection is far more cancers is strongly related to sunlight exposure.
important in the etiology of oropharyngeal carci- Based on the combination of staging of the
noma which tends to affect younger males without primary tumor (T), nodal (N), and distant metas-
a history of excessive intake of alcohol or use of tases (M), OC-SCC is divided into stages I, II, III,
tobacco when compared to older patients with IVA, IVB, and IVC. Early stages (I and II) are
HPV-negative carcinoma (Cantrell et al. 2013). treated with a single treatment modality, either
Cystic nodal metastases are very suggestive of surgery or radiotherapy. Local disease control
HPV-positive disease which typically shows an and overall survival are similar, but surgery is
excellent response to chemoradiotherapy and the preferred modality because of the significant
good prognosis. side effects of radiotherapy.
202 A. Whyte et al.
Fig. 24 Adenoid cystic carcinoma of the right sublingual saturation T2 sequence (c). The magnified T1 image (d)
salivary gland. There is a large ovoid mass (white arrows) demonstrates the normal neurovascular bundle (lingual
expanding the right sublingual space, arising from the nerve, hypoglossal nerve, and lingual vein) in the left
sublingual salivary gland. The mass deviates the right sublingual space (dotted white oval) but not on the right.
genial muscles and midline fatty septum of the tongue to US-guided FNAC (e) of the tumor (white arrows): the
the left (white dotted arrow) as seen on the coronal biopsy needle is clearly visualized (dashed white arrows).
T1-weighted images (a and d). Following contrast, the Histological evaluation of the tumor following surgical
tumor demonstrates heterogeneous enhancement (b). It is excision demonstrated perineural involvement of the lin-
of variable, intermediate-to-high signal on the fat gual nerve
OC-SCC is almost always preceded by visible nodal metastases (N+) are present, the neck is
changes in oral mucosa, and simple screening by treated with a neck dissection. If imaging shows
periodic oral examination has been shown to be an no evidence of nodal metastases (N0), the options
effective screening method for detecting the 36% are either regular observation (including repeat
of oral cancers that present at an early stage: I and imaging) or an elective neck dissection/irradia-
II. However, most OC-SCC present at an tion, the latter approach being recommended for
advanced stage (III and IV) and have a poor prog- advanced primary tumors (stages III and IV).
nosis. In an effort to achieve optimal locoregional
control, advanced disease is treated with multi- a. Imaging in the primary assessment of
modality therapy: radical surgery followed by OC-SCC. Imaging can be used to stage the
concurrent chemoradiation. primary tumor (T), assess cervical lymph
Imaging is essential to stage accurately not nodes (N), and exclude distant metastases (M).
only the primary tumor (T) but also for N- and Primary tumor (T-staging): OC-SCC is
M staging. Nodal metastases are seen in 45% of diagnosed by clinical examination and biopsy.
OC-SCC at presentation and are the single most Imaging is required to evaluate submucosal or
important prognostic factor, halving survival. If deep soft tissue spread which may not be
Fig. 25 Salivary gland calculi and sequelae. Post-contrast indicating sialadenitis. Images (c) and (d) demonstrate a
CT in the axial (a and c) and oblique sagittal (b and d) large calculus (black arrow) in the posterior margin of a
planes. Several small calculi in the mildly dilated right large pyocele (black dotted arrows) in the enlarged and
submandibular duct (a and b) associated with a hyper- hypervascular right submandibular salivary gland (white
vascular right submandibular salivary gland (SMG) dotted arrows). Multiple additional calculi are present
evident clinically, to exclude involvement of in the different planes and comparison with
critical neurovascular structures (which are additional imaging studies. CBCT also accu-
adverse prognostic findings) and to confirm or rately depicts osseous invasion, but the absence
exclude osseous involvement of the mandible of soft tissue contrast precludes the routine use
or maxilla. of this technique. The “puffed-cheek” tech-
Post-contrast MDCT is the most commonly nique is routinely used when scanning
used imaging technique and is the optimal OC-SCC: the patient distends the cheeks with
method for evaluating mandibular invasion, air (while breathing quietly through the nose),
which is a priority with gingival, buccal, moving apposing mucosal surfaces away from
retromolar trigone, and lip SCC (Arya et al. the primary tumor, which is hence more clearly
2013). The volume data set of the scan includes visualized (Fig. 38).
the skull base to the mediastinum (tracheal MRI is optimal for evaluation of tongue
carina) with the images being reconstructed and floor of mouth SCC where soft
onto soft tissue and bone algorithms and sub- tissue contrast resolution is paramount. MRI
sequently evaluated on a workstation allowing is also useful in cases where CT is degraded
multiplanar reconstructions, cross-referencing by beam-hardening (streak) artefact from
204 A. Whyte et al.
Fig. 26 Ranula: this represents a mucocele of the sublin- T2 axial (c) and coronal (d) MRI scans showing a fluid
gual salivary gland. Post-contrast CT in the axial (a) and signal intensity plunging ranula which extends around the
coronal (b) planes demonstrating a simple ranula (black posterolateral border of mylohyoid (myh) from the sublin-
dashed arrows) in the right sublingual space of the floor of gual gland into the submandibular space (white dashed
the mouth as a fluid-density, thin-walled lesion which arrow). The ranula displaces the submandibular gland
crosses the midline anteriorly. The sublingual salivary (SMG) inferiorly
glands (SLG) are demonstrated bilaterally. Fat saturation
dental restorations. High-resolution contrast- overestimation of tumor depth, and it is there-

enhanced MRI is mandatory in cases where fore important that imaging be performed
perineural tumor spread is suspected (see prior to biopsy.
below). For most OC-SCC, there is little benefit in
Intraoral US using a small high-frequency supplementing CT or MRI with PET-CT for
probe is a fast and reliable means of measuring staging of the primary tumor. This differs
the dimensions and depth of tongue SCC with from oropharyngeal SCC, where small or
the same accuracy as MRI (Yesuratnam et al. occult primary lesions are relatively common
2014). A tumor thickness of greater than 4 mm in subsites such as the tonsil and tongue base,
is associated with a significant risk of nodal and a common clinical presentation is with
micro-metastases that are not detected by cervical lymphadenopathy, especially in
imaging, and the evidence-based consensus patients with HPV-positive disease. In these
is that primary prophylactic neck dissection cases, PET-CT can be used to detect the occult
should be performed in these cases (Fig. 39). primary lesion as well as the extent of nodal
Biopsy-related changes can lead to metastases (Fig. 9).
Fig. 27 Sialosis. Post-contrast axial CT at the level of secondary to infiltration with fat as shown on this coronal
the parotid (a) and submandibular (b) salivary reconstruction (c)
glands. The glands are enlarged and of low attenuation
The patterns of soft tissue spread of separate entity to “perineural invasion” of

OC-SCC depend on the location of the primary small nerves, which is reported on histopatho-
lesion. Tongue and floor of mouth carcinomas logical evaluation of excision specimens and is
can involve extrinsic tongue musculature, confined to the main tumor bulk. MRI with
cross the midline, and infiltrate the contents of contrast is mandatory to accurately stage
the sublingual space: lingual and hypoglossal these advanced tumors and determine if exten-
nerves, lingual vein and artery, submandibular sive surgical resection is a realistic treatment
duct, and sublingual salivary gland (Fig. 40). option (Baulch et al. 2015).
OC-SCC of all types, especially retromolar Floor of mouth, gingival, retromolar tri-
trigone tumors, can spread posteriorly to the gone, buccal, and palatal SCC have a predilec-
tongue base (oropharynx) and when very tion for bone invasion (Fig. 41). Multiple
advanced, to the carotid sheath, masticator studies have evaluated the sensitivity and spec-
space, parapharyngeal space, and superiorly ificity of various imaging modalities in pre-
to the skull base giving the highest grade of dicting mandibular or maxillary infiltration by
T-staging: T4b. In OC-SCC, perineural tumor tumor. The OPG has low specificity for man-
spread occurs in 5–10% of cases and is defined dibular erosion but is useful for providing an
as macroscopic tumor spread away from the overview of the dental status prior to treatment
primary site along a large nerve which repre- for OC-SCC. SPECT bone radioisotope scan-
sents the path of least resistance. This is a ning has 100% sensitivity for bone invasion but
206 A. Whyte et al.
Fig. 28 Mikulicz disease (IgG4-related disease). Post- the parotid glands, (b) axial of the submandibular glands,
contrast CT demonstrates homogeneous attenuation and and (c) coronal of the major salivary glands
enhancement of the major salivary glands. (a) Axial of
very low specificity as it is unreliable in depends mainly on the subsite of the primary
distinguishing between involvement by tumor lesion in the oral cavity (the superior contrast
and concurrent dental disease. High-resolution, resolution of MRI being advantageous at sev-
multiplanar reconstructions from a staging eral sites, as discussed above). The benefits of
MDCT are highly accurate in assessing bone CT over MRI include wider availability, lower
invasion by OC-SCC: 94% sensitivity and 90% cost, and much faster scan times (and therefore
specificity are reported for the evaluation of less chance of patient movement).
mandibular invasion by retromolar trigone car- Imaging techniques for evaluation of nodal
cinoma (Arya et al. 2013). MRI also has very metastases have been discussed previously. In
high sensitivity but much lower specificity; most studies, CT performs as well as or better
it overestimates bone invasion presumably than MRI in staging the neck (Arya et al.
because of tumor-related edema which would 2014). US with FNAC is the most sensitive
not be detected on CT scanning because of its and specific technique in the detection of cer-
lower contrast resolution (Arya et al. 2014). vical nodal metastases in head and neck cancer.
Neck nodal metastases (N-staging): Either However, it is not widely available in some
CT or MRI can be used to stage both the pri- countries, it is time-consuming and requires
mary site and the neck nodes. The choice considerable expertise in the sonographic
Fig. 29 Sjögren’s syndrome (SS). In the subacute and or dilated peripheral ducts and acini (sialectasis). The
acute phase of SS the inflamed salivary glands are echogenic dots (white dotted arrows) are microcalculi.
enlarged. Color Doppler US (a) demonstrates profuse Axial CT (c) and coronal T1-weighted MRI (d) of chronic
hypervascularity of an enlarged, hypoechoic gland. In the SS demonstrate atrophic, fat-replaced glands with a nodu-
chronic phase (b), the glands contain hypoechoic foci lar texture. PG = parotid gland, SMG = submandibular
(white arrows) representing lymphoepithelial aggregates gland
Fig. 30 Sjögren’s syndrome (SS). Modified MRI gland texture is heterogeneous due to fat and hyperintense
sialogram (thin heavily T2-weighted sequence) of chronic foci of varying size. The small, punctate hyperintense foci
SS (a and b) demonstrate marked dilatation of the main probably represent sialectatic cavities (white dotted
duct with “beading” due to strictures (white arrows). The arrows)
208 A. Whyte et al.
Fig. 31 Sjögren’s syndrome (SS) and MALT lymphoma. (b) scans. The lymphoma deposits (white arrows) are
MALT lymphoma may develop in patients with chronic mildly hyperintense on this fat saturation T2-weighted
SS. The parotid glands (black dotted ovals) are enlarged by sequence (c) and hypoechoic and hypervascular (white
multiple round lesions of varying size representing lym- dashed arrows) on color Doppler US (d) of the same
phoma on T1-weighted MRI axial (a) and coronal patient
assessment and selection of nodes to biopsy, neck which could alter radiation therapy fields
the imaging-guided procedure itself, and also or the extent of neck dissection (Enders et al.
the cytological evaluation. US-guided FNAC 2011; Castaldi et al. 2013).
can be used selectively after CT or MRI staging Distant metastases (M-staging): The inci-
for evaluation of suspicious or equivocal cer- dence of distant metastases at presentation of
vical nodes where the result is likely to alter OC-SCC is relatively low; it is more common
management (Fig. 36). Sentinel node biopsy in with locally advanced tumors and those with
early stage OC-SCC shows great promise in extensive nodal spread (Arya et al. 2014). The
predicting the likelihood of nodal metastases frequently involved organs are the lungs, bone,
with an overall sensitivity of 93% (Alkureishi and liver. PET-CT is the optimal technique for
et al. 2010). demonstrating metastases and second primary
Several studies have shown no additional tumors. If PET-CT is unavailable, CT of the
value in the use of PET-CT over CT and MRI chest and upper abdomen can be performed.
in evaluating the clinically negative neck or the b. Assessment of treated OC-SCC. Early-stage
primary tumor. The current role of PET-CT in OC-SCC is treated with a single modality,
head and neck SCC for pretreatment nodal either surgery or radiotherapy. For locally
evaluation lies in delineation of the extent of advanced cancer without distant metastases,
regional nodal metastases in the N-positive multimodality treatment is performed: surgery
Fig. 32 Kuttner’s pseudotumor (IgG4-related disease). dotted arrows) which is also hypervascular on color Dopp-
Post-contrast CT coronal reconstruction (a) showing a ler analysis (c). US-guided FNAC (open white arrows in d)
hypervascular protuberance from the inferolateral margin confirmed chronic sclerosing focal sialadenitis (Kuttner’s
of the left submandibular gland (SMG). US (b) shows a pseudotumor)
geographical-shaped lesion of reduced echogenicity (white
followed by adjuvant radiation therapy, with or understanding of both resection and recon-
without chemotherapy, depending on the his- struction techniques.
topathological findings. The aim of multi- Three main types of flap are used in recon-
modality treatment is to optimize cure rates struction: local, pedicle, and free flaps. Soft
while preserving speech and swallowing func- tissue flaps initially appear as a pseudomass
tion with an acceptable cosmetic result. of similar attenuation and signal intensity to
Curative resection requires wide local exci- muscle on CT and MRI, respectively
sion to obtain negative surgical margins. Small (Fig. 42). These flaps will gradually show
tumors of the lateral tongue can be treated with denervation atrophy, which causes volume
this technique. More extensive lesions require loss and fatty replacement of the muscle
a partial or total glossectomy resulting in (Saito et al. 2012).
asymmetry on post-surgical CT or MRI. If Tumor recurrence usually occurs within the
30% or more volume loss following excision first 2 years after treatment, most commonly in
is expected, reconstruction is planned. For the surgical bed or at its margins, including in
advanced OC-SCC requiring extensive resec- the flap used for reconstruction. Clinical eval-
tion of soft tissue and bone, complex recon- uation will detect superficial recurrence, but
structive techniques are often required to close recurrent tumor deep to a reconstruction flap
the defect and maintain function. Clinicians is not visible and is usually impalpable. Recur-
and radiologists should have a basic rent tumor usually has an infiltrative pattern of
210 A. Whyte et al.
Fig. 33 Pleomorphic adenoma of the left parotid gland. defined mass in the left parotid gland (white dotted
T1 (a), fat saturation T2 (b), and post-contrast T1 fat arrows). The tumor has a lobulated margin and is markedly
saturation (c) axial MRI scans demonstrating a well- hyperintense on the T2-weighted sequence
growth and demonstrates heterogeneous dissection is limited to removal of a group or

enhancement on CT or MRI. The major differ- groups of nodes within the neck and results in
ential is of vascularized scar (early fibrosis). lower morbidity. The main indication for radical
Follow-up imaging will show contraction of neck dissection is extensive metastatic cervical
vascularized scar whereas tumor will progress. lymphadenopathy, extracapsular spread of
In addition, the apparent diffusion coefficient nodal tumor, and invasion into adjacent tissues.
(ADC) measured on DWI as part of an MRI Imaging demonstrates asymmetry of the neck
allows distinction between tumor and scar secondary to unilateral resection of additional
(Thoeny et al. 2012; Payne et al. 2015). PET- structures in addition to cervical nodes. Fat
CT usually shows more intense metabolic planes are obliterated, and CT and MRI demon-
activity in recurrent tumor than vascularized strate a circumferential “cuff” of scar around the
scar, but distinction may still be difficult. carotid sheath (Fig. 42).
The three major types of neck dissection are Radiation for head and neck cancer pri-
radical, modified radical, and selective neck dis- marily consists of external beam radiother-
sections. Both radical and the more conserva- apy. This uses photon beam (or less
tive, modified radical neck dissections remove commonly electron beam, or proton beam)
all of the ipsilateral neck nodes. A selective neck radiation delivered from a source external to
Fig. 34 Multiple Warthin’s tumors. Three tumors are tumor in the inferior half of the left parotid gland (a) is also
present, two in the left parotid gland and single lesion in depicted on color Doppler US (c) which demonstrates a
the right parotid gland (white arrows). Post-contrast CT (a, lobulated contour, internal vascularity (color flow), and
b, and d) demonstrates that all lesions are ovoid in shape sonolucent foci corresponding to fluid on the CT (white
and situated in the inferior half of each gland. The tumors dashed arrows)
demonstrate moderate contrast enhancement. The largest
the patient, typically with a dose of 66–70 Gy Late complications are defined as sequelae
delivered daily over a period of 7 weeks. In of treatment that manifest more than 90 days
the past 15 years, intensity-modulated radio- after the completion of radiation therapy. They
therapy (IMRT) has become the favored tech- may take months to years to emerge and are
nique for administering external beam photon often irreversible. They include salivary gland
therapy to patients with head and neck cancer atrophy, osteoradionecrosis, soft tissue necro-
because it provides better conformation of sis, and radiation-induced vascular complica-
radiation dose to the tumor while sparing tions (Saito et al. 2012).
adjacent organs. Osteoradionecrosis (ORN) is a condition
Early changes after radiation therapy in which irradiated bone becomes devitalized
are those occurring up to 90 days after com- and exposed through the overlying skin or
pletion of treatment and include edema mucosa, persisting without healing for at
and inflammation which usually resolve least 3 months. A meta-analysis of the litera-
within several weeks. Imaging demonstrates ture reported a 7% incidence of ORN after
mucositis, diffuse soft tissue edema, and conventional radiotherapy (Deshpande et al.
enlargement and hypervascularity of the 2015). It usually presents 1–3 years after radi-
major salivary glands. ation therapy and most commonly occurs in
212 A. Whyte et al.
Fig. 35 Mucoepidermoid carcinoma of the left parotid the anterior margin of the tumor consistent with large nerve
gland. A slightly ill-defined mass (white arrows) with perineural tumor spread (white dotted arrows). Metastatic
foci of calcification (black arrow) in the medial margin of nodes (white dashed ovals in c and d) are present both
the tumor is seen on post-contrast CT (a), T1-weighted (b), within the inferior aspect of the gland and in the upper neck
and post-contrast T1-weighted fat-saturated (c) MRI. A deep to the left sternomastoid muscle
thickened and enhancing facial nerve branch is present at
patients who receive high radiation doses trend to the use of IMRT reduces the dose to
(greater than 70Gy) or radiotherapy after sur- the mandible and therefore the risk of ORN.
gery. Later presentation of ORN can occur CT is the preferred imaging modality, and
and is thought to be due to low-grade trauma typical imaging findings include cortical ero-
in a chronic hypoxic environment. The man- sions, medullary lysis, surrounding sclerosis,
dible is the most common site of ORN mixed lysis and sclerosis, bone fragmentation,
because of its superficial location and rela- sclerotic sequestra, and gas within a bone cav-
tively poor blood supply. Additional risk fac- ity (Fig. 43). Pathological fractures may occur.
tors include neo-adjuvant chemotherapy, poor Soft tissue abnormalities can occur in ORN,
oral hygiene, periodontitis, alcohol, and including enlargement and enhancement of the
tobacco use as well as the proximity of the adjacent muscles of mastication to form a
primary tumor to the mandible. The current pseudomass.
Fig. 36 SCC of the floor of the mouth with metastatic compressing the salivary gland (SMG) and in the left
nodes. Post-contrast axial CT (a) shows a small primary jugulodigastric region (dotted white arrows). US-guided
lesion of the anterior floor of the mouth (white open FNAC of the left jugulodigastric node (d) confirmed the
arrow). There is extensive metastatic lymphadenopathy diagnosis
(b and c) in the left submandibular space (white arrows)
Distinction from recurrent tumor and post-treatment sequelae to a stable and accept-
infection may be difficult; cortical erosions able level for evaluation.
distant from a soft tissue mass or the site of
the original tumor are more suggestive of Initial assessment:
ORN as is a late onset (over 2 years after the
completion of radiotherapy). Routine MRI • MDCT of the oral cavity and neck (skull base
and PET-CT do not improve specificity, but to carina).
diffusion-weighted imaging (DWI) can
improve distinction between recurrent tumor Post-contrast, puffed-cheek, and bone and soft
and ORN (Thoeny et al. 2012). tissue reconstructions
c. Imaging guidelines. Recommendations for
imaging can be divided into the initial assess- • MRI added for tongue and floor of mouth
ment and subsequent follow-up of treated tumors, or when CT is degraded by severe
OC-SCC. A delay of 12 weeks after surgery streak artefact, or when advanced tumor and
or the completion of radiotherapy decreases the perineural tumor is suspected.
214 A. Whyte et al.
Fig. 37 Masseteric hypertrophy. T1 coronal (a) and T2 accessory parotid tissue. The medial pterygoid (mp) and
axial (b) MRI demonstrating symmetric masseteric temporalis (t) muscles are of normal size in this individual
(M) hypertrophy. There is inferolateral displacement of
Fig. 38 “Puffed-cheek” technique for mucosal malig- reconstructions. There is a small protuberant SCC at the
nancy. Post-contrast CT with oral distension in the axial junction of gingiva and mucosa in the 37/38 region (open
and coronal plane with soft tissue (a) and bone (b) white arrows). No bone erosion is evident
• US-guided FNA of suspicious neck nodes, • For the first 2 years, repeat imaging according
where this will alter management. to local guidelines; most institutions would
• PET-CT added for advanced tumors. repeat imaging at least twice.
• DPT for general dental assessment.
Restaging for clinically suspected primary
Post-treatment assessment (surveillance
(T) or nodal (N) recurrence:
imaging):
• Baseline MDCT of the oral cavity and neck for • PET-CT for T, N, and M assessment
early stage tumors treated with a single modal- • MRI for optimal staging of the recurrent pri-
ity, 12 weeks post-treatment. mary tumor (T)
• PET-CT added for advanced tumors, 12 weeks • Surgical biopsy for recurrent T and US-guided
post-treatment. FNAC for N
Fig. 39 Tongue cancer. Post-contrast CT (a) and post- US (d) in demonstrating tumor depth and diameter for
contrast T1-weighted MRI (b) in the coronal plane dem- prognosis and staging. Both methods indicate a depth of
onstrate a small tumor of the right lateral tongue (white 7 mm (white dotted lines)
arrows). Comparison of magnified MRI (c) and intraoral
Imaging of Osteomyelitis osseous edema are MRI and isotope bone scans
and Osteonecrosis of the Jaws (ideally using SPECT-CT). Labeled white cell
scans can confirm that the inflammation is due to
Osteomyelitis represents inflammation of the bone, infection (Boeddinghaus and Whyte 2008).
commencing in the medullary cavity and extending If osseous inflammation persists for more than
to the cortex and periosteum. It predominates in 4 weeks due to inadequate treatment, bacterial
adult males and in the posterior mandible. Acute load, or impaired host resistance, the condition
osteomyelitis of the jaws is usually due to pyogenic is known as secondary chronic osteomyelitis
infection resulting from periapical sepsis. Periodon- (chronic suppurative osteomyelitis). CT optimally
titis, pericoronitis, and compound fractures are other demonstrates mixed sclerosis and lysis within
potential causes. The prompt and widespread use of marrow, periosteal new bone formation, sclerotic
antibiotics for dental sepsis has led to a marked sequestra of dead bone, and inflammatory swell-
decline in the incidence of acute osteomyelitis. ing of the muscles of mastication (Fig. 44).
Inflammatory edema leads to radiolucency of the Primary chronic osteomyelitis (chronic
involved bone, but this takes 2–3 weeks to be visible non-suppurative osteomyelitis) is not preceded
on a radiograph. CT is more sensitive but the most by acute infection. Sclerosis is the dominant fea-
accurate means of establishing the diagnosis of ture, and it is of unknown cause. Pus and sequestra
216 A. Whyte et al.
Fig. 40 Spread of SSC of the floor of the mouth. Normal post-contrast T1-weighted MRI (c) demonstrate a large
anatomy of the floor of the mouth on a T1-weighted MRI SCC of the anterior floor of the mouth with midline cross-
image (a) where slg = sublingual salivary gland, over (white arrows) with subtle erosion of the lingual
SMG = submandibular salivary gland, gm = genial mus- cortex (white open arrow in c). The tumor is more clearly
cles, and mh = mylohyoid. The mandibular cortex is demarcated by MRI. A larger tumor with extensive infil-
hypointense (black) and the marrow is hyperintense tration of the anterior mandible and spread into the labial
(white) due to its fat content. Post-contrast CT (b) and sulcus is demonstrated on axial post-contrast CT (d)
are absent. It includes several conditions, which the receptor activator of nuclear factor kappa-B
can be divided into juvenile and adult forms and ligand (RANKL). Antiangiogenic drugs (e.g.,
secondarily by variants which only involve the bevacizumab) block the formation of new
mandible and those which affect bones outside blood vessels and are a relatively new means of
the jaws. treating certain cancers; they can also cause ONJ.
Osteonecrosis of the jaws (ONJ) was initially The remodeling rate of alveolar bone exceeds
described in patients who had undergone treat- most other skeletal sites. The jaws are vulnerable
ment with intravenous bisphosphonates (hence to medication which inhibit bone turnover. In
bisphosphonate-related ONJ or BRONJ), usually addition, antiangiogenic drugs predispose to avas-
to manage complications of metastatic malig- cular necrosis. Inflammation, infection, and
nancy to the bone. Bisphosphonates are one mucosal trauma are strongly associated with
class of antiresorptive agents that cause ONJ, the ONJ, and tooth extraction is a common precipi-
other being denosumab, which is an inhibitor of tating event.
Fig. 41 Osseous invasion by oral carcinoma. Post- retromolar trigone SCC smoothly erodes the lingual aspect
contrast CT scan shows SCC of the right maxillary buccal of the right retromolar fossa shown on axial (c) and coronal
mucosa/gingiva (white arrows) eroding the alveolar pro- (d) CT. Tumor spreads posteromedially along the
cess shown on axial soft tissue CT (a) and extending into pterygomandibular raphe toward the oropharynx (white
the inferior aspect of the right maxillary sinus shown on a dotted arrows). There is a small metastatic node in the
coronal bone-algorithm reconstruction (b). A right right submandibular triangle (N)
The current position paper on ONJ from the in the mandible. The appearance of ONJ
American Academy of Oral and Maxillofacial on radiographs and CT is variable and
Surgeons in 2014 recommends the term “medica- includes ill-defined areas of lucency, cortical
tion-related osteonecrosis of the jaws” (MRONJ). permeation and destruction, sequestra, a
Patients have MRONJ if the following criteria are periosteal reaction, sclerosis, and a
fulfilled (Ruggiero et al. 2014): non-healed extraction socket (Fig. 45). Path-
ological fractures can occur in all types of
1. Treatment with antiresorptive or anti- osteonecrosis.
angiogenic agents
2. Exposed bone or bone that can be probed Imaging of Temporomandibular
through a fistula in the maxillofacial region Disorders
that has persisted for more than 8 weeks
3. No history of radiation and no evidence of The TMJ can be involved by a spectrum of disor-
metastases to the jaws ders similar or identical to those in other synovial
The radiological appearances of ONJ joints. Temporomandibular disorder (TMD) is a
are similar to osteoradionecrosis; both collective term involving several disorders of
conditions are significantly more common muscles, the TMJ, or both. Patients with TMJ
218 A. Whyte et al.
Fig. 42 Postsurgical appearances of the neck. Post- cases (a and b), there has been compensatory hypertrophy
contrast CT (a) demonstrates a left radical neck dissection of the levator scapulae muscle on the side of surgery which
(RND). An RND requires removal of sternomastoid (SM), can simulate a “mass” on clinical examination. A series of
the internal jugular vein (IJV), and the cervical nodes axial post-contrast CT images (c) from superior to inferior
(black dashed oval). The left common carotid artery shows a right pectoralis major flap (white dotted arrows)
remains in situ surrounded by low-density scar. Post- situated anterior to the vessels of the carotid sheath, trans-
contrast CT (b) shows a right modified neck dissection posed to replace a right parotidectomy defect (not shown).
(MND). Either the IJV, SM, or both are preserved with an The superior portion of the graft in the parotid bed consists
MND, and in this case the right SM has been removed in of fat and the right sternomastoid has been removed as part
addition to the nodal chain (black dotted oval). In both of a MND
disorders most frequently present with pain, lim- The most common TMDs in adults are masti-
ited or asymmetric mandibular motion, and joint catory myalgia, disc displacement, intra-articular
noises. inflammation, osteoarthritis, and rheumatoid
The prevalence of TMJ symptoms is high, but arthritis. Other disorders specifically affecting
only 5–10% of those with symptoms require treat- children and teenagers are juvenile idiopathic
ment, and it has been estimated that in up to 40% arthritis (JIA) and the entity of idiopathic condylar
of patients, the symptoms resolve spontaneously. resorption (ICR). Both can cause TMJ pain and
TMDs primarily involve young- to middle-aged limited opening.
patients and are significantly more common in
females. The etiology of these disorders is com- a. Indications for imaging of TMDs. Imaging is
plex and multifactorial (Scrivani et al. 2008) and rarely indicated for masticatory myalgia unless
is detailed in the chapters on TMD. there is a history of a precipitating event, such
Fig. 43 Osteoradionecrosis (ORN). Initial post-contrast (white dashed ovals) of the mandible with a non-healed
CT (a) showing a large tongue base SCC (black oval) with 36 socket (c). ORN was significantly more extensive on the
bilateral metastatic lymphadenopathy (black arrows). No right. As shown on this oblique sagittal reconstruction (d),
dental or bony abnormality was evident (b). 3 years fol- there is early ORN of the right posterior maxilla (white
lowing radiotherapy, there is extensive bilateral ORN dashed ovals)
as dental treatment or trauma, or if there are and when the diagnosis of TMD is in doubt, for
other symptoms and signs such as significant example, when there is pain of an atypical char-
trismus (Fig. 46). acter, a palpable mass, and sensory or motor
dysfunction.
Internal derangement is defined as interfer-
ence with a joint’s smooth action and in the b. Comparison of imaging modalities. The
TMJ is most commonly due to disc displace- OPG provides an overview of the dentition
ment. MRI studies have shown mild degrees of and maxillofacial region. If of high quality, it
disc displacement in one third of asymptomatic is a useful screen for moderate to marked TMJ
volunteers, but disc displacement is more com- arthritis and asymmetric condylar morphology
mon in symptomatic patients, and the degree of and size.
disc displacement is more severe (Petscavage-
Thomas and Walker 2014). Although most CBCT has replaced conventional tomography
patients improve on long-term follow-up, MRI as an imaging technique that provides very
evidence of advanced internal derangement good bone detail and multiplanar 2D and 3D
and arthritis is associated with a poor pro- reconstructions of the TMJ and adjacent skull
gnosis. The principal indications for imaging base but no information concerning the soft
include suspected advanced internal derange- tissue components of the joint. Its advantages
ment, arthritis, failure of nonsurgical treatments, and disadvantages have been discussed
220 A. Whyte et al.
Fig. 44 Osteomyelitis. 6 months post-open reduction and dotted arrows) in the left mandibular body with focal
internal fixation of right parasymphyseal and left mandib- lucency around the most mesial screw of the mini-plate
ular body fractures of the mandible. Presented with pain (b and c, black arrow) which traverses the distal apex of
and swelling associated with the left mandible. The right 36. There is a small sequestrum buccal to the screw head
parasymphyseal fracture has healed (a, solid white (b, white open arrow). A gallium scan (d) confirms abnor-
arrows). There is extensive buccal and to a lesser extent mal uptake in the left body consistent with osteomyelitis
lingual periosteal new bone formation (a and b, white but not in the right parasymphyseal region
previously. Widespread availability of CBCT to Current CT technology (Multidetector CT:

the dental profession has been associated with a MDCT) also provides multiplanar 2D and 3D
proliferation in dental and maxillofacial imaging, bone detail of the TMJ similar to or better than
with numerous publications pertaining to its CBCT mainly due to the fact that, although CT is
value in assessing TMJ disorders. Overall, of lower spatial resolution than CBCT, CT images
CBCT has a similar, high accuracy to conven- are less affected by image noise from the dense
tional CT in detecting cortical abnormalities of bone of the skull base. The radiation dose of
the TMJ (Larheim et al. 2015). A major review MDCT is usually higher than that of CBCT, but
article analyzing the published literature con- as previously discussed, this difference is not as
cluded that there was a lack of knowledge about great as in the past (Boeddinghaus and Whyte
the impact of CBCT changing the outcome of 2013). The major advantage of CT over CBCT is
patents with TMJ disorders (Palconet et al. its far superior soft tissue contrast, which allows
2012). detection of significant internal derangement and
Fig. 45 Osteonecrosis of the jaws (ONJ). Sagittal CT extraction sockets were present on intraoral examination.
reconstruction (a) showing sclerotic metastases from car- An axial reconstruction (c) shows bilateral MRONJ (open
cinoma of the prostate involving the basiocciput, sternum white arrows) which is severe and extensive on the left.
(white arrows), and the cervical and partially visualized 38 is unerupted and there is carious destruction of the
thoracic spine. The patient was treated with high-dose crowns of 34 and 35 (b)
bisphosphonates, and bilateral non-healing molar
Fig. 46 Hematoma in the medial pterygoid muscle. Pre- consistent with a needle-induced hematoma. The left man-
sented with severe trismus 6 days following a left inferior dibular foramen is indicated (black arrows). The normal
alveolar block. The left medial pterygoid muscle (black right medial (MP) and lateral (LP) pterygoid muscles are
dashed ovals, a and b) is swollen and slightly hyperdense shown for comparison
222 A. Whyte et al.
Fig. 47 CT of the TMJs. Sagittal closed- (a) and open- coronal (d) reconstructions (white open arrow). Axial soft
mouth (b) soft tissue window images showing an anteri- tissue reconstruction (e) through the right parotid gland in a
orly displaced disc (D) which is not recaptured on mouth patient with right TMJ pain. The irregular mass (white
opening; there is normal condylar translation. Minimal arrows) was proven to represent undifferentiated carci-
superior condylar cortical flattening, sclerosis, and focal noma with proximal perineural tumor spread along the
irregularity are shown on the bone window sagittal (c) and right facial nerve (white dotted arrows)
extra-articular pathology (including neoplastic bone including remodeling, cortical changes,

causes of TMJ pain and otalgia) that would not sclerosis, erosions, and osteophytes (Larheim
be detected on CBCT (Fig. 47). et al. 2015). However, most of this evidence
Magnetic resonance imaging (MRI) is the opti- comes from studies performed prior to 2010,
mal imaging technique for evaluating patients including a frequently referenced study from
with TMJ disorders (Whyte et al. 2006; Hasan 1987 comparing CT and MRI (Westesson et al.
and Abdelrahman 2014; Petscavage-Thomas and 1987). With state-of-the-art MRI, there is accurate
Walker 2014). The excellent soft tissue contrast depiction of cortical integrity, adaptive changes to
combined with the high signal-to-noise ratio of internal derangement, erosions, and established
modern scanners using dedicated surface coils osteoarthritis. Erosions (especially within the con-
and a high magnetic field strength of 3 Tesla pro- dyle) are commonly associated with marrow
vides exquisite soft tissue, cortical, and bone mar- edema (which is not visible on CT or CBCT),
row evaluation. The size, morphology, position, and both correlate with the severity of symptoms.
and integrity of the disc can be assessed as can CT (or CBCT) may still be preferred for evalua-
the bilaminar zone and lateral ligament. MRI tion of TMJ disorders in middle-aged to elderly
is the only technique reliably showing all the patients where the symptoms are more likely to be
soft tissue sequelae of either acute or chronic due to arthritis rather than internal derangement.
inflammation including joint fluid, intra-articular Ultrasound (US) has been proposed as a useful
synovitis, capsular or peri-capsular edema, and and cheap technique in evaluating internal
structural changes in the lateral pterygoid muscle. derangement, but only the lateral aspect of the
CT and especially CBCT have been extensively disc, lateral capsule, and lateral joint can be visu-
reported to be superior to MRI in evaluating the alized (Petscavage-Thomas and Walker 2014). In
addition, it is highly operator dependent, and find- c. Imaging of the major causes of TMD.
ings are not always reproducible. It has been use- Excluding masticatory myalgia, the major
ful in assessing joint fluid, synovitis, and erosions types of TMD which require imaging in adults
in the lateral aspect of the joint in young patients include disc displacement, osteoarthritis, and
with JIA (Ringold and Cron 2009; Mohammed inflammatory arthritis (especially rheumatoid
et al. 2012). US is reliable for guiding needle arthritis). JIA, by definition, commences in
placement into the TMJ for injection of intra- children younger than 16 years, and idiopathic
articular corticosteroids for symptom relief. It condylar resorption occurs almost exclusively
can replace other methods of needle placement in teenage or young adult females.
including palpation and fluoroscopic or CT
guidance. Disc displacement. The fibrocartilaginous
Structural osseous changes within the TMJ are articular disc (meniscus) is biconcave in sagittal
the result of abnormal metabolic activity which is section with an anterior band, a slightly thicker
detected as increased activity on an isotope bone posterior band, and a thin intermediate zone.
scan. Although a highly sensitive technique to the There is a bilaminar zone posterior to the posterior
presence of osseous disease, it is nonspecific and band, attaching it to the temporal bone and the
involves a high radiation dose (Petscavage- condyle. The disc separates the joint into superior
Thomas and Walker 2014). and inferior compartments. The normal position
Functional brain imaging studies support the of the disc is usually defined such that the junction
concept that TMJ disorders are very similar to of the posterior band and bilaminar zone is at the
other chronic pain disorders and may be related 12 o’clock position on a sagittal view (Fig. 48).
to abnormal pain processing in the trigeminal Using this criterion, 34% of asymptomatic indi-
system. Masticatory muscle disorders appear to viduals will have disc displacement. Therefore, it
have little, if any, abnormality of the muscles or has been suggested that minor degrees of disc
peripheral tissues and may represent a pain- displacement are probably a normal variant and
producing process caused by central sensitization that the normal position should be defined as
(Scrivani et al. 2008). 12 o’clock +/ 10 degrees.
Fig. 48 MRI of the TMJ: normal sagittal appearances in between the junction of posterior band and bilaminar zone
the closed- (a) and open-mouth (b) positions. The bicon- being at or close to the 12 o’clock position (12). Impor-
cave fibrous disc is of uniform low signal and consists of an tantly, the narrowest part of the disc (IZ) corresponds to the
anterior band (AB), intermediate zone (IZ), and a slightly narrowest inter-bony distance (white dotted arrows) with
larger posterior band (PB). The thin bilaminar zone is the mouth closed and also during opening. Condylar trans-
indicated (blz). The normal disc position is described as lation is normal
224 A. Whyte et al.
Anterior and anterolateral disc displacement point of its articular surface is situated inferior
account for 63% of all cases, with anteromedial, to the most inferior point of the articular
medial, and lateral displacement being uncom- eminence), hypermobility, or hypomobility
mon, each accounting for about 10% of cases (restricted anterior translation).
(Whyte et al. 2006). Assessment of disc posi- Being composed of fibrocartilage, the disc
tion, especially the degree of mediolateral dis- is normally of uniform low signal. However,
placement, requires correlation of sagittal and depending on the type of MRI sequence, mild
coronal images. Assessment of mobility of the increased signal may be present in the posterior
disc and condyle as well as recapture of a band. Initially, with significant internal derange-
displaced disc (i.e., a return to its appropriate ment, there is edema or myxoid degeneration
position relative to the condyle with mouth of the swollen posterior band. Chronic discal
opening) is performed with a fast open-mouth changes include atrophy, change in shape, tears,
scan or with a sequence of low-resolution, fast and fragmentation (Hasan and Abdelrahman
scans performed as a gradual sequence of pro- 2014). Hypertrophy of the tendon of the superior
gressive mouth opening (Fig. 49). There may be belly of the lateral pterygoid muscle is also seen in
normal condylar movement (the most superior marked and longstanding disc displacement and
Fig. 49 MRI of internal derangement. Anterior disc dis- displacement without reduction (c and d): the anteriorly
placement with reduction (a and b): the disc is indicated displaced disc (white arrows) is not recaptured on mouth
(white arrows) and recaptured on mouth opening, the con- opening, although there is normal condylar translation
dyle being hypermobile (white open arrow). Anterior disc (white open arrow)
Fig. 50 MRI of chronic internal derangement of the TMJ. (d) Hypertrophy of the lateral pterygoid (LP) tendons: the
The margins of the disc are indicated with white arrows. crumpled disc is displaced anteriorly and medially; inferior
(a) Crumpled meniscus: there is a superior compartment to the disc are the hypertrophied tendons of LP giving a
effusion distending the anterior recess (white dashed “triple disc” appearance. (e) Coronal oblique image of
arrow). (b) Degenerate or edematous meniscus: diffuse the left TMJ: separated disc fragments (white arrows) in
increase in discal signal. (c) Small meniscal remnant: a the medial (med) and lateral (lat) aspect of the joint. The
small disc fragment is seen anterior to the condyle and degree of separation is shown by the dotted line
the bilaminar zone (blz) is retracted (white open arrow).
thought to be related to chronic muscle hyperac- MRI have generally correlated with the severity
tivity (Fig. 50). of pain (Farina et al. 2009).
In patients with more significant degrees of Osteoarthritis. From a rheumatologic stand-
disc displacement, often without recapture, point, osteoarthritis (OA) is now thought to be an
whose symptoms do not resolve or progress inflammatory condition involving all components
on nonsurgical management, an intra-articular of a joint rather than a purely degenerative process
inflammatory response is common. MRI will usu- (Berenbaum 2013; Larheim et al. 2015). In the
ally demonstrate joint effusion, predominantly TMJ, it is usually considered to arise secondary to
in the superior compartment. Synovitis may be internal disc derangement. Given the complexity
seen in the inferior compartment and around of the TMJ, excessive and prolonged mechanical
the bilaminar zone. Erosions usually involve loading exceeding the adaptive capacity of artic-
the condyle and when acute or subacute are ular cartilage and subchondral bone for
associated with marrow edema. Synovitis and remodeling is likely to be a significant factor in
active erosions enhance with gadolinium but pathogenesis. OA is usually seen in an older age
also have typical signal characteristics on group than internal derangement, and both disor-
fat-saturated T2-weighted sequences (Fig. 51), ders predominate in women. Most patients with
and therefore gadolinium is not routinely OA of the TMJ have a history of preceding inter-
required. The signs of joint inflammation on nal derangement, and available evidence suggests
226 A. Whyte et al.
Fig. 51 Intra-articular inflammation of the TMJ. Compar- show two cases of marked anterior disc displacement
ison of CBCT (a), proton density (b), and fat saturation (white arrows), hyperintense fluid in the distended anterior
T2 (c) MRI. All images show subtle articular surface recess of the upper joint space (dotted black arrow), and
irregularity of the condyle (open black arrow in a). The moderately hyperintense synovitis (white dotted arrows) in
anteriorly displaced disc (white arrows) is shown on MRI the inferior joint space and around the bilaminar zone.
(b and c) as is the irregular and edematous bilaminar zone There is subtle erosion of the posterosuperior condylar
(blz). Hyperintense marrow edema is shown on the fat cortex and diffuse marrow edema (white open arrows).
saturation T2 image (open white arrow in c), the most Perforation of the malformed disc and edematous
sensitive sequence for inflammation. Images d and e bilaminar zone (white arrowhead) is shown in (e)
that patients with severe internal derangement can Normal, B, Indeterminate, and C, Osteoarthritis
progress to OA after a variable interval, often (Ahmad et al. 2009). The described features in
several years. category B of condylar articular surface flattening
The imaging features of OA in the TMJ are and sclerosis are typical of adaptive remodeling.
identical to those seen in other affected joints: As is typical of this condition in any joint, the
asymmetric joint space narrowing, articular sur- changes seen on imaging correlate poorly, or not
face remodeling and flattening, cortical sclerosis at all, with symptoms (Palconet et al. 2012). Many
and thickening, subcortical cysts, osteophytes, patients may be pain-free despite advanced OA,
and calcified intra-articular bodies (Fig. 52). and the only complaint may be of joint noises or
Osseous changes are much more common in grating.
the condyle than in the articular eminence or Rheumatoid arthritis and related joint dis-
glenoid fossa (Boeddinghaus and Whyte 2013). eases. Rheumatoid arthritis (RA) is a systemic,
A simple imaging classification of OA in the autoimmune, inflammatory disorder which mani-
TMJ which is useful for longitudinal studies is fests as peripheral polyarthritis. Women are
that proposed by Ahmed et al. in 2009: A, affected more commonly than men (3:1) and the
Fig. 52 Osteoarthritis. CT of early (a and b), moderate advanced joint space loss, articular surface remodeling,
(c), and severe (d) osteoarthritis. Proton density MRI (e) and subcortical sclerosis (white arrow). CT (d) and PD
for comparison. Case (a) shows early erosion, flattening, MRI (e) images demonstrate marked joint space
and sclerosis of the superior condylar articular surface narrowing, articular surface flattening, cortical irregularity,
(open white arrow). Mild anterosuperior joint space a condylar osteophyte, subcortical sclerosis, and cysts
narrowing, condylar articular surface flattening, and a (white dotted arrows). An ossified intra-articular body is
small osteophyte (white arrow) are shown in case (b). shown by both modalities (black arrows)
With disease of moderate severity (c), there is more
disease predominates in the 35–45 year age group. produce articular surface erosion, but usually
Clinical evidence of TMJ involvement is found in there is also evidence of bone proliferation includ-
more than half of patients (Petscavage-Thomas ing periosteal new bone formation.
and Walker 2014). TMJ disorders in childhood. Disc derange-
Typical imaging findings in active RA are of ment disorders have a predilection for teenage and
erosions on both sides of the TMJ and symmetric young adult females. MRI is the optimal imaging
joint space narrowing without osseous prolifera- modality because of the excellent soft tissue detail
tion (Fig. 53). MRI demonstrates diffuse synovi- and absence of radiation. The imaging features of
tis, and the disc may be of abnormal morphology advanced derangement disorders with develop-
and displaced due to inflammation and weaken- ment of intra-articular inflammation, condylar
ing of the attachments. In chronic disease, espe- erosions, remodeling, and osteoarthritis are as
cially following treatment, the erosions will previously described.
heal, and secondary osteoarthritis may develop Idiopathic condylar resorption (ICR), also
with changes of osseous remodeling and known as progressive condylar resorption, is
proliferation including flattening, sclerosis, and thought to represent a severe and accelerated
osteophytes. form of condylar erosion that affects adolescent
Seronegative spondyloarthropathies such as females with disc derangement. Three phases
psoriatic arthritis and ankylosing spondylitis also of ICR are described: soft tissue, destructive
228 A. Whyte et al.
Fig. 53 Rheumatoid arthritis. CT (a) and fat saturation T2 displaced. The disc attachments are destroyed by inflam-
MRI (b) of active and severe rheumatoid arthritis with matory tissue. Less severe erosion of the articular surfaces
gross erosion and deformity of the articular surfaces. on both sides of the joint with remodeling and sclerosis in a
MRI demonstrates that the joint is distended by hyper- case of inactive disease (c). Ankylosis has developed fol-
intense synovial proliferation and fluid (white dotted lowing multiple episodes of inflammatory arthritis (d)
oval) with the deformed disc (D) being markedly anteriorly
(active), and reparative (Hatcher 2013). The soft MRI, as timing of orthodontic or orthognathic
tissue phase corresponds to disc derangement, treatment is crucial.
joint laxity, and intra-articular inflammation. Juvenile idiopathic arthritis (JIA) includes all
Combined with altered or excessive biomechan- forms of arthritis that develop before the age of
ical loading of the TMJ, perhaps in a specific 16 years, persist for at least 6 weeks, and have no
hormonal environment, the destructive phase identifiable cause. The TMJ is one of the most
ensues with extensive condylar erosion and frequently involved joints, involved in as many as
resorption (Fig. 54). Resorption and disturbance 75% of children with JIA, and involvement is
of condylar growth result in mandibular higher in those with the polyarticular form of the
retrognathism, an anterior open bite, and disease with systemic symptoms (Mohammed
increases in the maxillary-mandibular plane et al. 2012). MRI is the most sensitive technique
angle and anterior lower facial height. ICR is in the diagnosis of TMJ involvement, demonstrat-
usually bilateral but can be asymmetric, resulting ing joint fluid, synovitis, and erosions of both sides
in facial asymmetry. The final reparative phase of the joint. Most children with JIA are asymptom-
results in a flat articular surface with reformation atic at the time their TMJ arthritis is diagnosed but
of the cortex. The different stages should be are still at risk of long-term joint damage if not
assessed by imaging, either CBCT or preferably treated. Imaging-guided injection of intra-articular
Fig. 54 Idiopathic condylar resorption (ICR). ICR usu- condylar erosion/resorption (dotted white arrows), a wid-
ally involves teenage females, and mandibular ened joint space, diffuse edema of condylar marrow (open
retrognathism is a common associated factor (a, lateral white arrow), marked anterior disc displacement (D), and
cephalogram). Erosive, symptomatic phase of ICR shown intra-articular synovitis (white arrows)
on cone beam CT (b) and MRI (c): there is extensive
steroids shows promise in reducing the severity of pathology residing within the sensory distribution
intra-articular inflammation, resulting in improved of these cranial and upper cervical nerves can
joint opening and decreased pain in symptomatic potentially cause pain referred to the ear:
patients (Ringold and Cron 2009). referred otalgia (Chen et al. 2009) (Fig. 56). This
includes the nasopharynx, oropharynx, oral cav-
d. Referred pain to the TMJ region. In addition ity, larynx, paranasal sinuses, major salivary
to being the principal sensory nerve to the glands, maxilla, and mandible. Approximately,
TMJ, the auriculotemporal branch of the man- 75% of referred otalgia is thought to be dental or
dibular division of the trigeminal nerve TMJ in origin (Jaber et al. 2008). Upper cervical
(V3) also innervates the anterior wall of the facet degeneration (C2/C3 supply) is an important
external auditory canal, the pre-auricular area cause in the elderly (Kim et al. 2007).
and tragus, and the temporal scalp. It can be
difficult to distinguish between pain originat-
ing in the TMJ and pain from the ear (otalgia). Imaging of Orofacial Pain
Sensory innervation of the ear is complex and Advanced imaging of orofacial pain is guided by
includes the glossopharyngeal (IX), vagus (X), the findings of a thorough and comprehensive
and upper cervical (C2 and C3) nerves in addition history and examination by an experienced clini-
to the trigeminal (V) nerve (Fig. 55). Any cian, in conjunction with an OPG. Ideally, the
230 A. Whyte et al.
Fig. 55 Sensory innervation of the TMJ, external ear middle ear, mastoid air cells, and the upper pharynx,
canal, pinna, and skin. Cranial nerves V, VII, and X inner- including the tongue base. Branches of the cervical plexus
vate the external auditory canal (EAC) and lateral surface derived from C2 and C3 innervate the pinna and skin
of the tympanic membrane. Cranial nerve V extending anteriorly and inferiorly to the mandibular
(V3) innervates the TMJ, anterior wall of the EAC, tragus, angle (greater auricular nerve) as well as skin/scalp poste-
pre-auricular skin, and temporal scalp. Cranial nerve IX rior and superior to the scalp (lesser occipital nerve)
innervates the medial surface of the tympanic membrane,
likely etiology of pain can be confined to a limited (posterosuperior extent of scalp supplied by the
differential diagnosis, and imaging can be ophthalmic division: V1) to the C3/C4
targeted to confirmation of the exact cause. How- intervertebral disc level (to cover the submandib-
ever, in some patients this is not the case and ular glands and spinal trigeminal nucleus). A wide
imaging must be more comprehensive to exclude range of bone and soft tissue pathology which
potential end-organ, peripheral, skull base, and may not have been appreciated on clinical exam-
central causes of pain. This is best performed ination or OPG can be shown by this technique.
using state-of-the-art technology by radiologists This includes common causes of orofacial pain
who have an in-depth understanding of trigeminal such as subtle periapical pathology, internal
anatomy and the multiple potential causes of derangement, and arthritis of the TMJ, as well as
orofacial pain. uncommon causes including occult malignancy
(Fig. 57). If CT contrast is contraindicated, either
a. Application of imaging to the major causes non-contrast CT or CBCT can be performed, with
of orofacial pain the addition of MRI.
If there are other sensory symptoms (e.g.,
End-organ and peripheral causes: In addi- dysesthesia, paresthesia, or hypoesthesia) in addi-
tion to supplying the hard- and soft-tissue compo- tion to pain, dedicated MRI of the trigeminal
nents of the oral cavity, the trigeminal (V) nerve nerves with contrast enhancement is mandatory
also provides sensation to the anterior scalp, facial to exclude large nerve perineural tumor spread,
skin, nasal cavity and paranasal sinuses, orbits, particularly in patients who report prior excision
temporomandibular joints, external auditory or cryotherapy of skin lesions, even if these were
canal, and salivary glands. not known to be malignant (Fig. 58).
Post-contrast CT with soft tissue and bone Skull base causes. The skull base represents
window multiplanar reconstructions provides the interface between the maxillofacial region,
optimal imaging evaluation when a peripheral or pharynx, and neck below and the intracranial con-
end-organ cause is suspected. Scanning should tents above. Gross or subtle pathology within or
extend from the vertex of the skull adjacent to the skull base involving the trigeminal
Fig. 56 Otalgia and referred otalgia. Otalgia is defined as innervated by the multiple cranial nerves and branches of
pain originating from the ear: it is due to inflammatory or the cervical plexus which innervate the ear. It is seen in
(less commonly) neoplastic conditions of the ear and pre- older patients and may be myofascial, inflammatory,
dominates in young patients. Otitis externa and degenerative, or neoplastic in origin. Overall, 75% of
otomastoiditis is a common cause (a). There is skin thick- referred otalgia is dental or TMJ in origin; a further com-
ening in the external auditory canal: EAC (black dotted mon cause in elderly patients is upper cervical facet joint
oval) and multiple fluid levels in the mastoid air cells degeneration (c, white dotted rectangle). Occult malig-
(black arrows). Cholesteatoma is a misnomer: this inflam- nancy should always be considered. A large left-sided
matory lesion is an epidermoid (b) and is characterized by a tongue base carcinoma (d) extends anteriorly into the oral
focal soft tissue mass causing erosion of the posterior wall tongue and floor of the mouth (black arrows). The tumor
of the EAC (white arrows). Referred otalgia originates crosses the midline and also involves tissue innervated by
from outside the ear and originates from any structure cranial nerves V and IX (boundary: white dashed line)
nerve can cause V2 or V3 pain and be clinically demonstrated by a combination of MRI and
occult (Fig. 59). Tumors within the nasal cavity or CT. High-resolution 3-Tesla MRI can clearly
nasopharynx can erode the skull base from below, show the trigeminal ganglion and nerve rootlets
as can pituitary tumors or meningiomas from in Meckel’s cave, the trigeminal nerve divisions
above. Intrinsic skull base tumors are rare, and, (V1, V2, and V3) within and adjacent to the skull
in older patients and those with a history of malig- base foramina, as well as the cranial nerves (III,
nancy, a metastasis should always be considered. IV, V1, V2, and VI) within the cavernous sinuses
The bony skull base contains numerous foram- (Fig. 59).
ina and canals occupied by traversing cranial Central causes: These either involve the tri-
nerves and vessels. Both anatomy and intrinsic geminal sensory nuclei (within the brain stem and
or extrinsic skull base pathology are optimally upper cervical cord) or result from compression of
232 A. Whyte et al.
Fig. 57 Miscellaneous unsuspected causes of chronic left opaque, linear calculus (arrow) in the left parotid duct. (c)
facial pain detected on CT. (a) Chronic periapical abscess Elongated styloid process with hypertrophic degeneration
associated with 27, perforation of the sinus floor (white at two pseudo-arthroses (white dotted arrows). (d) Chronic
dotted arrow) and reactive mucosal thickening (white periapical abscess (white dotted arrows) associated with
arrows) in the floor of the left maxillary sinus. (b) Left 37 in a patient already commenced on medical treatment
parotitis (white dotted gland outline) with a tiny, faintly for “left V3 trigeminal neuralgia”
the cisternal segment of the V nerve (between its et al. 2016). Even if there are no visible lesions in
root entry to the pons and its passage through the the brain stem or cervical cord on imaging, the
porus trigeminus) (Fig. 60). MRI is the optimal presence of plaques elsewhere in the brain sug-
imaging technique and the study must extend gests that demyelination is the likely cause of
from the vertex to the cervical spinal cord trigeminal neuralgia in a patient with multiple
(C3/C4) to cover the entire sensory distribution of sclerosis.
the V nerve as well as the spinal trigeminal nucleus. Compression of the V nerve in the pre-pontine
Intrinsic brain stem pathology is a rare cause of cistern is a much more common cause of trigem-
orofacial pain (Leclercq et al. 2013). Multiple inal neuralgia. 90% of cases are caused by vascu-
sclerosis and tumors account for 3% and 0.8%, lar impingement, usually by the superior
respectively, of all causes of trigeminal neuralgia cerebellar artery (Fig. 62). Contact between a
and are clearly demonstrated by MRI (Fig. 61). vessel and the cisternal segment of the V nerve
Multiple sclerosis usually presents in patients occurs in 40% of asymptomatic subjects. In a
under age 40. There are updated imaging criteria patient with trigeminal neuralgia, the important
for diagnosis by MRI, dependent on the number imaging findings which are likely to be clinically
and distribution of demyelination plaques (Filippi relevant are arterial impingement on the proximal
Fig. 58 Melanoma involving the maxillary division of the contrast T1 scans (c and d) demonstrate large nerve peri-
left V nerve. The post-contrast T1 axial scan (b) shows a neural tumor spread along the left infra-orbital nerve (ION)
small, enhancing subcutaneous mass in the medial aspect in the orbital floor which extends proximally to the main
of the cheek (dotted white oval) which is difficult to appre- trunk of V2 nerve within the foramen rotundum (FR)
ciate on the non-contrast T1 axial scan (a). Coronal post-
50% of the nerve, known as the root entry zone. extend superiorly to the trigeminal nerve, and
This portion of the nerve has thinner central mye- petrous apex lesions can also compress the nerve
lin which is more vulnerable to vascular compres- at the porus trigeminus.
sion and focal demyelination than the distal,
peripherally myelinated nerve which has a thicker b. Optimizing imaging when the cause of
myelin sheath (Hughes et al. 2016). Distal orofacial pain is uncertain
impingement and veins are uncommon causes of
trigeminal neuralgia. MRI is the investigation of choice when the
Extra-axial tumors and other mass lesions are cause of orofacial pain is uncertain after clinical
responsible for 6.2% of cases of trigeminal neu- evaluation and OPG. The scan protocol must
ralgia. Nerve sheath tumors, especially vestibular cover the central, skull base, and peripheral course
schwannomas (acoustic neuromas) and meningi- of the trigeminal nerve with T1 and T2 sequences,
omas, are the most common tumors to compress including high-resolution 3D analysis of the cis-
the trigeminal nerve (Fig. 63). An epidermoid cyst ternal segment and post-gadolinium evaluation to
arising in the cerebellopontine angle cistern may exclude enhancing tumors (Leclercq et al. 2013).
234 A. Whyte et al.
Fig. 59 Cavernous sinus, Meckel’s cave, and the central The U-shaped trigeminal ganglion (TG) is clearly visual-
skull base. (a) Coronal post-contrast high-resolution ized (white arrow). (c and d) Post-contrast T1 coronal (c)
T1-weighted image through the cavernous sinus (CS). and axial (d) images of a homogeneously enhancing
The three divisions of the trigeminal (V) nerve are labeled meningioma which fills the right cavernous sinus and
(white arrows). V3 exits through foramen ovale (FO). Meckel’s cave (black arrows). The tumor encases the
Cranial nerves III and VI are also identified (white dotted right internal carotid artery (ICA, dashed white arrow)
arrows). (b) Coronal post-contrast high-resolution image and extends inferiorly along the V3 nerve and anteriorly
at a level posterior to (a), through Meckel’s cave (MC). along V2
Involvement of marrow of the skull base, max- If MRI is unavailable, post-contrast CT with
illa, or mandible by tumor or infection can be soft tissue and bone window reconstructions (cov-
appreciated on MRI before CT, CBCT, and (espe- ering the same anatomical extent as described for
cially) radiographs are abnormal. Nevertheless, MRI) is also an excellent and comprehensive
artefact from dental restorations is unpredict- examination. However, CT will miss demyelin-
able on MRI: it may be focally severe, obscuring ation and cannot show vascular impingement on
ipsilateral upper and lower quadrants. Periapical the cisternal segment of the trigeminal nerve.
pathology can be obscured and either CBCT
or CT should be performed for optimal c. Functional imaging and research for
dentoalveolar, TMJ, and sinonasal evaluation. orofacial pain
Neural impulses resulting from painful stimuli ganglion and pass via the cisternal segment of
in the orofacial region supplied by the divisions of the nerve to the pons. The nociceptive impulses
the trigeminal nerve relay in the trigeminal then descend in the spinal trigeminal tract of the
medulla to synapse in the nucleus caudalis
in the upper cervical cord, cross over into the
contralateral spinothalamic tract, and ascend to
synapse in posterior nuclei of the thalamus. Mod-
ulation of nociceptive impulses occurs in the brain
stem. Neural projection is principally to the pos-
terior insular cortex as well the sensory and ante-
rior cingulate cortices.
Pain is a complex and subjective perception
with sensory, cognitive, and emotional compo-
nents. Functional imaging of the response of
healthy volunteers to painful stimuli has led to
the characterization of a network of brain areas
forming a “pain matrix” (Fig. 64). This central
network mainly involves the thalamus, the amyg-
dala, the insular cortex, the supplementary motor
Fig. 60 Anatomy of the trigeminal nerve and nuclei area, the posterior parietal cortex, the prefrontal
within the pre-pontine cistern and the brain stem. An
ultra-high-resolution 3D T2 volumetric sequence demon-
cortex, the cingulate cortex, the periaqueductal
strates the position of the main sensory (S) and motor gray matter of the midbrain, the basal ganglia
(M) nuclei at the level of the pons as well as the cisternal and cerebellar cortex, and the primary and sec-
segment of V between the root-entry zone (REZ – black ondary sensory cortices. As a generalization, the
arrow) and the porus trigeminus (PT – white arrow). The
low signal trigeminal nerve rootlets are seen within
laterally situated areas are involved with sensation
Meckel’s cave contrasted by the hyperintense cerebrospi- and the medial areas with cognitive and affective
nal fluid components of pain. The components of the pain
Fig. 61 Multiple sclerosis presenting as trigeminal neu- attenuation inversion recovery (FLAIR) sequence shows
ralgia. (a) An axial proton density (PD) sequence shows addition triangular or cigar-shaped demyelination plaques
three hyperintense demyelination plaques in the pons adjacent to the corpus callosum (black arrows) overlying
(black arrows), and these are typically situated adjacent the lateral ventricle (LV)
to an interface with cerebrospinal fluid. (b) A sagittal fluid
236 A. Whyte et al.
Fig. 62 Compression of the V nerve by the superior impinging vessel (SCA: red arrow). The basilar (B) and
cerebellar artery (SCA) in a patient with right trigeminal internal carotid arteries (ICA) are also shown. (c) Magni-
neuralgia. (a) A high-resolution T2 sequence shows a loop fied image (a) showing the plane of sagittal reconstruction
of the SCA impinging on the root-entry zone of the right V through the right V nerve and SCA. The root entry zone
nerve to the pons. The cisternal segment of the right V (REZ) and Meckel’s cave (MC) are shown on the left side.
nerve is atrophic when compared to the normal left side. (d) Sagittal reconstruction showing the impingement on
(b) A flow-sensitive sequence: magnetic resonance angi- the cisternal segment of V from the SCA (red arrows)
ography (MRA) demonstrates arterial flow in the
matrix interact with each other to generate the addition, differences were seen in different neu-
individual perception of pain (May 2009; Moisset ropathic pain states, and specific neural signa-
et al. 2011). tures were evident for certain neuropathic pain
There has been extensive research with func- disorders (Scrivani et al. 2007).
tional imaging to elucidate the pathological Recent investigations using fMRI to evaluate
basis of neuropathic pain. Neuropathic pain central pain processing in patients with classical
results from a lesion or disease of the somato- TN have highlighted not only the value of the
sensory system and may be continuous or epi- technique in understanding the pathophysiology
sodic in nature, trigeminal neuralgia (TN) being but also demonstrating significant alteration fol-
the classic example of the latter. Recent studies lowing successful neurosurgical treatment
using functional MRI (fMRI) have demonstrated (DeSouza et al. 2014). Neurovascular conflict of
significant differences in the neuronal activity in the root entry zone of the cisternal segment of the
asymptomatic subjects versus pain patients. In trigeminal nerve causes focal demyelination
Fig. 63 Extra-axial tumors compressing the V nerve in meningioma (open white arrows) in the left
the posterior cranial fossa. Post-contrast T1 coronal (a) and cerebellopontine angle cistern which obscures the left tri-
high-resolution T2 axial (b) of a right acoustic neuroma geminal nerve and extends via the porus trigeminus
(vestibular schwannoma) extending laterally into the right (PT) into the left Meckel’s cave. The tumor causes com-
internal auditory canal and superiorly to compress the right pression of the brain stem and extends laterally into the
V nerve (open arrows). There is an associated arachnoid internal auditory canal (white arrow). The tumor forms
cyst (white dashed arrows) of fluid signal situated postero- obtuse angles with the petrous ridge (white dotted arrows),
lateral to the tumor. Post-contrast T1 (c) and T2 (d) axial characteristic of meningiomas
scans showing a large, enhancing hemispherical-shaped
and edema as measured by the MRI technique capacity for neuroplasticity (May 2009; DeSouza
of diffusion tensor imaging. Gray- and white mat- et al. 2015).
ter abnormalities occur in patients with TN
in structures involved in pain perception, pain
modulation, and motor function including the spi- Imaging of Sleep-Disordered Breathing
nal trigeminal nucleus, pain matrix structures, and
interconnecting white matter bundles such as the Sleep-disordered breathing represents a spec-
corpus callosum. Successful treatment using trum, ranging in severity from snoring to obstruc-
microvascular decompression results in correc- tive sleep apnea (OSA). Snoring is common,
tion of the abnormal indices measured on fMRI affecting about 40% of adults in developed coun-
as well as resolution or significant improvement tries. The OSA syndrome is defined as a clinical
of pain. This includes restoration of gray matter condition in which there is intermittent and
thickness in the anterior insula, indicating the repeated upper airway collapse during sleep,
238 A. Whyte et al.
Fig. 64 The “pain matrix.” (a) Midline sagittal T1 of the Dashed line rectangle = Peri-aqueductal gray matter. Dot-
brain: T = thalamus, AMYG = amygdala, PFC = pre- ted black line = trigeminal nuclei and tracts. (b) Para-
frontal cortex, CC = cingulate cortex, SMA = supplemen- sagittal through the Sylvian fissure showing the insular
tary motor area, S1 = sensory cortex (primary), S2 = sen- cortex (white dashed oval). Frontal (F) and temporal
sory cortex (secondary), PPC = posterior parietal cortex. (T) lobes
resulting in interrupted and irregular breathing at pharyngeal dilator muscles during sleep, com-
night and excessive sleepiness during the day. It bined with the negative intraluminal pressure dur-
predominantly affects obese, middle-aged males. ing inspiration, resulting in airway collapse. In
Diagnosis of OSA requires overnight poly- almost all cases, the etiological factors for
somnography (PSG) which measures an apnea- increased airway collapsibility are a combination
hypopnea index (AHI). OSA is graded as mild, of increased soft tissue narrowing the upper air-
moderate, and severe. Most cases of OSA are way lumen and reduced size of the bony
symptomatic. It is common in developed coun- and cartilaginous framework supporting the air-
tries: for example, it is estimated that 25% of way musculature (Barkdull et al. 2008; Enciso
males and 9% of females will have OSA in et al. 2010). This results in a narrow and elongated
Australia and 15% of these cases will be catego- upper airway (Fig. 65).
rized as moderate to severe (Mansfield et al. Imaging has played a major role in understand-
2013). ing the pathogenesis of OSA. The ideal modality
Blood gas disturbances (hypoxia and hyper- would image the airway in multiple dimensions
capnia) during cessation of breathing result in and evaluate the soft tissue and bone when the
chronic and repeated sympathetic overactivity patient is both supine and asleep; this ideal is
and hypercoagulability. There is a significant difficult to achieve.
association with increased risk of cardiovascular Lateral cephalogram. This has been the
events, hypertension, and diabetes. A 2.5–7 times mainstay of evaluation over the last 40 years and
increase in mortality is associated, proportional to continues to be relevant, especially in children. It
the severity of OSA. is cheap, widely available, and reproducible. It is
limited by giving information only in the sagittal
a. Value of imaging in understanding the path- dimension and in the erect position and awake.
ogenesis of OSA Measurement of adenoidal size in the nasophar-
ynx and an indication of size of the palatine and
The sleeper who suffers from OSA periodi- lingual tonsils are possible: these are of para-
cally struggles to breathe but is unable to inhale mount significance in children with sleep-
effectively because the airway has collapsed. It is disordered breathing. Research using this
a mechanical problem due to decreased tone in the technique, in conjunction with orthodontic
Fig. 65 Airway morphology and obstructive sleep apnea narrowing in the mediolateral dimension being greater
(OSA). The T1 sagittal and axial images on the left (NOR- than the anteroposterior narrowing (horizontal and vertical
MAL) are of an adult patient without OSA who has man- white lines). Other important findings in OSA are elonga-
dibular retrognathism (open white arrow). On the right tion and increased bulk of the soft palate (SP), enlargement
(OSA), the T2 sagittal and axial images demonstrate the of the lingual tonsil (LT), elongation and posteroinferior
typical changes in airway morphology in an adult patient prolapse of the tongue (white arrow), expansion of the fat
with OSA: elongation of the oropharynx (dotted white line) containing parapharyngeal spaces (PPS), and thickening of
and reduction in area of the airway with the degree of the lateral oropharyngeal walls
assessment, has shown an association between 2013). CBCT provides multiplanar, area, and
OSA and mandibular retrognathism, a high volumetric analysis of the airway in addition to
maxillary-mandibular plane angle (high anterior accurate assessment of the maxillofacial skel-
lower facial height), narrow maxilla, and inferi- eton, dentofacial relationship, hyoid bone, and
orly situated hyoid bone (Gungor et al. 2013). sinonasal cavity. In addition, CBCT is more acces-
Cone Beam CT (CBCT). There is a large body sible to the dental profession than CT or MRI, and
of literature advocating the use of CBCT for initial the relatively low dose is advantageous to young
and posttreatment assessment of patients with patients (Buchanan et al. 2016). The major disad-
sleep-disordered breathing, including OSA. vantages of CBCT are the absence of soft tissue
Many of these publications have significant meth- contrast, the standing or seated position required
odological flaws (Alsufyani et al. 2013; Choi et al. for nearly all scanners, and the variation in head
240 A. Whyte et al.
position in the same patient. There is an average factors such as measures of obesity. A recent
one-third (but unpredictable, and up to two-thirds) study demonstrated a strong correlation between
reduction in airway area and volume in the supine the AHI, obesity, and objective measurement of
(versus erect) position (Fig. 66) (Camacho et al. airway collapsibility during sleep with measure-
2014). Nonetheless, CBCT has contributed to ment of length of the tongue, length of the oro-
research showing increased airway dimensions pharyngeal airway, and position of the hyoid
and volume as a result of oral sleep appliances or bone (Genta et al. 2014). MDCT is rapid (about
orthognathic surgery. 5-s scan time), is widely available, and uses a
Multidetector CT (MDCT). Several well- relatively low radiation dose. A preliminary lat-
performed studies using MDCT in the supine eral digital planning scout view allows cephalo-
position (as well as a single study using a metric analysis in the supine position. From the
supine CBCT scanner) have measured airway volumetric scan data, multiplanar bone and soft
dimensions, airway area, and hyoid position in tissue reconstructions allow complete evaluation
patients with sleep-disordered breathing and of the airway dimensions and morphology as
have shown strong correlation with the AHI well as the soft tissue and bony factors contrib-
derived from polysomnography and other risk uting to narrowing.
Fig. 66 Reduction in airway size when changing from in the supine position (b). Similarly, a mild to moderately
erect to supine. Images performed within 24 h of each other reduced retropalatal airway area of 127 sq. mm in the erect
for two different patients. A CBCT performed on the first position (c) decreases to a critically narrowed airway area
patient (a) at the retroglossal level shows a capacious of 34 sq. mm in the supine position (d)
airway which reduces markedly when MRI was performed
The contribution of nasal factors to OSA is MDCT. Maximum reduction in airway area in
appreciated by physicians and surgeons specializ- patients with OSA is usually in the retropalatal
ing in sleep medicine but has received little region, corresponding to the upper oropharynx.
emphasis in the dental literature. Rhinitis, devia- Transverse narrowing of the airway is more
tion of the nasal septum, and nasal polyps are closely correlated with OSA than reduction in
highly significant because about half of normal the anterior-posterior dimension (Ogawa et al.
upper airway resistance occurs at the level of the 2007). Elongation of the oropharynx can be
nasal cavity. assessed and is associated with a low-lying
The airway can be narrowed by enlargement of hyoid bone and posterior prolapse of the tongue
several soft tissue structures: adenoidal lymphoid base (Fig. 67).
tissue in the nasopharynx, the palatine and lingual Magnetic resonance imaging (MRI). Limited
tonsils and tongue base in the oropharynx, the soft availability to the dental profession, relatively
palate, and the fat-filled parapharyngeal spaces. slow routine scan times, and the absence of visu-
These structures cannot be adequately evaluated alization of the hyoid bone are the major disad-
by CBCT because of its very poor soft tissue vantages of this technique. In addition, there is a
contrast resolution but are well shown with 5–10% failure rate due to claustrophobia, and
Fig. 67 CT of OSA. (a) Digital lateral cephalogram in the tongue base is infiltrated with fat (dashed white oval). (c)
supine position. This allows skeletal assessment and dem- Marked narrowing of the retropalatal oropharynx espe-
onstrates a low-lying hyoid bone. Obesity is evident. (b) cially in the mediolateral dimension and predominantly
Sagittal soft tissue reconstruction: the soft palate (S) is due to hypertrophy of the palatine tonsils (PT). (d) Marked
elongated (white arrow), and there is posterior and inferior narrowing of the retroglossal oropharynx most marked in
displacement of the tongue (open white arrow) which the anteroposterior dimension related to enlargement and
correlates closely with an inferiorly situated hyoid. The posterior prolapse of the tongue
242 A. Whyte et al.
grossly obese patients may not be able to be analysis of soft tissue using MRI spectroscopy
accommodated in the bore of the magnet. MRI provides accurate measurement of tongue volume
does not involve radiation and is performed with and the percentage of the tongue volume that is
the patient supine. MRI studies of OSA patients due to fat. There is a close correlation between
and volunteers without sleep-disordered breathing obesity (BMI), the severity of OSA (AHI), and the
have been performed with patients awake, tongue volume and percentage of fat. Large,
sedated, or during natural sleep, the cardiorespi- fat-replaced tongues tend to prolapse inferiorly
ratory status being monitored during this research and posteriorly resulting in elongation of the oro-
to ensure safety. Ultra-fast cine MRI allows “real- pharynx and inferior displacement of the hyoid
time” evaluation of the airway during sleep bone because of the attachments of extrinsic
cycles unlike CT or CBCT. MRI provides optimal tongue musculature (Kim et al. 2014; Kirkness
evaluation of the soft tissue factors potentially et al. 2014). In addition, replacement of the tongue
contributing to airway collapse (Fig. 68). Conven- by fat decreases the number and function of mus-
tional 3D sequences supplemented by chemical cle fibers and decreases stiffness as recently
Fig. 68 MRI of OSA with marked airway narrowing at (b) Axial T1 of the oropharynx through the narrowest
the upper (retropalatal) oropharynx but not at the retropalatal level (white dashed lines in a and c). (c) Mid-
retroglossal level. (a) Coronal T1 of the airway. The oro- line sagittal T1. The soft palate (S) is thick and the tongue
pharynx has an “hour-glass” configuration secondary to appears normal. (d) T1 axial through the tongue base
enlargement of the hyperintense, fat-filled parapharyngeal (white dotted lines in a and c). There is no airway compro-
spaces (black dashed arrows) and the palatine tonsils (PT). mise. The epiglottis (E) is shown
measured by MRI elastography in patients with severe OSA, there is often narrowing at multiple
OSA (Brown et al. 2015). levels.
Volume rendering software can also provide a
b. Indications for imaging 3D representation of the airway and volume mea-
surement which can show improvement following
OSA is not a diagnosis made by imaging. successful treatment. However, several studies
Certain skeletal and soft tissue features on imag- have shown a poor correlation between airway
ing correlate with sleep-disordered breathing. volume in patients who are awake and the severity
Imaging is a static examination performed on of OSA as measured by the AHI (Alsufyani et al.
patients who are awake, in quiet breathing with 2012). Static upper airway imaging during wake-
the added limitation of the erect position if CBCT fulness does not fully capture the reduction in
is the modality used. In contrast, sleep is a upper airway dimensions and increase in pharyn-
dynamic process with varying, repetitive phases. geal length that is characteristic of airway collapse
Airway collapse during sleep is dependent on during sleep.
diminished neuromuscular activity as well as pre-
disposing anatomical factors.
The clinical suspicion of sleep-disordered Imaging of Headache
breathing requires confirmation and evaluation
with polysomnography. Snorers and patients Headache is the most common neurological
with OSA treated with continuous positive air- symptom in patients presenting to primary care
ways pressure (CPAP) do not need imaging unless physicians. Correct diagnosis and treatment are
there are other clinical indications. Imaging is mandatory. The International Headache Society
advocated for those patients with nasal obstruc- produced an International Classification of Head-
tion, OSA treated primarily with a mandibular ache Disorders (ICHD) of which the third edition
advancement device (MAD), failed CPAP, or pre- was published in 2018. It divides headaches into
surgical assessment. three categories: primary, secondary, and a third
The choice of imaging will depend on local group consisting of cranial neuralgias, central and
availability and expertise. Low-dose MDCT primary facial pain, and other headaches (Head-
with assessment of the nasal cavity, sinuses, ache Classification Committee of the International
maxillofacial skeleton, hyoid position, airway, Headache 2018).
soft palate, lymphoid tissue of Waldeyer’s ring, Primary headaches account for 90% of head-
parapharyngeal spaces, and tongue is the opti- ache and are subdivided into migraines, tension-
mal examination in routine clinical practice. type headaches (TTH), trigeminal autonomic
Supine CBCT is an alternative imaging method cephalgias (a group which includes cluster head-
but lacks the important soft tissue information aches), and other primary headache disorders
provided by CT. Both modalities can assess (Headache Classification Committee of the Inter-
improvement in the airway by measuring the national Headache Society 2018). There is no
narrowest cross-sectional dimensions and area underlying disease or structural abnormality, and
before and after provision of a MAD or ortho- primary headaches tend to be recurrent and
gnathic surgery. These simple measurements chronic. In contrast, secondary headaches are
provide the closest correlation with the AHI due to an underlying disease and may be harmless
(Ogawa et al. 2007; Barkdull et al. 2008). The or dangerous; the latter often have an acute or
site or sites of reduction in dimensions and area subacute presentation.
of the upper airway are most commonly in the
nasal cavity, retropalatal region (upper orophar- Primary Headaches
ynx), and the retroglossal region (junction of the Obtaining an accurate headache history is the
inferior oropharynx and the hypopharynx). In cornerstone of diagnosis. This should elicit the
244 A. Whyte et al.
site, nature, associated symptoms, frequency, of outpatients with headache were scanned at an
duration, and precipitating and relieving factors. annual cost of $1 billion (Callaghan et al. 2014).
Usually the history allows distinction between the Other concerns are the risk from radiation from
two most common types of headache, TTH and the use of CT scans and the detection of incidental
migraine, although it is widely accepted that the findings which may lead to further investigations,
two conditions may overlap and form a contin- cost, and patient anxiety.
uum. A relevant physical examination is also Atypical symptoms, such as exacerbation of
mandatory. the headache by exertion or straining and change
Imaging has a limited role to play in making in the pattern or increased severity of headaches,
the diagnosis of the majority of primary head- are indications for imaging of primary head-
aches. Provided that the clinical examination is aches. Trigeminal autonomic headaches are
normal and that there are no concerning symp- uncommon; neuroimaging should be performed
toms to suggest a diagnosis other than TTH or as a proportion will have underlying structural
migraine, the yield from routine imaging of the pathology (Favier et al. 2007), most commonly
brain in patients with chronic headache is pituitary tumors, meningiomas, and aneurysms
extremely low. The incidence of significant abnor- (Fig. 69).
malities on imaging in three large review studies Despite reassurance that chronic headache is
was 1–3%, a comparable yield to that seen in not life-threatening and highly unlikely to be due
patients without headaches. Despite multiple to a serious underlying cause, patients may still
guidelines recommending against routine imaging insist on undergoing imaging to exclude a demon-
of patients with chronic headache, the use of strable cause for their symptoms. CT is widely
imaging is increasing in the USA. In 2014, 12% used by primary care physicians but MRI is the
Fig. 69 Meningioma of the cavernous sinus associated (red arrows). The tumor abuts and mildly displaces the
with narrowing of the internal carotid artery (ICA). Coro- pituitary gland (asterisk), which shows minimally less
nal post-gadolinium T1-weighted MRI with fat saturation enhancement than it. Reconstruction of the arteries of the
(a) showing an enhancing mass (white arrows) filling and circle of Willis from a time-of-flight MR angiogram
expanding the left cavernous sinus, and surrounding and (b) again shows narrowing of the left ICA (dotted arrow)
narrowing the cavernous segment of the ICA, which (Images courtesy of Dr Jolandi van Heerden, Perth Radio-
appears as a flow void, smaller than its right counterpart logical Clinic, Perth WA, Australia)
optimal study because of its higher contrast • A cerebral mass, hematoma, suspected infarct,
resolution and the absence of radiation when com- edema, and imaging signs of raised intracranial
pared to CT. If necessary, noninvasive MR angi- pressure
ography or venography can also be performed • Dilatation (hydrocephalus), compression, or
during the same examination. shift of the cerebral ventricles
• Evidence of intracranial or extracranial infec-
Secondary Headaches tion, including the paranasal sinuses, dentition,
A headache is secondary when it is caused by upper neck, and orbits
another condition. Warning symptoms and signs
that should alert clinicians to the diagnosis of a In patients presenting with an abrupt onset of
secondary headache are commonly called “red severe headache (a so-called thunderclap head-
flags” (Holle and Obermann 2013): ache), CT has 100% sensitivity and specificity
for the diagnosis of subarachnoid hemorrhage if
• First or worst headache performed within 6 h of the onset of the headache
• Abrupt onset without warning or progression (Perry et al. 2011). If subarachnoid hemorrhage is
• Fundamental change in the pattern of recurrent detected, patients may undergo CT angiography
headaches (CTA) to confirm or exclude an aneurysm
• Headaches commencing at unusual ages: (Fig. 70) or less commonly other types of vascular
5 years old and 50 years old abnormalities. Open surgery (craniotomy and sur-
• Failure to respond to appropriate therapy gical clipping of an aneurysm) and an endo-
• The presence of cancer, pregnancy, or HIV vascular procedure (coiling or embolisation) are
• Headaches exacerbated by coughing, sneez- the main therapeutic options.
ing, or straining CT also remains the mainstay of imaging for
• Headache onset: with seizure or syncope suspected acute stroke. It is fast, inexpensive,
• Headache onset: with exertion, sex, or a and readily available but has limited sensitivity
Valsalva maneuver in the acute setting. In the first 6 h following
• Abnormal physical examination: signs of arterial occlusion, it will detect 65–70% of
infection, altered level of consciousness, infarcts (Lev et al. 1999) (Fig. 71a). CTA can
signs of meningeal irritation, evidence of also demonstrate arterial stenosis or occlusion in
raised intracranial pressure, and focal neuro- acute stroke prior to thrombolytic therapy: a
logical signs proven technique for re-establishing perfusion
of the affected tissue thereby reversing or
Patients with secondary headache and an minimizing the ischemic sequelae of arterial
abnormal neurological examination are far more occlusion.
likely to have significant cerebral pathology dem- MRI is less widely available and is a much
onstrated by CT or MRI than those who have a slower imaging technique. The high magnetic
normal neurological examination. field and relatively narrow bore of the magnet
The majority of patients with “red flags” will raise more problems for monitoring of acutely ill
present to emergency departments and will patients. MRI is used to clarify the findings on
undergo CT of the brain as an integral and expe- CT on patients presenting with an acute onset
dited part of their assessment. Key imaging find- of secondary headache. In addition, it will not
ings include: uncommonly show relevant pathology when
non-contrast CT is negative. Diffusion-weighted
• Skull vault, skull base, or facial bone fractures imaging (DWI) is a rapid addition to the conven-
(despite no history of trauma) tional scan (Fig. 71b) and should always be
• Extradural, subdural, or subarachnoid performed when cranial MRI is undertaken
hemorrhage (Fig. 71c). It has a sensitivity and specificity of
246 A. Whyte et al.
Fig. 70 Sudden onset of a “thunderclap” headache in a subsequent CT angiogram in the frontal (c) and lateral
41-year-old female. A CT scan performed within 2 h of the projections (d) show a large saccular aneurysm projecting
event (a) shows hyperdense subarachnoid hemorrhage in inferiorly from the anterior communicating artery of the
the Sylvian fissures (dotted white arrows). Focal hyper- circle of Willis (open red arrows). ICA = internal carotid
dense hemorrhage (dotted white oval) is present in the artery (Images courtesy of Dr Jolandi van Heerden, Perth
suprasellar cistern (b). 3D reconstructions from a Radiological Clinic, Perth WA, Australia)
88–100% for the detection of stroke up to 7 days after injection of intravenous contrast are used
following the ischemic event (Srinivasan et al. (Fig. 72). Calcification within mass lesions is
2006). MR angiography can evaluate the flow also shown more clearly with CT than with
and morphology of intracranial arteries without MRI.
the need for intravenous injection of contrast
(Fig. 71d). Painful Cranial Neuropathies, Other
MRI has improved sensitivity and specificity Facial Pains, and Other Headaches
for the detection of other potential causes of For those patients thought to have a headache
secondary headache as compared with CT, which is in the third category of the ICHD classi-
with the exception of acute parenchymal or sub- fication, imaging has a definite role. Cranial nerve
arachnoid hemorrhage. CT remains a very use- neuralgias (most commonly involving the trigem-
ful technique especially when scans before and inal and glossopharyngeal nerves) and central and
Fig. 71 Acute infarct in the distribution of the right pos- to about 14 days after arterial occlusion. Time-of-flight
terior cerebral artery. Non-contrast CT (a) demonstrates a angiography of the circle of Willis (d) can be performed
wedge-shaped hypodense lesion in the right parietal and without injection of contrast. The right posterior cerebral
occipital lobes (dotted arrows). The infarct is hyperintense arteries (PCA) are patent and symmetric suggesting throm-
on T2-weighted MRI (b). On a diffusion-weighted image: bolysis of the clot or embolus which initially caused the
DWI (c), the acute infarct is hyperintense, in keeping with infarct (Images courtesy of Dr Jolandi van Heerden, Perth
restricted diffusion. Restricted diffusion, primarily due to Radiological Clinic, Perth WA, Australia)
cellular swelling, is seen in infarcts almost immediately, up
primary facial pain are imaged with high- To maximize the yield from this dedicated
resolution pre- and post-contrast MRI including investigation, the radiologist interpreting and
MR angiography. A dedicated and comprehensive reporting the study should have a comprehensive
study of this type allows evaluation of the possible understanding of anatomy and pathology involv-
central, skull base, and peripheral causes of neu- ing the brain, skull base, maxillofacial region, and
ralgia and pain. neck. CT (either multidetector or cone beam) and
248 A. Whyte et al.
Fig. 72 High-grade malignant glioma (glioblastoma dilated. Following contrast (b), the tumor enhances (dotted
multiforme). Non-contrast CT (a) demonstrates a mass in oval) and contains abnormal vessels. A coronal reconstruc-
the right cerebral hemisphere (dotted arrows). tion (c) from the post-contrast study also shows the dis-
Low-density edema is present around the tumor (solid placement of the midline to the left and the dilated left
arrows). There is compression and deviation of the ven- lateral ventricle (LV) (Images courtesy of Dr Jolandi van
tricular midline to the left (open arrow), resulting in Heerden, Perth Radiological Clinic, Perth WA, Australia)
obstruction of the left lateral ventricle (LV) which is
panoramic tomography have a role in evaluating et al. 2013). It has long been hypothesized that
osseous structures such as the skull base, para- these changes represent chronic small vessel cere-
nasal sinuses, midface, mandible, and dentition. brovascular disease. There is conflicting evidence
as to whether these white matter changes progress
Insights into the Pathogenesis with time.
of Headache from Structural Functional imaging has established the exis-
and Functional Imaging tence of a “pain matrix” consisting of specific
There is strong evidence that migraine is a risk regions in the cerebral hemispheres, thalami, and
factor for structural changes in the brain including brain stem which form a network which is acti-
white matter abnormalities and silent infarct-like vated by nociceptive stimuli. This was discussed
lesions. These are more common when the in the preceding section on the imaging of
migraine attack is preceded by an aura (Bashir facial pain.
Research using positron emission tomography examination, and aid the choice of optimal
(PET) and functional MRI (fMRI) has provided treatment.
new insights into the pathogenesis of headache, A basic understanding of the benefits, limita-
especially migraine and the trigeminal autonomic tions, and risks of different imaging techniques is
cephalgias (May 2009). These headaches are now essential for the specialist in oral medicine to
thought to neurovascular, rather than purely vas- avoid inappropriate investigations. This is espe-
cular in origin. Trigeminal innervation of cranial cially true for imaging involving ionizing radia-
vessels, especially the ophthalmic division (V1), tion; the potential benefit of an imaging test
leads to significant vasodilation. Pain, per se, trig- should always outweigh the potential risk.
gers changes in vessel caliber and not vice versa. Optimal results from imaging are achieved by
The brain stem has a crucial role in the etiology close liaison with a radiologist specializing in max-
of acute and chronic migraine. Activation of the illofacial and head and neck imaging. A wide range
dorsal aspect of the pons occurs in migraine; if the of pathology that can occur in this complex anatom-
headache is unilateral, activation is unilateral, and ical region has been illustrated in this chapter.
bilateral activation is seen with bilateral headache. The benefits of ultrasound as the initial imag-
Increase in cortical blood flow seen in migraine is ing investigation for many clinical conditions are
a consequence of this subcortical activation. An recognized by head and neck surgeons, and
aura precedes the migraine attack in 15–30% of should play a more important role in oral medicine
cases; decrease in cortical blood flow (“cortical in the future. The absence of soft tissue contrast
spreading depression”) occurs, especially in the is a significant disadvantage of cone beam CT
occipital lobes, and is associated with visual phe- imaging; computed tomography and magnetic
nomena. Patients with migraine with aura are at resonance imaging remain the mainstay of com-
increased risk of stroke as compared with patients prehensive cross-sectional evaluation when ultra-
without aura or control subjects; overall, there is a sound is not indicated or when further information
twofold increase in stroke in patients with is required.
migraine (Lee et al. 2016). Functional magnetic resonance imaging is an
In contrast, activation of the hypothalamus is important research tool that has improved under-
the specific and key factor involved in the etiology standing of the pathogenesis of chronic and neuro-
of trigeminal autonomic headaches. Functional pathic facial pain. In the future, this technique
imaging of patients with cluster headache led to should have a major role in classifying patients
successful deep stimulation of this area, and this is with facial pain, developing new pharmacological
now a recognized treatment option. approaches to treatment and assessing treatment
Using the MRI technique of voxel-based mor- response.
phometry (VBM), decrease in gray matter volume
in pain-processing areas has been demonstrated in Acknowledgment The authors acknowledge Dr Andrew
patients with the commonest forms of headache: Patrikeos (MBBS, MRCP(UK), FRANZCR,
migraine and TTH. This is presumably the result ANZAPNM), Perth Radiological Clinic, for advice and
input on nuclear medicine techniques.
of repeated and chronic nociceptive input (i.e., pain)
as the severity of cortical loss is proportional to the
duration of headaches.
Cross-References
▶ Arthritic Conditions Affecting the Temporo-

Conclusions and Future Directions mandibular Joint
▶ Clinical Evaluation of Oral Diseases
Imaging is an important adjunct to clinical exam- ▶ Clinical Evaluation of Orofacial Pain
ination. It can confirm or refute a suspected diag- ▶ Head and Neck Tumors
nosis, reveal pathology not evident on clinical ▶ Headache
250 A. Whyte et al.
▶ Internal Derangements of the Temporomandib- Avril L, Lombardi T, Ailianou A, Burkhardt K,

ular Joint Varoquaux A, Scolozzi P, Becker M. Radiolucent
lesions of the mandible: a pattern-based approach to
▶ Non-odontogenic Bone Pathology diagnosis. Insights Imaging. 2014;5(1):85–101.
▶ Odontogenic Pathology Barkdull GC, Kohl CA, Patel M, Davidson TM. Computed
▶ Oral Mucosal Malignancies tomography imaging of patients with obstructive sleep
▶ Pediatric Oral Medicine apnea. Laryngoscope. 2008;118(8):1486–92.
Bashir A, Lipton RB, Ashina S, Ashina M. Migraine and
▶ Orofacial Pain and Sleep structural changes in the brain: a systematic review and
▶ Salivary Gland Disorders and Diseases meta-analysis. Neurology. 2013;81(14):1260–8.
▶ Sleep Bruxism Baulch J, Gandhi M, Sommerville J, Panizza B. 3T MRI
▶ Soft and Hard Tissue Operative Investigations evaluation of large nerve perineural spread of head and
neck cancers. J Med Imaging Radiat Oncol.
in the Diagnosis and Treatment of Oral 2015;59(5):578–85.
Disease Berenbaum F. Osteoarthritis as an inflammatory disease
(osteoarthritis is not osteoarthrosis!). Osteoarthr
Cartil/OARS, Osteoarthr Res Soc. 2013;21(1):16–21.
Boeddinghaus R, Whyte A. Current concepts in maxillo-
References facial imaging. Eur J Radiol. 2008;66(3):396–418.
Boeddinghaus R, Whyte A. Computed tomography of the
Australian Radiation Protection and Nuclear Safety Agency. temporomandibular joint. J Med Imaging Radiat
Radiation protection and health [Internet]. 2015 Oncol. 2013;57(4):448–54.
[updated 2015 September 25; cited 2017 June 08]. Brown EC, Cheng S, McKenzie DK, Butler JE,
Available from http://www.arpansa.gov.au/Radiation Gandevia SC, Bilston LE. Tongue stiffness is lower in
Protection/Factsheets/is_ionising.cfm. patients with obstructive sleep apnea during wakeful-
Abdullah A, Rivas FF, Srinivasan A. Imaging of the sali- ness compared with matched control subjects. Sleep.
vary glands. Semin Roentgenol. 2013;48(1):65–74. 2015;38(4):537–44.
Ahmad M, Hollender L, Anderson Q, Kartha K, Buchanan A, Cohen R, Looney S, Kalathingal S, De
Ohrbach R, Truelove EL, John MT, Schiffman EL. Rossi S. Cone-beam CT analysis of patients with
Research criteria for temporomandibular disorders: obstructive sleep apnea compared to normal controls.
development of image analysis criteria and examiner Imaging Sci Dent. 2016;46(1):9–16.
reliability for image analysis. Oral Surg Oral Med Oral Burke CJ, Thomas RH, Howlett D. Imaging the major
Pathol Oral Radiol Endod. 2009;107(6): 844–60. salivary glands. Br J Oral Maxillofac Surg.
Ali T. Neck lymph nodes: characterization with diffusion- 2011;49(4):261–9.
weighted MRI. Egypt J Radiol Nucl Med. Callaghan BC, Kerber KA, Pace RJ, Skolarus LE,
2012;43(2):173–81. Burke JF. Headaches and neuroimaging: high utiliza-
Alkureishi LW, Ross GL, Shoaib T, Soutar DS, tion and costs despite guidelines. JAMA Intern Med.
Robertson AG, Thompson R, Hunter KD, 2014;174(5):819–21.
Sorensen JA, Thomsen J, Krogdahl A, Alvarez J, Camacho M, Capasso R, Schendel S. Airway changes in
Barbier L, Santamaria J, Poli T, Sesenna E, obstructive sleep apnoea patients associated with a
Kovacs AF, Grunwald F, Barzan L, Sulfaro S, supine versus an upright position examined using
Alberti F. Sentinel node biopsy in head and neck squa- cone beam computed tomography. J Laryngol Otol.
mous cell cancer: 5-year follow-up of a European mul- 2014;128(9):824–30.
ticenter trial. Ann Surg Oncol. 2010;17(9):2459–64. Cantrell SC, Peck BW, Li G, Wei Q, Sturgis EM,
Alsufyani NA, Flores-Mir C, Major PW. Three- Ginsberg LE. Differences in imaging characteristics
dimensional segmentation of the upper airway using of HPV-positive and HPV-negative oropharyngeal can-
cone beam CT: a systematic review. Dentomaxillofac cers: a blinded matched-pair analysis. AJNR Am J
Radiol. 2012;41(4):276–84. Neuroradiol. 2013;34(10):2005–9.
Alsufyani NA, Al-Saleh MAQ, Major PW. CBCT assess- Casselman JW, Gieraerts K, Volders D, Delanote J,
ment of upper airway changes and treatment outcomes Mermuys K, De Foer B, Swennen G. Cone beam CT:
of obstructive sleep apnoea: a systematic review. Sleep non-dental applications. JBR-BTR. 2013;96(6):
Breath. 2013;17(3):911–23. 333–53.
Arya S, Rane P, Sable N, Juvekar S, Bal M, Chaukar D. Castaldi P, Leccisotti L, Bussu F, Micciche F, Rufini V.
Retromolar trigone squamous cell cancers: a Role of (18)F-FDG PET-CT in head and neck squa-
reappraisal of 16 section MDCT for assessing mandib- mous cell carcinoma. Acta Otorhinolaryngol Ital.
ular invasion. Clin Radiol. 2013;68(12):e680–8. 2013;33(1):1–8.
Arya S, Rane P, Deshmukh A. Oral cavity squamous cell Chen RC, Khorsandi AS, Shatzkes DR, Holliday RA. The
carcinoma: role of pretreatment imaging and its influ- radiology of referred otalgia. AJNR Am J Neuroradiol.
ence on management. Clin Radiol. 2014;69(9):916–30. 2009;30(10):1817–23.
Choi JW, Kim HJ, Kim J, Kim HJ, Cha JH, Kim ST. and MR imaging manifestations. Radiographics.
Spindle cell lipoma of the head and neck: CT and MR 2012;32(7):1945–58.
imaging findings. Neuroradiology. 2013;55(1):101–6. Gadodia A, Seith A, Sharma R, Thakar A. MRI and MR
Cure JK, Vattoth S, Shah R. Radiopaque jaw lesions: an sialography of juvenile recurrent parotitis. Pediatr
approach to the differential diagnosis. Radiographics. Radiol. 2010;40(8):1405–10.
2012;32(7):1909–25. Gamss C, Gupta A, Chazen JL, Phillips CD. Imaging
De Vos W, Casselman J, Swennen GRJ. Cone-beam com- evaluation of the suprahyoid neck. Radiol Clin N Am.
puterized tomography (CBCT) imaging of the oral and 2015;53(1):133–44.
maxillofacial region: a systematic review of the litera- Genta PR, Schorr F, Eckert DJ, Gebrim E, Kayamori F,
ture. Int J Oral Maxillofac Surg. 2009;38(6):609–25. Moriya HT, Malhotra A, Lorenzi-Filho G. Upper air-
Deshpande SS, Thakur MH, Dholam K, Mahajan A, way collapsibility is associated with obesity and hyoid
Arya S, Juvekar S. Osteoradionecrosis of the mandible: position. Sleep. 2014;37(10):1673–8.
through a radiologist’s eyes. Clin Radiol. 2015; Guneyli S, Ceylan N, Bayraktaroglu S, Acar T, Savas R.
70(2):197–205. Imaging findings of vascular lesions in the head
DeSouza DD, Hodaie M, Davis KD. Abnormal trigeminal and neck. Diagn Interv Radiol (Ankara, Turkey).
nerve microstructure and brain white matter in 2014;20(5):432–7.
idiopathic trigeminal neuralgia. Pain. 2014;155(1): Gungor AY, Turkkahraman H, Yilmaz HH, Yariktas M.
37–44. Cephalometric comparison of obstructive sleep
DeSouza DD, Davis KD, Hodaie M. Reversal of insular apnea patients and healthy controls. Eur J Dent.
and microstructural nerve abnormalities following 2013;7(1):48–54.
effective surgical treatment for trigeminal neuralgia. Hasan NMA, Abdelrahman TEF. MRI evaluation of TMJ
Pain. 2015;156(6):1112–23. internal derangement: degree of anterior disc displace-
Devenney-Cakir B, Subramaniam RM, Reddy SM, ment correlated with other TMJ soft tissue and
Imsande H, Gohel A, Sakai O. Cystic and cystic- osseous abnormalities. Egypt J Radiol Nucl Med.
appearing lesions of the mandible: review. AJR Am J 2014;45(3):735–44.
Roentgenol. 2011;196(6 Suppl):WS66–77. Hatcher DC. Progressive condylar resorption: pathologic
Dunfee BL, Sakai O, Pistey R, Gohel A. Radiologic processes and imaging considerations. Semin Orthod.
and pathologic characteristics of benign and malig- 2013;19(2):97–105.
nant lesions of the mandible. Radiographics. Headache Classification Committee of the International
2006;26(6):1751–68. Headache Society. The International classification of
Enciso R, Nguyen M, Shigeta Y, Ogawa T, Clark GT. headache disorders, 3rd edition. Cephalalgia. 2018;
Comparison of cone-beam CT parameters and sleep 38(1):1–211.
questionnaires in sleep apnea patients and control sub- Hendee WR, O’Connor MK. Radiation risks of medical
jects. Oral Surg Oral Med Oral Pathol Oral Radiol imaging: separating fact from fantasy. Radiology.
Endod. 2010;109(2):285–93. 2012;264(2):312–21.
Enders J, Zimmermann E, Rief M, Martus P, Holle D, Obermann M. The role of neuroimaging in the
Klingebiel R, Asbach P, Klessen C, Diederichs G, diagnosis of headache disorders. Ther Adv Neurol
Bengner T, Teichgraber U, Hamm B, Dewey Disord. 2013;6(6):369–74.
M. Reduction of claustrophobia during magnetic res- Hughes MA, Frederickson AM, Branstetter BF, Zhu X, Sekula
onance imaging: methods and design of the RF Jr. MRI of the trigeminal nerve in patients with trigem-
"CLAUSTRO" randomized controlled trial. BMC inal neuralgia secondary to vascular compression. AJR
Med Imaging. 2011;11:4. Am J Roentgenol. 2016;206(3):595–600.
Farina D, Bodin C, Gandolfi S, De Gasperi W, Jaber JJ, Leonetti JP, Lawrason AE, Feustel PJ. Cervical
Borghesi A, Maroldi R. TMJ disorders and pain: spine causes for referred otalgia. Otolaryngol Head
assessment by contrast-enhanced MRI. Eur J Radiol. Neck Surg. 2008;138(4):479–85.
2009;70(1):25–30. Kanda T, Ishii K, Kawaguchi H, Kitajima K, Takenaka D.
Favier I, van Vliet JA, Roon KI, Witteveen RJW, High signal intensity in the dentate nucleus and globus
Verschuuren JJGM, Ferrari MD, Haan J. Trigeminal pallidus on unenhanced T1-weighted MR images: rela-
autonomic cephalgias due to structural lesions: a tionship with increasing cumulative dose of a
review of 31 cases. Arch Neurol. 2007;64(1):25–31. gadolinium-based contrast material. Radiology.
Filippi M, Rocca MA, Ciccarelli O, De Stefano N, 2014;270(3):834–41.
Evangelou N, Kappos L, Rovira A, Sastre-Garriga J, Kiesler K, Gugatschka M, Friedrich G. Incidence and
Tintore M, Frederiksen JL, Gasperini C, Palace J, clinical relevance of herniation of the mylohyoid mus-
Reich DS, Banwell B, Montalban X, Barkhof F, M. S. cle with penetration of the sublingual gland. Eur Arch
Group. MRI criteria for the diagnosis of multiple scle- Otorhinolaryngol. 2007;264(9):1071–4.
rosis: MAGNIMS consensus guidelines. Lancet Kim DS, Cheang P, Dover S, Drake-Lee AB. Dental
Neurol. 2016;15(3):292–303. otalgia. J Laryngol Otol. 2007;121(12):1129–34.
Fujita A, Sakai O, Chapman MN, Sugimoto H. IgG4- Kim AM, Keenan BT, Jackson N, Chan EL, Staley B,
related disease of the head and neck: CT Poptani H, Torigian DA, Pack AI, Schwab RJ. Tongue
252 A. Whyte et al.
fat and its relationship to obstructive sleep apnea. Mirghani H, Amen F, Moreau F, Lacau St Guily J. Do
Sleep. 2014;37(10):1639–48. high-risk human papillomaviruses cause oral cavity
Kirkness JP, Sowho M, Murano E. The interplay between squamous cell carcinoma? Oral Oncol. 2015;51(3):
tongue tissue volume, hyoid position, and airway 229–36.
patency. Sleep. 2014;37(10):1585–6. Mittal MK, Malik A, Sureka B, Thukral BB. Cystic masses
La’porte SJ, Juttla JK, Lingam RK. Imaging the floor of the of neck: a pictorial review. Indian J radiol Imaging.
mouth and the sublingual space. Radiographics. 2012;22(4):334–43.
2011;31(5):1215–30. Mohammed Y, Saeed O, Zaghloulb N, Samerc S,
Larheim TA, Abrahamsson AK, Kristensen M, Arvidsson Mahmudd S, Abdulah A. Juvenile idiopathic
LZ. Temporomandibular joint diagnostics using CBCT. arthritis and the temporomandibular joint. Alex J
Dentomaxillofac Radiol. 2015;44(1):20140235. Med. 2012;48(2):123–9.
Leclercq D, Thiebaut JB, Heran F. Trigeminal neuralgia. Moisset X, Villain N, Ducreux D, Serrie A, Cunin G,
Diagn Interv Imaging. 2013;94(10):993–1001. Valade D, Calvino B, Bouhassira D. Functional
Lee MJ, Lee C, Chung C-S. The migraine-stroke connec- brain imaging of trigeminal neuralgia. Eur J Pain.
tion. J stroke. 2016;18(2):146–56. 2011;15(2):124–31.
Lev MH, Farkas J, Gemmete JJ, Hossain ST, Hunter GJ, Ngu RK, Brown JE, Whaites EJ, Drage NA, Ng SY,
Koroshetz WJ, Gonzalez RG. Acute stroke: improved Makdissi J. Salivary duct strictures: nature and inci-
nonenhanced CT detection–benefits of soft-copy inter- dence in benign salivary obstruction. Dentomaxillofac
pretation by using variable window width and center Radiol. 2007;36(2):63–7.
level settings. Radiology. 1999;213(1):150–5. Ogawa T, Enciso R, Shintaku WH, Clark GT. Evaluation of
Ludlow JB, Ivanovic M. Comparative dosimetry of dental cross-section airway configuration of obstructive sleep
CBCT devices and 64-slice CT for oral and maxillofa- apnea. Oral Surg Oral Med Oral Pathol Oral Radiol
cial radiology. Oral Surg Oral Med Oral Pathol Oral Endod. 2007;103(1):102–8.
Radiol Endod. 2008;106(1):106–14. Palconet G, Ludlow JB, Tyndall DA, Lim PF. Correlating
Lustmann J, Regev E, Melamed Y. Sialolithiasis. A survey cone beam CT results with temporomandibular joint
on 245 patients and a review of the literature. Int J Oral pain of osteoarthritic origin. Dentomaxillofac Radiol.
Maxillofac Surg. 1990;19(3):135–8. 2012;41(2):126–30.
MacDonald DS. Maxillofacial fibro-osseous lesions. Clin Payne KF, Haq J, Brown J, Connor S. The role of diffusion-
Radiol. 2015;70(1):25–36. weighted magnetic resonance imaging in the diagnosis,
Mansfield DR, Antic NA, McEvoy RD. How to assess, lymph node staging and assessment of treatment
diagnose, refer and treat adult obstructive sleep apnoea: response of head and neck cancer. Int J Oral Maxillofac
a commentary on the choices. Med J Aust. Surg. 2015;44(1):1–7.
2013;199(8):S21–6. Pearce MS, Salotti JA, Little MP, McHugh K,
Mathews JD, Forsythe AV, Brady Z, Butler MW, Lee C, Kim KP, Howe NL, Ronckers CM,
Goergen SK, Byrnes GB, Giles GG, Wallace AB, Rajaraman P, Sir Craft AW, Parker L, Berrington de
Anderson PR, Guiver TA, McGale P, Cain TM, Gonzalez A. Radiation exposure from CT scans in
Dowty JG, Bickerstaffe AC, Darby SC. Cancer risk in childhood and subsequent risk of leukaemia and brain
680,000 people exposed to computed tomography tumours: a retrospective cohort study. Lancet.
scans in childhood or adolescence: data linkage study 2012;380(9840):499–505.
of 11 million Australians. BMJ. 2013;346:f2360. Perry JJ, Stiell IG, Sivilotti MLA, Bullard MJ, Emond M,
May A. New insights into headache: an update on func- Symington C, Sutherland J, Worster A, Hohl C, Lee JS,
tional and structural imaging findings. Nat Rev Neurol. Eisenhauer MA, Mortensen M, Mackey D, Pauls M,
2009;5(4):199–209. Lesiuk H, Wells GA. Sensitivity of computed tomog-
McDonald RJ, McDonald JS, Kallmes DF, Jentoft ME, Mur- raphy performed within six hours of onset of headache
ray DL, Thielen KR, Williamson EE, Eckel LJ. Intracra- for diagnosis of subarachnoid haemorrhage: prospec-
nial gadolinium deposition after contrast-enhanced MR tive cohort study. BMJ (Clinical research ed).
imaging. Radiology. 2015;275(3):772–82. 2011;343:d4277.
Mehra P, Jeong D. Maxillary sinusitis of odontogenic Petscavage-Thomas JM, Walker EA. Unlocking the jaw:
origin. Curr Infect Dis Rep. 2008;10(3):205–10. advanced imaging of the temporomandibular joint.
Menon S, Venkatswamy S, Ramu V, Banu K, Ehtaih S, AJR Am J Roentgenol. 2014;203(5):1047–58.
Kashyap VM. Craniofacial fibrous dysplasia: surgery Purohit BS, Ailianou A, Dulguerov N, Becker CD,
and literature review. Ann Maxillofac Surg. Ratib O, Becker M. FDG-PET/CT pitfalls in oncolog-
2013;3(1):66–71. ical head and neck imaging. Insights Imaging.
Miao LY, Xue H, Ge HY, Wang JR, Jia JW, Cui LG. 2014;5(5):585–602.
Differentiation of pleomorphic adenoma and Ringold S, Cron RQ. The temporomandibular joint in
Warthin’s tumour of the salivary gland: is long-to- juvenile idiopathic arthritis: frequently used and fre-
short diameter ratio a useful parameter? Clin Radiol. quently arthritic. Pediatr Rheumatol Online J.
2015;70(11):1212–9. 2009;7:11.
Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Vitali C, Carotti M, Salaffi F. Is it the time to adopt salivary
Aghaloo T, Mehrotra B, O’Ryan F. American Association gland ultrasonography as an alternative diagnostic tool
of Oral and Maxillofacial Surgeons position paper on for the classification of patients with Sjogren’s syn-
medication-related osteonecrosis of the jaw – 014 update. drome? Comment on the article by Cornec et al. Arthri-
J Oral Maxillofac Surg Official J American Assoc Oral tis Rheum. 2013;65(7):1950.
and Maxillofac Surg. 2014;72(10):1938–56. Westesson PL, Katzberg RW, Tallents RH, Sanchez-
Saito N, Nadgir RN, Nakahira M, Takahashi M, Woodworth RE, Svensson SA. CT and MR
Uchino A, Kimura F, Truong MT, Sakai of the temporomandibular joint: comparison with
O. Posttreatment CT and MR imaging in head and autopsy specimens. AJR Am J Roentgenol.
neck cancer: what the radiologist needs to know. 1987;148(6):1165–71.
Radiographics: A Review Publication of the Radio- Whyte A, Chapeikin G. Opaque maxillary antrum: a pic-
logical Society of North America, Inc. 2012;32(5): torial review. Australas Radiol. 2005;49(3):203–13.
1261–82. discussion 1282–1264 Whyte AM, McNamara D, Rosenberg I, Whyte AW.
Scrivani SJ, Becerra L, DaSilva A, Moulton E, Pendse G, Magnetic resonance imaging in the evaluation
Morris S, Aiello-Lammens M, Borsook D. Functional of temporomandibular joint disc displacement–a
brain imaging of facial pain: functional magnetic reso- review of 144 cases. Int J Oral Maxillofac Surg.
nance imaging (FMRI) studies of the trigeminal sys- 2006;35(8):696–703.
tem. Oral Surg Oral Med Oral Pathol Oral Radiol Woo EK, Connor SE. Computed tomography and mag-
Endod. 2007;103(6):795. netic resonance imaging appearances of cystic
Scrivani SJ, Keith DA, Kaban LB. Temporomandibular lesions in the suprahyoid neck: a pictorial review.
disorders. N Engl J Med. 2008;359(25):2693–705. Dentomaxillofac Radiol. 2007;36(8):451–8.
Srinivasan A, Goyal M, Al Azri F, Lum C. State-of-the-art Yabuuchi H, Fukuya T, Tajima T, Hachitanda Y, Tomita K,
imaging of acute stroke. Radiographics: A Review Koga M. Salivary gland tumors: diagnostic value
Publication of the Radiological Society of North Amer- of gadolinium-enhanced dynamic MR imaging
ica, Inc. 2006;26(Suppl 1):S75–95. with histopathologic correlation. Radiology.
Sumi M, Ichikawa Y, Katayama I, Tashiro S, Nakamura T. 2003;226(2):345–54.
Diffusion-weighted MR imaging of ameloblastomas Yesuratnam A, Wiesenfeld D, Tsui A, Iseli TA, Hoorn SV,
and keratocystic odontogenic tumors: differentiation Ang MT, Guiney A, Phal PM. Preoperative evaluation
by apparent diffusion coefficients of cystic lesions. of oral tongue squamous cell carcinoma with intraoral
AJNR Am J Neuroradiol. 2008;29(10):1897–901. ultrasound and magnetic resonance imaging-
Thoeny HC, De Keyzer F, King AD. Diffusion-weighted comparison with histopathological tumour thickness
MR imaging in the head and neck. Radiology. and accuracy in guiding patient management. Int J
2012;263(1):19–32. Oral Maxillofac Surg. 2014;43(7):787–94.
Laboratory Medicine and Diagnostic
Pathology
Tim Hodgson, Barbara Carey, Emma Hayes, Richeal Ni Riordain,

Priya Thakrar, Sarah Viggor, and Paula Farthing
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256
Hematology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
Full Blood Count . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
Bleeding Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
Clinical Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262
Glucose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262
Liver Biochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262
Renal Biochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
Bone Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
Hematinics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
Fasting Lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
Acute-Phase Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
Fecal Calprotectin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
Zinc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
Serum Angiotensin-Converting Enzyme . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
Immunosuppressive Medication Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
Short SynACTHen Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
Glucose-6-phosphate Dehydrogenase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
Immunology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
C1 Esterase Inhibitor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
Complement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
Human Leucocyte Antigen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
Amyloid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
Indirect Immunofluorescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
T. Hodgson · B. Carey · E. Hayes · R. Ni Riordain ·

P. Thakrar · S. Viggor
Eastman Dental Hospital, London, UK
e-mail: Tim.Hodgson@ucl.ac.uk; barbara.carey@nhs.net;
Emma.Hayes1@nhs.net; r.niriordain@ucl.ac.uk;
Priya.thakrar@nhs.net; Sarah.Viggor@uclh.nhs.uk
P. Farthing (*)
School of Clinical Dentistry, University of Sheffield,
Sheffield, UK
e-mail: p.farthing@sheffield.ac.uk

https://doi.org/10.1007/978-3-319-72303-7_4
256 T. Hodgson et al.
Immunoglobulins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273
Autoantibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
Microbiology and Serology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
Syphilis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
Mycobacterium tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
Mycoplasma pneumoniae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
Toxoplasma gondii . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278
Methicillin-Resistant Staphylococcus aureus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278
Brucellosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278
Candida Culture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278
Pathological Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
Laboratory Processing of Biopsy Specimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284
Histopathological Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
Application of Molecular Biology Techniques in Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
Interpretation of Biopsy Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
Precision Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
Abstract basis for accurate and meaningful diagnosis

Laboratory tests play an important role in and management strategies in oral medicine.
clinical diagnosis, and the results often
direct patient management. Tests should be Keywords
requested appropriately in order to refine the Diagnostic tests · Laboratory tests · Laboratory
differential diagnosis, and it is important to investigations · Oral disease · Hematology,
understand the theoretical basis of such tests Clinical chemistry · Histopathology ·
and to be able to interpret their findings. This Immunology · Microbiology · Anatomic
chapter covers the common laboratory tests pathology · Diagnostic pathology · In vitro
that may be requested in clinical oral medicine diagnostics · Molecular pathology · Precision
including hematology, clinical chemistry, medicine · Personalized medicine
immunology, and pathological investigations.
The reasoning behind the use of such tests in
diagnosis is explained, together with their Introduction
interpretation and relevance to diseases
affecting the oral and maxillofacial complex. Diagnostic tests are important aids to medical care
A more precision-based approach to clinical delivery, defined as investigations performed on
care is being mirrored in oral medicine by samples taken from the body used in a broad range
tailored laboratory investigations relying on of applications. These tests may be referred to as
molecular pathology approaches such as next- “in vitro diagnostics.” Results can be used to
generation sequencing. These will soon make assist the patient, physician, and caregiver in
their way into clinical practice and transform decision-making. Depending on the test and
patient care, so it is imperative that clinicians the methods used, testing can be performed in a
keep up to date with advances in technology, laboratory, at the hospital bedside, in the clini-
techniques, and their underlying scientific cian’s office, in the clinic, in the workplace, and
Laboratory Medicine and Diagnostic Pathology 257
even at home. Diagnostic tests may be the least will usually sacrifice sensitivity by increasing its
expensive component of the care pathway, but false-negative rate. This makes a highly sensitive
they influence more than 70% of healthcare deci- test ideal for a screening examination. Highly
sions. All tests should be requested by the physi- specific tests are best utilized in a confirmatory
cian to answer a specific question. The requesting role. Test results are not always easily interpreted.
clinician should make sure the test is fit for pur- Problems arise interpreting the results in the con-
pose, they receive the result in a timely manner, text of the patient or considering the risks or
and they are able to interpret the results in relation consequences for the patient’s treatment.
to the clinical presentation of the patient. From the Discoveries about the human genome have
perspective of health economics, all tests should opened the door to precision medicine approaches
be considered as positive additions to the diagnos- that can tailor medical treatments to individual
tic process. It is not appropriate to order a test as a patient needs, transforming modern medicine.
“general health screen” in an oral medicine clinic. The information provided by diagnostic tests
Diagnostic tests provide objective information informs decisions made throughout the healthcare
about a person’s health. Some tests are used for continuum. Tests can be used to screen for a
risk assessment to determine the likelihood a med- disease or to provide early disease identification,
ical condition is or will become present. Other to diagnose a disease, to provide prognostic infor-
tests are used to monitor the course of a disease mation by assessing the degree of disease progres-
and assess patient response to therapy or guide the sion or severity, to assist in selecting drugs or
selection of further intervention and treatment. targeting medical treatment, and to monitor the
Every clinical encounter begins with an initial course of a disease or condition (Table 1). Tests
clinical impression and a subjective pretest prob- suggested for confirmation of common clinical
ability of disease. The ultimate goal of diagnostic diagnoses relevant to the practice of oral medicine
testing is to refine this pretest probability to the and initiation of systemic immunosuppression are
point where the physician can confidently make detailed in Table 2.
a treat or no-treat decision. Each diagnostic test
results in a change in the physician’s probability
of disease, the posttest probability. Hematology
Most commonly, test results provide informa-
tion that, with the patient’s history and other med- Full Blood Count
ical information, helps the clinician work with the
patient to decide the appropriate actions for addi- Full Blood Count (Complete Blood Count) is
tional testing or treatment. On some occasions, the normally collected in a 5 ml tube anticoagulated
information from a single test is sufficient to pre- with dry potassium EDTA (ethylenediaminete-
vent a cascade of sophisticated medical interven- traacetic acid) or citrate. Blood cells are usually
tions; and sometimes it is what is needed to end automatically analyzed, and blood films are pre-
them. More often, diagnostic tests provide infor- pared from the same sample if indicated by the
mation, along with other tests and observations, history or blood count results.
which help determine whether or not a disease is A full blood count would normally be
present, has progressed, or has changed its course. requested for oral medicine patients presenting
This allows the physician to make a judgment on with:
what treatment regimen might be most appropri-
ate for a particular patient at a given time. 1. Clinical orofacial signs suggestive of anemia:
Different diagnostic tests for the same disease • Persistent or recurrent oral ulceration
often trade sensitivity for specificity or vice • Evidence of angular cheilitis or chronic
versa. In general, the more sensitive a test is for fungal infection
a disease, the higher its false-positive rate, lower- • A persistent sore or burning sensation of the
ing its specificity. A test with a higher specificity mouth
Table 1 The application of diagnostic tests

Test use Purpose Example
Screening, early To detect asymptomatic disease or a Fecal calprotectin inflammatory bowel disease
disease detection predisposition to disease in order to take Blood cholesterol tests/heart disease
action to prevent it by modifying a risk Fecal occult blood tests/colorectal cancer
factor or to treat it earlier
Diagnosis To make a diagnosis when symptoms, Brain natriuretic peptide (BNP) and NT pro-BNP/
abnormalities on physical examination, or heart failure
other evidence suggests, but does not prove, Incisional biopsy for lichen planus
that a disease may be present Direct immunofluorescence for MMP and
pemphigus vulgaris
Disease staging, To determine the extent of disease Testing for comorbidities (e.g., hypertension,
prognosis progression or severity and the likelihood of cardiovascular disease, acute respiratory infection)
recovery or risk of future adverse health Blood clotting tests for presurgical risk assessment
outcomes (e.g., cancer relapse) Cardiac marker testing (e.g., troponin T and I and
CK-MB, myoglobin)/rapid assessment of heart
injury, heart attack
Proteins in Sjógren’s syndrome
Drug selection, To allow accurate and targeted treatment HLA and carbamazepine prescription
treatment selection tailored to individual needs HIV, HBC, and HCV testing prior to
monitoring immunosuppressant prescription e.g., Azathioprine
prescription
Full blood picture liver biochemistry for
immunosuppressant treatment e.g., Azathioprine
monitoring
Disease or To understand the course of the disease or Pemphigus antibody titer for disease response
condition the effect of a therapy in order to evaluate Blood glucose tests and HbA1c tests for diabetes
monitoring and the success of treatment and the need for monitoring
management additional testing or treatment Viral load, CD4 count to assess treatment response
in HIV patients
Cholesterol tests to monitor effectiveness of lipid-
lowering drug therapy
2. Recalcitrant oral disease Anemia is usually caused by one or more of the

3. Clinical signs suggestive of immunosuppres- following:
sion or underlying hematological malignancy
4. Increased oral bleeding or mucosal petechiae • Hemorrhage (blood loss)
(low platelets) • Failure of erythropoiesis (red cell production)
5. Prior to initiation and for monitoring of • Abnormally increased breakdown of red blood
immune-modulating therapy cells (hemolysis)
• Increased plasma volume (pregnancy)
The cause of anemia can be further elicited
by assessing the hematocrit, red cell indices Deficiencies of iron, vitamin B12, and folate are
(mean corpuscular volume (MCV), mean cor- the most common cause of a low hemoglobin
puscular hemoglobin (MCH), mean corpuscular level in North America and Europe. Iron defi-
hemoglobin concentration (MCHC)), differen- ciency is typically microcytic and hypochromic
tial white cell count, blood film, and hematinic with poikilocytosis (low MCV, MCH, and
levels. A simple guide to interpretation of hema- MCHC), whereas vitamin B12 and folate defi-
tological tests is shown in Table 3 (Longmore ciency lead to production of large red blood cells
et al. 2014). with a high MCV (macrocytosis). Some red cells
Table 2 Tests indicated for common oral medicine diag- Table 2 (continued)
noses and for commencing systemic immunosuppressive
Varicella zoster antibodies
therapy
Fasting blood glucose/HbA1c
Pemphigus Glucose 6 phosphate dehydrogenase (dapsone)
Incisional biopsy of lesional and perilesional tissue TB risk assessment for latent disease and if suspected
Indirect immunofluorescence Quantiferon test
Work-up for immunosuppressant therapy
Mucous membrane pemphigoid
Incisional biopsy of lesional and perilesional tissue
will be primitive and nuclei may remain present
Indirect immunofluorescence
Work-up for immunosuppressant therapy (megaloblastic).
Recurrent mouth ulcers with no identified systemic Other causes of anemia include autoimmune
cause disease such as rheumatoid arthritis, drugs
Full blood count/complete blood count (including dapsone), chronic alcohol misuse,
Vitamin B12
Ferritin/iron studies
and renal failure. In sickle cell disease, a gene
Red cell folate defect causes production of abnormal β globin
In some cases: chains, resulting in the production of HbS rather
Anti-tissue transglutaminase antibodies than HbA. Homozygosity for HbS (i.e., HbSS)
Anti-endomysial antibodies
results in sickle cell anemia, while heterozygos-
Sjógren’s syndrome
Full blood count ity for HbS (i.e., HbAS) results in sickle-cell
Hematinic screen trait. Patients with sickle-cell trait will only
Erythrocyte sedimentation rate (ESR) develop sickling in severe hypoxia. Sickle cell
C-reactive protein (CRP) disease patients are at risk of severe infections
Antinuclear antibodies (ANA)
Extractable nuclear antigens (ENA) and aseptic bone necrosis. Thalassemia is caused
Rheumatoid factor by reduced production of one or more of the
Complement hemoglobin chains leading to imbalanced hemo-
Lymphocyte subsets globin synthesis. This leads to ineffective eryth-
Cryoglobulins
Serum immunoglobulins +/ subclasses ropoiesis and hemolysis. There are two types: α
Granulomatous disorders thalassemia and β thalassemia. Both produce a
Incisional biopsy of lesional tissue hypochromic, microcytic anemia and are associ-
Full blood count ated with recurrent infections and bony abnor-
Hematinic screen malities. Analysis of a blood film may be
ESR, CRP
Serum angiotensin-converting enzyme (ACE) requested to confirm the above diagnoses. Other
Fecal calprotectin inherited conditions causing anemia include hered-
In some cases: itary spherocytosis, glucose 6 phosphate dehydro-
Quantiferon test for TB genase deficiency, and pyruvate kinase deficiency.
Oral dysesthesia
Polycythemia is caused by a proliferation of red
Full blood count
Ferritin/iron studies blood cells and may be primary (polycythemia rubra
Vitamin B12 vera) or secondary to a number of disorders includ-
Red cell folate ing renal disease and congenital heart disease. There
Fasting blood glucose
may be an associated bleeding tendency.
Commencing immunosuppressant therapy
Full blood count
An abnormal white cell count may indicate
Renal function infection or underlying immunosuppression. It
Liver function is important to exclude immunosuppression in
Thiopurine methyltransferase (TPMT) (azathioprine/ patients due to commence immune-modulating
6-mercaptopurine)
HBV
medication, such as azathioprine or myco-
HCV phenolate mofetil. A markedly increased white
HIV antibody cell count may indicate an underlying hematolog-
(continued) ical malignancy, such as leukemia. A basic guide
Table 3 Simple guide to interpretation of full blood count (complete blood count)a
Measurement Reference range Increased Decreased Comments
260
Hemoglobin (Hb) Males 13–18 g/dl Polycythemia Reduced erythropoiesis (e.g., hematinic deficiency, renal Can be affected by age,
Females failure) gender, pregnancy,
11.5–16 g/dl Hemorrhage (menstruation, gastrointestinal pathology) altitude, and cigarette
Hemolysis (autoimmune disease, drugs) smoking
Hereditary conditions (sickle cell anemia, thalassemia)
Hematocrit Males 40–54% Dehydration Overhydration, pregnancy, hemorrhage, bone marrow
Females 38–47% Polycythemia failure, nutritional deficiency
Preeclampsia
Red cell count (RBC) 4.5–6.5 1012/L Polycythemia Hemorrhage, bone marrow failure, nutritional deficiency,
Congenital heart disease overhydration
Renal disease
Dehydration
Mean corpuscular 76–96 fl Vitamin B12 or folate deficiency, Iron deficiency anemia, thalassemia, pregnancy, hemolytic Classified into three
volume (MCV) chronic lung disease, liver disease, anemia, bone marrow disorders types: microcytic (low
bone marrow disorders, alcoholism, MCV), normocytic
drug effects, e.g., dapsone, (normal MCV), and
azathioprine, metronidazole macrocytic (high MCV)
Mean corpuscular 27–32 pg Vitamin B12 and folate deficiency Iron deficiency
hemoglobin (MCH)
Mean corpuscular 30–36 g/dL Iron deficiency, hemorrhage, pregnancy, anemia of chronic
hemoglobin disease
concentration
(MCHC)
Red cell distribution 11.6–14.6% Iron deficiency
width (RDW) Hemolytic anemia
White cell count 4–10 109/l Stress, extreme cold or heat, Drug therapy (e.g., azathioprine), autoimmune disease,
(WCC) exercise, pregnancy, infection, viral infection, bone marrow disease
inflammation, trauma, leukemia and
other malignancy
Platelets 150–400 109/l Essential thrombocytosis, Reduced production in the bone marrow (aplastic anemia,
inflammation, surgery, hemorrhage, acute leukemia, malignancy, drugs, vitamin B12 or folic
hyposplenism acid deficiency)
Increased platelet destruction (immune thrombocytopenic
purpura (ITP))
Increased rate of consumption (disseminated intravascular
coagulation (DIC), drugs)
a
Laboratory reference ranges may vary. Clinicians should check with their local laboratory
T. Hodgson et al.
Table 4 Basic guide to interpretation of the differential white cell counta

Cell type Reference range Increased Decreased
Neutrophils 2.0–7.5 109/l Bacterial infections Viral infections (HIV)
Inflammation (Myocardial Drugs (chemotherapy, sulfonamides)
infarction, rheumatoid arthritis) SLE
Myeloproliferative disorders Hemolytic anemia
Drugs (corticosteroids) Bone marrow failure
Disseminated malignancy Racial variant (Afro Caribbean)
Physiological (exercise, pregnancy) (If the neutrophil count falls below
Stress (trauma, burns, hemorrhage) 0.5 x109 risk of serious bacterial
infection)
Lymphocytes 1.5–4.5 109/l Acute viral infection SLE
Chronic bacterial infections HIV
(brucellosis, syphilis, Drug treatment (corticosteroids,
toxoplasmosis) azathioprine, mycophenolate mofetil)
Leukemia and lymphoma
Eosinophils 0.04–0.4 109/l Parasitic infections
Allergic disease (hay fever, asthma)
Drug reactions (Stevens-Johnson
syndrome)
Skin disease (pemphigus, psoriasis,
dermatitis herpetiformis)
Lymphoma and leukemia
Basophils 0–0.1 109/l Myeloproliferative disease
Viral infection
Hypersensitivity reactions
Inflammatory disorders
(rheumatoid arthritis, ulcerative
colitis)
Monocytes 0.2–0.8 109/l Chronic infection (TB, brucellosis)
Granulomatous disease
(sarcoidosis)
Malignancy
a
Laboratory reference ranges may vary. Clinicians should check with their local laboratory
to the differential white cell count is shown in 4. Patients taking anticoagulant medication or
Table 4 (Longmore et al. 2014). those with suspected or confirmed liver disease
who are due to undergo oral biopsy
Bleeding Disorders A full blood count will detect any abnormali-

ties in platelet count, a blood film will show any
Bleeding disorders are caused by either abnormal- alteration in the morphology, and platelet function
ities in platelet number or function or coagulation tests will detect abnormalities in platelet hemo-
defects. These can be hereditary or acquired. static function.
An assessment of clotting function would Coagulation screening tests typically include
normally be carried out on oral medicine patients the following:
presenting with the following:
1. Spontaneous gingival bleeding of unknown 1. Prothrombin time (PT). This is the most sensi-
cause tive marker and assesses the extrinsic pathway
2. Oral mucosal purpura, petechiae, or ecchymoses of the clotting cascade. It is usually expressed
3. Excessive bruising of the skin or a history of as a ratio compared to control (international
prolonged bleeding following tooth extraction normalized ratio or INR).
2. Activated partial thromboplastin time (APTT). • Diabetic-related salivary hypofunction.

This assesses the intrinsic pathway of the • In those patients presenting with fatigue as
clotting cascade. part of their presenting complaints such as
3. Thrombin time. This assesses conversion of Sjógren’s syndrome.
fibrinogen to fibrin.
Abnormalities will prompt onward referral to Liver Biochemistry

a hematologist for investigation (Platt 2007).
Further specific tests are likely to be required to A typical liver biochemistry panel (LBP) test
accurately diagnose any bleeding disorder. includes bilirubin, alkaline phosphatase, alanine
transaminase, and albumin. International normal-
ized ratio (INR) and gamma-glutamyl trans-
Clinical Chemistry peptidase (γGT or GGT) are also blood tests
used to assess liver function. Clotting factors II,
Glucose VII, IX, and X are produced in the liver, and hence
an elevated INR is indicative of potential liver
The requirement for glucose by the human body is inflammation in the absence of other known
continuous, and it is the preferred fuel source for causes. INR, albumin, and bilirubin are the best
all tissue types. A water-soluble molecule crossing markers to assess liver function.
the blood brain barrier makes it an unique energy Alkaline phosphatase is found in both the cells
source for the brain. Sources of glucose include lining the bile duct as well as bone. Hence damage
diet, gluconeogenesis, and glycogenolysis. Phys- to either of these sites releases the enzyme into
iological concentrations of glucose range between the blood and causes elevated levels. It is the
3.9 and 6.7 mmol/L. Diabetes mellitus is a meta- commonest marker of biliary obstruction. However
bolic disease and is characterized by high blood natural elevations are noted in the 3rd trimester of
glucose levels. This can be due to the inability to pregnancy and in adolescence. γGT is also found in
produce enough insulin (type 1) or cellular resis- the bile ducts, so in the presence of a raised alkaline
tance to insulin (type 2). Biochemical tests used phosphatase, assessing the γGT can help differen-
to measure glycemic control include random glu- tiate the cause of a raised alkaline phosphatase
cose, fasting glucose, post glucose challenge, and between the bone and liver. Alkaline phosphatase
glycosylated hemoglobin (HbA1c.) The fasting and γGT are markers of cholestasis, and transami-
glucose and post glucose challenge are commonly nases are markers for hepatocellular disease.
used to help diagnose diabetes mellitus, while the Alanine transaminase (ALT) and aspartate
HbA1c gives a long-term view of glycemic transaminase (AST) are both transaminases, and
control. levels of either/both may occur and be found on
The conditions that would require an oral med- an LBP dependent upon the laboratory used.
icine specialist to consider assessing glycemic They are strong markers of liver disease as they
control include: are found within the hepatic cell cytoplasm or cell
mitochondria. Elevated ALT or AST levels can be
• Corticosteroid monitoring. For patients secondary to viral infection, medications, chronic
who require long-term corticosteroid treatment alcohol use, and cirrhosis. An ALT greater than
such as those with active immunobullous 1000 u/L is probably indicative of viral hepatitis.
disease, a baseline HbA1c is required in order Liver biochemistry should be requested by an
to monitor the patient for development of dia- oral medicine specialist:
betes. A random glucose is of little value as
glucose levels are variable and related to eating 1. Before commencing systemic immuno-
and drinking. suppression, for example, azathioprine/
• Suspected oral candidosis. mycophenolate mofetil
2. Monitoring of patients on particular systemic Bone Profile

medications, for example, azathioprine and
mycophenolate mofetil A blood bone profile can include the following:
3. Prior to the use of systemic azole antifungal calcium, corrected calcium, albumin, and alkaline
medications phosphatase.
4. For those patients with suspected liver disease The use of these tests within oral
(persistent heavy alcohol intake requiring medicine is normally disease specific and
mucosal biopsy) are additional tests following the results of other
investigations such as radiographs. Examples
The request for INR and γGT should be based include metabolic bone disorders, Paget’s dis-
on clinical judgment and the result of liver eases, and hyperparathyroidism.
biochemistry.
Liver function abnormalities are a poor marker
for hepatitis C (HCV) infection as the function Hematinics
may be unaffected for many years. While the
literature documents an association between oral Vitamin B12
lichen planus (OLP) and HCV, if a clinician sus- Strictly speaking, the term “vitamin B12” should
pects HCV in refractory OLP, then virology tests be defined as cyanocobalamin. This form does not
should be carried out rather than a surrogate test of occur in vivo. Cyanocobalamin releases a cyanide
liver function alone. group for every molecule of B12 that is used.
Albumin is a protein made by the liver; it is However, it is incorrect that hydroxocobalamin
a large molecule and found distributed in the is the active form of the vitamin. There are two
plasma. Persistently low albumin levels are usually active forms of the B12 enzyme in the human cell.
a marker of either liver or kidney disease. It is a test First, methylcobalamin acts as a coenzyme for
used in conjunction with other biochemistry tests. the conversion of homocysteine to methionine.
It is not necessarily required in every day oral Methionine subsequently acts as a methyl-donor
medicine practice unless clinically justified. to a great number of reactions that need a methyl
group, including the synthesis of myelin, serotonin,
dopamine, noradrenalin, DNA, and phospholipids.
Renal Biochemistry Secondly, adenosylcobalamin is a coenzyme for
the conversion of L-methylmalonyl-CoA into suc-
A standard renal profile includes sodium, potas- cinyl-CoA that feeds into the citric acid cycle.
sium, creatinine, urea, and an eGFR (estimated Vitamin B12 has an essential role in red blood
Glomerular Filtration Rate). This test provides cell production. Deficiency causes a macrocytic
an overall view of kidney function. It may be anemia.
requested for those at risk of developing renal Vitamin B12 deficiency is commonly a result of
disease (renal hypertension) or for monitoring a poor diet or impaired absorption, including gas-
purposes for those with known kidney disease. trectomy, ileal disease such as Crohn’s disease,
In oral medicine, a clinician may wish to and coeliac disease.
request renal biochemistry for: Common causes of elevated vitamin B12
include hematological malignancies, liver dis-
1. Pre-prescription of systemic therapy, for exam- ease, and polycythemia rubra vera.
ple, azathioprine and mycophenolate mofetil In the practice of oral medicine, a clinician may
2. Drug monitoring (e.g., immunosuppressant request vitamin B12 studies for:
therapy, colchicine, or carbamazepine)
3. Suspected systemic lupus erythematous (SLE) 1. Investigation of recurrent oral ulceration
especially prior to immunosuppression for 2. Investigations of oral mucosal burning/
severe mucosal disease dysesthesia
3. Oral candidosis 1. Recurrent oral ulceration

4. Investigation of the impact of inflammatory 2. Oral candidosis
bowel disease 3. Oral mucosal burning/dysesthesia
5. Patients presenting with fatigue as part of 4. Investigation of inflammatory bowel disease
the wider clinical context, such as Sjógren’s 5. Fatigue
syndrome 6. Patients presenting with fatigue as part of the
wider clinical context
Methylmalonic acid (MMA) testing is rarely
requested, sometimes along with homocysteine, Folate
to help diagnose an early or mild B12 deficiency. There are two well-known laboratory tests for
It may be requested as a follow-up to a vitamin measuring folate levels: serum folate and red
B12 test result that is in the lower end of the blood cell folate. Serum folate is closely matched
normal range. Until more data supports its use to recent folate intake, and therefore it cannot
and consensus on its clinical utility and long- differentiate between transient dietary changes as
term benefits are demonstrated, it will probably a cause of deficiency or true chronic deficiency.
not be routinely used by clinicians. It should Red blood cell folate is a measure of long-term
be noted, failing to correct folate levels prior to deficiency. Erythrocytes take up folate at the
treating vitamin B12 deficiency may lead to an erythropoiesis stage. The life span of the cell is
irreversible peripheral neuropathy. 120 days. Clinicians need to ensure they supple-
ment for at least 4 months prior to retesting to
Iron Studies observe any change.
Investigation of iron levels and stores often involves The common causes of low folate levels
more than one biochemical test. Ferritin acts as an include dietary deficiency, malabsorption, drug
intracellular iron store and serum ferritin is an indi- interaction, and alcohol excess.
rect marker of the bodies iron stores. It is the most Within oral medicine, a clinician may request
sensitive marker for iron deficiency; however, cli- folate studies for:
nicians must be aware that it is an acute-phase
protein and hence can give rise to false-negative 1. Oral mucosal burning/soreness
results. A reading below the lower reference level 2. Drug monitoring. For example, carbamazepine
can therefore be relied upon as a true deficiency. 3. Oral candidosis
Iron studies may also be requested and include 4. Recurrent oral ulceration
total iron-binding capacity (TIBC) that is high in
iron deficiency, transferrin saturation which is low
in iron deficiency and total iron. Fasting Lipids
Common causes of iron deficiency:
This test includes low-density lipoproteins (LDL),
1. Poor diet high-density lipoproteins (HDL), total choles-
2. Blood loss. For example, heavy menstruation, terol, and triglycerides. Within the practice of
gastrointestinal blood loss: cancer, inflamma- oral medicine, clinicians have previously tested
tory bowel disease, and gastric ulceration lipids in patients requiring long-term corticoste-
3. Pregnancy roid treatment, at both initiation and monitoring
4. Malabsorption during therapy, as well as monitoring systemic
5. Hook worm infestation (most common cause retinoids. Recent studies in rheumatoid arthritis
in tropical regions) patients given corticosteroids for over 3 months
showed no significant difference in lipid profiles
Within the practice of oral medicine, a clinician when compared to those not prescribed cortico-
may request ferritin studies or iron studies for: steroids suggesting that in this group of patients,
this test is not required (Schroeder et al. 2015). Numerous factors may influence the baseline
Retinoids are associated with significant adverse level of CRP, including age and gender, with a
lipid values including high trigylcerides and formula available reflecting the increases seen
total cholesterol, and a lipid profile before and with advancing age and female gender. The refer-
after 2 months of therapy is indicated (Hansen ence range commonly reported for CRP is less
et al. 2016). than 5 mg/L; although in the absence of disease,
99% of patients will have a CRP of less than
10 mg/L (Shine et al. 1981).
Acute-Phase Proteins CRP is not an investigation used for any spe-
cific condition managed in the scope of practice of
Acute-phase proteins are defined as those pro- oral medicine. It is frequently used in allied med-
teins whose serum concentrations increase ical fields, especially in the assessment of patients
(positive acute-phase proteins) or decease (neg- with connective tissue and rheumatological dis-
ative acute-phase proteins) by at least 25% dur- ease. For example, the measurement of CRP is
ing inflammatory states (Gabay and Kushner considered a key component in the monitoring of
1999; Jain et al. 2011). Cytokines, primarily disease activity in rheumatoid arthritis (RA). It is
interleukin-6, are considered to be the principal recommended in the decision-making process
agents responsible for stimulating the production with regard to increasing the medication used in
of acute-phase proteins (Tanaka and Kishimoto the management of RA and can be incorporated
2014; Gabay and Kushner 1999). Positive acute- into the disease activity score based on the assess-
phase proteins include C-reactive protein, ferri- ment of 28 joints (DAS28) (National Institute for
tin, and elements of the complement system (C3, Health and Care Excellence 2009). With regard to
C4, C9) and components of the coagulation and systemic lupus erythematosus (SLE), studies have
fibrinolytic system (fibrinogen, plasminogen, demonstrated that almost two thirds of patients
and protein S). Proteins such as albumin, have CRP levels greater than 10 mg/L (ter Borg
alpha-fetoprotein, and factor XII are among et al. 1990; Becker et al. 1980); however, these
those classified as negative acute-phase proteins clinically significant levels of CRP were not found
(Mizejewski 2015; Poudel-Tandukar et al. 2017). to correlate with disease activity (Dima et al.
These negative acute-phase proteins will not be 2016). The rise in CRP in patients with SLE
discussed further due to present irrelevance to is generally considered to be modest or muted
oral medicine practice. (Gaitonde et al. 2008) and therefore is not used
as a diagnostic test nor as a marker of disease
C-Reactive Protein activity. Similarly with primary Sjógren’s syn-
C-reactive protein (CRP) is a positive acute-phase drome (pSS), it has been long established that
protein that is produced by hepatocytes in CRP is not a good indicator of disease activity
response to tissue injury, inflammation, or infec- (Moutsopoulos et al. 1983) as is it considered to
tion. It has multiple roles in response to inflam- be only moderately raised in patient with pSS
mation and infection including recognition of (Pertovaara et al. 2009).
foreign pathogens due to its ability to bind In gastroenterology, CRP is evaluated in
phosphocholine in injured cells, complement acti- patients suspected to have inflammatory bowel
vation, binding to phagocytic cells, induction disease (IBD) or irritable bowel syndrome (IBS)
of tissue factor and cytokines in monocytes, but is not considered diagnostic for either condi-
and prevention of neutrophil to endothelial cell tion (National Institute for Health and Care Excel-
adhesion (Gabay and Kushner 1999). Secretion of lence 2008). CRP is upregulated in both ulcerative
CRP begins 4–6 h after a stimulus (and peaks colitis (UC) and Crohn’s disease (CD); however,
at 36–50 h, with a reported half-life of 19 h) there is no consistency with regard to the rise in
(Vigushin et al. 1993). CRP. There is a more marked rise in CRP levels
seen in patients with CD than those with UC The DAS28 used in the monitoring of disease
with no sound evidence to support the discrep- activity in patients with rheumatoid arthritis
ancy in CRP between the conditions (Vermeire commonly incorporates ESR, although CRP can
et al. 2006). be used as mentioned previously. In patients with
SLE, ESR and CRP measured together can help to
Erythrocyte Sedimentation Rate differentiate between an exacerbation of SLE and
Erythrocyte sedimentation rate (ESR) is a concurrent infection in patients with SLE. In an
considered an acute-phase nonprotein or an indi- exacerbation of SLE, the ESR will be raised but
rect acute-phase reactant. It is the coagulation not CRP (Fernando and Isenberg 2005).
and fibrinolytic system acute-phase proteins, spe-
cifically fibrinogen that is directly correlated Ferritin
with ESR. ESR is defined as the rate (expressed The acute-phase protein ferritin is an iron storage
in mm/hr) at which erythrocytes suspended protein, and therefore serum ferritin can reflect the
in plasma have fallen after 1 h in a vertical body’s iron stores. A correlation between serum
column of anticoagulated blood under the influ- ferritin and iron stores has shown that 1 μg/L of
ence of gravity. Although the reference range of serum ferritin corresponds to 8–10 mg of stored
0–15 mm/h is commonly seen on laboratory iron (Walters et al. 1973). Low ferritin provides
reports, age and gender can influence ESR. evidence of iron deficiency and is recommended
A number of erythrocyte specific factors to be included in the first-line investigations of
can also influence ESR such as size, shape, and a microcytic anemia (WHO 2011). Its role as a
number. ESR will be decreased in sickle cell positive acute-phase reactant is due to the induc-
disease and iron deficiency anemia, while an tion of the synthesis of ferritin by a number of
increased ESR will be seen in severe anemia and interleukins, including IL-1 and IL-6, tumor
macrocytosis. Conditions or diseases that result necrosis factor (TNF)-α in hepatocytes. As ferritin
in elevated levels of fibrinogen, including preg- levels can be elevated in response to inflammation
nancy, diabetes mellitus, end-stage renal failure, or infection, a normal serum ferritin does not
and malignancy, will also cause a rise in ESR exclude iron deficiency anemia. However, a ferri-
(Brigden 1999). tin level >100 μg/L in a patient with a microcytic
As with CRP, ESR is not used in the diagnosis anemia can be considered to exclude iron defi-
or monitoring of any disease specific to oral med- ciency anemia (Zhu et al. 2010).
icine clinical practice but in allied medical spe- Normal values of serum ferritin vary across lab-
cialties. ESR is a component of the diagnostic oratories. Independent of iron overload and inflam-
criteria of polymyalgia rheumatica and giant cell mation, serum ferritin can be raised in alcohol
arteritis. Although neither of these conditions are excess, viral hepatitis, nonalcoholic steatohepatitis
commonly managed in an oral medicine setting, and renal failure (Adams et al. 2005).
giant cell arteritis can present with headache and In an oral medicine setting, patients with oral
jaw pain so may be included in the differential ulceration and oral burning symptoms are com-
diagnosis of these conditions. ESR is considered monly investigated for anemia. Due to the recom-
the gold standard marker of inflammation in mon- mendation of the use of serum ferritin in the
itoring both polymyalgia rheumatica and giant investigation of microcytic anemia, this test will
cell arteritis with a marked decrease seen within be carried out and interpreted in these patients
a few days of commencing systemic corticoste- (Scully and Porter 2008; Renton 2011).
roids (Salvarani et al. 2005). Caution must be
taken in over dependence on ESR in patients
with polymyalgia rheumatica and giant cell arter- Fecal Calprotectin
itis, as there is a subgroup among this cohort of
patients in which ESR remains normal (Salvarani Calprotectin is a zinc- and calcium-binding protein
et al. 2008). found in the cytosol of inflammatory cells (Smith
and Gaya 2012). It is derived mostly from neutro- reservoir of this essential trace element,
phils and monocytes and considered a valuable although no concrete evidence supports this
marker of neutrophil activity (Muthas et al. 2017). claim (Lynch 2011).
The function of calprotectin has not been clarified, According to a recent review, up to 17% of the
but it is thought to have bactericidal and fungicidal population worldwide has insufficient dietary
properties (Steinbakk et al. 1990). It can remain in intake of zinc. It is found in meat and fish, with
stool samples at room temperature for 7 days and is poor bioavailability in vegetables (Bhattacharya
measured using ELISAwith as little as a 5 g sample et al. 2016). Zinc status of individuals is difficult
(Muthas et al. 2017; Yousefi et al. 2007). to assess. It is recommended to use of zinc con-
The investigation is not carried out in oral centrations in hair to determine dietary zinc, while
medicine but is recommended by the British urinary zinc is a marker of plasma zinc concentra-
Society of Gastroenterology (BSG) in the diagno- tions (Lowe 2016).
sis of IBD. Research has been carried out indicat- Although zinc is ubiquitous in the human body
ing the predictive value of fecal calprotectin and commonly found in the hard and soft tissues
in determining relapse of both UC and CD (Mao of the oral cavity, it has a limited role in oral
et al. 2012). It is not specific to IBD as it can medicine clinical practice. Deficiency in zinc has
also be raised in gastric and colorectal cancer, historically been associated with taste distur-
colorectal polyps, and with the used of nonsteroi- bance, a symptom reported by patient that may
dal anti-inflammatory medications (Khoshbaten lead to a referral to oral medicine for further
et al. 2014; Rendek et al. 2016). investigation. This association was first proposed
It has been used in research regarding orofacial following a 1972 US-based trial of the efficacy
granulomatosis (OFG) in oral medicine popula- of zinc supplementation in the management of
tion as a component of the diagnostic process in hypogeusia (Schechter et al. 1972). Subsequent
determining those patients who may in fact have studies, in the late 1970s and early 1980s, have
Crohn’s disease (Gale et al. 2015). demonstrated contradictory evidence regarding
the role of zinc supplementation in the manage-
ment of taste loss (Henkin et al. 1976; Mahajan
Zinc et al. 1980). A recent review, however, stated that
a deficiency in zinc is unlikely to be the cause of
Zinc is an essential trace element found in tis- hypogeusia (Cowart 2011).
sues including muscle, bone, and skin with Zinc is incorporated into oral health products,
approximately 2 g of zinc distributed throughout as it is effective at controlling plaque and calculus
the human body (Thomas and Bishop 2007). formation along with a noted reduction in oral
The biological functions of zinc can be broadly malodor. In an oral medicine setting, patients may
categorized as catalytic, regulatory, and struc- present with oral malodor, which may be contrib-
tural. It is considered a vital component of uted to by odiferous compounds including volatile
numerous enzymes and proteins along with a sulfur compounds (VSCs). It is suggested that zinc
proposed role in the stimulation of bone growth compounds, such as zinc chloride, are efficient at
and mineralization (Yamaguchi et al. 1988; removing VSC (Scully and Greenman 2012).
Yamaguchi and Uchiyama 2004). It is an ele- Oral submucous fibrosis (OSF) is a long-
ment considered essential for growth and devel- standing progressive condition leading to stiffening
opment in humans (Bhattacharya et al. 2016). In of the oral mucosa and subsequent limitation of
the oral cavity, zinc is present in plaque, saliva, mouth opening (Tilakaratne et al. 2016). Although
and enamel. During the development of the den- this condition is the most common in south Asian,
tition, significant amounts of zinc are incorpo- many patients with OSF are managed in oral med-
rated into enamel, while variable concentrations icine units across the world. Oral zinc supplemen-
of zinc have been found in plaque. It is proposed tation has demonstrated a positive effect on OSF
that the oral mucosa is an important intraoral (Warnakulasuriya and Kerr 2016). This effect is
thought to be due to the role of zinc in chelating adenosine deaminase levels may be found in
copper, a causative factor in the development of serum and bronchoalveolar lavage fluid in sar-
OSF (Kumar et al. 1991). coidosis patients. The clinical utilization of aden-
osine deaminase is limited given the low
sensitivity and specificity (Gungor et al. 2015).
Serum Angiotensin-Converting Serum KL-6 levels are elevated in pneumonitis
Enzyme of various causes including sarcoidosis. These
tests may eventually find a role in diagnosis and
The primary source of serum angiotensin- monitoring.
converting enzyme (ACE) is the endothelium of
the lung. The reference interval for pediatric
patients may be up to 50% higher than that of Immunosuppressive Medication
adults. The serum ACE level is elevated in 75% Metabolism
of untreated patients with sarcoidosis (Studdy and
Bird 1989). Other disease processes that have Immunosuppression is a common method of
been associated with an elevated serum ACE controlling mucosal inflammatory diseases.
include tuberculosis, silicosis, asbestosis, histo- These medications have multiple serious adverse
plasmosis, coccidiomycosis, diabetes mellitus, effects that may be mitigated by the measurement
Gaucher disease, Hodgkin disease, hypersensitiv- of enzyme levels required for detoxification and
ity pneumonitis, hyperthyroidism, leprosy, lung pathway end products.
cancer, and primary biliary cirrhosis. Approxi-
mately 5% of the healthy population has raised Thiopurine Methyltransferase
levels. It has limited utility as a diagnostic test Thiopurine methyltransferase (TPMT) is an impor-
for sarcoidosis due to poor sensitivity and tant enzyme-metabolizing immunosuppressive
specificity with almost a 10% false-positive result drug such as azathioprine (AZA) and 6-mercapto-
(Ungprasert et al. 2016). Nevertheless serum ACE purine (6-MP). TPMT is therefore measured prior
activity, which reflects the total amount of sarcoid to commencing treatment with AZA/6-MP. High
granulomas, has been proposed as a marker for the levels of TPMT are found in erythrocytes. Varia-
activity of sarcoidosis. The ACE level may tions in TPMT allow shunting of 6-MP/AZA into
decline in response to treatment or disease resolu- 6-methylmercaptopurine when levels are normal or
tion with time. Corticosteroids independently sup- high. Trimodal population activity of TPMT has
press ACE levels, and reducing the dose may lead been demonstrated (Lennard et al. 1989). Approx-
to a rise in ACE level without a worsening of imately 89% of the population has wild-type
disease activity. TPMT, which is associated with normal or high
Serologic markers such as serum amyloid A, TPMT enzyme activity. High metabolizers
soluble interleukin-2 receptor, lysozyme, adeno- (>55 nmol/g) may catabolize the intermediaries
sine deaminase, and the glycoprotein KL-6 have so rapidly that they may remain refractory to con-
been examined for potential roles in diagnosis ventional doses of AZA/6-MP (Benmassaoud et al.
and monitoring disease activity in sarcoidosis 2016). Higher doses or alternative agents may be
(Gungor et al. 2015). Serum amyloid A has necessary. Eleven percent are heterozygous with
been found to be increased in sarcoidosis, but it intermediate TPMT enzyme activity and may be
has not been shown to be clinically useful. Solu- subject to delayed bone marrow toxicity (Zur et al.
ble interleukin-2 receptor has been suggested as a 2016). Importantly, 0.3% of the population is
useful marker for determination of extra- homozygous for mutations of TPMT and thus has
pulmonary involvement in sarcoidosis patients negligible activity. This causes AZA/6-MP to be
(Grutters et al. 2003). Serum lysozyme is ele- preferentially metabolized to produce high levels
vated in the same way as ACE but in a smaller of 6-TG, which then leads to bone marrow sup-
number of patients with sarcoidosis. Elevated pression (Zur et al. 2016).
Assessment of TPMT activity may require There are limitations to using metabolite levels
repeated measurements, while patients are taking to guide drug dosing. There may be substantial
AZA/6-MP, since AZA and 6-MP can induce an variation in levels between measurements in indi-
increase in TPMT activity. Similarly, it is impor- vidual patients. Adverse reactions can also occur
tant to consider drug interactions that can affect unrelated to elevated levels. Therefore, measure-
AZA/6-MP metabolism. 5-Amino salicylic acid ment of 6-TG and 6-MMP levels cannot replace
drugs, including sulfasalazine and mesalazine, regular monitoring for toxicity (González-Lama
can reversibly inhibit TPMT activity and thus and Gisbert 2016).
lead to corresponding increases in 6-TG with
resultant leukopenia. Allopurinol inhibits the
enzyme xanthine oxidase and should normally Short SynACTHen Test
be avoided. In some specialist units, allopurinol
may be given with low-dose azathioprine to cause The use of potent topical corticosteroids such as
shunting of 6-MMP metabolites with a resultant clobetasol applied to the oral mucosa, or injected
shift in metabolism toward 6-TG (Sparrow et al. corticosteroids such as triamcinolone, may result in
2007; Hullah et al. 2015). adrenocortical suppression (Decani et al. 2014).
This is not clinically significant in most patients;
Thioguanine Nucleotides however, in those with compatible symptoms such
Assessing 6-thioguanine nucleotides (6-TG) as fatigue, hypotension, and weight loss, it should
and 6-methylmercaptopurine (6-MMP) concen- be referred for specialist endocrinology review and
trations, end products of AZA/6-MP metabolism, investigated for iatrogenic suppression of the
has been shown to be clinically useful (Lee et al. hypothalamic-pituitary-adrenal axis with a short
2015). Measurement of 6-TG levels, the active synACTHen test. This involves checking the base-
end-product of AZA/6-MMP metabolism, corre- line cortisol and rechecking it 30 min after injection
lates with therapeutic efficacy and toxicity. of a synthetic ACTH. A rise in serum cortisol of
Several studies of AZA and 6-MMP have demon- greater than 200 nmol/L represents a normal
strated that therapeutic efficacy correlates with response and therefore no adrenal suppression.
concentrations of 6-TG levels between 230 and A short synACTHen test, along with an ACTH
400 pmol/8 108 red blood cells and bone marrow level, should be performed if Addison’s disease is
suppression is more likely with concentrations of suspected as the cause of hyperpigmentation, in
6-TG greater than 400 pmol/8 108 red blood cells which case there will be raised levels of ACTH
(Osterman et al. 2006; Goldenberg et al. 2004). but an inadequate response to the synACTHen. A
While no correlation has been found between ther- random cortisol is not recommended to exclude
apeutic efficacy and 6-MMP levels, hepatotoxicity adrenal insufficiency, as the diurnal variation
correlates with concentrations of 6-MMP greater and effects of stress make the results difficult to
than 5000 pmol/8 108 red blood cells (Dubinsky interpret. However a midmorning cortisol in non-
et al. 2000). Thiopurine metabolites are usually stressed individuals may predict the short syn-
measured at 4 weeks to confirm adherence, to opti- ACTHen outcome (Lee et al. 2003).
mize dosing, and to identify early evidence of
hypermethylation. The metabolite level is then
rechecked at 12–16 weeks when it has reached a Glucose-6-phosphate Dehydrogenase
steady-state concentration. Levels should be
repeated 4–6 weeks after any change in therapy. Glucose-6-phosphate Dehydrogenase (G6PD)
Adherence to AZA/6-MMP can also be assessed catalyzes the conversion of glucose-6-phosphate
by monitoring the levels of 6-TG and 6-MMP. Low to 6-phosphogluconate. Absence of functional
or absent 6-TG levels in non-responding patients may G6PD (1–5% of normal activity) impairs the
indicate non-compliance, use of a sub-therapeutic reduction of NADP to NADPH via the pentose
dose of AZA/6-MMP, or 6-MMP resistance. phosphate pathway, which is the only method of
NADPH generation in erythrocytes. Dapsone is C1 Esterase Inhibitor

used in an oral medicine setting for management
of mucous membrane pemphigoid. Dapsone has C1-esterase inhibitor is a control protein of the
long been recognized as a cause of oxidative classical pathway. The key indication for testing
hemolysis and methemoglobinemia. Underlying in oral medicine is angioedema occurring without
G6PD deficiency predisposes individuals to urticaria at any age. If urticaria is present, the
severe hemolysis. Most prescribers measure diagnosis is almost never C1-esterase inhibitor
G6PD prior to commencing treatment. deficiency. Normal immunochemical range in
G6PD deficiency is an X-linked (Xq28) condi- adults is 0.18–0.54 g/L. The functional range,
tion. It is the most common enzymatic disorder of reported as percentage activity compared with
red blood cells in humans, affecting 400 million normal, is 80–120%.
people worldwide. The World Health Organization Two main types of hereditary angioedema
has classified the different G6PD variants according (HAE) are recognized. Both are inherited as auto-
to the level of enzyme deficiency and the severity of somal dominant conditions.
hemolysis (WHO Working Group 1989). Class I
variants have severe enzyme deficiency (<10% of • Type I (common, 80%): absence of immuno-
normal) and have chronic hemolytic anemia. Class chemical C1-esterase inhibitor
II variants also have severe enzyme deficiency, but • Type II (rare, 20%): presence of nonfunctional
there are usually only intermittent episodes of acute C1-esterase inhibitor, due to point mutations
hemolysis associated with infection, drugs, or affecting enzyme active site
chemicals. Class III variants have moderate enzyme
deficiency (10–60% of normal) with intermittent In type I, there is a low C1-inhibitor level
episodes of acute hemolysis usually associated immunochemically, and this will become
with infection, drugs, or chemicals. Class IV vari- undetectable in an acute attack. If immunochem-
ants have no enzyme deficiency. Class V variants ical C1-esterase inhibitor is low/absent, there is
have increased enzyme activity. Absence of func- no additional value in measuring functional
tional G6PD (1–5% of normal activity) impairs the C1-esterase inhibitor. In type II, a normal or high
NADPH system of oxidative metabolism. The level of inhibitor will be measured immunochem-
nitroblue-tetrazolium (NBT) test is diagnostic and ically, but function will be low or absent. C4 level
enzyme activity can be measured. Hemolytic ane- is a useful screen. A normal C4 level during an
mia is often present and can be triggered by certain attack excludes C1-esterase inhibitor deficiency.
foods (fava beans) and drugs including dapsone, If C4 level is low in a patient with angioedema and
primaquine, and salicylates. These drugs interact immunochemical C1-esterase inhibitor is normal
with hemoglobin and oxygen, leading to the intra- or high, type II HAE should be suspected and the
cellular formation of H2O2 and other oxidizing rad- C1-esterase inhibitor function should be assessed
icals. As these oxidants accumulate within enzyme- (Bowen et al. 2010).
deficient cells with low glutathione levels, hemoglo- C1 inhibitor deficiency may be acquired
bin and other proteins are oxidized, leading to eryth- secondary to SLE, myeloma, and splenic villous
rocyte death. Dapsone should be avoided in patients lymphoma. These may be distinguished from
with G6PD deficiency. HAE by a reduction in C1q, although this is not
always reliable (Zingale et al. 2006). Attacks are
triggered by similar stimuli to HAE. The develop-
Immunology ment of angioedema in an older patient should
lead to a search for a paraprotein (serum immuno-
The number of immunological tests continues to globulins, serum and urine electrophoresis, serum
increase. There is potential use in oral medicine so free light chains, and β-microglobulin). Detection
investigation choice, and the ability to interpret of autoantibodies (antinuclear antibody (ANA),
test outcomes, remains extremely important. dsDNA, and extractable nuclear antigen (ENA)
antibodies) may be necessary to exclude connec- Human Leucocyte Antigen

tive tissue disease, although this will usually be
obvious. ACE level should be checked to exclude The human leukocyte antigen (HLA) system is
ACE deficiency. synonymous with the human major histocompat-
ibility complex (MHC). These terms describe a
group of genes on chromosome six that encode a
Complement variety of cell surface markers, antigen-presenting
molecules, and other proteins involved in immune
Complement was first identified as a heat-labile function. HLAs are proteins that assist the body’s
component in blood that “complemented” the immune system to differentiate between its own
ability of antibodies to destroy bacteria. Levels cells and harmful substances. Over 100 diseases
of C3 and C4 are commonly used in clinical are associated with classical human leukocyte
practice. The measurement of C3 and/or C4 can antigen (HLA) I and II genes, as well as with
assist in the diagnosis of certain diseases, as well some of the non-HLA genes in the major histo-
as in monitoring the course of the disease. Both compatibility complex (MHC) region (Shiina
C3 and C4 are acute-phase proteins, and levels et al. 2004).
may remain within normal range even with rapid Data regarding the relationship of human leu-
consumption. Testing for C3 breakdown products kocyte antigen (HLA) antigens to disease suscep-
are more valuable as markers of complement tibility remain at the level of associations, not
turnover. disease mechanisms.
Testing in oral medicine may be requested, but HLA region has been subdivided into three
other than for angioedema is not the first diagnos- regions: class I, class II, and class III.
tic investigation of choice:
• Class I region The class I region contains
• Suspected SLE (low C3 and C4, raised C3d) the genes encoding the “classical” class I
• Suspected Sjógren’s syndrome (low C4 and C3 HLA antigens: HLA-A, B, and C. Class I anti-
or C3 alone) gens are expressed on almost all cells of the
• Suspected hereditary angioedema (C3, C4, body, except erythrocytes and trophoblasts.
C1q, C1 esterase inhibitor, immunochemical, • Class II region The class II region contains the
and functional) genes encoding the HLA class II molecules,
• Suspected anaphylaxis (anaphylatoxins C4a, HLA-DR, DQ, and DP. Class II antigens are
C5a) constitutively expressed on B cells, dendritic
cells, and monocytes and can be induced dur-
Complement deficiency is common (especially ing inflammation on many other cell types that
C4 and C2 deficiency) and predisposes to recur- normally have little or no expression.
rent neisserial disease, bacterial infections, and • Class III region The region in between class I
immune complex disease (Table 5). Patients with and class II is known as the class III region.
low C4 complement levels at the time of diagnosis Although this region does not contain any of
of Sjógren’s syndrome display an increased risk of the HLA genes, it does contain many genes of
developing lymphoproliferative disease (Table 5). importance in the immune response including
Table 5 Interpretation of level of C3 and C4 testing

Low C4, normal C3 Normal C4, low C3 Low C4, low C3
Genetic deficiency Streptococcal GN Sepsis
SLE (active) Nephritic factor SLE (active)
Sjőgren’s syndrome Gram-negative sepsis Subacute bacterial endocarditis
Hereditary angioedema
Type II cryoglobulins
several complement components, tumor necro- become available. The pathology in all forms of
sis factor, and heat shock protein genes. amyloidosis involves the extracellular deposition
of protein as characteristic fibrillar aggregates that
Many diseases relevant to oral medicine are interfere with tissue structure and function. Amy-
associated with classical HLA I and II genes, as loid fibrils are derived from different unrelated
well as with some of the non-HLA genes in proteins in the different forms of the disease but
the MHC region. HLA associations that are repro- share many common properties, including the
ducible and robust provide important clues about capacity to bind the normal plasma protein
the development of certain diseases. serum amyloid P component. Thirty-one types of
Higher prevalence of HLA-B51 has been found extracellular, fibrillar proteins involved with
in Behçet’s disease patients in Italy, Germany, and human amyloidosis have been identified (Sipe
Middle Eastern and Far Eastern countries along the et al. 2014).
Silk Road (63% vs. 9% in controls) and of Amyloid deposition is usually confirmed by
HLA-B52 (21% vs. 9%) in Israel (Salvarani et al. demonstration of apple-green birefringence on
2001; Arber et al. 1991). HLA-B5101 and, to a Congo red staining on histological examination.
lesser extent, HLA-5108 alleles have been most Measurement of serum immunoglobulins and elec-
closely linked in patients along the Silk Road. trophoresis, serum free light chains, β -micro-
Other HLA alleles may increase (HLA-B15, globulin, and CRP is essential if amyloid is
HLA-B27, HLA-B57, HLA-26) or decrease suspected. Head and neck amyloidosis is rarely
(HLA-B49, HLA-A03) the risk for Behçet’s dis- seen and is frequently associated with the immu-
ease in various populations (Hatemi et al. 2015). noglobulin light chain-derived amyloid deposition
Other well-established relationships include: (AL amyloidosis) secondary to plasma cell dyscra-
sias (Penner and Műller 2006; Gouvêa et al. 2012);
• HLA-B*15:02 with carbamazepine-induced it may affect the larynx, sub-glottis, thyroid, and
Stevens-Johnson syndrome/toxic epidermal less frequently the oral cavity (Matsuo et al. 2016).
necrolysis (SJS/TEN) in South-East Asian Other amyloidosis subtypes, like the familial
populations (AF) and (Apo) serum amyloid A (AA) amyloid-
• HLA-B27 with seronegative spondylo- oses, are much rarer in the head and neck, and data
arthropathy is limited to a very few case reports. While the AF
• HLA-DQ8 and HLA-DQ2 with celiac disease type is related to autosomal dominant diseases, AA
• HLA-DQB1*0201 with vulvovaginal gingival is associated with chronic diseases, including rheu-
variant of lichen planus matoid arthritis and chronic infections. Appropriate
• HLA-DQB1*0301 with ocular mucous mem- referral to hematology should be arranged to diag-
brane pemphigoid nose the underlying disease.
HLA testing is not routinely performed in an

oral medicine clinical setting and the interpreta- Indirect Immunofluorescence
tion of results is complex.
Indirect immunofluorescence (IIF) testing is used
to detect circulating antibodies. To perform this
Amyloid test, the patient’s serum is overlaid on an epithelial
tissue substrate, incubated, and then stained for
Amyloid deposition is associated with a diverse fluorescent detection of antibodies. In oral medi-
range of disorders that includes Alzheimer’s cine, indirect immunofluorescence studies and
disease, type II diabetes mellitus, and dialysis antigen-specific serologic testing may be utilized
arthropathy. Although less common, systemic to aid in the diagnosis and assessment of disease
AA and AL amyloidosis remain important activity in autoimmune blistering disease. If the
because effective treatments have increasingly target of circulating antibodies is known, antigen-
specific testing can be used to detect the presence by IIF (Di Zenzo et al. 2016). The substrate used
of antibodies in serum. influences the test sensitivity. Monkey esophagus
is the preferred substrate for the diagnosis of pem-
Mucous Membrane Pemphigoid phigus vulgaris. The transitional epithelium of
Mucous membrane pemphigoid (MMP) may pre- murine (rat) bladder is the preferred substrate in
sent with IgG and IgA autoantibodies directed patients with paraneoplastic pemphigus (PNP).
against a variety of antigens, including BP180, When performed on rat bladder epithelium, esti-
BP230, α6β4 integrin subunits in the hemides- mates for the sensitivity and specificity of this test
mosome, laminin 332, and collagen VII in the have ranged from 74% to 86% and 83% to 100%,
adhesion complex. Early studies of MMP showed respectively (Leger et al. 2012; Poot et al. 2013;
IIF was positive in fewer than a third of patients. Joly et al. 2000). IIF is usually performed after
Serum samples from MMP patients contain auto- positive DIF studies are obtained, to help guide
antibodies at low titers (usually 1:10–1:40) and prognosis and therapy (Ishii 2015). Serum dem-
only in 50–80% of cases (Chan 2012). However, onstrates a characteristic netlike intercellular
the use of human basement membrane zone-split staining of IgG with an epithelial substrate.
skin and/or concentrated serum may increase ELISA for IgG antibodies to desmoglein 1 and
the sensitivity of this technique (Setterfield et al. desmoglein 3 provides a simple and highly sensi-
1998). IIF on a basement membrane zone-split tive approach to confirm the initial diagnosis of
skin substrate may identify circulating autoanti- PV. ELISA is more sensitive and specific than IIF
bodies in up to 91% patients for IgG and 64% for the diagnosis of pemphigus vulgaris, with a
patients with IgA (Setterfield et al. 1998). Dual sensitivity exceeding 90%. ELISA may aid with
antibody response with IgG and IgA signifies monitoring disease activity since desmoglein anti-
a more severe and persistent disease. There is a body levels often fall in response to treatment.
significant relationship between the titer of IgG ELISA for antibodies against envoplakin and
and the presence of IgA with the severity of the periplakin has been utilized in studies of patients
disease. In MMP, basement membrane zone-split with paraneoplastic pemphigus. In one study,
skin IIF is particularly useful for recognizing an ELISA based on the N-terminal fragment of
patients at risk for malignancy-associated laminin envoplakin had a sensitivity and specificity for
332 MMP; antibodies are found along the dermal PNP of 81% and 99%, respectively; the ELISA
side. Antigen-specific testing for basement mem- for periplakin had a sensitivity and specificity of
brane zone antibodies other than BP180 and 74% and 96% (Probst et al. 2009).
BP230 remains limited to research laboratories Additional antigen-specific serological tests
and specialized centers (Amber et al. 2016). Fur- may be used for the diagnosis of pemphigus,
ther research on the detection of salivary IgA and including immunoblotting and immunoprecipita-
IgG antibodies to BP180 NC16A by ELISA as a tion. Both tests are highly sensitive and specific
useful diagnostic biomarker is necessary (Ali et al. methods that have been used to detect autoanti-
2016). Immunoprecipitation and immunoblotting bodies in PNP. The availability of such tests is
are additional serologic tests that have been uti- limited (Poot et al. 2013).
lized in MMP. However, these tests are more labor
intensive to perform than IIF and ELISA and are
infrequently used in the clinical setting. Neverthe- Immunoglobulins
less, they may be the only way to definitively
identify laminin-332 pemphigoid. Measurement of serum immunoglobulins does
not provide categorical diagnosis in any disease.
Pemphigus Vulgaris Normal serum immunoglobulins do not exclude
More than 80% of patients with pemphigus immunodeficiency. Measurement of serum immu-
vulgaris (PV) have circulating antibodies directed noglobulin in an oral medicine setting is indicated
against desmoglein 1 and desmoglein 3 detectable in the following diseases:
• Sarcoidosis (diagnosis) There are few indications for testing IgE

• Sjögren’s syndrome (raised IgG1 with normal levels. Conditions associated with elevated
or reduced IgG2, IgG3, and IgG4) serum IgE include atopic disease, infectious dis-
• Suspected immunodeficiency, 1 or 2 ease (candidosis, CMV, EBV, HIV, tuberculosis,
(diagnosis) parasitic infections), Hodgkin lymphoma,
• Mycoplasma pneumoniae (raised IgM) pemphigus vulgaris, bullous pemphigoid, some
• Suspected myeloma (diagnosis) primary immunodeficiencies, Churg-Strauss vas-
• Lymphoma culitis, and hyper-IgE syndrome (Esposito et al.
• Liver disease (1 biliary cirrhosis, hepatitis, 2012). Therefore, elevated total serum IgE is not
cirrhosis) specific to allergic disease.
Significant allergic disease is possible with
There are no absolute indications for IgG sub- low levels of total IgE (including anaphylaxis).
class testing, as significant immunodeficiency can The level does not correlate with severity of
occur in the presence of normal subclasses. clinical reactions. Patients with undetectable
IgG4-related systemic disease (IgG4-RSD) is a IgE are unlikely to have allergic disease. It is
rare entity comprised of a collection of features important to recognize that levels above the
including tumor-like swelling of involved organs, normal range are compatible with no clinical
with a lymphoplasmocytic infiltrate enriched in allergic disease. Levels of total IgE rarely
IgG4-positive plasma cells and elevated serum provide information about IgE to specific aller-
levels of IgG4 (Kamisawa and Okazaki 2017). gens, and the presence of IgE to a specific aller-
All patients with recurrent infections should gen does not necessarily equate to a clinical
be referred to an immunologist for further inves- allergic response to that substance. The results
tigation. Any patient presenting with recurrent must be interpreted in the context of the clinical
infections and reduced serum immunoglobulins history. Causes of hypergammaglobulinemia
has an immunological problem until proven and hypogammaglobulinemia are outlined in
otherwise. Table 6.
Table 6 Causes of hypergammaglobulinemia and hypogammaglobulinemia

Causes of hypergammaglobulinemia Causes of hypogammaglobulinemia
Chronic infection: all immunoglobulins " Immunodeficiency:
Osteomyelitis X-linked agammaglobulinemia: all immunoglobulins
Bacterial endocarditis low/absent
Tuberculosis Common variable immunodeficiency: low
Sjögren’s syndrome: " IgG immunoglobulins
SLE, rheumatoid arthritis: all immunoglobulins " Hyper-IgM syndrome: normal/raised IgM, low/absent
Sarcoidosis: " IgG and IgA IgG, IgA
Liver disease: Selective IgA deficiency: absent IgA, $ IgG, IgM
Primary biliary cirrhosis (IgM may be very high) Severe combined immunodeficiency: all
Alcohol-related (" IgA). immunoglobulins low
Autoimmune hepatitis (" IgG, IgA) Lymphoma: # IgM, IgA normal, IgG normal or low;
Hodgkin’s disease: IgE " (also eosinophilia) disease, chemotherapy, or radiotherapy
Viral infections: Infections:
Acute common viral infections: " IgM, $ IgG and IgA Acute bacterial infections
Human immunodeficiency virus (HIV) – all Measles/rubella
immunoglobulins " (IgG very high but polyclonal) Herpes viruses (rare)
Epstein-Barr virus (EBV) – all " Drugs: immunosuppressives, e.g., cyclophosphamide,
azathioprine, chemotherapy
Plasmapheresis
Renal loss: IgM $, IgG and IgA #
Gastrointestinal loss: IgM normal, IgG, and IgA #
Autoantibodies value in serial monitoring of RhF as the titer

correlates poorly with disease activity. Raised
Autoantibodies are generally divided into organ levels are also found in healthy elderly (asymp-
specific and organ non-specific. Clinical testing tomatic), chronic bacterial (SBE) and viral
infrequently follows this pattern. Autoantibodies infections (HIV, HCV, acute viral infections),
can be of any class but in most circumstances IgG myeloma, lymphoma, and connective tissue dis-
antibodies are usually sought. IgA autoantibodies eases (SLE, Sjögren’s syndrome, systemic sclero-
may also be diagnostically useful in celiac disease sis, polymyositis, undifferentiated connective
where IgA endomysial antibodies have the tissue disease). Requesting RhF is not helpful, as
highest sensitivity and specificity. Autoantibodies positive results do not necessarily indicate disease
can also appear after infections, such as EBV (Shmerling and Delbanco 1991). Anti-cyclic
adenovirus, HIV, and acute and chronic bacterial citrullinated peptide antibodies are found in sera
infections. They usually disappear after 6 months of about 75% rheumatoid patients and are about
and are not usually associated with clinical dis- 96% specific for rheumatoid arthritis. They appear
ease. Drugs may also induce autoantibodies. earlier than RhF, are unaffected by treatment, and
These may cause disease and may persist after predict the development of erosions and localized
the drug is withdrawn. tissue damage (Gavrilă et al. 2016).
The most common autoantibodies associated
with infections are: Antinuclear Antibodies
Antinuclear antibodies (ANA) is a general
1. Rheumatoid factor (any infection) term encompassing the group of antibodies to
2. Antinuclear antibodies – (adenovirus in chil- intranuclear antigens. The ANA test is one of
dren), HIV, Gram-negative bacteria the most unusual in medicine because a positive
3. Smooth muscle antibodies (adenovirus) result represents a classification criterion for the
4. Liver-kidney microsomal antibodies (HCV) diagnosis of autoimmune disease, while at the
5. Cardiolipin antibodies (EBV) same time, ANA positivity is present in a sub-
6. dsDNA antibodies – rare (HIV) stantial proportion of the healthy population. It is
often thought of as a screening test for SLE or
The most common autoantibodies associated other connective tissue diseases. Although ANA
with drugs are: is positive in 99% of cases of SLE, it is not
specific and can be positive in numerous situa-
1. Antinuclear antibodies (anti-histone) – (pro- tions including healthy individuals, hepatic dis-
cainamide, hydralazine, ACE-inhibitors, ease (primary biliary cirrhosis), pulmonary
chlorpromazine, minocycline) disease (primary pulmonary hypertension),
2. Non-M2 mitochondrial antibodies (alcohol) chronic infections, malignancy, or may be drug-
induced. It should, therefore, be interpreted only
Rheumatoid Factor in the context of clinical symptoms (Pisetsky
The test for rheumatoid factor (RhF) is widely 2017). Most clinical laboratories report ANA as
misused by clinicians. It is not a screening test a titer and the staining pattern produced by the
for rheumatoid arthritis and is positive in only patient’s serum. The titer is determined by the
70–80% of patients. The normal ranges vary lowest dilution at which the fluorescence can still
with age. RhF is a non-specific test as it detects be seen. A 1/40 titer, therefore, is less significant
immunoglobulins of any class reactive with the than a 1/2560 titer. Nuclear staining patterns
Fc region of other immunoglobulins. The only include homogeneous, speckled, centromere,
indication for this test is when patients have clin- and nucleolar. Antibodies in the serum of
ical rheumatoid arthritis. A high titer in patients Sjögren’s syndrome patients are likely to pro-
with known rheumatoid arthritis is a risk factor duce speckled or homogenous staining.
for extra-articular manifestations. There is little Low-titer positive ANAs in the elderly should
be interpreted in the context of relevant clinical diagnosed patients as the antibody pattern may
signs and symptoms. Positive ANA is useful for change with time, and this may correlate with
the diagnosis of SLE and systemic sclerosis and changes in the clinical profile. Normally laborato-
somewhat useful for the diagnosis of Sjögren’s ries will carry out a six-antigen screen: Ro, La,
syndrome and polymyositis/dermatomyositis. ribonucleoprotein (RNP), Sm, Jo-1, and Scl-70.
Detection of a strong positive ANA is an indica- Results are reported qualitatively.
tor for confirmatory tests with ENA and dsDNA Antibodies to extractable nuclear antigens
to fully investigate antigenic specificities identi- (ENA) are listed below:
fied. Changes in ANA titer are not helpful
in disease monitoring in patients diagnosed 1. Anti-Ro/SSA – SLE, Sjögren’s, syndrome,
with an ANA-associated autoimmune disease. neonatal lupus, neonatal congenital complete
Once a positive test has been obtained, repeat heart block
measurements of ANA are not indicated 2. Anti-La/SSB – SLE, Sjögren’s syndrome, neo-
(Pisetsky 2017). natal lupus, neonatal congenital complete heart
block
Antineutrophil Cytoplasmic Antibodies 3. Anti-RNP – Undifferentiated connective tissue
Antineutrophil cytoplasmic autoantibodies disease (if present alone); SLE (if present with
(ANCA) are antibodies directed against the lyso- dsDNA)
somal compartment of neutrophils and mono- 4. Anti-Sm – Highly specific marker for SLE
cytes. ANCA is often thought to be a screening 5. Anti- Jo-1 – Polymyositis, dermatomyositis
test for vasculitis (Bossuyt et al. 2017). In adults, 6. Anti-Scl-70 – Systemic sclerosis
it is normally undetectable. The presence of 7. Anti-Pm-Scl (PM1) – Scleroderma-myositis
cytoplasmic-staining ANCA (cANCA) and pro- overlap
teinase 3 (PR3) in combination has been reported 8. Anti-Ku, Ki- Rare – SLE, UCTD, Sjögren’s
to be 99% specific (and ~55% sensitive) for syndrome, polymyositis
granulomatosis with polyangiitis. Similarly, 9. Anti-Mi-2- Rare – Steroid-responsive
the presence of perinuclear-staining ANCA polymyositis
(pANCA) and myeloperoxidase (MPO) together
is associated with microscopic polyangiitis Anti-Ro (SSA) have been found in patients
(approximately 90% specific) and Churg-Strauss with a range of autoimmune disorders, including
vasculitis. However, ANCA may be positive in SLE, Sjögren’s syndrome, idiopathic inflamma-
many other situations including infection, scle- tory myopathies, systemic sclerosis, rheumatoid
rosing cholangitis, malignancy, and inflamma- arthritis, as well as primary biliary cholangitis and
tory bowel disease. Therefore the full clinical undefined connective tissue disease (UCTD).
picture must be used in making treatment deci- Sjögren’s syndrome (SS) is characterized by the
sions, and reliance should not be put on ANCA autoantibodies anti-Ro (SSA) and anti-La (SSB)
alone. In granulomatosis with polyangiitis, serial that play a key role in the classification of the
monitoring of cANCA is useful as a rising titer in disease (Maślińska et al. 2017). Anti-Ro (SSA)
a patient in clinical remission heralds relapse positivity is present in 50–70%, and dual positiv-
(Fussner et al. 2016). Whether there is any ity for anti-Ro (SSA) and anti-La (SSB) is found
value in serial monitoring of pANCA is less in approximately 30–60% of cases of primary
certain. SS. Anti-Ro (SSA) antibodies are found in
approximately 50% of patients with SLE. It is
Antibodies to Extractable Nuclear exceedingly rare to find patients with single anti-
Antigens La (SSB) antibodies positivity.
This test should always be carried out in patients Seropositivity in primary SS is associated
with suspected connective tissue disease. Moni- with an earlier age of disease onset as well as
toring at yearly intervals should be carried out in more frequent parotitis, and extraglandular
features, especially purpura and vasculitis. where commensal treponemes may also be
Sialogram abnormalities are more frequently present (Koek et al. 2006).
found in patients with anti-Ro (SSA) positivity.
Lip infiltration is more common in anti-La (SSB)
positive primary SS. Seropositivity and titers for Mycobacterium tuberculosis
anti-Ro (SSA) and anti-La (SSB) remain rela-
tively constant throughout the course of the dis- In the oral medicine clinic, the usual indication
ease (Goules and Tzioufas 2016). for testing for tuberculosis (TB) is to prevent
reactivation of undiagnosed latent TB prior to
the patient commencing medications that will
Microbiology and Serology cause immunosuppression. This can be done
with an interferon-γ release assay, in which there
Syphilis is quantification of the interferon-γ released from
lymphocytes incubated with a protein from
Syphilis serology is used in both diagnosis and M. tuberculosis (Doan et al. 2017). A patient
treatment monitoring. Once a diagnosis of syphi- with an indeterminate or positive result should
lis is confirmed, care should be handed over to a be referred to an infectious diseases physician
genitourinary specialist for further management for further assessment. The results of an inter-
(Kingston et al. 2016). feron-γ release assay are not influenced by BCG
Treponemal antibody tests can be classified vaccination status, unlike the Mantoux test.
into:
1. Non-specific (cardiolipin, lipoidal, reagin, Mycoplasma pneumoniae

or nontreponemal) tests: Venereal Disease
Research Laboratory (VDRL) carbon antigen IgM and IgG levels can be tested for if
test/RPR test. Mycoplasma pneumoniae is suspected as a trigger
2. Specific (treponemal) tests: treponemal for erythema multiforme based on the clinical
enzyme immunoassay (EIA) or treponemal history of a preceding respiratory illness. An
chemiluminescent assay (CLIA); Treponema IgM over 770 U/ml is significantly positive,
pallidum hemagglutination assay (TPHA); although it may not start to rise until 7 days after
Treponema pallidum particle agglutination infection. It can stay raised for many months post-
assay (TPPA), fluorescent treponemal antibody infection. It may not rise with reinfection, and
absorption test (FTA-abs), Treponema therefore IgG should be tested for simultaneously.
pallidum immunoblot. Most of these tests The normal range for IgG is less than 0.9 U/ml.
are now based on recombinant treponemal A fourfold increase in IgG indicates a current
antigens and detect treponemal IgG and infection (samples taken 2–3 weeks apart). Over
IgM antibody. the past decade, there have been significant
3. T. pallidum-specific IgM antibody tests: anti- advancements in the methods used for detecting
treponemal IgM EIA and immunoblot. and characterizing M. pneumoniae, a common
cause of respiratory illness and community-
Demonstration of T. pallidum from infected acquired pneumonia worldwide. The range of
lymph nodes is by dark field microscopy and available molecular diagnostics has expanded
should be performed by experienced observers from nucleic acid amplification techniques to
(Wheeler et al. 2004). It is less reliable in exam- more sophisticated characterizing methods
ining rectal and non-penile genital lesions and not including multi-locus variable-number tandem-
suitable for examining oral lesions due to the repeat analysis, multi-locus sequence typing,
presence of commensal treponemes. Polymerase matrix-assisted laser desorption ionization-time-
chain reaction can be used on oral or other lesions of-flight mass spectrometry, single nucleotide
polymorphism typing, and numerous macrolide 72 patients (70.8%) achieved definitive diagnosis
susceptibility profiling methods (Diaz and based on isolation of bacteria of the genus
Winchell 2016). Brucella. Blood cultures were positive in 50%,
and pleural fluid culture was positive in 60.9%
in whom it was performed. Brucella spp. was
Toxoplasma gondii isolated in only 2 out of the 21 sputum cultures.
Diagnosis was based on indirect methods in the
The most usual presentation to an oral medicine remaining 21 patients. Standard tube agglutina-
clinic would be cervical lymphadenopathy, tion was initially positive in 15 patients and was
and the diagnosis is more likely to be obtained positive during the course of the disease in another
via ultrasound guided FNA sample, which may 4 patients. The other two patients were diagnosed
show tachyzoites. The diagnosis of toxoplasmosis by PCR in one case and by detection of IgM and
can be carried out by a number of methods, IgG antibodies using enzyme-linked immunosor-
including isolation of blood or body fluid bent assay (ELISA) in the other case (Solera and
tachyzoites, parasite histological determination Solís García Del Pozo 2017).
in tissue, and protozoan DNA determination by
polymerase chain reaction and by antibody detec-
tion using serological tests. The latter is the most Candida Culture
currently used method, providing serological evi-
dence of immunoglobulin (IgG, IgM, IgA, and Candida culture and sensitivities can be
IgE antibodies specific to T. gondii antigens). requested to ensure that treatment provided is
However, these tests may display sensitivity and appropriate. This is not usually used at the
specificity problems, leading to false-positive or initial assessment, but rather if the patient has
false-negative results (Zhang et al. 2016). failed to respond to first-line therapy such as
amphotericin, nystatin, miconazole, or flucona-
zole. Patients with immunosuppression or muco-
Methicillin-Resistant Staphylococcus cutaneous candidosis are particularly more likely
aureus to have rare opportunistic Candida present. A
swab of the lesion, or a saliva sample, is plated
A swab for bacterial sensitivity and culture should on Sabouraud’s dextrose agar to allow Candida
be taken from any lesion that does not respond to colonies to grow. These are subsequently identi-
first-line therapy to guide future management. fied and the sensitivity to antifungal medication
A sterile swab is rubbed over the lesion, and this is assessed. Alternative methods to identify can-
is used to culture the bacteria present, which may dida include smears, which allows identification
be pathogenic or commensal. The species are of the blastospores and pseudohyphae but
subsequently identified as well as the antibiotics does not provide sensitivities to guide treatment.
they are sensitive to. Candida may also be seen on histological
examination, but the species and sensitivity will
not be identified. The usefulness of undertaking
Brucellosis routine measurements of the presence of oral
yeast, and the level of amount of yeast present
This is not a commonly investigated condition in in the oral cavity, during clinical apparent disease
oral medicine, but should be considered in is questionable (Manfredi et al. 2013). However,
patients with erythema multiforme, particularly these methods have been used in research to shed
if there is a history of contact with infected light on the role of oral yeast in oral mucosal
animals such as cattle or consumption of disease and currently should not be routinely
unpasteurized milk in countries where animals requested (McCullough et al. 2002; Alnuaimi
are not vaccinated. In a systematic review, 51 of et al. 2016).
Pathological Investigations possible to indicate on the card the orientation of

the specimen if that is deemed clinically neces-
Biopsy sary. However, in most cases an adequate-sized
specimen can be placed directly in fixative with-
A biopsy of the patient’s tissues may be taken and out these additional measures. It is especially
referred for histopathological examination either important that the area to be biopsied is repre-
to confirm a clinical diagnosis or to establish the sentative of the lesion and none more so than in
diagnosis where there is clinical doubt and treat- oral cancer and potentially malignant disorders
ment critically depends on confirming the diagno- where failure to either initially recognize the
sis. There are many mucosal lesions where disorders or to biopsy the most appropriate rep-
a biopsy is indicated. These include malignant resentative part can have adverse consequences
lesions such as squamous cell carcinoma, poten- for the patient.
tially malignant disorders including leukoplakia Vital stains such as toluidine blue have been
and erythroplakia, vesiculobullous disorders, and used as an adjunct to identify oral cancer and
ulceration of unknown cause. However, there may potentially aid diagnosis, but at the current time,
be instances when a biopsy is contraindicated due there is no evidence that its use significantly
to an underlying medical condition. Examples increases detection rates (Su et al. 2010). A thor-
include patients with a bleeding disorder, such as ough knowledge of the clinical features of
hemophilia, or patients taking anticoagulants, oral cancer and potentially malignant disorders
such as warfarin. In these cases, if there is a degree (Napier and Speight 2008) remains essential to
of clinical certainty about the diagnosis, for exam- identify these lesions and to determine which area
ple, in a patient with typical bilateral lesions of to biopsy so the diagnosis is accurate and timely.
oral lichen planus, then a biopsy may not be There are very few indications for using a
necessary. In other patients with more sinister punch biopsy in the oral cavity as access is usually
lesions, then it may be necessary to adjust the good and there are major disadvantages from a
patient’s medication or arrange for the biopsy to pathological point of view. The most important is
be taken under appropriate specialist care. that the core of tissue produced by such biopsies
There are many different types of biopsy and it is very difficult to orientate, particularly if it is
is important that the correct biopsy is taken other- a 4-mm punch biopsy or less. The resulting
wise diagnosis may be delayed. difficulties mean that the sections taken from the
mucosal specimen are frequently not at right
Incisional Biopsy angles to the surface and this can make it
An incisional biopsy involves taking a represen- extremely difficult or even impossible to establish
tative sample(s) of the patient’s lesion. This type the diagnosis. This may delay the diagnosis and
of biopsy is particularly suitable for large mucosal the patient may require a second biopsy.
lesions such as lichen planus and other types of Sometimes it is necessary to biopsy a lesion
white patch, suspected potentially malignant deep to the mucosa in the underlying connective
disorders or malignant lesions, ulceration, and tissues or salivary glands. Many such lesions
vesiculobullous disorders. From a pathological can be biopsied by raising a flap, but if the lesion
point of view, an ellipse of tissue as large as is very deep, such as in a salivary gland or a
possible should be excised and should include lymph node, then a core biopsy under ultrasound
the underlying connective tissue and also the guidance may be indicated. Such biopsies are
edge of the lesion. If a very shallow, friable biopsy usually carried out by radiologists, and, as the
is taken, it may curl and distort when placed cores are very small, it is important to ensure that
in fixative, and this may make it difficult for the they are representative of the lesion. Lesions for
pathologist to orientate the specimen correctly. To which a core biopsy may be indicated include
overcome this, it is useful if the clinician sutures salivary gland neoplasms in the parotid and sub-
the specimen to a card to keep it flat. It is also mandibular glands, other causes of salivary
swelling, and patients with enlarged cervical times be used to treat and confirm the diagnosis
lymph nodes. without using an incisional biopsy to establish the
diagnosis prior to surgery. In these cases, detailed
Fine Needle Aspiration Biopsy radiological investigation is used together with
An aspiration or fine needle aspiration biopsy the clinical features to establish whether the
(FNAB) is very rarely used for histopathological lesion is benign or malignant and to determine
diagnosis of mucosal disease in the oral cavity and the appropriate treatment. The lesion is removed
associated structures, as core biopsies are prefer- in its entirety and sent for histopathological
able (Novoa et al. 2012). FNAB fails to provide examination.
diagnostic material in 10–15% of cases compared It is important that the pathologist knows
with 5% of core biopsies. In addition, a systematic whether the biopsy is incisional or excisional as
review has shown that core biopsies have a higher the way the tissue sample is examined may differ.
specificity (99% compared with 96%), greater For example, some excisional biopsies are used to
accuracy (96% compared with 93%), and greater remove a sinister lesion in its entirety, and
negative predictive value (95% compared with a pathologist will make sure that all excision mar-
90%) than those of fine needle aspiration in gins are sampled and examined to ensure com-
detecting malignancy. Core biopsies were also pleteness of excision. If the pathologist is sent
shown to have a higher sensitivity in the diagnosis an incisional biopsy of a sinister lesion, it is not
of lymphoma than fine needle aspiration (92% necessary to examine the excision margins but
vs. 74%) (Novoa et al. 2012). Fine needle aspira- rather the body of the lesion to establish a
tion biopsies are however useful to establish diagnosis.
whether a lesion is pus filled and infective or for
microbiological analysis but are not indicated for Transport of Biopsies
pathological diagnosis. Almost all biopsies are placed and fixed in 10%
formalin-buffered saline and sent with the appro-
Excisional Biopsy priate clinical information and patient details to
Excisional biopsies are used to remove the lesion the histopathology laboratory (Table 7). However,
in its entirety, and this may be an essential part of occasionally it is necessary to send a fresh
the management of the lesion. In some cases, the biopsy so that specific tests such as immunofluo-
diagnosis has been established prior to the proce- rescence can be carried out. This is particularly
dure, for example, oral squamous cell carcinoma; appropriate for biopsies from patients with
however, in other situations, such as fibrous autoimmune vesiculobullous disorders that
hyperplasia and mucoceles, where the diagnosis
is made clinically, an excisional biopsy is used in Table 7 Information that should be supplied on a biopsy
an attempt to provide both definitive treatments, request form
as well as to confirm the diagnosis. Excisional Patients name, address, date of birth, hospital number on
biopsies may also be used to remove small, both request form and specimen jar
nodular, well-circumscribed lesions deep to the Requesting consultants name and hospital of origin
mucosa without a firm clinical diagnosis. Exam- Date biopsy was taken
Clinical details including size, shape, color consistency,
ples of such lesions include small neoplasms of
distribution, duration of any symptoms, lesions
the minor salivary glands (common in the upper elsewhere
lip and cheek) and neural tumors. Conversely it is Site of biopsy
safer to perform an incisional biopsy on larger, Relevant details from medical and social history
deep lesions with ill-defined borders in order to Indicate whether previous biopsy has been taken and
establish the diagnosis before definitive treatment. provide details
Excisional biopsy of salivary gland tumors of the Provisional diagnosis or differential diagnosis
parotid and submandibular gland may also at Indicate whether incisional or excisional biopsy
normally require direct immunofluorescence for

an accurate diagnosis.
A fresh biopsy should be sent to the laboratory,
immediately after it has been taken in the clinic, so
it may be frozen promptly in liquid nitrogen. It
is good practice to let the laboratory know in
advance that such a biopsy has been planned so
there is no delay in processing the tissue once it
has arrived. Fresh tissue may be sent wrapped in a
gauze soaked in saline or placed in a drop of saline
in a sealed pot if the tissue is to be transported
immediately. If there is a delay of more than
30 min, then it is prudent to send the specimen
in a transport medium such as Michel’s medium
(Vaughan Jones et al. 1995). Transport of biopsies
from the clinic to the laboratory should always
follow established protocols. These may differ
between hospitals in the same country and also Fig. 1 Screw topped jar and a two-compartment sealable
between countries. It is important that the oral plastic bag
medicine specialist familiarizes themselves with
these and it is good practice to liaise closely with
the laboratory to ensure accuracy appropriate pro- sufficient material to absorb the liquid from the
cedures and safety. specimen jar. The secondary container should be
The usual minimum requirement, if the speci- placed in a rigid strong out container and labeled
men is to be transported locally without the use of “Biological substance category B” (Fig. 2).
couriers or other forms of transport, is that the
biopsy specimen is placed in a screw-topped spec- High-Risk Specimens
imen jar and then placed in a two-compartment, Biopsies from patients who are known to be HIV
sealable plastic bag (Fig. 1). positive or suffering from tuberculosis or other
The specimen jar should be placed in one com- infectious diseases should always be placed in
partment and the request form in the other. If a 10% formalin-buffered saline and should never
two-compartment bag is not available, then the be sent fresh as they present a hazard to the labo-
specimen jar should be placed in one bag, sealed, ratory staff. A “high-risk” sticker should be placed
and then placed in another bag together with the on both the specimen pot and the request form to
request form. It is essential that the two, the spec- alert the laboratory staff who will use special pro-
imen jar and the request form, are not separated cedures to handle these specimens safely.
and are transported together. The bagged speci-
men should be placed in a suitable, sealed con- Information Required by a Pathologist
tainer for transport to the laboratory. It is particularly important for an accurate diagno-
The United Nations has produced guidelines sis that all relevant clinical information is pro-
for the transport of biological specimens through vided to the pathologist. The patient’s details
the post or by courier. The packaging must must be on the accompanying request form as
comply with IATA 650 regulations (http://www. well as on the biopsy specimen jar itself. It is
un3373.com/info/regulations). The specimen jar also essential that the name of the consultant or
must be placed in a sealed bag as outlined above the clinician sending the biopsy is provided as
together with the request form and then placed well as the address or hospital and the date the
in a leak-proof secondary container filled with biopsy was taken (Table 7).
Fig. 2 An outline of the Carriage of specimens in the post: must comply

IATA 650 guidelines for the with IATA 650 packing instructions.
transport of biological
specimens by post
UN3373 Biological Substance Category 3.
Absorbent
Senders name, material
Itemised contents
address and
telephone Leak proof
number secondary
container
Biological
substance
category B
Rigid strong
outer container
Clinical information is important to making an If the patient had been prescribed antifungal
accurate pathological diagnosis. A good example is therapy prior to taking the biopsy, the fungal
lichen planus and lichenoid reactions, that are hyphae may not be present although some
essentially a clinicopathological diagnosis. It is not histopathological features including pseudo-
possible to reliably distinguish between lichen epitheliomatous hyperplasia may still be evident.
planus and a lichenoid reaction to amalgam or a This causes diagnostic difficulties for the pathol-
lichenoid drug reaction on histopathological fea- ogist as pseudoepitheliomatous hyperplasia may
tures alone, although there are some pointers be seen in a number of other lesions affecting the
(Thornhill et al. 2006). Thus, it is important for the oral cavity that are not associated with Candida. It
pathologist to know if there are bilateral or unilateral is helpful for accurate diagnosis not to prescribe
lesions, which sites are affected, and whether or not antifungal therapy before taking the biopsy. If it is
there are skin lesions. Furthermore, whether the necessary to do so, then that information should
lesions are related to amalgam restorations or be provided on the request form.
whether the patient is taking any relevant drugs. In It could be argued that a course of antifungal
rare cases patients who have had bone marrow therapy should be prescribed before taking a
transplant may have graft versus host disease that biopsy of a white patch so that any histopatholog-
may resemble oral lichen planus. Again, this infor- ical changes caused by the candida, and which
mation is essential to make an accurate diagnosis. may make the diagnosis of dysplasia difficult,
Drug history is also important not only for the are minimized. An example of where candidal
accurate diagnosis of lichenoid reactions but in infection is associated with dysplasia is shown
the diagnosis of fungal infections such as chronic in Fig. 4.
hyperplastic candidosis. The diagnosis is made on When pseudoepitheliomatous hyperplasia is
characteristic histopathological features including not observed histopathologically, it will remain
pseudoepitheliomatous hyperplasia (deep exten- unclear if the dysplasia is or is not the result of
sions of epithelium into the underlying connective the Candida infection. In an attempt to resolve
tissue) associated with the presence of fungal this issue, the pathologist may examine, if at all
hyphae in the superficial epithelial layers (Fig. 3). possible, the degree of dysplasia away from the
Fig. 3 Hematoxylin and eosin stained section of chronic hyperplastic candidosis showing pseudoepitheliomatous
hyperplasia (*) (a). The associated fungal hyphae are identified by Periodic-Acid Schiff (PAS) stain (b)
difficult to distinguish from each other, both clin-

ically and histologically. The differential diagno-
sis varies from well-differentiated squamous cell
carcinoma, verrucous carcinoma, proliferative
verrucous leukoplakia (a clinicopathological
diagnosis), and verruciform hyperplasia to reac-
tive lesions of both low- and high-risk human
papilloma virus (HPV). In these cases, it is essen-
tial that the size, site, and duration of the lesion is
given as well as a history of other lesions else-
where. Furthermore, if a previous biopsy of the
lesion has been taken, it is essential to note this so
a comparison can be made.
Fig. 4 Hematoxylin and eosin stained section of dysplasia Clinical information about systemic disease is
with Candida infection. No evidence of pseudo- essential even if it may not obviously be related
epitheliomatous hyperplasia is seen to the current lesion. An example is of a distant
malignancy arising in the kidney, breast, or pros-
tate. Such malignancies can metastasize to the
Candida infection, to observe if it is still present oral cavity, and if the pathologist knows in
or is of a less extent. If it is not possible to advance the detailed patient history, it will
determine whether Candida is playing a role in speed diagnosis.
the dysplasia, then the clinician should consider Information on the patient’s habits is also impor-
prescribing antifungal therapy and re-biopsy to tant to the diagnosis. For example, smoking and
determine whether the dysplasia has reduced in alcohol consumption are important risk factors in
grade or has resolved. This approach reduces the the development of oral cancer, but smoking is also
necessity to prescribe antifungal therapy associated with other specific changes in the oral
irrespective of whether there is firm evidence of mucosa. These changes include a chevron pattern
Candida infection. of hyperkeratosis (Fig. 5) as well as pigmentary
Another example of where clinical formation is incontinence where melanin from the basal
essential is in the accurate diagnosis of papilloma- keratinocytes drops out into the underlying connec-
tous lesions. Simple, small papillomas are relative tissue and is taken up by macrophages (Fig. 6).
tively easy to diagnose; however, there are a group It is important to provide a provisional diag-
of verruciform lesions that may be diagnostically nosis or differential diagnosis on the request
Laboratory Processing of Biopsy

Specimens
Upon arrival in the laboratory, specimens are

logged and assigned an accession number by
which they are subsequently identified. Particular
care is taken to check that the details on the
accompanying request form are the same as
those on the specimen jar. If there are discrepan-
cies, then such specimens are not accepted for
further processing until the differences have
Fig. 5 Hematoxylin and eosin stained section of a “chev- been clarified by the clinician responsible for tak-
ron” pattern of hyperkeratosis associated with smoking
ing the biopsy. This is an essential step to ensure
that the correct biopsy specimen, and hence result
is attributed to the correct patient.
Sampling of Tissue Specimens

The pathologist examines each biopsy specimen
and decides whether all the tissue or only selected
parts will be processed by the laboratory. The
pathologist then cuts the tissue appropriately.
This is known as “cutting up” or “trimming” the
specimens.
For incisional biopsies, it is usual that all tissues
are processed. Mucosal specimens are routinely cut
at right angles to the mucosal surface and either
bisected along their long axis or cut transversely
into multiple strips. Further discussion on these
differing approaches is outside the scope of this
chapter. The cut specimen is then placed cut surface
down in a labeled perforated cassette and sent for
Fig. 6 Hematoxylin and eosin stained section of oral processing (Fig. 7). Placing mucosal tissue on the
lichen planus showing pigmentary incontinence (arrows). cut surface in this way and maintaining that orien-
Melanin from the basal keratinocytes has been engulfed by tation throughout processing mean that the tissue is
macrophages (melanophages)
sectioned at right angles to the mucosal surface and
the entire thickness of the epithelium and underly-
form. This information may be used to deter- ing connective tissue is available for the pathologist
mine the way the specimen is handled. For to assess on the slides. This is essential for accurate
example, if a potentially malignant lesion is diagnosis. It has already been mentioned that trim-
suspected, then the pathologist may order more ming of specimens, identification of the mucosal
tissue sections to be cut than for a routine biopsy. surface, and maintaining that orientation are more
If this is done at the laboratory stage of the difficult if a small punch rather than an elliptical
specimen processing, it saves time and provides biopsy is used.
a speedier result. Similarly, if the clinician sus- Incisional biopsies of non-mucosal tissues
pects a fungal lesion such as chronic hyperplas- such as deep connective tissue, salivary glands,
tic candidosis, then a Periodic acid Schiff (PAS) and neural tumors are trimmed in the same way as
stain may be ordered at an early stage to detect mucosal biopsies, but the orientation is not as
the Candida hyphae. critical for diagnosis.
Fig. 7 A perforated
cassette and lid that will
house the biopsy specimen
during processing
Excision biopsies may be trimmed or cut dif-

ferently. If the specimen is a benign lesion such as
a fibrous polyp and examination of the excision
margins is not essential for diagnosis and further
management, it may be bisected in the same way
as mucosal specimens. If however the specimen is
an excisional biopsy of a malignancy, then it is
essential that the excision margins are examined
to determine whether excision of the lesion is
complete. The pathologist must know the orienta-
tion of the specimen and be able to identify the
different excision margins. For mucosal resec-
tions of malignant tumors, accurate labeling of
the margins by the clinicians while the specimen
is being taken is essential. If, for whatever reason,
Fig. 8 An excisional biopsy specimen marked where
the specimen has either not been orientated or blocks of tissue will be taken for histopathological assess-
there are discrepancies in the labeling, then ment of excision margins
the pathologist may ask the responsible clinician
to confirm the orientation. However, once the number taken will depend on the nature and size
tissue is removed from the patient and placed in of the specimen. Particular care is taken to mark
fixative, its appearance changes significantly and the surgical margins with ink and an accurate
orientation by the clinician may be difficult, if not description of where the tissue block has been
impossible. In these cases, the pathologist will be taken is recorded. For most resections it is good
unable to give an accurate report on excision practice to take a photograph of the resection
margins to the detriment of the patient. specimen and mark where the tissue blocks have
A pathologist will usually take a block of tissue been taken (Fig. 8). These photographs can also
at right angles to the surgical margin, and the be used to indicate where the margin is not clear if
appropriate and thus aid the surgeons. Further

discussion of the principles of trimming speci-
mens is outside the scope of this chapter.
Tissue Processing
Once the biopsy specimen has been examined,
cut, and placed in a cassette, it remains in formol
saline until it is processed. The aim of tissue
processing of fixed tissue is to infiltrate the tissue
with wax so it forms a solid block that can be cut
with a microtome to form tissue sections. For
fresh tissues, a block is formed by freezing the
tissue in liquid nitrogen and further processing is
not necessary. In most laboratories the cassettes
are processed in an automatic tissue processor
overnight that dehydrates the tissue using increas-
ing concentrations of alcohol. After dehydration
the tissue is “cleared” with xylene to remove the
alcohol.
Using an embedding center, a specialist labora-
tory scientist will then open the cassette, place the
tissue in a mold, and carefully check if the speci-
Fig. 9 A tissue block from the excision margin of a
men is still orientated correctly. The mold is then malignancy. The tissue is embedded in wax and the mar-
filled with molten wax and a cassette is placed on gins are marked with blue ink
top and the whole thing is allowed to solidify on a
cold plate. A tissue block is thus formed (Fig. 9).
Cutting and Staining Tissue Sections

Very thin sections, approximately 4–5 μ in thick-
ness, are cut from the paraffin blocks using
a microtome. This is a skilled procedure and is
carried out by a laboratory scientist who has to
ensure the sections transferred to the glass slides
are representative of the tissue sample. It is par-
ticularly important that the whole of the cut sur-
face of the specimen is present in the section.
Once the sections have been cut, they are gently
placed in a warm water bath to allow them to
“spread.” The sections are then transferred to a
glass slide and allowed to dry in an oven to
increase adherence of the tissue sections.
Before staining of the tissue sections can take
place, the wax must be removed using a solvent,
which is usually xylene. Once the staining is
completed, a coverslip is placed over the tissue
sections to make a permanent mount (Fig. 10).
Almost all tissue sections are examined initially
using a routine hematoxylin and eosin stain Fig. 10 A hematoxylin and eosin stained section
Table 8 Common histochemical stains used in histopathological diagnosis

Purpose Stains used Indications
Detection of fungi such as Periodic-Acid Schiff Fungal infections of oral cavity and sinuses, e.g., chronic
Candida albicans Grocott hyperplastic candidosis, aspergillosis in antrum
Detection of Ziehl Neelsen Distinguishes tuberculosis from other causes of granulomatous
Mycobacterium Auramine inflammation
tuberculosis Rhodamine
To identify amyloid Congo red Distinguishes amyloid from other eosinophilic/hyaline deposits.
Does not distinguish between types
To detect melanin Masson Fontana Important in diagnosis of pigmented lesions: distinguishes
melanin from iron
To detect hemosiderin and Perls’ Prussian Blue Important in diagnosis of pigmented lesions: distinguishes iron
iron deposition from melanin
To detect glycogen and Periodic acid Schiff Important in the diagnosis of salivary gland tumors
mucins Periodic acid Schiff
with diastase
Alcian blue
(H&E). Hematoxylin is a basic dye that stains

nuclei blue/purple and eosin is an acidic dye
that stains the cytoplasm and extracellular connec-
tive tissues pink. Sometimes special stains are
used in diagnosis and these are described below.
Histopathological Diagnosis
A pathologist will initially read the request form

from the clinician and examine the appropriate
H&E stained slides provided by the laboratory.
In many cases they are able to make a firm diag-
nosis based on the histopathological features of Fig. 11 Periodic-Acid Schiff stain of superficial oral epi-
thelium in chronic hyperplastic candidosis. Fungal hyphae
the sample and the clinical information provided.
are indicated by black arrows and glycogen in the epithelial
In some cases, it is necessary to examine more cells and neutrophils by asterisks (*)
tissue to ensure the correct diagnosis. A request
is sent to the laboratory for “levels” – additional
sections usually taken at 100 μ apart. numbers if possible. This may be essential to
The pathologist may also need additional monitor progression of a lesion over time.
clinical information and often it is helpful to see
clinical images, especially if the clinical informa- Histochemical Stains
tion given is scant. If the lesion is intra-bony, it is Almost all tissue sections are examined using a
often essential for accurate diagnosis that the routine H&E stain that stains nuclei blue/purple
pathologist can examine the appropriate radiolog- and the cytoplasm of cells pink/red. However
ical imaging. sometimes other stains are required to detect addi-
It is good practice for a pathologist to review tional histopathological features, such as fungal
slides from previous biopsies if they are relevant hyphae and microorganisms (Table 8) (Figs. 11,
to the current biopsy. It is useful if the clinician 12, 13, and 14). It is not necessary for an oral
indicates whether previous biopsies have been medicine specialist to request these, but it
taken and also give the relevant accession does help the pathologist if adequate clinical
Fig. 12 Hematoxylin and eosin stained section of amyloid deposition in oral mucosa (a). The amyloid shows positive
staining with Congo red (b)
Fig. 13 Hematoxylin and eosin stained section showing hemosiderin deposition in hemangioma (a). The hemosiderin
stains positively for iron with Perls’ Prussian Blue (b)
information and a provisional diagnosis indicat- denatures the autoantibodies and renders their
ing their potential presence are given. detection impossible. It is good practice to take
two biopsies, one from the lesion placed in for-
Immunofluorescence malin and a second for immunofluorescence from
Immunofluorescence is used to detect autoanti- adjacent clinically unaffected mucosa, placed in
bodies in the patient’s tissues and occasionally Michel’s solution or sterile saline.
the serum and is particularly relevant in the diag- All antibodies have a similar structure with a
nosis of pemphigus and pemphigoid and other variable and a fixed region. The variable region
autoimmune vesiculobullous disorders. Tissue binds the antigen leaving the fixed tail region free.
should be sent fresh to the laboratory as fixative The structure of the fixed tail region is constant
Fig. 14 Hematoxylin and eosin stained section of a muco-epidermoid carcinoma showing cystic spaces (a). Staining
with Periodic-Acid Schiff with Diastase shows the cysts are filled with mucin (b)
Fig. 15 Diagram showing

the theoretical basis of
direct immunofluorescence. Fluorescent
The autoantibody is the labelled
patient’s antibody that is mouse/rat/rab
bit
directed towards specific
anti-human
self-antigens depending
antibody
upon the disease, for
example desmoglein 1 or
3 in pemphigus vulgaris.
The fluorescently labelled Autoantibody
anti-human antibody can be binding to
epithelial cells
raised in a number of
different animals and is
usually directed against a
specific antibody isotope, Epithelial
such as human IgG cells
within any given antibody class so that all IgG patient’s serum is incubated with either normal
antibodies have the same fixed tail region as do all oral mucosa, skin, or monkey esophagus (Aoki
IgA antibodies and so forth. The immunofluores- et al. 2010). The autoantibodies in the patient’s
cence test uses antibodies raised in another spe- serum will bind with the appropriate antigen in the
cies, such as mouse, rabbit, or rat, against the fixed skin or mucosa. These autoantibodies are detected
tail region of human IgG, IgA, and IgM to detect using fluorescent-labeled antihuman antibodies in
the autoantibodies bound in the patient’s tissues. the same manner as direct immunofluorescence.
These antihuman antibodies (mouse, rat, or rab- The sensitivity of indirect immunofluorescence
bit) are linked to a fluorescent marker that can using normal mucosal or skin is relatively low in
be visualized using a fluorescent microscope subepithelial blistering disorders, such as bullous
(Fig. 15). In addition to immunoglobulins, direct and mucosal pemphigoid, and may be improved
immunofluorescence can also be used to assess by the use of salt split skin (Woodley 1990). The
the presence of complement (C3) again using skin is incubated in a 1 M NaCl (sodium chloride)
antihuman antibodies raised in another species. solution that results in artificial separation of the
Indirect immunofluorescence assesses skin through the basement membrane at the level
whether autoantibodies are present in the serum of the lamina lucida. This exposes the antigens
in vesiculobullous disorders. In this test the and increases the sensitivity (Kneisel and Hertl
2011). It also aids in diagnosis since the autoanti- against desmoglein 1 and their effects are
bodies may bind either on the epidermal or the counteracted by high levels of desmoglein 3
dermal side of the split. For example, the autoan- (Mahoney et al. 1999).
tibodies bind to the epidermal side of the split in Pemphigoid, whether bullous or mucous mem-
bullous pemphigoid and to the dermal side of the brane, is characterised by a linear deposition of
split in epidermolysis bullosa acquisita (Kneisel autoantibody at the basement membrane zone
and Hertl 2011). (Fig. 17). Usually IgG and/or C3 is deposited,
The diagnosis of pemphigus, pemphigoid, and but in addition occasionally IgA and/or IgM may
other autoimmune blistering disorders is con- be seen (Chan et al. 2002). Linear IgA disease is
firmed by the pattern of staining and the type of characterized by IgA and occasionally IgM
antibody deposited (Kershenovich et al. 2014). deposition (Betts et al. 2009). Other patterns of
For example, in pemphigus vulgaris IgG (which immunoglobulin deposition are seen in other
binds to the desmosomal component desmoglein blistering disorders. For example, in dermatitis
3) and C3 are deposited around the surface of the herpetiformis, there may be granular deposition
keratinocytes in the prickle cell layer resulting in of IgA in the connective tissue at the tips of the
a fish-scale appearance (Fig. 16). In pemphigus connective tissue papillae.
foliaceus, IgG and C3 may be deposited higher up Direct and indirect immunofluorescence
in the prickle cell layer than seen in pemphigus does not detect which antigens are targeted by
vulgaris. Pemphigus foliaceus is very rare in the autoantibodies merely where in the tissue the
the oral cavity as it is characterized by antibodies autoantibodies are present. Thus, it is not possible
to distinguish between different pemphigoid
subtypes whose antibodies target different
components of the hemidesmosomes or basement
membrane zone. Other tests are required to
do this.
Fig. 17 Direct immunofluorescent staining in pemphigoid

Fig. 16 Direct immunofluorescent staining in pemphigus showing a linear deposition of IgG at the basement mem-
vulgaris showing a “fish-scale” pattern of IgG around the brane reproduced by kind permission of Jaypee Brothers
cells in the prickle cell layer Medical Publishers (P) Ltd
Enzyme-linked immunosorbent assay (ELISA) Immunohistochemistry

is a method that can be used to detect either anti- Immunohistochemistry is used in the diagnosis of
bodies or antigen. In vesiculobullous disorders, certain pathological lesions when it is necessary
ELISA is usually used to detect specific autoanti- to reliably identify a tissue, cell, or organism. The
bodies (Heymann 2009). The basis of the test is basis of the test is that antibodies that are either
that a microtiter plate is coated with the appropriate directly or indirectly linked to a detection system,
antigen, for example, BP180, and then the patient’s such as hydrogen peroxidase or alkaline phospha-
serum is added. If antibodies that recognize BP180 tase, are used to detect antigens that are specific to
are present, they will bind to the plate and may be a cell or a restricted range of cell types (Table 9).
detected by antihuman antibodies conjugated to The immunostaining pattern is always interpreted
either alkaline phosphatase or horseradish peroxi- together with the H&E stained section and other
dase. These two enzymes are detected by chemical information. For example, S100 may be used to
means, and the strength of the reaction gives an identify nerves, Langerhans cells, myoepithelial
indication not only which antibodies are present cells, melanocytes, melanocytic nevi, melanoma,
but also their titre. ELISA may therefore be used as nerve sheath tumors, and granular cell tumors so
an adjunct to the diagnosis of vesiculobullous dis- it has a broad staining pattern (Figs. 18, 19, 20,
orders (Huang et al. 2007) as well as to monitor the 21, 22, 23, and 24). The significance of its expres-
effect of treatment and the progression of the dis- sion in a cell or group of cells is determined by
ease (Daneshpazhooh et al. 2007; Heymann 2009). other histopathological diagnostic criteria of the
ELISA has been shown to be more sensitive than particular lesion. Immunohistochemistry is useful
indirect immunofluorescence in detecting serum in diagnosing malignant neoplasms of uncertain
levels of autoantibodies in pemphigus vulgaris origin or type and also in the diagnosis of lym-
(Ishii et al. 1997), although this does not appear phoma. Most antibodies work on fixed paraffin
to be true in the diagnosis of pemphigoid where no embedded tissue and it is not necessary to send
difference in either sensitivity or specificity was tissue fresh.
found (Sárdy et al. 2013). Recent evidence sug-
gests that ELISA may be used to monitor salivary Molecular Diagnostic Pathology
levels of autoantibodies in mucosal pemphigus Genetic material is carried on chromosomes
vulgaris (Ali et al. 2016). that are composed of double-stranded deoxyri-
Immunoblotting (or western blotting) may also bonucleic acid (DNA). Each strand is made up
be used in the diagnosis of vesiculobullous disor- of bases: adenine, cytosine, guanine, and thymine.
ders, although it is more often used in research. Adenine on one-strand binds with thymine on the
Extracts of keratinocytes containing the putative opposing strand and guanine binds with cytosine.
antigenic targets are separated on a SDS-polyacryl- Portions of DNA that code for functionally impor-
amide gel by electrophoresis. The proteins are then tant ribonucleic acid (RNA) are known as genes.
transferred to a nitrocellulose membrane where When a gene, which codes for a polypeptide, is
they are reacted with antibodies contained within transcribed, an enzyme called RNA polymerase
the patient’s serum. Binding of these antibodies is uses the base pair sequence on the DNA to make
detected using an antihuman antibody conjugated complementary RNA. The resulting messenger
to either horseradish peroxidase or alkaline phos- RNA (mRNA) travels from the nucleus into the
phatase that is visualized by enzymatic means. cytoplasm where it enters the ribosomes. The
In summary diagnosis of vesiculobullous dis- mRNA is decoded to make the corresponding
orders is the result of careful clinical evaluation polypeptide.
and identification of autoantibodies in the tissues Polymerase chain reaction (PCR), real-time
and serum. This may be carried out by a combi- PCR, and reverse transcriptase (RT)-PCR are
nation of direct immunofluorescence, indirect means of generating multiple copies of the gene
immunofluorescence, ELISA, and more infre- of interest. The basic principle is that the DNA
quently immunoblotting. sequence of the gene is known and small primers
Table 9 Commonly used antibodies in histopathological diagnosis

Antibody
against Identifies Usage
Cytokeratins Intermediate filaments in epithelial cells; Identification of epithelial cells. Identification of
epithelial cells of differing origins have anaplastic carcinoma; origin of metastatic tumors;
different cytokeratin profiles diagnosis of salivary gland tumors
CD45 Lymphocytes Diagnosis of lymphoma and cells of uncertain
origin
S100 S100 protein on nerves, melanocytes, Diagnosis of nerve sheath tumors, melanoma,
Langerhans dendritic cells, myoepithelial cells salivary gland tumors
Desmin Intermediate filaments in muscle Diagnosis of leiomyoma and rhabdomyosarcoma
Smooth Intermediate filament in muscle, Useful to differentiate smooth muscle from striated
muscle actin myofibroblasts, and myoepithelial cells muscle. Also identifies myoepithelial cells in
(SMA) salivary gland tumors
p63 (and p40) Nuclear transcription factors strongly Diagnosis of squamous origin in undifferentiated
expressed in myoepithelial cells and squamous carcinomas. Useful myoepithelial marker in
epithelium salivary gland tumors
Kappa and Heavy chains on plasma cells Distinguishes plasmacytoma (monoclonal for
Lambda either kappa or lambda) from reactive (polyclonal)
plasma cell proliferations including plasma cell
gingivostomatitis
P16 Cell cycle protein regulator that is Acts as a surrogate marker to identify
overexpressed in response to high-risk HPV HPV-positive oropharyngeal carcinomas
infection
Ki 67 Cell cycle protein that is only expressed in Indicates the proliferative fraction of a tissue.
mitotically active cells and not seen in resting Important in diagnosis of malignancy
cells
Fig. 18 Hematoxylin and eosin staining of a peripheral epithelium are highlighted by immunohistochemistry for
odontogenic fibroma (a). Islands of odontogenic epithe- cytokeratins (b)
lium in the connective tissue as well as the surface
are generated that hybridize with the base of multiple copies of the gene that can then be
sequences either side of the gene. A heat stable visualized by electrophoresis on a gel. The advan-
DNA polymerase enzyme catalyzes the formation tages of this technique are that it is quick and
Fig. 19 Nasopharyngeal carcinoma stained with hema- staining for cytokeratins identifies the carcinoma cells (b).
toxylin and eosin: It is difficult to distinguish the carci- Immunohistochemical staining for CD45 identifies the
noma from the infiltrating lymphocytes that are lymphocytes (c)
characteristic of the malignancy (a). Immunohistochemical
sensitive, and it is robust in that it is able to early stages. The more copies of the gene that
amplify badly degraded DNA. However, its use are present in the tissues at the start of the reaction,
in diagnostic pathology is limited as the tissue is the greater the copy number will be early on in the
destroyed when the genetic material is removed reaction.
and it is only possible to indicate whether a par- Reverse transcriptase PCR (RT-PCR) is used
ticular gene is present, not where it is present in to detect mRNA in tissues or sample. A reverse
the tissue, nor in what quantity. transcriptase enzyme is able to generate cloned
Real-time PCR is a modification of the tech- DNA (cDNA) complementary to the mRNA of
nique that allows the amount of DNA present in a interest. The cDNA is then amplified by PCR or
sample to be quantified. It does this by tagging real-time PCR. The advantages of this technique
the sequence with a fluorescent dye and uses it to are the same as those of PCR, but the disadvantage
measure the amount of DNA generated in the is that it destroys the tissue sample and for
Fig. 20 Hematoxylin and eosin staining of a nerve sheath tumor (schwannoma) (a). The schwannoma stains positively
for S100 protein by immunohistochemistry (b)
pathological diagnosis the location of the mRNA Molecular techniques have been used to refine
is important. the classification of certain salivary gland tumors
In situ hybridization is used to detect mRNA and also to predict their behavior (Fonseca et al.
in tissue sections. A single-stranded RNA probe 2016). For example, specific translocations
is generated that is complementary to the mRNA have been detected by molecular techniques
of interest. The probe hybridizes with high effi- in mucoepidermoid carcinomas (Martins et al.
ciency to the mRNA and is detected by either 2004; Tonon et al. 2003), and the expression of
fluorescence (FISH) or biochemical means. In this CRTC1-MAML2 translocation is predictive
situ hybridization may also be used to detect of a better prognosis. Similarly, an ETV6-NTRK3
DNA sequences and gene rearrangements in tis- gene translocation identified a subset of acinic
sue sections. The advantage of in situ hybridiza- cell carcinomas that are now recognized as
tion is that it identifies where in the tissue the a new entity, known as mammary analogue
mRNA or DNA is expressed and it is used more secretory carcinoma of salivary glands (Skalova
frequently than PCR or RT-PCR in pathological et al. 2010).
diagnosis. Some viral infections may be detected by the
use of immunohistochemistry that identifies viral
proteins on tissue sections. However, it will only
Application of Molecular Biology detect viral infections that contain replicating
Techniques in Diagnosis virus and are producing protein and does not
detect latent or transcriptionally active virus. In
Molecular techniques are beginning to play situ hybridization is most commonly used to iden-
an increasingly important role in the diagnosis of tify specific viral mRNA or DNA in tissue sam-
malignancy and infectious disease affecting the ples as the technique preserves tissue integrity.
head and neck. At the current time, these include
salivary gland tumors, oropharyngeal cancers, Human Papilloma Virus
soft tissue neoplasms, and viral infections, Human papilloma virus (HPV) is a ubiquitous
although it is likely the range of diseases will virus that has recently come to prominence in
increase in the future. diseases of the oral cavity and oropharynx. It is a
Fig. 21 Hematoxylin and eosin staining of a basal cell immunohistochemical staining for P63 (c). The ductal cells
adenoma (a). The myoepithelial cells surrounding the duc- are identified by immunohistochemical stains for
tal cells are highlighted by immunohistochemical staining cytokeratin (d)
for SMA (b). The myoepithelial cells are also identified by
double-stranded DNA virus with up to 200 sub- However, the same is not true for oropharyn-
types identified to date (McBride 2017). The geal carcinoma and a small subset (less than 6%)
virus infects mucosa and skin and has a propen- (Lingen et al. 2013) of oral cancers that are
sity to infect cells in the basal layer. It then associated with high-risk HPV subtypes 16 and
replicates in the suprabasal cells and is shed 18 (but also 31 and 33). The incidence of oropha-
when the surface epithelial cells desquamate. ryngeal HPV-associated cancers is rising, and in
Human papilloma virus causes a number of the USA there has been a threefold increase
infections on the skin, in the oral cavity, and in between 1988 and 2004 (Chaturvedi et al. 2011).
the cervix. Some of the viruses are the so-called Similar increases have been reported in
low-risk subtypes (e.g., types 6, 8, 13, 32) and Western Europe, and it has been estimated that
are associated with squamous papilloma, verruca the number of HPV-positive oropharyngeal can-
vulgaris, condyloma acuminatum, and multi- cers will outnumber cervical cancers in the near
focal epithelial hyperplasia (Heck’s disease). future (Chaturvedi et al. 2011; Berman and
These lesions have specific histological features, Schiller 2017).
and it is unusual to request in situ hybridization Two proteins produced during the infection
to confirm the diagnosis. with high-risk HPV, E6 and E7 play a role in

eosin staining section of an
HPV-associated
non-keratinizing squamous
cell carcinoma of the
oropharynx (a). The
carcinoma stains positively
for P16 by
immunohistochemistry (b)
Fig. 23 Hematoxylin and eosin stained section of amy- light chains indicative of a monoclonal proliferation (b).
loid in the oral mucosa associated with dense accumula- Very few plasma cells staining positively for lambda light
tions of plasma cells (a). Immunohistochemistry shows a chains are evident (c)
predominance of plasma cells staining positively for kappa
with high-risk HPV. These lesions have been

detected on the basis of specific histological fea-
tures with confirmation of high-risk HPV infec-
tion using P16 and in situ hybridization (McCord
et al. 2013). At the present time, it is not clear
whether they have a higher risk of transforming
into oral cancer.
Herpes Viruses
Herpes are a family of DNA viruses that are
associated with a number of diseases affecting
the oral cavity. Those viruses that cause oral
symptoms or lesions include herpes simplex, var-
Fig. 24 A salivary neoplasm stained for Ki67 by immu- icella zoster, cytomegalovirus, Epstein-Barr virus,
nohistochemistry indicating the proliferative fraction of and human herpes eight (HHV8) virus. A biopsy
epithelial cells
is very rarely used in the diagnosis, but there are
two pathologies where a biopsy is frequently
driving the malignant transformation by interfering taken and it is necessary to determine the presence
with the cell cycle pathway. E7 inactivates the reti- of viral particles to confirm the diagnosis: hairy
noblastoma gene protein that results in the accumu- leukoplakia and Kaposi’s sarcoma. Hairy leuko-
lation of the tumor suppressor protein p16 (McBride plakia is associated with Epstein-Barr viral infec-
2017). HPV-positive tumors have different histo- tion, and this is detected by in situ hybridization
pathological features and a better prognosis than for the viral particle EBER (Fig. 25). Kaposi’s
HPV negative tumors, in that they may show a sarcoma is associated with HHV8 that may be
better response to chemo/radiotherapy (Wang et al. detected by immunohistochemistry (Fig. 26).
2015; Stevens and Bishop 2017). The WHO have Antibodies are also available to HSV1 and
recently classified these lesions as HPV-associated cytomegalovirus if tissue is taken as part of the
nonkeratinizing squamous cell carcinomas of the diagnostic procedure.
oropharynx (International Agency for Research on
Cancer 2017). For this reason, it is necessary to
confirm the HPV status of the cancer so that the Interpretation of Biopsy Results
treatment may be optimized. The best and most
specific method for identification of HPV is to use It is good practice to have a close working relation-
PCR or in situ hybridization, but these are not ship with the pathologist who will report the biop-
widely available and may be expensive. In routine sies taken. This is important so the pathologist has
practice therefore, staining for p16 by immunohis- confidence in the clinical information and biopsy
tochemistry in oropharyngeal carcinoma is specimen provided, and the oral medicine specialist
a surrogate marker, which is interpreted together has confidence in and is able to understand and
with the specific histopathological features (Westra interpret the pathologist’s report. Dialogue between
2014; Stevens and Bishop 2017). In squamous cell the two is essential in difficult cases.
carcinoma arising outside the oropharynx, p16
staining is not necessarily indicative of HPV infec- Histopathological Prognostic Factors
tion (Lingen et al. 2013), and if HPV infection is in Oral Potentially Malignant Disorders
suspected, it is necessary to confirm HPV infection and Oral Malignancy
by in situ hybridization or PCR.
Related to HPV-positive oropharyngeal can- Dysplasia
cers, it is now becoming apparent there is a subset Oral potentially malignant disorders are lesions
of oral dysplastic lesions that are also associated that have an increased risk of progressing to oral
Fig. 25 Hematoxylin and eosin stained section of hairy staining (b). Clear evidence of Epstein Barr viral infection
leukoplakia (a). Dense accumulations of fungal hyphae in identified by in-situ hybridization (c)
the superficial epithelial layers are identified by PAS
diseases or disorders that carry no increased risk for

cancer” (Warnakulasuriya et al. 2007). In order to
confirm the diagnosis and exclude other lesions, a
biopsy is necessary. The pathologist will report on
the histopathological features to confirm whether
the lesion is indeed a potentially malignant disor-
der. The degree of dysplasia is used as an indicator
of the risk of malignant transformation (Bouquot
et al. 2006; Reibel et al. 2017).
Dysplasia is the term given to abnormalities in
both the appearance and differentiation of cells
(known as atypia) as well as the architecture of
the oral epithelium.
Fig. 26 Immunohistochemical staining for HHV8 in
Kaposi sarcoma
There are a number of ways to grade the degree
of dysplasia, but that recommended by the WHO
divides dysplasia into mild, moderate, and severe
cancer (Warnakulasuriya and Ariyawardana (including carcinoma in situ) based on assessment
2016). Oral leukoplakia is the most common of of defined architectural and cytological changes
these lesions and is defined as a “white plaque of (International Agency for Research on Cancer
questionable risk having excluded (other) known 2017) (Table 10).
Table 10 Architectural Cytological changes Architectural changes

and cytological changes in
Abnormal variation in nuclear size Irregular epithelial stratification
the diagnosis of epithelial
dysplasia (International Abnormal variation in nuclear shape Loss of polarity of basal cells
Agency for Research on Abnormal variation in cell size Drop-shaped rete pegs
Cancer 2017) Abnormal variation in cell shape Increased numbers of mitotic figures
Increased nuclear to cytoplasmic ratio Abnormally superficial mitotic figures
Atypical mitotic figures Premature individual cell keratinization
Increased number and size of nucleoli Keratin pearls within rete ridges
Hyperchromasia Loss of epithelial cell cohesion
Table 11 Criteria for grading of oral epithelial dysplasia. (Adapted from Speight 2007)
Levels
Grade involved Cytological changes Architectural changes
Mild Lower Cell and nuclear pleomorphism Basal cell hyperplasia
third Nuclear hyperchromatism
Moderate Up to Cell and nuclear pleomorphism Disordered maturation from basal to
middle Anisocytosis and anisonucleosis squamous cells
third Nuclear hyperchromatism Loss of polarity Increased cellular density
Increased and abnormal mitotic Basal cell hyperplasia
figures Bulbous drop-shaped rete pegs
Severe (including Up to the Cell and nuclear pleomorphism Disordered maturation from basal to
carcinoma in situ) upper third Anisocytosis and anisonucleosis squamous cells
Nuclear hyperchromatism Increased cellular density
Increased and abnormal mitotic Basal cell hyperplasia
figures Dyskeratosis (premature keratinization
Enlarged nuclei and cells and keratin pearls deep in epithelium)
Hyperchromatic nuclei Increased Bulbous drop-shaped rete pegs
number and size of nucleoli Secondary extensions (nodules) on rete
Apoptotic bodies tips
Acantholysis
In general terms, mild dysplasia is diagnosed if the severity of the cytological and the architectural
cytological atypia affects the epithelial cells in the changes within a particular level. For instance,
lower third of the epithelium, moderate dysplasia marked cellular atypia and severe architectural
if it affects the epithelial cells in the lower two changes occurring within the lower third of the
thirds, and severe dysplasia where more than two epithelium may be sufficient to grade the dyspla-
thirds of the epithelium are affected by cellular sia as severe.
atypia. In the diagnosis of dysplasia in the uterine Diagnosis of the degree of dysplasia is to
cervix where human papilloma virus (HPV) is a certain degree subjective, and there is both
important in the etiology, this rule of grading intra- and interobserver variability with several
atypia depending on the extent or level of the studies showing only poor to moderate agreement
epithelium affected is more strictly applied. How- (Abbey et al. 1995; Karabulut et al. 1995; Bosman
ever, in the oral cavity, architectural changes also 2001; Warnakulasuriya et al. 2008; Speight et al.
play an important role in determining the degree 2015). However, there is a high level of agreement
of dysplasia (Table 11) (Figs. 27, 28, and 29). The between pathologists trained at the same institu-
grade of dysplasia may also change depending on tion, and a recent study has shown good
Fig. 27 Mild dysplasia.

Basal cell crowding,
nuclear hyperchromatism,
and enlargement as well as
anisonucleosis
(abnormality in shape) is
evident in the basal third of
the epithelium
(Hematoxylin and eosin
stain)
Fig. 28 Moderate
dysplasia. The epithelium
has a bulbous rete pattern,
and basal cell crowding,
nuclear enlargement,
anisonucleosis, and
individual cell
keratinization is seen in the
lower two thirds of the
epithelium (Hematoxylin
and eosin stain)
agreement on the grade of dysplasia between two diagnosis of dysplasia, one study demonstrated
pathologists (agreed 69.6% of diagnoses) that that there was highest agreement between pathol-
increased to 92.7% agreement after adjudication ogists on the number of mitotic figures, drop-
by a third pathologist (agreement of two out of shaped rete ridges, increased nuclear size, and
three pathologists) (Speight et al. 2015). In an abnormal variation in cell shape (Kujan et al.
attempt to ascertain which histopathological fea- 2007). There was least agreement on abnormal
tures contributed most to the variability of epithelial stratification, abnormal mitoses and
Fig. 29 Severe dysplasia.

The epithelium has a
proliferative bulbous rete
peg pattern, disordered
maturation, epithelial
crowding, and loss of
polarity; it shows marked
cellular atypia including
nuclear hyperchromatism,
anisonucleosis, and
anisocytosis. These changes
extend beyond the lower
two thirds of the epithelium
stain)
nuclear hyperchromatism, loss of basal cell polar- Thus it can be seen that the greater degree of
ity, and variation in nuclear size. These authors dysplasia, the greater the risk of malignant trans-
proposed an alternative binary method of grading formation. This correlates with the finding that
that divides dysplasia into low and high grade nonhomogeneous leukoplakia have a higher risk
(Kujan et al. 2006). In this system, the pathologist of malignant transformation than homogeneous
must decide whether the lesion has high-risk or leukoplakia and show a higher incidence of dys-
low-risk dysplasia. There is no intermediate cate- plasia (Schepman et al. 1998; Warnakulasuriya
gory. At present this grading system remains to and Ariyawardana 2016). However, there have
be fully validated, and it does not appear to been several studies that show dysplastic lesions
improve reliability of grading between patholo- do not necessarily progress but may stay the same
gists (Warnakulasuriya et al. 2008). The WHO or even regress (Silverman et al. 1976; Holmstrup
recommends the three-tier grading system should et al. 2006). For an individual patient, it is there-
continue to be used (International Agency for fore difficult to predict the risk of transformation
Research on Cancer 2017). based on dysplasia alone (Schepman et al. 1998;
The risk overall of leukoplakia transforming Napier and Speight 2008; Dost et al. 2014).
into malignancy is low, in the region of 0.1–2% There has been a considerable amount of work
(Bouquot et al. 2006; Speight 2007), but this to identify biomarkers that might predict whether
increases when dysplasia is taken into account or not a lesion will transform into squamous cell
(Mehanna et al. 2009). Approximately 50% of carcinoma. These include aneuploidy that shows a
leukoplakia show dysplasia, and the average positive correlation with malignant transforma-
transformation rate for lesions with severe dyspla- tion and severe dysplasia, oncogenes such as
sia is 16% with a range of 7–50% (Bouquot et al. EGFR (epidermal growth factor receptor) that
2006; Speight 2007). For lesions with moderate are responsible for cell growth and differentiation,
dysplasia, the transformation rate is 3–15%, and and tumor suppressor genes such as P53 that
for those with mild dysplasia, a very low transfor- effect cell signaling, genes controlling apoptosis,
mation rate of less than 5% is seen (Speight 2007). and loss of heterozygosity (Pitiyage et al. 2009;
Hunt et al. 2014). At the current time, although than those that are greater than 5 mm. A T1 tumor
these studies indicate the genetic changes that has a surface diameter <2 cm and a depth of
are taking place in potentially malignant disor- invasion less than 5 mm. A T2 tumor has either a
ders, they do not predict the risk of malignant surface diameter of less than 2 cm and a depth of
transformation. Thus dysplasia remains the best invasion between 5 and 10 mm or a surface diam-
current method to predict the risk of malignant eter between 2 and 4 cm and a depth of invasion of
transformation. <10 mm. A T3 tumor has a surface diameter
Some lesions have marked architectural of >4 cm or a tumor of any size with a depth of
changes and are considered high risk even though invasion of >10 mm.
the degree of cytological atypia is minimal. Infiltration of a tumor from the regional
Verruciform lesions, which may be present in lymph nodes through the lymph node capsule and
proliferative verrucous leukoplakia, are one into the surrounding tissues is known as extranodal
such example (Pentenero et al. 2014). It is there- extension (ENE). Although this may be detected
fore important for an oral medicine specialist to by imaging or clinical examination, it is best deter-
have a close working relationship with the pathol- mined by pathological examination (Fig. 30). ENE
ogist over such cases so the patient is treated has now been added to the latest pTNM staging as
appropriately. it is recognized that it has an adverse effect on
prognosis (Amin and Edge 2017).
Oral Cancer A pathologist may also report on other parame-
There have been many attempts to identify histo- ters that indicate prognosis. Guidelines on what is
pathological features that will reliably predict the considered “core” material and which should be
prognosis of a carcinoma, in particular the risk of included in a report are produced in several coun-
recurrence and metastasis. Identification enables tries including Australia, the USA, and the UK to
a clinician to reliably stage the cancer and plan ensure consistency in reporting (Dahlstrom et al.
management. 2012; Helliwell and Woolgar 2013; Richardson
The TNM system of clinical staging oral et al. 2012). In addition to the parameters of surface
cancer utilizes the surface diameter of the tumor diameter, depth of invasion, and ENE outlined
(T) and the presence of nodal (N) and distant above, the degree of differentiation and the pattern
metastasis (M) as measured clinically and radio- of invasion are important. The degree of differen-
logically (International Agency for Research on tiation is based on the original description of
Cancer) (Table 12). This staging system correlates Broders in 1922 and adopted by the WHO and is
well with prognosis. The pathological staging of a defined as well, moderately, or poorly differenti-
tumor measures the same parameters but takes ated (International Agency for Research on Cancer
place after the tumor has been excised. Thus the 2017). The most poorly differentiated part of the
surface diameter of the tumor and the presence of tumor is used as the grade and is prognostically
lymph node metastasis are more accurately deter- useful. The pattern of invasion of the tumor is most
mined. This staging is known as the pTNM sys- valuable in predicting metastasis particularly at the
tem, and at the end of a report on the excision of invasive front (Helliwell and Woolgar 2013;
cancer, it is usual to state the pTNM stage. Woolgar and Triantafyllou 2009). The pattern of
In the latest 8th edition of the TNM classifica- invasion measures how dis-cohesive the tumor
tion (Lydiatt et al. 2017; Brierley et al. 2016), the islands are and is reported as “cohesive” or “non-
depth of invasion of the tumor has been combined cohesive” (Fig. 31). A dis-cohesive pattern of inva-
with the surface diameter as the standard prognos- sion is associated with a higher risk of metastasis
tic indicator for oral cancer. Depth of invasion is and recurrence (Helliwell and Woolgar 2013). If
measured vertically from the level of the basement this is assessed at the advancing front, there is a
membrane of the adjacent epithelium, and 5 mm closer correlation with recurrence and metastasis
appears to be associated with a better prognosis (Woolgar and Scott 1995; Odell et al. 1994).
Table 12 Staging of oral cancer using the TNM clinical classification (adapted from the 8th Edition) (Brierley 2016)
T – Primary Tumor TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ
T1 Tumor 2 cm or less in greatest dimension and 5 mm or less depth of invasiona
T2 Tumor 2 cm or less in greatest dimension and more than 5 mm but no more than
10 mm depth of invasion or tumor more than 2 cm but not more than 4 cm in greatest
dimension and depth of invasion no more than 10 mm
T3 Tumor more than 4 cm in greatest dimension or more than 10 mm of invasion
T4a (Lip) Tumor invades through cortical bone, inferior alveolar nerve, floor of mouth,
or skin (of the chin or the nose)
T4a (Oral cavity) Tumor invades through the cortical bone of the mandible or maxillary
sinus, or invades the skin of the face
T4b (Lip and oral cavity) Tumor invades masticator space, pterygoid plates, or skull
base, or encases internal carotid artery
N – Regional Lymph NX Regional lymph nodes cannot be assessed
Nodes N0 No regional lymph node metastasis
N1 Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension
without extranodal extension
N2 Metastasis described as:
N2a Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than
6 cm in greatest dimension without extranodal extension
N2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest
dimension, without extranodal extension
N2c Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in
greatest dimension, without extranodal extension
N3a Metastasis in a lymph node more than 6 cm in greatest dimension without
extranodal extension
N3b Metastasis in a single or multiple lymph nodes with clinical extranodal extensionb
M – Distant metastasis M0 No distant metastasis
M1 Distant metastasis
pTNM Pathological Classification
The pT categories correspond to the clinical T categories
pN – Regional lymph pNX Regional lymph nodes cannot be assessed
nodes pN0 No regional lymph node metastasis
Histological examination pN1 Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension
of a selective neck without extranodal extension
dissection specimen will pN2 Metastasis described as:
ordinarily include 10 or pN2a Metastasis in a single ipsilateral lymph node, less than 3 cm in greatest
more lymph nodes. dimension with extranodal extension or more than 3 cm but not more than 6 cm in
Histological examination greatest dimension without extranodal extension
of a radical or modified pN2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest
radical neck dissection dimension, without extranodal extension
specimen will ordinarily pN2c Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in
include 15 or more lymph greatest dimension, without extranodal extension
nodes pN3a Metastasis in a lymph node more than 6 cm in greatest dimension without
pN3b Metastasis in a lymph node, more than 3 cm in greatest dimension with extranodal
extension or multiple ipsilateral or any contralateral or bilateral node(s) with extranodal
extension
Stage
Stage 0 Tis N0 M0
Stage I Tl N0 M0
Stage II T2 N0 M0
Stage III T3 N0 M0
T1, T2, T3 N1 M0
(continued)
Stage IVA T4a N0, N1 M0
T1, T2, T3, T4a N2 M0
Stage IVB Any T N3 M0
T4b Any N M0
Stage IVC Any T Any N M1
Note:
a
Superficial erosion alone of bone/tooth socket by gingival primary is not sufficient to classify a tumor as T4a
b
The presence of skin involvement or soft tissue invasion with deep fixation/tethering to underlying muscle or adjacent
structures or clinical signs of nerve involvement is classified as clinical extranodal extension
representative the incisional biopsy is of the

lesions as a whole.
A pathologist will also report on completeness
of excision for cancer resections and will measure
the distance of the cancer in millimeters from
the mucosal and deep margins. A tumor that is
greater than 5 mm from the margin is considered
completely excised, one that is between 1 and
5 mm from the margin is closely excised, and
one that is less than 1 mm from the margin is
incompletely excised (Woolgar 2006; Helliwell
and Woolgar 2013). A closely excised tumor, or
one with severe dysplasia at the margin, shows an
increased risk of local recurrence (Bradley et al.
2007; Langendijk et al. 2010). These features,
together with those outlined in the above para-
Fig. 30 Extra-nodal extension of tumor. Hematoxylin and graphs, provide information for the multi-
eosin staining of a lymph node containing metastatic tumor disciplinary cancer team meetings that discuss
that has extended through the capsule and into the sur- management of the patient.
rounding tissues
A pathologist will write a report based on the
provided material as well as the results of previous
Evidence of perineural extension ahead of the tests, the clinical history of the patient, and the
advancing front of the tumor is a bad prognostic current clinical features. This information is essen-
sign and predicts local recurrence and nodal tial for the pathologist to examine the tissue in the
metastases (Sethi et al. 2009; Rahima et al. appropriate manner, to order appropriate tests, and
2004; Binmadi and Basile 2011; Woolgar 2006). to issue a meaningful report. In addition, it is essen-
Evidence of invasion into lymphatic’s and blood tial that there are good lines of communication
vessels should also be reported, although surpris- between the oral medicine specialist and the pathol-
ingly it is a weak predictor of nodal metastases ogist. Failure at any of these points may lead to an
(Suzuki et al. 2007). Severe dysplasia adjacent to inaccurate report to the detriment of the patient.
a carcinoma and within 5 mm of the resection
margin is also one of the core items to be included.
Bone invasion is important in tumor staging. Precision Medicine
These parameters may be commented upon in
both incisional and excisional biopsies, but the Recently, the term “precision medicine”
accuracy of the assessment of some of these has become popular, fueled by scientific and
in an incisional biopsy depends on how political perspectives. It has superseded the term
Fig. 31 Hematoxylin and eosin stained section of carcinoma of the lip with a cohesive invasion pattern (a). Carcinoma of
the tongue showing a dis-cohesive invasion pattern (b)
“personalized medicine,” which was defined syn- reactions, in relation to genetic variants of metab-
onymously but then dismissed with the argument olism enzymes, transporters, or genes active in
physicians have always treated patients at a per- the immune responses underlying idiosyncratic
sonalized level. Many common medicines pre- reactions. HLA allele B*1502 is a marker for
scribed are ineffective in treating large numbers carbamazepine-induced Stevens-Johnson syn-
of patients. Adverse drug reaction (ADR) rates drome and toxic epidermal necrolysis in Han
in the USA increased between 1999 and 2006, Chinese. Genotyping all Asian individuals for
with higher ADR death rates observed among the allele has been recommended for patients
elderly individuals (Shepherd et al. 2012). In two prescribed carbamazepine (Ferrell and McLeod
Australian hospitals, the proportion of over 2008). Similarly TPMT levels aid systemic immu-
65 year olds with potential ADR-related medical nosuppressant selection and dose of azathioprine
admissions was 18.9%. Most (88.5%) ADR- and decrease the risk of bone marrow suppression
related admissions were considered preventable. (Hullah et al. 2015). Measuring glucose-6-phos-
The most frequently implicated drug classes phate dehydrogenase levels before prescribing
were diuretics (23.9%), agents acting on the dapsone prevents hemolytic anemia.
renin angiotensin system (16.4%), β-blocking The meaning of precision medicine and how
agents (7.1%), antidepressants (6.9%), and it is related to or different from other popular
antithrombotic agents (6.9%) (Nair et al. 2017). terms such as “stratified medicine,” “targeted ther-
Moreover, healthcare costs are increasing with an apy,” or “deep phenotyping” remains unclear.
aging population alongside chronic disease that Commonly used definitions of precision medicine
becomes more prevalent. include the following aspects.
Precision medicine starts with the patient. • Focus on result. Personalized treatment
However, rather than having a unique treatment strategies: some define precision medicine as
for each individual person, patients are subdivided “treatments targeted to the needs of individual
into groups based on their “molecular makeup,” patients on the basis of genetic, biomarker, phe-
using biomarkers. Through stratification, medical notypic or psychosocial characteristics that distin-
interventions can be tailored to be more effica- guish a given patient from other patients with
cious in a particular group of patients than similar clinical presentations” (Jameson and
under the currently dominant “one size fits all” Longo 2015).
approach. In addition, clinical implementation of • Focus on process and utilized data. Others
genomic biomarkers may allow the prediction of emphasize the data by describing precision med-
which patients are at high risk of serious adverse icine as a model that integrates clinical and other
data to stratify patients into novel subgroups; it is carcinoma (HNSCC) help better understand the
hoped that these have a common basis of disease genetic aspects of a tumor traditionally considered
susceptibility and manifestation and thus poten- environmental. An extensive literature detailing
tially allow for more precise therapeutic solu- the molecular changes involved in the develop-
tions (McGrath and Ghersi 2016). Some ment, prognosis, and management of HNSCC
potential advantages offered by this new now exists (Jessri and Farah 2014; Foy et al.
approach include: 2017; Li et al. 2018).
Numerous genetic mutations have been asso-
• Ability to make more informed medical ciated with susceptibility to chronic mucocutane-
decisions ous candidosis. It has been 5 years since
• Higher probability of desired outcomes thanks heterozygous gain-of-function mutations of
to better-targeted therapies STAT1 (STAT1-GOF) were first shown to cause
• Reduced probability of adverse reactions to an intriguing familial susceptibility to severe
medicines superficial fungal infection alongside autoim-
• Focus on prevention and prediction of disease mune disease. These mutations lead to defective
rather than reaction to it responses in type 1 and type 17 helper T cells (Th1
• Earlier disease intervention than has been pos- and Th17), which, depending on the mutation,
sible in the past also predispose to infection with Staphylococci,
• Improved healthcare cost containment Mycobacteria, and Herpesviridae. STAT1-GOF
mutations are the most common genetic etiology
The move toward precision medicine can be for chronic mucocutaneous candidosis (CMC),
seen as an evolutionary rather than revolution- and mutation analysis should be considered in
ary process. Although some precision medicine these patients. Identifying specific genetic defects
approaches have been introduced, we remain at in patients with CMC confirms the diagnosis,
an early stage of implementation. The imple- facilitates genetic counseling, and allows
mentation of precision medicine will result in a improved risk stratification and improved thera-
steep increase in the number of new screening peutic management strategies (Toubiana et al.
or diagnostic tests administered in clinical 2016).
practice. We have no validated screening tests advo-
cated for use in oral medicine practice. While it
is widely acknowledged, oral disease may be the
Conclusions and Future Directions presenting feature of a generalized disease pro-
cess, investigations should be appropriately
Evidence supports the transition of next- selected to answer the diagnostic question pro-
generation sequencing (NGS) technology from posed and not used as a “fishing exercise” for
research to clinical practice. While our knowledge the presence of other diseases unrelated to the
of the relationship between disease pathogenesis presenting symptoms and signs. The smallest
and genetic variations continues to expand, the number of tests should be ordered to provide the
cost to NGS equipment and operation continues greatest diagnostic yield. For example, if pemphi-
to fall. Ultimately this will enable relatively cheap gus vulgaris is suspected, an incisional biopsy
exploration of specific nucleic acid regions, large with direct immunofluorescence is the first-line
gene panels, whole exomes, genomes, trans- investigation and will provide a diagnosis. If the
criptomes, and the methylome. presentation is severe and systemic immunosup-
Although more than 90% of head and neck pression is needed, a further group of appropriate
tumors are squamous cell carcinoma, recent stud- tests should be requested. These should include
ies have revealed this tumor is very heteroge- a baseline indirect antibody titer to monitor
neous. NGS studies of head and neck squamous response to therapy. Investigations are expensive
and resources can be wasted by indiscriminate Alnuaimi AD, Ramdzan AN, Wiesenfeld D,
test use. Investigations should only be requested O’Brien-Simpson NM, Kolev SD, Reynolds EC,
McCullough MJ. Candida virulence and ethanol-
when they have impact on diagnosis, they con- derived acetaldehyde production in oral cancer
tribute directly to disease management, and the and non-cancer subjects. Oral Dis. 2016;22
outcomes are reviewed and actioned. Clinicians (8):805–14.
requesting any investigation need to understand Amber K, Bloom R, Hertl M. A systematic review with
pooled analysis of clinical presentation and immunodi-
the limitations of the test and be able to interpret agnostic testing in mucous membrane pemphigoid:
the result. association of anti-laminin-332 IgG with oropharyn-
geal involvement and the usefulness of ELISA. J Eur
Acad Dermatol Venereol. 2016;30(1):72–7.
Amin MB, Edge SB. AJCC cancer staging manual. 8th
Cross-References Edition, New York, Springer; 2017.
Aoki V, Sousa JX Jr, Fukumori LM, Périgo AM,
▶ Clinical Evaluation of Oral Diseases Freitas EL, Oliveira ZN. Direct and indirect immuno-
▶ Clinical Immunology in Diagnoses of Maxillo- fluorescence. An Bras Dermatol. 2010;85(4):490–500.
Arber N, Klein T, Meiner Z, Pras E, Weinberger A. Close
facial Disease association of HLA-B51 and B52 in Israeli patients
▶ Diagnostic Imaging Principles and Applica- with Behcet’s syndrome. Ann Rheum Dis. 1991;
tions in Head and Neck Pathology 50(6):351–3.
▶ Gingival Pathology Becker GJ, Waldburger M, Hughes GR, Pepys MB. Value
of serum C-reactive protein measurement in the inves-
▶ Head and Neck Tumors tigation of fever in systemic lupus erythematosus. Ann
▶ Interface Between Oral and Systemic Disease Rheum Dis. 1980;39(1):50–2.
▶ Non-odontogenic Bacterial Infections Benmassaoud A, Xie X, Alyafi M, Theoret Y, Bitton A,
▶ Oral and Maxillofacial Fungal Infections Afif W, Bessissow T. Thiopurines in the management
of Crohn’s disease: safety and efficacy profile in
▶ Oral and Maxillofacial Viral Infections patients with normal TPMT activity – a retrospective
▶ Oral Manifestations of Systemic Diseases and study. Can J Gastroenterol Hepatol. 2016;2016:
Their Treatments 1034834.
▶ Oral Mucosal Malignancies Berman TA, Schiller JT. Human papillomavirus in cervical
cancer and oropharyngeal cancer: one cause, two
▶ Oral Vesicular and Bullous Lesions diseases. Cancer. 2017;123:2219.
▶ Pigmented Lesions of the Oral Mucosa Betts A, Yeoman C, Farthing P. Oral mucosal involvement
▶ Soft and Hard Tissue Operative Investigations as the sole or main manifestation of linear IgA disease:
in the Diagnosis and Treatment of Oral Disease case report and review of the literature. Oral Surg.
2009;2(4):198–204.
▶ White and Red Lesions of the Oral Mucosa Bhattacharya PT, Misra SR, Hussain M. Nutritional
aspects of essential trace elements in oral health and
disease: an extensive review. Scientifica. 2016;2016:
5464373.
References Binmadi NO, Basile JR. Perineural invasion in oral squa-
mous cell carcinoma: a discussion of significance and
Abbey LM, Kaugars GE, Gunsolley JC, Burns JC, review of the literature. Oral Oncol. 2011;47(11):
Page DG, Svirsky JA, Eisenberg E, Krutchkoff DJ, 1005–10.
Cushing M. Intraexaminer and interexaminer reliability Bosman F. Dysplasia classification: pathology in disgrace?
in the diagnosis of oral epithelial dysplasia. Oral J Pathol. 2001;194(2):143–4.
Surg Oral Med Oral Pathol Oral Radiol Endod. Bossuyt X, Tervaert JC, Arimura Y, Blockmans D, Flores-
1995;80(2):188–91. Suárez LF, Guillevin L, Hellmich B, Jayne D,
Adams PC, Reboussin DM, Barton JC, McLaren CE, Jennette JC, Kallenberg CG. Position paper:
Eckfeldt JH, McLaren GD, Dawkins FW, Acton RT, revised 2017 international consensus on testing of
Harris EL, Gordeuk VR. Hemochromatosis and iron- ANCAs in granulomatosis with polyangiitis and
overload screening in a racially diverse population. microscopic polyangiitis. Nat Rev Rheumatol.
N Engl J Med. 2005;352(17):1769–78. 2017;13(11):683.
Ali S, Kelly C, Challacombe S, Donaldson A, Bhogal B, Bouquot JE, Speight PM, Farthing PM. Epithelial dyspla-
Setterfield J. Serum and salivary IgG and IgA anti- sia of the oral mucosa – diagnostic problems and
bodies to desmoglein 3 in mucosal pemphigus vulgaris. prognostic features. Curr Diagn Pathol. 2006;12(1):
Br J Dermatol. 2016;175(1):113–21. 11–21.
Bowen T, Cicardi M, Farkas H, Bork K, Longhurst HJ, Doan TN, Eisen DP, Rose MT, Slack A, Stearnes G,
Zuraw B, Aygoeren-Pürsün E, Craig T, Binkley K, McBryde ES. Interferon-gamma release assay for the
Hebert J. 2010 International consensus algorithm for diagnosis of latent tuberculosis infection: a latent-class
the diagnosis, therapy and management of hereditary analysis. PLoS One. 2017;12(11):e0188631.
angioedema. Allergy Asthma Clin Immunol. 2010; Dost F, Le Cao K, Ford P, Ades C, Farah C. Malignant
6(1):24. transformation of oral epithelial dysplasia: a real-world
Bradley PJ, MacLennan K, Brakenhoff RH, Leemans evaluation of histopathologic grading. Oral Surg Oral
CR. Status of primary tumour surgical margins in squa- Med Oral Pathol Oral Radiol. 2014;117(3):343–52.
mous head and neck cancer: prognostic implications. Curr Dubinsky MC, Lamothe S, Yang HY, Targan SR, Sinnett D,
Opin Otolaryngol Head Neck Surg. 2007;15(2):74–81. Théorêt Y, Seidman EG. Pharmacogenomics and
Brierley J, Gospodarowicz M, Wittekind C. TNM classifi- metabolite measurement for 6-mercaptopurine therapy
cation of malignant tumours. 8th ed. Chichester: Wiley; in inflammatory bowel disease. Gastroenterology.
2016. 2000;118(4):705–13.
Brigden ML. Clinical utility of the erythrocyte sedimenta- Esposito L, Poletti L, Maspero C, Porro A, Pietrogrande MC,
tion rate. Am Fam Physician. 1999;60(5):1443–50. Pavesi P, Dellepiane RM, Farronato G. Hyper-IgE syn-
Chan LS. Ocular and oral mucous membrane pemphigoid drome: dental implications. Oral Surg Oral Med Oral
(cicatricial pemphigoid). Clin Dermatol. 2012;30(1): Pathol Oral Radiol. 2012; 114(2):147–53.
34–7. Fernando MM, Isenberg DA. How to monitor SLE
Chan LS, Ahmed AR, Anhalt GJ, Bernauer W, Cooper KD, in routine clinical practice. Ann Rheum Dis. 2005;
Elder MJ, Fine J, Foster CS, Ghohestani R, 64(4):524–7.
Hashimoto T. The first international consensus on Ferrell PB, McLeod HL. Carbamazepine, HLA-B* 1502
mucous membrane pemphigoid: definition, diagnostic and risk of Stevens–Johnson syndrome and toxic
criteria, pathogenic factors, medical treatment, and epidermal necrolysis: US FDA recommendations.
prognostic indicators. Arch Dermatol. 2002;138(3): Pharmacogenomics. 2008;9:1543.
370–9. Fonseca FP, Sena Filho M, Altemani A, Speight PM,
Chaturvedi AK, Engels EA, Pfeiffer RM, Hernandez BY, Vargas PA. Molecular signature of salivary gland
Xiao W, Kim E, Jiang B, Goodman MT, Sibug- tumors: potential use as diagnostic and prognostic
Saber M, Cozen W. Human papillomavirus and rising marker. J Oral Pathol Med. 2016;45(2):101–10.
oropharyngeal cancer incidence in the United States. Foy J, Saintigny P, Goudot P, Schouman T, Bertolus C. The
J Clin Oncol. 2011;29(32):4294–301. promising impact of molecular profiling on treatment
Cowart BJ. Taste dysfunction: a practical guide for oral strategies in oral cancers. J Stomatol Oral Maxillofac
medicine. Oral Dis. 2011;17(1):2–6. Surg. 2017;118:242.
Dahlstrom J, Coleman H, Johnson N, Salisbury E, Fussner LA, Hummel AM, Schroeder DR, Silva F, Cartin-
Veness M, Morgan G. Oral structured reporting proto- Ceba R, Snyder MR, Hoffman GS, Kallenberg CG,
col. Surry Hills: The Royal College of Pathologists of Langford CA, Merkel PA. Factors determining the
Australasia; 2012. clinical utility of serial measurements of antineutrophil
Daneshpazhooh M, Chams-Davatchi C, Khamesipour A, cytoplasmic antibodies targeting proteinase 3. Arthritis
Mansoori P, Taheri A, Firooz A, Mortazavi H, Rheumatol. 2016;68(7):1700–10.
Esmaili N, Dowlati Y. Desmoglein 1 and 3 enzyme- Gabay C, Kushner I. Acute-phase proteins and other
linked immunosorbent assay in Iranian patients with systemic responses to inflammation. N Engl J Med.
pemphigus vulgaris: correlation with phenotype, sever- 1999;340(6):448–54.
ity, and disease activity. J Eur Acad Dermatol Venereol. Gaitonde S, Samols D, Kushner I. C-reactive protein
2007;21(10):1319–24. and systemic lupus erythematosus. Arthritis Care Res.
Decani S, Federighi V, Baruzzi E, Sardella A, Lodi G. 2008;59(12):1814–20.
Iatrogenic Cushing’s syndrome and topical steroid ther- Gale G, Östman S, Rekabdar E, Torinsson Naluai Å,
apy: case series and review of the literature. J Dermatol Högkil K, Hasséus B, Saalman R, Jontell M.
Treat. 2014;25(6):495–500. Characterisation of a Swedish cohort with orofacial
Di Zenzo G, Amber KT, Sayar BS, Müller EJ, granulomatosis with or without Crohn’s disease. Oral
Borradori L. Immune response in pemphigus and Dis. 2015;21(1):e98.
beyond: progresses and emerging concepts. Semin Gavrilă B, Ciofu C, Stoica V. Biomarkers in Rheumatoid
Immunopathol. 2016;38:57–74. Springer Arthritis, what is new? J Med Life. 2016;9(2):144.
Diaz MH, Winchell JM. The evolution of advanced molec- Goldenberg BA, Rawsthorne P, Bernstein CN. The utility
ular diagnostics for the detection and characterization of 6-thioguanine metabolite levels in managing patients
of Mycoplasma pneumoniae. Front Microbiol. 2016; with inflammatory bowel disease. Am J Gastroenterol.
7:232. 2004;99(9):1744–8.
Dima A, Opris D, Jurcut C, Baicus C. Is there still a place González-Lama Y, Gisbert JP. Monitoring thiopurine
for erythrocyte sedimentation rate and C-reactive pro- metabolites in inflammatory bowel disease. Frontline
tein in systemic lupus erythematosus? Lupus. 2016; Gastroenterol. 2016. https://doi.org/10.1136/flgastro-
25(11):1173–9. 2015-100681.
Goules AV, Tzioufas AG. Primary Sjӧgren’s syndrome: of autoantibodies in pemphigus using antigen-
clinical phenotypes, outcome and the development of specific enzyme-linked immunosorbent assays with
biomarkers. Autoimmun Rev. 2016;15(7):695–703. baculovirus-expressed recombinant desmogleins.
Gouvêa AF, Ribeiro ACP, León JE, Carlos R, J Immunol. 1997;159(4):2010–7.
de Almeida OP, Lopes MA. Head and neck amyloid- Jain S, Gautam V, Naseem S. Acute-phase proteins: as diag-
osis: clinicopathological features and immunohisto- nostic tool. J Pharm Bioallied Sci. 2011;3(1): 118–27.
chemical analysis of 14 cases. J Oral Pathol Med. Jameson JL, Longo DL. Precision medicine – personal-
2012;41(2):178–85. ized, problematic, and promising. Obstet Gynecol Surv.
Grutters JC, Fellrath J, Mulder L, Janssen R, van 2015;70(10):612–4.
den Bosch JMM, van Velzen-Blad H. Serum soluble Jessri M, Farah CS. Next generation sequencing and its
interleukin-2 receptor measurement in patients with application in deciphering head and neck cancer. Oral
sarcoidosis: a clinical evaluation. Chest. 2003;124:186. Oncol. 2014;50(4):247–53.
Gungor S, Ozseker F, Yalcinsoy M, Akkaya E, Joly P, Richard C, Gilbert D, Courville P, Chosidow O,
Can G, Eroglu H, Genc NS. Conventional markers Roujeau J, Beylot-Barry M, D’Incan M, Martel P,
in determination of activity of sarcoidosis. Int Lauret P. Sensitivity and specificity of clinical, histo-
Immunopharmacol. 2015;25(1):174–9. logic, and immunologic features in the diagnosis
Hansen TJ, Lucking S, Miller JJ, Kirby JS, Thiboutot DM, of paraneoplastic pemphigus. J Am Acad Dermatol.
Zaenglein AL. Standardized laboratory monitoring 2000;43(4):619–26.
with use of isotretinoin in acne. J Am Acad Dermatol. Kamisawa T, Okazaki K. Diagnosis and treatment of IgG4-
2016;75(2):323–8. related disease. In K Okazaki (ed) IgG4-Related Dis-
Hatemi G, Seyahi E, Fresko I, Talarico R, Hamuryudan V. ease. Current Topics in Microbiology and Immunology,
Behçet’s syndrome: a critical digest of the 2014–2015 Cham, Springer; 2017;401:19–33.
literature. Clin Exp Rheumatol. 2015;33(6 Suppl 94): Karabulut A, Reibel J, Therkildsen MH, Praetorius F,
S3–14. Nielsen H, Dabelsteen E. Observer variability in the
Helliwell T, Woolgar J. Dataset for histopathology histologic assessment of oral premalignant lesions.
reporting of mucosal malignancies of the oral cavity. J Oral Pathol Med. 1995;24(5):198–200.
London, The Royal College of Pathologists; 2013. Kershenovich R, Hodak E, Mimouni D. Diagnosis and
Henkin RI, Schecter PJ, Friedewald WT, Demets DL, classification of pemphigus and bullous pemphigoid.
Raff M. A double blind study of the effects of zinc Autoimmun Rev. 2014;13(4):477–81.
sulfate on taste and smell dysfunction. Am J Med Sci. Khoshbaten M, Pishahang P, Nouri M, Lashkari A,
1976;272(3):285–99. Alizadeh M, Rostami-Nejad M. Diagnostic value of
Heymann WR. Enzyme-linked immunosorbent assay fecal calprotectin as a screening biomarker for gastro-
and immunobullous disease. J Am Acad Dermatol. intestinal malignancies. Asian Pac J Cancer Prev.
2009;60(4):676–8. 2014;15(4):1667–70.
Holmstrup P, Vedtofte P, Reibel J, Stoltze K. Long-term Kingston M, French P, Higgins S, McQuillan O,
treatment outcome of oral premalignant lesions. Oral Sukthankar A, Stott C, McBrien B, Tipple C,
Oncol. 2006;42(5):461–74. Turner A, Sullivan A. UK national guidelines on
Huang C, Chen C, Wang C, Chang Y, Liu H. Using the management of syphilis 2015. Int J STD AIDS.
desmoglein 1 and 3 enzyme-linked immunosorbent 2016;27(6):421–46.
assay as an adjunct diagnostic tool for pemphigus. Kneisel A, Hertl M. Autoimmune bullous skin diseases.
J Chin Med Assoc. 2007;70(2):65–70. Part 2: diagnosis and therapy. J Dtsch Dermatol Ges.
Hullah E, Blaker P, Marinaki A, Escudier M, 2011;9(11):927–47.
Sanderson J. A practical guide to the use of thiopurines Koek A, Bruisten S, Dierdorp M, van Dam A,
in oral medicine. J Oral Pathol Med. 2015;44(10): Templeton K. Specific and sensitive diagnosis of syph-
761–8. ilis using a real-time PCR for Treponema pallidum.
Hunt JL, Barnes L, Lewis JS, Mahfouz ME, Slootweg PJ, Clin Microbiol Infect. 2006;12(12):1233–6.
Thompson LD, Cardesa A, Devaney KO, Gnepp DR, Kujan O, Oliver RJ, Khattab A, Roberts SA, Thakker N,
Westra WH. Molecular diagnostic alterations in squa- Sloan P. Evaluation of a new binary system of grading
mous cell carcinoma of the head and neck and potential oral epithelial dysplasia for prediction of malignant
diagnostic applications. Eur Arch Otorhinolaryngol. transformation. Oral Oncol. 2006;42(10):987–93.
2014;271(2):211–23. Kujan O, Khattab A, Oliver RJ, Roberts SA, Thakker N,
International Agency for Research on Cancer. WHO clas- Sloan P. Why oral histopathology suffers inter-observer
sification of head and neck tumours. 4th ed. France, variability on grading oral epithelial dysplasia: an
IARC; 2017. attempt to understand the sources of variation. Oral
Ishii K. Importance of serological tests in diagnosis of Oncol. 2007;43(3):224–31.
autoimmune blistering diseases. J Dermatol. 2015; Kumar A, Sharma S, Sharma P, Chandra O, Singhal K,
42(1):3–10. Amit N. Beneficial effect of oral zinc in the treatment
Ishii K, Amagai M, Hall RP, Hashimoto T, Takayanagi A, of oral submucous fibrosis. Indian J Pharmacol. 1991;
Gamou S, Shimizu N, Nishikawa T. Characterization 23(4):236.
Langendijk JA, Ferlito A, Takes RP, Rodrigo JP, Suárez C, Mao R, Xiao Y, Gao X, Chen B, He Y, Yang L, Hu P,
Strojan P, Haigentz M, Rinaldo A. Postoperative strat- Chen M. Fecal calprotectin in predicting relapse of
egies after primary surgery for squamous cell carci- inflammatory bowel diseases: a meta-analysis of pro-
noma of the head and neck. Oral Oncol. 2010;46(8): spective studies. Inflamm Bowel Dis. 2012;18(10):
577–85. 1894–9.
Lee MT, Won JGS, Lee TI, Yang HJ, Da Lin H, Tang KT. Martins C, Cavaco B, Tonon G, Kaye FJ, Soares J,
The relationship between morning serum cortisol and Fonseca I. A study of MECT1-MAML2 in mucoepi-
the short ACTH test in the evaluation of adrenal insuf- dermoid carcinoma and Warthin’s tumor of salivary
ficiency. Chin Med J (Taipei). 2003;65(12):580–7. glands. J Mol Diagn. 2004;6(3):205–10.
Lee MN, Kang B, Choi SY, Kim MJ, Woo SY, Kim JW, Maślińska M, Mańczak M, Wojciechowska B,
Choe YH, Lee SY. Relationship between azathioprine Kwiatkowska B. The prevalence of ANA antibodies,
dosage, 6-thioguanine nucleotide levels, and therapeu- anticentromere antibodies, and anti-cyclic citrullinated
tic response in pediatric patients with IBD treated peptide antibodies in patients with primary Sjögren’s
with azathioprine. Inflamm Bowel Dis. 2015;21(5): syndrome compared to patients with dryness symptoms
1054–62. without primary Sjögren’s syndrome confirmation.
Leger S, Picard D, Ingen-Housz-Oro S, Arnault J, Aubin F, Reumatologia. 2017;55(3):113.
Carsuzaa F, Chaumentin G, Chevrant-Breton J, Matsuo FS, Barbosa de Paulo LF, Servato JPS,
Chosidow O, Crickx B. Prognostic factors of para- de Faria PR, Cardoso SV, Loyola AM. Involvement
neoplastic pemphigus. Arch Dermatol. 2012;148(10): of oral tissues by AL amyloidosis: a literature review
1165–72. and report of eight new cases. Clin Oral Investig.
Lennard L, Van Loon JA, Weinshilboum RM. Pharmaco- 2016;20(8):1913–20.
genetics of acute azathioprine toxicity: relationship to McBride AA. Oncogenic human papillomaviruses. Philos
thiopurine methyltransferase genetic polymorphism. Trans R Soc Lond B Biol Sci. 2017;372(1732). https://
Clin Pharmacol Ther. 1989;46(2):149–54. doi.org/10.1098/rstb.2016.0273.
Li C, Shen Z, Bavarian R, Yang F, Bhattacharya A. Oral McCord C, Xu J, Xu W, Qiu X, McComb RJ, Perez-
cancer: genetics and the role of precision medicine. Ordonez B, Bradley G. Association of high-risk
Dent Clin North Am. 2018;62(1):29–46. human papillomavirus infection with oral epithelial
Lingen MW, Xiao W, Schmitt A, Jiang B, Pickard R, dysplasia. Oral Surg Oral Med Oral Pathol Oral Radiol.
Kreinbrink P, Perez-Ordonez B, Jordan RC, 2013;115(4):541–9.
Gillison ML. Low etiologic fraction for high-risk McCullough M, Jaber M, Barrett A, Bain L, Speight P,
human papillomavirus in oral cavity squamous cell Porter S. Oral yeast carriage correlates with presence
carcinomas. Oral Oncol. 2013;49(1):1–8. of oral epithelial dysplasia. Oral Oncol. 2002;
Longmore M, Wilkinson I, Baldwin A, Wallin E. Oxford 38(4):391–3.
handbook of clinical medicine. Oxford: Oxford McGrath S, Ghersi D. Building towards precision medi-
University Press; 2014. cine: empowering medical professionals for the next
Lowe NM. Assessing zinc in humans. Curr Opin Clin Nutr revolution. BMC Med Genomics. 2016;9(1):23.
Metab Care. 2016;19(5):321–327. Mehanna HM, Rattay T, Smith J, McConkey CC. Treat-
Lydiatt WM, Patel SG, O’Sullivan B, Brandwein MS, ment and follow-up of oral dysplasia – a systematic
Ridge JA, Migliacci JC, Loomis AM, Shah JP. Head review and meta-analysis. Head Neck. 2009;31(12):
and neck cancers – major changes in the American 1600–9.
Joint Committee on cancer eighth edition cancer Mizejewski G. Alpha-fetoprotein (AFP) and inflammation:
staging manual. CA Cancer J Clin. 2017;67(2): is AFP an acute and/or chronic phase reactant?
122–37. J Hematol Thrombo Dis. 2015;3:191.
Lynch RJ. Zinc in the mouth, its interactions with dental Moutsopoulos HM, Elkon KB, Mavridis AK,
enamel and possible effects on caries; a review of the Acritidis NC, Hughes GR, Pepys MB. Serum
literature. Int Dent J. 2011;61(s3):46–54. C-reactive protein in primary Sjogren’s syndrome.
Mahajan SK, Prasad AS, Lambujon J, Abbasi AA, Clin Exp Rheumatol. 1983;1(1):57–8.
Briggs WA, McDonald FD. Improvement of uremic Muthas D, Reznichenko A, Balendran CA, Böttcher G,
hypogeusia by zinc: a double-blind study. Am J Clin Clausen IG, Kärrman Mårdh C, Ottosson T, Uddin M,
Nutr. 1980;33(7):1517–21. MacDonald TT, Danese S. Neutrophils in ulcerative
Mahoney MG, Wang Z, Rothenberger K, Koch PJ, colitis: a review of selected biomarkers and their poten-
Amagai M, Stanley JR. Explanations for the clinical tial therapeutic implications. Scand J Gastroenterol.
and microscopic localization of lesions in pemphigus 2017;52(2):125–35.
foliaceus and vulgaris. J Clin Invest. 1999;103(4): Nair NP, Chalmers L, Bereznicki BJ, Curtain C,
461–8. Peterson GM, Connolly M, Bereznicki LR. Adverse
Manfredi M, Polonelli L, Aguirre-Urizar J, Carrozzo M, drug reaction-related hospitalizations in elderly
McCullough M. Urban legends series: oral candidosis. Australians: a prospective cross-sectional study in two
Oral Dis. 2013;19(3):245–61. Tasmanian hospitals. Drug Saf. 2017;40(7):597–606.
Napier SS, Speight PM. Natural history of potentially periplakin in paraneoplastic pemphigus. Clin Chim
malignant oral lesions and conditions: an overview of Acta. 2009;410(1):13–8.
the literature. J Oral Pathol Med. 2008;37(1):1–10. Rahima B, Shingaki S, Nagata M, Saito C. Prognostic
National Institute for Health and Care Excellence. Irritable significance of perineural invasion in oral and oropha-
bowel syndrome in adults: diagnosis and management. ryngeal carcinoma. Oral Surg Oral Med Oral Pathol
National Institute of Health and Care Excellence, Lon- Oral Radiol Endod. 2004;97(4):423–31.
don; 2008. Reibel J, Gale N, Hille J. Ch 4; Section 4-3. World Health
National Institute for Health and Care Excellence. Organization classification of tumours of the head and
Rheumatoid arthritis in adults: management. London, neck. 4th ed. Lyon, France, IARC; 2017.
National Institute for Health and Care Excellence; Rendek Z, Falk M, Grodzinsky E, Wahlin K, Kechagias S,
2009. Svernlöv R, Hjortswang H. Effect of oral diclofenac
Novoa E, Gürtler N, Arnoux A, Kraft M. Role of intake on faecal calprotectin. Scand J Gastroenterol.
ultrasound-guided core-needle biopsy in the assess- 2016;51(1):28–32.
ment of head and neck lesions: a meta-analysis and Renton T. Burning mouth syndrome. Rev Pain. 2011;
systematic review of the literature. Head Neck. 2012; 5(4):12–7.
34(10):1497–503. Richardson MS, Barnes L, Carlson DL, Chan J, Ellis G,
Odell EW, Jani P, Sherriff M, Ahluwalia SM, Hibbert J, Harrison LB, Hunt JL, Shah J, Thompson LD, Hills C.
Levison DA, Morgan PR. The prognostic value of Protocol for the examination of specimens from
individual histologic grading parameters in small patients with carcinomas of the lip and oral cavity.
lingual squamous cell carcinomas. The importance 7th ed. Northfield: College of American Pathologists
of the pattern of invasion. Cancer. 1994;74(3): (CAP); 2012.
789–94. Salvarani C, Boiardi L, Mantovani V, Olivieri I, Ciancio G,
Osterman MT, Kundu R, Lichtenstein GR, Lewis JD. Cantini F, Salvi F, Malatesta R, Molinotti C, Govoni M,
Association of 6-thioguanine nucleotide levels and Trotta F, Filippini D, Paolazzi G, Viggiani M. Associ-
inflammatory bowel disease activity: a meta-analysis. ation of MICA alleles and HLA-B51 in Italian patients
Gastroenterology. 2006;130(4):1047–53. with Behcet’s disease. J Rheumatol. 2001;28(8):
Penner CR, Műller S. Head and neck amyloidosis: a clin- 1867–70.
icopathologic study of 15 cases. Oral Oncol. 2006; Salvarani C, Cantini F, Niccoli L, Macchioni P,
42(4):421–9. Consonni D, Bajocchi G, Vinceti M, Catanoso MG,
Pentenero M, Meleti M, Vescovi P, Gandolfo S. Oral pro- Pulsatelli L, Meliconi R. Acute-phase reactants and the
liferative verrucous leucoplakia: are there particular risk of relapse/recurrence in polymyalgia rheumatica:
features for such an ambiguous entity? A systematic a prospective followup study. Arthritis Care Res.
review. Br J Dermatol. 2014;170(5):1039–47. 2005;53(1):33–8.
Pertovaara M, Jylhava J, Uusitalo H, Pukander J, Helin H, Salvarani C, Cantini F, Hunder GG. Polymyalgia
Hurme M. Serum amyloid A and C-reactive protein rheumatica and giant-cell arteritis. Lancet. 2008;
concentrations are differently associated with markers 372(9634):234–45.
of autoimmunity in patients with primary Sjogren’s Sárdy M, Kostaki D, Varga R, Peris K, Ruzicka T. Com-
syndrome. J Rheumatol. 2009;36(11):2487–90. parative study of direct and indirect immunofluores-
Pisetsky DS. Antinuclear antibody testing – misunderstood cence and of bullous pemphigoid 180 and 230
or misbegotten? Nat Rev Rheumatol. 2017;13(8):495. enzyme-linked immunosorbent assays for diagnosis of
Pitiyage G, Tilakaratne W, Tavassoli M, Warnakulasuriya S. bullous pemphigoid. J Am Acad Dermatol. 2013;69
Molecular markers in oral epithelial dysplasia. J Oral (5):748–53.
Pathol Med. 2009;38(10):737–52. Schechter PJ, Friedewald WT, Bronzert DA, Raff MS,
Platt A. Understanding and treating disorders of the Henkin RI. Idiopathic hypogeusia: a description of the
clotting system. JAAPA. 2007;20(12):21–6. syndrome and a single-blind study with zinc sulfate. Int
Poot A, Diercks G, Kramer D, Schepens I, Klunder G, Rev Neurobiol. 1972;1:125–40.
Hashimoto T, Borradori L, Jonkman M, Pas H. Schepman K, van der Meij E, Smeele L, van der Waal I.
Laboratory diagnosis of paraneoplastic pemphigus. Malignant transformation of oral leukoplakia: a follow-
Br J Dermatol. 2013;169(5):1016–24. up study of a hospital-based population of 166 patients
Poudel-Tandukar K, Jacelon CS, Bertone-Johnson ER, with oral leukoplakia from The Netherlands. Oral
Palmer PH, Poudel KC. Serum albumin levels Oncol. 1998;34(4):270–5.
and depression in people living with Human Immuno- Schroeder LL, Tang X, Wasko MCM, Bili A. Glucocorti-
deficiency Virus infection: a cross-sectional study. coid use is associated with increase in HDL and no
J Psychosom Res. 2017;101:38–43. change in other lipids in rheumatoid arthritis patients.
Probst C, Schlumberger W, Stöcker W, Recke A, Rheumatol Int. 2015;35(6):1059–67.
Schmidt E, Hashimoto T, Zhu XJ, Zillikens D, Scully C, Greenman J. Halitology (breath odour:
Komorowski L. Development of ELISA for the specific aetiopathogenesis and management). Oral Dis.
determination of autoantibodies against envoplakin and 2012;18(4):333–45.
Scully C, Porter S. Oral mucosal disease: recurrent Steinbakk M, Naess-Andresen C, Fagerhol M, Lingaas E,
aphthous stomatitis. Br J Oral Maxillofac Surg. Dale I, Brandtzaeg P. Antimicrobial actions of calcium
2008;46(3):198–206. binding leucocyte L1 protein, calprotectin. Lancet.
Sethi S, Lu M, Kapke A, Benninger MS, Worsham MJ. 1990;336(8718):763–5.
Patient and tumor factors at diagnosis in a multi-ethnic Stevens TM, Bishop JA. HPV-related carcinomas of the
primary head and neck squamous cell carcinoma head and neck: morphologic features, variants, and
cohort. J Surg Oncol. 2009;99(2):104–8. practical considerations for the surgical pathologist.
Setterfield J, Shirlaw PJ, Kerr-Muir M, Neill S, Bhogal BS, Virchows Arch. 2017;471(2):295–307.
Morgan P, Tilling K, Challacombe SJ, Black MM. Studdy P, Bird R. Serum angiotensin converting enzyme in
Mucous membrane pemphigoid: a dual circulating anti- sarcoidosis – its value in present clinical practice. Ann
body response with IgG and IgA signifies a more severe Clin Biochem. 1989;26(1):13–8.
and persistent disease. Br J Dermatol. 1998; Su W, Yen A, Chiu S, Chen T. A community-based RCT
138(4):602–10. for oral cancer screening with toluidine blue. J Dent
Shepherd G, Mohorn P, Yacoub K, May DW. Adverse Res. 2010;89(9):933–7.
drug reaction deaths reported in United States vital Suzuki M, Suzuki T, Asai M, Ichimura K, Nibu K,
statistics, 1999–2006. Ann Pharmacother. 2012;46(2): Sugasawa M, Kaga K. Clinicopathological factors
169–75. related to cervical lymph node metastasis in a patient
Shiina T, Inoko H, Kulski J. An update of the HLA geno- with carcinoma of the oral floor. Acta Otolaryngol.
mic region, locus information and disease associations: 2007;127(Suppl 559):129–35.
2004. Tissue Antigens. 2004;64(6):631–49. Tanaka T, Kishimoto T. The biology and medical implica-
Shine B, de Beer F, Pepys M. Solid phase radioimmuno- tions of interleukin-6. Cancer Immunol Res. 2014;
assays for human C-reactive protein. Clin Chim Acta. 2(4):288–94.
1981;117(1):13–23. ter Borg EJ, Horst G, Limburg PC, van Rijswijk MH,
Shmerling RH, Delbanco TL. The rheumatoid factor: an Kallenberg CG. C-reactive protein levels during dis-
analysis of clinical utility. Am J Med. 1991;91(5): 528–34. ease exacerbations and infections in systemic lupus
Silverman S, Bhargava K, Mani N, Smith LW, erythematosus: a prospective longitudinal study.
Malaowalla A. Malignant transformation and natural J Rheumatol. 1990;17(12):1642–8.
history of oral leukoplakia in 57,518 industrial workers Thomas B, Bishop J. Manual of dietetic practice. Chiches-
of Gujarat, India. Cancer. 1976;38(4):1790–5. ter, West Sussex UK, Blackwell Publishing; 2007.
Sipe JD, Benson MD, Buxbaum JN, Ikeda S, Merlini G, Thornhill MH, Sankar V, Xu X, Barrett AW, High AS,
Saraiva MJ, Westermark P. Nomenclature 2014: amy- Odell EW, Speight PM, Farthing PM. The role
loid fibril proteins and clinical classification of the of histopathological characteristics in distinguishing
amyloidosis. Amyloid. 2014;21(4):221–224. amalgam-associated oral lichenoid reactions and oral
Skalova A, Vanecek T, Sima R, Laco J, Weinreb I, Perez- lichen planus. J Oral Pathol Med. 2006;35(4):233–40.
Ordonez B, Starek I, Geierova M, Simpson RH, Tilakaratne WM, Ekanayaka RP, Warnakulasuriya S.
Passador-Santos F, Ryska A, Leivo I, Kinkor Z, Oral submucous fibrosis: a historical perspective
Michal M. Mammary analogue secretory carcinoma and a review on etiology and pathogenesis. Oral
of salivary glands, containing the ETV6-NTRK3 Surg Oral Med Oral Pathol Oral Radiol. 2016;122
fusion gene: a hitherto undescribed salivary gland (2):178–91.
tumor entity. Am J Surg Pathol. 2010;34(5):599–608. Tonon G, Modi S, Wu L, Kubo A, Coxon AB, Komiya T,
Smith LA, Gaya DR. Utility of faecal calprotectin O’Neil K, Stover K, El-Naggar A, Griffin JD. t(11;19)
analysis in adult inflammatory bowel disease. World J (q21;p13) translocation in mucoepidermoid carcinoma
Gastroenterol. 2012;18(46):6782–9. creates a novel fusion product that disrupts a Notch
Solera J, Solís García Del Pozo J. Treatment of pulmonary signaling pathway. Nat Genet. 2003;33(2):208–13.
brucellosis: a systematic review. Expert Rev Anti Infect Toubiana J, Okada S, Hiller J, Oleastro M,
Ther. 2017;15(1):33–42. Lagos Gomez M, Aldave Becerra JC, Ouachee-
Sparrow MP, Hande SA, Friedman S, Cao D, Hanauer SB. Chardin M, Fouyssac F, Girisha KM, Etzioni A, Van
Effect of allopurinol on clinical outcomes in inflamma- Montfrans J, Camcioglu Y, Kerns LA, Belohradsky B,
tory bowel disease nonresponders to azathioprine or Blanche S, Bousfiha A, Rodriguez-Gallego C, Meyts I,
6-mercaptopurine. Clin Gastroenterol Hepatol. 2007; Kisand K, Reichenbach J, Renner ED, Rosenzweig S,
5(2):209–14. Grimbacher B, Van de Veerdonk FL, Traidl-
Speight PM. Update on oral epithelial dysplasia and pro- Hoffmann C, Picard C, Marodi L, Morio T,
gression to cancer. Head Neck Pathol. 2007;1(1):61–6. Kobayashi M, Lilic D, Milner JD, Holland S,
Speight PM, Abram TJ, Floriano PN, James R, Vick J, Casanova JL, Puel A, International STAT1 Gain-of-
Thornhill MH, Murdoch C, Freeman C, Hegarty AM, Function Study Group. Heterozygous STAT1 gain-of-
D’Apice K. Interobserver agreement in dysplasia grad- function mutations underlie an unexpectedly broad
ing: toward an enhanced gold standard for clinical clinical phenotype. Blood. 2016;127(25):3154–64.
pathology trials. Oral Surg Oral Med Oral Pathol Oral Ungprasert P, Carmona EM, Crowson CS, Matteson EL.
Radiol. 2015;120(4):474–82.e2. Diagnostic utility of angiotensin-converting enzyme in
sarcoidosis: a population-based study. Lung. 2016; and Mineral Nutrition Information System. Geneva,
194(1):91–5. World Health Organization, 2011 (WHO/NMH/NHD/
Vaughan Jones S, Palmer I, Bhogal B, Eady R, Black M. The MNM/11.2). http://www.who.int/vmnis/indicators/
use of Michel’s transport medium for immunofluores- serum_ferritin.pdf, Accessed 1 May 2018.
cence and immunoelectron microscopy in autoimmune Woodley DT. Immunofluorescence on salt-split skin for the
bullous diseases. J Cutan Pathol. 1995;22(4):365–70. diagnosis of epidermolysis bullosa acquisita. Arch
Vermeire S, Van Assche G, Rutgeerts P. Laboratory Dermatol. 1990;126(2):229–31.
markers in IBD: useful, magic, or unnecessary toys? Woolgar JA. Histopathological prognosticators in oral and
Gut. 2006;55(3):426–31. oropharyngeal squamous cell carcinoma. Oral Oncol.
Vigushin DM, Pepys MB, Hawkins PN. Metabolic 2006;42(3):229–39.
and scintigraphic studies of radioiodinated human Woolgar JA, Scott J. Prediction of cervical lymph
C-reactive protein in health and disease. J Clin Invest. node metastasis in squamous cell carcinoma of the
1993;91(4):1351–7. tongue/floor of mouth. Head Neck. 1995;17(6):
Walters GO, Miller FM, Worwood M. Serum ferritin con- 463–72.
centration and iron stores in normal subjects. J Clin Woolgar JA, Triantafyllou A. Pitfalls and procedures in the
Pathol. 1973;26(10):770–2. histopathological diagnosis of oral and oropharyngeal
Wang MB, Liu IY, Gornbein JA, Nguyen CT. HPV-positive squamous cell carcinoma and a review of the role
oropharyngeal carcinoma: a systematic review of treat- of pathology in prognosis. Oral Oncol. 2009;45(4):
ment and prognosis. Otolaryngol Head Neck Surg. 361–85.
2015;153(5):758–69. Yamaguchi M, Uchiyama S. Receptor activator of NF-κB
Warnakulasuriya S, Ariyawardana A. Malignant transfor- ligand-stimulated osteoclastogenesis in mouse marrow
mation of oral leukoplakia: a systematic review of culture is suppressed by zinc in vitro. Int J Mol Med.
observational studies. J Oral Pathol Med. 2016; 2004;14(1):81–5.
45(3):155–66. Yamaguchi M, Oishi H, Suketa Y. Zinc stimulation of bone
Warnakulasuriya S, Kerr AR. Oral submucous fibrosis: a protein synthesis in tissue culture: activation of
review of the current management and possible direc- aminoacyl-tRNA synthetase. Biochem Pharmacol.
tions for novel therapies. Oral Surg Oral Med Oral 1988;37(21):4075–80.
Pathol Oral Radiol. 2016;122(2):232–41. Yousefi R, Imani M, Ardestani SK, Saboury AA, Gheibi N,
Warnakulasuriya S, Johnson N, van der Waal I. Nomen- Ranjbar B. Human calprotectin: effect of calcium and
clature and classification of potentially malignant dis- zinc on its secondary and tertiary structures, and role of
orders of the oral mucosa. J Oral Pathol Med. 2007; pH in its thermal stability. Acta Biochim Biophys Sin.
36(10):575–80. 2007;39(10):795–802.
Warnakulasuriya S, Reibel J, Bouquot J, Dabelsteen E. Zhang K, Lin G, Han Y, Li J. Serological diagnosis of
Oral epithelial dysplasia classification systems: predic- toxoplasmosis and standardization. Clin Chim Acta.
tive value, utility, weaknesses and scope for improve- 2016;461:83–9.
ment. J Oral Pathol Med. 2008;37(3):127–33. Zhu A, Kaneshiro M, Kaunitz JD. Evaluation and treat-
Westra WH. Detection of human papillomavirus (HPV) in ment of iron deficiency anemia: a gastroenterological
clinical samples: evolving methods and strategies for perspective. Dig Dis Sci. 2010;55(3):548–59.
the accurate determination of HPV status of head and Zingale LC, Castelli R, Zanichelli A, Cicardi M. Acquired
neck carcinomas. Oral Oncol. 2014;50(9):771–9. deficiency of the inhibitor of the first complement
Wheeler HL, Agarwal S, Goh BT. Dark ground micros- component: presentation, diagnosis, course, and con-
copy and treponemal serological tests in the diagnosis ventional management. Immunol Allergy Clin North
of early syphilis. Sex Transm Infect. 2004;80(5):411–4. Am. 2006;26(4):669–90.
WHO Working Group. Glucose-6-phosphate dehydroge- Zur R, Roy L, Ito S, Beyene J, Carew C, Ungar W.
nase deficiency. Bull World Health Organ. 1989; Thiopurine S-methyltransferase testing for averting
67(7):601. drug toxicity: a meta-analysis of diagnostic test accu-
WHO. Serum ferritin concentrations for the assessment of racy. Pharmacogenomics J. 2016;16(4):305–11.
iron status and iron deficiency in populations. Vitamin
Clinical Immunology in Diagnoses of
Maxillofacial Disease
Nathaniel Treister, Arturo Saavedra, and Alessandro Villa
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
Basic Review of Clinical Immunology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
Innate Immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
Adaptive Immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
Oral Mucosal Immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
Indications for Immunological Work-Up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
Diagnostic Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320
Blood Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320
Flow Cytometry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320
Serology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320
Diagnosis of Oral Medicine Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
Allergic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
Connective Tissue Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
Mucocutaneous Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
Autoimmune Vesiculobullous Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
Infectious Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
Immunodeficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334
N. Treister (*)
Department of Oral Medicine, Infection and Immunity,
e-mail: ntreister@partners.org
A. Saavedra
Department of Dermatology, Massachusetts General
Hospital, Harvard Medical School, Boston, MA, USA
e-mail: asaavedra@partners.org
A. Villa
Division of Oral Medicine and Dentistry, Brigham and
e-mail: avilla@bwh.harvard.edu

https://doi.org/10.1007/978-3-319-72303-7_5
316 N. Treister et al.

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
Abstract As the immune system plays a central role in

There is an immunological basis for a wide the pathogenesis of a wide range of diseases that
spectrum of oral medicine conditions, ranging affect the oral cavity, clinical immunology is use-
from autoimmunity to infection. While patient ful and often essential in both diagnosis and mon-
history and physical examination serve as the itoring of such diseases. This chapter provides an
cornerstones for clinical diagnosis, in many overview of the main constituents and functions
situations additional laboratory testing is nec- of the immune system and the role of clinical
essary in order to arrive at a definitive diagno- immunology in the diagnosis and management
sis. As such, a comprehensive understanding of oral diseases.
of clinical immunology and its relevance to the
pathogenesis and diagnosis of oral medicine
conditions is essential. This chapter provides Basic Review of Clinical Immunology
an overview of the immune system, indications
for immunological work-up, a summary of The immune system is remarkably complex
clinical immunology tests relevant to the prac- and highly coordinated, composed of cells and
tice of oral medicine, and a discussion of the proteins that provide the human body with
oral medicine conditions for which clinical the capacity to protect the host from pathogens,
immunological testing may be indicated. cancer cells, and toxins. The immune system
can be broadly categorized into innate immunity
Keywords and adaptive immunity, with distinct but comple-
ELISA · Immunoblotting · mentary mechanisms and functions (Table 1)
Immunofluorescence · Antibody titer analysis · (Warrington et al. 2011).
Connective tissue disease · Serology · Allergy
testing · Prick testing · Patch testing · Innate Immunity
Histopathology · Oral immunology · Oral
vesiculobullous disorders Innate immunity is the first line defense mecha-
nism to an external insult. The innate immune
response is nonspecific, characterized by rapid
Introduction onset and antigen-independent mechanisms
(Turvey and Broide 2010). The major cells
The oral cavity represents a unique interface involved in the innate immune response include
between the human body (host) and the environ- phagocytes (e.g., neutrophils and macrophages),
ment, with frequent exposure to pathogens, die- natural killer (NK) cells, dendritic cells, basophils,
tary products, and other foreign substances. The mast cells, and eosinophils (Table 1). Neutrophils
immune system provides a highly coordinated are short-lived circulating cells that migrate to the
response to such exposures and challenges, site of infection by chemotaxis and eliminate
maintaining and protecting host homeostasis pathogens via phagocytosis and release of antimi-
through complex inflammatory pathways. It can crobial granules (Mantovani et al. 2011). Macro-
be dysregulated leading to a variety of autoim- phages are long-lived cells with phagocytic
mune and immune-mediated conditions, or properties that also play a critical role as antigen
suppressed, leading to immunosuppression and presenting cells (APCs) to T cells in activation of
increased risk of infection and cancer. the adaptive immune system. Dendritic cells are
Table 1 Features of the innate and adaptive immune systems
Innate immune system Adaptive immune system
Response Immediate Delayed
time
Immunologic None Rapid and effective response on a second encounter with a pathogen
memory (longlasting protection)
Cell type Dendritic Macrophages Natural Neutrophils Mast cells Basophils Eosinophils T cells B cells
cells killer cells T helper cells T Regulatory Memory B Plasma
(TH) cytotoxic T-cells (or effector)
cells (TC) (TReg) cells
Location Blood, Circulates Circulates Migrates from Mucous Circulate Circulate Thymic Thymic Primary Bone Bone
Clinical Immunology in Diagnoses of Maxillofacial Disease
epithelial in blood in blood blood into the membrane in blood in blood medulla and medulla and marrow, marrow
tissues and and tissue and and and blood and secondary lymph
and migrate migrate connective migrate migrate blood lymphoid nodes,
lymph into the into the tissues into the into the follicles and spleen
nodes tissue tissue tissue tissue
Function Presentation Phagocytic Destroy Phagocytosis Bind IgE; Act Kill Initiation and Detect Suppress Recognition Produce and
of foreign cells infected and release of an initial against bacteria maximization and kills potentially of specific secrete
antigens to Antigen cells or granules to allergic parasites releasing of the infected deleterious foreign antibodies
TH presenting tumor eliminate response Responsible toxins immune cells activities antigens
lymphocytes cells cells pathogenic for allergic Responsible response of TH
Antibody- microorganism responses for tissue (both T and B
dependent damage cells)
cell killing
317
another type of APC that act as a liaison between with a continuous renewal of epithelial cells.
innate and adaptive immunity and can also recog- Saliva, tears, and mucous secretions possess
nize pathogens and produce reactive oxygen spe- intrinsic antimicrobial properties and effectively
cies, reactive nitrogen species, IL-12, and wash away external pathogens. Finally, the phys-
interferon, which possess antimicrobial properties iologic body temperature inhibits the growth of
and interfere with viral replication. NK cells are certain pathogens, and the presence of an acidic
effector lymphocytes that have the ability to environment (pH 3–5) in the stomach kills the
destroy infected cells by releasing perforins and majority of ingested microorganisms.
granzymes and also act to control several types of
tumors by limiting secondary tissue damage
(Vivier et al. 2008). Mast cells, basophils, and Adaptive Immunity
eosinophils play a major role in acute inflamma-
tory responses (such as asthma and allergy). Baso- Adaptive immunity is characterized by a slower,
phils usually reside in the circulation, whereas antigen-specific response with long-lived immu-
mast cells are found in the connective tissue nological memory. The adaptive immune system
around blood vessels. Both mast cells and baso- mainly involves both T lymphocytes (cell-medi-
phils are sources of proinflammatory mediators ated immune response) and B lympho-
during acute, immunoglobulin-E (IgE)-dependent cytes (humoral or antibody-mediated immune
allergic reactions. Mast cells play an important response) (Bonilla and Oettgen 2010).
role in mediating allergic inflammation, releasing Cell-mediated immune responses are the
histamine, proteases, and cytokines (in particular most important defense mechanisms of the
TNF-alpha), which leads to the synthesis and human body. T lymphocytes arise from
release of leukotrienes and prostaglandins the hematopoietic stem cells in the bone marrow,
(Voehringer 2013). Eosinophils have phagocytic enter the circulation, and reach maturation in the
properties and are responsible for the destruction thymus gland where they express the T-cell
of large parasites. receptor and further differentiate into T-helper
The complement system is another critical (TH) cells and T-cytotoxic (TC) cells. TH cells
component of innate immunity that consists of usually display the CD4 membrane glycoprotein,
several plasma proteins. The complement cas- while Tc display the CD8. In order to recognize
cade can be activated in three ways: (1) the clas- antigens and become activated, T-cell receptors
sical pathway, triggered by direct binding of bind to the APCs, which express cell-membrane
complement component C1q to the pathogen proteins known as the major histocompatibility
surface or antibody; (2) the mannan-binding lec- complex (MHC) molecules. Most nucleated cells
tin pathway, triggered by normal serum constit- express Class I MHC, whereas Class II MHC
uent (lectin) that binds bacteria; and (3) the expression is restricted to APCs (such as macro-
alternative pathway, which is triggered when phages, dendritic cells, and B cells). APCs can
the C3b protein directly binds to the pathogen induce two types of TH cell responses: TH1 or
surfaces. Complement activation leads to a cas- TH2. During TH1 responses, interferon-gamma
cade of proteolytic events, which ends in (IFN- γ) is released to activate macrophages
opsonization and lysis of the pathogen as well and subsequent release of other cytokines that
as in the generation of a series of inflammatory induce B cell-mediated opsonization and release
responses that help fight infection (Dunkelberger of neutralizing antibodies. In TH2 responses,
and Song 2010). cytokines (IL-4, 5 and 13) are released and acti-
The innate immune system also comprises ana- vate and/or recruit immunoglobulin E (IgE)
tomic mechanical barriers (such as the mucous antibody-producing B cells, mast cells, and
membranes and skin) and physiologic defensive eosinophils (e.g., asthma or allergic reactions).
barriers (low pH, soluble molecules, and temper- TH promotes the initiation and maximization of
ature) (Warrington et al. 2011). The skin and other the immune response, whereas TC cells directly
epithelial surfaces retard the entry of pathogens target and kill infected cells.
Clinical Immunology in Diagnoses of Maxillofacial Disease 319
Regulatory T-cells (TReg) are a unique subset leukocytes reside in the lamina propria and serve
of T-cells that maintain immunological self- as first-line of defense. Keratinocytes recognize
tolerance and immune homeostasis. Defects in pathogens by the activation of toll like receptors
TReg function may contribute to the development (a group of receptors expressed in macrophages
of autoimmunity, while excess TReg activity may and dendritic cells able to detect pathogens;
lead to the suppression of tumor immunity TLR) with a subsequent activation of signaling
(Sakaguchi et al. 2007). pathways leading to the production of pro-
B cells migrate from hematopoietic stem cells inflammatory and anti-inflammatory chemokines
in the bone marrow and, following maturation, and cytokines. Keratinocytes also produce antimi-
populate the follicles around germinal centers of crobial peptides such as beta defensins and
the spleen, tonsils, and lymph nodes. Foreign histatins that have antifungal and antibacterial
antigen-driven activation of B cells leads to the properties. Dendritic cells are activated interstitial
proliferation of memory B cells or plasma Langerhans cells and mediate initiation of the
(antibody-secreting) cells. Plasma cells live for a adaptive immune response, leading to TReg-cell
few days and then undergo apoptosis when the priming in the draining lymph nodes and promote
pathogen responsible for the immune response is the activation of T cells as well as the differentia-
eliminated. Memory B cells have a longer life and tion of B cells. The oral mucosa is regularly
upon antigen re-exposure respond quickly and exposed to a large number of microorganisms;
effectively. however, few of these pathogens are able to
Plasma cells produce five different types of cause infection due to peripheral immune toler-
antibodies, with each having unique biological ance to commensal microorganisms. This is
and clinical properties: IgA, IgD, IgE, IgG, and the result of a lack of T cell activation after the
IgM (Schroeder and Cavacini 2010). IgA and IgM exposure to an antigen, or it may occur when
isotypes are found in secretions (such as saliva), effector T-cells are suppressed by TReg cells
while serum contains IgG with lesser amounts of (Feller et al. 2013).
IgM, IgE, and IgA. IgM are the primary anti-
bodies released followed by IgG and are involved
in the activation of the complement. IgG plays an Indications for Immunological
important role in the secondary antibody Work-Up
response. IgE binds to basophils and mast cells
and stimulates the release of histamine during The immune system plays a central role in the
allergic reactions. pathophysiology of a wide spectrum of diseases
that can affect the orofacial region. Disease man-
ifestations may be limited to the oral cavity or
Oral Mucosal Immunity may be part of a multisystem presentation. Spe-
cific immunological features, whether evaluated
The oral cavity has a unique immune environ- locally at the site of disease involvement in a
ment, characterized by the oral mucosa barrier, biopsy specimen or measured systemically
lymphatic tissue, innate and adaptive immune through peripheral blood sampling and serologi-
system components within the mucosa and saliva, cal testing, may be essential in the work-up and
and the presence of oral commensal microorgan- definitive diagnosis of oral medicine conditions.
isms. The oral epithelium provides a protective The decision to order tests should always follow a
mechanical barrier and prevents entry of external complete medical history and comprehensive
pathogens while also minimizing colonization by physical examination. When ordering specific
constant surface shedding (Feller et al. 2013). tests, there should be a clear justification and
The saliva contains enzymes and proteins with rationale based on a working differential diagno-
antibacterial, antifungal, and antiviral effects sis, and the ordering clinician must anticipate how
(e.g., defensins, agglutinins, lactoferrin, secretory the test results will be interpreted and incorporated
IgA) (Dawes et al. 2015). Macrophages and into clinical decision-making. It is optimal for a
patient to be evaluated by a clinician experienced C reactive protein (CRP) and erythrocyte sedi-
in the diagnosis and management of oral diseases mentation rate (ESR), can also be useful as a
(e.g., an Oral Medicine specialist) to ensure general screen for immune-mediated inflamma-
appropriate and cost effective utilization of immu- tory disorders. Abnormal findings may then pro-
nological testing (Smetana et al. 2007). mpt additional secondary immunological testing
Immunological tests may be necessary to (D’Cruz 2002).
definitively confirm a patient’s clinical diagnosis
(Bhagat et al. 2014). Certain conditions require a
tissue biopsy of affected tissue demonstrating dis- Flow Cytometry
tinct and diagnostic features. In such cases, the
specific immuno-histopathological profile and With flow cytometry, distinct immune cell
pattern of immune cells/mediators provides the populations are stained with monoclonal anti-
specific information necessary for diagnosis. bodies that have been conjugated to a fluorescent
Serological tests may be indicated when the dif- dye molecule that can be detected by one or more
ferential diagnosis includes systemic immune- laser beams (Virgo and Gibbs 2012). Quantitative
mediated or autoimmune diseases (e.g., Sjögren’s output includes both the number of cells
syndrome, systemic lupus erythematosus), or to expressing the antigen of interest, and antigen
measure antibody responses to suspected infec- density on individual cells. This can be used to
tion (e.g. herpes simplex virus infection). The evaluate levels and relative amounts of immune
detection, concentration, and combination of spe- cells and subtypes (Virgo and Gibbs 2012).
cific immunological mediators can support spe-
cific diagnoses. Once a diagnosis is established,
ongoing immunological testing may be indicated Serology
to assess disease activity as well as to evaluate
response to and/or the need for new or additional Immunoglobulin Testing
therapy. Allergy work-up, including blood tests Testing for immunoglobulin levels, subtypes, and
and skin patch testing, is essential for the diagno- specific antibodies is important in the diagnosis of
sis of recurrent angioedema and other allergic certain diseases. Quantitative testing evaluates for
conditions that can affect the orofacial region. excess or deficiency of the three major classes of
Unexplained recurrent or atypical orofacial infec- immunoglobulin including IgG, IgM, and IgA;
tions may suggest an underlying immune defi- abnormalities prompt further testing. Additional
ciency and prompt a more broad-based testing for IgG subclass levels should generally
immunological work-up. In any situation, defini- be restricted to patients with selective antibody
tive diagnosis always requires careful clinical cor- deficiency (sIgAD), suspected common variable
relation, and any inconsistent test results should immune deficiency (CVID), or rarely in pemphi-
be confirmed by retesting. gus vulgaris when trying to exclude non-
pathologic antibodies. Follow-up testing of
functional antibody responses is important to
Diagnostic Tests determine clinical significance and potential
need for immunoglobulin replacement therapy
Blood Tests (Abraham 2012).
For the diagnosis of herpes simplex virus
The initial test as part of any immunological (HSV) infection, detection of IgM and IgG anti-
work-up is a complete blood count with differen- bodies to HSV-1 and HSV-2 can help determine
tial (Bhagat et al. 2014). This is an important primary versus recrudescence (IgM only in pri-
screening test that can quickly identify key abnor- mary infection, if IgG present then recrudescent)
malities, such as leukopenia and neutropenia. and subtype. However, measuring levels of IgM
Nonspecific markers of inflammation, including and IgG cannot determine if there is active
recrudescence, and in early primary infection IgM assay (ELISA), nephelometry, immunoblotting,
may be negative. Once infected, IgG remains and immunoprecipitation. Indirect immunofluo-
positive for life and can therefore indicate sero- rescence detects circulating antibodies in the
conversion if there is a previous negative test. In serum. The patient’s serum is reacted against a
most cases, HSV testing also depends on micro- standard tissue substrate (e.g., monkey esophagus
biological tests (e.g., viral culture, Direct Fluores- is commonly used in suspected autoimmune
cent Antibody (DFA), polymerase chain reaction vesiculobullous diseases), resulting in similar
(PCR)) (Anderson et al. 2014, LeGoff et al. 2014). detection patterns to direct immunofluorescence
Of note, varicella zoster virus (VZV) is very dif- (DIF) (Kneisel and Hertl 2011). In skin and muco-
ficult to culture and a negative result never sal tissue, the most common immunoreactants
excludes the diagnosis. evaluated are IgG, IgM, IgA, complement C3,
fibrinogen, and albumin. The latter two are used
Autoimmunity Testing to evaluate for specificity of binding. Autoanti-
The diagnosis of autoimmune disease is largely bodies that target different auto-antigens that
dependent on the detection of specific autoanti- co-localize microscopically cannot be differenti-
bodies (Aggarwal 2014; Self 2010). Some auto- ated based on IIF patterns alone and therefore
antibodies, such as rheumatoid factor (RF) and require immunoassays such as ELISA for charac-
antinuclear antibody (ANA), are nonspecific and terization of molecular specificity necessary for
elevated in many autoimmune diseases and there- diagnosis. Nephelometry measures the amount
fore serve as a general screening test, while others, of light that passes through a sample (or scatter)
such as Scl-70 for progressive systemic sclerosis, at an angle as an indirect measure of concentra-
are highly specific to one disease and are therefore tion. ELISA utilizes color change from an enzy-
ordered following initial screening. As autoanti- matic reaction to indicate the presence of an
bodies can be present in a multitude of diseases, as antibody actively binding to a supplied antigenic
well as in normal health, test results must be target. During the process of immunoblotting,
carefully interpreted by an experienced clinician antibodies are used to target proteins separated
(Bhagat et al. 2014; Stinton and Fritzler 2007). from one another across a spectrum based on
Those with greatest relevance to the diagnosis of molecular weight created by electrophoresis.
oral diseases are summarized in Table 2. Finally, immunoprecipitation, a process by
The various tests used for detection of autoan- which an antibody is used to precipitate a protein
tibodies include indirect immunofluorescence out of solution, is occasionally used to detect
(IIF) assay, enzyme-linked immunosorbent autoantibodies against various cellular and
Table 2 Autoantibody testing with relevance for the diagnosis of oral medicine conditions
RF
Associated prevalence Antigenic Prevalence
autoimmune disease (%) ANA pattern specificity (%) Clinical significance
Systemic lupus 15–30 Homogeneous/ dsDNA 50–75 Correlates with renal activity
erythematosus Rim Sm 15–30 Specific for SLE
Speckled Ro 25–50 Neonatal lupus
La 10–30 Neonatal lupus
Systemic sclerosis 20–30 Speckled Scl-70 20–60 Diffuse disease
Sjögren’s syndrome 75–85 Speckled Ro 40–70
La 30–60
Note that this represents a limited list of autoantibodies considered clinically relevant within the context of an oral
medicine work-up. Screening with ANA and RF should be followed by more specific autoantibody testing. Additional
autoantibody testing (not included) may be indicated for more comprehensive evaluation for systemic lupus
erythematosus and systemic sclerosis. Adapted from Aggarwal (2014) and Stinton and Fritzler (2007)
Fig. 1 Common ANA patterns on Hep-2000 cell line (d) Fine speckled pattern. Reprinted from Hepburn and
substrate. (a) Homogeneous pattern with chromatin Charles (2002)
staining. (b) Coarse speckled pattern. (c) Nucleolar pattern.
subcellular antigenic determinants of mucosal patient’s sample can be diluted and still produce
disease. recognizable staining. ANA staining can be
Rheumatoid factor (RF) is an autoantibody nuclear or cytoplasmic, and specific patterns of
(in most cases IgM) that targets aggregated IgG staining can predict antigenic specificity, thereby
and that is present in many autoimmune condi- helping to rationally determine additional autoan-
tions (Bhagat et al. 2014). RF is typically mea- tibody tests to order (Fig. 1). The test report
sured by nephelometry, with values above includes the pattern of staining, the titer (highest
20 international units considered significant and dilution in which test remains positive), and sub-
with values above 50 considered to be of higher strate used. A positive ANA test is then followed
diagnostic value. While anticitrullinated peptide by additional tests to identify subspecific
antibody (ACPA) test is more specific for rheu- ANAs which collectively help support a clinical
matoid arthritis than RF, ACPA is not used as a diagnosis.
more general autoantibody screening test and Antidouble-stranded DNA antibody test
therefore has limited relevance in the diagnosis (ds DNA) is ordered following a positive ANA
of oral medicine conditions (Aggarwal 2014). screen in patients suspected to have systemic
ANA is a widely used screening test for auto- lupus erythematosus (SLE). Serial monitoring
immunity that if positive, prompts additional test- correlates with disease activity, and rising titers
ing that can be diagnostic (Abeles and Abeles may signify disease relapse.
2013; Agmon-Levin et al. 2014). While ANA Nucleosomes consist of dsDNA wrapped
has traditionally been evaluated by IIF, due to around histones and are generated during apopto-
multiple steps and labor-intensive nature of the sis. Antinucleosomal antibody test is not widely
assay, ELISA and laser bead assays are been available, but has greater sensitivity and specific-
used more frequently. While there are no absolute ity than anti-dsDNA antibodies for the diagnosis
standards among laboratories, ANA samples are of SLE.
typically screened at dilutions of 1:40 and 1:160, Antibodies to extractable nuclear antigens
with the ANA titer being the level to which a (ENAs) can define subspecificities of ANA that
have associations with specific diseases. Both Allergy Testing

anti-Ro and anti-La antibodies are ENAs that are Complement testing is an essential component of
used in the work-up for Sjögren syndrome. Titers the work up for angioedema. Tests include C1
of ENAs generally have poor correlation with inhibitor (C1-INH) concentration and function
disease activity so once identified as positive (activity), C4 and C1q levels, and anti-C1-INH
there is no need to repeat the tests. autoantibody levels (Farkas et al. 2016). C1-INH
Anti-Ro antibodies (or Sjögren’s syndrome- function assays measure inhibition of C1s prote-
related antigen A, SS-A) are present in several ase via a colorimetric substrate assay or by
autoimmune diseases, with highest prevalence ELISA. C1-INH concentration is determined by
(40–60% positive) in Sjögren’s syndrome. The immunochemical methods (e.g., nephelometry,
presence of anti-Ro antibodies in association turbidimetry, or radial immunodiffusion) that uti-
with other autoimmune diseases increases the lize specific antibodies, with “low” considered
risk of secondary or Sjögren’s syndrome, or below 50% of the normal value. C4 concentration
“sicca syndrome.” is measured in the same manner as C1-INH, with
Anti-La antibodies (or Sjögren’s syndrome- “low” also considered below 50% of the normal
related antigen B, SS-B) typically coexist with value. C1q levels are measured by radial immu-
anti-Ro antibodies but with a lower prevalence. nodiffusion or ELISA. Autoantibodies against
The La antigen has been reported to bind several C1-INH are detected based on the binding of
viruses, raising the possibility that antigen mim- IgG, IgA, or IgM autoantibodies to an ELISA
icry is important in the pathogenesis of Sjögren plate covered with C1-INH protein.
syndrome (Franceschini and Cavazzana 2005). Patch testing is the gold standard in diagnosing
While there are a number of additional ENAs allergic contact dermatitis and can also be used in
that can be tested for in the work-up of autoim- the evaluation of suspected oral mucosal involve-
mune disease (e.g., anti-RNP, anti-Sm, anti-Scl ment, as well as in the evaluation of dermatitis
70, anti-Jo1), these are not routinely ordered as (stomatitis) related to systemic allergen exposure
part of the clinical immunological work-up of an (Mowad et al. 2016). Patients are typically
oral medicine patient. exposed to a standard or screening series of aller-
Antineutrophil cytoplasmic antibodies gens using commercially available kits/reagents.
(ANCA) are directed against primary granules Selection of specific allergens depends on the
of the neutrophil cytoplasm (Sinico and Radice individual patient’s history and suspected causa-
2014). ANCA positivity is associated with small tive products. Even if evaluating for oral mucosal
vessel vasculitis and is positive in nearly 100% of disease, patch testing is performed on the skin of
patients with granulomatosis with polyangiitis the upper back, with occlusive placement of aller-
(Wegner granulomatosis). Longitudinal testing gens for two days, followed by removal and
of ANCA can be useful in monitoring disease assessment. Reading and grading results is some-
activity and response to therapy. When alcohol- what subjective and simple irritation must be dis-
fixed neutrophils are used as the IIF test substrate, tinguished from true allergic response. There are
three patterns of staining can be recognized: no well-characterized or validated protocols for
(1) cANCA pattern with diffuse cytoplasmic performing intraoral patch testing directly on the
staining with central accumulation, (2) pANCA oral mucosa.
pattern with perinuclear linear staining around the Food allergy testing includes food-specific
nucleus, and (3) atypical pattern with diffuse cyto- IgE tests, oral food challenge testing, and skin
plasmic staining or both cytoplasmic and nuclear testing (Stukus and Mikhail 2016). In vitro test-
staining. All positive ANCA findings should be ing directly measures food-specific IgE in the
further confirmed by ELISA as the combination serum by ELISA. Test assays can vary widely
approach provides nearly 99% specificity and with various IgE cutoff levels proposed but not
approximately 70% sensitivity for vasculitis validated. While comprehensive panels are avail-
(Savige et al. 2003). able, these are generally not recommended as
there is high risk of false positives and misinter- (intra- versus subepithelial) in the case of autoim-
pretation of results. mune vesiculobullous conditions (Kneisel and
Double-blind placebo-controlled oral food Hertl 2011). In the case of suspected autoimmune
challenge is considered the gold standard to diag- vesiculobullous disease, the biopsy should be
nose food allergy. However, due to the required obtained peri-lesionally and away from ulcera-
time and resources, single blind or open label food tion. With other conditions, the biopsy should be
challenge is more commonly utilized. This test is obtained from a representative area of lesional
generally safe but must be conducted in a physi- involvement, although areas of frank ulceration
cian’s office with emergency resuscitation equip- should be avoided due to lack of epithelium for
ment available. Patients gradually eat increasing analysis.
amounts of a food in a short amount of time and Immunohistochemical staining can be used to
are observed over a 2–3 hour period for develop- identify specific infiltrating immune cells/com-
ment of allergic symptoms. ponents within formalin fixed histopathology
Skin prick tests involve percutaneous introduc- specimens. Immunohistochemical analysis can
tion of a small amount of allergen extract to provide information on location, distribution,
potentially reactive mast cells within the epider- and relative quantity of cells of interest (Elliott
mis. Skin prick tests are typically applied to the et al. 2015).
upper back of forearm and multiple allergens can Direct immunofluorescence (DIF) microscopy
be tested simultaneously, with results available is considered the gold standard for diagnosis of
within 15–20 minutes. Negative (saline) controls autoimmune vesiculobullous disorders (Mihai
are necessary to validate results. If specific IgE and Sitaru 2007). Biopsy tissue must be placed
toward the specific allergen is present, a wheal/ in saline or Michel’s solution, or immediately
flare response will develop, and the diameter of snap-frozen and maintained at a temperature of
this lesion is measured and compared with con- 70 C, rather than formalin. If the tissue is not
trols to determine clinical relevance. collected or preserved properly, there is signifi-
cant risk of false negative results. Like the case
Tissue Biopsy for IIF, in DIF the most commonly used
Histopathology of involved lesional tissue pro- immunoreactants are IgG, IgM, IgA, complement
vides immunological information on both the C3, fibrinogen and albumin. The type and pattern
characterization of inflammatory infiltrate as of tissue bound antibodies is diagnostic for spe-
well as presence and level of loss of adhesion cific diseases (see Table 3).
Table 3 Immunopathological features of autoimmune vesiculobullous diseases

Target
Disease Direct immunofluorescence Indirect immunofluorescence autoantigens
Pemphigus vulgaris Intercellular IgG and C3 Intercellular IgG (monkey Dsg 3, Dsg 1
(Fig. 3) esophagus)
Mucous membrane Linear IgG, IgA and C3 at the Epithelial or subepithelial IgG BP180, Laminin
pemphigoid (Fig. 4) basement membrane junction IgA (requires salt-split skin) 5, α6β4 integrin
Linear IgA disease Linear IgA and C3 at the basement Epithelial or subepithelial IgA LAD-1, Type VII
(Fig. 5) membrane junction (requires salt-split skin) collagen
Epidermolysis Linear IgG, IgA, and C3 at the Subepithelial IgG (requires Type VII
bullosa acquisita basement membrane junction salt-split skin) collagen
(Fig. 6)
Paraneoplastic IgG and C3 intercellularly and at the Intercellular IgG (monkey Dsg 3, Dsg
pemphigus (Fig. 7) basement membrane junction esophagus or rat bladder) 1, plakines
Adapted from Mihai and Sitaru 2007 and Kneisel and Hertl 2011
Diagnosis of Oral Medicine Conditions has been noted in some patients with anti-
C1INH antibodies or with an underlying malig-
Allergic Diseases nancy (C1-INH).
Angioedema Oral Allergy Syndrome

Angioedema is a hypersensitivity reaction charac- Oral allergy syndrome (OAS) is a form of
terized by rapid swelling of the submucosa or IgE-mediated hypersensitivity reaction, which
deep dermis, affecting any area of the body with occurs after the ingestion of raw vegetables
predilection for the head and neck region. and fruits, in patients who are sensitized to
Angioedema is characterized by excess produc- plant pollens (Ausukua et al. 2009, Popescu
tion of bradykinin, a potent vasodilator (typically 2015). The diagnosis of OAS is made through a
released after tissue injury), which promotes careful patient history of symptoms (such as
edema and tissue permeability. Bradykinin pro- pruritus, tingling, and swelling of the oral
duction is typically regulated by C1 esterase mucosa within 5–10 minutes of ingesting the
inhibitor (C1-INH), an acute-phase reactant and food) and physical examination. In the presence
inhibitor of the classical complement, coagula- of an obvious causative agent, immunological
tion, fibrinolytic, and kinin-generating pathways. testing may not be indicated. Otherwise, work-
The diagnosis of angioedema is usually based on up includes testing for specific IgE to food and/or
the patient history and clinical findings. pollen, and possible oral food challenge
Two forms exist: hereditary (autosomal dominant) (Ortolani et al. 1988). Positive tests may result
and acquired (Agostoni et al. 2004). Hereditary from the cross reactivity of allergens in the same
angioedema may be secondary to C1-INH defi- family of foods products, without being the ones
ciency (type I) or dysfunction (type II). In cases of causing OAS (Rodriguez et al. 2000). Testing for
recurrent angioedema, laboratory work-up allergens involves the “prick-by-prick” skin test,
includes levels and functional measurements of using either commercial extract or fresh fruit
the complement protein C4, C1q, as well as injected into the skin of the patient. The sensitiv-
C1-INH quantitative protein (or antigenic) ity of the prick-by-prick method is higher with
(Zuraw et al. 2013). Type I patients present with fresh products than the testing with commercial
decreased C1-INH levels and function, low C4 extracts (Dreborg and Foucard 1983, Ortolani
level, and normal C1q level, while type II patients et al. 1989).
demonstrate normal or elevated C1-INH antigenic
levels, but low C4 and C1-INH functional levels Plasma Cell Gingivitis/Gingivostomatitis
and normal C1q level (Farkas et al. 2016). A third Plasma cell gingivitis is believed to be a contact
type of hereditary angioedema has normal allergic reaction, characterized by a delayed
C1-INH levels; some of these patients present hypersensitivity response. The diagnosis of
with mutations in the coagulation factor XII plasma cell gingivitis is based upon the patient
although the pathogenic mechanism of this muta- history, clinical findings, and histopathology.
tion is unclear. Histopathological examination shows an intense
Acquired angioedema may be idiopathic, plasma cell infiltrate (polyclonal on immunohis-
associated with medication exposure or related tochemistry) within the lamina propria, epithelial
to allergy. The idiopathic variety is the most hyperplasia with spongiosis, loss of normal kera-
common of all types, affecting almost 40% of tinization, and leukocyte exocytosis. Russell
patients with angioedema. The majority of bodies and lymphocytes may be seen (Woo
patients with acquired angioedema present 2012). Although the etiology of plasma cell gin-
with low C4, C1q, and low or normal C1-INH givitis is still poorly understood, there is
antigenic level (Pappalardo et al. 2000). Defi- generally no indication for allergy testing (Kerr
ciency or dysfunction of complement C1-INH et al. 1971).
Oral Lichenoid Reactions

Oral lichenoid hypersensitivity reactions are the
clinical representation of the cellular immunity
response to antigens found in certain materials
(e.g., dental amalgams, cinnamic aldehyde-
containing products and other flavoring agents)
or medications (e.g., allopurinol, carbamazepine,
hydrochlorothiazide, and other antihypertensive
agents, sulfasalazine, and some monoclonal anti-
bodies) (Yuan and Woo 2015; De Rossi and
Ciarrocca 2014).
The diagnosis of lichenoid reactions can often
be based on clinical presentation alone, with his-
topathological features providing confirmation Fig. 2 Lupus band test with direct immunofluorescence
demonstrating significant deposits of IgG at the basement
when indicated. Lichenoid reactions are indistin- membrane. Reprinted from Systemic Lupus
guishable histologically from classic lichen Erythematosus: Basic, Applied and Clinical Aspects,
planus (see section below). Edited by George C. Tsokos, Chapter 35 – The Mechanism
of Skin Damage, Pages 299–306., Copyright (2016), with
permission from Elsevier
Connective Tissue Disease

antibodies have high specificity for LE
Lupus Erythematosus (Migliorini et al. 2005). Antibodies against Ro
The basic mechanisms of disease in lupus (SSA) and La (SSB) are helpful to identify, par-
erythematosus (LE) involve autoantibody forma- ticularly in patients who desire pregnancy as there
tion. The gold standard for diagnosis according to is a higher risk of congenital heart block in neo-
the American College of Rheumatology position nates born to mothers who express anti-Ro in high
statement includes immunofluorescence antinu- titers. In addition, Ro can be an important deter-
clear antibody (ANA) testing using Human Epi- minant of photosensitivity. Direct immunofluo-
thelial type 2 (HEp-2) substrate. The sensitivity of rescence studies (DIF) in skin tissue show
this assay exceeds 95% for LE, though specificity granular IgM and/or IgG, C3 and less likely IgA
can be as low as 57%. Other assays have been deposition in the basement membrane (Fig. 2).
developed due to their relative ease of use and
decreased cost. However, up to 35% of patients Rheumatoid Arthritis
with systemic LE and a positive test by immuno- Rheumatoid arthritis is characterized by rheuma-
fluorescence can be negative on solid phase toid factor (RF) positivity where heterogeneous
assays. Though some controversy exists about IgM antibodies against the Fc portion of IgG
what constitutes a positive dilution, and results are expanded. This reaction may exhibit
are dependent on the assay used and laboratory as cryoglobulins where monoclonal IgM to poly-
reference measures, a recent study showed that clonal IgG (Type 2) or polyclonal IgM to poly-
31.7% of healthy subjects test ANA positive at a clonal IgG (type 3) complexes are formed.
1:40 dilution, only 13.3% at 1:80, and less than Though upwards of 80% of patients will have
5% at 1:160 (Tan et al. 1997). RF positivity at one point in the course of their
In addition to a high ANA titer, positive anti- disease, its presence is not diagnostic. RF positiv-
dsDNA, anti-Smith, or antiphospholipid anti- ity has been reported in Sjögren syndrome, sys-
bodies are part of the immunologic testing criteria temic sclerosis, polymyositis, acute and chronic
for LE. Anti-dsDNA is best detected via ELISA or viral infection, bacterial infection, myeloma, lym-
the Farr assay (Sherer et al. 2004). Anti-Smith phoma, and in healthy individuals. Furthermore,
as few as 30% of patients may have evidence of noted adjacent to normal glandular tissue (see
RF positivity at the onset of arthritis. Anticyclic chapter on “▶ Salivary Gland Disorders and
citrullinated peptide is more specific in spite of Diseases”).
being found in only up to 60–70% of patients and
is often helpful in predicting early and more Granulomatosis with Polyangiitis
aggressive arthritis before RF becomes positive (Wegener Granulomatosis)
(Habash-Bseiso et al. 2005). Previously termed Wegener granulomatosis, this
disease is characterized by necrotizing granulo-
Systemic Sclerosis mas and pauci-inflammatory vasculitis. Patients
In systemic sclerosis, endothelial cell damage is may present with nasal, pulmonary, mucocutane-
thought to result from immune-mediated vascular ous, and rheumatologic symptoms. About 80% of
damage (Abraham et al. 2009). Microchimerism patients exhibit antineutrophil cytoplasmic anti-
has also been detected in some patients in whom bodies (c-ANCA), but their presence does not
blood and skin lesions harbor fetal cells (Nelson exclude the need for biopsy to document necro-
1998). ANA as detected by immunofluorescence tizing vasculitis. The absence of these antibodies
has a sensitivity of 85% for systemic sclerosis does not reliably exclude the diagnosis. c-ANCA
(Agmon-Levin et al. 2014). In a recent study, reacts with proteinase 3, a human enzyme found
about 84% of patients show positivity to at least in white blood cell lysosomes. Though it is the
one of the following autoantibodies but preva- most common serologic finding, a minority of
lence was low: anti-Scl70 (40%), anticentromere patients (<10%) do test positive for the peri-
(21%), and antinucleolar (27%) (Ferri et al. 1991). nuclear form (p-ANCA) which targets
Anti-Scl70 antibodies generally imply a more myeloperoxidase. Immunoassay testing should
severe clinical course. Antinucleolar antibodies be confirmed by immunofluorescence in patients
are neither sensitive nor specific for systemic scle- where diagnostic ambiguity exists (Savige et al.
rosis (Ho and Reveille 2003). 1999). Titers do not correlate with disease activity
or response to treatment. Nonetheless, some prac-
Sjögren Syndrome titioners consider these in follow-up when their
Ro/SSA autoantibodies are fairly specific for concentration decreases in a patient who is clini-
Sjögren syndrome with 50% of patients demon- cally improved.
strating positivity. Anti-La/SSB antibodies are
rarely found in a patient with Sjögren syndrome Sarcoidosis
who does not also have anti-Ro/SSA antibodies. Sarcoidosis is a diagnosis of exclusion caused by
Neither of these antibodies is helpful in correlat- noninfectious granulomatous infiltration of sev-
ing disease activity to measured titer levels. The eral organ tissues, though the respiratory system
presence of anti-alpha-fodrin antibody is more is most commonly affected (Iannuzzi et al. 2007).
reliable in the juvenile form of the disease Histiocytes and multinuclear giant cells predomi-
(Maeno et al. 2001). ANA positivity is found in nate. Generally, CD4+ T lymphocyte expansion,
about 70% of patients. RF, lupus anticoagulant, and a decrease in CD8+ T cell suppressors,
and antiphospholipid antibodies may be present, B cells and immunoglobulin are noted. T-helper
but they are not diagnostic. Elevated levels of 1 immune responses are most significant
serum IgG4 are not detected. Whereas Sjögren and T-regulatory cell function is impaired
syndrome is characterized by lymphocytic infil- (Loke et al. 2013). Clinically, IL-2 receptor and
trate of target organs, B lymphocyte hyperactivity IL-8 levels are elevated in patients with sarcoidal
and CD4+ T cells have been most closely corre- disease (Grutters et al. 2003). Angiotensin-
lated to tissue destruction (Hayashi 2011). converting enzyme (ACE) levels, serum
Salivary gland biopsy has utility in diagnosis, amyloid A, and glycoprotein KL-6 are often con-
where focal lymphocytic sialoadenitis may be sidered markers of disease, but the former is most
commonly used to follow patients serially. ACE largely clinical but testing for associated diseases
levels suffer from poor sensitivity and specificity comprises most of the serologic work-up. RAS is
at the time of diagnosis (about 60% each). covered in more detail in the chapter on ▶ “Oral
Ulcerative Lesions”.
IgG4-Related Disease In Behçet disease, a multisystem auto-
IgG4-related diseases describe a group of disor- inflammatory disease of unknown etiology, RAS
ders that share elevation in serum IgG4 levels represents the most significant diagnostic finding.
(seen in 70% of patients) as well as IgE and total Tissue biopsy of involved organs may show neu-
eosinophilic count. Pancreatitis, retroperitoneal trophilic infiltration and evidence of vasculitis.
fibrosis causing ureteral obstruction, cholangitis, Most laboratory findings are nonspecific but
mucosal and glandular infiltration, as well as cuta- include increased C-reactive protein levels, eryth-
neous manifestations have been reported both rocyte sedimentation rate, IgA, IgG, IgM levels,
individually and in combination. A positive and immune complex deposition. In the setting of
IgG4 test is generally considered 135 mg/dL specific HLA types (B27), an elevated serum IgD
although it does not perfectly correlate with extent level may be helpful in diagnosis (Sakane et al.
of disease or treatment responsiveness. In addi- 1999). Rarely, p-ANCA antibodies and anti-
tion, blood plasmablast count may be performed phospholipid antibodies can be detected but play
via peripheral blood flow cytometry, which is no role in diagnosis.
considered by some a more reliable way to follow Studies have also shown that a significant num-
patients (Mattoo et al. 2014). Involved organs are ber of patients with RAS (>5%) may have anti-
often edematous, may present with mass effect, bodies to gliadin IgA, and to endomysium with
and are infiltrated by IgG4-positive plasma cells corresponding histopathologic changes consistent
(Stone et al. 2012). However, because IgG4+ with celiac disease (Aydemir et al. 2004). Screen-
plasma cells are a component of chronic inflam- ing with serological markers and follow-up endo-
mation, particularly in mucosal sites, care must be scopic examination is recommended when this
taken to prevent over-diagnosis of the condition. diagnosis is suspected.
Usually, IgG4+ plasma cells exceeding greater Finally, RAS may be a presenting symptom of
than 100 per high power field, and a ratio of inflammatory bowel disease even in the absence
IgG4+/IgG >40% correlate with the diagnosis of gastrointestinal symptoms (see “Inflammatory
(Cottom et al. 2015). Unlike other collagen vas- Bowel Disease”, below).
cular diseases, autoantibody formation is not
common. Lichen Planus
Oral lichen planus (OLP) is an idiopathic chronic
immune-mediated mucosal inflammatory condi-
Mucocutaneous Disease tion that typically presents with classic hyperker-
atotic reticulations, with varying degrees of
Recurrent Aphthous Stomatitis (RAS) associated erythema and ulceration and that may
RAS commonly arises as a result of defects in or may not be associated with extra-oral involve-
cell-mediated immunity and on the activity of ment of the skin and genital mucosa (Al-Hashimi
tumor necrosis factor-α (Preeti et al. 2011). This et al. 2007). Lichen planus is thought to be sec-
common diagnosis presents as well-demarcated, ondary to alloreactive T cells that directly attack
painful oval or round ulcerations with an erythem- keratinocytes. Though earlier studies suggested
atous halo that can last for up to 2 weeks. Minor an increase in the ratio of CD4+ to CD8+ T cells
aphthosis is the most common form, but larger in lesional tissue, most authorities agree
(>1 cm) and more painful lesions (major that the predominant effector cell is CD8+. Mono-
aphthosis) can complicate over 15% of cases. clonal rearrangements have been seen in the
Rarely, herpetiform aphthosis may be confused TCR-γ chain gene (Shiohara et al. 1992).
for infection by herpes viruses. Diagnosis is Histopathology shows interface dermatitis,
variable degrees of lichenoid inflammatory cell seen in erythema multiforme or drug eruptions.
infiltrate, and so-called apoptotic keratinocytes The National Institutes of Health Consensus
or colloid bodies. In keratinizing skin, wedge- Development Project on Criteria for Clinical Tri-
shaped hyper-granulosis is noted, a feature that als in Chronic Graft-versus-Host Disease iden-
is attenuated, if not lacking, in mucosa. Direct tifies “lichen planus-like changes, characterized
immunofluorescence (DIF) demonstrates globular by hyperkeratotic white lines and lacy-appearing
deposits of IgM in the connective tissue and lesions on the oral mucosa,” with or without asso-
clearly differentiates OLP from autoimmune ciated erythema or ulceration, as the only diag-
vesiculobullous disorders due to lack of IgG. Indi- nostic feature of oral chronic GVHD (Jagasia et al.
rect immunofluorescence (IIF) is of limited utility 2015). Histopathologic changes can be confirma-
and is most often negative. Cytotoxicity is thought tory of clinical impression, but are never sufficient
to result in response to antigen mimicry. A role for on their own. Such findings, which are indistin-
hepatitis C virus, the TT virus, Helicobacter guishable from lichen planus, may show dermal
pylori, and allo-antigens have been proposed. sclerosis, interface vacuolar dermatitis, epidermal
Lichen planus is seen with increased frequency dysmaturation, and variable pockets of peri-
in patients with HLA-B27, HLA-B51, HLA-DR1, vascular and interstitial lymphocytic infiltrate.
HLA-Bw57, and HLA-DR9, the last two HLA Despite efforts, no validated tests in serum have
types most often noted in those with oral disease been developed for GVHD diagnosis or response
(Shiohara et al. 1992). For more detail refer to the to treatment.
chapter on ▶ “Oral Lichen Planus”.
Erythema Multiforme (EM)
Graft-Versus-Host Disease (GVHD) Erythema multiforme is usually a self-limited dis-
Considered the major complication of hematopoi- ease with abrupt onset showing association with
etic cell transplantation, GVHD is also the major HLA-DQw3, DRw53, and Aw33 (Kampgen et al.
cause of nonrelapse mortality in these patients. 1988). Histopathology demonstrates lymphocyte-
Several immunologic mechanisms have been pos- induced cytotoxicity against keratinocytes and
tulated that nonexclusively may explain clinical necrosis is present in severe cases. Biopsy is nec-
disease: donor T cell expansion, absence of recip- essary in cases where diagnostic ambiguity exits
ient/donor tolerance-promoting cells, secretion of with autoimmune vesiculobullous disorders or
inflammatory and fibrosing cytokines, promotion lichen planus. Most laboratory work is directed
of B-cell activation and autoantibody production, towards identifying potential causal agents, such
and tissue cytolytic destruction (Lee 2005). The as herpes virus, mycoplasma, Epstein-Barr virus,
use of T-cell depleted grafts may decrease the and histoplasmosis. DIF immunofluorescence
incidence of GVHD, while the use of donor lym- shows IgM, C3, IgG, and rarely IgA in connective
phocyte infusions after transplantation can cause tissue vessels. IIF is negative. No specific labora-
GVHD to flare. tory work up is necessary, however, to arrive at a
In spite of its immunologic basis, diagnosis is diagnosis that continues to rely on the clinical
mostly clinical. Acute GVHD affecting the exam. Lip crusting and irregular and diffuse oral
oral cavity is clinically characterized by irregular ulcers with or without typical targetoid lesions in
nonspecific erythema and ulcerations of the skin are strongly supportive of the diagnosis.
keratinized and nonkeratinized mucosa, almost Whereas Stevens Johnson Syndrome (SJS) and
always occurring in combination with skin Toxic Epidermal Necrolysis (TEN) are in the
involvement. Lichenoid striations typical of oral spectrum of adverse cutaneous drug reactions,
chronic GVHD are not observed (Ion et al. 2014). they are considered different from EM in their
Oral biopsy findings are notable for interface der- etiology, pathophysiology and management.
matitis and so-called satellitosis (a term that While the diagnosis is mostly clinical, and histo-
describes a lymphocyte near dyskeratotic or apo- pathology is used to exclude other etiologies,
ptotic keratinocytes). These findings may also be some immunological tests may be helpful in the
screening of patients prior to prescribing specific

medications (HLA-B*5801 shares strong associ-
ation with allopurinol-induced SJS/TEN and
HLA-B*1502 has been associated with
carbamazepine-induced SJS/TEN (Somkrua
et al. 2011; Mehta et al. 2009).
Autoimmune Vesiculobullous
Disorders
Classification of autoimmune vesiculobullous dis-

orders requires understanding of immunofluores-
cence testing. DIF and IIF help in delineating the Fig. 3 Direct immunofluorescence in pemphigus vulgaris.
Perilesional tissue is immunoreactive against IgG, IgA,
site of antibody deposition (intercellular versus IgM, C3, and fibrinogen. In this example, note the
dermoepidermal junction, papillary, vascular intercellular deposition of IgG along most layers of the
deposition). Results describe its morphology epidermis, though it is more pronounced in the lower
(linear, granular, or mixed), and the type of immu- layers. This is consistent with desmoglein 3-predominant
disease (Image courtesy of Dr Lisa Lerner, StrataDx &
noglobulin or complement involved (IgA, IgG, Strata Pathology Services Lexington, MA, USA)
IgM, C3) (Table 3). Yet, close clinical inspection
is paramount as clinico-pathologic correlation is
often necessary in order to arrive at the correct “chicken-wire” distribution (Fig. 3). Antibody
diagnosis. titers (anti-Dsg1, anti-Dsg3) are often helpful at
making an initial diagnosis as these have higher
Pemphigus Vulgaris utility than IIF testing. Though some patients may
In pemphigus vulgaris, autoantibodies are created create nonpathogenic antibodies, in general, anti-
against desmoglein 1 and 3 (Dsg1 and Dsg3), body titers correlate with clinical extent and prog-
which are critical components of the desmosome. nosis of disease (Bhol and Ahmed 2002). As a
These proteins belong to the cadherin family and result, these titers may be used in chronic follow-
aid in cell-to-cell adhesion. Because pathogenic up of patients, or in those who flare after achieving
antibodies circulate in systemic circulation in remission but diagnostic considerations still con-
pemphigus vulgaris, this condition is best consid- found clinical presentation. Because most patients
ered a systemic disease. Whereas Dsg1 is require systemic immunosuppressants, it is
expressed at greater quantities in the upper zone important to secure the diagnosis before initiating
of the epidermis and in keratinizing skin, Dsg3 is therapy.
highly expressed in mucosa and in the lower por-
tions of the epidermis. This tissue and zonal dis- Mucous Membrane and Bullous
tribution of protein expression explains where Pemphigoid
disease may be found in patients with specific In the pemphigoid family of disorders, antibodies
serologic findings. In cutaneous-predominant dis- are generated against components of the
ease (cutaneous pemphigus vulgaris, pemphigus hemidesmosome in the basement membrane.
foleaceous), anti-Dsg1 antibodies predominate Antigenic targets such as bullous pemphigoid
and in mucosal disease (mucosal pemphigus), antigen 1 (BpAg1) and bullous pemphigoid
anti-Dsg3 antibodies are readily detected in antigen 2 (BpAg2) are measurable in systemic
patient sera. circulation, but unlike in pemphigus vulgaris,
Histopathology shows acantholysis, mostly at titers do not correlate as closely with clinical
the deeper portions of the epidermis, and DIF extent of disease or treatment response. Bullous
demonstrates intercellular deposition of IgG in a pemphigoid presents primarily as a pruritic
disease and can affect the oral mucosa. Generally,

lesions heal without scarring. In mucosal mem-
brane pemphigoid or cicatricial pemphigoid,
lesions disproportionately affect the eyes, mouth,
and genital mucosa and often heal with scarring.
In tissue biopsies of pemphigoid, eosino-
phils are the distinguishing feature, often
tagging the dermo-epidermal junction. Nonethe-
less, paucicellular and neutrophilic variants have
also been reported. Acantholysis is not a histo-
logic feature of pemphigoid, but rather, a cleft is
formed along the dermo-epidermal junction
manifesting itself clinically as a deeper, tense
blister. Histopathologic features may be Fig. 4 Direct immunofluorescence in bullous
pemphigoid. Tissue is immunoreactive against IgG, IgA,
non-specific in mucosal samples, however, and IgM, C3, and fibrinogen. In this example, note linear depo-
most authorities believe that the diagnosis is best sition of C3 along the basement membrane (Image cour-
secured via immunofluorescence in these sites. tesy of Dr Lisa Lerner, StrataDx & Strata Pathology
DIF shows linear C3 deposition (most commonly) Services Lexington, MA, USA)
and IgG deposition along the basement membrane
(Fig. 4). A higher proportion of samples from
patients with cicatricial pemphigoid show IgA
deposition on DIF when compared to patients
with bullous pemphigoid. IIF shows IgG deposi-
tion in the basement membrane zone, but it is only
seen in 25% of cases of mucosal pemphigoid as
opposed to nearly 75% cases of bullous
pemphigoid.
Those patients with mucous membrane
pemphigoid and antibodies against laminin
5 (antiepiligrin) may be at higher risk of malig-
nancy (Egan et al. 2003). For more detailed dis-
cussion of pemphigus and pemphigoid, refer to
Fig. 5 Linear IgA disease. Image used with permission
the chapter on ▶ “Oral Vesicular and Bullous from John J. Zone, MD
Lesions” (Figs. 5, 6, and 7).
Paraneoplastic Autoimmune particularly in patients with lichenoid disease

Multisystem Syndrome (PAMS) (Cummins et al. 2007).
In paraneoplastic autoimmune syndrome, Diagnostic criteria for this syndrome include
patients may present with up to six different clin- both major and minor criteria (Table 4). Three
ical variants. Subcellular auto-antigens include major criteria or two major and two minor criteria
desmoglein 1 and 3 as well as a myriad of other are needed to make the diagnosis.
antibodies some of which are intracellular and
desmosomal (desmoplakin, envoplakin, peri- Inflammatory Bowel Disease
plakin). Antibodies against these components The incidence of inflammatory bowel disease
may be measured in serum, though commercial (IBD) continues to increase. Whereas symptom-
assays are harder to find. Diagnosis may be atology may initially be non-specific, the role of
difficult to make early in the course of disease as the physical exam and laboratory work-up is
immunofluorescence may be negative, paramount as oral findings may precede
gastrointestinal or radiographical evidence in many

instances (Franch et al. 2010). For more detailed
discussion of IBD, refer to the chapters on ▶ “Oral
Ulcerative Lesions” and ▶ “Oral Manifestations of
Systemic Diseases and Their Treatments”.
Crohn’s Disease
Various genes have been implicated in the devel-
opment of Crohn’s disease that are related to
homeostasis of the endoplasmic reticulum
(XBP1) and the ability of macrophages to phago-
cytose organisms (ATG16L1) (Fritz et al. 2011;
Fig. 6 Epidermolysis bullosa acquisita. Direct immuno-
fluorescence performed on perilesional skin biopsy speci- Kaser et al. 2008). Various immunological mech-
men from a patient with epidermolysis bullosa acquisita anisms have been described including: (1) T cell
detects a linear band of immunoglobulin G deposit along alloreactivity and autoimmunity, (2) over-activity
the dermoepidermal junction. Image reprinted with permis-
in Th1 and Th17 cytokines, and (3) macrophage
sion from Lawrence S Chan, MD, University of Illinois
College of Medicine, published by Medscape Drugs & dysfunction and inability to phagocytose
Diseases (http://emedicine.medscape.com/), 2017, avail- (Baumgart and Sandborn 2012).
able at: http://emedicine.medscape.com/article/1063083- Whereas the small bowel (and ileum in spe-
overview)
cific) is most commonly affected, the disease can
affect the entire gastrointestinal tract from mouth
to anus. In contrast to colitis, in Crohn’s disease
the entire thickness of the bowel is affected. Yet
histopathologic sampling may be complicated by
skip lesions, in which pathologic findings may be
absent. Such findings include transmural inflam-
mation with cryptitis (or involvement of crypts
by neutrophils and lymphocytes). Noncaseating
granulomas are the most specific feature, but
they are not invariably found in all tissue biopsies.
In oral Crohn’s disease, a Th1 CD4+ lympho-
cytic infiltrate predominates. Unlike in oral
Crohn’s disease, in oral granulomatosis over-
Fig. 7 Paraneoplastic pemphigus. Direct immunofluores-
cence microscopy performed on epithelial biopsy speci- stimulation of Th2 CD4+ lymphocytes is seen
men obtained from a patient with pemphigus vulgaris (Lankarani et al. 2013). Biopsy of oral, cutaneous,
detects IgG deposits at the epithelial cell surfaces. Image or gastrointestinal involvement is needed to make
reprinted with permission from Medscape Drugs & Dis- the diagnosis and only few immunological assays
eases (http://emedicine.medscape.com/), 2017, available
at: http://emedicine.medscape.com/article/1064452- can aid in diagnosis (see below).
overview
Ulcerative Colitis
Table 4 Diagnostic Features in Paraneoplastic Autoim- Unlike Crohn disease, ulcerative colitis usually
mune Multisystem Syndrome affects only colonic mucosa, lacks transmural
Major Criteria Minor Criteria inflammation, and is not as commonly plagued
Polymorphous Positive IIF on rat by “skip” lesions that may make histopathologic
mucocutaneous eruption bladder sampling complicated. The etiologic factors,
Concurrent internal neoplasia Positive DIF genetics, and pathophysiology are less well under-
Serum immunoprecipitation Acantholysis on tissue stood than in Crohn’s disease, but environmental,
findings biopsy
infectious, and genetic contributions have all been
raised. Whereas Crohn’s disease is associated between primary and recrudescent infections. Fol-
with a Th1 and Th17 response, ulcerative colitis lowing the infection with HSV-1 or HSV-2, IgM
has been loosely linked to Th2 responses (Caprioli antibodies appear transitorily and are followed by
et al. 2013). production of IgA and IgG antibodies, which per-
A role for atypical p-ANCA and anti-Saccha- sist over time. IgG antibodies are usually negative
romyces cerevisiae antibodies (ASCA) has been in primary infections as they become detectable
raised in differentiating Crohn’s disease from 2 weeks to 3 months following the onset of symp-
ulcerative colitis. In general, positivity for atypi- toms. As such, primary HSV infections can be
cal pANCA is associated with ulcerative colitis; a detected by using serology to show seroconver-
negative ASCA increases specificity for this dis- sion with paired sera. Serological testing for
ease. On the other hand, a positive ASCA and a detection of HSV antibodies reflects the adaptive
negative p-ANCA add credence to the diagnosis immune system’s response to infection and can be
of Crohn’s disease (Mokhtarifar et al. 2013). useful in distinguishing primary from recrudes-
These serologies appear to be more reliable at cent disease, as well as in identifying asymptom-
differentiating Crohn’s disease and ulcerative atic carriers (Singh et al. 2005). A positive
colitis from each other than from establishing the serology for HSV-1 can be consistent with either
diagnosis amongst a broader list of options. anogenital or oral infection and is indicative of a
Pyostomatitis vegetans can precede other clin- current or previous infection. Of note, false-
ical evidence of IBD and its diagnosis in the negative results may occur at the beginning
absence of symptoms consistent with IBD still phases of infection. In recurrent oral HSV infec-
warrants screening. If IBD has already been diag- tions, the majority of patients are already
nosed, pyostomatitis vegetans usually correlates HSV-seropositive therefore testing for antibodies
with flare of disease. Histopathological findings is usually of little help.
include neutrophils, lymphocytes, eosinophilic A variety of Food and Drug Administration
micro-abscesses, and edema. Negative DIF for (FDA)-approved type-specific HSV serologic
IgA, IgG, and C3 help distinguish this finding tests are available, utilizing surface glycoproteins
from pemphigus vulgaris. It is also important to gG1 for detection of HSV-1, and gG2 for HSV-2.
rule out infection with the use of both stains and Serological testing can be helpful in both
cultures prior to making this diagnosis. (1) establishing sero-status in patients at-risk for
recrudescence (e.g. immunosuppressed patients,
HIV patients, pregnant women), (2) in patients
Infectious Diseases with a history of oral lesions with a negative
HSV culture; in individuals with negative PCR,
Detailed description of infectious diseases outlined (3) in individuals with an atypical presentation or
in this section can be found in chapters on ▶ “Oral recurrent episodes of erythema multiforme (see
and Maxillofacial Viral Infections” and ▶ “Oral section above), and (4) to possibly predict the
and Maxillofacial Fungal Infections”. recurrence of infection (Ashley 2001; Prince
et al. 2000; Workowski 2015; Sokumbi and
Oral Herpes Simplex Virus Wetter 2012).
The diagnosis of oral HSV infection is typically
made based on the patient’s history and clinical Varicella-Zoster Virus (VZV)
examination. However, if the pattern of lesions is VZV infections can cause varicella (chicken pox)
not classic, laboratory testing can provide confir- and herpes zoster (shingles). VZV infection is
mation, especially when clinical features alone usually diagnosed by patient’s history and clinical
are not diagnostic. In addition to microbiological findings. In atypical cases or immunocompro-
tests (e.g., cytology, viral culture), serologic eval- mised individuals, additional testing with real-
uation of anti-HSV antibodies can be useful time PCR and direct fluorescent antibody (DFA)
in confirming a diagnosis and differentiating may be helpful. The real-time PCR assays confirm
the presence of VZV from clinical specimens are several CMCC subtypes: autosomal recessive
usually obtained from body fluids (e.g., cerebro- autoimmune polyendocrinopathy candidosis with
spinal fluid (CSF) and bronchoalveolar lavage) or ectodermal dystrophy (secondary to mutations in
active vesicular skin lesions. Diagnosis of VZV the autoimmune regulator, AIRE gene), autoso-
infection can also be obtained with a rapid turn- mal dominant CMCC (with mutations in coiled-
around time (approximately 1.5 hours) by using coil domain of signal transducer and activator of
DFA on skin lesions (Chan et al. 2001; Dahl et al. transcription 1, STAT1), and autosomal recessive
1997). IgG antibodies to VZV are indicative of a CMCC. The diagnosis of CMCC relies on clinical
positive history of varicella and protection against examination (chronic, noninvasive candidosis)
subsequent infections. The most used assay is the and microbiological tests. All patients diagnosed
fluorescent antibody to membrane antibody (Wil- with CMCC should be tested for possible primary
liams et al. 1974). Viral culture is usually not and secondary immunodeficiencies, including a
indicated due to low sensitivity and relatively complete blood count with differential, immuno-
long (days) turnaround time. globulin levels, and B- and T-cell subsets. CMCC
patients may show low IgG2 and IgG4 and
Human Papillomavirus (HPV) hypogammaglobulinemia.
Oral mucosa HPV associated infections may man- In addition, those patients with STAT1 muta-
ifest as both benign and malignant conditions tions should be tested for STAT1 function by
(Stojanov and Woo 2015). The diagnosis of polymerase-chain-reaction assay in freshly
benign oral HPV lesions is typically made through obtained peripheral blood lymphocytes as these
a careful patient history, clinical examination, patients may present with a gradual decline of T,
and histopathology. Clinical immunological B, and natural NK cells, as well as deteriorating T
approaches for diagnosis of HPV include the cell function (Sharfe et al. 2014). Patients with
detection of HPV DNA through DNA hybridiza- defects in the AIRE gene present with autoanti-
tion (e.g., southern blot, dot blot, and in situ bodies to IL-17 and IL-22 (Th17 cells) which are
hybridization). Other methods include enzyme- fundamental for mucosal antifungal immunity
linked immunosorbent assay for IgG antibody and show a selective inability to respond to Can-
against HPV 16 capsid. However, these methods dida in vitro (T cell proliferation) or in vivo (cuta-
are currently used in research settings and serol- neous delayed-type hypersensitivity) (van de
ogy is not used diagnostically. Sero-surveillance Veerdonk et al. 2011; Kalfa et al. 2003).
has been used in population-based studies to mon-
itor HPV exposure in prevaccine settings or to
measure vaccine effectiveness. Immunodeficiency
A wide variety of HPV assays are available
commercially and are used to detect high risk Immunodeficiencies are a group of conditions
HPV type. The Food and Drug Administration characterized by defects of the immune system
(FDA) has approved three tests to detect levels and an increased risk for infections. Primary
of the high-risk HPV types: the Digene HC2 immunodeficiencies are hereditary, while second-
High-Risk HPV DNA test (Qiagen, Gaithersburg, ary immunodeficiencies are acquired. Secondary
MD), the Cervista™ HPV HR test (Hologics, immunodeficiencies are more frequent and may
Bedford, MA), and the cobas 4800 HPV test be encountered in patients with other systemic
(Roche Molecular Systems, Pleasanton, CA). disorders such as uncontrolled diabetes mellitus,
HIV infection, and malnutrition, or in patients who
Chronic Mucocutaneous Candidosis undergo immunosuppressive medical therapies.
Chronic mucocutaneous candidosis (CMCC) is While the oral medicine clinician would not typ-
associated with defects in cell-mediated immunity ically order tests for the work-up and diagnosis of
(e.g., patients with (SCID) or DiGeorge syndrome immunodeficiency, there must be familiarity with
or severely immunodepressed patients). There the appropriate tests for assessing immune status
and infection risk for a given immunodeficiency T cells defects are usually detected by flow
condition. cytometry for B and T cell markers. The
most severe form of CID is known as severe
Primary Immunodeficiency combined immunodeficiency (SCID). Individuals
Primary immunodeficiency (PID) is a group of with SCID are born with deficiencies of both
rare disorders, usually inherited, and all neonates T-lymphocyte function and numbers and, in some
with suspected immunodeficiency should receive cases, do not possess B and NK lymphocytes.
consultation with an immunologist for a correct Some of these patients may also have decreased
diagnosis and management. PIDs can be catego- levels of serum immunoglobulin. The two most
rized in disorders caused by defects of the adap- common forms of SCID are the autosomal reces-
tive immune system and in disorders caused by sive adenosine deaminase (ADA) deficiency and
defects in the innate immune system (TLRs, IFNs, X-linked. ADA is an enzyme employed in the
NK cells) (Dropulic and Cohen 2011). Defects breakdown of purines, which converts adenosine
during B-cell development or maturation result to inosine and deoxyadenosine to deoxyinosine
in B-cell immunodeficiency disorders, while (Perez-Aguilar et al. 2012). In patients with no
defects in T-cell development, differentiation, ADA, adenosine builds up and leads to an increase
and maturation lead to T-cell disorders. in metabolites that are toxic to lymphocytes. Treat-
B-cell disorders are the most common ment for antibody deficiencies is primarily Ig
type of PIDs and are characterized by an replacement therapy.
increased risk for bacterial sinopulmonary Other CIDs with important defects in the innate
infections, mainly Haemophilus influenzae, and immune system include Wiskott-Aldrich syn-
Streptococcus pneumoniae. These include X- drome, DiGeorge syndrome, and ataxia-
linked agammaglobulinemia, selective IgA defi- telangiectasia. Wiskott–Aldrich syndrome is a
ciency, and common variable immunodeficiency disorder characterized by mutations of the WAS
(CVID). X-linked agammaglobulinemia is char- gene which can affect the function of T and B
acterized by a mutation in the Bruton’s tyrosine cells, as well as platelets. Patients with DiGeorge
kinase (BTK) gene, which is involved in B-cell Syndrome have a chromosome 22q11.2 deletion
formation and maturation. The diagnosis is and may present with a small or absent thymus,
established by genetic studies (e.g., direct DNA which impairs T-cell development with secondary
analysis, single-strand confirmation polymor- quantitative T-cell defects (Burnside 2015).
phism, denaturing gradient gel electrophoresis, Ataxia-telangiectasia is an autosomal recessive
or reverse transcriptase–PCR) to identify the condition caused by a defective gene on chromo-
mutations in the gene coding for BTK. IgA some 11q22.3, characterized by cerebellar ataxia,
deficiency is caused by a maturation defect in progressive neurological impairment, abnormal
B cells to produce IgA. The diagnosis is made eye movements, cutaneous and ocular telangiec-
when there are undetectable serum levels of tasias, immune dysfunction, and predisposition to
IgA (<5–7 mg/dL), with normal IgG and IgM cancer (Ambrose and Gatti 2013). Genetic studies
levels. CVID is a group of diseases characterized for mutations are necessary to confirm the diag-
by an inability to produce adequate levels of all nosis of these PIDs.
classes of antibodies, particularly IgG and IgA Chronic Granulomatous Disease (CGD) is
(Park et al. 2008). All these conditions present at another inherited PID caused by mutations of
an early age with recurrent respiratory tract infec- nicotinamide adenine dinucleotide phosphate
tions and patients are at risk for other infections, (NADPH) oxidase in phagocytes (Holland
autoimmune diseases, allergies, GI diseases, and 2013). Deficits in phagocytes lead to recurrent
malignancies. fungal and bacterial infections and granuloma
Most of the time patients present with a com- formation. The nitroblue tetrazolium (NBT) slide
bination of B and T cell defects that lead to com- test is indicated to test the oxidase activity of
bined immunodeficiency disorders (CIDs). B and individual cells in CGD patients.
Secondary Immunodeficiency response to therapy. Effective coordination and

Secondary immunodeficiency results from an communication among clinicians, clinical patholo-
altered immune function that may be secondary gists, and laboratory technicians helps to ensure
to systemic conditions, medication use, or envi- appropriate use and interpretation of laboratory
ronmental exposure (e.g., ultraviolet radiation and tests. With advances in the understanding of the
chemicals) (De Marie 1993). Patients with sec- immunological basis of disease and available clin-
ondary immunodeficiency are at risk for infec- ical immunological testing technologies, it is impor-
tions, autoimmune diseases, and malignancies. tant that the oral medicine specialist’s knowledge
For example, patients with diabetes mellitus may and competence in this area remains up to date.
develop neutrophil dysfunction which places
them at a higher risk for infectious complications.
Other conditions that may impair immune func- Cross-References
tion include HIV, cirrhosis, and malnutrition.
Immunosuppressive pharmacological agents ▶ Clinical Evaluation of Oral Diseases
(e.g., glucocorticoids, methotrexate, calcineurin ▶ Cutaneous Pathology of the Head and Neck
inhibitors) and targeted biological agents (e.g., ▶ Gingival Pathology
anti-TNF-alpha inhibitors, rituximab) may com- ▶ Interface Between Oral and Systemic Disease
promise the host defense and therefore lead to ▶ Laboratory Medicine and Diagnostic Pathology
immunologic complications (Teo et al. 2016; ▶ Oral and Maxillofacial Fungal Infections
Lonial et al. 2016). The risk of oral complications ▶ Oral and Maxillofacial Viral Infections
depends on the specific medication(s) used ▶ Oral Lichen Planus
(including dose and duration), the type of disease, ▶ Oral Manifestations of Systemic Diseases and
and patient-related factors. Their Treatments
Clinical Implications ▶ Oral Vesicular and Bullous Lesions
Immunodeficient patients are more susceptible to ▶ Pharmacotherapeutic Approaches in Oral
oral viral, bacterial, and fungal infections. Fur- Medicine
thermore, immunocompromised individuals may ▶ Salivary Gland Disorders and Diseases
present with severe, persistent, recurrent, or ▶ Soft and Hard Tissue Operative Investigations
refractory oral infections. Oral infections in in the Diagnosis and Treatment of Oral Disease
patients with primary or secondary immunodefi- ▶ White and Red Lesions of the Oral Mucosa
ciency may require intensive and prolonged ther-
apy. A team approach involving oral medicine,
infectious diseases, and immunology is essential References
to provide effective management.
Abeles AM, Abeles M. The clinical utility of a positive
antinuclear antibody test result. Am J Med.
2013;126(4):342–8.
Conclusions and Future Directions Abraham RS. Relevance of antibody testing in patients
with recurrent infections. J Allergy Clin Immunol.
A wide spectrum of oral medicine conditions have 2012;130(2):558–9. e6
an immunological basis, and correct diagnosis is Abraham DJ, Krieg T, Distler J, Distler O. Overview of
pathogenesis of systemic sclerosis. Rheumatology
paramount so that safe and appropriate therapy
(Oxford). 2009;48(Suppl 3):iii3–7.
can be provided. While never a substitute for Aggarwal A. Role of autoantibody testing. Best Pract Res
patient history and physical examination, clinical Clin Rheumatol. 2014;28(6):907–20.
immunological testing provides essential infor- Agmon-Levin N, Damoiseaux J, Kallenberg C, Sack U,
Witte T, Herold M, et al. International recommenda-
mation necessary for arriving at a definitive diag-
tions for the assessment of autoantibodies to cellular
nosis and in some situations may also be useful for antigens referred to as anti-nuclear antibodies. Ann
determining prognosis as well as evaluating Rheum Dis. 2014;73(1):17–23.
Agostoni A, Aygoren-Pursun E, Binkley KE, Blanch A, Cummins DL, Mimouni D, Tzu J, Owens N, Anhalt GJ,
Bork K, Bouillet L, et al. Hereditary and acquired Meyerle JH. Lichenoid paraneoplastic pemphigus in
angioedema: problems and progress: proceedings the absence of detectable antibodies. J Am Acad
of the third C1 esterase inhibitor deficiency Dermatol. 2007;56(1):153–9.
workshop and beyond. J Allergy Clin Immunol. Dahl H, Marcoccia J, Linde A. Antigen detection: the
2004;114(3 Suppl):S51–131. method of choice in comparison with virus isolation
Al-Hashimi I, Schifter M, Lockhart PB, Wray D, and serology for laboratory diagnosis of herpes zoster
Brennan M, Migliorati CA, et al. Oral lichen planus in human immunodeficiency virus-infected patients.
and oral lichenoid lesions: diagnostic and therapeutic J Clin Microbiol. 1997;35(2):347–9.
considerations. Oral Surg Oral Med Oral Pathol Oral Dawes C, Pedersen AM, Villa A, Ekstrom J, Proctor GB,
Radiol Endod. 2007;103(Suppl:S25):e1–12. Vissink A, et al. The functions of human saliva: a
Ambrose M, Gatti RA. Pathogenesis of ataxia- review sponsored by the World workshop on oral med-
telangiectasia: the next generation of ATM functions. icine VI. Arch Oral Biol. 2015;60(6):863–74.
Blood. 2013;121:4036. D'Cruz D. Testing for autoimmunity in humans. Toxicol
American College of Rheumatology Position Statement: Lett. 2002;127(1–3):93–100.
Methodology of Testing for Antinuclear Antibodies. De Marie S. Diseases and drug-related interventions affect-
https://www.rheumatology.org/Portals/0/Files/Methodo ing host defence. Eur J Clin Microbiol Infect Dis.
logy%20of%20Testing%20Antinuclear%20Antibodies 1993;12(Suppl 1):S36–41.
%20Position%20Statement.pdf. De Rossi SS, Ciarrocca K. Oral lichen planus and lichenoid
Anderson NW, Buchan BW, Ledeboer NA. Light micros- mucositis. Dent Clin N Am. 2014;58(2):299–313.
copy, culture, molecular, and serologic methods for Dreborg S, Foucard T. Allergy to apple, carrot and potato
detection of herpes simplex virus. J Clin Microbiol. in children with birch pollen allergy. Allergy.
2014;52(1):2–8. 1983;38(3):167–72.
Ashley RL. Sorting out the new HSV type specific anti- Dropulic LK, Cohen JI. Severe viral infections and
body tests. Sex Transm Infect. 2001;77(4):232–7. primary immunodeficiencies. Clin Infect Dis.
Ausukua M, Dublin I, Echebarria MA, Aguirre JM. Oral 2011;53(9):897–909.
allergy syndrome (OAS). General and stomato- Dunkelberger JR, Song WC. Complement and its role in
logical aspects. Med Oral Patol Oral Cir Bucal. innate and adaptive immune responses. Cell Res.
2009;14(11):e568–72. 2010;20(1):34–50.
Aydemir S, Tekin NS, Aktunc E, Numanoglu G, Ustundag Y. Egan CA, Lazarova Z, Darling TN, Yee C, Yancey
Celiac disease in patients having recurrent aphthous sto- KB. Anti-epiligrin cicatricial pemphigoid: clinical find-
matitis. Turk J Gastroenterol. 2004;15(3):192–5. ings, immunopathogenesis, and significant associa-
Baumgart DC, Sandborn WJ. Crohn’s disease. Lancet. tions. Medicine (Baltimore). 2003;82(3):177–86.
2012;380(9853):1590–605. Elliott K, McQuaid S, Salto-Tellez M, Maxwell P. Immu-
Bhagat M, Sehra ST, Shahane A, Kwan M. Utility of nohistochemistry should undergo robust validation
immunologic testing in suspected rheumatologic dis- equivalent to that of molecular diagnostics. J Clin
ease. Curr Allergy Asthma Rep. 2014;14(1):405. Pathol. 2015;68(10):766–70.
Bhol KC, Ahmed AR. Production of non-pathogenic human Farkas H, Veszeli N, Kajdacsi E, Cervenak L, Varga L. “Nuts
monoclonal antibodies to desmoglein 3 from pemphigus and Bolts” of Laboratory Evaluation of Angioedema.
vulgaris patient. Autoimmunity. 2002;35(2):87–91. Clin Rev Allergy Immunol. 2016;51:140–51.
Bonilla FA, Oettgen HC. Adaptive immunity. J Allergy Feller L, Altini M, Khammissa RA, Chandran R,
Clin Immunol. 2010;125(2 Suppl 2):S33–40. Bouckaert M, Lemmer J. Oral mucosal immunity.
Burnside RD. 22q11.21 deletion syndromes: a review Oral Surg Oral Med Oral Pathol Oral Radiol.
of proximal, central, and distal deletions and 2013;116(5):576–83.
their associated features. Cytogenet Genome Res. Ferri C, Bernini L, Cecchetti R, Latorraca A, Marotta G,
2015;146(2):89–99. Pasero G, et al. Cutaneous and serologic subsets of
Caprioli F, Marafini I, Facciotti F, Pallone F, systemic sclerosis. J Rheumatol. 1991;18(12):1826–32.
Monteleone G. Targeting T cells in chronic inflamma- Franceschini F, Cavazzana I. Anti-Ro/SSA and La/SSB
tory bowel diseases. J Clin Cell Immunol. 2013;4:1–6. antibodies. Autoimmunity. 2005;38(1):55–63.
Chan EL, Brandt K, Horsman GB. Comparison of Franch A, Soriano YJ, Sarrion Perez MG. Dental manage-
Chemicon SimulFluor direct fluorescent antibody ment of patients with inflammatory bowel disease.
staining with cell culture and shell vial direct J Clin Exp Dent. 2010;2:191–5.
immunoperoxidase staining for detection of herpes Fritz T, Niederreiter L, Adolph T, Blumberg RS, Kaser A.
simplex virus and with cytospin direct immunofluores- Crohn’s disease: NOD2, autophagy and ER stress con-
cence staining for detection of varicella-zoster virus. verge. Gut. 2011;60(11):1580–8.
Clin Diagn Lab Immunol. 2001;8(5):909–12. Grutters JC, Fellrath JM, Mulder L, Janssen R, van den
Cottom H, Mighell AJ, High A, Bateman AC. Are plasma Bosch JM, van Velzen-Blad H. Serum soluble
cell-rich inflammatory conditions of the oral mucosa interleukin-2 receptor measurement in patients
manifestations of IgG4-related disease? J Clin Pathol. with sarcoidosis: a clinical evaluation. Chest.
2015;68(10):802–7. 2003;124(1):186–95.
Habash-Bseiso DE, Yale SH, Glurich I, Goldberg JW. Sjogren’s syndrome in children. J Rheumatol. 2001;28
Serologic testing in connective tissue diseases. Clin (4):860–4.
Med Res. 2005;3(3):190–3. Mantovani A, Cassatella MA, Costantini C, Jaillon S.
Hayashi T. Dysfunction of lacrimal and salivary glands in Neutrophils in the activation and regulation of
Sjogren's syndrome: nonimmunologic injury in pre- innate and adaptive immunity. Nat Rev Immunol.
inflammatory phase and mouse model. J Biomed 2011;11(8):519–31.
Biotechnol. 2011;2011:407031. Mattoo H, Mahajan VS, Della-Torre E, Sekigami Y,
Hepburn A, Charles P. Antinuclear Factor. Rheumatology Carruthers M, Wallace ZS, et al. De novo oligoclonal
(Oxford). 2002;41(3):343–345. expansions of circulating plasmablasts in active and
Ho KT, Reveille JD. The clinical relevance of autoantibodies relapsing IgG4-related disease. J Allergy Clin
in scleroderma. Arthritis Res Ther. 2003;5(2):80–93. Immunol. 2014;134(3):679–87.
Holland SM. Chronic granulomatous disease. Hematol Mehta TY, Prajapati LM, Mittal B, Joshi CG, Sheth JJ,
Oncol Clin North Am. 2013;27(1):89–99. Patel DB, Dave DM, Goyal RK. Association of
Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. HLA-B*1502 allele and carbamazepine-induced Ste-
N Engl J Med. 2007;357(21):2153–65. vens-Johnson syndrome among Indians. Indian J
Ion D, Stevenson K, Woo SB, Ho VT, Soiffer R, Antin JH, Dermatol Venereol Leprol. 2009;75(6):579–82.
et al. Characterization of oral involvement in acute Migliorini P, Baldini C, Rocchi V, Bombardieri S. Anti-Sm
graft-versus-host disease. Biol Blood Marrow Trans- and anti-RNP antibodies. Autoimmunity. 2005;38(1):47–54.
plant. 2014;20(11):1717–21. Mihai S, Sitaru C. Immunopathology and molecular diag-
Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, nosis of autoimmune bullous diseases. J Cell Mol Med.
Cowen EW, et al. National Institutes of Health Consen- 2007;11(3):462–81.
sus development project on criteria for clinical trials in Mokhtarifar A, Ganji A, Sadrneshin M, Bahari A,
chronic graft-versus-host disease: I. The 2014 diagno- Esmaeilzadeh A, Ghafarzadegan K, et al. Diagnostic
sis and staging working group report. Biol Blood Mar- value of ASCA and atypical p-ANCA in differential
row Transplant. 2015;21(3):389–401. e1 diagnosis of inflammatory bowel disease. Middle East J
Kalfa VC, Roberts RL, Stiehm ER. The syndrome of Dig Dis. 2013;5(2):93–7.
chronic mucocutaneous candidiasis with selective anti- Mowad CM, Anderson B, Scheinman P, Pootongkam S,
body deficiency. Ann Allergy Asthma Immunol. Nedorost S, Brod B. Allergic contact dermatitis: patient
2003;90(2):259–64. management and education. J Am Acad Dermatol.
Kampgen E, Burg G, Wank R. Association of herpes 2016;74(6):1043–54.
simplex virus-induced erythema multiforme with the Nelson JL. Microchimerism and the pathogenesis of systemic
human leukocyte antigen DQw3. Arch Dermatol. sclerosis. Curr Opin Rheumatol. 1998;10(6):564–71.
1988;124(9):1372–5. Ortolani C, Ispano M, Pastorello E, Bigi A, Ansaloni R.
Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, The oral allergy syndrome. Ann Allergy. 1988;61(6 Pt
Tilg H, et al. XBP1 links ER stress to intestinal inflam- 2):47–52.
mation and confers genetic risk for human inflamma- Ortolani C, Ispano M, Pastorello EA, Ansaloni R,
tory bowel disease. Cell. 2008;134(5):743–56. Magri GC. Comparison of results of skin prick tests
Kerr DA, McClatchey KD, Regezi JA. Allergic gingivos- (with fresh foods and commercial food extracts) and
tomatitis (due to gum chewing). J Periodontol. RAST in 100 patients with oral allergy syndrome.
1971;42(11):709–12. J Allergy Clin Immunol. 1989;83(3):683–90.
Kneisel A, Hertl M. Autoimmune bullous skin diseases. Pappalardo E, Cicardi M, Duponchel C, Carugati A,
Part 2: diagnosis and therapy. J German Soc Dermatol. Choquet S, Agostoni A, et al. Frequent de novo muta-
2011;9(11):927–47. tions and exon deletions in the C1inhibitor gene of
Lankarani KB, Sivandzadeh GR, Hassanpour S. Oral man- patients with angioedema. J Allergy Clin Immunol.
ifestation in inflammatory bowel disease: a review. 2000;106(6):1147–54.
World J Gastroenterol. 2013;19(46):8571–9. Park MA, Li JT, Hagan JB, Maddox DE, Abraham RS.
Lee SJ. New approaches for preventing and Common variable immunodeficiency: a new look at an
treating chronic graft-versus-host disease. Blood. old disease. Lancet. 2008;372(9637):489–502.
2005;105(11):4200–6. Perez-Aguilar MC, Goncalves L, Bonfante-Cabarcas R.
LeGoff J, Pere H, Belec L. Diagnosis of genital herpes Adenosine deaminase in severe combined immunode-
simplex virus infection in the clinical laboratory. Virol J. ficiency syndrome. Investig Clin. 2012;53:315–24.
2014;11:83. Popescu FD. Cross-reactivity between aeroallergens and
Loke WS, Herbert C, Thomas PS. Sarcoidosis: food allergens. World J Methodol. 2015;5(2):31–50.
immunopathogenesis and immunological markers. Preeti L, Magesh K, Rajkumar K, Karthik R. Recurrent
Int J Chronic Dis. 2013;2013:928601. aphthous stomatitis. J Oral Maxillofac Pathol.
Lonial S, Durie B, Palumbo A, San-Miguel J. Monoclonal 2011;15(3):252–6.
antibodies in the treatment of multiple myeloma: cur- Prince HE, Ernst CE, Hogrefe WR. Evaluation of an
rent status and future perspectives. Leukemia. enzyme immunoassay system for measuring herpes
2016;30(3):526–35. simplex virus (HSV) type 1-specific and HSV type
Maeno N, Takei S, Imanaka H, Oda H, Yanagi K, 2-specific IgG antibodies. J Clin Lab Anal.
Hayashi Y, et al. Anti-alpha-fodrin antibodies in 2000;14(1):13–6.
Rodriguez J, Crespo JF, Lopez-Rubio A, De La Cruz- Stojanov IJ, Woo SB. Human papillomavirus and Epstein-
Bertolo J, Ferrando-Vivas P, Vives R, et al. Clini- Barr virus associated conditions of the oral mucosa.
cal cross-reactivity among foods of the Rosaceae Semin Diagn Pathol. 2015;32(1):3–11.
family. J Allergy Clin Immunol. 2000;106(1 Pt 1):183–9. Stone JH, Khosroshahi A, Deshpande V, Chan JK,
Sakaguchi S, Wing K, Miyara M. Regulatory T cells – Heathcote JG, Aalberse R, Azumi A, Bloch DB, Brugge
a brief history and perspective. Eur J Immunol. WR, Carruthers MN, Cheuk W, Cornell L, Castillo CF,
2007;37(Suppl 1):S116–23. Ferry JA, Forcione D, Klöppel G, Hamilos DL,
Sakane T, Takeno M, Suzuki N, Inaba G. Behcet’s disease. Kamisawa T, Kasashima S, Kawa S, Kawano M,
N Engl J Med. 1999;341(17):1284–91. Masaki Y, Notohara K, Okazaki K, Ryu JK, Saeki T,
Savige J, Gillis D, Benson E, Davies D, Esnault V, Falk RJ, Sahani D, Sato Y, Smyrk T, Stone JR, Takahira M,
et al. International Consensus statement on testing and Umehara H, Webster G, Yamamoto M, Yi E,
reporting of antineutrophil cytoplasmic antibodies Yoshino T, Zamboni G, Zen Y, Chari S. Recommenda-
(ANCA). Am J Clin Pathol. 1999;111(4):507–13. tions for the nomenclature of IgG4-related disease and
Savige J, Dimech W, Fritzler M, Goeken J, Hagen EC, its individual organ system manifestations. Arthritis
Jennette JC, et al. Addendum to the international Con- Rheum. 2012;64(10): 3061–7.
sensus statement on testing and reporting of anti- Stukus DR, Mikhail I. Pearls and pitfalls in diagnosing
neutrophil cytoplasmic antibodies. Quality control IgE-mediated food allergy. Curr Allergy Asthma Rep.
guidelines, comments, and recommendations for test- 2016;16(5):34.
ing in other autoimmune diseases. Am J Clin Pathol. Tan EM, Feltkamp TE, Smolen JS, Butcher B, Dawkins R,
2003;120(3):312–8. Fritzler MJ, et al. Range of antinuclear anti-
Schroeder HW Jr, Cavacini L. Structure and function of bodies in “healthy” individuals. Arthritis Rheum.
immunoglobulins. J Allergy Clin Immunol. 1997;40(9):1601–11.
2010;125(2 Suppl 2):S41–52. Teo EC, Chew Y, Phipps C. A review of monoclonal
Self SE. Autoantibody testing for autoimmune disease. antibody therapies in lymphoma. Crit Rev Oncol
Clin Chest Med. 2010;31(3):415–22. Hematol. 2016 Jan;97:72–84.
Sharfe N, Nahum A, Newell A, Dadi H, Ngan B, Turvey SE, Broide DH. Innate immunity. J Allergy Clin
Pereira SL, et al. Fatal combined immunodeficiency Immunol. 2010;125(2 Suppl 2):S24–32.
associated with heterozygous mutation in STAT1. van de Veerdonk FL, Plantinga TS, Hoischen A,
J Allergy Clin Immunol. 2014;133(3):807–17. Smeekens SP, Joosten LA, Gilissen C, et al. STAT1
Sherer Y, Gorstein A, Fritzler MJ, Shoenfeld Y. Autoanti- mutations in autosomal dominant chronic mucocu-
body explosion in systemic lupus erythematosus: more taneous candidiasis. N Engl J Med. 2011;365(1):
than 100 different antibodies found in SLE patients. 54–61.
Semin Arthritis Rheum. 2004;34(2):501–37. Virgo PF, Gibbs GJ. Flow cytometry in clinical pathology.
Shiohara T, Moriya N, Nagashima M. Induction and con- Ann Clin Biochem. 2012;49(Pt 1):17–28.
trol of lichenoid tissue reactions. Springer Semin Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S.
Immunopathol. 1992;13(3–4):369–85. Functions of natural killer cells. Nat Immunol.
Singh A, Preiksaitis J, Ferenczy A, Romanowski B. The 2008;9(5):503–10.
laboratory diagnosis of herpes simplex virus infections. Voehringer D. Protective and pathological roles of
Can J Infect Dis Med Microbiol. 2005;16(2):92–8. mast cells and basophils. Nat Rev Immunol.
Sinico RA, Radice A. Antineutrophil cytoplasmic anti- 2013;13(5):362–75.
bodies (ANCA) testing: detection methods and clinical Warrington R, Watson W, Kim HL, Antonetti FR. An
application. Clin Exp Rheumatol. 2014;32(3 Suppl 82): introduction to immunology and immunopathology.
S112–7. Allergy, Asthma Clin Immunol. 2011;1(7 Suppl):S1.
Smetana GW, Landon BE, Bindman AB, Burstin H, Davis Williams V, Gershon A, Brunell PA. Serologic response
RB, Tjia J, et al. A comparison of outcomes resulting to varicella-zoster membrane antigens measured by
from generalist vs specialist care for a single direct immunofluorescence. J Infect Dis.
discrete medical condition: a systematic review 1974;130(6):669–72.
and methodologic critique. Arch Intern Med. 2007; Woo SB. Oral pathology: a comprehensive atlas and text
167(1):10–20. 2012.
Sokumbi O, Wetter DA. Clinical features, diagnosis, and Workowski KA. Centers for Disease Control and Preven-
treatment of erythema multiforme: a review for tion sexually transmitted diseases treatment guidelines.
the practicing dermatologist. Int J Dermatol. Clin Infect Dis. 2015;61(Suppl 8):S759–62.
2012;51(8):889–902. Yuan A, Woo SB. Adverse drug events in the oral cavity.
Somkrua R, Eickman EE, Saokaew S, Lohitnavy M, Oral Surg Oral Med Oral Pathol Oral Radiol.
Chaiyakunapruk N. Association of HLA-B*5801 2015;119(1):35–47.
allele and allopurinol-induced Stevens Johnson syndrome Zuraw BL, Bernstein JA, Lang DM, Craig T, Dreyfus D,
and toxic epidermal necrolysis: a systematic review and Hsieh F, et al. A focused parameter update: hereditary
meta-analysis. BMC Med Genet. 2011;12:118. angioedema, acquired C1 inhibitor deficiency,
Stinton LM, Fritzler MJ. A clinical approach to autoanti- and angiotensin-converting enzyme inhibitor-
body testing in systemic autoimmune rheumatic disor- associated angioedema. J Allergy Clin Immunol.
ders. Autoimmun Rev. 2007;7(1):77–84. 2013;131(6):1491–3.
Soft and Hard Tissue Operative
Investigations in the Diagnosis
and Treatment of Oral Disease
Marieke T. Brands, Ivan Alajbeg, Peter A. Brennan, and

Camile S. Farah
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
Why Perform a Biopsy? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
When to Perform a Biopsy? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346
Who should Perform a Biopsy? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346
What to Do before the Biopsy? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
Where to Biopsy? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
White Light . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
Toluidine Blue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
Optical Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352
How to Perform a Biopsy? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
Incisional Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356
Excisional Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356
Operative Diagnostic Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358
Mucosal Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358
Labial Salivary Gland Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363
Submucosal Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365
M. T. Brands (*) · P. A. Brennan

Department of Oral and Maxillofacial Surgery, Queen
e-mail: m.t.brands@gmail.com; Peter.
brennan@porthosp.nhs.uk
I. Alajbeg
University of Zagreb School of Dental Medicine,
Zagreb, Croatia
e-mail: alajbeg@sfzg.hr
C. S. Farah
UWA Dental School and Oral Health Centre of
Western Australia, Faculty of Health and Medical
Sciences, University of Western Australia, Perth, WA,
Australia
e-mail: camile.farah@uwa.edu.au

https://doi.org/10.1007/978-3-319-72303-7_10
342 M. T. Brands et al.
Hard Tissue Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365

Brush Cytology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367
Fine Needle Aspiration Cytology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370
Suturing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372
Suture Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372
Needle Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374
Suture Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
Simple Interrupted Sutures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
Aftercare . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
Communication with the Pathologist . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379
Other Operative Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381
Laser . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381
Cryotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382
Sialoendoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385
Arthrocentesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386
Special Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388
Oral Potentially Malignant Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388
Mucocele . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
Ranula . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
Vesiculobullous Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
Orofacial Granulomatosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
Vascular Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396
Abstract lesions · Diagnostic procedures · Surgery ·

Specialists in oral medicine frequently carry Laser · Cryotherapy · Suturing
out interventional procedures in the oral cavity.
These procedures are usually for diagnostic
purposes, but in many instances oral medicine
specialists also undertake minor oral surgical Introduction
procedures as definitive treatment for either
mucosal, soft tissue, or hard tissue lesions. The accurate diagnosis of lesions in the oral
This chapter provides an overview of the cavity often requires histological confirmation.
most common diagnostic procedures used in This chapter addresses the indications, tech-
the oral cavity including soft and hard tissue niques, pitfalls, and medicolegal concerns in
biopsies. Ancillary techniques such as fine nee- using operative techniques in the diagnosis and
dle aspiration biopsy, the use of fluorescence, treatment of lesions and diseases of the oral cav-
toluidine blue, cryotherapy, and lasers are also ity and maxillofacial region. This chapter is
discussed. Biopsy technique, indications, and intentionally not exhaustive or overly detailed,
pitfalls in addition to medicolegal consider- and clinicians wishing to carry out these opera-
ations are covered. tive techniques are advised to undertake appro-
priate education and training. The authors
Keywords acknowledge that not all oral medicine special-
Biopsy · Incisional · Excisional · Fine needle ists will have training in all these procedures, or
aspiration · Cytology · Malignancy · Oral indeed wish to carry them out. Some specialist
Soft and Hard Tissue Operative Investigations in the Diagnosis and Treatment of Oral Disease 343
training programs around the world place signif- why the practice of clinical oral medicine relies
icant emphasis on surgical procedures, while heavily on biopsy, as it offers assistance in provi-
others revert some or all of these to surgical sion of a correct diagnosis. Sometimes, biopsy is
colleagues. Clinicians should remember to prac- the sole method for reaching a diagnosis.
tice within the scope of their training and exper-
tise and also within the recognized regulatory
frameworks within their countries. Detailed Why Perform a Biopsy?
knowledge of head and neck anatomy and vari-
ants thereof is of paramount importance for The development of a reasonable differential
clinicians wishing to undertake operative proce- diagnosis is of prime importance in determining
dures in the oral and maxillofacial region. if biopsy is indicated. Furthermore, the differen-
Operative investigations and surgical proce- tial diagnosis aids the clinician in selecting the
dures can be used for diagnostic purposes while appropriate technique if biopsy is necessary.
formulating a diagnosis, or for definitive treat- A waiting period of 2 weeks often helps in
ment. This chapter explores both, but greater forming the differential diagnosis given that
emphasis is placed on diagnostic operative tech- lesions related to infection, inflammation, or
niques and investigations given the central role local trauma may resolve during this time. Biopsy
that biopsy plays in contemporary oral medicine is strongly recommended for the evaluation of
practice. Although a greater emphasis is placed on most lesions that persist for 2 weeks or longer
biopsy techniques in this chapter, it does, how- after potential irritants are removed.
ever, cover other operative approaches used in A biopsy, even though it may be the gold
oral medicine, such as cryotherapy, laser therapy, standard for some diagnosis, is not always indi-
sialendoscopy, and arthrocentesis. Many of these cated for every oral mucosal lesion. It is impor-
procedures are also covered in context in dedi- tant to make a clinical diagnosis first and look for
cated chapters where they are more applicable, causal agents such as smoking, amalgam fillings,
such as arthrocentesis in ▶ “Arthritic Conditions trauma, infection, or systemic disease. Unless the
Affecting the Temporomandibular Joint,” cryo- suspicion of malignancy is very high, it is usu-
therapy in ▶ “Salivary Gland Disorders and Dis- ally safe to monitor for resolution of a lesion for a
eases,” or use of sclerozing agents for vascular few weeks, such as for a suspected traumatic
lesions in ▶ “Head and Neck Tumors.” The reader ulcer. If the lesion has not improved or resolved,
is also directed to dedicated chapters on ▶ “Nor- a biopsy should be considered. Figures 1 and 2
mal Variation in the Anatomy, Biology, and His- contain flow-charts for guiding decisions to
tology of the Maxillofacial Region,” ▶ “Clinical biopsy or not, for different types of lesions in
Evaluation of Oral Diseases,” and ▶ “Laboratory the oral cavity (Meleti et al. 2008; van der Waal
Medicine and Diagnostic Pathology” for full 2010).
exploration of these related topics that either There are several main reasons why a clinician
form preludes to undertaking operative investiga- may perform a biopsy:
tions or follow on from them. Although this chap-
ter explores adjunctive techniques in terms of 1. To rule out possible cancer or potentially can-
directing biopsy location, these are also explored cerous pathology or to monitor the possible
in greater detail in the chapter on ▶ “Oral Mucosal malignant transformation of an oral potentially
Malignancies.” malignant disorder (OPMD). This is especially
Oral mucosal diseases can take on many pre- important when one encounters white, red,
sentations and as such biopsy plays an important indurated, and/or ulcerated lesions.
part in the diagnosis. Different oral mucosal con- 2. To help in establishing the diagnosis when the
ditions may look alike; likewise a single condition clinician has doubts, regardless of the nature of
may present with various shapes or forms. This is the pathology. Appropriate treatment can only
Non-pigmented lesion
Possible etiological factors present: No etiological factors present Suspicion of systemic disease
- Smoking
- Contact lesion (medication, amalgam filling,
betel)
- Suspicion of candidosis
- Mechanical trauma (cheek biting, sharp Referral to the appropriate specialty
tooth or filling, ill fitting dentures)
- Medication related ulcer
Low clinical suspicion for malignancy: maximal 6

weeks of observation and monitoring of treatment If requested
effects
Effective:
monitor patient Not effective
until lesion has
resolved
Biopsy
Fig. 1 Flowchart for non–pigmented mucosal lesions. (Adapted from van der Waal 2010)
Pigmented lesion of
the oral cavity or lips
(Medical) history allows distinction (Medical) history does not allow

between melanocytic and non- distinction between melanocytic and
melanocytic lesions non-melanocytic lesions
Melanocytic
Non-melanocytic lesion
lesion
Is the lesion suspicious for malignancy based

on the following risk factors? Diagnosis possible
- ABCD checklist: Asymmetry, Border based on clinical
irregularities, Color variation and grounds alone
Diameter >6mm)
- Location on palate or gingiva
Diagnosis not possible
- Clinical history of the lesion
based on clinical
- Age
grounds alone
High clinical Low clinical

suspicion of suspicion of
malignancy malignancy
Biopsy
Fig. 2 Flowchart for pigmented lesions. (Adapted from Meleti et al. 2008)
be commenced if the clinician has confirmed a 2. All white hyperkeratotic lesions for which a
diagnosis, and many times this requires histo- cause is not obvious, especially speckled
pathological confirmation in addition to clini- non-homogeneous white and red lesions.
cal (and/or radiographic) findings. 3. Any lesion suspicious of a neoplasm (presence
3. To satisfy concerned patients who are of growth, ulceration, induration, with or with-
cancerophobic. out painful symptoms).
4. Lesions interfering with function (e.g.,
If a malignancy is suspected, a biopsy should fibroepithelial polyps).
not be delayed. A study on the accuracy of clinical 5. Tissue from draining sinus tracts when there is
diagnosis of oral lesions showed that dentists and no probable cause.
specialists are able to clinically recognize malig- 6. Lesions in the jaw bones that cannot be diag-
nancies with high accuracy (Kondori et al. 2011). nosed radiographically, especially if they cause
Maxillofacial surgeons misdiagnosed lesions as symptoms, such as pain or altered sensations.
benign in 4.1% of cases (Forman et al. 2015).
For general dental practitioners and specialists, There are no absolute contraindications for
the clinical diagnosis of a benign lesion often performing a biopsy, yet one should keep in
does not match histological diagnosis with mind several issues that may help mitigate
40–49.6% misdiagnosis reported (Kondori et al. unwanted complications. In general, biopsy
2011; Patel et al. 2011). Concordance of histolog- should be avoided if the general medical condition
ical and clinical diagnosis is reportedly 51% for of the patient is poor. In case of acute pyogenic or
specialists and 49.4% for dentists (Patel et al. viral infection, one should refrain from biopsy
2011). The highest concordance was reported for until the patient has recovered or after a course
salivary gland lesions (58.6%) and the lowest in of medical treatment.
lesions of the gingiva (44.4%). These results show There are instances in which the clinician must
that, given the high mismatch between clinical exercise utmost caution. If a patient is on anti-
and histological diagnoses, it is wise to have a coagulation therapy or suffers from a serious bleed-
low threshold to perform a biopsy before starting ing disorder, then modifications to the biopsy
therapy. At risk for mismatch between clinical and approach may be required. If a patient has previ-
histological findings are patients who have had ously undergone head and neck irradiation or has
radiation therapy and to a lesser extent male used injectable bisphosphonates or osteonecrosis-
patients and older patients (Forman et al. 2015). inducing medications, one should discuss potential
Clinicians are obliged to perform a biopsy risks with the patient, taking into account the neces-
when they encounter any of the situations listed sity for the biopsy in the first instance. If necessary,
below, provided that the clinician is competent in undertaking a biopsy close to or involving nerves,
oral medicine, so that morphological variations, major blood vessels, major salivary glands, and
such as geographic or fissured tongue, are clini- their ducts are best left to surgically skilled clini-
cally recognized as innocuous, and therefore not cians (Kumaraswamy et al. 2012).
biopsied. Additionally, there are anatomical locations
Indications to perform a biopsy include: that should draw special attention and should be
avoided if at all possible while obtaining a tissue
1. Lesions (especially manifesting as a red patch sample for investigation. The utmost attention
or having inflammatory features) persisting for should be exercised when performing a biopsy
more than 2 weeks and: (a) without apparent on a lesion involving the hard palate mucosa, so
etiopathogenic factors, and/or (b) after removal as not to puncture the greater palatine artery
of identifiable irritating factors, and/or (c) after (a. palatina major). This is particularly hazardous
empirical treatment has been attempted. if a biopsy is planned mid-way between the molar
teeth and palatal midline. Puncturing the artery recurs, causes symptoms, etc. This allows pursuit
may cause hemorrhage warranting emergency of several possible management paths:
surgical intervention.
Another area of caution is the gingival margin (a) Treating empirically, in accordance with
and papilla, so as not to cause dehiscence or loss of experience or observation guided by a list of
its contour. The floor of mouth can be difficult to differential diagnosis.
access, and due to its vascularization, there is a (b) Performing a biopsy of the lesion first and
tendency for hematoma formation. Floor of obtaining a histopathological diagnosis
mouth epithelium is also fragile and tears easily. before commencing therapy.
Thus, suturing in this area requires delicate han-
dling, without pulling and or tightening of tissues, With the empirical approach, the precision of
especially the salivary gland orifices. It should also treatment would heavily depend upon the clinical
be borne in mind that undertaking a biopsy of the experience of the treating clinician. Review of the
vermillion portion of the lip, or removing large patient is mandatory in both cases, as assessment of
mucoceles close to the vermillion, can have cos- success of treatment must be undertaken. If empir-
metic consequences. The labial salivary gland ical treatment is successful, one may have a diag-
biopsy or biopsy of the mandibular sulcus can nosis “ex juvantibus.” However, if success is
damage the mental nerve. In the case of the former, lacking, then one is obligated to reassess the con-
nerve visualization and avoidance is necessary, and dition and likely require histopathological confir-
in the case of the latter, only shallow surface biopsy mation through provision of a biopsy anyway.
is considered safe to perform. As in any surgical The empirical approach may be seen as con-
procedure, there are inherent risks. Anticipating troversial. If the treatment consists of eliminating
these will minimize adverse consequences (Lynch identified irritating factors, such as mechanical
and Morris 1990; James et al. 2011). trauma, this would be an acceptable approach.
Any abnormal tissue excised from the oral and However, in the absence of obvious irritating fac-
maxillofacial region should be submitted to a tors, when empirical treatment consists of topical
pathologist, regardless of how certain a clinician steroids, there can be a possible pitfall. One can
may be about the diagnosis (Melrose et al. 2007). speculate that steroids could affect the clinical
An issue that is important to address in this con- presentation, due to their anti-inflammatory and
text is pathological misdiagnosis. In most cases, vasoconstrictor effects. Perhaps this could even
the pathologist is liable for these mistakes. But as occur in the case of malignancy or oral potentially
a pathological diagnosis should always be malignant disorder (OPMD) and could be mis-
interpreted in conjunction with the patient’s his- leading. Therefore, sound judgment dictates that
tory, clinical examination and operative factors, topical steroid therapy should not be considered if
being satisfied with a pathological diagnosis that a diagnosis is uncertain. In such cases, a biopsy is
does not match the clinical picture might bring on recommended rather than to empirically treat and
liability to the clinician as well. to review. Again, the best approach will depend
upon clinical experience and expertise of the cli-
nician. The clinician’s provisional diagnosis is
When to Perform a Biopsy? very important for the reporting pathologist, as it
will help narrow the diagnosis.
It is sometimes difficult to establish a final diag-
nosis of an oral lesion using only clinical skills
and information reported by the patient. Thus, one Who should Perform a Biopsy?
should firstly collect as much etiological and clin-
ical data as possible. This includes data on sys- A question that often arises in the context of
temic conditions, medications, habits, the practicing oral medicine is “Who should perform
duration of the lesion, whether it changes in size, the diagnostic operative procedure?” A good rule
of practice is that the person who will treat the medicine specialists include biopsy for small reac-
lesion or patient should perform the initial diag- tive fibroma/fibro-epithelial polyps, epulides, and
nostic procedure, usually a biopsy (Oliver et al. angiogranulomas (Oliver et al. 2004). The goal of
2004). However, this does not hold true for every biopsy in these cases, besides confirming the diag-
case and may vary from country to country, nosis, is the removal of the whole lesion, which
depending on local practices, access to specialist should be designed to represent the final treatment
care and availability, and expertise of team as well.
members. In countries without oral medicine specialists
A prerequisite for performing biopsies or any or training programs, referral should be arranged
other diagnostic procedure in the oral cavity is to oral and maxillofacial surgeons. Ear nose and
having the surgical skills to perform them and throat specialists are generally less exposed to
more importantly being able to manage the possi- patients with oral mucosal lesions, especially
ble complications of any procedure undertaken. OPMDs but can offer assistance when biopsies
Pathways should be in place to ensure timely are required, especially for difficult to access tis-
processing of biopsy material by a pathologist. sues. If a biopsy is indicated for a major salivary
The person who performs the biopsy should be gland, or neck lump, the patient is better served by
able to interpret the results and realize when the having an oral and maxillofacial surgeon or head
histological results do not correlate with the clin- and neck surgeon carry out the procedure given
ical appearance of the lesion (Chen et al. 2016). involvement of deeper structures.
Typically, general dental practitioners do not For most practitioners, a time may come where
have sufficient knowledge of oral diseases nor they might have to defend their decisions and
sufficient clinical experience in undertaking biop- treatment in court. It is important to realize that
sies to routinely perform them and interpret their the professional undertaking the procedure is only
results for the ultimate benefit of the patient. Oral bound by the law of the specific country or region
medicine specialists are much more likely to fulfill in which they practice. This may be further com-
these conditions and are the preferred designated plicated by the fact that professionals who per-
professionals to perform biopsies for clinical form the same procedure may be bound by
interpretation. Of course oral and maxillofacial different laws in the same country (i.e., dentists
surgeons are also trained to undertake biopsy pro- and doctors). It is not within the remit of this
cedures, but they typically are less focused on chapter to cover all the specific local rules and
ongoing patient management beyond the biopsy regulations relating to risk management in oral
or surgical treatment and may in fact subsequently medicine. The issues that are most relevant to
revert care to an expert in oral medicine. This performing operative procedures in the oral cavity
is commonly done in the case of chronic inflam- include competency to perform a procedure.
matory or immune-mediated conditions or Clinicians are usually allowed to perform
vesiculobullous diseases, in addition to OPMD. minor surgical procedures based on their dental
In countries where oral medicine is a recog- or medical license. It can be necessary to demon-
nized specialty, it would be best that these spe- strate that the person is skilled to perform the
cialists undertake biopsies for suspected oral procedure by following specific training (for
lichen planus and other non-malignant mucosal example, a specialization in oral medicine, oral
disease. It should be emphasized that in cases of surgery, or oral and maxillofacial surgery). Being
white, red, hard, or non-healing ulcerative lesions, able to produce a certificate of training does not
patients should be biopsied by an experienced oral make a practitioner competent. If the professional
medicine specialist. This also accounts for lesions never performs the procedure or does not know
suggestive of serious and potentially life threaten- how to manage all complications that may arise,
ing conditions, such as vesiculobullous diseases he or she is not competent to perform the proce-
or erythema multiforme (James et al. 2011). Con- dure. As general dentists usually do not perform
ditions that could easily be performed by oral biopsies in many countries, higher requirements
may be set for them to prove that they are 5. Symptoms: Does the lesion cause symptoms
competent. such as spontaneous or provoked pain, or is
there numbness? Oral squamous cell carcinoma
(OSCC) is usually not painful in the earlier
What to Do before the Biopsy? stages; however, experience shows that pres-
ence of painful symptoms in ulcerated or eroded
Before undertaking a biopsy, clinicians should epithelium does not exclude malignancy.
complete a thorough consultation with the patient,
paying particular attention to the medical, social The following sequence should then be
and oral histories. This information, in conjunc- followed to capture as much information about
tion with findings from a detailed clinical exami- the lesion in a systematic manner (James et al.
nation, will help narrow possible diagnoses. A 2011). This provides determination of morpho-
detailed understanding of the patient’s systemic dis- logical and topographical features, which should
eases and review of systems are required to ascertain be provided to the reporting pathologist.
any oral manifestations of these. The clinician
should know if the patient smokes tobacco or con- 1. Look: Determine site, shape, morphology,
sumes alcohol, as these may have contributed to the color, sharpness, and regularity of border, and
development of the lesion. The patient’s current whether the lesion is single or multiple.
medications should be known, as many drugs have 2. Feel: Determine consistency (soft, firm, hard),
adverse oral effects. Finally, the patient’s dental description of surface (smooth, lobulated,
status or any oral habits that may cause local trauma irregular, verruciform), tenderness, associated
should be identified. Historical data on trauma, symptoms (e.g., discharge) and pulsations
parafunction, ill-fitting dentures, or topical self- (e.g., vascular lesions).
administered oral treatments should be recorded. 3. Move: Determine tethering (fixation to
Specific questions asked of the patient should mucosa, skin or underlying structures).
provide helpful information about the lesion, and 4. Measure: Determine size (using a ruler or
should be gathered before assessment of the calipers for exact measurement).
patient is undertaken (James et al. 2011). These 5. Examine: Determine presence of head and
include: neck lymph nodes (necessary part of every
oral examination, always performed before
1. Size: How large is the lesion? Does it cross biopsy).
anatomical boundaries? Has it changed size 6. Photography: Record the exact appearance
over time or since it was noted? and size for future reference.
2. Shape: Has the lesion changed in shape? For 7. Radiography: Perform if possible dental or
example, has a blister become an ulcer? This bony involvement is suspected.
may signify autoimmune vesicullobulous
condition. Before any procedure is commenced, a patient
3. Progression: Is the lesion static, or has it should always give informed consent. Whether or
changed over time? Has this occurred slowly not consent has to be obtained in writing depends
or quickly, alternatively has it regressed? Have on local practices. For example, it is often a
there been alternating periods of increase or requirement to obtain written consent for a biopsy
decrease in size, or quiescent periods? If a under local anesthesia in the United Kingdom,
lesion progresses rapidly, then it may be more while this is not mandatory, for example, in the
sinister. This information is biased by the Netherlands. If a procedure is done frequently, a
patient’s perception. standardized consent form could be considered. In
4. Duration: How long has the lesion been pre- any case, consent should be documented in the
sent? If the lesion has been present for years, it notes. The essential elements of consent are
is more likely to be benign in nature. described in Table 1.
Table 1 Essential elements of consent for a minor surgi- alternative treatment makes the disclosure of
cal procedure risks even more important.
1. The intended procedure Standards seem to evolve towards a more
- description of the procedure patient-centered approach where individual fac-
- laterality of the procedure
tors are taken into account. For the average
2. The aim of the procedure
patient, the risk of some numbness of the lower
3. The risks that are involved in the procedure
4. Any additional procedures that might become
lip after minor salivary gland biopsy might not be
necessary during the procedure significant, while only a very small risk of numb-
ness of the lower lip might be totally unacceptable
to a professional flute player. The United King-
Every patient should be informed about the dom’s General Medical Council Guidelines on
possible risks of a procedure. Consent is given consent state that the doctor has an obligation to
by a patient who is mentally capable to give vol- “find out about a patient’s individual needs and
untarily consent. This means that they should be priorities” (Janssen 2006). If a patient is consented
able to understand the information given about the for a high-risk procedure, it may be wise to do this
treatment. A patient should have a clear under- well in advance, so the patient has time to consider
standing of what the goal, possible benefits, risks, all the risks involved. On the day of the procedure,
and alternatives to the procedure are. The risks whether the procedure is high risk or low risk, the
that have been explained to the patient should also consent must be confirmed with the patient.
be documented in the notes. If a patient, after
thorough explanations of the risks and benefits
refuses a procedure, this should also be carefully Where to Biopsy?
documented in the notes.
Patients should be informed about what they White Light
reasonably should know about the procedure. In
the literature this is also called the significant risk Assessment of biopsy site can be difficult espe-
of a procedure (Janssen 2006). What the definition cially when dealing with OPMD. Over recent
of a significant risk is debatable. Risk thresholds years, there has been an enhanced understanding
varying from 0.1–10% have been accepted in that better assessment and more accurate diagnosis
court as significant risks (Brands 2006). If the of oral mucosal lesions, and OPMD in particular, is
probability of a certain risk is high and/or the facilitated by the use of white light supplemented
consequences for the patient are considerable, with optical magnification in a combination of
the higher the duty to disclose the risk is (Janssen loupes and headlights commonly used in dentistry
2006). In certain judicial systems, such as in Ger- and otorhinolaryngology (McIntosh et al. 2009; Vu
many, the duty to discuss a risk is even higher et al. 2015). Assessment with white LED (light
because the most determining factor for disclosing emitting diode) light in comparison to halogen or
a risk is the severity of the consequence for the incandescent provides better color contrast and
patient and not the probability of the risk (Janssen truer color distinction (Fig. 3), thus facilitating the
2006). Another factor that has to be taken into assessment of mucosal lesions and allowing better
account is the nature of the procedure. If a proce- discrimination for determination of biopsy site
dure is not medically indicated, such as a cosmetic (McIntosh et al. 2009; Vu et al. 2015). This also
procedure, higher demands are placed on has implications for biopsy technique and manage-
informed consent in most countries (Janssen ment strategies, as better illumination and visuali-
2006). zation can lead to more accurate determination of
If the procedure is a routine procedure, such as lesion homogeneity, and this is well known to
an intraoral biopsy, the need for disclosing very influence treatment options and site of biopsy, but
rare risks are less than with a rare experimental also prognosis of a lesion (Dost et al. 2013; 2016).
procedure (Janssen 2006). The option of an Addition of optical, or even digital, magnification
Fig. 3 Oral mucosal lesion viewed with traditional light (a) and with Microlux/DL™ intraoral visualization (b). (Used
with permission from Elsevier; McIntosh et al. 2009)
Fig. 4 Surgical loupes

(magnification 2.5 fold)
with LED headlight
illumination
allows better assessment of surface textural dysplastic or malignant area, leading to a poten-
changes (McIntosh et al. 2009; Vu et al. 2015) tially false negative diagnosis. Diffuse field
and once again leads to enhanced appraisal of sus- changes can also make it difficult to determine
picious lesions that may be otherwise discounted. It the borders of lesions. Toluidine blue (TB) has
can also direct better determination of incisional been proposed to help determine the most dys-
biopsy site or excisional biopsy margins. The com- plastic site and better demarcate edges of lesions
bination of white light illumination and magnifica- (Sridharan and Shankar 2012). It has been used
tion is a powerful combination that should be used for over 50 years as a vital stain to highlight
when assessing any oral mucosal lesion (Fig. 4). OPMD and to identify early OSCC. TB stains
tissues with high nucleic acid content. As prema-
Toluidine Blue lignant tissues have a high DNA content, they
stain more intensely than normal tissues. Dysplas-
In large areas of diffuse field change, it may be tic and neoplastic cells contain more nucleic acids
difficult to establish which site represents the most than normal tissues (high density of nuclear
Fig. 5 Toluidine blue staining. Ulcerated lesion of the left medicament. Lesion after staining with toluidine blue (b).
dorsal tongue corresponding to an area of possible trauma Lesion after staining with toluidine blue and rinsing (c).
from a denture in a nonsmoking patient (a). The lesion Despite the atypical location and painful symptoms, a
remained unchanged after removal of denture-induced irri- biopsy showed early oral squamous cell carcinoma
tation and 2-week application of topical steroid
material), and increased mitotic activity. The nonsuspicious lesions showing TB retention
result is increased dye uptake and facilitated pen- (as reparatory and re-epithelization mechanisms
etration, which can easily be observed clinically also contain increased mitotic activity and thus
(Fig. 5) (Epstein et al. 1992; Gandolfo et al. 2006). can stain falsely) should be re-assessed after
During post-treatment follow-up, TB can be 2 weeks of treatment. If TB positivity still persists,
applied to identify recurrences, second primaries, the lesion should be considered suspicious and
or multicentric tumors in the same fashion as used biopsy should be performed to rule out carcinoma
for detection of primary tumors. Sometimes pat- (Fig. 6) (Sridharan and Shankar 2012).
terns show frank “field cancerization” (Lingen Analysis of 14 studies on vital staining in a
et al. 2008). Cochrane review, found a sensitivity of 0.84
TB has very high sensitivity but lower speci- (0.74–0.90) and a specificity of 0.70 (0.59–0.79)
ficity for oral cancer detection, but is far less with a high number of false positives (Macey et al.
sensitive and specific for dysplasia, with a signif- 2015). This analysis also compared vital staining
icant rate of false-negative results. False-positive with cytology finding a statistically significant
results are of less concern than false-negative difference in specificity (p = 0.003) but no statis-
results, thus any positive findings should be tical difference in sensitivity (Macey et al. 2015).
checked on biopsy in order to confirm dysplasia The same study also found no statistically signif-
or frank carcinoma. Conversely, clinically icant difference in sensitivity and specificity
tongue and orifices of palatal minor salivary

glands (Mashberg 1980; Hedge et al. 2006).
Optical Imaging
Fluorescence is a method that is based on the

phenomenon that all tissues emit a specific color
of light after being excited by a light with a spe-
cific wavelength (Balasubramaniam et al. 2015).
The fluorophores in oral epithelium such as kera-
tin, collagen, and elastin all excite green light
Fig. 6 Toluidine blue staining. With the help of toluidine when excited with light wavelength between
blue, the edges and most suspicious parts of a leukoplakic 375 and 440 nm (Rashid and Warnakulasuriya
lesion were determined. Biopsy showed microinvasive oral 2015). Fluorescence is able to discover premalig-
squamous cell carcinoma. Note “satellite” lesions reveal-
nant lesions in normal looking mucosa and differ-
ing “field cancerization.” There is a clinical leukoplakia on
the lingual frenulum, which histopathologically showed entiate between lesions that have malignant
moderate dysplasia potential based on loss of autofluorescence (i.e.,
whereby tissues appear darker) (Farah et al.
between vital staining and light-based detection 2012). This change can be caused by heightened
methods (Macey et al. 2015). Because of the low metabolic activity in the epithelium, increased
sensitivity and specificity, it has been blood flow, inflammation, breakdown of the con-
recommended that vital staining is used by expe- nections between the basement membrane, and
rienced clinicians only for surveillance or for lamina propria, all hallmarks of potentially malig-
selecting a suitable biopsy site (Macey et al. nant transformation of tissues (De Veld et al.
2015). In an early study by Epstein et al., clinical 2005).
unaided assessment identified 78% of carcinoma The best known light-based autofluorescence
in situ or invasive malignant lesions. When TB device is the VELscope ®. VELscope ® uses blue
was utilized, all (100%) carcinoma in situ or light with a wavelength of 400–460 nm to excite
invasive malignant lesions were identified and the oral mucosa (Farah et al. 2012). The tissue is
no false-negative findings were observed. How- examined while holding the device about 5 cm
ever, no differences were found between clinical away from the tissues. Pathological mucosa will
examination and toluidine application in the appear darker than normal mucosa, which appears
detection of dysplastic lesions (Epstein et al. green (Fig. 7).
1997). A meta-analysis that compared conventional
Before TB application, the mouth is rinsed oral examination, oral cytology, toluidine blue
twice with water for 20 s to remove debris. Sub- staining, laser-induced-autofluorescence spec-
sequently, 1% acetic acid is applied for 20 s to troscopy, and diffuse reflectance spectroscopy
remove saliva and to expose the lesion to staining. found that the fluorescence-based techniques had
Toluidine blue 1% is applied for 20 s on and the highest sensitivity. One study found a reason-
around the lesion using a cotton swab. The able inter-observer agreement of 60.7% when
mouth is then rinsed twice with 1% acetic acid to using the VELscope ®, compared to 71.4% of the
remove excess and non-retained stain, and subse- clinical diagnoses (Farah et al. 2012). In the liter-
quently rinsed once again with water. Guidance ature fluorescence is mostly used to monitor
on possible malignancy is based on the intensity lesions, rather than normal mucosa. The sensitiv-
of blue staining. Oral areas normally retaining ity and specificity in normal populations is likely
light blue color include filiform papillae of the to be lower due to a lower prevalence of disease
Fig. 7 Fluorescence. Lesion on lower lip examined with showing poor visualization with conventional oral exami-
conventional oral examination (a); same lesion examined nation on lower lip (c); same lesion with VELscope ®
with VELscope ® displaying loss (dark area) and gain displaying loss of fluorescence (d). Histopathological diag-
(lighter area) of fluorescence (b). Histopathological diagnosis was actinic cheilitis. (Used with permission from
nosis was oral squamous cell carcinoma. Separate lesion Elsevier; Bhatia et al. 2014)
(Fuller et al. 2015). The use of VELscope ® in Other fluorescence based devices include
screening for oral cancer or potentially malignant Identafi® and Bio/Screen ® amongst others.
lesions has not been proven (Rashid and These work on the same principles but at slightly
Warnakulasuriya 2015). Normal tissue is known different wavelengths and have additional
to give a signal that is comparable to malignancy features to those of VELscope ®. Identafi ® is
especially in the vermilion border and the papillae more difficult to use for biopsy site deter-
of the tongue, so care in interpretation is para- mination given that it is an intraoral device,
mount (Fuller et al. 2015). Farah concludes that but otherwise performs similar to VELscope ®
conventional clinical examination is essential (Fig. 9). Narrow Band Imaging is another
when interpreting the results of the VELscope ® optical technology that has proven useful for
and should always be carried out before a fluores- the identification of OPMD and OSCC
cence examination is undertaken (Farah et al. (Fig. 10), and importantly for the accurate
2012). Diascopy can be helpful in determining determination of clean surgical margins improv-
what the nature of the pathology is, with inflam- ing patient survival and minimizing local recur-
matory and vascular lesions blanching under pres- rence (Vu and Farah 2014; Vu et al. 2015; Farah
sure and regaining the normal autofluorescence et al. 2016; Vu and Farah 2016; Farah 2018).
pattern (Fig. 8). Diascopy may change the imper- Fluorescence has also been used to determine
ative to biopsy or biopsy site if blanching is not molecularly clear excisions margins for OPMD
complete (Farah et al. 2012). (Farah et al. 2017).
Fig. 8 Diascopic fluorescence. Oral lichen planus on left displaying diascopic fluorescence on application of pres-
buccal mucosa displaying loss of autofluorescence when sure (b–d), returning to its original appearance when pres-
visualized using VELscope ® (a). The same lesion sure is removed (e)
Fig. 9 Oral lichen planus on left buccal mucosa visualized under violet light with Identafi ® (b), and microvasculature
with Identafi ® using its white light feature (a). The same of the lesion is highlighted with the green-amber light (c).
lesion displaying loss of autofluorescence when visualized
Fig. 10 Narrow band imaging (NBI) endoscopic stack (b) and in NBI mode (c) demonstrating Type IV IPCL
with large screen display (a). Oral squamous cell carci- pattern
noma of the gingiva viewed with endoscopic white light
Additional information on the application of the most satisfactory specimen. Other techniques
white light assessment and optical adjunctive include the use of a needle, biopsy punch, biopsy
devices and their utility, particularly as applied forceps, laser, or electrocautery device. Needles
to OPMD and OSCC, can be found in the chapter may be appropriate in sampling cells from mass
on ▶ “Oral Mucosal Malignancies.” lesions, but they are of no benefit in the evalua-
tion of surface lesions. Electrocautery produces
thermal damage and artifact, which make evalu-
How to Perform a Biopsy? ation of the specimen difficult; therefore, elec-
trosurgery should be avoided during oral
Numerous methods can be used to collect tissue mucosal biopsy. Electrosurgery may be of bene-
samples from the oral mucosa for histopatho- fit for wide local excisions of known intraoral
logic examination. Performing biopsy with a malignancies or OPMD after a scalpel is used to
scalpel is the standard and generally produces atraumatically obtain marginal specimens for
frozen sections or obtain a histopathological principle that guides site selection for incisional
diagnosis. biopsy should be the acquisition of the most rep-
A carbon dioxide or Nd:YAG laser produces a resentative sample of the suspected condition. A
zone of thermal coagulation smaller (approxi- fervent attempt to include the periphery of a lesion
mately 500 μm) than that of electrocautery. If a with clinically healthy tissue may inadvertently
laser is used for incisional or excisional biopsy, a lead to a missed diagnosis or an under-diagnosis.
0.5 mm margin should be maintained between the Persistent diffuse color and textural changes on
cut and the representative area to be sampled. oral mucosal surfaces may signify the presence of
Although this technique may result in good local underlying oral epithelial dysplasia. Specimens of
hemostasis and minimal postoperative discom- similarly affected mucosa may yield adjacent
fort, it is associated with potential shortcomings, zones of mild-to-severe dysplasia, carcinoma in
including impingement on the specimen, particu- situ, or micro-invasive squamous cell carcinoma.
larly at the deep margin, and the generation of This result raises the question of how a clinician
excessive heat with inadequate removal of the knows whether incisional biopsy samples are suf-
charred layer. The laser may be of great value in ficient for the most important histologic diagnosis
managing the wound left by scalpel biopsy in of a diffuse area of mucosal change. Incisional
areas of the mouth where closure is difficult or biopsy can lead to a diagnosis of mild or moderate
inappropriate. dysplasia despite the presence of invasive cancer
The use of a punch biopsy in oral mucosal within millimeters of the biopsy site. Therefore, a
lesions may be of some value. Punch biopsy diagnostic adjunct may be used to guide the clini-
may be difficult on freely movable oral tissues cian to the biopsy site that is most likely to be
and probably offers no advantage compared with associated with carcinoma in situ or invasive can-
scalpel biopsy. The technique may be appropriate cer. As previously discussed, toluidine blue and
in the hard palate mucosa and other sites with optical adjunctive technologies, such as optical
better support, or tissue that is bound down, and fluorescence imaging or Narrow Band Imaging,
it is likely to produce a satisfactory specimen. The can be considered when deciding on a biopsy site.
wound heals by secondary intention, and discom- The minimal requirements for an adequate
fort may persist longer than anticipated by the incisional specimen vary somewhat with the
clinician and the patient. nature of the pathologic entity. As a general rule,
Despite the availability of various biopsy including tissue subjacent to the epithelium and
methods, scalpel biopsy is still the most com- removing a wedge of manageable size is desir-
monly used in oral medicine practice and offers able. Therefore, a minimal depth of 3 mm, mini-
significant advantages over other methods. Imper- mal length of 3–6 mm, and minimal width of
ative in this approach is utility of the microsurgi- 1–2 mm are advised (Fig. 11). In the case of
cal triad of illumination, magnification, and exophytic lesions, deep, narrow incisional biop-
increased precision of surgical skills (Belcher sies are recommended to ensure sampling the
2001). underlying normal tissue. These might extend
5–6 mm deep.
Incisional Biopsy
Excisional Biopsy
When incisional biopsy is contemplated, the
biopsy site should be carefully considered. Site Given a differential diagnosis that includes only
selection is particularly important in an ulcerated benign entities, the clinician may elect to remove a
oral lesion. Selecting only the center of an ulcer lesion in its entirety. The size of the lesion is only
results in an inadequate specimen devoid of one of several factors that may affect the decision
mucosa. This same principle can be applied to to perform an excisional biopsy. The location of
nonulcerated lesions as well. The overriding the lesion, the nature of its attachment to the
Fig. 11 Acquisition of a
sample by incisional biopsy
underlying tissue, the accessibility of the lesion,

and the regional anatomy all contribute to the
decision. Small, pedunculated, exophytic masses
in accessible areas are excellent candidates for
excisional biopsy.
For excisional biopsy, two incisions forming an
ellipse are made around the lesion with the blade
angled toward the lesion. These incisions produce
a wedge-shaped specimen that is deepest under the
center of the lesion and leaves a wound that is
simple to close. Closure is facilitated by develop-
ing an ellipse that is three times longer than it is
wide (Fig. 12). In general, properly designed ellip-
tical wounds can be closed easily; however,
depending on the location of the biopsy and the
size of the resultant wound, mucosal undermining
may help in producing a tension-free closure.
Fig. 12 Excisional biopsy showing a wedge-shaped spec-
The elliptical excision is the classic approach
imen with a length-to-width ratio of 3:1
for removing an approximately round or linear
lesion. An excision of this shape is preferred
because of the subsequent ease of its closure. A and the longer axis should be 3–4 times this
round excision larger than a 4-mm punch is diffi- length. Alternatively, the angle between two
cult to close without leaving excess outpouchings lines drawn from an edge of the long axis to the
of tissue. bilateral midpoint edges of the ellipse should be
The ellipse should be long enough so it can be about 30 (Fig. 13).
sutured together without outpouchings of tissue, The orientation of the ellipse is important. Ide-
but no longer than necessary to minimize the ally, the long axis should lie parallel to the relaxed
length of the scar. The process begins by marking mucosal tension lines. By placing the ellipse
the lesion to be removed. A permanent skin along relaxed tension lines, the surgeon ensures
marker may be used to circle the target lesion. that the final scar is parallel to these lines. If the
Often, a free margin of several millimeters must scar is thin and small, it may be barely noticeable,
be removed from around the primary lesion, and appearing as merely another crease to the
the mark for this margin can be drawn as a larger untrained observer. Undermining the area around
concentric circle. Then, an ellipse should be the edges of the removal site can be helpful.
marked around the larger circle. The diameter of Undermining decreases both the vertical and lat-
the circle should form the short axis of the ellipse, eral tension on the final closure, improving the
Fig. 13 In an elliptical
excision, the edges are at an
internal angle of 30 . The
angle defines the
relationship between the
edge to the central lesion
being removed
esthetics of the final result. When tension is not

great or when the wound is small, undermining
may not be necessary. Similarly, if the mainte-
nance of hemostasis is a challenge, undermining
may only exacerbate the problem.
The excision of lip lesions requires planning
and tissue stabilization. In general, excision lines
should be parallel to the nerves and vessels; how-
ever, a substantial excision from the lip parallel to
its long axis may result in a decrease of visible
vermilion after healing. Although this excision is
unlikely to produce a major deformity, esthetics
may be compromised. Excisions made perpendic- Horizontal incisions – Vertical incisions –
Parallel to Perpendicular to
ular to the long axis of the lip are far less likely to long axis of lip long axis of lip
produce this type of distortion (Fig. 14); however,
with the 3:1 rule, excision of a lesion near the
Fig. 14 Elliptical excisions created parallel (horizontal) or
vermilion border may necessitate that the clinician perpendicular (vertical) to the long axis of the lip
cross onto the skin to produce a wound that can be
closed correctly. This incision may result in a scar
that is more visible and more troublesome to the manner to facilitate use of instruments and mini-
patient than one confined to only the labial mize possibility of sharps injuries. Patients should
mucosa. An advantage of an excision made per- be laid back in the chair, covered with sterile
pendicular to the long axis of the lip and surgical drape and protective eyewear. Patients
maintained on labial mucosa not crossing the ver- should not see the surgical tray to minimize their
million is that the resultant scar can be hidden anxiety about the procedure. Clinicians should
amongst creases of the lip. follow sterile technique.
Lesions that have a very high probability of
being malignant are best biopsied after imaging
Operative Diagnostic Techniques has been carried out unless they are very large.
The biopsy leads to an inflammatory response that
Mucosal Biopsy is readily visible on CT and MRI that might over-
estimate the size of the lesion and affect staging.
Prior to undertaking a mucosal biopsy all neces- The biopsy site should be carefully selected.
sary instruments and equipment should be laid The most pronounced part of the lesion should
out on the surgical tray in a uniform systematic be chosen for the biopsy. As the histological
Fig. 15 The armamentarium for biopsy includes: mirror holder, fine-tipped scissors, curved scissors, gauze
appropriate for the site, blade handle with a No. 15 blade, sponges, suction tip, local anesthetic solution and syringe,
fine tissue forceps with teeth, College tweezers, needle and suture material for closure
diagnosis often depends on the visibility of the anesthesia is used when a malignancy is suspected.
border between healthy and diseased tissue, nor- Needles used to infiltrate around a suspected malig-
mal looking tissue should be included in the nancy should not be used to give a nerve block as
biopsy. For large lesions with a heterogeneous this might cause tumor seeding, although this is
appearance or when the biopsy is taken to diag- rare. For most indications, a 33 gauge extra short
nose dysplasia, multiple biopsies may be advis- (14 mm) needle is used.
able. It can be useful to mark the biopsy site with Figure 15 shows the materials that are neces-
surgical pen before local anesthesia is given, sary to perform a biopsy. Biopsies can be taken
because the appearance of the lesion might change with a 15-blade or a punch biopsy device. The
afterwards. depth, size, and shape of a biopsy can be better
Local anesthesia is administered. Commonly, customized with a blade. In cases where it is
lidocaine hydrochloride 2% with epinephrine important to get additional depth, as for example
1:100,000 or articaine hydrochloride 4% with epi- in malignancies, it is advised to use a blade and
nephrine 1:100,000 are used. Infiltration around the take a large elliptical biopsy. Figure 16 shows the
lesion is useful for hemostatic purposes but can be stepwise procedure of an excisional biopsy.
painful. It may be advisable to give a regional nerve Punches are available in many diameters and suit-
block first. Injecting into the biopsy site may pro- able to biopsy benign lesions but should be used
duce artifacts such as vacuolization due to connec- sparingly (Fig. 17). It is not advisable to use a
tive tissue cleavage. Likewise, inserting a needle punch technique in bullous lesions, as the tissue
into the lesion may cause tearing of capillaries and structure is readily distorted. The biopsy should
extravasated blood may alter the microscopic be handled with care as compression of the tissues
tissue appearance. When possible, no infiltration with forceps can impair the histological diagnosis.
Fig. 16 Application of 2% topical lidocaine with a cotton insertion for tissue elevation and orientation if required (c).
swab before local anesthetic is administered (a). Peri- Excision of lesion (d). Tongue after biopsy and insertion of
lesional infiltration local anesthesia containing adrenaline single silk interrupted suture (e). Tongue after suturing (f)
for excisional biopsy of a fibroepithelial polyp (b). Suture
A technique utilizing a scalpel can accommo- biopsy but can be used virtually anywhere, includ-
date all situations and indications for biopsy. It ing attached tissues (gingiva, hard palate) and free
may be more technique-sensitive than a punch moving tissues (floor of mouth, soft palate). All
Fig. 17 Punch biopsy. Punch biopsy (4 mm) of hyperker- surrounding tissue and cut the bottom of the specimen
atotic white lesion (plaque-like lichen planus) on the right (b). A blade could also be used. Postbiopsy site with
buccal mucosa (a). While tissue forceps elevate the cylin- circular margins (c). Biopsy site after placement of single
drical tissue, curved scissors are press down on the silk interrupted suture (d)
for holding and elevating the specimen and for

suturing, fine sharp scissors for separating the
specimen and for cutting suture, 5–0 or 4–0
sutures, a needle holder, sterile gauze, and a spec-
imen container with formalin, saline or Michel’s
solution, depending on the type of investigation to
be carried out.
The incision should be planned as an ellipse,
as this shape facilitates repositioning and closure
of the wound edges, suturing and obtaining pri-
mary healing. In case of doubt regarding the
diagnosis, a clinical margin of 2–3 mm beyond
Fig. 18 Number 12 (above) and 15 (below) blades the lesion should be incorporated into the ellip-
tical design if possible. If the lesion is benign in
instruments and materials should be sterile and nature, narrow margins are acceptable, as wider
include a scalpel blade, usually No. 15, (Fig. 18) excision is unnecessary. Sometimes is it useful to
for incision and separation of tissue, fine serrated place a suture through the tissue to be excised
tissue pliers (12 “Adson,” “Gerald,” or similar) without tying a knot, especially if the lesion is a
lump that requires elevation or manipulation. silk) in preparation of further definitive treatment
The suture can also be used for orientation pur- (i.e., wide local excision of the scar or
poses when submitted with the sample to the radiotherapy).
pathology laboratory. Tissue forceps are often Once the biopsy is completed, the lesion is sent
used for stabilizing tissue being excised. Caution to the pathologist either fresh or in formalin,
should be taken to avoid excessive squeezing of depending on the transport and process times.
the sample leading to artifact creation and tissue Lesions sent for immunofluorescence, such as
destruction. suspected bullous diseases, are sent in Michel’s
Most biopsies can be carried out without the solution to preserve tissue-deposited immuno-
use of suction. Use of sterile gauge is often globulins as formalin does not allow for immu-
enough to control bleeding in the surgical field. nofluorescence techniques. Michel’s solution
If suction is to be used, care should be exercised so should be kept at 4 C until required and trans-
as not to inadvertently suction the specimen. Suc- ported to the laboratory immediately after a
tion can also damage the wound or cause more sample is obtained. The most commonly used
bleeding, in addition to increasing the risk of loss fixative agent for standard histopathological
of the sample. examinations is 10% neutral buffered formalin
Very small lesions (several millimeters) are (NBF), which is solution of 4% formaldehyde in
best completely excised to obtain enough tissue phosphate buffered saline. This can be obtained
for pathological diagnosis. Lesions that are most from the pathology service and kept ready until
likely benign and permit excision without major required.
morbidity can also be completely excised. An Hemostasis can be obtained using sutures,
incisional biopsy is taken if a malignancy is silver nitrate, or bipolar diathermy. If imaging is
suspected. If the lesion is a suspected malignancy planned after the biopsy, it is advisable to use
but is too small to obtain a representative sample silver nitrate or bipolar diathermy as these results
with an incisional biopsy, an excisional biopsy in less inflammation on imaging than sutures.
should be undertaken but the biopsy site should This will leave a black slough on the wound for
be marked with non-resorbable sutures (such as which the patient has to be warned (Fig. 19).
Fig. 19 Silver nitrate stick (a) applied to open wound biopsy site ensuring hemostasis staining the tissue silver (b)
Fig. 20 Gingival peripheral

fibroma (a) was removed
and the surgical wound
covered with COE pack
periodontal dressing (b)
Silver nitrate use on attached gingiva is associ- Labial Salivary Gland Biopsy
ated with the risk of permanently staining hypo-
mineralized enamel and composite resin A labial salivary gland biopsy is a highly sensi-
restorations, and therefore should be used with tive and specific diagnostic test in the histologic
caution especially in esthetic zones (Sadiq et al. assessment of Sjögren’s syndrome, but it can
2002). Some sites can be unsuitable for suturing. also assist in the differentiation of Sjögren’s syn-
One example is the attached gingiva that can be drome from sarcoidosis when clinical presenta-
packed with a commercially available material tions are similar (Levy et al. 2001). This is best
such as COE-PAK (Fig. 20) (non-eugenol peri- taken from the lower lip as the minor salivary
odontal dressing) or Reso-Pac (hydrophilic cel- glands are most pronounced in this location.
lulose based periodontal dressing) (Baghani and Local infiltration anesthesia is given sub-
Kadkhodazadeh 2013), where the tissues are left mucosally near the biopsy site. The mucosa of
to heal by secondary intention (Fig. 21). In some the lower lip is incised once vertically (i.e., per-
cases biopsies from the floor of the mouth can be pendicular to the long axis of the lip and parallel
left open after meticulous hemostasis (Fig. 22). to nerves and vessels) about 2 cm lateral to the
It is well known that dysplasia is not a firm midline, where the most minor salivary glands
predictor of a lesion’s malignant transformation are present. Vertical incision technique was been
potential, and conversely, cancer may arise associated with less pain (p < 0.001), less swell-
from initially nondysplastic tissue or unaffected ing (p < 0.05), less scar formation (p < 0.05), and
mucosa. DNA ploidy status may become more less difficulty in eating (p < 0.05) when com-
helpful in predicting a lesion’s malignant behav- pared with horizontal incision technique
ior in the future (Sperandio et al. 2016). At (Saruhanoglu et al. 2013). No statistically sig-
present, there are no defined and well-tested nificant differences were observed between the
molecular biomarkers for malignant transforma- two groups in terms of hematoma, paresthesia
tion (Pitiyage et al. 2009), so histopathological and speech difficulty, but two subjects in the
demonstration of dysplasia remains one of horizontal incision group revealed permanent
the most important prognostic features for paresthesia during the follow-up period of
OPMDs. 2 years (Saruhanoglu et al. 2013).
Fig. 21 Removal of a gingival angiogranuloma without the teeth and the lesion is reflected (c). The subgingival
raising of flap. Angiogranuloma covering the upper left tissues are curetted (d) and all affected tissues removed
incisors (a), with stalk connected to the gingival margin before coverage with COE pack periodontal dressing (e).
between the upper left central and lateral incisors (b). Surgical site 1 week after surgery (f). Histopathology con-
Vertical incisions are placed parallel to the long axis of firmed an angiogranuloma
Five to six salivary glands are subsequently as 5–0 gut or vicryl rapide. Assessment of pres-
dissected out without damaging the nerve ence of focal lymphocytic sialadenitis with a
fibers that travel through the lower lip. The focus score 1 focus/4 mm2 in labial salivary
incision is closed with a resorbable suture such gland biopsy samples is required for
scissors. The mass is then typically delivered

through the overlying incision, after which the
surgical bed is examined for complete removal.
The incision is then closed with 5–0 gut or vicryl
rapide sutures.
Submucosal lumps in the palate can be
approached through various mucoperiosteal flap
designs, but the semilunar design is often ade-
quate to expose the underlying mass and deliver
the lump with minimal operative complications.
This approach can be used for cystic lesions
(Fig. 24) or benign tumors (Fig. 25).
Hard Tissue Biopsy

Fig. 22 Biopsy of the floor of the mouth, left open after
hemostasis If a hard tissue biopsy is taken, it is advisable to
have preoperative radiographs available, such as
confirmation of a diagnosis of Sjogren’s syn- an orthopantomogram or Cone Beam CT. The
drome, in addition to other clinical and serolog- biopsy should be taken from the part of the lesion,
ical criteria. ideally on the border of normal and abnormal,
which is easiest to reach and has the least risk of
complications such as damage to nerves or adja-
Submucosal Biopsy cent teeth. The biopsy site is anesthetized with the
same rules applying for needle and tumor hygiene
Soft tissue lesions arising from mesenchymal tis- as for mucosal biopsies.
sue such as lipomas or benign salivary gland It is inadvisable to perform a hard tissue biopsy
tumors lie below the epithelium and typically when there is suspicion of a vascular lesion
appear as dome-shaped swellings. The overlying because of the risk of uncontrollable bleeding.
epithelium is often intact but can take on the hue Redness of the oral mucosa, mobile teeth, and
of the submucosal lump reflecting its tissue of palpable pulsations are indications of an arterial
origin or contents. Lipomas appear yellow in hemangioma. In cases where a brisk bleed is
color, while vascular lesions appear red/purple, encountered, packing usually results in
while mucinous mucoceles can take on a blue hemostasis.
hue. If submucosal lumps are less than 1 cm in If a biopsy is taken from an area of exposed
size, they are typically conducive to excision. If an bone, such as an area of osteoradionecrosis
incisional sample is to be obtained, the represen- (ORN), it is often not necessary to raise a flap,
tative biopsy sample must be of sufficient depth, and bone can be harvested with a small bone
but the appropriate depth varies from one lesion to nibbler. If the lesion is not evident then, a
another, depending on the thickness and location mucoperiosteal flap should be raised. Different
of the mass. flap designs are shown in Fig. 26. A few basic
Excisional removal of a submucosal lesion rules apply. First, the incision of the flap should be
typically commences with creation of an incision supported by undamaged bone following the
through the surface mucosa to expose the mass biopsy to optimize wound healing. It is also
beneath (Fig. 23). In the case of many benign important not to cut through the middle of a
entities, the tumor is not tethered to underlying papilla and make a cut perpendicular through the
structures and can be lifted from position by care- attached gingiva. These principles are not only
ful blunt dissection with curved or straight important for lifting flaps for hard tissue biopsy
Fig. 23 Removal of submucosal lump. A yellow colored the lump to further expose it (e). The lump is then grasped
submucosal mass is obvious lying beneath the mucosal with tissue forceps (f), and removed. The surgical bed is
surface in the lower labial sulcus (a). An incision is created inspected (g) and the wound closed with resorbable sutures
overlying the lump to expose it (b). Curved scissors are (h). Histopathology confirmed a lipoma
used to carefully blunt dissect around (c) and beneath (d)
Fig. 24 Removal of submucosal cyst from palate. A palate (green arrows), suggestive of a mucous retention
dome-shaped, raised submucosal lump (dashed oval) is cyst or minor salivary gland tumor (b). A semilunar inci-
noted in the mid-right hard palate (a). The surface epithe- sion was created and the mass removed (c). The incision
lium is of normal color. CT showed a 10 mm diameter was closed with three resorbable gut sutures (d), and the
submucosal predominantly fluid-filled lesion causing wound was healing satisfactorily 2 weeks postoperatively
smooth scalloping of the right side of the posterior hard (e). Histopathology confirmed a mucous retention cyst
but equally apply for removal of gingival lesions clinicians undertake biopsy of soft tissues that
such as angiogranuloma, peripheral fibroma, and have replaced destroyed bone such as in the case
peripheral giant cell granuloma (Fig. 27). In cer- of Langerhans cell histiocytosis, giant cell granu-
tain instances however, excision of the gingival loma, or myeloma. Rarely, malignant metastatic
lump extending onto the attached mucosa without deposits or even intraosseous squamous cell car-
lifting a flap and allowing the tissue to heal by cinoma are sampled. Bone tissue requires decal-
secondary intention can be adequate (see Fig. 21). cification before it can be processed. Depending
Once a flap is lifted for hard tissue biopsy, a on the sample size, this process requires time and
small round bur is used to make a rectangular delays histological interpretation.
cortical bone window (Fig. 28). The bone block
can be harvested with help of a small chisel or
osteotome, though this can be uncomfortable for Brush Cytology
the patient biopsied under local anesthetic. The
bone cuts should be deep enough to pass through Cytology is an easy noninvasive method of sam-
the cortical bone. The edges of the biopsy site pling lesions in the oral cavity. However, there are
should be rounded with a larger round bur and very limited indications for exfoliative cytology,
the area irrigated to prevent irritation from small mostly due to the considerable percentage of false
bone fragments before closing with resorbable positive diagnoses and the fact that it is impossible
sutures. to make a reliable difference between dysplasia
It is infrequent that oral medicine specialists and an invasive lesion (Macey et al. 2015; Sekine
perform biopsies of bony structures. Typically et al. 2017). Cochrane meta-analysis of cytology
Fig. 25 Removal of submucosal tumor from palate. A and periosteal elevator were used to separate the lump from
dome-shaped, raised submucosal lump (dashed oval) is the underlying structures of the palate (c), delivering the
noted in the left soft palate suspicious of a benign salivary tumor intact (d). Resorbable gut sutures were placed to
gland tumor (a). A semilunar incision is created (b) and the close the wound (e). Healing was uneventful 2 weeks
overlying mucosal tissues teased away from the lump with postoperatively (f). Histopathology confirmed a pleomor-
curved scissors and blunt dissection. A spoon excavator phic adenoma
for the diagnosis of oral cancer and premalignant In OSCC and dysplastic lesions, most changes
lesions found a sensitivity of 0.91 (0.81–0.96) and occur in the deeper layers of the epithelium which
a specificity of 0.91 (0.81–0.95) (Macey et al. are difficult to sample with a brush alone, leading
2015). It has not replaced biopsy as the gold to misdiagnosis if only superficial cells are sam-
standard for diagnosis and lesions suspicious for pled (Sekine et al. 2017). The nuclear morphology
malignancy should never be diagnosed by cytol- of the squamous cells is also affected by inflam-
ogy alone. mation, which would lead to false positive
Fig. 26 Types of mucoperiosteal flaps. Three corner flap (a), semilunar flap (b), crevicular flap (c), and four corner flap (d)
diagnosis with cytology (Sekine et al. 2017). A When compared to other methods to diagnose
promising application for oral brush cytology is in oral (pre) malignancies, exfoliative cytology has
the monitoring of OPMDs, since a larger area can been found to have a higher specificity compared
be sampled than by incisional biopsy alone to both cytology and light-based detection
(Moralis et al. 2007). Some authors have com- methods (Macey et al. 2015). However, a meta-
bined brush cytology with the use of toluidine analysis found no statistical difference in sensitiv-
blue (Gupta et al. 2007). ity (Macey et al. 2015). Different types of brushes
As cells from the deeper layers of the mucosa can be used, each with their own reported benefits.
need to be sampled, some of the upper layers of These include OralCDx ® (OralScan Laboratories,
epithelium need to be removed and this can be Suffern, New York) and Orcellex ® (Rovers Med-
successfully completed by using moderate force ical Devices, NL, Netherlands) brushes that
with a cytological brush (Fig. 29) (Mehrotra et al. reportedly harvest deep layers of the epithelium
2009). Sensitivity of 79–97% and specificity of and provide better representative samples than
95–100% have been reported using this method traditional exfoliative cytology (Sciubba 1999).
(Mehrotra et al. 2009). Other more invasive sam- Samples are also assessed in varying manners,
pling methods such as curettes and wooden or either with the utility of computer-assisted analy-
metal spatulas have comparable or lower sensitiv- sis in the case of OralCDx ® (Sciubba 1999) or
ity and specificity (Mehrotra et al. 2009). ThinPrep™ staining and processing as has been
Fig. 27 Removal of a gingival angiogranuloma with rais- reflected off underlying periosteum with periosteal eleva-
ing of flap. Angiogranuloma associated with the upper tor (c). Tissue is resected (d) and periodontal ligaments
right lateral incisor and canine (a). Lesion has held with curetted (e). Tissues are closed with multiple interrupted
guiding suture (b) to allow reflection off underlying peri- silk sutures. Postoperative healing 2 weeks after procedure
osteum while relieving incisions are made (b). Tissue is (f). Histopathology confirmed an angiogranuloma
recently reported (Kujan et al. 2018) (Fig. 30). (FNAB), is useful for diagnosis of a lump that is
Additional information about the utility of brush unsuitable for biopsy, such as a subcutaneous or
cytology can be found in the chapter on ▶ “Oral submucosal lymph node or salivary gland (Stan-
Mucosal Malignancies.” ley 2002). Complications vary from infections to
the development of a hematoma but are generally
Fine Needle Aspiration Cytology very low (Stanley 2002).
A neck swelling can have a wide differential
Fine Needle Aspiration Cytology (FNAC), also diagnosis including benign or malignant salivary
known as Fine Needle Aspiration Biopsy gland tumors, branchial cysts, or lymph nodes
Fig. 28 Hard tissue biopsy. Lesion after raising of the flap osteotome and achieving sufficient depth in the part of
(a). Outline of the biopsy (b). A small portion of buccal the bone where the lesion is located. The mucoperiosteal
bone is included in the biopsy to facilitate placing the flap is supported by bone after the biopsy is taken
Fig. 29 Traditional brush

cytology kit including
cervical brush, spatula, and
glass slide
(Stanley 2002). The results of an FNAC should be carcinoma (Stanley 2002). Trauma to the cells
interpreted with caution for several reasons. caused by FNAC can also lead to alterations of
Firstly, the cells that are aspirated can show their cytological appearance, impairing interpre-
changes that are superimposed on the changes tation of any subsequent FNAC. It is even possi-
that are already present in the cell and may com- ble to see changes that mimic malignancy,
plicate the diagnosis (Stanley 2002), or for exam- especially in case of Warthin’s tumor (Di Palma
ple when there is infection in a salivary gland et al. 2006). The reported sensitivity and specific-
neoplasm. Secondly, the lesion might be sampled ity of FNAC in the literature ranges widely and
selectively, making it impossible to exclude a has been reported from 57–100% and 79–100%,
carcinoma ex-pleomorphic adenoma on the basis respectively (Singh Nanda et al. 2012).
of a FNAC result. It may also be difficult to The use of ultrasound guidance to target the
differentiate between a branchial cyst and a cystic right part of a lesion increases the chances of an
lymph node metastasis of a squamous cell adequate sample, especially important in smaller
Fig. 30 Oral brush biopsy sampling from oral mucosa ThinPrep™ preserving solution for liquid-based cytology
using Orcellex ® Brush Oral Cell Sampler (Rovers Medical staining and processing (b)
Devices, NL, The Netherlands) (a). Cells are transported in
lumps such as lymph nodes. Ultrasound can also tissue is in the cortex of a node, cells are ideally
help differentiate if a mass is cystic or solid. aspirated from that area. The cells are transferred
FNAC results should be interpreted with clinical to a glass slide and smeared out with a glass slide,
correlation (Singh Nanda et al. 2012), though they fixed with a cytology fixative and transported to
can often give a firm diagnosis (such as metastatic the pathology department.
squamous cell carcinoma).
Ultrasound guided core biopsy whereby a
larger gauge cutting needle is used to obtain a Suturing
core of tissue under local anesthesia is often useful
for making a diagnosis of lymphoma or when Suture Materials
FNAC has been unsuccessful. The risks of tumor
seeding particularly with regards to salivary gland The most frequently used suturing materials in
lesions such as pleomorphic adenoma and malig- oral medicine practice include gut, vicryl, or silk.
nancy are rare, and these risks do not generally Gut and vicryl can be used in a resorbable form,
preclude this technique being used widely. which will resorb in about 7–10 days, otherwise
The armamentarium and procedure for silk is a non resorbable suture (Fig. 32).
obtaining a FNAC are shown in Fig. 31. The Gut sutures have mild tensile strength and are
skin through which the mass is to be approached resorbed by the body’s enzymes. Catgut sutures
is cleaned. The lesion is usually not anesthetized, are composed of highly purified connective tissue
although topical spray or local anesthetic cream derived from either beef or sheep intestines. The
may be used in a child or anxious patient. The membrane is chemically treated, and slender
mass is stabilized with one hand. With a dispos- strands are woven together to form a suture. A
able syringe and 23G or 25G needle, the mass is disadvantage to their use is that its knot-handling
approached from the lateral side, making it easier properties are inferior to that of silk or vicryl
to estimate the relationship between it and the sutures. Gut sutures may untie, so care must be
needle point. As the chances of finding viable taken not to cut the ends too short. Additionally
Fig. 31 Fine needle aspiration cytology. FNAC kit retracted (b). The cells are transferred onto a slide (c).
including needle, glass slide, and syringe (a). The needle Cells on glass slide are then fixed before sending to the
is inserted into the lesion and the syringe plunger is laboratory (d)
gut sutures may irritate the tissues. Chromic gut gut sutures. It resorbs in 7–10 days but has better
sutures have moderate tensile strength and are handling characteristics than gut.
resorbed in 7–10 days. This suture is more practi- The silk suture is a braided non-resorbable
cal than gut sutures. Chromic catgut is treated with suture that is easy to use, has smooth handling,
chromium salt solution to resist body enzymes and ensures good knot security. A disadvantage
and slow the absorption process thus supporting of its use is that plaque accumulates on the suture
the wound for longer periods. and may infect the wound if kept longer than
Synthetic polyglycolic acid sutures (Vicryl) are 1 week. Another non-resorbable suture is the poly-
a synthetic, absorbable, surgical suture composed ester suture (nylon monofilament or poly-
of 100% glycolide, coated with polycaprolactone tetrafluoroethylene sutures). The polyamide nylon
and calcium stearate. It has good tensile strength suture is a monofilament non-resorbable suture
and resorbs slowly (within 3–4 weeks) and is composed of a macromolecule with repeating
broken down through hydrolysis. units linked by amide bonds synthesized by ring
Vicryl Rapide is a braided absorbable synthetic opening polymerization of caprolactam. It has a
suture composed of a copolymer made from 90% smooth texture resulting in minimal tissue trauma.
glycolide and 10% L-lactide and has similar per- The polyester suture is a multifilament braided
formance characteristics to that of collagen and non-resorbable suture that can be kept in the
Fig. 32 Various types of suture material, suture sizes, and needle sizes
mouth for 2–3 weeks with little risk of infection. A minimizes the opening made by the needle as it
disadvantage of its use is that it is likely to untie if enters the tissues and any subsequent trauma to
extreme care is not exerted when tying the knot. the tissues. Frequently, for mucosal biopsy, 5 0
or 4–0 sutures are indicated, although 6–0 sutures
can be used for delicate areas such as lips and floor
Needle Characteristics of mouth. The higher the number, the finer the
sutures.
The most common curvature of needles used in Surgical suture needles are constructed of three
oral medicine practice is the three-eighths inch sections. The point is the sharpest portion and is
(10 mm) and the half inch (12.7 mm), the former used to penetrate the tissue. The body represents
being the most common. Small needles enable the mid portion of the needle, and the swage is the
precise closure of the mending tissues in more thickest portion of the needle to which the suture
refined procedures. An accepted surgical practice material is attached (Fig. 33).
is to use the smallest suture possible to hold the Two main types of needles are used: cutting
mending tissues adequately (Fig. 33). This and reverse cutting. Both needles have a triangular
body. A cutting needle has a sharp edge on the directed away from the wound edge, which
inner curve of the needle that is directed toward reduces the risk of the suture pulling through the
the wound edge. A reverse cutting needle has a tissue. For this reason, the reverse cutting needle
sharp edge on the outer curve of the needle that is is used more often than the cutting needle in
mucosal surgery.
Suture Techniques
In the oral cavity, the most frequently used types

of suture technique are simple interrupted sutures
or the running suture. Figure 34 shows a sche-
matic representation of the most frequently used
suturing techniques.
The simple interrupted sutures are easy to
place, have greater tensile strength, and have less
potential for causing wound edema and impaired
circulation. Interrupted sutures also allow the sur-
geon to make adjustments as needed to properly
align wound edges as the wound is brought
together. Disadvantages of interrupted sutures
include the length of time required for their place-
ment and the greater risk of crosshatched marks
(train track appearance) across the suture line. The
risk of crosshatching can be minimized by remov-
ing sutures early to prevent the development of
suture tracks.
Simple running sutures are useful for long
wounds in which wound tension has been mini-
Fig. 33 Needle sizes. 12 mm (above), 16 mm (middle)
mized with properly placed deep sutures and in
and 18 mm (below) 3/8 circle needles
which approximation of the wound edges is
Fig. 34 Different suturing techniques. Simple interrupted suture (a), horizontal mattress suture (b), and vertical mattress
suture (c)
adequate. Theoretically, less scarring occurs with across the wound. Horizontal mattress sutures
running sutures compared with interrupted may be left in place for a few days if wound
sutures because fewer knots are made, however tension persists after placement of the remaining
the number of needle insertions remains the same. stitches. In areas of extremely high tension at risk
Advantages of the simple running suture include for dehiscence, horizontal mattress sutures may be
quicker placement and more rapid left in place even after removal of the superficial
re-approximation of wound edges, compared sutures; however, they have a high risk of produc-
with simple interrupted sutures. Disadvantages ing suture marks if left in place for longer than
include possible crosshatching, the risk of dehis- 7 days.
cence if the suture material ruptures, difficulty in
making fine adjustments along the suture line, and
wrinkling of the suture line when the stitches are Simple Interrupted Sutures
placed in thin tissue such as floor of mouth or lip.
A vertical mattress suture is especially useful in By suturing, the wound edges are brought
maximizing wound eversion, reducing dead together in order to promote wound healing, pro-
space, and minimizing tension across the wound. mote hemostasis, and prevent infection. Suturing
One of the disadvantages of this suture is is a skill that should be learned and improved by
crosshatching. The risk of crosshatching is greater frequent practice. Some basic principles are
because of increased tension across the wound discussed.
and the four entry and exit points of the stitch in The needle holder (15 cm) is lightly grasped in
the tissue. a way that promotes the most flexibility of the
The horizontal mattress suture is useful for hand and wrist. Figure 35 shows two different
wounds under high tension because it provides grasps. The needle is placed in the needle holder
strength and wound eversion. This suture may at 2/3 of its curvature (Nelson 2015), generally at
also be used to temporarily approximate wound 90 angle in the needle holder (Fig. 36). This can
edges, allowing placement of simple interrupted be modified however, so as to place the needle in a
sutures. The temporary sutures are subsequently direction that facilitates insertion of the needle
removed after the tension is evenly distributed perpendicular through the tissue, while making
Fig. 35 Grasping the needle holder. The needle holder is be held at approximately three quarters from the tip of the
held through the loops between the thumb and the fourth needle along the swage of the needle. Holding the needle
finger, and the index finger rests on the fulcrum of the too close to the end results in slippage and bending of the
instrument (a). The needle holder can be held in the shaft
palm, allowing greater dexterity (b). The needle should
Fig. 37 Proper entry and exit points, angle, and distance

of a suturing needle. The needle enters the tissue at point
(a) and exists at point (b), both of which are equidistant
(approximately 2–3 mm) from the edge of the wound. The
needle should enter and exit the tissues at a 90 angle
Fig. 36 The needle is placed in the needle holder at
two-third of its curvature, generally at a 90 angle in the peripherally from the wound border. Then the
needle holder
needle holder is released, and the emerging needle
is re-grasped after half of it has surfaced. Care
use of the curve of the needle instead of pushing it should be taken not to grasp the tip, i.e., not to
through in a linear fashion. damage and dull the needle. An equal amount of
Suturing forceps can be used to stabilize the tissue should be engaged on both sides of the
tissues that are sutured. It is recommended to first wound. If the incision is deep, or a large amount
start the suture in the raised flap and then go of tissue is missing, the suture should first be
through the tissue that is still attached in its orig- placed through one flap, and then reloaded, before
inal location. This is best to feel the maximum being passed through the second flap, directing its
stretch and tension, the tissue is put under when surfacing at 3 mm peripherally. The suture is
tying the knot. The forceps should never be used through both flaps and ready to tie a knot.
to squeeze the tissue because this will damage it. The knot is tied by rotating the long end of the
The tissues should be everted and the tissue suture around the tip of the needle holder twice in
edges should be in the same plane in order to a clockwise manner, and then grasping the short
prevent an unsightly scar. Dead space should be end (3 cm) of the suture with the needle holder
minimized; this can be done by suturing in two before tightening. The short end of the suture is
layers. The oral mucosa is very rarely sutured in grasped with the tip of the needle holder and is
two layers. When a through and through defect in kept under tension while the knot is pushed down
the lip is sutured, it is important to restore the with one finger. The needle holder is then gently
muscle layer as well. pulled in the opposite direction to achieve good
The edges should be re-approximated and the tightening. This is repeated two times, one time
needle inserted at a right angle to the tissue sur- anti-clockwise and another time clockwise, thus
face, as an acute angle may cause tissue tearing completing the tied knot. The sutures ends are
(Fig. 37). Entrance of the needle is situated about then cut at 3 mm length. Sutures are typically
3 mm away from the wound border. The needle is placed every 5–10 mm. The sutured tissues are
forced through the tissue by rotating the wrist, and typically covered with sterile gauze to help with
the curved needle emerges from the mucosal sur- hemostasis and to prevent direct contact with the
face of the other flap, equidistantly 3 mm surgical site.
Aftercare biopsy is performed at the sublingual area or

around Stenson’s papilla.
Complications from biopsies include postopera- • Diet and hygiene: Patients should be advised
tive bleeding, swelling, infection, pain, and pares- to eat soft foods, maintain good oral hygiene,
thesia. The patient should be instructed, both and to avoid hot drinks and exercising on the
before and after a procedure, verbally and in writ- day of surgery to minimize swelling and
ing, concerning the following points: bleeding.
• Trauma: Patients should be advised to avoid
• Pain relief: Normally patients will have rela- irritating the surgical site, and in case of lip
tively little postoperative pain. Patients are biopsies of surgical treatment advised to mini-
advised to take their first painkiller of choice mize stretching the tissues. Patients should be
(paracetamol 1000 mg tid, or a non-steroidal careful not to chew at the biopsy site, and to
anti-inflammatory drug such as ibuprofen avoid sharp foods such as potato chips, nuts,
400 mg qid) before the local anesthesia has popcorn, and the like.
worn off to help minimize pain and swelling. • Rinsing: Patients should be advised to main-
• Swelling: This is normal after surgical proce- tain proper oral hygiene measures on the day of
dures depending on the location and size of the surgery and to commence rinsing with salted
procedure. Patients should be advised to expect water (1 teaspoon of salt in a cup of lukewarm
this within 24 h after treatment, and that it may water) 24 h after treatment at least three times
increase for a couple of days after that. Patients daily or at least after meal times, to aid clean-
should be informed to use ice packs for 20 min liness and healing. On the day of surgery,
intervals, pausing for 20 min, during the first patients should refrain from rinsing.
48 h if indicated to minimize swelling. • Antiseptics: Patients should be specifically
• Bleeding: After an intraoral biopsy, it is nor- advised not to rinse with alcohol-containing
mal to have some bloody saliva. Patients antiseptic mouthwashes as this often irritates
should be advised that some bleeding or ooz- the underlying condition for which they
ing is normal after biopsy and to apply pressure received a biopsy. Chlorhexidine-based alco-
with gauze over the biopsy area if there is hol-free mouthwashes may be use for a short
active bleeding. To prevent postoperative period of time if surgery has been undertaken
bleeding, patients should not rinse for 24 h on gingival tissues preventing good oral
after the procedure. Bleeding from a neck hygiene measures.
FNAC is rare but pressure should be applied, • Sutures: Patients should be informed that
and urgent medical attention sought if swelling sutures may dislodge partially or completely
develops. even if they are non-resorbable. Patients
• Scarring: This is important from an esthetic should not be alarmed if this occurs, especially
viewpoint and can occur particularly on the lip if there is no bleeding as sutures are generally
vermilion. needed for the initial stage of healing to bring
• Paresthesia: This includes numbness of the together wound edges and stabilize the
lower lip that can be transient or permanent blood clot.
and may occur following a labial salivary
gland biopsy (diagnostic work-up for Usually, patients can return to work on the
Sjogren’s syndrome or sarcoidosis) or deep same day of their biopsy if they wish, or they
lip biopsy (when orofacial granulomatosis is may elect to rest at home. During the post-biopsy
suspected), and following deeper tongue week, patients should be allowed to call the prac-
biopsy, or after some hard tissue biopsies. tice in case of an emergency. However, adhering
• Blockage: Disruption of salivary gland flow if to the instructions listed here will minimize post-
damage occurs to the duct orifice when a biopsy discomfort, reassure the patient, and limit
the need for the patient to revisit the practice with Communication with the pathologist does not
unnecessary concern. only entail communication about the clinical
An appointment should be made for review of aspects and differential diagnosis of the lesion
pathology results, removal of sutures and assess- (Brennan et al. 2017). This process also involves
ment of healing. The suture removal appointment correct labeling of specimens with patient’s name,
should be scheduled for 5–7 days in case of date of birth, and identification number. Laterality
non-resorbable sutures or after 7–10 days if and location where the specimen was taken from
resorbable materials have been used. As biopsy should also be included on both the specimen
is normally a minor procedure, sutures may some- container and the pathology form. A histological
times be used only to stabilize a coagulum. diagnosis may lead to treatment with significant
Aligning the suture removal appointment with comorbidities; therefore, it is of the greatest
the discussion of the pathological findings is importance to avoid errors in labeling of
always best to minimize inconvenience to the specimens.
patient and to allow reporting of findings to the The clinician must also ensure the safety of the
referring practitioner in a timely manner. pathologist by clearly communicating infectious
If non-resorbable sutures are used, they should diseases and sharps such as needles that may be
be removed at the review appointment using a pair present in the specimen (Brennan et al. 2017). The
of pointed sharp curved scissors. An antiseptic authors recommend doing this in a systematic
chlorhexidine mouthwash may be used to mini- fashion to ensure safety and have developed a
mize passing of the contaminated suture through novel checklist to enhance hand over from the
the wound, although realistically this is not operating theatre/clinic to the pathologist
required as good tissue vascularization prevents (Table 2) (Brennan et al. 2017).
contamination of the inner tissues by the passing Tissue artifacts can arise as a consequence of
suture. poor biopsy technique that can hamper provision
of a correct diagnosis. A tissue artifact is an arti-
ficial alteration of specimen appearance seen at
Communication with the Pathologist the microscopic level caused by inappropriate
tissue manipulation. It usually refers to fragmen-
It is very important to provide the pathologist with tation or crushing of the specimen with forceps,
as much information as possible about the clinical by pulling, injecting anesthetic solution, hemor-
course and appearance of the lesion when sending rhage, or splitting. For example, splitting can
tissue for analysis. Insufficient or incorrect infor- occur in the epithelium or at basement membrane
mation may impair a diagnosis and even endanger zone, leading to resemblance of vesiculobullous
patient safety. diseases and to an incorrect diagnosis. It has been
Previous treatments such as radiotherapy or shown that general dental practitioners cause sig-
certain surgical treatments can influence histolog- nificantly more tissue artifacts than oral surgeons
ical appearances. A pathologist might wonder (crush injury 27.1%; hemorrhage 19.8%; splits
why skin epithelium is seen in an oral biopsy if 11.3%; and fragmentation 6.2% for general den-
he/she does not know that a biopsy was taken tists compared to crush injury 10.2%; hemorrhage
from an area with a previous microvascular free 8.5%; splits 13%; and fragmentation 2.3% for oral
flap transfer. Information on possible contact of surgeons) (Seoane et al. 2004), thus careful
the lesion with an amalgam filling will help the manipulation of tissues is warranted and will aid
pathologist differentiate between a lichenoid reac- the reporting pathologist.
tion and lichen planus (Patel et al. 2011). A dif- Punch biopsies reportedly yield less tissue arti-
ferential diagnosis, especially in cases where a facts than scalpel biopsy (Moule et al. 1995),
rare disease is suspected, helps guide the pathol- although this is not universally accepted (Seoane
ogist in making the diagnosis. et al. 2002). Given that scalpel biopsy is indicated
Table 2 Checklist for surgical specimen handover for improving communication and safety between the operating
theatre/clinic and pathology laboratory. (Adapted from Brennan et al. 2017)
Patient details (place sticker here)

Forename:
Surname:
DOB: Hospital details added here if required
Hospital number:
Theatre to pathology laboratory handover checklist
Has the patient got any infectious diseases?
Any pins/needles in specimen(s)?
Any staples/clips in specimen(s)?
Responsible clinician/surgeon
Date of operation
Side of operation (Left/Right/Bilateral)
Clinical staging
Has the patient had chemotherapy/radiotherapy?

Laryngeal tumors only:
Are the vocal cords mobile?
Specimen
Fresh/in formalin
(If in formalin, time placed in it)
Is there any bone in the specimen(s)?
Are there any implants/ crowns in the specimen?

Is the specimen orientated on board or with
diagram included?
Previous frozen section(s) at this operation?
Lymph node levels removed (e.g., I–III, II–V)

Other non-nodal structures included in neck
dissection
Number of specimens correlating with those on
request form
Any specific information which may assist pathologist or laboratory staff
Check correct patient d e t a i l s on specimen/form? Tick to confirm

in most circumstances of mucosal pathology, this lead to destruction or evaporation of the tissue
should be the overriding selection criterion and (Roodenburg et al. 2002). A small focused beam
not the percentage of tissue artifact created by one can also be used for excision of lesions
technique compared to another. (Roodenburg et al. 2002).
In the oral cavity, the CO2, Argon, Diode, and
Nd:YAG lasers have been used (Fig. 38)
Other Operative Techniques (Roodenburg et al. 2002). CO2 lasers are readily
absorbed by tissues with high water content and
Laser therefore suitable to evaporate a controlled shal-
low area of tissue such as a leukoplakic lesion.
Lasers have a wide field of application in surgery Only about 10% of leukoplakic lesions recur after
that can vary from surgical procedures to nonin- CO2 evaporation, and the percentage of malignant
vasive procedures. The application is dependent transformation is lower compared to lesions that
on the type and wavelength of the laser used. As did not receive any treatment (van der Hem et al.
the laser beam is absorbed by the tissues, heat is 2005).
created that causes thermal damage to the tissues. The water absorption coefficient of the CO2
To what extent the tissues are damaged, depends laser is lower compared to the YAG laser, the
on the type and wavelength of the laser that is used CO2 laser has a higher thermocoagulation effect,
(Shokrollahi et al. 2004). Thermal damage is also which means less bleeding during the procedure.
dependent on the radiant exposure that is the The disadvantage is relatively more extensive
energy the beam emits per cm2 (Shokrollahi damage to the histopathological specimen (Suter
et al. 2004). Another factor is the pulse duration, et al. 2017).
which determines the time of exposure of the The CO2 laser is the most frequently used for
tissues (Shokrollahi et al. 2004). This makes it intraoral surgical procedures (Tuncer et al. 2010).
possible to target specific tissues with a particular The advantage of the CO2 laser is the reduced
wavelength (Shokrollahi et al. 2004). If a laser is postoperative pain and reduced need for postop-
used with high absorption by tissue, the penetra- erative analgesia (Tuncer et al. 2010). It is also
tion depth will be less and the high absorption will known to reduce postoperative bleeding by
Fig. 38 Fibroepithelial polyp (a) removed with diode laser (b)

et al. 2012). CO2 laser tissue damage was found

to be more extensive in epithelium, muscle, and
connective tissue than salivary gland tissue, based
on their respective water content (Pogrel et al.
1990). The width of the zone with thermal damage,
however, was only 0.5 mm (Pogrel et al. 1990). An
animal study reported a 0.22 mm zone of thermal
damage for both laser and monopolar diathermy,
suggesting that this may be clinically relevant in
small biopsy specimens (Silverman et al. 2007).
No difference in the width of damaged zones has
been reported between the use of continuous wave-
length or pulsed mode (Suter et al. 2012). Studies
show that the clinical relevance of thermal damage
is questionable, with one study finding that use of
CO2 laser in 133 intraoral excisional biopsies did
Fig. 39 Post-electrocautery of resected lesion of the right not impair histological diagnosis (Bornstein et al.
ventrolateral tongue in a 65-year-old male diagnosed his- 2005). This has been confirmed by other authors
topathologically with moderate to epithelial severe dyspla- (Tuncer et al. 2010).
sia. (Image courtesy of Dr Maryam Jessri, Division of Oral
Medicine and Dentistry, Brigham and Women’s Hospital,
Boston, MA, USA)
Cryotherapy
sealing peripheral blood vessels, which aids a
clear vision of the lesion (Tuncer et al. 2010). Cryotherapy is the deliberate destruction of tissue
Wounds that are made by CO2 laser heal slower by the application of extreme cold and has been
compared to wounds that are made by a steel indicated as a treatment modality for the manage-
blade, but faster compared to electrosurgical ment of commonly occurring benign oral pathol-
instruments such as a monopolar (Fig. 39) ogies. Previous studies report cryotherapy for the
(Liboon et al. 1997; Sinha and Gallagher 2003; management of benign lesions such as mucoceles,
Tuncer et al. 2010). vascular malformations, and oral leukoplakia,
A laser that is frequently used for treating although use of cryotherapy for the latter should
vascular lesions is the Nd:YAG laser, which can be discouraged. Benign lesions such as mucoceles
penetrate deep into the tissues due to its poor and vascular malformations while not malignant
absorption by water (Vesnaver and Dovsak can pose functional, psychological, and social
2006). When laser is used to target a vascular obstacles to patients (Dieterich-Miller and Safford
lesion, the laser beam is selectively absorbed by 1992). Therefore, it is imperative to determine the
hemoglobin. This causes damage to the blood most effective treatment modality and optimal
vessel following which an inflammatory reaction conditions needed for pathology elimination. Tra-
is promoted (Shokrollahi et al. 2004). ditionally, treatments of these lesions include
Controversy exists about the use of laser or invasive techniques such as surgery or other min-
electrocautery for taking biopsies, because the ther- imally invasive techniques such as electro-
mal damage may leave the tissue edges unsuitable cauterization, laser ablation, or photodynamic
for reliable histological diagnosis and cause delays therapy (Kawczyk-Krupka et al. 2012; Garg
in wound healing. Both laser and electrocautery et al. 2014). Nevertheless, these techniques are
cause tissue damage (Pogrel et al. 1990), with reported to cause pain, anxiety, and discomfort
conflicting evidence in the literature as to which and have been associated with lesion recurrence
causes the most thermal damage, much of which is (Kawczyk-Krupka et al. 2012). Cryotherapy,
dependent on instrument settings (Schoinohoriti which is the application of low temperatures
through the delivery of cyrogens for the deliberate

destruction of tissue through cryogenic coagula-
tion and necrosis, is a suitable alternative and can
be carried out using an open or closed system
(Sako et al. 1972; Yeh 2000; Farah and Savage
2006; Kawczyk-Krupka et al. 2012; Yu et al.
2014). It is a minimally painful, minimally scar-
ring procedure that typically does not cause bleed-
ing, with a history of effective lesion eradication
and low risk of secondary infections (Sako et al.
1972; Yeh 2000; Farah and Savage 2006; Fig. 40 Cryopen™ and 8g nitrous oxide (N2O) cartridge
with a white dot applicator providing application width of
Kawczyk-Krupka et al. 2012; Yu et al. 2014). 2–5 mm and penetration of up to 4 mm. The Cryopen™
The commonly used cryogens include liquid emits a fine jet of nitrous oxide under high pressure allo-
nitrogen ( 196 C), nitrous oxide ( 89 C), car- wing freezing of tissue to a depth of 2 mm in 10 seconds,
bon dioxide in solidified form ( 78 C), propane and 4 mm in 20 seconds. The 8g N2O cartridge provides up
to 120 seconds of continuous gas flow
( 42 C), chlorodifluromethane ( 41 C), and
dimethyl ether ( 24 C). Liquid nitrogen, being
the coldest makes it highly effective in treating initiates a decrease in tissue temperature by the
intraoral lesions owing to its inherent properties Joule-Thomson expansion principle. This refers
(Yeh 2000). It is inert, odorless, and nonflamma- to the movement of nitrous oxide from the high-
ble. Furthermore, it does not release toxic gases, pressure unit within the cryoprobe into the
has poor heat and electrical conductivity, and low-pressure cryoprobe tip and results in a drop
good thermal capacity (Rezende et al. 2014). in temperature at the site of tissue contact (Gage
The low cost, ease of access and usage for clini- and Baust 1998). It facilitates a more controlled
cians make it an attractive choice (Yeh 2000). delivery of the cryogen and permits effective
Currently there are two main systems (open administration of freeze-thaw cycles. A number
and closed) for delivering cryogens, which utilize of advantages are yielded by the Joule-Thompson
a process of rapid freezing and slow thawing that principle including the ability to monitor the
is repeated as needed. The open system achieves cooling that occurs at the tip by temperature
the decrease in tissue temperature via the direct gauges, which provide the practitioner with
application of the cryogen (generally liquid nitro- greater control over maintaining a constant low
gen or nitrous oxide) to the tissue by cotton swab temperature to produce predictable depth of
or a spray applicator, known as a cryogun necrosis (Gage and Baust 1998). Although this
(Yu et al. 2014). This method is advantageous to system requires expensive and complex equip-
clinicians as the armamentarium required to carry ment, the accuracy of this equipment makes it
out this procedure is readily accessible (Farah and highly suitable for intraoral use (Fig. 42) (Gage
Savage 2006). However limitations associated and Baust 1998; Yeh 2000).
with the inability of cotton swabs to carry suffi- A multitude of variables are implicated in cryo-
cient quantities of cryogen and maintain a suffi- therapy treatment. Identifying the optimal vari-
ciently low temperature exist (Farah and Savage able for lesion regression or eradication is
2006; Yu et al. 2014). Furthermore, use of a spray pivotal. The mechanism involves subjecting the
applicator should be used with caution intraorally tissues to freeze-thaw cycles. Commonly
and by experienced clinicians as it lacks in control accepted protocols suggest that tissues should be
over temperature, area of cryogen exposure and subjected to rapid freezing at lethal cellular tem-
depth of cryogen penetration (Figs. 40 and 41) peratures, while maintaining safe lesion margin.
(Farah and Savage 2006). This is followed by a slow-thaw process, and the
By comparison, the closed system uses a com- freeze-thaw cycle is repeated. In tissues that are
plex instrument known as a cryoprobe, which frozen, there are variations in the freezing/thawing
Fig. 41 Cryotherapy procedure. Freezing (a–c) and thawing (d–f) of a resolving mucocele at the fourth and final
cryotherapy session
Fig. 42 Cryotip applied to a vascular lesion on the right immediately after the freezing process showing the depth
buccal mucosa of a 62-year-old female during the freezing and size of freezing obtained with a nitrous oxide cryo-
process (a). The tissue undergoing freezing is seen in white probe (b). (Used with permission from John Wiley & Sons;
surrounding the tip of the cryoprobe. Freeze ball Farah and Savage 2006)
parameters, where those closest to the cryogen Additionally, smaller lesions require shorter
cool quicker when compared to those further 20–30 s freeze/thaw cycles and accordingly,
away (Farah and Savage 2006). In effect, the larger lesions require 3 lots of 2-min freeze/thaw
cryolesion bears a steep thermal profile and vari- cycles (Farah and Savage 2006). Determining the
able thermal history, which permits the categorical duration of freezing for each lesion type will facil-
analysis and modulation of aspects of the treat- itate the effective management of patients under-
ment (Gage and Baust 1998; Baust and Gage going cryotherapy. Repetitive cooling predisposes
2005; Farah and Savage 2006). the cells to a more rapid and extensive cooling
The optimal time for which the tissues should process. The initial freeze-thaw cycle causes cel-
be held in the frozen state is important for optimal lular damage thereby increasing the thermal con-
treatment outcomes. For benign lesions, the cur- ductivity of the tissues. Upon exposure to the
rent recommendation is an exposure time of the second cycle, the tissues undergo additional dele-
order of 1–2 min overall (Farah and Savage 2006). terious physiochemical changes. The level of
necrosis post second cycle is expected to be at number of freeze-thaw cycles will aid in the effec-
80% of the previously frozen volume (Gage and tive management of lesions. Vascular
Baust 1998; Baust and Gage 2005). As a result of malformations typically require up to five cryo-
the repeated process, the volume of frozen tissue therapy sessions for resolution (Fig. 43), whereas
enlarges and the periphery of tissue destruction mucoceles can typically be managed in three ses-
moves closer to the outer limit of the frozen tissue sions (Fig. 44).
(Baust and Gage 2005). This is augmented by the
deleterious physiochemical changes that tissues
are subjected to. The enhanced lethal effects of Sialoendoscopy
repeated freeze-thaw cycles are best seen at lower
temperatures in the 20 C to 30 C range A sialolith is a calcification within a salivary
(Baust and Gage 2005). However, if the tissue gland. Factors that promote sialolith formation
temperature is less than 50 C, complete are chronic inflammation, duct strictures, and
destruction can occur in a single cycle (Baust anti-cholinergic drugs. There is no clear relation-
and Gage 2005), reducing the benefit of repeated ship between diet and sialolith formation. Most
cycles (Gage and Baust 1998). Determining the salivary gland stones present in the
Fig. 43 Vascular malformation on the right lateral tongue thaw cycles at two separate visits one month apart. (Used
of a 59-year-old female before (a) and after (b) cryotherapy with permission from John Wiley & Sons; Farah and
treatment. The lesion was treated with 220 second freeze/ Savage 2006)
Fig. 44 Mucocele on the lower right lip of a 6-year-old at one visit. (Used with permission from John Wiley &
girl before (a) and after (b) cryotherapy treatment. The Sons; Farah and Savage 2006)
lesion was treated with 220 second freeze/thaw cycles
submandibular gland (>80%), and the parotid from moving proximally. If the stone is located
gland is involved in 5–15%. The sublingual closer to the hilum of the gland, the stone is first
gland has the lowest prevalence of sialoliths. identified by palpation. Subsequently the floor of
The high prevalence in the submandibular gland the mouth is incised parallel to the duct. Meticu-
is related to the fact that it is more prone to stasis, lous hemostasis is paramount for optimal orienta-
has thicker saliva production, and with higher tion to and recognition of neighboring structures
calcium and phosphate concentrations as well as such as the lingual nerve. The lingual nerve is
the anatomical position of its duct (Delli et al. identified as it crosses the duct that is also identi-
2014). When requesting imaging, it is worth fied. The duct is then incised over the stone and
remembering that not all sialoliths are sufficiently the stone is removed. The duct itself is not
calcified to show on a radiograph. sutured, but the floor of the mouth can be sutured
It is not recommended to remove a sialolith in with 5–0 vicryl or gut sutures, although this is not
any acute presentation. The choice of therapy always necessary. If the stone is removed using an
depends on the position of the stone in the gland intraoral approach, it is always advisable that the
and the size of the stone. If the stone is positioned patient chew gum and use acidic drops to stimu-
distally and is small (this will usually be under late salivary flow during the recovery period to
4 mm), it may be reached by a sialoendoscope and ensure duct patency.
can subsequently be removed using a basket or If the stone cannot be reached by
grasper. If the stone is larger and an endoscopic sialoendoscopy or surgical removal, and if it is
technique is chosen, it may be removed in pieces causing chronic symptoms for the patient, the
after endoscopic laser fragmentation (McGurk gland will require removal. This is a procedure
et al. 2005). A sialoendoscope can also be used with a much higher morbidity than an endoscopic
for to identify strictures or stones in a diagnostic procedure.
procedure. Strictures can be dilated using a bal- In selected cases, extracorporeal shock wave
loon. Dilatation of a stricture is a procedure that lithotripsy may be applied to break up salivary
can also be performed by an interventional radi- gland stones. The stones are subsequently shed
ologist, while performing a sialogram. by normal salivary flow (Delli et al. 2014). This
Sialoendoscopies will mostly be carried out in method is proven to be more successful for
specialist centers by oral and maxillofacial sur- smaller calculi and more successful in parotid
geons or oral medicine specialists with an interest rather than submandibular calculi (Iro et al.
salivary gland endoscopy. The procedure can be 2009). The stone is broken up in several sessions,
performed under general or local anesthesia. First, where the time between sessions can vary from
local anesthesia is given around the opening of the 1 week to 8 weeks (Iro et al. 2009; Kondori et al.
duct. The duct is identified and a guiding wire is 2011).
passed into the duct, which is used to guide dila-
tors into the duct until an endoscope can be passed
through. Under irrigation with saline, the endo- Arthrocentesis
scope is passed through the duct and obstructions
are identified. The most frequently performed temporomandib-
If the stone is located very distally or if the ular joint (TMJ) procedure is arthrocentesis, in
stone is very large, transoral removal is chosen. which the upper joint compartment is flushed
This has the potential disadvantage of damaging with saline (Guarda-Nardini et al. 2008). The pro-
the lingual nerve. Local infiltration anesthesia is cedure is applied in patients with internal derange-
given around the stone location, which is pal- ment of the TMJ, after nonsurgical measures such
pated. If the stone is very close to the surface as patient-education, pharmacotherapeutics, oral
and easily identifiable, the duct is incised and the appliances, and physiotherapy have failed to
stone is easily removed (Fig. 45). It can be helpful relieve the complaints sufficiently. The procedure
to place a suture posterior to the stone to prevent it will not change the position of the articular disc,
Fig. 45 Removal of sialolith from the left submandibular a sialolith (b). Careful incision over the submandibular
duct. Clinically, a hard swelling is noted involving the duct (c) allows removal of the sialolith (d)
anterior floor of mouth (a). An extraoral radiograph reveals
but is thought to be effective because of the expan-

sion of the joint space through flushing and the
washing out of inflammatory mediators (Monje-
Gil et al. 2012). Patients report an improvement in
mouth opening with decreased pain (Neeli et al.
2010). A meta-analysis has shown that
arthrocentesis led to a significant improvement
of pain when compared to conservative measures
(Bouchard et al. 2017). No significant effect on
maximum mouth opening was found however
(Bouchard et al. 2017).
Arthrocentesis can be performed under local or
general anesthesia. If the patient is under general Fig. 46 Holmlund line. First entry point corresponding
anesthesia, a nasal tube is requested because dur- with the glenoid fossa (A). Second entry point
ing the procedure the mandible must be manipu- corresponding with the articular eminence (B)
lated freely. The patient is positioned flat, with the
head turned so the TMJ can be easily reached. The glenoid fossa and is situated 10 mm anterior to the
area that is treated is disinfected. Local anesthesia midpoint of the tragus and 2 mm inferior to the
is given. The Holmlund line is drawn from the line. The second point corresponds with the prom-
midpoint of the tragus to the lateral canthus of the inence of the articular eminence and is situated
eye. On this line, the entry points of the needles 20 mm anterior to the midpoint of the tragus and
are marked. The first point corresponds with the 10 mm inferior to the line (Fig. 46). Variations on
the second insert point have been described such sample and not of the entire lesion. One may
as a point 12–13 mm anterior from the midpoint miss a clinically representative area, or multifocal
of the tragus and 2 mm inferior to the Holmlund dysplasia, which may be present.
line (Tozoglu et al. 2011). Others have used a There are also inherent limitations regarding
point 7 mm anterior to the middle of the tragus the prognostic value of dysplasia. Albeit diagnos-
and 2 mm inferior to the Holmlund line (Alkan tically very important and uniquely valuable in
and Etoz 2010). Some authors use only the first addition to a lesion’s clinical appearance, the
insertion point, with the advantage of less trauma prognostic value of dysplasia is inconsistent.
due to insertion of a second needle and less Firstly, it has been shown that the histological
postoperative discomfort (Guarda-Nardini et al. diagnosis of dysplasia is highly subjective and
2008). depends upon the pathologist, with poor to mod-
The mandible is opened and protruded by the erate agreement rates in spite of a set of criteria
patient or assistant. Two 19 gauge needles are known for 40 years. Secondly, not all lesions with
inserted into the joint space, no further than features of dysplasia undergo malignant transfor-
25 mm measured from the skin insert. Before mation, and some may even regress, although it is
inserting the second needle, the joint is irrigated known that those that demonstrate dysplasia bear
with 2 ml of saline. The first needle is used to a higher risk for transformation. Thirdly, oral can-
irrigate the joint with saline, while the second cer can develop from lesions without epithelial
needle is used to permit outflow of the saline. dysplasia (Reibel 2003).
The joint is flushed with 200 ml of saline (Neeli Surgical excision with histology is the first-line
et al. 2010). The volume of saline that is used treatment for small OPMD, whereas in cases of
can vary greatly, between 50–500 ml (Monje-Gil large or multifocal lesions, one may opt for an
et al. 2012). Afterwards, the joint is injected incisional biopsy. By far, most diagnostic biopsies
with corticosteroids (Monje-Gil et al. 2012). performed by oral medicine specialists are
Some authors advocate the use of sodium incisional.
hyaluronate, because it may reduce the levels Excisional biopsy means the complete removal
of nitric oxide in the joint space and cause vaso- of a lesion (both in surface and in depth). When a
dilatation and vascular permeability (Monje-Gil malignancy is not suspected, and the lesion is
et al. 2012). small enough to be removed,and if removal of
Alternatively, this procedure is performed with the lesion represents the accepted treatment
the help of an arthroscope so the joint can be modality, excisional biopsy is indicated. Small
visualized. If a second canula is used, probes and lesions, usually up to 1 cm in diameter are gener-
shavers can be used to debride the joint. If a third ally excised. One may consider excision of larger
canula is inserted, a discopexy can be performed. lesions if they carry some risk, and if there is a fair
A discopexy is the fixation of the articular disc chance that the procedure might be final. Leuko-
after releasing and repositioning it in a correct plakia up to 2–3 cm can be excised; however, this
position. depends on the location, because of accessibility
and to prevent damage to deeper functional struc-
tures (salivary gland ducts, vessels, nerves, mus-
Special Considerations cles). In excisional biopsies, a margin of
surrounding clinically normal tissue should be
Oral Potentially Malignant Lesions included. Suggested margins are 2–3 mm.
Narrower margins may be used for benign lesions.
Mucosal biopsy is frequently used for the diagno- In case of suspected malignancy, margins should
sis, or exclusion of, malignancy and as such sam- be at least doubled, although oral medicine spe-
pling of representative tissue is critical. One major cialists would not be expected to perform exci-
limitation of an incisional biopsy is that the spec- sional biopsy on frank carcinoma as definitive
imen is only diagnostic of the representative treatment. Rather, the patient would be best
referred to a head and neck surgeon, who would mucoceles do not cause significant discomfort
perform aggressive surgical treatment, including (Baurmash 2003); however, they interfere with
safe deep margins, even at the expense of nerves, speech, mastication, and swallowing and may
blood vessels, and periosteum under general anes- cause external swelling depending on the location
thesia. In cases of a recurrence of previously and size of the lesion (Baurmash 2003).
excised dysplastic leukoplakia, excisional biopsy A retention mucocele is caused by obstruction
with margins of 2–3 mm would normally be of the gland, causing ballooning of the duct. Sev-
undertaken. eral treatment modalities have been proposed in
It should be noted that although biopsy is the literature for management of mucoceles (Garg
essential in diagnosing OPMD, information et al. 2014). These vary from excision of the
about the whole lesion cannot be provided unless lesion, marsupialization, micro-marsupialization,
an excisional biopsy is performed. There is an carbon dioxide laser, gamma-linolenic acid,
inherent risk of failing to prove the malignant Erbium laser, and cryotherapy (Baurmash 2003;
status of a lesion if only an incisional biopsy is Farah and Savage 2006; Garg et al. 2014). The
performed. Sampling the most severe portion with treatment option of choice is excision, together
an incisional biopsy is paramount. When possible, with the underlying salivary gland, carried out
it is suggested to include a small portion of clin- with care so as not to damage other minor salivary
ically unaffected tissue, i.e., the edge of the lesion glands. While surgical excision may seem an ideal
with adjacent clinically normal epithelium. There treatment option for mucoceles, these lesions
are several reasons why including normal tissue is occur primarily in children and adolescents who
beneficial. It helps confirm that the tumor arises pose a challenge for management (Garg et al.
from epithelial tissue, rather than from deeper 2014). Additionally, mucoceles that occur in the
tissues or metastatic process. It is also helpful to floor of the mouth may be treated with a non-
assess the invasive tumor front, which can provide surgical approach as surgery may render compli-
some prognostic information (Bankfalvi and cations (Garg et al. 2014). This is due to the close
Piffko 2000). Clinicians should avoid undertaking proximity to important structures like the subman-
a biopsy of necrotic tissues in ulcerated tumors, as dibular duct and lingual nerve and artery, which
the material is of less diagnostic value. In the case may be severed with surgery (Garg et al. 2014).
of an erythroleukoplakia, increased clinical suspi- For surgical excision, the site is anesthetized
cion is justified, as these are more likely to be with infiltration of local anesthesia, and an ellip-
dangerous compared to leukoplakia alone. In tical incision centered on the swelling is made
such cases, the erythematous area should be through the mucosa. The ellipse is undertaken
included in the biopsy sample. Samples should vertically along the axis of the nerve and vascular
be of a reasonable size to permit proper represen- supply of the lower lip. The mucocele, often blu-
tation and to allow accurate histopathological ish in color, is carefully dissected out using scis-
interpretation. Biopsies should be 8 x 6 mm in sors or a small vascular clip. Ideally, the mucocele
size and 3–4 mm in depth (Figs. 47 and 48). More is taken out together with the connected salivary
detail on surgical management of OPMD and gland but this is often not possible (Fig. 49). The
OSCC can be found in the dedicated chapter defect is sutured with resorbable 5–0 sutures.
▶ “Oral Mucosal Malignancies.” An alternative treatment option is sclerother-
apy using an intralesional injection of sclerozing
agent such as pingyangmycin, which causes invo-
Mucocele lution of the lesion (Cai et al. 2014). The effective
use of corticosteroids in the treatment of
A mucocele is often caused by trauma to the mucoceles has also been reported (Sinha et al.
minor salivary glands, usually of the lower lip. 2016). Another treatment option is cryotherapy.
Trauma causes the saliva to pool in the submuco- These alternatives to surgical excision have the
sal tissue (extravasation mucocele). Traditionally advantage of being less invasive, but frequently
Fig. 47 Incisional biopsy of keratotic lesion on the lower and an area of gain of fluorescence corresponding to the
left lip (a). Same lesion viewed with VELscope ® (b) dem- keratosis noted under white light. The lesion is marked
onstrating loss of fluorescence extending to the vermilion with surgical skin marker and incisions undertaken with
require more than one treatment visit to achieve processed as a fresh sample in saline or Michel’s
complete resolution of the lesion. solution, in order to preserve tissue-deposited
immunoglobulins. Michel’s solution contains
ammonium sulphate, N-ethyl-maleimide, potas-
Ranula sium citrate buffer, magnesium sulfate, and dis-
tilled water. Michel’s solution is preferred if a
Ranulas mostly originate from saliva extravasation sample cannot be processed within 24 h (Fischer
from the main duct of the sublingual salivary gland 2006). Saline is acceptable and seems to yield
resulting in a submucosal collection in the floor of more accurate immunofluorescence reactions,
the mouth. Ranulas are essentially pseudocysts as but samples must be processed (frozen) in the
they have no epithelial lining. Plunging ranulas laboratory within 24 h (Patel et al. 2013).
extend through the mylohyoid muscle causing a For vesiculobullous lesions, one must obtain
neck swelling. These should be removed together solid epithelium in which the immunofluores-
with the sublingual gland, but this is usually out- cence pattern can be observed. Typical flaws
side the scope of the oral medicine specialist, and would be to biopsy an ulcerated area, as this
particular care is needed so as not to damage the lacks any epithelium for immunofluorescence.
lingual nerve and submandibular duct. Conversely, for histopathology, it is mandatory
A ranula in the floor of the mouth can be treated to include the transition from normal epithelium
by simple marsupialization in the first instance. to bulla, as acantholysis or basement membrane
Local anesthesia is given around the lesion. As zone cleavage can be topographically observed.
the lesion will collapse soon after the first incision The best possible option would be to obtain the
is placed to marsupialize it, it is useful to delineate whole bulla in the sample, which in case of oral
the outline of the lesion with a marker pen. The lesions is virtually impossible. The sample should
roof of the lesion is removed with scalpel and be fixed in formalin.
scissors. The remainder of the lesion is left open. Desquamative gingivitis is seen as a conse-
If the lesion recurs, the entire lesion together with quence of many immune-mediated oral or muco-
the sublingual gland should be removed. Cryother- cutaneous conditions. One would usually suspect
apy can also be used to treat ranulas by clinicians mucous membrane pemphigoid, pemphigus
experienced with this procedure (Fig. 50). vulgaris, lichen planus, or some other bullous
condition. In case of desquamative gingivitis,
biopsy of the attached gingiva is required. This
Vesiculobullous Conditions may require use of an elevator to detach the gin-
giva from underlying periosteum. Care should be
If a vesiculobullous condition is suspected (pem- taken, as the tissue can easily tear.
phigus vulgaris, mucous membrane pemphigoid,
etc.) careful consideration should be given to
choose perilesional unaffected tissue for direct Orofacial Granulomatosis
immunofluorescence, and a sample from the
edge of the bulla (or erosion) for routine hema- When performing a biopsy in order to diagnose
toxylin and eosin histopathology. The first will be orofacial granulomatosis (OFG), the aim is to
Fig. 47 (continued) the tip of a No. 15 blade running which the sample is released completely (f). The edges of
parallel to the long axis of the lip (c). The edge of the the wound are then undermined with the tip of the blade (g)
specimen is released from the underlying tissues (d), and to allow better approximation of the wound edges. Gut
then the sample is carefully excised by running the blade sutures are placed at equal lengths to close the wound (h)
beneath the tissue and excising parallel to the lip (e), after
Fig. 48 Incisional biopsy of a lichenoid lesion on the dorsal underlying muscle (c). The first suture is placed by inserting
tongue. Incision lines are created (a), after which the edge of the needle at a 90 angle through one edge (d) of the wound
the lesion is lifted and grasped with a fine rat tooth tweezers and then through the second (e). The suture material is then
(b). The sample is then removed by placing the No. 15 blade pulled through (f) and a knot is tied (g). Other sutures are
beneath the lesion and excising parallel to the long axis of the placed until the wound is completely closed (h)
Fig. 49 Removal of mucocele. The mucosal tissues of the minor salivary gland tissues then also removed (b). The
lip are excised vertically (i.e., perpendicular to the long excised unruptured cyst with associated minor salivary
axis of the lip) (a) revealing the underlying cystic lesion. glands (c) in same orientation as that noted in image (a)
The cyst is removed without rupturing, and associated
Fig. 50 Ranula involving the floor of mouth of a 13-year- following cryotherapy treatment (b). (Used with permis-
old boy before cryotherapy (a). New orifice to submandib- sion from John Wiley & Sons; Farah and Savage 2006)
ular salivary gland has formed in the healing tissue
retrieve a specimen that contains non-caseating biopsy should always be performed in order to
granulomas, which are classically present and increase the likelihood of locating granuloma. In
diagnostic for the condition. One of the typical many cases, this would be a deep biopsy of the
clinical findings in OFG is enlargement of the lip affected lip. A large specimen is required, roughly
(cheilits granulomatosa). Very deep mucosal 10 mm deep and at least 5 mm in diameter.
Cylindrical sampling using a fully inserted blanches upon pressure application and show
5–6 mm punch is obtained for histopathology. characteristics of spontaneous or post trauma
Nevertheless, one may still miss frank and well- hemorrhage (Dilsiz et al. 2009). These lesions
organized granulomas. Instead of granuloma, his- are primarily cutaneous and involve the skin,
tological findings may show nonspecific inflam- lips, and deeper structures; mucosal, involving
mation including perivascular and interstitial the lining of the oral cavity; intramuscular, involv-
infiltrates of inflammatory cells composed of ing masticator and perioral muscles; or intra-
edema, lymphocytes, plasma cells, and mast osseous, involving the mandible and/or maxilla
cells in subepithelial stroma, which would also (Dilsiz et al. 2009).
fit the diagnosis of OFG. If OFG affects gingival Various treatment options have been presented
tissue as well, this should be chosen as the pre- for the treatment of vascular malformations
ferred biopsy site, since granulomas are identified including no treatment as some lesions may spon-
there in very high percentage (van der Waal et al. taneously regress (Dilsiz et al. 2009). Surgical
2002). excision is a commonly used technique and can
be carried out with relative ease for smaller
lesions; however, surgical excision for larger
Vascular Lesions lesions may pose a challenge as a wider surgical
approach is required leading to disfigurement
The oral medicine clinician will come across (Kocer et al. 2004; Dilsiz et al. 2009).
several types of vascular lesions ranging from Additionally, as these commonly occur in chil-
vascular malformations to hemangiomas. Heman- dren, a surgical approach is not ideal due to fear
giomas are usually treated in a specialist treatment and reluctance of the pediatric patient to undergo
center. Initially hemangiomas are usually surgery, when otherwise suitable alternative
observed, however, in selected indications, for approaches exist. Other treatment options include
example when the tumor interferes with vision oral corticosteroids, intralesional injection of
or the airway, treatment is considered. Treatment fibrozing agents, interferon α-2b, radiation,
can consist of intralesional or systemic corticoste- electrocoagulation laser therapy, embolization,
roids, interferon, or beta blockers. In some cases, and surgical excision (Silverman 1991; Dilsiz
the lesion is surgically excised. et al. 2009).
The most frequently encountered group of Cryotherapy is ideal for the management of
lesions in oral medicine practice is vascular vascular malformations as there is minimal dis-
malformations, of which lesions with a small turbance or trauma caused to the patient, making
dimension can potentially be treated by the oral it a viable treatment for the pediatric patient.
medicine specialists. Large lesions, especially Additionally, it has a low complication rate and
those with bone involvement, should be treated a predictable volume of tissue destruction. This
in a specialist center. is important especially when located near
Vascular malformations are common soft tis- structures that may cause complications as well
sue lesions that result from a benign proliferation as extensive superficial lesions. Furthermore,
and malformation of blood vessels (Silverman repetitive treatment cycles may be performed
1991; Dilsiz et al. 2009). They consist of progres- with no significant loss in time to the patient or
sively enlarging and aberrant vessels that take a pain. Additionally, it has a lower incidence of
diverse morphology ranging from arteries, veins, scarring that is important particularly in deeply
lymphatic vessels, venules, capillaries, or mixed functional and esthetic areas such as facial
type. They are named by their predominant vessel skin and anatomical sulci. Given the high success
type (Buckmiller et al. 2010). Clinically, they are rate of lesion resolution and the minimal
recognized as a soft, smooth/lobulated, sessile/ associated complications, cryotherapy is an
pedunculated mass of varying diameter. They excellent option for the management of vascular
may assume a pink/purplish red color that malformations.
Larger lesions can be treated with sclerother- thrombosing reaction (Horbach et al. 2016). Eth-
apy, which has a success rate of 70–100% (Costa anol is an effective agent with response rates of
et al. 2011). The inner lining of the vessels is 84–100%. However, sclerotherapy with ethanol is
damaged by the sclerozing agent. This causes an more painful compared to other agents and has a
inflammatory and thrombosing effect that leads to higher complication rate, due to its high toxicity
regression of the lesion (Costa et al. 2011). The (Odeyinde et al. 2013). Its nerve toxicity is also
procedure itself is fast and simple. There are, high (Horbach et al. 2016), which is an important
however, some potential side effects such as parameter to consider in the head and neck region.
pain, scarring, and necrosis (Costa et al. 2011). OK-432 or picibanil induces damage to the
Some lesions might require more than one inner lining of the vessel trough a localized
sclerozing treatment, while others can require sur- inflammatory response by triggering cytokines.
gery to fully remove the lesion (Costa et al. 2011). It is a derivate of the Streptococcus pyogenus
There are several sclerozing agents in use bacterium (Horbach et al. 2016). Reported
(Horbach et al. 2016). The most frequently used response varies from 50–95%. It is mostly
sclerozants in the head and neck area are applied in lymphatic malformations (Horbach
pingyangmycin, ethanol, ethanolamine oleate, et al. 2016). The literature on this subject is
OK-432, and bleomycin. Other sclerozants in use sparse. There is a great variation in treatment
are polidocanol, doxycycline, and sodium tetra- protocols, therefore it is difficult to advise on
decyl sulfate (Mishra et al. 2017). Pingyangmicin the optimal protocol for treating a vascular lesion
is chemically similar to bleomycin, the structural (Horbach et al. 2016).
difference being a terminal amine group. Both
agents have similar working mechanisms and
side-effects, the most serious being pulmonary Conclusions and Future Directions
fibrosis (Horbach et al. 2016). Pingyangmicin is
said to be more cost-effective and has few side The range of operative techniques and procedures
effects, reported response rate is 43–100% in available to the oral medicine specialists to help
venous malformations (Horbach et al. 2016). To diagnose and treat oral and maxillofacial condi-
prevent serious side effects such as pulmonary tions is wide-ranging and varied. These include
fibrosis, it is advised to keep the dosage under simple incisional biopsy techniques that most
1 mg/kg and limit injections to once a week clinicians are accustomed to performing, to more
(Zheng et al. 2009). Other side effects include invasive and complicated procedures such as wide
necrosis, ulceration, and nerve damage (Zheng local excision, sialendoscopy, or arthrocentesis.
et al. 2009; Horbach et al. 2016). For lesions The range of procedures undertaken by the oral
over 5 cm, other sclerozing agents such as ethanol medicine specialists should be based on their
are advised (Zheng et al. 2009). There are few training, expertise, and ability to manage resultant
comparative studies (Horbach et al. 2016). One consequences and complications. A multi-
study showed a statistical difference between disciplinary approach to management of malig-
intralesional injection of bleomycin and ethanol, nancy, bone pathology, or salivary gland
in favor of the latter agent (Zhang et al. 2013). pathology is always in the best interests of
Bleomycin has a higher rate of side-effects when patients. Clinicians wishing to partake in any
compared to ethanol. For low doses of bleomycin, operative procedure should receive advanced
no pulmonary side effects have been reported training, have access to suitable referral pathways
(Horbach et al. 2016). The reported response rate for managing complications, and practice within
of bleomycin injections in the head and neck area the scope of their training and expertise.
is 68–100% (Horbach et al. 2016). Careful manipulation of tissues, use of micro-
The working mechanism of ethanol consists of surgical principles, and adherence to general sur-
damaging the inner lining of the vessels by dena- gical standards are essential elements of
turing its cellular proteins thereby inducing a successful operative procedures. Use of
magnification and lighting should form the basis Bouchard C, Goulet JP, El-Ouazzani M, Turgeon AF.
of standard of care for surgical procedures of the Temporomandibular lavage versus nonsurgical treat-
ments for temporomandibular disorders: a systematic
oral cavity and maxillofacial region. Clinicians review and meta-analysis. J Oral Maxillofac Surg.
should only undertake operative procedures for 2017;75(7):1352–62.
diagnosis or treatment when it is in the best inter- Brands WG. The standard for the duty to inform patients
ests of their patients. Clinicians should also be about risks: from the responsible dentist to the reason-
able patient. Br Dent J. 2006;201(4):207–10.
prepared to develop their skills with evolving Brennan PA, Brands MT, Caldwell L, Fonseca FP,
technological advances. Turley N, Foley S, Rahimi S. Surgical specimen hand-
over from the operating theatre to laboratory-can we
improve patient safety by learning from aviation and
other high-risk organisations? J Oral Pathol Med.
Cross-References 2017;47:117–20.
Buckmiller LM, Richter GT, Suen JY. Diagnosis and man-
▶ Arthritic Conditions Affecting the Temporo- agement of hemangiomas and vascular malformations
mandibular Joint of the head and neck. Oral Dis. 2010;16(5):405–18.
Cai Y, Wang R, Yang SF, Zhao YF, Zhao JH. Sclerotherapy
▶ Clinical Evaluation of Oral Diseases for the mucoceles of the anterior lingual salivary glands
▶ Head and Neck Tumors with pingyangmycin. Oral Dis. 2014;20(5):473–6.
▶ Laboratory Medicine and Diagnostic Pathology Chen S, Forman M, Sadow PM, August M. The diagnostic
▶ Normal Variation in the Anatomy, Biology, and accuracy of incisional biopsy in the oral cavity. J Oral
Maxillofac Surg. 2016;74(5):959–64.
Histology of the Maxillofacial Region Costa JR, Torriani MA, Hosni ES, D'Avila OP, de Figuei-
▶ Oral Mucosal Malignancies redo PJ. Sclerotherapy for vascular malformations in
▶ Salivary Gland Disorders and Diseases the oral and maxillofacial region: treatment and follow-
up of 66 lesions. J Oral Maxillofac Surg. 2011;69(6):
e88–92.
De Veld DC, Witjes MJ, Sterenborg HJ, Roodenburg JL.
References The status of in vivo autofluorescence spectroscopy
and imaging for oral oncology. Oral Oncol. 2005;41
Alkan A, Etoz OA. A new anatomical landmark to simplify (2):117–31.
temporomandibular joint arthrocentesis. Br J Oral Delli K, Spijkervet FK, Vissink A. Salivary gland diseases:
Maxillofac Surg. 2010;48(4):310–1. infections, sialolithiasis and mucoceles. Monogr Oral
Baghani Z, Kadkhodazadeh M. Periodontal dressing: a Sci. 2014;24:135–48.
review article. J Dent Res Dent Clin Dent Prospects. Di Palma S, Simpson R, Skalova A, Leivo I. Major and
2013;7(4):183–91. minor salivary glands. In: Slootweg P, Cardesa A, edi-
Balasubramaniam AM, Sriraman R, Sindhuja P, tors. Pathology of the head and neck. Berlin/Heidel-
Mohideen K, Parameswar RA, Muhamed Haris KT. berg: Springer; 2006. p. 132–70.
Autofluorescence based diagnostic techniques for oral Dieterich-Miller CA, Safford PL. Psychosocial develop-
cancer. J Pharm Bioallied Sci. 2015;7(Suppl 2):S374–7. ment of children with hemangiomas: home, school,
Bankfalvi A, Piffko J. Prognostic and predictive factors in health care collaboration. Child Health Care. 1992;
oral cancer: the role of the invasive tumour front. J Oral 21(2):84–9.
Pathol Med. 2000;29(7):291–8. Dilsiz A, Aydin T, Gursan N. Capillary hemangioma as a
Baurmash HD. Mucoceles and ranulas. J Oral Maxillofac rare benign tumor of the oral cavity: a case report.
Surg. 2003;61(3):369–78. Cases J. 2009;2:8622.
Baust JG, Gage AA. The molecular basis of cryosurgery. Dost F, Do L, Farah CS. Lesion evaluation, screening and
BJU Int. 2005;95(9):1187–91. identification of oral neoplasia study: an assessment of
Belcher JM. A perspective on periodontal microsurgery. high-risk Australian populations. Community Dent
Int J Periodontics Restorative Dent. 2001;21(2):191–6. Oral Epidemiol. 2016;44(1):64–75.
Bhatia N, Matias MA, Farah CS. Assessment of a decision Dost F, Le Cao KA, Ford PJ, Farah CS. A retrospective
making protocol to improve the efficacy of analysis of clinical features of oral malignant and
VELscope™ in general dental practice: a prospective potentially malignant disorders with and without oral
evaluation. Oral Oncol. 2014;50(10):1012–9 epithelial dysplasia. Oral Surg Oral Med Oral Pathol
Bornstein MM, Winzap-Kalin C, Cochran DL, Buser D. Oral Radiol. 2013;116(6):725–33.
The CO2 laser for excisional biopsies of oral lesions: a Epstein JB, Oakley C, Millner A, Emerton S, van der
case series study. Int J Periodontics Restorative Dent. Meij E, Le N. The utility of toluidine blue application
2005;25(3):221–9. as a diagnostic aid in patients previously treated for
upper oropharyngeal carcinoma. Oral Surg Oral Med Hedge MC, Kamath PM, Shreedharan S, Dannana NK,
Oral Pathol Oral Radiol Endod. 1997;83(5):537–47. Raju RM. Supravital staining: It's role in detecting
Epstein JB, Scully C, Spinelli J. Toluidine blue and Lugol's early malignancies. Indian J Otolaryngol Head Neck
iodine application in the assessment of oral malignant Surg. 2006;58(1):31–4.
disease and lesions at risk of malignancy. J Oral Pathol Horbach SE, Rigter IM, Smitt JH, Reekers JA, Spuls PI,
Med. 1992;21(4):160–3. van der Horst CM. Intralesional bleomycin injections
Farah CS. Narrow band imaging-guided resection of oral for vascular malformations: a systematic review and
cavity cancer decreases local recurrence and increases meta-analysis. Plast Reconstr Surg. 2016;137(1):
survival. Oral Dis. 2018;24(1–2):89–97. 244–56.
Farah CS, Dalley AJ, Nguyen P, Batstone M, Iro H, Zenk J, Escudier MP, Nahlieli O, Capaccio P, Katz P,
Kordbacheh F, Perry-Keene J, Fielding D. Improved Brown J, McGurk M. Outcome of minimally invasive
surgical margin definition by narrow band imaging for management of salivary calculi in 4,691 patients.
resection of oral squamous cell carcinoma: a prospec- Laryngoscope. 2009;119(2):263–8.
tive gene expression profiling study. Head Neck. James K, Toner M, Stassen LF. Performing mucosal tissue
2016;38(6):832–9. biopsies in general dental practice. J Ir Dent Assoc.
Farah CS, Fox SA, Dalley AJ. Integrated miRNA-mRNA 2011;57(4):203–8.
spatial signature for oral squamous cell carcinoma: a Janssen AJ. Informing patients about small risks: a com-
prospective profiling study of narrow band imaging parative approach. Eur J Health Law. 2006;13(2):
guided resection. Sci Rep. 2018;8(1):823. 159–72.
Farah CS, Kordbacheh F, John K, Bennett N, Fox SA. Kawczyk-Krupka A, Waskowska J, Raczkowska-
Molecular classification of autofluorescence excision Siostrzonek A, Kosciarz-Grzesiok A, Kwiatek S,
margins in oral potentially malignant disorders. Oral Straszak D, Latos W, Koszowski R, Sieron A.
Dis. 2018;24(5):732–740. Comparison of cryotherapy and photodynamic therapy
Farah CS, McIntosh L, Georgiou A, McCullough MJ. in treatment of oral leukoplakia. Photodiagn Photodyn
Efficacy of tissue autofluorescence imaging Ther. 2012;9(2):148–55.
(VELScope) in the visualization of oral mucosal Kocer U, Ozdemir R, Tiftikcioglu YO, Karaaslan O. Soft
lesions. Head Neck. 2012;34(6):856–62. tissue hemangioma formation within a previously
Farah CS, Savage NW. Cryotherapy for treatment of oral excised intraosseous hemangioma site. J Craniofac
lesions. Aust Dent J. 2006;51(1):2–5. Surg. 2004;15(1):82–3.
Fischer EG. To fix or not to fix: Michel's is the solution. Int Kondori I, Mottin RW, Laskin DM. Accuracy of dentists in
J Surg Pathol. 2006;14(1):108. the clinical diagnosis of oral lesions. Quintessence Int.
Forman MS, Chuang SK, August M. The accuracy of 2011;42(7):575–7.
clinical diagnosis of oral lesions and patient-specific Kujan O, Pemberton MN, Schwarz M, Sloan P. Evaluation
risk factors that affect diagnosis. J Oral Maxillofac of an innovative oral brush for potential applications
Surg. 2015;73(10):1932–7. using liquid based cytology. J Oral Sci. 2018;60(1):
Fuller C, Camilon R, Nguyen S, Jennings J, Day T, Gilles- 45–50.
pie MB. Adjunctive diagnostic techniques for oral Kumaraswamy KL, Vidhya M, Rao PK, Mukunda A. Oral
lesions of unknown malignant potential: systematic biopsy: oral pathologist’s perspective. J Cancer Res
review with meta-analysis. Head Neck. 2015;37(5) Ther. 2012;8(2):192–8.
:755–62. Levy O, Topilski M, Brazowski E, Yaron M, Tishler M.
Gage AA, Baust J. Mechanisms of tissue injury in cryo- Sarcoidosis presenting as primary Sjogren’s syndrome.
surgery. Cryobiology. 1998;37(3):171–86. Isr Med Assoc J. 2001;3(1):63–4.
Gandolfo S, Pentenero M, Broccoletti R, Pagano M, Liboon J, Funkhouser W, Terris DJ. A comparison of
Carrozzo M, Scully C. Toluidine blue uptake in poten- mucosal incisions made by scalpel, CO2 laser,
tially malignant oral lesions in vivo: clinical and histo- electrocautery, and constant-voltage electrocautery.
logical assessment. Oral Oncol. 2006;42(1):89–95. Otolaryngol Head Neck Surg. 1997;116(3):379–85.
Garg A, Tripathi A, Chowdhry S, Sharma A, Biswas G. Lingen MW, Kalmar JR, Karrison T, Speight PM. Critical
Cryosurgery: painless and fearless management of evaluation of diagnostic aids for the detection of oral
mucocele in young patient. J Clin Diagn Res. 2014; cancer. Oral Oncol. 2008;44(1):10–22.
8(8):ZD04–6. Lynch DP, Morris LF. The oral mucosal punch biopsy:
Guarda-Nardini L, Manfredini D, Ferronato G. indications and technique. J Am Dent Assoc.
Arthrocentesis of the temporomandibular joint: a pro- 1990;121(1):145–9.
posal for a single-needle technique. Oral Surg Oral Med Macey R, Walsh T, Brocklehurst P, Kerr AR, Liu JL,
Oral Pathol Oral Radiol Endod. 2008;106(4):483–6. Lingen MW, Ogden GR, Warnakulasuriya S,
Gupta A, Singh M, Ibrahim R, Mehrotra R. Utility of Scully C. Diagnostic tests for oral cancer and poten-
toluidine blue staining and brush biopsy in precancer- tially malignant disorders in patients presenting with
ous and cancerous oral lesions. Acta Cytol. 2007; clinically evident lesions. Cochrane Database Syst Rev.
51(5):788–94. 2015;5:CD010276.
Mashberg A. Reevaluation of toluidine blue application as mucosal lesions. J Oral Maxillofac Surg. 2011;
a diagnostic adjunct in the detection of asymptomatic 69(1):125–33.
oral squamous carcinoma: a continuing prospective Pitiyage G, Tilakaratne WM, Tavassoli M,
study of oral cancer III. Cancer. 1980;46(4):758–63. Warnakulasuriya S. Molecular markers in oral epithe-
McGurk M, Escudier MP, Brown JE. Modern management lial dysplasia: review. J Oral Pathol Med. 2009;
of salivary calculi. Br J Surg. 2005;92(1):107–12. 38(10):737–52.
McIntosh L, McCullough MJ, Farah CS. The assessment Pogrel MA, McCracken KJ, Daniels TE. Histologic eval-
of diffused light illumination and acetic acid rinse uation of the width of soft tissue necrosis adjacent to
(Microlux/DL) in the visualisation of oral mucosal carbon dioxide laser incisions. Oral Surg Oral Med Oral
lesions. Oral Oncol. 2009;45(12):e227–31. Pathol. 1990;70(5):564–8.
Mehrotra R, Hullmann M, Smeets R, Reichert TE, Rashid A, Warnakulasuriya S. The use of light-based (opti-
Driemel O. Oral cytology revisited. J Oral Pathol cal) detection systems as adjuncts in the detection of
Med. 2009;38(2):161–6. oral cancer and oral potentially malignant disorders: a
Meleti M, Vescovi P, Mooi WJ, van der Waal I. Pigmented systematic review. J Oral Pathol Med. 2015;44(5):
lesions of the oral mucosa and perioral tissues: a flow- 307–28.
chart for the diagnosis and some recommendations for Reibel J. Prognosis of oral pre-malignant lesions: signifi-
the management. Oral Surg Oral Med Oral Pathol Oral cance of clinical, histopathological, and molecular bio-
Radiol Endod. 2008;105(5):606–16. logical characteristics. Crit Rev Oral Biol Med.
Melrose RJ, Handlers JP, Kerpel S, Summerlin DJ, Tomich 2003;14(1):47–62.
CJ, American Academy of Oral and Maxillofacial Rezende KM, Moraes Pde C, Oliveira LB, Thomaz LA,
Pathology. The use of biopsy in dental practice. The Junqueira JL, Bonecker M. Cryosurgery as an effective
position of the American Academy of oral and maxil- alternative for treatment of oral lesions in children.
lofacial pathology. Gen Dent. 2007;55(5):457–61; quiz Braz Dent J. 2014;25(4):352–6.
462–453, 488 Roodenburg JL, Witjes MJ, de Veld DC, Tan IB, Nauta JM.
Mishra M, Singh G, Gaur A, Tandon S, Singh A. Role of Lasers in dentistry 8. Use of lasers in oral and maxillo-
sclerotherapy in management of vascular malformation facial surgery. Ned Tijdschr Tandheelkd. 2002;
in the maxillofacial region: our experience. Natl J 109(12):470–4.
Maxillofac Surg. 2017;8(1):64–9. Sadiq Z, Moss C, Stocker J. Staining from silver nitrate. Br
Monje-Gil F, Nitzan D, Gonzalez-Garcia R. Temporoman- Dent J. 2002;193(6):299.
dibular joint arthrocentesis. Review of the literature. Sako K, Marchetta FC, Hayes RL. Cryotherapy of intraoral
Med Oral Patol Oral Cir Bucal. 2012;17(4):e575–81. leukoplakia. Am J Surg. 1972;124(4):482–4.
Moralis A, Kunkel M, Reichert TE, Kosmehl H, Saruhanoglu A, Atikler M, Ergun S, Ofluoglu D,
Driemel O. Identification of a recurrent oral squamous Tanyeri H. Comparison of two different labial salivary
cell carcinoma by brush cytology. Mund Kiefer gland biopsy incision techniques: a randomized clinical
Gesichtschir. 2007;11(6):355–8. trial. Med Oral Patol Oral Cir Bucal. 2013;18(6):
Moule I, Parsons PA, Irvine GH. Avoiding artefacts in oral e851–5.
biopsies: the punch biopsy versus the incisional biopsy. Schoinohoriti OK, Chrysomali E, Iatrou I, Perrea
Br J Oral Maxillofac Surg. 1995;33(4):244–7. D. Evaluation of lateral thermal damage and
Neeli AS, Umarani M, Kotrashetti SM, Baliga S. reepithelialization of incisional wounds created by
Arthrocentesis for the treatment of internal derange- CO2-laser, monopolar electrosurgery, and radiosur-
ment of the temporomandibular joint. J Maxillofac gery: a pilot study on porcine oral mucosa. Oral
Oral Surg. 2010;9(4):350–4. Surg Oral Med Oral Pathol Oral Radiol. 2012;113(6):
Nelson WJ. Guide to suturing. J Oral Maxillofac Surg. 741–7.
2015;73(8 Suppl):1–62. Sciubba JJ. Improving detection of precancerous and can-
Odeyinde SO, Kangesu L, Badran M. Sclerotherapy for cerous oral lesions. Computer-assisted analysis of the
vascular malformations: complications and a review of oral brush biopsy. U.S. Collaborative OralCDx Study
techniques to avoid them. J Plast Reconstr Aesthet Group. J Am Dent Assoc. 1999;130(10):1445–57.
Surg. 2013;66(2):215–23. Sekine J, Nakatani E, Hideshima K, Iwahashi T, Sasaki H.
Oliver RJ, Sloan P, Pemberton MN. Oral biopsies: methods Diagnostic accuracy of oral cancer cytology in a pilot
and applications. Br Dent J. 2004;196(6):329–33; quiz study. Diagn Pathol. 2017;12(1):27.
362 Seoane J, Varela-Centelles P, Ramirez JR, Romero MA, De
Patel AN, Simpson RC, Cohen SN. In a patient with an La Cruz A. Artefacts produced by suture traction dur-
immunobullous disorder, is transportation of the skin ing incisional biopsy of oral lesions. Clin Otolaryngol
biopsy in normal saline adequate for direct immunoflu- Allied Sci. 2002;27(6):549–53.
orescence analysis? A critically appraised topic. Br J Seoane J, Varela-Centelles PI, Ramirez JR, Cameselle-
Dermatol. 2013;169(1):6–10. Teijeiro J, Romero MA. Artefacts in oral incisional
Patel KJ, De Silva HL, Tong DC, Love RM. Concordance biopsies in general dental practice: a pathology audit.
between clinical and histopathologic diagnoses of oral Oral Dis. 2004;10(2):113–7.
Shokrollahi K, Raymond E, Murison MSC. Lasers: prin- Tuncer I, Ozcakir-Tomruk C, Sencift K, Cologlu S.
ciples and surgical applications. J Surg. 2004;2(2): Comparison of conventional surgery and CO2 laser
28–34. on intraoral soft tissue pathologies and evaluation of
Silverman EB, Read RW, Boyle CR, Cooper R, Miller the collateral thermal damage. Photomed Laser Surg.
WW, McLaughlin RM. Histologic comparison of 2010;28(1):75–9.
canine skin biopsies collected using monopolar elec- van der Hem PS, Nauta JM, van der Wal JE, Roodenburg
trosurgery, CO2 laser, radiowave radiosurgery, skin JL. The results of CO2 laser surgery in patients with
biopsy punch, and scalpel. Vet Surg. 2007;36(1):50–6. oral leukoplakia: a 25 year follow up. Oral Oncol.
Silverman RA. Hemangiomas and vascular malformations. 2005;41(1):31–7.
Pediatr Clin N Am. 1991;38(4):811–34. van der Waal I. Potentially malignant disorders of the oral
Singh Nanda KD, Mehta A, Nanda J. Fine-needle aspira- and oropharyngeal mucosa; present concepts of man-
tion cytology: a reliable tool in the diagnosis of salivary agement. Oral Oncol. 2010;46(6):423–5.
gland lesions. J Oral Pathol Med. 2012;41(1):106–12. van der Waal RI, Schulten EA, van der Meij EH, van de
Sinha R, Sarkar S, Khaitan T, Kabiraj A, Maji A. Scheur MR, Starink TM, van der Waal I. Cheilitis
Nonsurgical Management of Oral Mucocele by granulomatosa: overview of 13 patients with long-
Intralesional Corticosteroid Therapy. Int J Dent. term follow-up – results of management. Int J
2016;2016:2896748. Dermatol. 2002;41(4):225–9.
Sinha UK, Gallagher LA. Effects of steel scalpel, ultra- Vesnaver A, Dovsak DA. Treatment of vascular lesions
sonic scalpel, CO2 laser, and monopolar and bipolar in the head and neck using Nd:YAG laser.
electrosurgery on wound healing in guinea pig oral J Craniomaxillofac Surg. 2006;34(1):17–24.
mucosa. Laryngoscope. 2003;113(2):228–36. Vu A, Farah CS. Narrow band imaging: clinical applica-
Sperandio M, Klinikowski MF, Brown AL, Shirlaw PJ, tions in oral and oropharyngeal cancer. Oral Dis.
Challacombe SJ, Morgan PR, Warnakulasuriya S, 2016;22(5):383–90.
Odell EW. Image-based DNA ploidy analysis aids pre- Vu AN, Farah CS. Efficacy of narrow band imaging for
diction of malignant transformation in oral lichen detection and surveillance of potentially malignant and
planus. Oral Surg Oral Med Oral Pathol Oral Radiol. malignant lesions in the oral cavity and oropharynx: a
2016;121(6):643–50. systematic review. Oral Oncol. 2014;50(5):413–20.
Sridharan G, Shankar AA. Toluidine blue: a review of its Vu AN, Matias M, Farah CS. Diagnostic accuracy of
chemistry and clinical utility. J Oral Maxillofac Pathol. Narrow Band Imaging for the detection of oral poten-
2012;16(2):251–5. tially malignant disorders. Oral Dis. 2015;21(4):
Stanley MW. Selected problems in fine needle aspiration of 519–29.
head and neck masses. Mod Pathol. 2002;15(3): Yeh CJ. Simple cryosurgical treatment for oral lesions. Int J
342–50. Oral Maxillofac Surg. 2000;29(3):212–6.
Suter VG, Altermatt HJ, Bornstein MM. A randomized Yu CH, Lin HP, Cheng SJ, Sun A, Chen HM. Cryotherapy
controlled clinical and histopathological trial compar- for oral precancers and cancers. J Formos Med Assoc.
ing excisional biopsies of oral fibrous hyperplasias 2014;113(5):272–7.
using CO2 and Er:YAG laser. Lasers Med Sci. Zhang J, Li HB, Zhou SY, Chen KS, Niu CQ, Tan XY,
2017;32(3):573–81. Jiang YZ, Lin QQ. Comparison between absolute eth-
Suter VG, Altermatt HJ, Dietrich T, Reichart PA, Bornstein anol and bleomycin for the treatment of venous mal-
MM. Does a pulsed mode offer advantages over a formation in children. Exp Ther Med. 2013;6(2):
continuous wave mode for excisional biopsies 305–9.
performed using a carbon dioxide laser? J Oral Zheng JW, Yang XJ, Wang YA, He Y, Ye WM, Zhang ZY.
Maxillofac Surg. 2012;70(8):1781–8. Intralesional injection of Pingyangmycin for vascular
Tozoglu S, Al-Belasy FA, Dolwick MF. A review of tech- malformations in oral and maxillofacial regions: an
niques of lysis and lavage of the TMJ. Br J Oral evaluation of 297 consecutive patients. Oral Oncol.
Maxillofac Surg. 2011;49(4):302–9. 2009;45(10):872–6.
Pharmacotherapeutic Approaches in
Oral Medicine
Sandra Goncalves, Ray A. Dionne, Geraldine Moses, and

Marco Carrozzo
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402
Pharmacological Profiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403
Antibacterials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403
Antiseptics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405
Salivary Substitutes and Sialogogues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
Antifungals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408
Antiviral Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413
Glucocorticoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415
Immunosuppressive and Anti–inflammatory Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421
Biologic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
Therapeutic Protocols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429
Oral Candidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429
Primary and Recurrent Herpes Simplex Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430
Herpes Zoster . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430
S. Goncalves
Oral Medicine Department, Charles Clifford Dental
Hospital, Sheffield, UK
e-mail: Sandra.Goncalves@nuth.nhs.uk
R. A. Dionne
Department of Pharmacology and Toxicology, Brody
School of Medicine, and Department of Foundational
Sciences, School of Dental Medicine, East Carolina
University, Greenville, NC, USA
e-mail: dionner@ecu.edu
G. Moses
Academic Practice Unit, Pharmacy Services, Mater Public
Hospital, South Brisbane, QLD, Australia
e-mail: Geraldine.moses@mater.org.au
M. Carrozzo (*)
Center for Oral Health Research, Department of Oral
Medicine, School of Dental Sciences, Newcastle
University, Newcastle upon Tyne, UK
e-mail: Marco.Carrozzo@newcastle.ac.uk

https://doi.org/10.1007/978-3-319-72303-7_11
402 S. Goncalves et al.
HSV-Induced Erythema Multiforme . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431

Recurrent Aphthous Stomatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431
Erythema Multiforme . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431
Oral Lichen Planus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434
Mucous Membrane Pemphigoid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434
Pemphigus Vulgaris . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437
Orofacial Pain Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437
Peripheral and Central Mechanisms of Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437
Drugs for Management of Chronic Orofacial Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 440
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462
Abstract Introduction
While the management of oral and maxillofa-
cial diseases continues to progress, clinicians Oral medicine is a rapidly evolving specialty. One
continue to use a constantly expanding range of the most exciting and progressive changes in
of medications and thus must be aware of oral medicine has certainly been the medical man-
their adverse effects, interactions, and dosages. agement of oral diseases. It is worthwhile to
The aim of this chapter is to provide a remember that a sound management plan starts
concise and evidence-based guide to the from a solid, accurate, and well-considered diag-
pharmacotherapeutic management of common nosis, as a common reason for therapeutic failure
oral and maxillofacial diseases. It must is incorrect diagnosis. Another important princi-
be acknowledged however, that in many ple of therapy is to address the patient as a whole,
instances, prescriptions for oral medicine con- remembering that one of the fundamentals of ther-
ditions are used off-label, and mostly based on apy is to avoid harm to the patient. Communica-
expert opinion and experience. This chapter is tion is also paramount, as the clinician should
divided into three sections. Firstly, it will dis- explain both the advantages and disadvantages
cuss the principal pharmacological profile of of different treatment strategies in understandable
topical and systemic antibacterials, antiseptics, lay language. For complex disorders, cooperation
salivary substitutes and sialogogues, antifun- and consultation with various allied specialties is
gals, antivirals, immunosuppressive, anti- generally useful and encouraged. The aim of this
inflammatory, and biologic drugs. Secondly, chapter is to provide a concise, and where feasi-
concise therapeutic protocols will give clini- ble, evidence-based guide to the management of
cians practical guidance on the management oral diseases. To achieve this scope, this chapter
of the most common oral diseases treated in relies mostly on the outcome of systematic
oral medicine. The final part of this chapter reviews and meta-analyses. However, since a sig-
discusses the main drugs used for the manage- nificant portion of medications used in oral med-
ment of orofacial pain. icine do not have official indication for use in the
oral cavity, and randomized-controlled trials
Keywords (RCTs) are still relatively scarce, an attempt has
Pharmacotherapeutics · Oral medicine · been made to be practical and outline therapeutic
Topical and systemic · Antibacterial · guidance accordingly.
Antiseptics · Salivary substitutes · The first section of this chapter discusses the
Sialogogues · Antifungals · Antivirals · principal pharmacological profile of commonly
Immunosuppressive · Anti-inflammatory · used medications in oral medicine including top-
Biologics drugs · Facial pain ical and systemic antibacterials, antiseptics,
Pharmacotherapeutic Approaches in Oral Medicine 403
salivary substitutes and sialogogues, antifungals, 2013). Oral penicillins are absorbed from the
antivirals, immunosuppressives, anti-inflamma- upper gastrointestinal tract, although the rate of
tory agents, and biologic drugs. A section follows absorption is dependent upon their stability in the
this on concise therapeutic protocols aimed at acidic environment of the stomach and the pres-
providing the clinician with practical guidance ence of food (Seymour and Hogg 2008).
on the management of the most common oral This first penicillin was designated benzylpe-
and maxillofacial diseases treated in oral medi- nicillin (Penicillin G) and is very active against
cine. The final part of this chapter discusses gram-positive cocci that frequently cause oral,
the main drugs used for the management of pharyngeal, and pulmonary infections, as well as
orofacial pain. against Neisseria gonorrheae and Treponema
pallidum. Indeed, penicillin G is still a first-line
agent for treating the two most common venereal
Pharmacological Profiles diseases, syphilis and gonorrhea, that can cause
lesions localized in the oral cavity. For primary
Antibacterials and secondary syphilis, penicillin G 2.4 million
units intramuscularly is given once. In penicillin-
Antibacterial medications are those used for the allergic patients, tetracycline, 500 mg orally four
treatment of infections caused by bacteria. Fortu- times daily for 14 days, or doxycycline, 100 mg
nately, microorganisms associated with oral infec- orally twice for 14 days, can be prescribed
tions are well characterized, and a relatively small (Ficarra and Carlos 2009). Penicillins and cepha-
number of antimicrobial agents are required to losporins are generally well tolerated but can
effectively manage dental infections. Antibiotics cause hypersensitivity reactions even if genuine
should not be used indiscriminately, as prolonged IgE-mediated allergic reactions are not common
courses of antibiotic treatment can facilitate the (Stern 2012). Other unwanted effects include diar-
development of drug resistance. Therefore, the rhea, which seems to be more prevalent with
prescribing of antibiotics must be kept to a mini- usage of the broad-spectrum agents. Persistent
mum and used only when there is a clear indica- diarrhea should be investigated for possible anti-
tion and need. The emergence and spread of biotic colitis.
antibiotic resistance is a global concern and a Ampicillin was the first derivative of penicillin
major threat to public health. The use of broad- to have an extended spectrum that includes sev-
spectrum antibiotics has also been associated with eral gram-negative bacteria, such as Hemophilus
the rise in Clostridium dificile–associated disease influenza, that can cause maxillary sinus infec-
observed in both primary and secondary care tions. Amoxicillin has the identical spectrum of
(Beacher et al. 2015). Antibiotics used in oral activity of ampicillin, but exhibits greater oral
medicine can be broadly categorized into a few bioavailability, as absorption is not affected by
classes namely beta-lactam derivatives (penicil- food, and longer half-life. Amoxicillin is com-
lins and cephalosporins), macrolides, tetracy- monly prescribed for odontogenic and oropharyn-
clines, nitroimidazoles, and lincosamides. geal infections at doses varying from 1.5 g daily
up to 3 g daily in a titrated manner (250–500 mg
Beta-Lactam Derivatives every 8 h), according to the severity of signs and
The molecular structures of beta-lactam deriva- symptoms (Becker 2013). Duration of therapy is
tives (penicillins and cephalosporins) have in generally 5–7 days.
common a β-lactam ring that accounts for their Ampicillin and amoxicillin are not β-lactamase
antibacterial ability to inhibit cell wall synthesis in stable and are available in formulations that
susceptible microorganisms. However, this is also include so-called beta-lactamase inhibitors,
the target for resistant species, such as Staphylo- sulbactam and clavulanic acid, respectively. The
coccus aureus and Haemophilus influenzae that combination of amoxicillin and clavulanic acid
produce a variety of beta-lactamases (Becker (250 mg every 8 h for 5 days) can be used for
severe refractory odontogenic and periodontal little activity against periodontal pathogens, and
infections with spreading cellulitis, or sinus infec- in recent years, their activity against streptococcal
tions that can become colonized by penicillin- species has declined (Becker 2013). Nausea,
resistant Bacteroides and Prevotella species or vomiting, and diarrhea are common and signifi-
Hemophilus influenza. Various formulations of cant unwanted effects, particularly associated
amoxicillin and clavulanic acid are available with erythromycin, whereas roxithromycin,
including 500 mg amoxycillin and 125 mg azithromycin, and clarithromycin are better toler-
clavulanic acid, or 875 mg amoxycillin and ated (Seymour and Hogg 2008). All macrolides
125 mg clavulanic acid. Flucloxacillin is a are associated with increased risk of cardiac
β-lactamase-resistant penicillin (Seymour and arrhythmias due to QT prolongation in susceptible
Hogg 2008) that can be used to treat osteomyelitis patients (Becker 2013). The risk becomes partic-
of the jaw. ularly significant when a macrolide is added to a
Cephalosporins can generally be used in regimen of other drugs associated with QT pro-
patients allergic to penicillin. Although cross- longation, as the risk becomes cumulative. These
reactive allergy between penicillins and cephalo- drugs should never be added to a patient’s regi-
sporins is rare, it may occur when they share men without first checking for pharmacodynamic
similar side chains. Cross-reaction within the and pharmacokinetic interactions.
cephalosporin group is also very rare and as such
patients should not be labelled “cephalosporin- Lincosamides
allergic.” A history of a penicillin allergy should Lincosamides are structurally similar to macro-
not rule out the use of cephalosporins, and a lides and have the same mode of action.
history of a specific cephalosporin allergy should Clindamycin indeed binds to the 50S subunit of
not rule out the use of other cephalosporins bacterial ribosomes to suppress protein synthesis
(Yuson et al. 2018). Cephalosporins are also but, unlike the macrolides, it is bacteriocidal
active against Staphylococcus aureus and certain (Becker 2013) and has a longer half-life (21 h)
agents have pharmacokinetic advantages that (Seymour and Hogg 2008). Clindamycin is
allow less frequent dosing; however, they are active against gram-positive cocci, including
rarely indicated for oral infections (Becker 2013). many penicillin-resistant staphylococci, and
anaerobic species such as Bacteroides species.
Macrolides It can be used if the patient has not responded
Macrolide antibiotics exert their antibacterial to amoxicillin or metronidazole. It should be
action by binding to the 50S ribosomal subunit noted that clindamycin has previously been con-
of susceptible organisms, resulting in inhibition of sidered one of the principle causes of serious
protein synthesis (Seymour and Hogg 2008 adverse effects of Clostridium difficile-associ-
Becker 2013). Erythromycin was the first proto- ated colitis. However, there is now good evi-
typic macrolide and has been in clinical use for dence that all broad-spectrum antibiotics carry
some 40 years. Newer macrolides include risk for C. difficile infection and the risk is
azithromycin, roxithromycin, and clarithromycin. equally high for third and fourth generation
All the macrolide-related compounds are avail- cephalosporins, quinolones, and lincosamides
able for oral use and clarithromycin is also avail- (Clifford McDonald et al. 2018). If diarrhea
able as an intravenous infusion (Seymour and develops, the drug should be stopped immedi-
Hogg 2008). All macrolides are well absorbed ately, and the patient should be carefully moni-
from the gastrointestinal tract and diffuse readily tored for resolution of diarrhea. If it persists for
into most tissues. Macrolides have been pre- more than 2 days, then the patient should be
scribed historically as an alternative for patients referred to a gastroenterologist. Clindamycin
allergic to penicillin because they were thought to (150 mg four times a day) can be used for the
have reasonable activity against most penicillin- treatment of dento-alveolar abscess resistant to
sensitive microbes. However, macrolides have amoxicillin and metronidazole.
Tetracyclines (Seymour and Hogg 2008). Metronidazole is a

Tetracyclines are a group of broad-spectrum antibi- prodrug that is converted to a toxic radical within
otics that are bacteriostatic and exert their antimi- anaerobic microbes. The radical destroys existing
crobial effect by binding to the 30S subunit of the DNA and other vital compounds, rendering it
bacterial ribosome to inhibit protein synthesis bactericidal against most anaerobic organisms.
(Becker 2013). Microbial resistance to tetracyclines For this reason, it is very useful for treating severe
has increased to the extent that they are seldom first- odontogenic and periodontal infections (Becker
line agents for medically treated infections. In den- 2013). Metronidazole is a useful alternative to
tal practice, tetracyclines are useful adjuncts for penicillin for the treatment of oral infections
managing periodontal infections as they are highly particularly caused by β-lactamase-producing
active against many of the microorganisms impli- anerobes. It is also the drug of first choice for the
cated in gingival and periodontal disease and treatment of acute necrotizing ulcerative gingivi-
exhibit high bioavailability in the gingival sulcus tis and pericoronitis. Metronidazole can also be
(Becker 2013). Tetracycline and minocycline also used as an adjunct to amoxicillin in patients with
have some anti-inflammatory properties. Doxycy- spreading infection or pyrexia (SDCEP 2016).
cline and minocycline are generally preferred for The drug is well absorbed after oral administration
treatment of periodontal infections. Hypersensitiv- and a mean peak plasma concentration is pro-
ity reactions are rarely encountered with tetracy- duced in 1–2 h. The plasma half-life is 8 h (Sey-
clines but they can cause dental, oral, and skin mour and Hogg 2008). Numerous adverse effects
blue-gray pigmentation. Photosensitivity is a recog- have been associated with metronidazole use.
nized unwanted effect of tetracycline, and patients These are commonly gastrointestinal, notably
should avoid sun-bedding and excessive sun nausea, vomiting, dyspepsia, diarrhea, and consti-
exposure when taking these antibiotics. Rare pation. Furthermore, rare but serious psychiatric
but serious adverse effects also associated with side effects including acute agitation, confusion,
tetracyclines include benign intracranial hyper- and akathisia, with neurological side effects
tension and liver dysfunction. Subantimicrobial including seizures and peripheral neuropathy,
doses of doxycycline (20 mg twice a day for can also rarely occur, especially in children
3–9 months) is the only systemic host response (Kuriyama et al. 2011). It is not unusual for the
modulator specifically indicated as an adjunctive patient to complain of a bitter, metallic taste. Skin
treatment for periodontitis, and it has been rashes are rare. Metronidazole delays the metab-
approved by the US Food and Drug Administra- olism of warfarin and must always be avoided.
tion (FDA), the UK Medicines and Healthcare Patients prescribed metronidazole and tinidazole
products Regulatory Agency, and by similar should always be advised to avoid alcohol
agencies in other countries throughout the throughout treatment as these drugs impair the
world (Preshaw 2008). metabolism of alcohol and can cause the
so-called “disulfiram reaction” from the accumu-
Nitroimidazoles lation of acetaldehyde. The usual dosage of met-
The discovery of nitroimidazole antibiotics dates ronidazole for oral infections is 200 mg three
back to the early 1950s when azomycin, a times a day for 3 days. More severe infections
2-nitroimidazole, was first isolated from a crude may require a higher dosage (400 mg twice a
extract of Streptomyces bacteria (Ang et al. 2017). day) for a period of 5 days (Seymour and Hogg
Nitroimidazoles are a class of antimicrobial drugs 2008).
that have remarkable broad-spectrum activity
against parasites, mycobacteria, and anaerobic
Gram-positive and Gram-negative bacteria. Antiseptics
One compound, 1-(b-hydroxyethyl)-2-methyl-5-
nitroimidazole, now called metronidazole, Due to the growing issue of antibiotic resistance,
was originally used as an antiprotozoal agent antiseptics such as chlorhexidine and povidone
iodine appear to be suitable candidates as alterna- also available as a spray formulation (0.12–0.2%),
tive or adjunctive agents to antibiotics to prevent or as a dental gel (0.12–1%) for application to
and treat infections in general oral health settings teeth or recurrent aphthous ulcers, and as a dental
(Slots 2012). Antiseptics are especially important varnish (1%, 10%, 40%) to be used in dental
in the treatment of biofilm infections, which may caries prophylaxis. CHX can also be found in
be unresponsive even to high concentrations of toothpastes, gels for cleaning teeth and dental
antibiotics. Oral antiseptics can potentially not flosses. CHX can have impact in the treatment of
only improve gingival and oral health but also be halitosis, especially in reducing the levels of
of aid in serious medical conditions, such as anaerobic bacteria related with bad breath
ventilator-associated pneumonia (VAP) and endo- (Fedorowicz et al. 2008). Oral hygiene care,
carditis (Elshibly et al. 2014; Hua et al. 2016). including CHX mouthwash or gel, reduces the
risk of developing ventilator-associated pneumo-
Chlorhexidine nia in critically ill patients but does not seem to
Chlorhexidine (CHX), a bisbiguanide antiseptic influence the outcomes of mortality, duration of
is used extensively in dental and medical treat- mechanical ventilation, or duration of intensive
ment. CHX was developed in the 1940s and care unit stay (Hua et al. 2016).
marketed as a topical antiseptic for skin wounds
in 1954. CHX was later employed in obstetrics, Iodine
gynecology, and urology. In dentistry, CHX was Iodine is a bactericidal, fungicidal, and virucidal
initially used in endodontics and for presurgical agent. Iodine is widely used in hospitals for the
disinfection of the mouth (Slots 2012). CHX disinfection of skin and mucous membranes
exerts broad activity against bacteria, mainly before surgery, for cleansing open wounds, for
Gram-positive, fungi, and lipophilic viruses adjunctive burn treatment, and for the treatment
(such as HSV, HIV, CMV and influenza virus), of vaginitis (Slots 2012). Aqueous and alcohol
and it may be sporicidal at elevated temperatures solutions of iodine have been employed as dental
(Karpinski and Szkaradkiewicz 2015). The anti- antiseptics since the last century, but early iodine
microbial effect of CHX is dose-dependent. CHX formulations caused surface staining and irritation
at low concentrations (0.02–0.06%) has bacterio- of mucosa and skin (Slots 2012). Iodophors devel-
static activity whereas at higher concentrations oped in the 1950s largely overcame these negative
(>0.12%) acts as a bactericidal (Jenkins et al. aspects of iodine formulations (Selvaggi et al.
1988). Common adverse effects of CHX are 2003). Iodophors are 7.5–10% solutions of iodine
brown discoloration of the teeth and tongue, and complexed with an organic carrier, such as
temporary taste alterations (Karpinski and povidone, to provide controlled release of iodine.
Szkaradkiewicz 2015). Excessive concentrations The most common commercial form of povidone-
of CHX can also produce oral mucosal burns. iodine is a 10% solution in water. Povidone-iodine
Allergic reactions from CHX are rare, but when has bactericidal effect similar to that of pure
they do occur, may be severe especially in the iodine and is effective against most bacteria
perioperative setting where exposure may arise including putative periodontal pathogens, fungi,
from equipment soaked in chlorhexidine (Krishna mycobacteria, viruses, and protozoa (Schreier
et al. 2014). Anaphylaxis as a consequence of et al. 1997). Differently from CHX, povidone-
chlorhexidine-containing mouthwash used as iodine does not show cytotoxic effects on human
irrigation solution for treating dry socket has cells (Niedner 1997). Povidone-iodine can cause
been reported and is possibly under-reported allergic reactions, mainly in patients with a history
(Pemberton 2016). Very robust evidence has con- of allergy to iodine or shellfish. As prolonged
firmed the antiplaque and antigingivitis effects of iodide intake may inhibit synthesis of the thyroid
CHX (James et al. 2017). CHX gluconate is used hormone and cause goiter, myxedema, or hyper-
in dentistry as a 0.12–0.2% mouthwash applied in thyroidism, povidone-iodine should not be used
a volume of 15 ml for 30 s, twice a day. CHX is routinely in patients with thyroid dysfunction
(Slots 2012). Studies have shown an improvement Where residual salivary gland function remains,
in the periodontal status after treatment with saliva stimulants or sialogogues may also be con-
povidone-iodine. Moreover, the American Heart sidered (Dost and Farah 2013).
Association and the American Dental Association
have recommended rinsing periodontal sites with Salivary Substitutes and Oral Lubricants
povidone-iodine before dental-invasive proce- A recent Cochrane review concluded that there
dures to reduce the risk of bacteremia (Dajani was no evidence to suggest that any commercial
et al. 1997). saliva substitute was effective in relieving symp-
toms associated with salivary gland hypofunction
(Furness et al. 2011). However, oral health pro-
Salivary Substitutes and Sialogogues fessionals and patients routinely use topical
agents for xerostomia management, and in this
Saliva plays an important role in maintaining oral chapter, we provide some helpful guidance with-
health and function (Humphrey and Williamson out an intent to be exhaustive. Frequent sipping of
2001). Salivary glands secrete approximately water, along with avoidance of certain foods,
0.6 L/day of a complex fluid from the major alcohol, and caffeine alleviate xerostomia to an
salivary glands (the parotid, submandibular, and acceptable level. Natural lubricants such as olive
sublingual glands) which accounts for about 90% oil and milk can provide some benefit.
of the saliva production whereas 10% is derived Commercial oral lubricants use chemicals of
from minor salivary glands. The salivary flow rate high viscosity to mimic the physical properties of
has a circadian variation with a peak in the late natural saliva. Carboxymethylcellulose, a water-
afternoon. The parotid glands produce a watery, soluble polymer, is commonly used in pharma-
serous saliva rich in amylase and proline-rich pro- ceuticals as a suspension matrix, otherwise
teins, whereas the other glands produce a mixed, hydroxyethylcellulose is used (Dost and Farah
more viscoelastic saliva containing greater 2013; Villa et al. 2015).
amounts of mucin. Saliva substitutes that include antimicrobial
Xerostomia is the chronic and subjective sen- agents and have potentially some remineralization
sation of dry mouth (Dost and Farah 2013). In and buffering capabilities should be favored over
most cases, the condition is the result of salivary oral lubricants that provide only symptomatic
gland hypofunction, most commonly induced by relief. The combination of lactoferrin, lysozyme,
medications or caused by systemic conditions, and lactoperoxidase incorporates antimicrobials
such as Sjogren’s syndrome and type 2 diabetes found naturally in human saliva and has
or head and neck irradiation. Several other disor- been utilized by several drug companies to pro-
ders, particularly connective tissue disorders such duce salivary substitutes (e.g., Biotene;
as rheumatoid arthritis or systemic lupus GlaxoSmithKline, BioXtra; Bio-X Healthcare
erythematosus, or infectious agents such as hepa- and Oral7; Pharma777 Ltd) (Dost and Farah
titis C virus, may also trigger salivary gland hypo- 2013). In dentate patients, care must be taken as
function (von Bultzingslowen et al. 2007). some preparations such as Glandosane artificial
Alternatively, xerostomia may be experienced in saliva spray (TM Glandosane, Fresenius Kabi,
the absence of salivary gland hypofunction and Runcorn, England) have an acidic pH and
reduced saliva flow. repeated use can result in noncarious tooth surface
Even without precise epidemiological data, it loss. Other preparations (for example, Saliva
is estimated that 30% of the general population Orthana™ spray) are not acidic and contain fluo-
suffers from xerostomia, which significantly ride but they contain porcine mucin (Carr et al.
impacts on quality of life (Thomson et al. 2006). 2012). Animal mucin is usually added to decrease
Management of xerostomia is mostly palliative the carboxymethylcellulose content and the vis-
and consists largely of topical therapies mainly cosity/surface tension of artificial saliva (Levine
based on saliva substitutes and oral lubricants. et al. 1987). Salivary substitutes are available in
several formulations as gel, spray, suspension, or is normally given in doses of 30 mg up to three

mucoadhesive lipid-based bioerodable tablet. times a day for at least 3 months (von
Patient preference varies and will dictate the Bultzingslowen et al. 2007). Side-effects and
most effective preparation because, as already safety profile are similar to pilocarpine and there
stated, no agent has shown to be superior to is no evidence that medically compromised indi-
others. viduals tolerate cevimeline better (Grisius 2001).
Sialogogues
A topical sialogogue spray containing 1% malic Antifungals
acid may be of benefit for xerostomic patients,
although it can potentially lead to enamel erosion The management of oral candidosis requires iden-
(Gomez-Moreno et al. 2013). Chewing gum is tification and management of any underlying
associated with increased saliva production in causes or risk factors (such as HIV infection, can-
the majority of those with residual capacity and cer, diabetes, anemia, or hematinic deficiencies),
its use should be encouraged (Furness et al. 2013). and it varies according to the anatomic location of
Systemic sialogogues usually provide a longer the infection, the patient’s underlying disease and
effect than topical therapies. Pilocarpine is a para- immune status, patients’ risk factors for infection,
sympathomimetic, muscarinic-stimulating cholin- the specific species of Candida responsible for
ergic agonist. This alkaloid causes pharmacologic infection, and the susceptibility of the Candida
stimulation of exocrine glands in humans enhanc- species to specific antifungal drugs.
ing both salivary and lacrimal gland secretion. Antifungal agents fall into three main catego-
Pilocarpine is commonly given at doses of 5 mg ries: the polyenes (nystatin and amphotericin B);
up to three times a day for at least 3 months before the ergosterol biosynthesis inhibitors – the azoles
the treatment effect can be evaluated (Aframian (miconazole, clotrimazole, itraconazole, flucona-
et al. 2007). Common side effects include gastro- zole, posoconazole and voriconazole), allylami-
intestinal upset, sweating, tachycardia, bradycar- nesthiocarbamates, and morpholines; DNA
dia, increased pulmonary secretions, increased analog 5-fluorocytosine, and newer agents such
smooth muscle tone, and blurred vision. Risk to as caspofungins (Tables 1, 2, and 3). Oropharyn-
the patient must be considered when administering geal candidosis can be treated with either topical
pilocarpine to individuals with heart disease, or systemic antifungal agents or both. As these
asthma, angina pectoris, chronic bronchitis, antifungals are available as topical as well as
chronic obstructive pulmonary disease, or history systemic preparations, they have not been divided
of myocardial infarction. Systematic reviews report in this chapter, but they have been separated
conflicting results on pilocarpine efficacy in within Tables 1, 2, and 3.
radiation-induced xerostomia (Davies and Thomp-
son 2015 Mercadante et al. 2017), with one Amphotericin B
Cochrane review highlighting the high overall Amphotericin B is a polyene antifungal.
side effect rate, with 6% to 15% of patients with- According to UK NICE Guidelines, oral
drawing the medication as a result of adverse amphotericin is not recommended for oropharyn-
effects (Davies and Thompson 2015). geal candidosis as there is a lack of trial evidence
Cevimeline is a further cholinergic agonist to show its efficacy in the treatment of this infec-
believed to bind more specifically to M3 receptors tion (Excellence 2018). However, the Australian
instead of M1 and M2 receptors, which primarily Therapeutic Guidelines recommend amphotericin
effect the cardiovascular and respiratory systems lozenges for this purpose (Limited 2018). It is
(Grisius 2001). Cevimeline was approved in 2000 sometimes used as an adjunct to other systemic
by the US Food and Drug Administration for the antimycotic drugs.
treatment of xerostomia in patients with Sjögren’s The most common and serious adverse effect
syndrome (SS) but is not universally available. It of amphotericin B, when it is administered by
Table 1 Topical antifungal drugs

Agent Classification Mechanism of action Administration Side effects
Nystatin Polyene antifungal It targets fungal cell Oral suspension Nystatin contain
agent derived from membranes, which 100,000 IU/ml 6 hourly sucrose, which can
the Streptomyces contain ergosterol for at least 14–21 days. increase the risk for
species. forming pores that dental cavities and
disrupt the permeability worsen diabetes
of the fungal cell mellitus.
membrane. May cause
gastrointestinal
disturbance and
nausea if swallowed.
Miconazole Topical imidazole As an imidazole agent, it 20 mg mucoadhesive Miconazole is a strong
antifungal agent has fungistatic buccal tablet, 25 mg/ml inhibitor of CYP2C9
Also functions as properties, inhibiting gel. 50 mg daily for at and will interact with
antistaphylococcal ergosterol synthesis in least 14–21 days. drugs metabolized via
agent. the fungal plasma 50 mg/g denture this pathway, such as
membrane. lacquer applied weekly anticoagulants,
for at least 2 weeks (not enhancing the effect of
available in the USA). warfarin. Avoid in
pregnancy.
Clotrimazole Topical imidazole Used as a topical agent Mouthwash contains
antifungal agent (cream or mouthwash) sucrose.
with in the USA due to Less effective than
antistaphylococcal potential other azoles in patients
properties. gastrointestinal and with HIV infection.
neurologic toxicity. Not available in the
10 mg 6-hourly for at UK.
least 14 days. Vaginal cream
available in Australia.
intravenous infusion, is nephrotoxicity and it can primarily fungistatic. It is used topically due to
potentiate nephrotoxicity of other agents, such as potential gastrointestinal and neurological toxic-
aminoglycosides and cyclosporine. Topical for- ity. Clotrimazole is known to suppress candidal
mulations of amphotericin B including ointment, adhesion to human buccal epithelial cells, a factor
suspension, cream, and lozenges carry none of which may aid its therapeutic efficacy (Macura
these safety issues and are effective. 1988). The cream is applied two to three times
daily for 3 weeks. One teaspoonful of the solution
Caspofungin should be used to rinse the mouth three to four
Caspofungin is an antifungal agent of the novel times daily for 3 weeks. However, this drug is not
echinocandin class and is administered intrave- available worldwide. When applied topically, clo-
nously. Caspofungin appears to possess an effi- trimazole is well tolerated with rare adverse side
cacy comparable to that of a standard dose of effects including nausea, vomiting, and skin irri-
amphotericin B in the management of oropharyn- tation although hypersensitivity can occur.
geal and esophageal candidosis (Zhang et al.
2016) and may provide a better-tolerated alterna- Fluconazole
tive to amphotericin for patients with azole- Fluconazole is a triazole antifungal agent and has
refractory candidal infections. a broad spectrum of antifungal activity that
includes most strains of Candida albicans but is
Clotrimazole less active against non-albicans Candida species,
Clotrimazole is a topical imidazole antifungal particularly Candida krusei and Candida
agent with antistaphylococcal properties and is glabrata that are resistant to the drug. Fluconazole
Table 2 Oral antifungal drugs

Agent Classification Administration Side effects
Fluconazole Triazole antifungal agent that is 50–200 mg/day capsules or Mild and include
metabolized and excreted suspension 50 mg/5 ml for at gastrointestinal upset. Fewer
primarily by the kidneys. least 14 days. drug interactions than
ketoconazole. There is a
potential risk for hepatotoxicity
and myelosuppression.
Flucoanazole is a strong
inhibitor of CYP2C19 and
moderate inhibitor of CYP2C9
and 3A4; thus it will interact
with drugs metabolized via
these pathways, such as
anticoagulants, and
antihyperglycemics.
Avoid in pregnancy.
Itraconazole Triazole antifungal agent useful 100–200 mg/day for at least Dizziness, headache,
for targeting candidal strains 14 days capsule or 10 mg/ml gastrointestinal upset, hepatic
that are resistant to fluconazole, liquid twice daily for at least dysfunction, and hypokalemia.
including C glabrata and C 14 days. Observe precautions for use in
krusei. Metabolized by the *Absorption dependent on patient with heart failure or liver
liver. gastric acid so any drugs that dysfunction.
increase gastric pH can May interact with anticoagulants,
decrease antifungal antigylcemics., cyclosporin,
absorption. cisapride, midazolam, phenytoin,
repaglinide, rifabutin, statins,
tacrolimus.
Posaconazole Triazole antifungal agent that, 400 mg twice daily for at least Contraindicated in cardiac and
like itraconazole, is used for 14 days. liver disease. Best avoided in
candidal strains resistant to Available as suspension first trimester. Contraindicated
fluconazole. It is metabolized 200 mg/5 ml. when used with drugs
by the liver. metabolized via CYP3A4
including St John’s wort. Avoid
during breastfeeding.
Posaconazole is a strong
inhibitor of CYP3A4 and will
significantly increase levels of
drugs metabolized via this
pathway. Concomitant use of
some CYP3A4 substrates are
even contraindicated.
Voriconazole For fluconazole resistant 200–400 mg/day for at least Voriconazole is a potent
C. albicans or C. krusei 14 days. inhibitor of CYP3A4 and
Available as suspension moderate inhibitor of
200 mg/5 ml. CYP2C19 and will significantly
increase levels of drugs
metabolized via these
pathways.
Contraindicated in cardiac and
liver disease. Avoid in
breastfeeding.
is given either orally or intravenously and gastrointestinal tract, with a very long serum
is well absorbed after oral administration. half-life of 27–37 h. Oral fluconazole has been
What distinguishes fluconazole from many recognized as a first-line therapeutic for oropha-
other azoles is excellent absorption from the ryngeal candidosis, because it is well tolerated
Table 3 Intravenous antifungal drugs

Dosage and
Agent Classification duration Side effects
Amphotericin B Polyene topical 0.5 mg/kg for at Risk of nephrotoxicity, arrhythmias, neuropathies.
antifungal least
agent 10–14 days
Caspofungin Infusion 50 mg For fluconazole resistant C. albicans.
i.v. daily Contraindicated in cardiac disease, liver disease, and
pregnancy.
Micafungin Infusion Prophylaxis of candidosis in hematopoietic stem cell
100 mg transplantation when fluconazole, itraconazole or
i.v. daily posaconazole cannot be used.
Risk for hepatotoxicity.
Contraindicated in liver disease, renal disease, and
pregnancy.
by patients, convenient, and may be taken with cola or juice to ensure gastric pH is low. Side
irrespective of food intake. However, its poten- effects of itraconazole include dizziness, head-
tial for interactions with other drugs may make ache, gastrointestinal upset, hepatic dysfunction,
its use untenable. and hypokalemia. Given that treatment with this
Unlike other azoles, fluconazole is not metab- drug is usually for many weeks, itraconazole
olized in humans and is excreted largely through should not be used at all during pregnancy.
the kidney unchanged. Thus, it does not share Women of child-bearing age should not take
the hepatotoxic effects with other azoles. The itraconazole unless effective contraceptive mea-
side effects of fluconazole are usually mild and sures are in place (Drugs.com 2018). There
include gastrointestinal upset and headache. are many significant drug interactions with
Due to inhibition of CYP enzymes 2C9, 2C19, itraconazole due to its potent inhibition of CYP
and 3A4, fluconazole may interact with many 3A4 enzymes and p-glycoprotein drug transport.
significant medications by decreasing their As with other azoles, cyclosporine metabolism is
hepatic metabolism and increase of their serum reduced by itraconazole increasing serum concen-
concentrations and effects. These drugs include trations substantially so cyclsoporin serum levels
anticoagulants, antihyperglycemics, cyclospor- should be monitored frequently. Similarly, simul-
ine, cisapride, midazolam, phenytoin, statins, taneous use of itraconazole and terfenadine is
estrogens, progestogens, and tacrolimus. A sin- contraindicated due to the risk of life-threatening
gle dose of fluconazole in pregnancy is consid- arrhythmias. Itraconazole can also increase
ered safe, but repeated dosing may be digoxin concentrations due to inhibition of clear-
teratogenic if taken in the first trimester. Flucon- ance via p-glycoprotein drug transporters.
azole is available as oral or intravenous formu- Itraconazole capsules should be taken at a dosage
lations and the suggested dosage is 200 mg daily of either 100 or 200 mg daily for 14 days or
for 7–14 days. 200 mg three times daily for 3 days if the patient
has severe or recalcitrant disease. There is also a
Itraconazole solution form of 100 to 200 mg daily for 14 days
Itraconazole is a triazole antifungal useful for that has greater bioavailability than the capsule
treatment of candidal strains resistant to flucona- form.
zole, such as Candida glabrata and Candida
krusei. In the community, it is used for treating Miconazole
fungal infections of the lungs, skin, and nails. Oral Miconazole is a synthetic imidazole antifungal
absorption of this drug varies widely between drug that also functions as an antistaphylococcal
individuals, so it must be taken on a full stomach agent. It inhibits the enzyme cytochrome P450
14α-demethylase that leads to inhibition of ergos- altering the permeability of the yeast cell mem-
terol synthesis, an essential component of the brane, resulting in leakage of cell constituents and
fungal cell membrane. Miconazole also affects death. Nystatin is not absorbed when orally
the synthesis of triglycerides and fatty acids and administered and is too toxic for parenteral use,
inhibits oxidative and peroxidative enzymes, therefore topical use is the most common route of
increasing the amount of reactive oxygen species administration (Samaranayake et al. 2009). This
within the cell. drug is associated with a low incidence of drug
Similar to other azole antifungals, miconazole interactions; however, interactions with warfarin
can interact with many significant drugs due to have been reported (Kovac et al. 2012). The most
inhibition of CYP 3A4 and 2C9 enzymes. Limited common adverse effects of topical nystatin are the
absorption from topical application usually allows poor taste in some formulations in some countries
this to be ignored, but when large volumes are and gastrointestinal disturbance when high doses
used or miconaozle is applied to oral mucosa, are employed. A recent meta-analysis showed that
sufficient systemic absorption can occur to cause nystatin pastilles are significantly superior to pla-
significant drug interactions. Concomitant admin- cebo in treating denture-associated stomatitis,
istration of warfarin and miconazole oral gel can while nystatin suspension is not superior to flu-
lead to potentially life-threatening interactions conazole in treating oral candidosis in infants,
due to dramatic increase in warfarin concentra- children, or HIV/AIDS patients. Indirect evidence
tions and should be avoided (O0 Reilly et al. 1992; from a descriptive study demonstrated that admin-
Miki et al. 2011). Miconazole has broad- istration of nystatin pastille alone, or pastille and
spectrum activity against multiple Candida spe- suspension in combination, is more effective than
cies including C. albicans, C. krusei, C. tropicalis, that of suspension alone (Lyu et al. 2016). Nysta-
C. glabrata, C. parapsilosis, and C. dubliniensis. tin can be used as dissolved pastilles (100,000 IU;
This agent is available in different topical formu- one to two pastilles three to four times a day), and
lations namely buccal tablets, chewing gum, oral oral suspension (100,000 IU, four times a day)
gel, cream, ointment, and lacquer. A recent continued for several days after post-clinical res-
systematic review and meta-analysis indicated olution of the infection. Due to lack of oral
that miconazole may be an optional choice for absorption, topical nystatin is safe for use preg-
treatment of oral candidosis, especially for nancy and lactation.
acute pseudomembranous candidosis. For
HIV-infected patients, there is no significant dif- Posaconazole
ference in the efficacy between miconazole and Posoconazole is a broad-spectrum, second-gener-
other antifungals (Zhang et al. 2016). The gel is ation triazole that was approved by the FDA in
applied three to four times daily for 2–4 weeks 2006, for prophylaxis against invasive Aspergil-
and the cream twice daily for 2–3 weeks. The lus and Candidal infections in severely immuno-
lacquer form is applied over denture surfaces, compromised adults and adolescents at risk for
although the gel formulation can be likewise these infections. The most common adverse
used. The relapse rate of miconazole oral gel effects associated with the use of posaconazole
may be lower than that of other formulations include headache, fever, nausea, vomiting, and
(Zhang et al. 2016). diarrhea. Posaconazole is a potent inhibitor of
CYP3A4 and is associated with many significant
Nystatin drug interactions. It has been shown to increase
Nystatin is a membrane-active polyene macrolide the serum concentrations of tacrolimus and cyclo-
produced by Streptomyces noursei strains and is sporine, so serum concentrations should be
available in various forms, such as oral suspen- frequently monitored, and phenytoin should
sion, topical cream, and oral pastille (Wong et al. be avoided because co-administration of phenyt-
2014). Nystatin prevents the biosynthesis of oin and posaconazole significantly reduces
ergosterol in the fungal cell membrane thus posaconazole exposure and increases phenytoin
levels. Posoconazole is available as an oral sus- 1–2 (HSV-1 and HSV2) and recurrent outbreaks
pension, and the dose for oral candidosis refrac- of varicella-zoster virus (VZV), called zoster or
tory to itraconazole and/or fluconazole is 400 mg shingles. Antivirals are also given for
twice a day, with the length of therapy dependent HSV-induced erythema multiforme (EM) (Woo
on the patient’s clinical response. and Challacombe 2007).
HSV-1 is frequently associated with oral and
Voriconazole perioral infections and HSV-2 generally causes
Voriconazole is a second-generation triazole, with genital infections. Recurrent herpes labialis, com-
a broader spectrum of activity than fluconazole monly known as cold sores, is a common infective
that has been used in the treatment of esophageal condition caused primarily by HSV-1, but occa-
candidosis, candidemia, and invasive fungal sionally also HSV-2. The aim of antiviral therapy
infections. Well-known adverse effects of is to block viral replication to shorten the duration
voriconazole include hepatotoxicity, visual distur- of symptoms and to accelerate healing of the
bances, and phototoxicity. Most concerning is the lesions.
increased risk of cutaneous malignancies, primar- Antivirals for the treatment of HSV/VZV man-
ily squamous cell carcinoma (SCC) that seems to ifestations are either topical or systemic, all of
be duration-dependent, and moreover, the associ- which target viral DNA replication and belong to
ated malignancies tend to be more aggressive and three classes of drugs: acyclic guanosine ana-
multifocal (Wojenski et al. 2015; Mansh et al. logues (acyclovir, famcyclovir, gancyclovir,
2016; Williams and Arron 2016). As with other pencyclovir, valacyclovir, valgancyclovir), acy-
azole antifungals, voriconazole has significant clic nucleotide analogues (cidofovir, adefovir
drug interactions with many agents due to potent dipivoxil), and pyrophosphate analogues (foscar-
inhibition of CYP enzymes 3A4 and 2C19 and. net) (Jiang et al. 2016). Acyclovir (ACV) and its
This medication can be delivered either orally and derivatives (Table 4) are widely used for the treat-
intravenously (Tables 1, 2, and 3). ment of HSV infections. However, long-term
treatment with these anti-herpes drugs may lead
to drug resistance, particularly in immunocom-
Antiviral Agents promised patients (Jiang et al. 2016). Although
ACV resistance may be attributed to alteration in
Oral viral infections that are treated with medica- DNA polymerase, it is most frequently caused by
tions in oral medicine are essentially primary and the deficiency of or mutations in the thymidine
recurrent manifestations of human herpesvirus kinase (TK) gene that is responsible for sequential
Table 4 Main systemic antivirals used in the management of herpes simplex infection and herpes zoster is immuno-
competent patients
Acyclovir Valacyclovir Famcyclovir
Activity against HSV-1, HSV-2, HSV-1, HSV-2,VZV, EBV, CMV HSV-1, HSV-2, VZV, EBV
VZV, EBV, CMV
Most common Nausea, Vomiting, Headache, Nausea, Vomiting, Headache, Nausea, Diarrhea,
side effects Diarrhea Dizziness, Abdominal pain Fatigue, Abdominal pain
Less common HeadacheMalaise Dysmenorrhea Arthralgia Renal Vomiting Dysmenorrhea Flatulence
side effects Renal failure failure Migraine Renal failure
Bioavailability 10–20% 55% 77%
Half-life 2.5 0.5 10–20
(hours)
Major route of Renal Renal Renal
elimination
HSV-1/HSV-2 Herpes simplex virus types 1 and 2, VZV varicella-zoster virus, EBV Epstein-Barr virus, CMV
cytomegalovirus
phosphorylation of acyclic guanosine analogues the drug is by glomerular filtration and active
(Fatahzadeh and Schwartz 2007). tubular secretion (Razonable 2011). The major
adverse effect of adefovir is nephrotoxicity. The
Acyclovir dosage for HSV is not clearly established, and
Acyclovir is a purine nucleoside analogue and a renal function must be monitored (Piret and
potent antiviral agent selectively active against Boivin 2011).
viruses of the herpes group. The acyclic guano-
sine analog binds viral DNA polymerase, acting Cidofovir
as a chain terminator and ending replication. Its Cidofovir is an acyclic nucleoside
mechanism of action requires early administration 5-monophosphate which upon phosphorylation
because replication may end as soon as 48 h into a by host kinases selectively inhibits viral DNA
recurrence. polymerase. It causes renal impairment and is
Oral bioavailability is only 10–20% after oral usually reserved for treatment of HSV disease
administration and consequently, acyclovir must resistant to acyclovir and foscarnet, but it is not
be taken in an oral dose of 200 mg (tablets or oral licensed worldwide for that use (Fatahzadeh and
suspension) five times daily, which is difficult for Schwartz 2007). Cidofovir has a long half-life and
patients, thus adherence to this regimen is often is administered once weekly by intravenous route
poor. Improved compliance and higher serum at 5 mg/kg per week during the first 2 weeks, then
concentrations can be achieved with intravenous 5 mg/kg every other week, with sufficient hydra-
administration but switching to newer antiviral tion and under cover of probenecid to prevent
medicines is a more practical solution. nephrotoxicity (De Clercq 2004).
The half-life of acyclovir is about 2.5 h, and the
dosage must be adjusted in patients with renal Famcyclovir
failure. To overcome the oral absorption barrier, Famcyclovir is a prodrug of pencyclovir and a
some prodrugs with enhanced solubility (such as guanosine analogue particularly useful against
valacyclovir) and different delivery systems such HSV. It is converted into its active compound
as matrix tablets and polymeric films have been within the infected cell by contact with an enzyme
reported to improve its bioavailability (Dhaliwal from the virus. Famcyclovir has higher bioavail-
et al. 2008; Palmberger et al. 2008; Tao et al. ability of 77%. It remains active in the body
2009; Gandhi et al. 2014). longer than acyclovir (half the dose is still active
Mucoadhesive polymers can prolong the resi- after 10–20 h) and, like valacyclovir, requires less
dent time of drugs at the site of absorption and frequent dosing of two or three times a day.
minimize drug dilution. They also enhance the
transmucosal transport and the bioavailability Foscarnet
(Di Colo et al. 2008). Acyclovir is a safe and Foscarnet is a non-nucleoside pyrophosphate ana-
well-tolerated drug. logue that is given intravenously for the treatment
of herpesviruses. This drug is mainly used for
Adefovir Dipivoxil Cytomegalovirus infection (CMV) diseases in
Adefovir dipivoxil is an ester prodrug of the immunocompromised patients but also for the
nucleoside reverse transcriptase inhibitor adefovir treatment of acyclovir-resistant HSV in immune-
(PMEA), the prototype compound of the acyclic impaired hosts (Fatahzadeh and Schwartz 2007).
nucleoside phosphonates. This drug has mainly Foscarnet has no oral bioavailability so there is no
been used for HIV and Hepatitis B virus infection, oral formulation, and the drug is given IV or
but it can be effective in acyclovir and foscarnet topically. Foscarnet 3% cream reduces HSV shed-
resistant HSV infections, particularly in immuno- ding and may reduce lesion size and duration.
compromised patients. Oral adefovir dipivoxil is However, it is recommended that foscarnet only
rapidly absorbed and converted to adefovir. Its be used if lesions are known to be acyclovir-
oral bioavailability is about 59%. Excretion of resistant (Woo and Challacombe 2007).
Gancyclovir intestinal or hepatic metabolism. The bioavailabil-

Gancyclovir is an acyclic 20 -deoxyguanosine ana- ity of gancyclovir after valgancyclovir adminis-
logue that is mainly employed for the manage- tration is about 60% (Razonable 2011). This drug
ment of CMV. It is available in oral and parenteral can be used for recurrent VZV infections in immu-
formulations. Oral gancyclovir is poorly nocompromised patients such as organ transplant
absorbed, with a bioavailability of only 5%. patients (Tan and Goh 2006).
Gancyclovir is generally approved for the treat-
ment of CMV retinitis in patients with AIDS, the
treatment of herpes simplex keratitis, and CMV Glucocorticoids
prophylaxis in transplant recipients.
Corticosteroids are synthetic analogues of the nat-
Pencyclovir ural steroid hormones produced by the adrenal
Pencyclovir is a synthetic acyclic guanine derivate gland cortex. Corticosteroids can be broadly
with a similar mechanism of action to that of divided into glucocorticoids (GC) and mineralo-
acyclovir. Both compounds are selectively phos- corticoids. Mineralocorticoids are primarily
phorylated only within virus-infected cells by involved in the regulation of electrolyte and
viral thymidine kinase (TK). Further phosphory- water balance, whereas glucocorticoids are pre-
lation by cellular enzymes leads to the production dominantly involved in carbohydrate, fat and pro-
of acyclovir or pencyclovir triphosphate, both of tein metabolism, and have anti-inflammatory,
which compete with the natural nucleotide, dGTP, immunosuppressive, anti-proliferative, and vaso-
resulting in the selective inhibition of viral DNA constrictive effects. Since their discovery in the
polymerase. Incorporation of the analogue tri- 1940s, GCs have become one of the most widely
phosphate into the growing DNA chain prevents used and effective treatments for various inflam-
continued extension of the DNA chain (Elion matory and autoimmune disorders (Liu et al.
1993). Acyclovir triphosphate is an obligate 2013).
DNA chain terminator whereas pencyclovir tri-
phosphate allows limited DNA chain elongation Systemic Corticosteroids
(short-chain terminator). Pencyclovir has more The natural GC (cortisol) is secreted from the
bioavailability and a longer intracellular effect adrenal glands at around 20–30 mg/day peaking
than acyclovir. It is generally more effective top- in the early morning hours. The hypothalamus,
ically than topical acyclovir, and it is only avail- pituitary, and adrenal glands (HPA) axis is respon-
able as a cream. sible for cortisol release. Under ordinary
circumstances, the hypothalamus produces corti-
Valacyclovir cotropin-releasing hormone (CRH) and the ante-
Oral valacyclovir is a prodrug of acyclovir with rior pituitary responds to CRH with synthesis of
the advantage of being better absorbed than oral adrenocorticotropic hormone (ACTH) that stimu-
acyclovir and subsequently increasing the oral lates the inner adrenal cortex to generate and
bioavailability (to about 55%). Valacyclovir is release cortisol.
converted to acyclovir in the intestine and liver. A number of synthetic corticosteroids (Table 5)
The main advantage of this agent is the higher that mimic cortisol used either for hormone
concentration of acyclovir in the bloodstream replacement therapy (in hypoadrenocorticism) or
without added toxicity. Thus, valacyclovir as anti-inflammatory agents have been produced
requires less frequent dosing than acyclovir. (Barnes 2006). Their chemical structure com-
prises three hexane rings and one pentane ring.
Valgancyclovir After oral intake, GC are absorbed in the jejunum,
Valgancyclovir is the L-valyl ester prodrug of reach a peak plasma concentration between
gancyclovir. Oral valgancyclovir is well absorbed 30 and 90 min and bind with high affinity to the
and converted to gancyclovir by first-pass cortisol-binding protein called transcortin (95%),
Table 5 Most commonly used systemic glucocorticosteroids in oral medicine

Anti-
Equivalent inflammatory Na+/H2O Formulations available
Glucocorticoid dose Half-life potency Retention in the USA *
Betamethasone 750 μg 36–72 h 25 0 Tablets 500 μg; soluble
tablets 500 μg
Deflazacort 6 mg 1.1–1.9 h 3 0 Tablets 1 mg, 6 mg,
30 mg
Dexamethasone 750 μg 36–72 h 25 0 Tablets 500 μg;
oral solution 2 mg per
5 ml
Methylprednisolone 4 mg 12–36 h 5 0.5 Tablets 2 mg, 4 mg,
16 mg, 100 mg
Prednisolone 5 mg 18–36 h 4 0.8 Tablets 1 mg, 2.5 mg,
5 mg, 25 mg;
soluble tablets 5 mg
Systemic GC differ in potency, relative mineralocorticoid activity (Na+/H2O retention) and half-life. Doses listed are daily
physiologic baselines. *Available formulation can vary according to country. Consult national formularies for more
detailed and specific information
Steroids
Mechanism of acon:
Supress prostaglandin synthesis by
inhibiting the release of arachidonic
acid by blocking phospholipase A2
Fig. 1 Mechanism of action of corticosteroids, such as prostaglandins. (Original diagram by Dr Hala Al Janaby,
prednisolone, inhibit the release of arachidonic acid from Perth WA, Australia)
phospholipids, thereby reducing the formation of
and with lesser affinity to albumin (5%). The disappears from the circulation rapidly, their bio-
portion of the drug that is not protein bound is logical effects initiated at the tissue level may
referred to as free glucocorticoid and is the active persist for hours or days (Fig. 1).
moiety (Georgakopoulou and Scully 2014). GC All GC have genomic and non-genomic effects
are metabolized mainly in the liver but also in the (De Bosscher and Haegeman 2009). The genomic
kidney and excreted in the urine. Even if GC effects are mediated by the cytosolic
glucocorticosteroid receptor (GCR) that is present women have greater risks than men as a result of
in all cells, not just immunocytes, explaining why slower metabolism and clearance of GC second-
GC can exert a wide variety of desirable and ary to estrogen, lower bone density, and dosages
undesirable effects in all body systems. When that are often not adjusted based on weight
bound to GCs, the GCR–steroid complex trans- (Table 6).
locates to the nucleus where GC exert effects Postmenopausal women are much more prone
via modification of transcriptional and transla- to osteoporosis, as well as all elderly patients with
tional activities (Baschant and Tuckermann decreased physical activity. Children also have a
2010). Here GC decreases the synthesis of significant incidence of osteoporosis from exoge-
pro-inflammatory molecules such as cytokines nous GC, along with possible temporary retarda-
and proteases. GC can also reduce the concentration of growth.
tion of arachidonic acid, a precursor of prostaglan- Osteoporosis is the most common side effect of
dins and leukotrienes. Administration of GC long-term GC therapy, and it occurs in 30–50% of
decreases the number of monocytes, eosinophils, patients treated without proper preventive mea-
and lymphocytes and increases circulating poly- sures. Osteoporosis occurs most rapidly within
morphonuclear leukocytes. GC reduces both the first 6–12 months of GC therapy, as 80% of
Th1 and Th2 cytokines, causing a transient bone mineral density is lost in the first 3 months.
lymphopenia of helper, suppressor, and cytotoxic Skeletal effects of GCs are dose dependent with:
T-cells, and they also decrease some functions of doses 7.5 mg/day resulting in significant bone
macrophages. High GC doses are required in loss and increased fracture risk. Patients on long-
order to inhibit antibody-mediated immune term GC therapy should be given vitamin D and
responses. calcium supplements and they should be started
The biological effects of the different GC vary concomitantly on a bisphosphonate, such as
qualitatively and quantitatively (Table 5). Prednis- alendronic acid 70 mg per week (Jackson et al.
olone and its prodrug prednisone have relatively 2007; Overman et al. 2014).
few mineralocorticoid properties compared with Tapering of the GC dose is not necessary in
betamethasone, dexamethasone, and deflazacort. very short-term therapy but is very important
However, betamethasone and dexamethasone when treatment has lasted longer than a few
have a longer half-life and are more potent as a weeks, so as to allow for the delay in adrenal
result. In prolonged treatment, prednisolone or a recovery. Reduction of GC dose that is too rapid
similar drug is preferred due to low affinity for can trigger the so-called “corticosteroid with-
transcortin, resulting in satisfactory therapeutic drawal syndrome” symptoms of which include
results and lower risk of adverse effects. On the arthralgias, myalgias, mood changes, fatigue,
other hand, despite having lower mineralocorti- headache, and gastrointestinal complaints
coid activity, deflazacort is less potent than pred- (Dixon and Christy 1980). A return to previous
nisolone and higher doses must be prescribed. It is doses with slower tapering alleviates this
worth noting that comparative doses of various syndrome.
glucocorticoids, for example, a 4 mg dose of Tapering prednisolone is usually achieved by
dexamethasone is equivalent to 25 mg of 20 mg reduction when being taken at doses
prednisone. greater than 60 mg/day, 10 mg reduction when
Systemic GC can be used for short-term and taken between 30 and 60 mg/day, and 5 mg reduc-
long-term therapy. Short-term therapy usually tion when taken between 30 mg and the physio-
lasts for approximately 3 weeks or less, whereas logic dose range. Once the physiologic dose range
when GC intake is longer than 3 weeks, this is of 5–7.5 mg/day of prednisone is reached, a more
defined as a long-term treatment. Short-term treat- gradual reduction in 1 mg decrements may be
ments are safer than long-term therapies as sum- necessary to allow for adrenal recovery (Jackson
marized in Table 6. Some patients have a higher et al. 2007). An alternative method of GC dosage
risk of side effects from GC (Fig. 2). Commonly, tapering is to convert from daily to alternate-day
Table 6 Side effects of glucocorticosteroids (Liu et al. function alone can be tested by using the short
2013; Oray et al. 2016) Synacthen test in which serum cortisol levels are
Short-term ( measured after injection of synthetic ACTH.
3 weeks) Long-term (>3 weeks) Systemic GC remains the mainstay therapy for
Fluid, sodium retention Psychosis; sleep bullous disorders, particularly for moderate and
disturbances; pseudotumor
cerebri severe oral manifestations of mucous membrane
Hyperglycemia Osteoporosis; avascular bone pemphigoid (MMP) and pemphigus vulgaris
necrosis; myopathy; (PV). The introduction of systemic GC has dra-
sarcopenia matically reduced mortality from PV, but there is
Gastrointestinal Cataracts; glaucoma still a lack of consensus about the most effective
intolerance
therapeutic regimens for these disorders (McMil-
Increased risk of Nausea; Vomiting; Peptic
infections ulcer; Intestinal perforation;
lan et al. 2015).
Gastrointestinal bleeding Systemic GC may be occasionally indicated
Increased appetite, Hypertension; Fluid and for severe recalcitrant erosive oral lichen planus
weight gain sodium retention; (OLP) or for patients with diffuse mucocutaneous
Hyperlipidemia involvement (Carbone et al. 2003). Occasionally,
Accelerated coronary artery
disease; Hyokalemic severe flare-ups of recurrent aphthous stomatitis
alkalosis (RAS) or erythema multiforme can benefit from a
Delayed wound healing Hyperglycemia (with or short course of GC.
without diabetes); The therapeutic dosage of prednisolone for oral
Hyperlipidemia; Non-ketotic
disorders ranges from 0.5 up to 2 mg/kg of body
hyperosmolar stress
weight. Higher dosages (1–2 mg/kg of body
Mood changes, Acne; Facial erythema;
irritability, agitation, Striae; Atrophy of skin; weight) and longer treatments are commonly
insomnia Lanugo hair; Alopecia required in bullous disorders such as PV and
Amenorrhea Suppression of HPA axis; MMP, whereas for the vast majority of other oral
Growth retardation ulcerative disorders, therapy can last 1–2 weeks
Secondary amenorrhea;
Obesity
and doses can be set around 0.5 mg/kg of body
Increased incidence of weight.
infections
Acneiform eruptions Neutrophilia; Lymphopenia; Topical Glucorticosteroids
Leukocytosis Historically, topical corticosteroids have been
Inhibition of wound healing; developed to treat skin conditions and thus
Subcutaneous tissue atrophy
their use in the mouth is commonly “off-label.”
Off-label is the use of pharmaceutical drugs for
an unapproved indication or in an unapproved
therapy once a prednisolone dose of 20–30 mg/ age group, dosage, or route of administration.
day is reached. The therapeutic efficacy of topical GC is known
After chronic GC therapy for many months to derive from their anti-inflammatory and
to years at dosages equal to or higher than immunosuppressant properties. When prescrib-
5–7.5 mg/day, the HPA axis might be suppressed ing topical GC, it is important to consider the
and ACTH levels may not return to normal for diagnosis as well as steroid potency, delivery
several months. Full recovery of the adrenal glands vehicle, frequency of administration, duration
with normal serum cortisol levels may take even of treatment, and side effects. Topical cortico-
longer, sometimes up to 1 year (Jackson et al. 2007). steroids are available in a variety of potencies
The primary test for basal function of the HPA and preparations.
axis is the morning serum cortisol level. Impaired The preferred way to determine topical ste-
basal HPA axis function is suggested by serum roid potency is the vasoconstrictor assay, which
cortisol levels below 10 μg/100 dL. Adrenal classifies steroids based on the extent to which
Psychiatric
Behavioral changes Ophthalmic
Emotional disturbances Cataract
Mood changes Glaucoma
Increase in appetite
Anxiety, Mania, Cardiovasular
Depression Hypertension
Psychosis, Insomnia Cardiac hypertrophy
Appearance
Moon face Endocrine
Buffalo hump Diabetes mellitus
Fat deposition (abdomen & back of neck) Adrenal suppression
Thin extremities
Obesity Gastointesnal
Peptic ulcers
Reproducve system
Females Immunologic
Amenorrhea Immunosuppression
Hirsutism Poor wound healing
Skin Increased risk of infection
Abdominal striae
Acne
Edema Musculoskeletal
Petechiae Osteoporosis
Bruising Asceptic bone necrosis
Thin, wrinkled skin Muscle atrophy
Fig. 2 Diagram illustrating the potential side effects of corticosteroids. (Original drawing by Dr Hala Al Janaby, Perth
WA, Australia)
the agent causes cutaneous vasoconstriction According to the UK British National For-
(“blanching effect”) in normal, healthy persons. mulary (BNF), beclomethasone dipropionate,
The clinical potency of topical corticosteroids budesonide, fluticasone propionate, and
is classified in the European classification system mometasone furoate appear to be equally effec-
into four levels in descending order of potency: tive, but a direct comparison of their efficacy for
very potent (class I), potent (II), moderately potent oral disorders is not available. Similarly, no
(III), and mildly potent (IV). The USA ranks the consistent data are available to recommend
potency of topical corticosteroids in a different these preparations instead of topical GC or
way, which may cause some confusion. Topical vice versa.
GC are classified in the USA into seven levels of In the oral cavity, topical GC is often used as an
potency ranging from very-high potency (group I) ointment because creams have a bitter taste and do
to low potency (group VII). The fundamental not match well with adhesive gel, whereas gels
difference is that both drug concentration and can burn because they usually contain alcohol.
formulation are considered in the US potency The greatest problem when using topical GC in
ranking. As a result, the European and American the oral cavity is the decreased adherence to the
classifications do not completely overlap mucosa for the period required. For this, adhesive
(Table 7). gels such as carboxymethylcellulose (for exam-
Oral medicine specialists occasionally pre- ple, Orabase) or hydroxyethylcellulose can be
scribe inhaled GC in the mouth. Those prepara- employed, mixed in equal parts (1:1) with the
tions have indications mainly for asthma, and they given topical GC. Twice or three times daily
cannot be compared to traditional topical application is recommended for most prepara-
GC. Sometimes, inhaled GC are dispersed in tions. The duration of the application varies
water but their final concentration as well as the between 4 and 30 minutes, and the patient should
safety profile are uncertain, and publications on avoid talking, eating, drinking, or rinsing during
this matter are scant, thus recommendation is the application period. In the case of gingival
problematic. lesions, it is useful to use a custom-made tray
Table 7 Most commonly used topical glucocorticosteroid in oral medicine

Topical European classification of US classification of
glucocorticosteroid potency (class) potency (class) Delivery vehicle
Hydrocortisone 0.1–2.5% Mildly potent (IV) Low potency (VII) Mucoadhesive
buccal tablets
Betamethasone valerate Potent (II) Mid potency (IV and V) C, O
0.1%
Fluocinolone acetonide Potent (II) Mid potency (IV and V) C, O
0.025%
Fluticasone propionate Potent (II) Mid potency (IV and V) C, O
0.05%
Mometasone furoate 0.1% Potent (II) Mid potency (IV and V) C, O
Triamcinolone acetonide Potent (II) Mid potency (IV and V) C, O
0.1%
Betamethasone Potent (II) High potency (III) C
dipropionate 0.05%
Triamcinolone acetonide Potent (II) Mid to High potency (III C, O
0.5% and IV)
Fluocinonide 0.05% Potent (II) High potency (II) C, O
Betamethasone Potent (II) High potency (II) O
dipropionate 0.05%
Clobetasol propionate Very Potent (I) Very High potency (I) C, O
0.05%
C cream, O ointment
The above list is not meant to be comprehensive and it may not apply to every country. Consult national formularies for
more detailed and specific information
prepared in transparent soft resin or silicone that mainly when patients overuse very highly potency
allows occlusive therapy. GC (Decani et al. 2014).
Topical and systemic GC can also be prepared Medium- to high-potency topical GC can be
as a solution for mouth rinsing, particularly if effective for the treatment of the erosive-bullous
lesions are widespread or not amenable to oint- diseases such as OLP, erythema multiforme,
ment/cream application. Clobetasol propionate, MMP, and localized and very mild PV. In other
dexamethasone, and betamethasone sodium phos- milder ulcerative oral disorders such as RAS,
phate can be used as oral solution to rinse and spit. particularly the minor variety or in children, less
However, there is some evidence that, when used potent topical GC can be employed.
in this manner GC are more likely to be absorbed
and cause systemic side effects including Cushing Intralesional Corticosteroids
appearance (Lehner and Lyne 1969; Gonzalez- Intralesional injection of GC is a relatively simple
Moles and Scully 2010). and effective method for delivering a higher drug
Generally speaking, topical GC can be safely concentration and avoiding possible side effects
used in the mouth and the most commonly of systemic administration. It has been used for
reported adverse-effect is acute candidosis that the management of localized lesions in patients
can be prevented matching the topical GC with a with erosive OLP (Xia et al. 2006; Lee et al. 2013)
topical antifungal drug such as miconazole and for lip swelling in patients affected by
(Carbone et al. 2003). Other possible and transi- orofacial granulomatosis (OFG).
tory adverse effects are stomatopyrosis and hypo- Triamcinolone acetonide (TA) 40 mg/ml has
geusia, whereas systemic side effects such as been mainly used as intralesional GC, and it
suppression of the hypothalamic-pituitary-adrenal appears to represent an effective therapeutic strat-
axis and Cushing’s syndrome are rare and occur egy to control the permanent disfiguring swelling
of OFG (Fedele et al. 2014). However, there is a became available in late 1970s (Wise and Callen
lack of consistency regarding the best regimen to 2007).
adopt. Such factors include whether local anesthe- The purines and pyrimidines are the substrates
sia is necessary, what interval should be used for DNA and RNA synthesis in which DNA is
between injections, and how many times should replicated and eventually duplicated. AZA inter-
the drug be injected every cycle (Mignogna et al. feres with this process and inhibits cell division
2004; Martini et al. 2010; Alajbeg et al. 2011; and causes cell death. The hematopoietic cells are
Mignogna et al. 2013). Evidence regarding extremely susceptible to drugs effecting DNA and
intralesional TA in OLP is even more scant than RNA synthesis because of their tendency for rapid
OFG, and this modality of management is not division (Mimouni and Nousari 2002). AZA
routinely used in OLP and is likely less effective is given orally and very well absorbed into the
than halogenated GC and calcineruin inhibitors. GI system. AZA can cross the placenta, and there-
fore it is contraindicated in pregnancy. Maximal
immunosuppression is achieved after 8–12 weeks
Immunosuppressive of intake. The active drug (6-mercaptopurine) is
and Anti–inflammatory Agents metabolized in three pathways: (a) hypoxanthine-
guanine phophoribosyltransferase (HGPRT)
Immunosuppressive and anti-inflammatory drugs produces the active metabolite; (b) xantine
are widely used in the treatment of immune- oxidase produces an inactive metabolite; and
mediated disorders, including those affecting the (c) thiopurine methytransferase (TPMT) produces
oral cavity exclusively, to help avoid adverse an inactive metabolite. Patients with low or absent
effects of long-term glucocorticosteroids. A activity of TPMT have extremely high levels of
major goal in the management of patients with the active metabolite that can lead to severe, life-
immunologically mediated diseases is the reduc- threatening myelosuppression (Mimouni and
tion of the patient’s cumulative exposure to sys- Nousari 2002). However, TPMT gene polymor-
temic corticosteroids. phisms predict hematological adverse drug reac-
Immunosuppressive agents can be broadly tions in just 5–10% of patients treated with
divided into four different categories: (a) calcineurin thiopurine drugs (Anstey et al. 2004). AZA is
inhibitors (cyclosporine, tacrolimus, pimecrolimus); generally well tolerated and apart from myelosup-
(b) inhibitors of purine and pyrimidine synthesis pression can cause adverse drug reactions in
(azathioprine, mycophenolate mofetil); (c) alky- 15–28% of patients, including nausea and
lating agents (cyclophosphamide); and (d) antime- vomiting, rash, pancreatitis, hypersensitivity, and
tabolites (methotrexate). These drugs not only have liver toxicity (Anstey et al. 2004). Important drug
glucocorticosteroid-sparing effects but also affect interactions are with warfarin (AZA may impair
B cells and T cells. Drugs with anti-inflammatory the anticoagulant effect), allopurinol and
rather than immunosuppressive action include col- sulfasalazine (increases toxicity of AZA), and
chicine, dapsone, tetracyclines, and thalidomide. ACE-inhibitors (can induce severe leukopenia
in AZA takers). Live vaccines are also
Systemic Immunosuppressive Agents contraindicated (Anstey et al. 2004). Patients tak-
ing AZA are at increased risk of opportunistic
Azathioprine infections as well as future malignancy, particu-
Azathioprine (AZA), a purine analogue, is a pro- larly cutaneous squamous cell and basal cell car-
drug of 6-mercaptopurine (6-MP) with no inher- cinoma (SCC and BCC respectively) and myeloid
ent immunosuppressive activity. Originally neoplasms (Jiyad et al. 2016; Ertz-Archambault
developed in early 1960s for the control of graft et al. 2017). Full blood count and liver and renal
rejection in transplant surgery, AZA plus predni- function tests should be routinely undertaken in
sone remained the mainstay of anti-rejection ther- patients taking AZA, and a preliminary TPMT
apy for more than a decade until cyclosporine assessment is recommended (Hullah et al. 2015).
The recommended dose is 1–3 mg/kg/day Cyclosporine

(Anstey et al. 2004). AZA is licensed only for Cycloporine (CsA) (also known as cyclosporin or
PV and systemic lupus erythematosus (SLE) but ciclosporin) is the first and oldest calcineurin
it has also been used in oral medicine for the inhibitor synthesized, and it is the only one that
management of MMP, OLP, OFG and rarely in can be used either as a systemic or a topical
patients with aggressive oral Behçet’s disease or medication for treatment of oral disorders. CsA
RAS (Hullah et al. 2015). AZA is mainly used as a is a lipophilic cyclic polypeptide extracted from
steroid-sparing agent but occasionally also in Tolypocladium inflatum, an ascomycete fungus.
isolation. Originally developed as an antifungal agent
before its immuno-modulatory properties were
Cyclophosphamide realized in the early 1970s and used in transplant
Cyclophosphamide is an alkylating agent, with medicine, CsA revolutionized the survival of
powerful cytotoxic and immunosuppressive transplant patients (Tedesco and Haragsim
effects. Cyclophosphamide is generally consid- 2012). CsA binds with the intracytoplasmic pro-
ered more effective than AZA or mycophenolate tein cyclophilin in target cells where the
mofetil (MMF) for oral disorders but a direct cyclosporine–cyclophilin complex inhibits
comparison is lacking, but it is certainly more calcineurin, a phosphatase required for the activa-
toxic than purine and pyrimidine inhibitors. tion of the nuclear factor of activated T cells
Cyclophosphamide is a biologically inactive pro- (NF-ATc). NF-ATc, a transcription factor specific
drug that undergoes extensive hepatic metabolism for T lymphocytes, translocates to the nucleus
into active and inactive metabolites (Kim and where it binds in the promoter region of genes
Chan 2017). The active metabolites have cell- responsible for the synthesis of inflammatory
cycle independent alkylating actions, resulting in cytokines including interleukin (IL)-2, IL-3,
inhibition of DNA replication and apoptosis IL-4, tumor necrosis factor alpha (TNF-α), inter-
(Levell et al. 1992; Al Johani et al. 2009; Tedesco feron-gamma (IFN-γ), transforming growth
and Haragsim 2012; Mays et al. 2013; Atzmony factor-beta, and granulocyte-macrophage colony-
et al. 2015; Georgakopoulou and Scully 2015c). stimulatory factor (Georgakopoulou and
Sensitivity to cyclophosphamide is greater in Scully 2015c).
B-cells than T-cells (Kim and Chan 2017). Cyclo- In stimulated T cells, calcineurin inhibitors
phosphamide is well absorbed orally and after inhibit activation principally by suppressing IL-2
being metabolized in the liver, it is eliminated production and IL-2 receptor expression. Inhibi-
primarily in metabolized form, but up to 25% is tion of IL-2 production blocks the activation of
excreted in urine unchanged (Germanas and T-helper cells, T-regulatory cells (autocrine loop),
Pandya 2002). The well-known toxicity profile natural killer cells, and monocytes. CsA can cause
of cyclophosphamide, includes myelosup- a number of side effects that are mainly dose
pression, increased risk of infections, teratogenic- related and relatively rare with usual dosage
ity, sterility, carcinogenesis (mainly bladder for oral disorders of <5 mg/kg/day. Common
cancer), and hemorrhagic cystitis (Atzmony side effects are hypertension, deranged renal func-
et al. 2015; Georgakopoulou and Scully 2015c). tion, headache, hypertrichosis, gingival hyperpla-
Thus, its use is generally limited to severe, recal- sia, and paresthesia. Other side effects include
citrant blistering diseases, where other steroid- gastrointestinal symptoms (diarrhea, nausea),
sparing immunosuppressants have failed or are musculoskeletal symptoms (joint pain, leg
contraindicated. Cyclophosphamide is generally cramps), peripheral/central nervous system symp-
not recommended in young patients or in anyone toms (headache, tremor, paresthesia), fatigue,
with plans to conceive. Oral cyclophosphamide metabolic abnormalities (hyperbilirubinemia,
doses are usually 1–5 mg/kg per day (Kim and hypercalcemia, hypomagnesemia, hyperuricemia,
Chan 2017). hyperlipidemia), and cancer risk (mainly
lymphomas and skin cancers) (Madan and species (Shen et al. 2012). Overall, MTX has
Griffiths 2007). good oral bioavailability but intestinal absorption
During continuous treatment with CsA, the is dose dependent, with increasing variability in
number of patients who experience an elevation absorption with doses higher than 15 mg (Shen
in serum creatinine value increases over time. et al. 2012). Adverse effects of MTX include
Thus, only a minority of patients can be gastrointestinal complaints (nausea, vomiting,
maintained continuously on CsA for 5 years or and diarrhea), oral ulceration, hematologic com-
more without experiencing changes in renal func- plications, and renal and liver toxicity. MTX is a
tion (Madan and Griffiths 2007). Drug interac- known teratogen agent and can increase the risk of
tions with CsA are common, and they can be lymphoma. Folic acid supplementation can
divided into three main types: (i) drugs that reduce complications. MTX in oral medicine has
increase CsA plasma levels (calcium antagonists, been used as a steroid-sparing agent in bullous
antimycotics, allopurinol, oral contraceptives); disorders, particularly PV, and in the management
(ii) drugs that increase the risk of nephrotoxicity of OLP (Gurcan and Ahmed 2009, Kanwar and
(NSAIDs, H2 antagonists, trimethoprim); and (iii) De 2013). Doses range from 10–50 mg weekly in
drugs with increased plasma levels (anti-gout PV and 15 mg weekly for OLP (Gurcan and
agents, colchicine, prednisolone). Ahmed 2009, Kanwar and De 2013).
CsA has mainly been used as a systemic med-
ication in OLP and PV treatment. Few studies Mycophenolate Mofetil
have shown CsA to be a useful adjuvant to oral Mycophenolate mofetil (MMF), an ester deriva-
corticosteroids in the treatment of PV at doses tive of mycophenolic acid (MPA) which is the
ranging from 5 up to 6 mg/kg/day (Madan and active compound, was originally isolated from a
Griffiths 2007; Atzmony et al. 2015). Too few fermentation product of Penicillium species and
patients with OLP have been treated with sys- originally used for psoriasis management in the
temic CsA to make conclusions about its efficacy 1970s (Mimouni and Nousari 2002). Similar to
(Levell et al. 1992). Systemic CsA, together with AZA, MMF inhibits purine and pyrimidine syn-
prednisone, is usually initiated to manage patients thesis and is rapidly absorbed when given orally.
with chronic graft versus host disease (cGvHD) Optimal immunosuppression is achieved after
where this is more than mild, with more than two 8–12 weeks of intake. The safety profile of
organs involved, or any organ score of 2 or more MMF is high and the most common adverse
(Mays et al. 2013). effects are gastrointestinal disturbances. MMF
may induce a greater susceptibility to infections
Methotrexate as well as increase lifetime risk of cancer, partic-
Methotrexate (MTX) is an antimetabolite that ularly BCC (Brewer et al. 2009). The rate of
suppresses DNA and RNA synthesis during the lymphoproliferative malignancy is probably
S-phase of cell cycle. MTX was originally con- slightly higher than with AZA (Strathie Page and
ceived as an antimalignancy drug, but it is now Tait 2015), but MMF may cause significantly less
likely the most commonly used immunosuppres- liver abnormalities. Other uncommon or rare side
sive agent in rheumatology and dermatology after effects are genitourinary disturbances and neuro-
GCs, particularly for rheumatoid arthritis and pso- logic symptoms, including progressive multifocal
riasis, respectively (Bangert and Costner 2007). leukoencephalopathy (Chahin and Berger 2015).
At low doses, MTX has potent anti-inflammatory Antacids, including proton pump inhibitors,
actions that appear to be mediated via pathways reduce MMF absorption. Initial recommended
separate from folate antagonism. The inhibition of MMF doses are 250–500 mg/day with titration
polyamines is thought to contribute to its anti- up to 2 g/daily. All oral medicine uses of MMF
inflammatory effects as well as increase in aden- are off-label and are roughly the same as AZA.
osine and the production of reactive oxygen Like AZA, MMF is mainly used together with
glucocorticosteroids but also as a single agent, and adherence of neutrophils and synthesis of
most commonly in recalcitrant OLP, vulvovagi- prostaglandins E2 (Georgakopoulou and Scully
nal–gingival syndrome, and OFG if associated 2015c). Dapsone is usually administered orally
with Crohn’s disease (Wee et al. 2012; Smith and is rapidly absorbed but has a long-elimination
and Cooper 2014). Mycophenolate is a confirmed half time (remaining in the circulation for as long
teratogen so must be avoided during pregnancy, as 35 days). Dapsone therapy may cause a variety
and women of child-bearing age should not be of adverse effects, which may be categorized as
prescribed this medicine unless two effective pharmacologic, dose dependent, and allergic or
forms of contraception are in place before, during, idiosyncratic reactions. Most dapsone adverse
and for 6 weeks following treatment with effects are supposed to be dose related and not
mycophenolate, unless abstinence is the chosen serious at daily doses below 100 mg but the evi-
contraceptive method. dence is controversial in this regard.
The most frequent and well-documented phar-
Systemic Anti-inflammatory Agents macologic reactions are the hematological side-
effects, such as methemoglobinemia, hemolysis,
Colchicine and anemia that are usually asymptomatic.
Colchicine is an alkaloid isolated from Colchicum Peripheral neuropathy is not uncommon and usu-
autumnaleit (Autumn crocus plant) and acts by ally involves the motor neurons or mixed senso-
blocking mitosis – mainly in neutrophils – thereby rimotor neurons and may affect upper, lower, or
inhibiting their mobility and activity (Molad both extremities. The two most serious idiosyn-
2002). Colchicine also inhibits leukotriene B4 cratic adverse effects are agranulocytosis and the
and interferes with inflammasome formation dapsone hypersensitivity syndrome. Dapsone is
both in granulocytes and monocytes (Molad strictly contraindicated in patients with glucose-
2002). Colchicine is traditionally used in manage- 6-phosphate dehydrogenase (G6PD) deficiency in
ment of gout and familial Mediterranean fever view of the likelihood of hemolysis, and patients
but has been of some value in managing should be tested for G6PD deficiency before treat-
oral ulceration in Behcet’s disease and RAS ment (Pamba et al. 2012).
(Georgakopoulou and Scully 2015c). Colchicine Dapsone has been mainly used as a single
can cause gastrointestinal adverse effects, alope- medication in mild MMP at doses ranging from
cia and hair loss, malabsorption syndrome, hepa- 25 to 200 mg/daily (Di Zenzo et al. 2014). While
totoxicity, myopathy, and neuropathy. Colchicine most patients with MMP improve, complete and
use should be avoided during pregnancy. It should permanent remissions are rare and the safety pro-
also be avoided in men planning to have children file is a concern (Di Zenzo et al. 2014). Dapsone’s
as colchicine use has been associated with utility as a steroid-sparing agent in PV is unclear
decreased sperm production (Drugs.com 2018). (Zhao and Murrell 2015) and the medication can
According to two Cochrane reviews, there is no occasionally also be used for OLP and Behcet’s
evidence that colchicine can help in either RAS or disease.
Behçet’s disease at doses ranging from 0.5 mg up
to 1.5 mg daily (Saenz et al. 2000; Brocklehurst Tetracycline
et al. 2012). Tetracyclines were discovered in 1945 as natural
fermentation products of the soil bacterium
Dapsone Streptomyces aureofaciens. Tetracyclines have
Dapsone is a chemotherapeutic agent primarily been used since the 1950s to treat immunologi-
used in a variety of infectious diseases, including cally mediated disorders as they have anti-
malaria, leprosy, and Pneumocystis carinii pneu- inflammatory and anti-collagenase properties
monia in patients with AIDS. Dapsone also has (Perret and Tait 2014). Minocycline and doxycy-
anti-inflammatory properties that have been cline are better absorbed than tetracycline as
known since the early 1950s. It inhibits migration they are more lipophilic. Minocycline is a
semisynthetic tetracycline widely used to treat total cumulative dose, and it can be slow to
acne. Minocycline has been proposed for the treat- resolve or may be irreversible (Wu et al. 2005).
ment of several bullous diseases including MMP Opioids, antipsychotics, and antihistamines
(Di Zenzo et al. 2014) in doses ranging from 50 to should be avoided as they may potentiate
200 mg/day (Carrozzo et al. 2009). However, high the somnolence induced by thalidomide
doses (200 mg/day) of minocycline, alone or in (Georgakopoulou and Scully 2015c). In oral med-
conjunction with topical steroids, may be of little icine, thalidomide is mainly used for managing
help in managing patients with predominantly aggressive RAS at doses from 100 up to 400 mg/
oral MMP. The benefits are limited by the frequent daily, and mainly if the patient is HIV-positive
side effects of the drug, particularly vertigo (Wu et al. 2005). Other oral indications include
(Carrozzo et al. 2009) but also including benign Behcet’s disease, GvHD, and discoid and sys-
intracranial hypertension, drug-induced lupus, temic lupus erythematosus.
serum sickness, and sun-exposed skin and tooth
discoloration (Gough et al. 1996; Harel et al. Topical Immunosuppressive Agents
1996; Knowles et al. 1996). Tetracycline, with or
without nicotinamide, is probably better tolerated Cyclosporine
by MMP patients, but efficacy is uncertain. Doxy- Topical cyclosporine has been reported to be
cycline at subantimicrobial doses (20 mg twice effective mainly in the management of OLP,
daily) has been shown to downregulate meta- although it appears to be possibly less effective,
lloproteinase activity in the periodontal tissues and certainly more expensive, than other topical
and has been used to treat RAS (Preshaw et al. medications for such disease (Conrotto et al.
2007), but according to a Cochrane review, there 2006; Al Johani et al. 2009; Thongprasom et al.
is insufficient evidence to support or refute its use 2011). Topical CsA can be used as suspension
at subantimicrobial doses for the treatment of (5 mL of 100 mg/mL swished and expectorated
RAS (Brocklehurst et al. 2012). Tetracyclines, after 5 min 3 times/day) or mixed with
either tetracycline 500 mg, 4 times daily, or doxy- hydroxyethylcellulose or carboxymethylcellulose
cycline 100 mg twice daily, or minocycline and applied twice daily. The evidence regarding
100 mg twice daily, can be helpful as steroid- the efficacy of topical CsA is more scant for other
sparing agents in PV and help reduce side effects diseases such as PV, MMP, or oral cGvHD
from more potent immunosuppressive agents (Al Johani et al. 2009).
(McCarty and Fivenson 2014). Tetracyclines
should be avoided during pregnancy as they may Tacrolimus
affect the formation of the baby’s bones and teeth Tacrolimus is a macrolide immunosuppressant
and cause tooth discoloration (Drugs.com 2018). derived from Streptomyces tsukubaensis.
Tacrolimus binds to tacrolimus-binding protein
Thalidomide (FK-506–binding protein; FKBP) and inhibits
Thalidomide is widely known for its serious tera- T-cell activation at 10–100 times lower concen-
togenic effects when used as a sedative (Lenz tration than CsA (Al Johani et al. 2009). Origi-
1988) leading to subsequent withdrawal of the nally formulated for topical application in the
drug from the market. Most of the biological management of atopic dermatitis, it is available
effects of thalidomide are related to its anti- as an ointment in two different concentrations,
inflammatory, immune-modulator, and anti- 0.03% and 0.1%, and can be used with or without
angiogenic properties, particularly selective sup- adhesive gels. Topical tacrolimus has been used
pression of TNF-α (Wu et al. 2005). Apart from for OLP, MMP, PV, cGVHD, and OFG. Despite
the teratogenicity risk in either gender, thalido- the lack of placebo-controlled studies, topical
mide has a FDA Black Box warning for the risk tacrolimus has been shown to be effective in
of thrombosis and may also cause peripheral neu- OLP in open labelled and comparative RCT stud-
ropathies. The neuropathy has no relation to the ies (Al Johani et al. 2009) and is now considered
the first second-line drug when very high potency potential efficacy of pimecrolimus (Thongprasom
topical steroids fail. Relatively common side et al. 2011). The carcinogenic potential of topical
effects are burning sensation and taste abnormal- pimecrolimus is still discussed, and there is a FDA
ities after oral application. Systemic absorption of Black Box warning attached to its use because of a
tacrolimus after topical application on the oral theoretical increased risk of malignancy (squa-
mucosa is possible, but only occasionally may mous cell carcinoma and lymphoma) in patients
cause systemic symptoms (Conrotto et al. 2006). using it for skin conditions (Ring et al. 2008).
The carcinogenic potential of topical tacrolimus is
still discussed, and there is a FDA Black Box Topical Anti-inflammatory Agents
warning attached to the use of tacrolimus and
pimecrolimus because of a theoretical increased Tetracycline
risk of malignancy (squamous cell carcinoma and Several tetracyclines, including tetracycline
lymphoma) in patients using topical tacrolimus/ hydrochloride, doxymycin, doxycycline, and
pimecrolimus for skin conditions (FDA 2017). minocycline, have been sparingly employed in a
There have also been two cases in whom topical variety of preparations for the topical manage-
tacrolimus potentially facilitated malignant trans- ment of several oral ulcerative disorders. RAS is
formation of OLP (Becker et al. 2006; Mattsson most likely the disease where topical tetracycline
et al. 2010). The usefulness of topical tacrolimus has been used most often, either as a mouthwash
in other oral disorders is less known, particularly alone (for example, 100 mg of doxycycline cap-
when it comes to autoantibody-mediated diseases. sules or 250 mg tetracycline stirred into
20–100 ml of water, 3–4 times daily), or mixed
Pimecrolimus with other agents (such as nystatin), or with adhe-
Pimecrolimus is the newest available topical sive media (Ylikontiola et al. 1997; Gorsky et al.
calcineurin inhibitor. It is derived from the macro- 2007).
lide ascomycin isolated from Streptomyces
hygroscopicus var. ascomyceticus (Jovanovic
and Golusin 2016). Pimecrolimus shares the Biologic Agents
same cellular binding protein (FK506-binding
protein-12) as tacrolimus and blocks the transcrip- Biologic agents (BAs) are a relatively recent cat-
tion of cytokines by inhibiting the calcineurin egory of immune modulating agents that have
pathway. Pimecrolimus has lower permeation been widely used in the treatment of inflammatory
through the skin than topical steroids or topical and neoplastic conditions. BAs are manufactured
tacrolimus, and is more selective than tacrolimus in, or extracted from, a biological source that
and CsA, and has no effect on Langerhans cells includes human (suffix “mab”), humanized (suffix
(Jovanovic and Golusin 2016). As 1% cream with “zumab”) or chimeric (mouse–human; suffix
or without adhesive gels, pimecolimus has mainly “ximab”) monoclonal antibodies or variant fusion
been used for OLP management (Al Johani et al. proteins (suffix “cept”). The number of new avail-
2009). According to a Cochrane review, there is able biologic agents is growing exponentially
no evidence from the three randomized-placebo (Table 8) and a comprehensive discussion of
controlled trials that topical pimecrolimus is better these is outside the scope of this chapter which
than placebo in reducing pain from OLP will focus on BAs used in the management of oral
(Thongprasom et al. 2011). However, a more disorders.
recent comparative RCT claims that pimecrolimus The use of biological therapy in the manage-
is as effective as tacrolimus for unresponsive ero- ment of inflammatory oral mucosal conditions is
sive OLP (Arduino et al. 2014). One common commonly off-label and rarely used by oral med-
problem of almost all the published studies is the icine specialists not least as these drugs are mostly
small sample size. Further and more powerful given by injection or infusion for which the
research is clearly warranted to clarify the patients need to be hospitalized. These drugs are
Table 8 Applications and oral adverse effects of main biologic agents (Adapted from Georgakopoulou and Scully
2015a, b)
Agent Target Indication Oral indication Oral adverse effects
Abatacept CD80/CD86 Transplant rejection, – Ulcers
rheumatoid arthritis
Abciximab Glycoprotein Coronary interventions – Gingival bleeding,
II/IIIa petechie, xerostomia
Adalimumab TNF-α Crohn’s disease, OFG, Behcet’s, OLP, EM, SCC,
rheumatoid arthritis, RAS candidosis
psoriasis
Alefacept CD2 (memory Psoriasis OLP –
effector T
lymphocites
Alemtuzumab CD52 Chronic lymphoid –
leukemia, rheumatoid
arthritis
Anakinra IL1-R Rheumatoid arthritis –
Basiliximab IL-2R Transplant rejection OLP Gingival swelling,
ulcers
Belatacept CD80/CD86 Transplant rejection – –
Bevacizumab VEGF Cancers (various) – EM, gingival swelling,
stomatitis, xerostomia
Bortezomib Proteasome Multiple myeloma –
Canakinumab IL-1β Juvenile arthritis –
Catumaxomab Epithelial cell Cancers –
adhesion
molecules
Certolizumab TNF-α Crohn’s disease, –
rheumatoid arthritis,
psoriasis
Cetuximab EGFR Head and neck cancer Oral SCC Stomatitis, taste
alteration, xerostomia
Daclizumab IL-2R Transplant rejection – ulcers
Denileukin IL-2R Lymphoma –
diftitox
Denosumab RANKL Osteoporosis – Osteonecrosis
Eculizumab C5 Paroxysmal nocturnal
hemoglobinuria
Etanercept TNF-α Crohn’s disease, MMP, Behcet’s Candidosis, SCC?,
rheumatoid arthritis, disease, RAS, SjS EM, OLP
psoriasis, sarcoid
Gemtuzumab CD33 Acute myeloid leukemia – –
Golimumab TNF-α Crohn’s, rheumatoid – –
arthritis, psoriasis,
Ibritumomab CD20 NHL – Candidosis, EM
Infliximab TNF-α Crohn’s disease, OFG, cGVHD, OLP, osteomyelitis,
rheumatoid arthritis, Behcet’s diease, ulcers, parotitis, EM
psoriasis, sarcoid SjS
Muromonab CD3 Transplant rejection – –
Natalizumab Integrin receptor Multiple sclerosis, Crohn’s – –
ihibitor disease
Omalizumab IGE Asthma – –
Panitumumab EGFR Cancers Mucositis
(continued)
Table 8 (continued)
Agent Target Indication Oral indication Oral adverse effects
Ranibizumab VEGF Age-related macular – –
degeneration
Rilonacept IL-1 Autoinflammatory disease – –
Rituximab CD20 NHL, rheumatoid arthritis PV, MMP, SjS Candidosis
Tocilizumab IL-6R Rheumatoid arthritis – –
Tositumomab CD20 NHL – Mucositis
Trastuzumab ErbB2 Breast cancer Mucositis, dysgeusia
Ustekinumab IL12-IL23 Psoriasis – –
EGFR Epidermal growth factor receptor, IL interleukin, RANKL receptor activator of nuclear factor-KB ligand, VEGF
vascular endothelial growth factor, OFG oro-facial granulomatosis, OLP oral lichen planus, MMP mucous membrane
pemphigoid, PV pemphigus vulgaris, cGVHD chronic graft versus host disease, EM erythema multiforme, RAS recurrent
aphthous stomatitis, SjS Stevens-johnson Sydrome
expensive and can have immediate and long-term (rheumatoid arthritis protocol [RAP]) (Veilleux
adverse effects such as immune toxicity, cardiac and Shear 2017). In bullous disorders, particularly
failure, cytokine storms, fatigue, arthralgias, PV, RAP has been mainly employed (Cirillo et al.
immunosuppression, autoimmunity, infections, 2012; Ahmed and Shetty 2015). Clinical remis-
and malignancy. Several BAs can also cause oral sion on therapy was observed in 90–95% of
adverse effects (Table 8). Despite these risks, bio- patients within less than 6 weeks. A complete
logics are increasingly used and can be highly resolution occurred within 3–4 months. A small
effective agents. percentage of patients were able to stay in clinical
BAs have been used in a variety of oral dis- remission without the need for additional sys-
eases including Behçet’s disease, severe RAS, temic therapy. The incidence of relapse was at
bullous diseases, OLP, Crohn’s disease/OFG, least 50% (Ahmed and Shetty 2015). The majority
Stevens-Johnson Syndrome (SjS), cGvHD, and of patients in clinical remission post-RTX therapy
in oral cancer therapy. By and large, bullous were still on GCs and immunosuppressive agents,
diseases and oral cancer are the oral disorders albeit at lower doses. In a study of 433 patients
for which BAs are mostly used, whereas for all with recalcitrant PV treated with RTX, serious
others, evidence is currently no more than adverse effects were seen in about 1%, mainly
anecdotal. infections and frequently associated with septice-
mia (Veilleux and Shear 2017). A very recent
Rituximab multicenter trial suggests that first-line use of
Rituximab (RTX) is a chimeric anti-CD20 mono- RTX plus short-term prednisone for patients with
clonal antibody that targets the CD20 transmem- pemphigus is more effective than using predni-
brane glycoprotein, which depletes B cells while sone alone, with fewer adverse events (Joly et al.
maintaining the terminally differentiated plasma 2017).
cells, as well as stem cells (Veilleux and Shear Complications of SjS such as fatigue,
2017). This monoclonal antibody is currently cryoglobulianemia, pulmonary disease, poly-
used for treating various autoimmune diseases, synovitis, arthralgia, and peripheral neuropathy
such as rheumatoid arthritis, but it has recently can also be managed with RTX; however, this
been approved in the UK for PV and MMP (NHS has little benefit in improving salivary flow
England 2018). (Pijpe et al. 2009). This drug is possibly effective
RTX is mainly used in two different regimens, in the treatment of SjS-associated lymphomas,
namely 375 mg/m2 through four weekly infusions although the therapeutic response in salivary
(lymphoma protocol [LP]) or 1000 mg/d admin- gland lymphoma is poor (O’Neill and Scully
istered as two intravenous infusions 2 weeks apart 2013).
TNF-a Inhibitors Cetuximab

TNF-α is a cytokine produced mainly by macro- Cetuximab is a recombinant, human/mouse chi-
phages and participates in the regulation of meric monoclonal antibody that targets the extra-
inflammation, cell death, and proliferation. This cellular ligand-binding domain of epidermal
cytokine has pro-inflammatory and immune- growth factor (EGFR) with high affinity (Moon
regulatory functions. TNF-α also affects the liver et al. 2010). Preclinical studies show that
as a mediator of hepatotoxicity and promotor of cetuximab inhibits the proliferation of cell lines
hepatocyte proliferation and liver regeneration expressing EGFR, including head and neck squa-
(Wullaert et al. 2007; Nielsen and Ainsworth mous cell carcinoma (HNSCC) cell lines, and
2013). increases the cytotoxic effects of chemotherapy
There are several anti-TNF-α agents currently and radiation.
approved for the induction and maintenance treat- Cetuximab is generally licensed, in combina-
ment of inflammatory bowel disease, namely tion with radiotherapy, for the treatment of locally
infliximab (IFX), adalimumab (ADA), golimumab, advanced HNSCC and in combination with
and certolizumab pegol. Infliximab has been platinum-based chemotherapy for recurrent or
shown to have a role in the management of Crohn’s metastatic HNSCC (Moon et al. 2010).
disease and OFG (Colombel et al. 2007; Elliott A recent Cochrane review found some evi-
et al. 2011). In a recent series, three initial induction dence that adding EGFR monoclonal antibody to
infusions of IFX at 5 mg/kg were given at 0, 2, and standard therapy for oral and oropharyngeal can-
6 weeks as standard induction followed by two cers may increase overall survival, progression-
monthly maintenance infusions if there was evi- free survival, and loco-regional control, while
dence of a satisfactory clinical response to induc- resulting in an increase in skin toxicity, mainly
tion (Elliott et al. 2011). In all cases, IFX was acneiform rashes (Chan et al. 2015).
trialed as the first-line TNF-α blocker, either alone
or with concomitant immunosuppression. There
was a short-term response to IFX in 71% of Therapeutic Protocols
cases, and follow-up data showed 57% of patients
still responsive after 1 year and 33% at 2 years Oral Candidosis
(Elliott et al. 2011). While use of TNF-α inhibition
in the setting of inflammatory bowel disease is Guideline recommendations from the Infectious
considered safe, there are potential serious adverse Diseases Society of America (IDSA) for the treat-
effects, which include infusion reactions, infection, ment of oropharyngeal candidosis are summa-
and increased risk of malignancy (O’Neill and rized in Table 9. Both IDSA and NICE UK
Scully 2012). recommend topical therapy as first-line treatment
Patients with Behçet’s disease also respond to for adult immunocompetent patients with an ini-
TNF-α inhibitors, including infliximab, tial and mild disease. Clotrimazole, miconazole,
etanercept, and adalimumab (Sfikakis et al. and nystatin are suitable drugs and should be
2007), and occasionally TNF-α inhibition with prescribed for 5–14 days. The recommended ini-
etanercept or adalimumab has been used for recal- tial treatment for moderate-to-severe disease is
citrant RAS (Robinson and Guitart 2003, oral fluconazole. NICE UK suggests 50 mg/day
Vujevich and Zirwas 2005) and OLP (Chao for 7–14 days whereas IDSA recommends
2009). However, several reports suggest that 100–200 mg (3 mg/kg) once daily for
anti-TNF-α agents can actually trigger oral 7–14 days. In cases resistant to fluconazole,
lichenoid lesions (Asarch et al. 2009; Andrade itraconazole, posoconazole, or voriconazole can
et al. 2015). TNF-α blockers (mainly infliximab be employed.
and etanercept) have also been used with usually Denture-associated erythematous stomatitis can
modest benefit in SjS (Mariette et al. 2004; Sankar be treated with either topical or systemic medica-
et al. 2004; Meijer et al. 2007). tion according to clinical severity. Moreover,
Table 9 Infectious Diseases Society of America guideline the optimal timing and dosage. Oral acyclovir
recommendations for oropharyngeal candidosis suspension (15 mg/kg) 5 times daily for a week,
Severity of Treatment (strength of valaciclovir 1 g twice a day for 1 week, and
infection recommendation) famciclovir 500 mg once or twice a daily for
Mild Clotrimazole troches (10 mg, five 1 week have been advocated, but the evidence is
times daily), nystatin suspension at a
concentration of 100,000 U/mL and limited.
a dosage of 4–6 mL qid, or 1–2 Most cases of herpes labialis recurrences are
nystatin pastilles (200,000 U each) generally mild and self-limiting with spontaneous
administered qid for 7–14 days, is healing occurring over 7–10 days. Patients should
recommended (B)
be educated on avoidance of precipitating factors
Moderate-to- Oral fluconazole 100–200 mg
severe (3 mg/kg) qd for 7–14 days is (for example, stress, oral trauma, or sun exposure).
recommended (A) For pain relief, topical lidocaine 5% ointment or
Refractory to Itraconazole solution 200 mg qd, or choline salicylate gel (Bonjela®) can be tried. Top-
fluconazole posaconazole suspension at 400 mg ical antivirals seem to have limited effectiveness
bid for 3 days, then 400 mg qd for up
and should be initiated best before the appearance
to 28 days, is recommended (A)
Voriconazole 200 mg bid, or a 1 mL of the vesicles, as soon as the first prodromal
oral suspension of AmB-d (100 mg/ symptoms appear. Some weak evidence suggests
mL qid), is recommended when that penciclovir may be more effective than acy-
treatment with other agents has
clovir, but it must be applied more frequently
failed (B)
Intravenous echinocandin or (every 2 instead of 3–4 h), and it is more expensive.
amphotericin B deoxycholate at a There is still controversy about the advantage
dosage of 0.3 mg/kg qd can be used of systemic over topical antivirals for the man-
for treating patients with refractory
agement of primary and recurrent oral manifes-
disease (B)
tations of HSV. Generally speaking, systemic
bid twice daily, qd once daily, qid four times daily
antivirals can be used in severe recurrences in
immunocompetent and in immunocompromised
patients should be advised to soak the denture in patients. The FDA has approved a short course of
disinfectant solutions (e.g., containing hypochlo- valaciclovir (2 g twice daily, every 12 h for 1 day)
rite or chlorhexidine), take the denture out at night, and famciclovir (1.5 g/day for 1 day) for recur-
and leave it in a dry covered pot. Chronic hyper- rent herpes labialis.
plastic candidosis can be treated with topical/sys- Prophylactic use of topical antivirals is ineffec-
temic drugs together with surgery but evidence is tive and also systemic antivirals have limited ben-
scant. Chronic mucocutaneous candidosis is gen- efit in preventing recurrences and may cause
erally treated with azoles, such as fluconazole at a significant adverse effects. However, prophylactic
dose of 100–400 mg/day or itraconazole at a dose therapy may be trialed for patients with frequent,
of 200–600 mg/day. The initial therapy from acute severe episodes, or immunocompromised individ-
infection is usually followed by maintenance ther- uals who are at risk of developing severe compli-
apy with the same azole. cations (Arduino and Porter 2006, Woo and
Challacombe 2007). Systemic acyclovir 400 mg
Primary and Recurrent Herpes Simplex two to three times a day or systemic valacyclovir
Infection 500–2000 mg twice a day are recommended for
HSV prophylaxis (Woo and Challacombe 2007).
Primary infection (primary herpetic gingivos-
tomatitis) typical occurs in children. For primary
HSV infection, oral antiviral therapy may be of Herpes Zoster
value, especially in severe infection, neonates, or
immunocompromised people (Scully and Felix Multiple randomized controlled trials shown that
2005). However, there is uncertainty regarding oral ACV (800 mg five times a day for
7–10 days), famciclovir (500 mg every 8 h for adhesive gel (1–3 applications/day) or
7 days), and valacyclovir (1 g three times a day for fluocinonide ointment (2–3/day) or clobetasol
7 days) reduce acute pain and the duration of ointment in adhesive gel (2/day) can be used
chronic pain in herpes zoster patients who are until resolution, according to clinical features.
treated within 72 h of rash onset (Stankus et al. Topical preparations should be applied by gently
2000, Schmader 2007). Compared with ACV, rubbing the medicament into the area of interest,
valacyclovir may be slightly better at decreasing after which patients should be advised to refrain
the severity of pain associated with herpes zoster, from eating, drinking, or rinsing for at least 30 min
as well as the duration of postherpetic neuralgia. after application.
Valacyclovir is also more bioavailable than ACV,
and oral administration produces blood drug levels Major Recurrent Aphthous Stomatitis
comparable to the intravenous administration of If the lesions are amenable to topical treatment,
ACV (Stankus et al. 2000). The advantages of clobetasol ointment in adhesive gel (two applica-
famciclovir are both its longer intracellular half-life tions/day) can be used with an antimycotic if
and its better bioavailability (Stankus et al. 2000). prolonged use for more than 1 week is anticipated.
Orally administered corticosteroids are commonly If there is no response or lesions are not amenable
used in the treatment of herpes zoster, but trials have to topical ointment treatment, a potent dexameth-
shown variable results. asone rinse can be used (2–4 mg dissolved in
100 ml of water used 2–3 times daily as a rinse
and expectorated). Alternatively, prednisolone
HSV-Induced Erythema Multiforme 30–50 mg/day can be used until there is at least
50% reduction of the lesions at which time the
Valacyclovir (500 mg twice a day) seems to be drug should be tapered slowly.
more effective than ACV in suppressing EM trig-
gered by HSV (Woo and Challacombe 2007). Herpetiform Recurrent Aphthous
Stomatitis
Prednisolone 50 mg daily per 3 days, 25 mg daily
Recurrent Aphthous Stomatitis per 3 days, then 25 mg on every other day can be
used until reduction of least 50% of lesions is
Until recurrent aphthous stomatitis (RAS) etiology achieved and then tapered slowly.
is fully understood, treatment options will remain
few and only partially effective. Recent trials have
focused primarily on local and topical treatments. Erythema Multiforme
These therapies in general carry lower risks of
systemic adverse effects and should be considered EM is an acute mucocutaneous condition that is
as first-line treatment (Baccaglini et al. 2011). It is most commonly caused by HSV infection and the
important to exclude predisposing factors or asso- use of certain medications (Sokumbi and Wetter
ciated diseases. It is acknowledged that systemic 2012). EM has been classified into a number of
interventions are often reserved for those patients variants, mainly minor and major forms, as it may
who have been unresponsive to topical treatments involve the mouth alone, or present as a skin
(Brocklehurst et al. 2012) (Fig. 3). eruption with or without oral or other lesions of
the mucous membrane (Scully and Bagan 2008).
Minor Recurrent Aphthous Stomatitis Treatment of EM is controversial, as there is no
Patients with minor RAS should be reassured, and reliable evidence (Fig. 4).
treatment only initiated with requested. Chlorhex-
idine solution or gel, benzydamine, or hyaluronic 1. Oral erythema multiforme (exclusively oral
acid can be applied three times daily. If there is no lesions): Any potential triggering drug should
or partial response, triamcinolone acetonide in be stopped. If lesions are topically treatable,
432
Diagnosis:
• History
• Objective examination
• (Biopsy, mostly not required)
Exclude potenal predisposing factors

• Deficiencies (iron, folate, vitamin B12)
• Behcet’s syndrome (oro-genital ulcers with uveitis)
• Food allergy
• Zinc deficiencies
• Sodium lauryl sulfate (in toothpaste)
• Celiac disease
• Periodic syndromes
• HIV infection
Presence of predisposing Absence of predisposing

factors factors
Major RAS Herpeform RAS Minor RAS

Treat the predisposing
factor, Topical corticosteroids with high to very Do not treat and reassure patients
or where necessary high potency in adhesive gel,
appropriately refer to a with antifungal agents
Specialist
Lack of response or Systemic Chlorhexidine, benzydamine
Complete response partial response corticosteroids mouthwashes, hyaluronic acid
Complete Lack of response

Recurrence
response or partial response
Consider colchicine / thalidomide for severe cases Topical corticosteroids
Fig. 3 Algorithm for the treatment of recurrent aphthous stomatitis (RAS). (Adapted from Gandolfo et al. 2006)
S. Goncalves et al.
Diagnosis:
• History
• Physical examination
• Biopsy (consider direct and indirect immunofluorescence)
• Microbiological tests (herpes simplex and mycoplasma pneumoniae)
• Dermatological assessment, where appropriate
Oral EM (exclusive oral lesions) Minor EM Major EM Toxic epidermal necrolysis

(Stevens-Johnson’s syndrome)
Localized lesions Widespread lesions Not induced by Herpes simplex induced Medication induced Mycoplasma induced Refer to a
and/or not amenable Herpes simplex specialist unit
to topical therapy
Pharmacotherapeutic Approaches in Oral Medicine
Topical Systemic Oral lesions Cutaneous lesions Systemic acyclovir Withdrawal of Systemic erythromycin
corticosteroids with corticosteroids putative medication
of high potency in
adhesive gel,
plus topical
Systemic anti- Systemic Lack of response
antifungals
histamines and corticosteroids and/or exacerbation
topical steroids
Complete response
Recurrence
According to clinical features
Fig. 4 Algorithm for the treatment of erythema multiforme (EM) (Adapted from Gandolfo et al. 2006)
433
clobetasol ointment can be used in adhesive gel gently rub the medicant over the affected area
(twice daily) until reduction of 50% of the and then to refrain from eating, drinking, or
lesions is achieved, then once daily until the rinsing for at least 30 min after application. In
complete resolution. The drug should be the case of gingival lesions, soft trays can be
applied by gently rubbing the medicament, used for occlusive therapy. Alternatively, a
and the patient should refrain from eating, dexamethasone rinse (2–4 mg/100 ml water)
drinking, or rinsing for at least 30 min after can be used 2–3 times per day. The patient
application. In the case of widespread oral should rinse for at least 2–3 min and be advised
lesions, prednisolone 50 mg/day for 3 days, to expectorate the solution and not swallow.
25 mg/day for 3 days, then 25 mg on every 2. Exclusively oral lesions not amenable to top-
other day for 3 days can be used. ical treatment or mucous-cutaneous lesions:
2. Minor erythema multiforme: If lesions are Prednisolone 50 mg/day for 3 days, 25 mg/day
related to HSV infection, acyclovir (1–2 g/ for 3 days, then 25 mg on every other day; or
day) can be used until improvement of at prednisone 50 mg/day can be used until
least 50% of lesions, then tapered. If lesions the resolution of at least 50% of lesions and
are not related to HSV, oral lesions can be then tapered slowly. Consider corticosteroid
treated as above, while cutaneous lesions can sparing agents (azathioprine or mycophenolate
be treated with hydroxyzine (50 mg daily) and mofetil) to reduce corticosteroid. Maintenance
topical steroids if required. should bewith topical medication as outlined
3. Major erythema multiforme (Stevens- above.
Johnson syndrome): If medication induced, 3. In case of lack of response to corticosteroids
then discontinue the drug, and manage with or if they are contraindicated: Tacrolimus
prednisolone 50 mg/day for 3 days, 25 mg/day 0.1% ointment with or without adhesive gel
for 3 days, then 25 mg on every other day until can be used.
improvement of 50% of lesions and then
taper. If caused by Mycoplasma pneumoniae,
use of erythromycin (0.5–1 g daily) can be
instigated. Mucous Membrane Pemphigoid
MMP is not a single entity, and it does not follow a

Oral Lichen Planus predictable course. In some patients, the disease is
mild and localized and does not cause complica-
Active medical treatment should be limited to tions; while in others, it is devastating with severe
symptomatic OLP, usually atrophic-erosive morbidity (Di Zenzo et al. 2014). Treatment
forms, after having considered the elimination of should be individualized for each patient
predisposing factors (Carrozzo and Thorpe 2009). depending on disease severity, age, general state
Topical corticosteroids are considered to be first- of health, associated medical problems, and con-
line treatment for OLP (Fig. 5), but there is insuf- traindications to the use of systemic agents.
ficient evidence to support the superior effective- Because of the relative rarity of MMP, random-
ness of any specific treatment (Thongprasom et al. ized controlled trials are scarce and most of the
2011). following recommendations are based on expert
opinion (Kirtschig et al. 2003) (Fig. 6).
1. Exclusive oral lesions, amenable to topical
treatment: Clobetasol propionate 0.05% oint- 1. Exclusively oral lesions amenable to topical
ment in adhesive gel (2/day) for 2 months, then treatment: Clobetasol propionate ointment
1/day for another month with antifungal pro- 0.05% in adhesive gel (2/day), with antifungal
phylaxis (miconazole gel or nystatin oral sus- prophylaxis (miconazole gel or nystatin oral
pension). The patient should be advised to suspension) can be used, until improvement
Diagnosis:
• History
• Biopsy (consider direct immunofluorescence)
• Liver function test (HCV)
Eliminaon of contribung factors:

• Excessive alcohol intake and tobacco
• Teeth in malocclusion or fractured
• Ill fitting dentures
• Poor oral hygiene
• Consider amalgam replacement
• Consider withdrawal of medication potentially
causing lichenoid drug reaction
Pharmacotherapeutic Approaches in Oral Medicine
Non-erosive asymptomatic OLP Erosive or symptomatic OLP
Follow-up Lack of response Topical steroids with high

potency (e.g. clobetasol
Complete response
propionate)
No contraindications to the Contraindications to the
with antimycotics
use of systemic steroids use of systemic steroids
Systemic corticosteroids Topical tacrolimus with Partial Response Follow-up

(and azathioprine / mycophenolate adhesive gel
mofetil
Maintenance with medium

potency topic steroids
Complete response Partial response
(such as triamcinolone or
Lack of response fluocinonide) and antimycotics
Follow-up
Photopheresis, methotrexate, biologics
Fig. 5 Algorithm for the treatment of oral lichen planus (OLP). (Adapted from Gandolfo et al. 2006)
435
436
Diagnosis:
• History
• Biopsy
• Direct Immunofluorescence; salt-split-skin indirect
immunofluorescence; ELISA (BP180/230, Laminin 332)
• Ophthalmological assessment
Widespread oral lesions and/or

Localized oral lesions
involvement more mucosal areas
Topical very high potency Additional topical therapy if necessary Systemic Steroids
corticosteroids
with antimycotics
Partial response
Not any contraindication to Complete response
the use of systemic steroids
Add azathioprine, or
Complete response Lack of response/ mycophenolate mofetil, or
progressive disease cyclophosphamide
Contraindication to the use
of systemic steroids
Dapsone or tetracycline with

or without nicotinamide Partial response Complete response
Maintenance Complete response

Taper systemic
If cicatricial outcomes, medications, maintain
Maintenance
Consider rituximab consider surgery with topical steroids
Fig. 6 Algorithm for the treatment of mucous membrane pemphigoid. (Adapted from Gandolfo et al. 2006)
S. Goncalves et al.
of at least 75% of lesions and then tapered et al. 2015) (Fig. 7). However, exclusively oral PV
slowly. The patient should gently apply the seems to have a more positive outcome than
medicant and should be advised to refrain mucocutaneous disease which is still the most
from eating, drinking, or rinsing for at least common cause of death among PV patients on
30 min after application. In the case of gingival systemic therapy (Cirillo et al. 2012). Most
lesions, soft trays can be used for occlusive reports describe medication courses of long dura-
therapy. Alternatively, dexamethasone tion before remission of therapy is achieved
(2–4 mg/100 ml water) rinse and expectorate (between 5 and 10 years in the majority of
regimen can be used three times daily. patients), but mild cases can be cured within
2. In the case of lack of response or progressive 2 years of treatment (Cholera and Chainani-Wu
disease or disease not amenable to topical 2016).
treatment: Prednisolone 0.5–2 mg/kg daily
according to clinical severity until improve- 1. Exclusively oral lesions amenable to topical
ment of at least 50% of lesions and then tapered treatment: These lesions may be treated with
slowly followed by topical therapy as detailed clobetasol propionate 0.05% ointment in adhe-
above. Alendronic acid (70 mg per week) can sive gel (twice daily) with antimycotic prophy-
be used with calcium and vitamin D3 for oste- laxis (miconazole or nystatin). However,
oporosis prophylaxis. significant therapeutic responses are rare with
3. In the case of lack of response or progressive topical approaches and systemic steroids
disease or not amenable to topical treatment (1–2 mg/kg daily) together with adjuvant immu-
but with lesions limited to the oral cavity nosuppressive agents are frequently required.
and contraindications to the use of systemic 2. In the case of widespread oral involvement
steroids: Dapsone 50 mg can be used for the and/or involvement of more mucosal areas
first 3 days, increased by 25 mg every 3 days and/or of skin: Prednisolone 30–100 mg daily
until arriving at a dose of 150 mg. plus azathioprine (50–200 mg daily) or
4. In the case of disease disseminated to the mycophenolate mofetil (250–2000 mg daily)
oral cavity and involving other tissues: Pred- or cyclophosphamide (0.5–2 mg/kg/day) are
nisolone 0.5–2 mg/kg daily should be insti- usually employed. Once positive results have
gated and escalated as detailed above, in been obtained, the corticosteroid can be
addition to azathioprine (1–2 mg/kg/day) or tapered.
cyclophosphamide (0.5–2 mg/kg/day) if ocular 3. If the disease does not respond to corticoste-
lesions are present, or dapsone (50 mg esca- roids and two immunosuppressive agents,
lated as above) or sulfapyridine (1.5–3 g/day) then Rituximab can be employed as detailed
in the case of prevailing oral lesions. Once earlier.
meaningful resolution is obtained, the corti-
costeroids are slowly tapered back and the
patient is maintained with secondary immuno-
suppressants and topical steroids as detailed Orofacial Pain Management
above.
Peripheral and Central Mechanisms
of Pain
Pemphigus Vulgaris
The detection of pain in the orofacial region is
PV is a rare, potentially lethal disease that very conveyed primarily by A delta and C fibers in the
commonly causes oral ulcerations. Published ran- nerves of the trigeminal system that project to the
domized trials are limited and existing evidence nucleus caudalis in the medulla that is the func-
does not allow ascertainment of the optimal ther- tional equivalent of the spinal dorsal horn (Fig. 8).
apy for this disease (Martin et al. 2009; McMillan The trigeminal nerve (fifth cranial nerve) consists
438
Diagnosis:
• History
• Biopsy
• Direct immunofluorescence
• Indirect immunofluorescence / ELISA anti DSG 1-3 (for checking the disease activity
• Dermatological assessment
Moderate or severe disease

Disease localized exclusively to the oral
(widespread oral involvement and/or involvement
cavity (not widespread)
of more mucosal areas and/or of the skin)
Topical corticosteroids with very high

If necessary, topical additional therapy Systemic corticosteroids
potency in adhesive gel with antimycotics
Complete response Partial response Lack of response/ Partial response Complete response
progression of the disease
Add dapsone, or
systemic tetracyclines Add azathioprine, or
mycophenolate mofetil, or
cyclophosphamide
Complete response Partial response

Complete response
Maintenance Therapy Minor or localized Severe or widespread

lesions lesions
Taper and maintenance therapy

Topical, or Rituximab; IV Ig;
intra-lesional corticosteroids plasmapheresis;
photopheresis
Fig. 7 Algorithm for the treatment pemphigus vulgaris. (Adapted from Gandolfo et al. 2006)
S. Goncalves et al.
Fig. 8 Diagrammatic representation of the sites and action of therapeutic targets for pain relief. (Original drawing by
Dr Hala Al Janaby, Perth WA, Australia)
of three branches: ophthalmic, maxillary, and craniofacial tissues terminate in laminae I, II, V,
mandibular, that innervate most of the face and and VI of the nucleus caudalis. The major projec-
anterior scalp, the teeth, and the mucous mem- tion from the brain stem in primates for nocicep-
brane of the mouth, gingiva, nasal cavities, tive information from the mouth and craniofacial
sinuses, meninges, jaw, and anterior two-thirds structures is the trigeminothalamic tract, which is
of the tongue. Fibers from the brain stem then composed of axons from both nociceptive and
project via the trigeminothalamic tract to the thal- wide dynamic range neurons. These axons cross
amus and eventually to the cortex. The facial to the contralateral side of the medulla and ascend
nerve, glossopharyngeal nerve, and the vagus rostrally to the thalamus, where additional neu-
nerve also provide sensory input from oral struc- rons convey this information to the cerebral cor-
tures to provide the peripheral innervation neces- tex. Descending neurons from central sites that
sary for the detection of cutaneous and dental pain integrate higher functions such as expectations
from the orofacial region. and recall of previous events also modulate the
The nucleus caudalis is the principal brain stem transmission of nociceptive information as part of
relay site for nociceptive information transmitted the endogenous pain inhibitory system.
via the trigeminal nerve. Its laminated structure, Several physiologic processes also influence
the type of cells, and the function in processing the perception of pain. Extensive convergent
nociceptive signals are similar to those of the afferent input pathways are characteristic of noci-
spinal cord. The small diameter afferents carrying ceptive and wide dynamic range neurons in the
nociceptive information from the various nucleus caudalis. The presence of cutaneous as
well as deep receptive fields for most of these roles in the pathogenesis and resolution of neuro-
neurons may explain the poor localization of pathic pain conditions. Bacterial infections also
deep pain as well as contribute to the spread and regulate pain through direct actions on sensory
referral of pain typical of pain conditions involv- neurons and may provide novel therapeutic strat-
ing the temporomandibular joint and associated egies to control neuroinflammation in the treat-
musculature. The frequent occurrence of pain ment of chronic pain.
referral in most toothaches and headaches may
also be related to convergence pathways from
tooth pulp and cerebrovascular afferents on to Drugs for Management of Chronic
nociceptive neurons. Orofacial Pain
Many inflammatory mechanisms that initiate
tissue damage also activate nociceptors and acti- The management of chronic orofacial pain differs
vate the early synthesis and release of pro-inflam- from acute pain management in several important
matory cytokines, inflammatory mediators, and ways: (1) medication safety issues become more
neuropeptides. A large body of evidence indicates problematic when duration of treatment extends
that the pro-inflammatory actions of cytokines beyond the short term of acute pain to weeks and
contribute to the pathogenesis of acute oral months of chronic pain, (2) the therapeutic objec-
inflammation and stomatitis through the response tive is more palliative as the underlying cause of
of inflammatory cells to mucosal signaling, the chronic pain often does not resolve and (3) the
resultant inflammatory cascade and the potential for significant morbidity or mortality
upregulation of proteolysis and apoptosis. The becomes a paramount limitation. Conversely, the
resultant nociceptive barrage can lead to pro- potential for iatrogenic injury is much less com-
longed functional alterations in the nucleaus pared to surgery or splint therapy and is often
caudalis known as central sensitization. Periph- directed at the physiologic basis for pain rather
eral sensitization also can contribute to hyper- than a symptom that may not be prognostic, for
algesia and allodynia by increasing the example, clicking and popping in the temporo-
excitability and decreasing the activation of mandibular joint. Physical medicine approaches
threshold of primary afferents. Chronic orofacial are often more likely to result in therapeutic
pain conditions likely involve a combination of improvement with parallel drug treatment
peripheral and central sensitization phenomena. directed towards pain management, especially
Management of acute orofacial pain is best for musculoskeletal pain due to overuse or stress.
accomplished in the periphery by attenuating The relative paucity of well-controlled clinical
nociceptive input at the receptor level with anti- trials in this area often limits generalization due
inflammatory drugs or by interfering with noci- to the limited number of patients, the heterogene-
ceptive transmission with local anesthetic drugs. ity of inclusion/exclusion criteria, and variability
The profound analgesic efficacy of opioid drugs in outcome measures and length of treatment.
results from their ability to mimic the actions of Very few studies have been published that evalu-
endogenous opioid peptides at multiple levels of ate the combination of a pharmacologic agent and
the central nervous system. Due to their poor oral a physical medicine modality to demonstrate the
efficacy, propensity to cause drowsiness, nausea, efficacy of each modality alone and their com-
vomiting, and their abuse potential, the use bined efficacy, thereby mimicking how patients
of opioids for orofacial pain is adjunctive. are treated in clinical practice. Despite these lim-
Descending noradrenergic projections from the itations, there is reasonable evidence to support
CNS to dorsal horn neurons contribute to the clinical efficacy and safety of several drug
descending analgesia and may explain the analge- classes that are used for chronic orofacial pain.
sic effects of antidepressants for chronic orofacial Several recent reviews of the literature have
pain. Non-neuronal cells such as immune cells, summarized the level of evidence for drugs used
glial cells, keratinocytes and stem cells play active for orofacial pain quantitatively (Clark et al.
2016), qualitatively (Merrill and Dionne 2017), alone did not demonstrate analgesic efficacy but
and comprehensively (Clark and Dionne 2012). the combination of ibuprofen with diazepam
Specific details on drug doses, contraindications resulted in a significant reduction in pain in com-
and adverse effects are best reviewed by consult- parison to placebo, suggestive of an additive
ing the approved product information in one’s effect for the combination (Singer and Dionne
own jurisdiction as well as drugs and therapeutics 1997). One study demonstrated pain relief in
compendia. patients with TMJ osteoarthritis who received
ibuprofen for 12 weeks (Thie et al. 2001). An
Nonsteroidal Anti-inflammatory Drugs evaluation of naproxen compared with celecoxib
(NSAIDs) and placebo demonstrated greater reduction in
The management of chronic inflammation due to pain from baseline over 6 weeks in the naproxen
osteoarthritis in joints other than the TMJ is often group (Ta and Dionne 2004). Retrospective indi-
undertaken with long-term administration of non- vidual responder analysis of patients who had
steroidal anti-inflammatory drugs (NSAIDs) greater than a 50% reduction in pain from baseline
(Fig. 9) despite their unfavorable side-effect pro- also supported the efficacy for celecoxib (Singer
file when administered for more than a few days and Dionne 1997). Administration of diclofenac
(Fig. 10). The limited data within the dental liter- sodium for 3 months also resulted in significant
ature does not permit meta-analysis so as to pro- pain reduction that was sustained at the 1-year
vide strong evidence of efficacy and safety for follow-up evaluation (Mejersjo and Wenneberg
NSAIDs for temporomandibular joint (TMJ) oste- 2008). Conversely, evaluation of piroxicam as an
oarthritis. Four of five published studies that have adjunct to an oral appliance did not find any
evaluated a NSAID for TMJ pain attributed to additive effect for the NSAID treatment (van den
osteoarthritis or secondary to disc displacement, Berghe et al. 1986). Taken together, these data
provide support for their efficacy when adminis- support a role for an NSAID as a primary treat-
tered for 4–12 weeks. Administration of ibuprofen ment for 1–3 months in the management of TMJ
NSAIDs
Mechanism of acon:
Suppression of prostaglandin synthesis
Fig. 9 The mechanism of action of nonsteroidal anti- prostaglandin synthesis from arachidonic acid. (Original
inflammatory drugs is via inhibiting the enzyme cycloox- diagram by Dr Hala Al Janaby, Perth WA, Australia)
ygenase (COX1 and COX2) and thus suppressing
Cardiovascular system
Inhibition of COX-2 > COX1:
• Myocardial infarction
Gastrointesnal mucosa
Inhibition of COX-1:
• Peptic ulcers
• Gastrointestinal bleeding
• Pain
Kidney
Inhibition of COX-1:
• Acute kidney injury
Fig. 10 Side effects of nonsteroidal anti-inflammatory incidences of peptic ulcers, bleeding, and pain. (2) The
drugs (NSAIDs). Prostaglandins are synthesised via cyclo- inhibition of COX-1 and COX-2 can affect the kidneys
oxygenase (COX-1 or COX-2) from arachidonic acid. The resulting in a decreased glomerular filtration rate which
mechanism of action of NSAIDs is via the suppression of ultimately leads to acute kidney injury. (3) In the cardio-
prostaglandin synthesis by blocking COX-1 and vascular system, there is a greater inhibition of COX-2 than
2 enzymes. COX- 1 and 2 have physiologic functions COX-1 which increases the risk for myocardial infarction
within the gastrointestinal mucosa, the kidneys and the and stroke. (Original drawing by Dr Hala Al Janaby, Perth
cardiovascular system that may be affected. (1) In the WA, Australia)
gastrointestinal mucosa, inhibiting COX-1 increases the
osteoarthritis or disc displacement, but the all these properties are produced by blocking the
adverse events usually attributed to this drug formation of prostaglandin by the cyclooxygenase
class need to be considered. Naproxen may have enzyme. Aspirin’s role as the mainstay of
cardioprotective properties when given chroni- non-opioid analgesic therapy was reduced with
cally, while celecoxib could result in less gastro- the introduction of the NSAIDs and acetamino-
intestinal complaints with chronic administration. phen (paracetamol). While still an effective anal-
gesic, the side effect profile of aspirin, its short
Salicylates duration of action, and its inhibition of hemostasis
Salicylates have been used for pain relief in natu- limits its role in pain management of all kinds,
rally occurring forms (willow bark), as the semi- including chronic orofacial pain.
synthetic form salicylic acid, and eventually in the Diflunisal is a salicylic acid derivative that
synthetic form as aspirin (acetylsalicylic acid), overcomes some of aspirin’s limitations. It dem-
first introduced in 1899. Aspirin has been widely onstrates greater analgesia in acute pain studies
used for pain relief, to lower body temperature in primarily due to its longer duration of action that
the presence of fever, and to reduce swelling, and results in greater summarized analgesic scores
over time (Forbes et al. 1982). When administered (paracetamol) due to its availability in multiple
in the 1000 mg formulation (Dolobid) followed formulations for a variety of indications has led
by 500 mg every 12 h, it can be administered to recognition that it produces hepatotoxicity
twice daily to provide relief of mild to moderate when administered chronically or in high doses,
pain. Diflunisal has fewer gastrointestinal and which can be fatal. Given the weak evidence to
hematologic adverse effects but produces gastritis support the use of acetaminophen (paracetamol)
when administered chronically. There is little evi- for chronic orofacial pain and the potential for
dence to support the use of diflunisal for chronic serious toxicity, its use should be limited to
orofacial pain, but it may be useful as alternative patients who cannot tolerate NSAIDs but for a
to aspirin, acetaminophen, or nonprescription short course of therapy, while other non-
doses of NSAIDs. pharmacologic modalities are being used to
relieve symptoms.
Acetaminophen (Paracetamol)
While structurally and mechanistically different Opioids
from the NSAIDs, acetaminophen (paracetamol) The widespread epidemic of opioid overdose
(Fig. 11) is often administered as a first choice or deaths combined with limited evidence to support
as an alternative for patients who cannot tolerate the efficacy of this drug class for chronic orofacial
an NSAID. Its rapid onset and short duration of pain limits the rationale for using traditional opi-
action (4–6 h) has value in acute exacerbations of oids for this indication. Given the likelihood of
TMJ osteoarthritis or internal derangement (Clark opioid administration to result in misuse, abuse,
et al. 2016). The basis for its use for chronic and eventual physical dependence, the use of opi-
orofacial pain is supported more by its chronic oids for chronic orofacial pain is best managed by
administration for osteoarthritis pain in joints a pain specialist working in a multidisciplinary
other than the TMJ, and for chronic musculoskel- pain clinic. One possible exception to this gener-
etal pain (Towheed et al. 2006). Conversely, a alization is the drug tramadol. It is classified as an
review of acetaminophen’s efficacy for chronic atypical opioid analgesic but binds to mu-opioid
lower back pain did not find any greater activity receptors in addition to inhibiting reuptake of both
than a placebo medication (Chou et al. 2017), norepinephrine and serotonin, an action similar to
suggesting that its clinical efficacy does not serotonin noradrenaline reuptake inhibitors
extrapolate to all forms of musculoskeletal (SNRI) antidepressant drugs used for chronic
pain. The widespread use of acetaminophen pain. These combined mechanisms of action
1. Analgesic effect
2. Antipyretic
Penetrate the blood-brain barrier
3. Weak anti-inflammatory
Block Cycloxygenase (COX-3) in the brain
Blocks the formation and release of prostaglandins in the CNS
Inhibits the action of endogenous pyrogens on the heat-regulating centers in the brain
Antipyertic effect
Fig. 11 The mechanism of action of acetaminophen (paracetamol). (Original diagram by Dr Hala Al Janaby, Perth WA,
Australia)
results in analgesic action on both ascending and limiting the duration of treatment to less than a
descending pain pathways. Tramadol is titrated week and then tapering the dose based on the
over 4 days to achieve at least a 50% reduction properties of the specific drug administered
in pain and then maintained at the doses when required, understanding that tapering
recommended in the package insert, usually in increases the duration of steroid exposure for the
combination with acetaminophen to provide addi- patient.
tive analgesia. Published studies support the use GCs are well established for management of
of tramadol for chronic musculoskeletal pain rheumatoid arthritis in combination with disease
(Russell et al. 2000), osteoarthritis (Fleischmann modifying drugs to minimize the amount of joint
et al. 2001), and neuropathic pain (Sindrup et al. destruction, cardiovascular complications, and
1999), suggesting that it should have efficacy for functional impairment that will otherwise occur.
chronic orofacial pain as well. As with all drugs There is minimal evidence to support systemic
acting at opioid receptors, tramadol may produce administration of GCs for chronic musculoskele-
dependence with prolonged administration and tal pain, except in the management of poly-
may result in both antidepressant and opioid with- myalgia rheumatica for whom there are few
drawal symptoms including seizures when the other disease modifying drugs, suggesting that
drug is discontinued. their efficacy for chronic orofacial pain would be
Tapentadol is mechanistically similar to minimal and outweighed by their toxic effects.
tramadol but higher affinity for mu-opioid recep- Neuropathic elements of chronic orofacial pain
tors and greater risk of abuse. Tapentadol is clas- are better managed with more specific drugs
sified in the USA as a Schedule 2 drug of abuse such as gabapentin. Steroids are advocated for
(a Schedule 8 medicine in Australia), the same acute treatment of cluster headache and as an
classification as highly abused opioids such as adjunct for medication withdrawal in patients
oxycodone and hydrocodone. Given the high with medication overuse headache.
morbidity and mortality associated with opioid Direct injection of the TMJ with a steroid is
drug abuse, tramadol is a more rationale alterna- based on the treatment of osteoarthritis in large
tive when non-opioids do not provide adequate joints, such as the knee and hip, when more con-
pain relief. servative pharmacologic approaches (acetamino-
phen, NSAIDs, hyaluronic acid formulations)
Glucocorticoids have failed to adequately control symptoms. Oste-
Glucocorticoids (GCs) are administered for both oarthritis is a disease of the bone, cartilage, and
acute and chronic orofacial pain, including direct supporting structures of a joint that is character-
injection into the TMJ and systemically. While the ized by degeneration of the cartilage, bone ero-
administration of GCs for acute inflammation sion, and osteophyte formation. The prevalence of
results in unequivocal efficacy with minimal osteoarthritic changes increases with age with an
potential for adverse effects (Troullos et al. observed prevalence of 17% in a sample of the
1990), their use for chronic inflammation is bal- population 65 years an older (Hiltunen et al.
anced by the likelihood of serious adverse events 2002). While osteoarthritis is regarded as a
(Waljee et al. 2017). This can be balanced some- non-inflammatory process, recent observations
what by only using systemic corticosteroids when suggest that inflammation is a part of the patho-
other more conservative nonpharmacologic and genesis in some phases of the disease process.
pharmacologic strategies have failed, adjusting This then provides a rationale for administering
the dose to the minimum that maintains a satisfac- a steroid directly into the TMJ to inhibit the dis-
tory response, limiting the duration of administra- ease process, alleviate symptoms, and screen for
tion and gradually withdrawing the drug when no possible responsiveness to subsequent treatment
longer indicated. A conservative approach (Clark with hyaluronic acid or its synthetic polymers.
and Dionne 2012) is to limit use of corticosteroids Clark and colleagues recommend 10 mg of triam-
for chronic orofacial pain to an exacerbation, cinolone injected into the superior joint space,
usually mixed with local anesthetic to minimize neuropathic pain management and have better
the pain of the injection (Clark et al. 2016). safety profiles and may be preferable for manag-
Repeated injections, however, increase the likeli- ing patients who cannot be managed by tradi-
hood of iatrogenic injury and infection and should tional, validated approaches.
be limited to a few trials to control symptoms
while conservative measures are being used in Serotonin Noradrenaline Reuptake
parallel. Inhibitor
The first serotonin noradrenaline reuptake inhibi-
Antidepressants tor (SNRI) in clinical practice was venlafaxine
A large number of drugs approved as antidepres- (Efexor). Launched in 1993, venlafaxine was no
sants are used for the treatment of chronic pain, more efficacious for depression than older antide-
including orofacial pain. The original rationale pressants but carried a much-improved side effect
was that depression and chronic pain often occur profile. Venlafaxine transitioned into management
together and that alleviating the symptoms of of neuropathic pain over the next decade and
depression would also decrease pain. Observa- although not approved for this purpose, it has
tions by an astute clinician in the 1970s were been used off-label.
subsequently confirmed by a number of controlled Duloxetine (Cymbalta) was released in 2008
clinical trials (Max et al. 1987; Sharav et al. 1987; and is now the main SNRI used in the manage-
McQuay et al. 1993) that demonstrated that ment of neuropathic pain. Duloxetine has a regis-
chronic pain is alleviated by tricyclic antidepres- tered indication for diabetic peripheral neuropathy
sants at doses lower than those needed to treat but is used off-label in the management of
depression and can be differentiated from placebo orofacial neuropathic pain, particularly trigeminal
treatment. The generally accepted mechanism of neuralgia and burning mouth syndrome.
action is inhibition of norepinephrine and seroto- It is thought that the mechanism by which
nin synaptic reuptake resulting in enhanced SNRIs help with neuropathic pain is that, by
descending serotonin inhibitory pathways and increasing levels of serotonin (5HT) and norepi-
modulation of effects on spinal noradrenergic nephrine (NE) in the central nervous system, they
pathways. enhance inhibition of descending pain pathways
The best documentation of efficacy for chronic in the brain and spinal cord. It is important to that
pain is for tricyclic antidepressants (Fig. 12), such patients understand that SNRIs are not “pain
as amitriptyline (Max et al. 1987; Sharav et al. killers” and do not relieve neuropathic pain
1987; McQuay et al. 1993); however, their clini- completely. They are best used added to a multi-
cal utility is limited by the profile of adverse modal pain management plan.
effects, especially in the elderly and patients Duloxetine has been shown to be effective in
with preexisting cardiovascular disease (arrhyth- the treatment of burning mouth syndrome and
mias, congestive heart failure, conduction disor- atypical odontalgia. In a study of 41 patients
ders). Other tricyclic antidepressants are better over a 12-week period, a dose of between 20 and
tolerated than amytriptline; however, their effi- 40 mg/day was shown to decrease almost 80%
cacy for chronic orofacial pain is not as well (79.3%) of patients’ pain by at least 30%, and
(Clark et al. 2016). Given the need to carefully slightly over 50% (51.7%) of patients had more
titrate antidepressants to balance dose-limiting than 50% pain relief. This study also considered
side effects, their potential for serious morbidity the influence of depressive symptoms in the
and mortality due to cardiovascular toxicity, and patients at the outset of the study, and the efficacy
their off-label use for chronic orofacial pain, oral of the medication on reducing pain was
medicine specialists should exercise caution when irrespective of depression (Nagashima et al.
considering use of drugs in this class to manage 2012). Common side effects of SNRIs include
neuropathic orofacial pain. Drugs such as pre- nausea, diarrhea, xerostomia, bruxism, increased
gabalin and gabapentin that are approved for anxiety, sweating, dizziness, hypertension
3. 5.
Neurotransmitters Amitriptyline
Re-uptake channels
(Norepinephrine and Serotonin)
Pre-synaptic nerve cell
Post-synaptic 1.
nerve cell 2.
4. 6.
Axon terminal Dendrites
Fig. 12 The mechanism of action of tricyclic antidepres- (4) this is packaged into vesicles and reused again. TCAs
sants (TCA), such as amitriptyline, is by increasing the block these reuptake channels (5), thus causing the neuro-
levels of two specific neurotransmitters, norepinephrine transmitter to be present in the synapse longer (6) and not
and serotonin. This is undertaken by: (1) interfering with being available for reuptake and reuse. (Original drawing
reuptake where (2) after the neurotransmitter released into by Dr Hala Al Janaby, Perth WA, Australia)
the synapse (3) the neurons “reuptake” the neurotransmit-
ter into the presynaptic cells through reuptake channels and
(infrequent with duloxetine), sexual dysfunction of action is most likely related to blockade of
(impotence), decreased libido, urine retention, voltage-sensitive sodium channels, which leads
insomnia, and tremor. to stabilization of hyperexcited cell membranes,
Drug interactions with SNRIs vary within the reduction of propagation of synaptic impulses,
class. Duloxetine is a substrate and an inhibitor of and/or inhibition of repetitive firing (Fig. 13).
CYP2D6 so can both cause and be subject to drug Dosage is initially 50–100 mg twice daily;
interactions via this enzyme. Duloxetine is a mod- increased gradually if necessary to 400–800 mg
erate inhibitor of CYP2D6 and can increase levels daily in 2–4 doses. Up to 1.2 g daily may be
of substrate drugs of CYP2D6. Abrupt withdrawal required.
should be avoided at all costs with these medicines A recent systematic review assessed four
to avoid antidepressant discontinuation syndrome. placebo-controlled trials, involving (147 patients)
People who have been on therapy continuously for demonstrated the efficacy of carbamazepine for
more than a month should withdraw from the drug treating patients with trigeminal neuralgia
slowly. Limited information is available on the (Di Stefano and Truini 2017). However, with-
safety of SNRIs in pregnancy, but evidence to drawal from treatment or a dosage reduction to
date suggests SNRIs do not increase the risk of an insufficient level can occur in many patients
serious birth defects. Use in late pregnancy may due to undesired effects cause.
result in self-limiting withdrawal symptoms such Adverse effects are dose dependent. The most
as irritability and tremor in newborns. common include dizziness, blurred or double
vision, fatigue, headaches, nausea, vomiting,
Carbamazepine sleepiness, and difficulty in concentration and
Carbamazepine has been first-line treatment for mood disturbance. Less frequent but serious side
trigeminal neuralgia for many years. It was first effects include severe allergic skin reactions, bone
synthesized in 1953 by the Swiss company, Geigy marrow suppression, blood dyscrasias, osteoma-
investigating tricyclic analogues of the antipsy- lacia, and osteoporosis. Electrolytes should be
chotic chlorpromazine (Largactil). The anticon- monitored as carbamazepine can induce hypo-
vulsant properties of carbamazepine were not natremia. Carbamazepine use has been associated
discovered until 10 years later, and its role in with severe skin reactions including exfoliative
corticosteroids in managing neuropathic pain not dermatitis, Stevens-Johnson syndrome, and toxic
harnessed until 20 years after that. Its mechanism epidermal necrolysis.
A. Open Na+ ion channels
B. Inactivated Na+ ion channels
Fig. 13 Mechanism of action of carbamazepine that binds the propagation of abnormal impulses to the brain, hence
to voltage-gated sodium channels to inactivate them. This alleviating pain. (Original drawing by Dr Hala Al Janaby,
will reduce the cell excitability and suppresses neuronal Perth WA, Australia)
firing. Suppressing repetitive neuronal firing will reduce
HLA-B*1502 allele significantly increases risk hypersensitivity syndrome. At-risk patients

of severe skin reactions, particularly Stevens- include those of Northern European or Japanese
Johnson syndrome and toxic epidermal necrolysis. ancestry; however, data are limited and routine
Consideration should be given to testing for this testing is not recommended. Allergy or rash with
allele before starting carbamazepine in at-risk other antiepileptics increases risk of rash with
patients such as those with Asian ancestry (espe- carbamazepine.
cially Han Chinese, Thai, Malay), and if the test is Carbamazepine should be avoided in preg-
positive, the drug should be avoided if possible. nancy if possible due to the increased risk of
HLA-A*3101 allele may also increase risk of skin neural tube defects. If use is necessary, high dose
reactions, particularly mild reactions and multiorgan folic acid supplementation (5 mg/day) must be
used. As carbamazepine is a potent inducer of vitamin K deficiency in newborns (Drugs.com

CYP3A4, drug interactions must always be con- 2018).
sidered. Drugs which are substrates for CYP3A4
are more rapidly metabolized resulting in lower Gabapentin and Pregabalin
serum concentration of the parent drug and Gabapentin and pregabalin are analogues of the
short half-life. Co-administration of contracep- neurotransmitter gamma-aminobutyric acid
tives containing ethinyl oestradiol with carbamaz- (GABA). Gabapentin was developed as an anti-
epine may render the contraceptive less effective convulsant under the brand name “Neurontin”
due to decreased plasma exposure. Breakthrough and was first approved for use in epilepsy in
bleeding and unintended pregnancies have been 1993 (Striano and Striano 2008). After many
reported. Carbamazepine induces liver metabo- years of somewhat controversial off-label use
lism of vitamin D. To avoid loss of bone density, for neuropathic pain, gabapentin eventually
continuous supplementation of vitamin D3 is obtained regulatory approval for this indication.
required when carbamazepine is taken long term. A limitation of gabapentin use is the high doses
(up to 3600 mg/day) required to exert its effect.
Oxcarbazepine The recommended dose for trigeminal neuralgia
Oxcarbazepine was developed in 1965 by the is 300 mg orally, once daily at night. If needed,
same company that discovered carbamazepine, the dose should be gradually increased every
with the intention of promoting it as an anticon- 3 to 7 days up to 600 and then to 1200 mg
vulsant with fewer side effects and drug interac- 3 times daily (Limited 2018).
tions. In the management of trigeminal neuralgia, Pregabalin (Lyrica) was developed by the same
there is strong evidence for using carbamazepine, company that developed gabapentin (Pfizer) ini-
but the safety profile of oxcarbazepine is often tially as an antiepileptic drug, but it was soon
much better especially in the elderly. approved for use in post-herpetic neuralgia, dia-
Oxcarbazepine has similar efficacy as carba- betic neuropathy, and was the first drug to be
mazepine in the treatment of trigeminal neuralgia approved for fibromyalgia. Because pregabalin is
yet has somewhat less side effects. In a 12-week more potent than gabapentin, it is able to achieve
trial of 35 patients unresponsive to treatment with efficacy at lower doses and is therefore better
carbamazepine, there was a significant decrease in tolerated. The dose of pregabalin for trigeminal
pain with efficacy from the first month of treat- neuralgia is 75 mg orally, once daily at night. The
ment (Gomez-Arguelles et al. 2008). Side effects dose should then be gradually increased every 3 to
of oxcarbazepine are similar to carbamazepine as 7 days up to 150 mg and then to 300 mg twice
they include nausea, vomiting, constipation, diar- daily as required.
rhea, rash, acne, alopecia, somnolence, fatigue, Both pregabalin and gabapentin share a similar
dizziness, headache, agitation, confusion, depres- mechanism of action (Fig. 14) binding to the
sion, tremor, amnesia, ataxia, nystagmus, diplo- alpha-2 delta protein subunit of high threshold
pia, blurred vision, and hyponatremia (Handbook voltage-dependent calcium channels, reducing
2018). calcium influx and neurotransmitter release, thus
Oxcarbazepine inhibits CYP2C19, so clini- reducing neuronal firing. Although structurally
cally significant drug interactions may occur related to the neurotransmitter GABA, it is
with drugs metabolized by that enzyme. The thought that GABA analogues do not significantly
dose of oxcarbazepine for trigeminal neuralgia influence GABA or its receptors.
starts at 300 mg orally, twice daily. If needed, An open trial assessing 42 patients with persis-
the dose is gradually increased after 7 days up to tent myofascial pain comparing the efficacy of
600 mg twice daily (Limited 2018). tricyclic antidepressant drugs (TCAs) and
Oxcarbazepine should be avoided during preg- gabapentin found good responses even in patients
nancy as it is considered to increase the risk of with severe pain, suggesting that gabapentin, at a
neural tube defects and may increase the risk of lower dose than previously reported, is a good
Fig. 14 The mechanism of action of pregabalin is by release of glutamate, norepinephrine, and substance
binding to presynaptic alpha2-delta subunit of voltage P. (Original drawing by Dr Hala Al Janaby, Perth WA,
dependent calcium channels in the CNS, inhibiting the Australia)
alternative for patients who do not respond to Baclofen

TCAs (Haviv et al. 2015). Thus, consideration Baclofen is another derivative of the neurotrans-
should be given to the use of gabapentin and mitter gamma-amino-butyric acid (GABA). First
pregabalin in these patients. marketed in 1962, it was intended to be used as an
Gabapentin and pregabalin share a very similar anticonvulsant but its therapeutic efficacy on epi-
side effect profile, most of which are dose-related. lepsy was disappointing. However, it was found to
Common adverse effects include drowsiness, diz- have a beneficial effect on muscle spasticity in
ziness, fatigue, memory dysfunction, confusion, certain people (Sneader 1989).
light-headedness, dry mouth, and increased risk of Baclofen’s mechanism of action is attributed to
falls. The elderly are at greater risk of these stimulation of GABA-B receptors leading to gen-
adverse effects, and therefore, doses used should eral central nervous system (CNS) depression.
be as low as possible in people aged 75 years or When administered as an intrathecal infusion,
older. Adverse effects will be exaggerated in baclofen is useful in treating muscle spasticity
patients on additional sedating agents as well, associated with spinal cord injury by decreasing
such as other anticonvulsants, hypnotics, narcotic frequency and amplitude of skeletal muscle
analgesics, or muscle relaxants. These drugs have spasms. It appears to act primarily at the spinal
also been associated with an increased risk of cord level by inhibiting spinal polysynaptic affer-
depression and suicidal ideation (Drugs.com ent pathways and, to a lesser extent, monosynaptic
2018). afferent pathways (Handbook 2018).
Since neither gabapentin nor pregabalin are Baclofen has been used for the treatment of
metabolized, there are no metabolic drug inter- trigeminal neuralgia and although studies
actions to consider. These drugs are excreted assessing its efficacy are dated and only involve
unchanged via the kidneys and doses should small numbers of patients, it was shown to be
also be reduced in declining renal function. effective and also appeared to enhance the effec-
There is limited data on the safety of gabapentin tiveness of carbamazepine (Fromm et al. 1980,
and pregabalin in pregnancy. Animal data sug- 1984).
gests they are not associated with malformations; Tolerability of baclofen is very similar to ben-
however, adverse effects on the developing fetus zodiazepines. Common side effects include
are possible. Use of these drugs during preg- drowsiness, dizziness, confusion, hypotension,
nancy should only be considered if the benefits respiratory depression, muscular weakness, myal-
outweigh the risks. Specialist advice should be gia, rebound insomnia, paresthesia, mood disinhi-
sought. bition, depression, hallucinations, ataxia, tremor,
nystagmus, blurred or double vision, and urinary medication to diminish the side effects of other,
disorders including enuresis and urinary retention. more effective medications, than use as a single
Less common but more serious adverse effects agent (Sidebottom and Maxwell 1995).
include dyskinesia, dysarthria, paradoxical Phenytoin is associated with a wide range of
increase in spasticity, arrhythmia, dyspnea, altered short- and long-term adverse effects. Common
liver function, and increased blood glucose. As short-term effects include blurred vision, drowsi-
baclofen is associated with CNS and respiratory ness, dizziness, agitation, vertigo, and behavioral
depression and hypotension, the administration disturbances. Symptoms of high phenytoin blood
with other drugs that also depress respiration, the levels include confusion, ataxia, nystagmus,
CNS or cause hypotension may add to these diplopia, and cardiac arrhythmias. Long-term
adverse effects. Like other GABA analogues, bac- adverse effects include gingival hypertrophy,
lofen is mostly cleared unchanged via the kidneys, osteomalacia, Rickett’s, vitamin D deficiency,
so the dosage requires reduction in renal impair- coarse facies, hirsutism, and elevated liver
ment. Toxicity has occurred after low doses in enzymes (Handbook 2018). Suicidal behavior
patients with severe renal impairment. and ideation has been associated with phenytoin
Prescribing information cautions that baclofen and indeed most anticonvulsants (Handbook
may aggravate psychiatric disorders, cerebrovas- 2018).
cular disease, epilepsy, Parkinson’s disease, respi- Patients of Asian ancestry (especially Han Chi-
ratory disease, and neurogenic bladder. Baclofen nese, Thai, Malay) are more likely to have
treatment must always be withdrawn slowly. Sud- HLA-B*1502 allele, which significantly increases
den withdrawal of oral baclofen may be followed risk of severe skin reactions such as Steven-
by anxiety, altered mental status, seizures (includ- Johnsons syndrome and toxic epidermal
ing status epilepticus), high fever, and rebound necrolysis. Commencement of phenytoin should
spasticity. Limited data is available on the safety be avoided if HLA-B*1502 is positive, although
of baclofen in pregnancy. However, an increased routine testing is not recommended. As it induces
risk of congenital malformations has been associ- many neurological changes over time, phenytoin
ated with baclofen, and neonatal seizures due to treatment should always be ceased slowly.
baclofen withdrawal have been reported follow- Phenytoin is associated with a wide range of
ing in utero exposure (Handbook 2018). potential drug interactions as it is a potent inducer
of CYP3A4 and several glucuronidation enzymes
Phenytoin (UGT1A1, UGT 1A9, UGT2B4) (Drugs.com
Phenytoin was first approved for use as an anti- 2018). Phenytoin should be avoided in pregnancy
convulsant by the US Food and Drug Administra- if possible, due to potential adverse neurological
tion in 1953 (Sneader 1989). It was the product of and morphological effects on the developing
systematic search for drugs to replace barbiturates fetus. Expert advice should be sought to establish
that were ubiquitous in medicine at the time. Phe- and evaluate the benefits versus the risk.
nytoin did not work well as a hypnotic agent, so it
was claimed to be the first anticonvulsant without Lamotrigine
sedative side effects, and it significantly improved Lamotrigine was first marketed in the UK in 1991
quality of life of people with epilepsy. Phenytoin and in the USA in 1994 (Shorvon et al. 2015).
was not used for management of neuropathic pain It was introduced for use as an add-on therapy for
until the 1980s and still is only used off-label for management of partial and generalized seizures.
this purpose. Its mechanism of action is through However, over the years, lamotrigine has found
inhibition of voltage- and use-dependent sodium a more significant place in management of
channels on neurons. bipolar disorder and prevention of cluster and
Phenytoin has been used in the management of migraine headache. It is also used occasionally
orofacial neuropathic pain and trigeminal neural- in the treatment of peripheral neuropathic pain
gia; however, this has been more as an add-on including trigeminal neuralgia (Limited 2018).
Lamotrigine’s mechanism of action involves sta- for anticonvulsant activity (Tomson et al. 2016). It
bilization of presynaptic neuronal membranes by was launched as an anticonvulsant in France in
blocking voltage-dependent and use-dependent 1967 and subsequently used in the management of
sodium channels and inhibiting glutamate release bipolar disorder and used off-label for migraine
(Handbook 2018). prevention and neuropathic pain.
The only study to assess the effectiveness of Sodium valproate works via multiple mecha-
lamotrigine thus far has been a crossover trial of nisms and prevents repetitive neuronal discharge
14 patients with refractory trigeminal neuralgia by blocking voltage- and use-dependent sodium
who were concurrently taking carbamazepine channels. Other actions include enhancement of
or phenytoin, and received either 400 mg GABA, inhibition of glutamate, and blockade of
lamotrigine daily or placebo, with lamotrigine T-type calcium channels (Handbook 2018). Due
showing superior pain intensity reduction to the high risk of adverse effects on the liver,
(Zakrzewska et al. 1997). Thus, lamotrigine may valproate should be avoided if possible in patients
have a role as an adjunct to the treatment of with hepatic impairment. The risk of valproate-
refractory trigeminal neuralgia. induced hepatic failure is increased in patients
Side effects of lamotrigine include diplopia, who are children, especially if <3 years of age,
blurred vision, dizziness, ataxia, headache, those with congenital metabolic or degenerative
somnolence, alopecia, and maculopapular rash. disorders, those with severe seizure disorders and
Mood disturbances have been reported including mental retardation, those with organic brain dis-
agitation, irritability, and aggression. As with ease, taking multiple antiepileptic drugs, those
most anticonvulsants, lamotrigine has been asso- with a family history of hepatic disease, those
ciated with suicidal behavior and ideation. The starting valproate within 3 months of liver disease,
most significant adverse effect associated with and those with certain mutations in the POLG
lamotrigine are the severe skin reactions including gene responsible for making the active alpha sub-
Stevens-Johnson syndrome and toxic epidermal unit of polymerase gamma (pol γ) (Handbook
necrolysis. Lamotrigine prescribing information 2018). There is limited data on the effectiveness
has a black box warning stating that severe, poten- of sodium valproate for orofacial pain, with only
tially life-threatening rashes have been reported in one case series reporting its effectiveness in
association with the use of lamotrigine, particu- reducing facial pain in a migrane sufferer
larly in children. Accordingly, lamotrigine should (Obermann et al. 2007).
be discontinued at the first sign of rash unless the Common side effects associated with use of
rash is clearly not drug related. Lamotrigine is valproate include nausea (reduced by taking with
metabolized via glucuronyl transferases in the food), increased appetite, weight gain, sedation,
liver, so concomitant use of medicines that inhibit tremor (dose-related), thinning or loss of scalp
or induce those enzymes may increase or decrease hair (usually temporary), paresthesia, drowsiness,
lamotrigine levels respectively. Specialized drug dizziness, memory impairment, ataxia, elevated
references should be consulted for dosing in the aminotransferase concentrations (dose-related),
presence of other drugs. Lamotrigine should not asymptomatic hyperammonemia, thrombocyto-
be used during pregnancy unless clearly needed. penia (dose-related), menstrual irregularities,
Its use has been associated with a increased risk of polycystic ovaries, and hyperandrogenism in
oral clefts although data are conflicting (Drugs. females.
com 2018). Valproate is metabolized by and induces
glucuronidation (UGT) enyzmes in the liver. It is
Sodium Valproate therefore prone to interactions with other drugs
Sodium valproate was first synthesized in 1882 that are substrates or inducers of these enzymes.
but discovered by French researchers in 1963 to Risk of adverse interactions is often compounded
have anticonvulsant properties when used as the by the use of multiple anticonvulsants as well.
solvent for a range of natural products being tested Valproate should be avoided in pregnancy if
possible due to increased risk of neural tube treatment of persistent idiopathic facial pain
defects (spina bifida) and other congenital (Volcy et al. 2006).
malformations (Handbook 2018). Most of the side effects of topiramate are dose
dependent. Like with all anticonvulsants, toler-
Topiramate ance can be more easily achieved by starting the
Topiramate was first approved in 1997 as a novel medication with a low dose (25 mg/day) that
anticonvulsant for treatment of partial seizures. is gradually titrated upward. Common short-
Within a few years, topiramate was successfully term side effects of topiramate include somno-
trialed and approved for use in migraine prophy- lence, headache, dizziness, confusion, amnesia,
laxis, for which it has greater efficacy than most impaired concentration, depression, emotional
anticonvulsants (Silberstein 2017). Studies dem- lability, nervousness, agitation, hallucinations,
onstrating topiramate’s potential benefit for neu- paresthesia, slurred speech, nephrolithiasis, and
ropathic pain appeared in the literature shortly weight loss. Topiramate has also been associated
thereafter (Chong and Libretto 2003; Dib 2004; with a range of more serious adverse effects which
Fowler et al. 2009). limit its usefulness in clinical practice (Handbook
Topiramate’s exact mechanism of action is 2018).
unknown, but four properties may contribute to
its antiepileptic and antimigraine efficacy. These Diazepam and Clonazepam
are blockage of voltage-dependent sodium chan- Benzodiazepines (diazepam and clonazepam)
nels, augmentation of GABA activity at some have been referred to as the most commercially
GABA-A receptor subtypes, antagonism of successful drugs of all time due to their undeni-
AMPA/kainate subtype of the glutamate receptor, able efficacy as sedatives, and antianxiety agents,
and inhibition of carbonic anhydrase (Chong and and longevity on the worldwide market (Fig. 15).
Libretto 2003). The first benzodiazepine, chlordiazepoxide, was
A Cochrane review investigating the analgesic marketed in 1958, but it was quickly superseded
efficacy of topiramate in neuropathic pain found by diazepam (Valium) marketed in 1963, as the
four studies (1684 participants) with no study latter was better tolerated and had more pro-
providing evidence of efficacy in neuropathic nounced anticonvulsant and muscle relaxant
pain whereas adverse event withdrawals were effects (Sneader 1989).
high (Wiffen et al. 2013). There has been only In general, benzodiazepines (BZs) act as
one case report of the use of topiramate in the depressants of the central nervous system (CNS)
Fig. 15 The mechanism of action of clonazepam is at the and result in an allosteric effect resulting in inhibition of
receptors for the neurotransmitter gamma-aminobutyric the activity of neurons. (Original drawing by Dr Hala Al
acid (GABA) acting at a subtype of the GABA receptor Janaby, Perth WA, Australia)
(GABAa). Benzodiazepines bind to the GABA receptor
producing symptoms, in a dose-dependent fash- period, with a mean pain score reduction of 4.7
ion, from mild sedation and anxiolysis to sleep points (Amos et al. 2011). More specifically,
and then coma. Although the precise mechanisms 16.7% of patients experienced partial relief, 47%
of action have not been completely established, it experienced marked relief, and 33.3% experi-
is believed that BZs enhance or facilitate the enced complete resolution of symptoms (Amos
action of gamma-aminobutyric acid (GABA), et al. 2011).
the major inhibitory neurotransmitter in the There has been considerable research on the
CNS, by causing it to bind more tightly to the efficacy of clonazepam in the treatment of BMS,
GABA type A receptor (Handbook 2018). In gen- both as a topical and systemic agent. Although a
eral, all BZs work in much the same way but differ recent Cochrane review reported that topical clo-
in their duration of action, half-life, and presence nazepam provided only modest relief of pain in
or absence of active metabolites. After single oral BMS (Lyu et al. 2016), use of 0.5 mg/mL mouth-
doses, onset of action depends largely upon wash solution without swallowing showed a 75%
absorption rate. Other effects such as ability to improvement in patient symptoms with very few
cause amnesia or influence sleep behaviors appear patients reporting serious adverse drug reactions
to be attributable to varying solubility character- (Kuten-Shorrer et al. 2017).
istics. The antianxiety and sedative-hypnotic Use of BZs is significantly limited by their
properties of BZs are believed to occur via wide ranging short- and long-term adverse effects.
enhancement of GABA-mediated blockade of Common short-term effects include drowsiness,
both cortical and limbic arousal following stimu- light-headedness, hypersalivation, ataxia, slurred
lation of the brain stem reticular formation (Hand- speech, blurred vision, hypotension, and
book 2018). increased risk of falls. Anterograde amnesia can
Diazepam is a long-acting BZ with a duration occur in patients using BZs for sedation or sleep.
of action of about 6–8 h from a single dose but a In children and some adults, BZs can cause para-
long half-life of 20–80 h and an active metabolite doxical excitation and euphoria due to their
desmethyldiazepam with an even longer half-life disinhibitory effects on the CNS. Long-term use
of up to 120 h. Diazepam continues to be pre- of BZs is generally discouraged due to the well-
scribed in oral medicine today for its sedative, known risk of physical and psychological depen-
antianxiety, and muscle relaxant properties. It is dence, which can occur even if used for short
particularly used as a muscle relaxant in temporo- periods. Continued use can also lead to
mandibular joint disorders. The mechanism by tachyphylaxis, tolerance, and misuse. Signs of
which BZs produce skeletal muscle relaxation is dependence include drug-seeking behavior, crav-
not fully elucidated but is thought to occur via ing, disturbed work, and personal function. Fac-
central inhibition of monosynaptic and polysyn- tors such as a history of drug or alcohol misuse,
aptic afferent pathways in the spinal cord. BZs marked personality disorder, high doses and reg-
may also directly depress motor nerve and muscle ular use increases the risk. Benzodiazepines
function. should be avoided in patients with a history of
Clonazepam is also a long-acting BZ with a alcohol or drug misuse (Handbook 2018).
half-life of 18–50 h but it does not accumulate Combination of BZs with other sedative med-
with repeated dosing like diazepam, as clonaze- icines, in particular opioid analgesics, z-drugs
pam has no active metabolites. Clonazepam has and/or alcohol, dramatically increases the risk
found a place in oral medicine for the treatment of for CNS and respiratory depression as well as
burning mouth syndrome (BMS) (Amos et al. adverse psychiatric effects. If such combinations
2011). In a retrospective study assessing com- are required, doses of both medicines should be
bined topical and systemic clonazepam therapy reduced.
in patients with BMS, it has been shown that a Diazepam is a substrate for CYP2C19 and 3A4
large proportion (80%) of patients obtained more so other drugs which inhibit or induce these
than a 50% reduction in pain over the treatment enzymes may increase serum concentrations of
diazepam and its active metabolites. Drug inter- or no psychoactivity, makes it the most popular
action resources should be consulted. Clonaze- cannabinoid for medical applications.
pam is a substrate of CYP3A4 exclusively for its Cannabidiol has little affinity for CB1 and
metabolism, so other drugs which inhibit or CB2 receptors but acts as an indirect antagonist
induce CYP3A4 enzymes will increase or of cannabinoid agonists.
decrease serum clonazepam concentrations, • Cannabinol (CBO) which is weakly psycho-
respectively (Handbook 2018). active and appears to block some of the effects
Short-acting BZs may be taken occasionally of THC as an antagonist at cannabinoid recep-
during the first and second trimester of pregnancy tors. It has greater affinity for CB2 receptors
but use during the third trimester should be than CB1 receptors.
avoided to prevent accumulation of the drug in
the fetus prior to delivery. Large doses and regular Two synthetic cannabinoids, dronabinol and
use create the risk of neonatal withdrawal syn- nabilone, have been used in clinical medicine for
drome (irritability), and hypertonicity in the new- over 30 years. In the USA, dronabinol has
born infant. Administration of high doses approved indications for the treatment of anorexia
(in particular if given IV) near term or during associated with weight loss in patients with
labor may cause neonatal complications, such as acquired immune deficiency syndrome (AIDS)
respiratory depression, hypothermia, and floppy and nausea and vomiting associated with cancer
infant syndrome (hypotonia, lethargy, and poor chemotherapy in patients who have failed to
suckling) (Handbook 2018). respond adequately to conventional antiemetic
treatments (Drugs.com 2018).
Cannabinoids A unique cannabinoid preparation currently in
Cannabinoids are chemical compounds that act on clinical use worldwide is GW Pharmaceutical’s
cannabinoid receptors in the body. These include cannabis-plant derived medicine, “Sativex”
the naturally occurring cannabinoids found in (GW-1000). This is a natural preparation that
cannabis and some other plants (phytocan- standardizes THC with cannabidiol in a fixed
nabinoids), endogenous cannabinoids found in ratio and is administered using sublingual spray.
humans and animals (endocannabinoids), and The combination of cannabinoids in Sativex is
those manufactured artificially to mimic the effect also referred to as “nabiximols” and has been
of cannabinoids (synthetic cannabinoids). approved in the UK since 2010, and now other
Medicines based on cannabinoids are emerg- countries, as a mouth spray to alleviate neuro-
ing as a promising class of drugs to treat neuropathic pain, muscle spasticity, overactive bladder,
pathic pain and have been tested for analgesic and symptoms of multiple sclerosis.
effects in a range of chronic pain conditions. Can- A preparation of cannabidiol known as
nabinoids work by targeting endogenous canna- Epidiolex ® has been registered in the USA for
binoid receptors in the peripheral and central treatment of seizures associated with Lennox-
nervous system. Gastaut syndrome (LGS) and Dravet syndrome.
Cannabis itself contains over 113 alkaloids Clinical trials have shown this preparation to be
(Aizpurua-Olaizola et al. 2014). Three main more effective than placebo.
phytocannabinoids are of interest for medical There have been no studies that have assessed
purposes: the use of these medications for orofacial pain.
Since clinical trials are still underway for most
• Tetrahydrocannabidiol (THC) which is the medicinal cannabis preparations, knowledge of
main psychoactive constituent, which produces the potential side effects and drug interactions is
the effects associated with cannabis by binding still in evolution. Since Sativex ® is the most
to the CB1 cannabinoid receptors in the brain. established product and according to the manu-
• Cannabidiol (CBD) which comprises 40% of facturer, has been undergoing a clinical trial pro-
the plant’s cannabinoids, and by carrying little gram which has involved over 1500 patients for
treatment of multiple sclerosis, this product can (Toth and Urtis 2004). Its central site of action
give an indication of the tolerability of a medicine also contributes to side effects, such as drowsi-
containing both THC and cannabidiol. According ness, and it can cause psychological and physical
to the product information, the most commonly dependence.
reported adverse reactions in the first 4 weeks of Cyclobenzaprine is also FDA-approved for the
exposure to nabiximols are dizziness, which treatment of acute musculoskeletal conditions. Its
occurs mainly during the initial titration period, chemical and pharmacologic profile is similar to
and fatigue. These reactions are usually mild to tricyclic antidepressants and acts as an antagonist
moderate and resolve within a few days even if at 5-HT receptor subtypes in the brain stem. Sev-
treatment is continued. When the recommended eral clinical trials and one meta-analysis support
dose titration schedule is used, the incidence of the efficacy of cyclobenzaprine for treatment of
dizziness and fatigue in the first 4 weeks is musculoskeletal pain associated with muscle
reduced. Further adverse reactions reported spasm, but with fatigue, sedation and dry-mouth
include significant psychoactivity and cognitive commonly reported (Herman et al. 2002;
impairment hallucinations, delusions, disorienta- Borenstein and Korn 2003; Tofferi et al. 2004).
tion, depression, euphoric mood, and homicidal There is also evidence to support the clinical
and suicidal ideation (Drugs.com 2018). utility of other muscle relaxants for the relief
of acute pain associated with muscle spasm
Muscle Relaxants including metaxalone, chlorzoxazone, and
Clinical examination of patients with chronic methcarbamol (Birkeland and Clawson 1968;
orofacial pain often reveals muscles that are Toth and Urtis 2004), but all with CNS side effects
described as firm or taut, leading to the assump- that can interfere with activities of daily living.
tion that these apparently hyperactive muscles are The duration of treatment should also be limited to
associated with the etiology of painful temporo- a few weeks and combined with physical medi-
mandibular disorders. In addition to physical cine modalities to facilitate discontinuing the drug
medicine approaches to relaxing muscles in as symptoms diminish.
spasm, skeletal muscle relaxants are often pre-
scribed to relax these muscles and thereby Botulinum Neurotoxin
improve function and reduce muscle pain. Despite Under anaerobic conditions, clostridium botuli-
this widely held belief, there is only limited evi- num produces neurotoxin (Ting and Freiman
dence to support the efficacy of muscle relaxants 2004), a chemo-denervating agent, widely
in the management of chronic orofacial pain known as botulinum toxin (BTX). BTX inhibits
(Svensson et al. 2003). The prominent adverse the release of acetylcholine from presynaptic
effects of systemically administered muscle relax- nerve terminals, hence limiting postsynaptic
ants include sedation and weakness, especially in nerve firing (Fig. 16). There are seven immuno-
the elderly, along with the risk of developing logically distinct forms of BTX (A-G); the A and
dependence. These limitations indicate that mus- B serotypes being widely used for therapeutic
cle relaxants should be considered adjunctive to benefits (Jankovic 2004). It is well established
other treatment strategies and prescribed with the that skeletal muscle paresis occurs within a few
same cautions as other CNS-acting drugs that are days after BTX injection whereby acethycholine
prone to misuse, abuse, and dependence. exotosis is diminished and new nerve ending
Carisoprodol is a centrally acting skeletal mus- sprouting occurs. The exocytosis resumes and
cle relaxant that is FDA-approved for the relief of regression of the new nerve sprouts begins
pain associated with acute musculoskeletal condi- approximately 3 months after the BTX is admin-
tions. It blocks interneurons in the spinal cord by istered. It is also postulated that BTX may have an
actions on GABA-A receptors. Published evi- anti-nociceptive effect on pain beyond its muscle
dence supports its efficacy for musculoskeletal relaxant properties, and this may be related to
conditions, such as acute neck or back pain inhibition of the release of substance-P (Aoki
Fig. 16 The mechanism of action of botulinum toxin. (a) botulinum toxin A: 5, Botulinum toxin A binds to the
The normal sequence of muscle contraction: 1, An action glycoproteins of cholinergic receptors via the heavy chain
potential travels down the axon of a nerve cell where and is internalized where 6, the light chain detaches and
2, calcium voltage gated channels are opened allowing cleaves associated proteins preventing 7, the docking of
the entry of calcium that 3, triggers the release of the acetylcholine to the cell membrane and thus inhibiting
neurotransmitter, acetylcholine by exocytosis and 4, acetyl- muscular contraction. (Original drawing by Dr Hala Al
choline binds to receptors on the motor end plate, resulting Janaby, Perth WA, Australia)
in muscle contraction. (b) The mechanism of action of
2001; Jankovic 2004; Dressler and Adib Saberi short lasting. The use of higher doses and more
2005). frequent injections increases the risk for antigenic
BTX is generally considered a safe and effec- potential and formation of neutralizing antibodies
tive treatment. Typical side effects from its injec- (Aoki 2001; Naumann et al. 2006).
tion include pain, edema, ecchymosis, headache, BTX is essentially used in all areas of medi-
and hyperesthesia. Also, excessive weakness of cine. In oral medicine practice, it may be used in
the treated muscles and untreated adjacent mus- the treatment of temporomandibular disorders,
cles through local diffusion are generally mild and bruxism, neuropathic pain, headache, and
oromandibular dystonia. BTX may be used for the of symptomatic sleep bruxism. Total sleep time
treatment of temporomandibular disorders with and number/duration of bruxing episodes
the aim to relief pain and decrease loading. improved in the BTX-A group (n = 13) compared
Injecting BTX is understood to decrease muscle to placebo (n = 9). Two patients suffered the side
contractions, although it may have direct analge- effect of an altered smile (Ondo et al. 2018).
sic effects. A prospective randomized double- Although BTX-A is a safe treatment option for
blind placebo-controlled study of masticatory sleep bruxism, ultimately, the primary consider-
myofascial pain, with or without functional disc ation for the use of BTX-A is its cost benefit in the
displacements, found an overall improvement in long-term. Repeat administrations of BTX-A will
pain scores and psychological status in the likely be necessary to manage sleep bruxism in the
BTX-A group compared to the saline group after long-term given its effectiveness diminishes
28 days (Kurtoglu et al. 2008). Similarly, a recent approximately 3 months post-treatment.
case series of 19 patients with chronic masticatory The effectiveness of BTX for the treatment of
myofascial pain found BTX-A to be a safe and oromandibular dystonia (OMD) by weakening the
effective treatment (Baker and Nolan 2017). In a dystonic muscle with or without the use of EMG
randomized, placebo controlled, crossover multi- guidance is well known, inspite of its limited
center study, BTX-A or saline was injected into clinical evidence (Balasubramaniam and Ram
the masseter muscles of patients with persistent 2008). An open-labelled, prospective trial
masticatory myofascial pain and followed-up at reported on 162 patients with OMD that included
1 and 3 months. BTX-A reduced the pain intensity the jaw opening, jaw closing, jaw deviation, or
by 33% and 30% compared to 40% and 33% for mixed subtypes treated over 10 years. 67.9% of
saline after 1 and 3 months, respectively. There patients had a definitive functional response with
was no significant difference in pain reduction BTX. The duration of peak effect and mean total
with either injection. Numbers need to treat was duration of clinical improvement was 13.4 and
11 and 7 after 1 and 3 months, respectively. Hence 16.4 weeks, respectively. There were a higher
BTX-A was ineffective for persistent masticatory number of patients with functional improvements
myofascial pain (Ernberg et al. 2011). Generally, with jaw closing compared to jaw opening and
BTX is an effective and safe treatment for masti- mixed OMDs. 31.5% patients had adverse effects
catory myofascial pain; however, its benefits are with at least one treatment visit, whereby the most
unclear for chronic masticatory myofascial pain. common complications were dysarthria and dys-
BTX has gained popularity as a treatment for phagia (Tan and Jankovic 1999). Similarly, a ret-
bruxism in general dental practice with the aim of rospective study of 116 patients with OMD
minimizing muscle contractions, reducing symp- (24 tardive and 92 idiopathic) found BTX-A to
toms in symptomatic patients, and protecting the be an effective treatment (Tan and Jankovic
dentition and restorations from damage. A sys- 2000).
tematic review assessed the treatment effects of More recently, BTX is being used for the treat-
BTX-A for sleep bruxism. Three randomized con- ment of neuropathic orofacial pain and postulated
trolled trials and two uncontrolled before and after to have a focal analgesic effect by acting on neu-
studies were included in the assessment. Overall rogenic inflammation (Restivo et al. 2003;
reduction in pain and jaw stiffness were noted Ranoux et al. 2008). BTX is an effective treatment
with BTX-A treatment. The two studies using for primary trigeminal neuralgia. Typically,
objective evaluations of sleep bruxism did not patients achieve 70–100% improvement in symp-
note a reduction in bruxism episodes; however, toms. Also in most studies the mean pain intensity
the intensity of muscle contractions decreased and frequency were reduced by 60–100%
(De la Torre Canales et al. 2017). A recent (Hu et al. 2013). A systematic review and meta-
double-blind placebo-controlled pilot trial tested analysis of randomized controlled trials found
the efficacy and safety of BTX-A injections into BTX-A to be an efficacious and safe treatment
the masseter and temporalis muscles for treatment for trigeminal neuralgia (Morra et al. 2016). In a
series of 4 cases, BTX-A was reported to be effec- and root planning. This approach can also be
tive in the treatment of burning mouth syndrome used for treatment of neuropathic pain when the
affecting the anterior tongue and lower lip. Pain etiologic focus is identifiable and amenable to
relief was noted within 48 h and lasted for at least topical treatment. The efficacy of the use of topi-
12 weeks (Restivo et al. 2017). Similarly, anec- cal lidocaine for the treatment of post herpetic
dotal reports of patients with painful traumatic neuralgia, for example, is supported by high-
trigeminal neuropathy reporting pain relief with level evidence (Stow et al. 1989; Attal et al.
BTX-A is slowly gaining recognition. 1999, Devers and Galer 2000). A formulation
BTX has been used as a prophylactic treatment containing 20% benzocaine in an adhesive oint-
for migraine, tension-type headache and chronic ment can be applied both intra-orally and
daily headache for over 20 years. A meta-analysis extra-orally to areas of neuropathic pain. A trans-
of BTX-A for prophylactic treatment of migraine dermal patch that contains 5% lidocaine is
and tension-type headache found BTX-A resulted FDA-approved for post-herpetic neuralgia pain.
in few chronic daily headaches and chronic Topical lidocaine is also marketed as a 5% viscous
migrane headaches (Jackson et al. 2012). solution that can be applied intraorally for severe
BTX-A did not have a significant benefit with oral mucositis. A paste that combines lidocaine
episodic migraine or chronic tension type head- 2.5% with prilocaine 2.5% is formulated as a
ache. Use of BTX-A was associated with eutectic mixture of local anesthetic (EMLA) that
increased risk for blepharoptosis, skin tightness, can be applied to the skin or mucosa to reduce
paresthesias, neck stiffness, neck pain, and muscle pain but with peak blood levels well below toxic
weakness. Overall, BTX-A has a small to modest levels. Toxic reactions including hypersensitivity,
benefit for chronic migraines and chronic daily arrhythmias and methemoglobinemia are uncom-
headaches (Jackson et al. 2012). mon but can occur with topically applied formu-
lations if large volumes and high concentrations
Topical Preparations are used, or administered inappropriately.
Drugs administered systemically have the major In cases where neuropathic pain originates
limitation of targeting neuronal activity associated peripherally or where central neural dysfunction
with pain while exposing virtually all organs and induces peripheral neural changes, topical appli-
other parts of the nervous system to the actions of cation of drugs for neuropathic pain can be effec-
the drug. This nonspecific distribution results in tive (Bennett 2010). Topically applied medicines
the pharmacologic effects of the medication being that have been used clinically for treatment of
manifested at other sites, and thus producing neuropathic pain include capsaicin, lignocaine,
adverse events, colloquially described as side tricyclic antidepressants (amitriptyline and
effects, that are extensions of the known proper- doxepin), NSAIDs, and clonidine.
ties of the drug. Further, unexpected effects that These medicines can provide benefit due to a
can range from mild to life threatening, such as the localized peripheral effect or a central activity
increased incidence of myocardial infarction asso- once they are systemically absorbed or both. In
ciated with COX2 inhibitors. A common strategy addition, topically applied medications can pro-
to minimize systemic toxicity is to administer the vide a synergistic benefit for neuropathic pain
drug directly to the target site, either by injection when used in conjunction with orally adminis-
or topically (Galer et al. 2000). Several drugs used tered medicines.
for chronic pain have proven effective with Management of orofacial pain, and in particu-
reduced adverse events when applied topically lar oral dysesthesia should involve ensuring that
and can be considered for chronic orofacial pain there are no other contributing causes of the pain,
as well. and a combination of topical medication, systemic
Topical anesthetics are widely used in dentistry medication, and behavioral therapy due to the
to minimize the pain of injection, as well as to multifactorial chronic neuropathic nature of this
alleviate the discomfort associated with scaling pain. Thus, pharmacologic agents can be used to
manage symptoms or address comorbid or under- The use of capsaicin in special populations
lying local, systemic, or psychological factors. such as children less than 12 years of age, the
Topical agents can be employed, including elderly (75 years or older), and in pregnancy and
capsaicin, lidocaine, amitriptyline, doxepin, clo- lactation has not been studied. Therefore, this
nidine, and diclofenac. The chapter on “▶ Oral medication should be avoided unless a compre-
Dysesthesia” should be consulted for more detail hensive assessment of risks and benefits has been
on management strategies relevant to this undertaken. There are no known significant drug
condition. interactions between capsaicin cream and other
drugs (Drugs.com 2018).
Topical Capsaicin The main adverse effect from topically applied
Capsaicin is the active component of hot chilli capsaicin is a warm, stinging, or burning sensation
pepper. It is thought to provide a pain reducing at the site of application, especially during the
effect by selectively stimulating unmyelinated C first few days of use. Although this sensation
fiber afferent neurons to cause the release and decreases in frequency and intensity within sev-
depletion of substance P and other neurotransmit- eral days of continued administration, it may per-
ters (Rains and Bryson 1995). Pharmacologically, sist up to 4 weeks or longer. This effect is related
it is classified as a transient receptor potential to the initial excitatory effect of capsaicin on type-
vanilloid 1 receptor (TRPV1) agonist that acti- C fibers. Application of capsaicin less than three
vates TRPV1 ligand-gated cation channels on or four times daily may prolong the burning sen-
nociceptive nerve fibers, resulting in depolariza- sation while not providing optimum pain relief.
tion, initiation of action potential, and pain signal The incidence of the burning sensation has
transmission to the spinal cord. Capsaicin expo- been variable in different studies and patient
sure results in subsequent desensitization of the populations. For example, patients with arthritis
sensory axons and inhibition of pain transmission generally experience less intense burning than
initiation (Drugs.com 2018). patients with peripheral neuropathies. Capsaicin
Capsaicin is available around the world as a has no known systemic side effects, although
cream, gel, liquid, or patch for topical application transient elevation in blood pressure has been
in strengths ranging from 0.025% to 8%. Topical reported in response to treatment-related pain.
capsaicin products are approved for use in the
management of neuropathic pain associated with Topical Lidocaine
diabetic neuropathy or post-herpetic neuralgia Lidocaine is a local anesthetic that inhibits sodium
and for temporary relief of pain associated with channels on nerve fibers, decreases ionic flux
osteoarthritis and rheumatoid arthritis. Off-label through the neuronal membrane, and thereby
uses include burning mouth syndrome, traumatic blocks both initiation and conduction of nerve
trigeminal dysesthesia pain associated with post- impulses. Topically applied lidocaine has been
mastectomy pain syndrome and reflex sympa- used for decades to numb skin prior to painful
thetic dystrophy syndrome (Canavan et al. incisions, injections or procedures. However, in
1994). It is important to recognize that capsaicin recent years, topically applied lidocaine has been
is not a local anesthetic, since it only blocks the shown to be efficacious in the management of
conduction of painful impulses carried by the some forms of neuropathic pain.
C-type nerve fibers, whereas local anesthetics Lidocaine in the form of a 5% dermal patch is
block the conduction of impulses in all afferent approved for the symptomatic relief of neuropathic
neurons, which impairs all sensations including pain associated with post-herpetic neuralgia. Off-
touch, pressure, heat, and vibration. Despite label uses include treatment of trigeminal neuralgia
causing a burning sensation on application, cap- and sciatica pain. Lidocaine is also available at 5%
saicin is also not a traditional counter-irritant ointment and extemporaneously prepared 10% gel
since it does not produce vasodilation (Drugs. that can be applied to the affected area for treatment
com 2018). of oral neuropathic pain.
The amount of lidocaine systemically absorbed neuropathic ingredients in the one cream. Consid-
from the dermal patch is directly related to both eration should always be given to the arbitrary
the duration of application and the surface area nature of these preparations, the paucity of stabil-
over which it is applied. At the maximum ity and efficacy data supporting their use and the
recommended dose (three patches applied simul- need to ensure informed consent from the patient
taneously for 12 h), approximately 3% (range for their use.
1–5%) of the total applied lidocaine dose is sys- Topical amitriptyline 2% or 10% by itself or in
temically available. This is similar for single and combination with ketamine is reported to relieve
multiple administrations (AusDI 2018). Topically neuropathic pain (Lynch et al. 2003; Kopsky et al.
applied lidocaine takes several days to reach its 2012). When compounded with Orobase, the top-
full effect due to prolonged half-life. Following ical formulation may be applied to an intraoral
application of the dermal patch, lidocaine half-life pain site within a neurosensory stent.
is 7.6 h and peak plasma concentrations are A 5% doxepin cream is approved for use in the
reached between 9 h and 12 h (AusDI 2018). UK for treatment of neuropathic pain. In the USA,
Lidocaine patch is well tolerated. The most a 5% doxepin cream is only approved for treat-
common adverse effects reported is an application ment of moderate pruritus in adult patients with
site reaction including application site burning, atopic dermatitis or lichen simplex chronicus
erythema, dermatitis, pain, pruritus, and vesicles. (Drugs.com 2018). Two open label studies found
Systemic allergic reactions including anaphylaxis doxepin mouthrinse effective in providing pain
have been reported, although are rare. Long-term relief for oral mucositis (Epstein et al. 2001,
use of topical lidocaine can be limited use to the 2008). Because significant plasma levels of
development of skin reactions (Bennett 2010). doxepin are detectable after topical application,
the doxepin 5% cream is contraindicated in
Topical Amitriptyline and Doxepin patients with untreated narrow angle glaucoma
Amitriptyline and doxepin are both tricyclic anti- or a tendency to urinary retention. Drowsiness
depressants. This class of drugs were first occurs in over 20% of patients treated with
marketed in the 1960s for treatment of agitated doxepin 5% cream especially in patients receiving
depression and have been used in the treatment of treatment to greater than 10% of their body sur-
neuropathic pain since the 1990s (Sneader 1989, face area. Patients should be warned about the
Thompson and Brooks 2015). Both drugs are possibility of sedation and cautioned against driv-
well-known inhibitors of norepinephrine and ing a motor vehicle or operating hazardous
serotonin reuptake, whereas amitriptyline has machinery. The sedating effects of alcoholic bev-
also been shown to block Na+, K+ and Ca+ erages, antihistamines, and other CNS depres-
voltage-gated ion channels (Vranken 2009; Kaur sants may be potentiated when doxepin 5%
et al. 2011). cream (Drugs.com 2018).
Despite low doses being used for pain manage- Since plasma levels following topical applica-
ment, both these antidepressants are still associ- tion of doxepin cream 5% can reach levels
ated with a wide range of significant side effects obtained with oral doxepin therapy, significant
when administered orally, particularly somno- drug interactions are possible. In particular, cau-
lence, weight gain, and dry mouth. Topical appli- tion should be taken when topical doxepin is used
cation of amitriptyline and doxepin has the concurrently with drugs that are inhibitors of
theoretical advantage of delivering the drug to CYP2D6 or 2C9, as they may increase doxepin
the site of action and minimizing systemic side levels and risk of adverse effects (Drugs.com
effects. 2018). Safety of doxepin cream in pregnancy has
Proprietary products of these agents are not not been established. However, oral use of
always available and may require extemporane- doxepin is considered safe in the first and second
ous preparation by a pharmacist. Compounding trimester but best avoided in the third trimester as
pharmacies often recommend multiple anti- some epidemiological data suggest an association
between TCAs and premature delivery. Self- broken skin due to the alcohol content of the gel.
limited withdrawal affects such as irritability, Allergic reactions have been reported. Since
altered muscle tone, and/or seizures may occur NSAIDS should be avoided during the first and
during the first hours or days after birth. Reducing third trimesters of pregnancy, topical NSAIDS
the dose in the week before delivery may reduce should be avoided at these times for the same
the chance of withdrawal symptoms in the neo- reason. Diclofenac may be safely used during
nate (Handbook 2018). Although tricyclic antide- lactation (Handbook 2018). One randomized
pressants have been used to treat postnatal trial found topical diclofenac 16 mg/ml
depression, doxepin should be avoided in preg- (10 drops 4 times daily for 14 days) to be equally
nancy if possible, as neonatal respiratory depres- effective as oral diclofenac (50 mg twice daily for
sion has been reported (Handbook 2018). 14 days) in the treatment of symptoms related to
temporomandibular dysfunction (Di Rienzo
Topical Clonidine Businco et al. 2004). Topical diclofenac has been
Clonidine is a centrally acting agonist at alpha-2 trialed with a range of other medicines
adrenoreceptors and imidazoline receptors. It was co-formulated in compounded gels, creams, and
originally developed as an antihypertensive as it ointments. It must be remembered that most
reduces blood pressure by reducing sympathetic compounded preparations have not been sub-
tone. However, it has since been approved for jected to formal studies and therefore, reliable
use in a range of other conditions, including vas- information on their efficacy, safety, and stability
cular headache and menopausal hot flushing. is unavailable.
Unapproved, but accepted uses include Attention
Deficit Hyperactivity Disorder (ADHD), manage-
ment of symptoms of opioid withdrawal, and as an Conclusions and Future Directions
adjunct analgesic for acute, chronic, and cancer
pain (Handbook 2018). In some countries, trans- Oral Medicine prescriptions are still largely off-
dermal clonidine has been used to treat peripheral label and mostly based on expert opinion. Regard-
neuropathy and improve allodynia (Bennett less of the disease and intervention, systematic
2010). One open label pilot trial of clonidine reviews have highlighted several methodologic
(0.2 mg/g) cream for oral neuropathic pain or issues in published interventional studies, the
neuralgia applied four times daily found it to most common issue being the heterogeneity of
effective for oral neuralgia pain more than oral outcome measures. Despite the increasing number
neuropathic pain (Lynch et al. 2003). Most topical of clinical trials and the resultant information
clonidine is extemporaneously prepared. As a gained from them in relation to the management
result, there is little published information on the of oral and maxillofacial diseases, the level of
pharmacokinetics and safety profile of topical evidence is still generally insufficient to make
clonidine. strong recommendations for pharmacological
interventions for most diseases. For some disor-
Topical Diclofenac ders, such as bullous diseases and temporoman-
Topical nonsteroidal anti-inflammatory drugs dibular disorders, validated and internationally
(NSAIDs) such as ibuprofen and diclofenac have agreed outcome measures are now available and
been used for many years in the form of creams, these will very likely facilitate the design and
patches, and gels to successfully and safely treat completion of good quality trials. However,
of musculoskeletal and joint pain. Commercial there are still a number of oral and maxillofacial
preparations of diclofenac are available in 1–5% disorders for which further qualitative and valida-
diclofenac sodium in a gel form. These gels are tion studies are required to investigate whether the
well tolerated due to extremely low systemic available outcome instruments are appropriate
absorption of the diclofenac. The main side effect and can be reliably used in interventional studies.
of topical diclofenac gel is burning and stinging to Moreover, future randomized controlled trials
must also be carefully planned and reported using Aizpurua-Olaizola O, Omar J, Navarro P, Olivares M,
universal guidelines, such as that provided in the Etxebarria N, Usobiaga A. Identification and quantifi-
cation of cannabinoids in Cannabis sativa L. plants by
Consolidated Standards of Reporting Trials high performance liquid chromatography-mass spec-
(CONSORT; www.consort-statement.org). It is trometry. Anal Bioanal Chem. 2014;406(29):7549–60.
anticipated that, using the results from such well- Al Johani KA, Hegarty AM, Porter SR, Fedele S.
conducted trials, pharmacotherapeutic treatment Calcineurin inhibitors in oral medicine. J Am Acad
Dermatol. 2009;61(5):829–40.
in oral medicine will continue to evolve so as to Alajbeg I, Rogulj AA, Hutinec Z. Orofacial
provide more specific, well targeted, and effective granulomatosis treated with intralesional triamcino-
treatment with minimum adverse outcome for lone. Acta Dermatovenerol Croat. 2011;19(3):165–9.
patients. Amos K, Yeoh SC, Farah CS. Combined topical and sys-
temic clonazepam therapy for the management of burn-
ing mouth syndrome: a retrospective pilot study.
J Orofac Pain. 2011;25(2):125–30.
Cross-References Andrade P, Lopes S, Albuquerque A, Osorio F, Pardal J,
Macedo G. Oral Lichen Planus in IBD Patients: A
Paradoxical Adverse Effect of Anti-TNF-alpha Ther-
▶ Clinical Evaluation of Oral Diseases apy. Dig Dis Sci. 2015;60(9):2746–9.
▶ Clinical Evaluation of Orofacial Pain Ang CW, Jarrad AM, Cooper MA, Blaskovich MAT.
▶ Clinical Immunology in Diagnoses of Maxillo- Nitroimidazoles: Molecular Fireworks That Combat a
facial Disease Broad Spectrum of Infectious Diseases. J Med Chem.
2017;60(18):7636–57.
▶ Gingival Pathology Anstey AV, Wakelin S, Reynolds NJ, British Association of
▶ Headache Dermatologists Therapy, Guidelines and Audit Sub-
▶ Interface Between Oral and Systemic Disease committee. Guidelines for prescribing azathioprine in
▶ Laboratory Medicine and Diagnostic Pathology dermatology. Br J Dermatol. 2004;151(6):1123–32.
Aoki KR. Pharmacology and immunology of botulinum
▶ Neuropathic Orofacial Pain toxin serotypes. J Neurol. 2001;248(Suppl 1):3–10.
▶ Non-odontogenic Bacterial Infections Arduino PG, Porter SR. Oral and perioral herpes simplex
▶ Oral and Maxillofacial Fungal Infections virus type 1 (HSV-1) infection: review of its manage-
▶ Oral and Maxillofacial Viral Infections ment. Oral Dis. 2006;12(3):254–70.
Arduino PG, Carbone M, Della Ferrera F, Elia A, Conrotto
▶ Oral Lichen Planus D, Gambino A, Comba A, Calogiuri PL, Broccoletti R.
▶ Oral Manifestations of Systemic Diseases and Pimecrolimus vs. tacrolimus for the topical treatment of
Their Treatments unresponsive oral erosive lichen planus: a 8 week ran-
▶ Oral Mucosal Malignancies domized double-blind controlled study. J Eur Acad
Dermatol Venereol. 2014;28(4):475–82.
▶ Oral Vesicular and Bullous Lesions Asarch A, Gottlieb AB, Lee J, Masterpol KS, Scheinman
▶ Orofacial Pain and Sleep PL, Stadecker MJ, Massarotti EM, Bush ML. Lichen
▶ Orofacial Pain in Patients with Cancer and planus-like eruptions: an emerging side effect of tumor
Mucosal Diseases necrosis factor-alpha antagonists. J Am Acad
Dermatol. 2009;61(1):104–11.
▶ Orofacial Pain in the Medically Complex Patient Attal N, Brasseur L, Chauvin M, Bouhassira D. Effects of
▶ Pediatric Oral Medicine single and repeated applications of a eutectic mixture of
▶ Salivary Gland Disorders and Diseases local anaesthetics (EMLA) cream on spontaneous and
evoked pain in post-herpetic neuralgia. Pain. 1999;
81(1–2):203–9.
Atzmony L, Hodak E, Leshem YA, Rosenbaum O,
References Gdalevich M, Anhalt GJ, Mimouni D. The role of
adjuvant therapy in pemphigus: A systematic review
Aframian DJ, Helcer M, Livni D, Robinson SD, and meta-analysis. J Am Acad Dermatol. 2015;
Markitziu A, Nadler C. Pilocarpine treatment in a 73(2):264–71.
mixed cohort of xerostomic patients. Oral Dis. AusDI. Lidocaine (Topical) – indipendent professional
2007;13(1):88–92. monograph. 2018
Ahmed AR, Shetty S. A comprehensive analysis of treat- Baccaglini L, Lalla RV, Bruce AJ, Sartori-Valinotti JC,
ment outcomes in patients with pemphigus vulgaris Latortue MC, Carrozzo M, Rogers RS 3rd. Urban leg-
treated with rituximab. Autoimmun Rev. 2015;14(4): ends: recurrent aphthous stomatitis. Oral Dis. 2011;
323–31. 17(8):755–70.
Baker JS, Nolan PJ. Effectiveness of botulinum toxin type Carrozzo M, Thorpe R. Oral lichen planus: a review.
A for the treatment of chronic masticatory myofascial Minerva Stomatol. 2009;58(10):519–37.
pain: A case series. J Am Dent Assoc. 2017;148(1): Chahin S, Berger JR. A risk classification for immunosup-
33–9. pressive treatment-associated progressive multifocal
Balasubramaniam R, Ram S. Orofacial movement disor- leukoencephalopathy. J Neurovirol. 2015;21(6):
ders. Oral Maxillofac Surg Clin North Am. 2008; 623–31.
20(2):273–85, vii Chan KK, Glenny AM, Weldon JC, Furness S,
Barnes PJ. Corticosteroids: the drugs to beat. Eur J Worthington HV, Wakeford H. Interventions for the
Pharmacol. 2006;533(1–3):2–14. treatment of oral and oropharyngeal cancers: targeted
Bangert CA, Costner MI. Methotrexate in dermatology. therapy and immunotherapy. Cochrane Database Syst
Dermatol Ther. 2007;20(4):216–28. Rev. 2015;12:CD010341.
Baschant U, Tuckermann J. The role of the glucocorticoid Chao TJ. Adalimumab in the management of cutaneous
receptor in inflammation and immunity. J Steroid and oral lichen planus. Cutis. 2009;84(6):325–8.
Biochem Mol Biol. 2010;120(2–3):69–75. Cholera M, Chainani-Wu N. Management of Pemphigus
Beacher N, Sweeney MP, Bagg J. Dentists, antibiotics and Vulgaris. Adv Ther. 2016;33(6):910–58.
Clostridium difficile-associated disease. Br Dent J. Chong MS, Libretto SE. The rationale and use of
2015;219(6):275–9. topiramate for treating neuropathic pain. Clin J Pain.
Becker DE. Antimicrobial drugs. Anesth Prog. 2013;60 2003;19(1):59–68.
(3):111–22; quiz 123 Chou R, Deyo R, Friedly J, Skelly A, Weimer M, Fu R,
Becker JC, Houben R, Vetter CS, Brocker EB. The carci- Dana T, Kraegel P, Griffin J, Grusing S. Systemic Phar-
nogenic potential of tacrolimus ointment beyond macologic Therapies for Low Back Pain: A Systematic
immune suppression: a hypothesis creating case report. Review for an American College of Physicians Clinical
BMC Cancer. 2006;6:7. Practice Guideline. Ann Intern Med. 2017;166(7):
Bennett M. Neuropathic pain. Oxford Pain Management 480–92.
Library. Oxford: Oxford University Press; 2010. Cirillo N, Cozzani E, Carrozzo M, Grando SA. Urban
Birkeland IW Jr, Clawson DK. Drug combinations with legends: pemphigus vulgaris. Oral Dis. 2012;18
orphenadrine for pain relief associated with muscle (5):442–58.
spasm. Clin Pharmacol Ther. 1968;9(5):639–46. Clark GT, Dionne RA. Orofacial pain. Chichester: Wiley
Borenstein DG, Korn S. Efficacy of a low-dose regimen of Blackwell; 2012.
cyclobenzaprine hydrochloride in acute skeletal muscle Clark GT, Padilla M, Dionne R. Medication Treatment
spasm: results of two placebo-controlled trials. Clin Efficacy and Chronic Orofacial Pain. Oral Maxillofac
Ther. 2003;25(4):1056–73. Surg Clin North Am. 2016;28(3):409–21.
Brewer JD, Colegio OR, Phillips PK, Roenigk RK, Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer
Jacobs MA, Van de Beek D, Dierkhising RA, Kremers SB, Panaccione R, Schreiber S, Byczkowski D, Li J, Kent
WK, McGregor CG, Otley CC. Incidence of and risk JD, Pollack PF. Adalimumab for maintenance of clinical
factors for skin cancer after heart transplant. Arch response and remission in patients with Crohn's disease:
Dermatol. 2009;145(12):1391–6. the CHARM trial. Gastroenterology. 2007;132(1):52–65.
Brocklehurst P, Tickle M, Glenny AM, Lewis MA, Conrotto D, Carbone M, Carrozzo M, Arduino P,
Pemberton MN, Taylor J, Walsh T, Riley P, Yates JM. Broccoletti R, Pentenero M, Gandolfo S. Ciclosporin
Systemic interventions for recurrent aphthous stomati- vs. clobetasol in the topical management of atrophic
tis (mouth ulcers). Cochrane Database Syst Rev. and erosive oral lichen planus: a double-blind, random-
2012;9:CD005411. ized controlled trial. Br J Dermatol. 2006;154
Canavan D, Graff-Radford SB, Gratt BM. Traumatic (1):139–45.
dysesthesia of the trigeminal nerve. J Orofac Pain. Dajani AS, Taubert KA, Wilson W, Bolger AF, Bayer A,
1994;8(4):391–6. Ferrieri P, Gewitz MH, Shulman ST, Nouri S,
Carbone M, Goss E, Carrozzo M, Castellano S, Newburger JW, Hutto C, Pallasch TJ, Gage TW,
Conrotto D, Broccoletti R, Gandolfo S. Systemic and Levison ME, Peter G, Zuccaro G Jr. Prevention of
topical corticosteroid treatment of oral lichen planus: bacterial endocarditis: recommendations by the Amer-
a comparative study with long-term follow-up. J Oral ican Heart Association. J Am Dent Assoc. 1997;
Pathol Med. 2003;32(6):323–9. 128(8):1142–51.
Carr AJ, Ng WF, Figueiredo F, Macleod RI, Davies AN, Thompson J. Parasympathomimetic drugs for
Greenwood M, Staines K. Sjogren's syndrome - an the treatment of salivary gland dysfunction due to
update for dental practitioners. Br Dent J. 2012;213 radiotherapy. Cochrane Database Syst Rev. 2015;10:
(7):353–7. CD003782.
Carrozzo M, Arduino P, Bertolusso G, Cozzani E, De Bosscher K, Haegeman G. Minireview: latest perspec-
Parodi A. Systemic minocycline as a therapeutic option tives on antiinflammatory actions of glucocorticoids.
in predominantly oral mucous membrane pemphigoid: Mol Endocrinol. 2009;23(3):281–91.
a cautionary report. Int J Oral Maxillofac Surg. 2009; De Clercq E. Antiviral drugs in current clinical use. J Clin
38(10):1071–6. Virol. 2004;30(2):115–33.
De la Torre Canales G, Camara-Souza MB, do Amaral CF, Epstein JB, Truelove EL, Oien H, Allison C, Le ND,
Garcia RC, Manfredini D. Is there enough evidence to Epstein MS. Oral topical doxepin rinse: analgesic effect
use botulinum toxin injections for bruxism manage- in patients with oral mucosal pain due to cancer or
ment? A systematic literature review. Clin Oral cancer therapy. Oral Oncol. 2001;37(8):632–7.
Investig. 2017;21(3):727–34. Ernberg M, Hedenberg-Magnusson B, List T, Svensson P.
Decani S, Federighi V, Baruzzi E, Sardella A, Lodi G. Efficacy of botulinum toxin type A for treatment of
Iatrogenic Cushing's syndrome and topical steroid ther- persistent myofascial TMD pain: a randomized, con-
apy: case series and review of the literature. trolled, double-blind multicenter study. Pain. 2011;
J Dermatolog Treat. 2014;25(6):495–500. 152(9):1988–96.
Devers A, Galer BS. Topical lidocaine patch relieves a Ertz-Archambault N, Kosiorek H, Taylor GE, Kelemen K,
variety of neuropathic pain conditions: an open-label Dueck A, Castro J, Marino R, Gauthier S, Finn L,
study. Clin J Pain. 2000;16(3):205–8. Sproat LZ, Palmer J, Mesa RA, Al-Kali A, Foran J,
Dhaliwal S, Jain S, Singh HP, Tiwary AK. Mucoadhesive Tibes R. Association of Therapy for Autoimmune Dis-
microspheres for gastroretentive delivery of acyclovir: ease With Myelodysplastic Syndromes and Acute
in vitro and in vivo evaluation. AAPS J. 2008; Myeloid Leukemia. JAMA Oncol. 2017;3(7):936–43.
10(2):322–30. Excellence, N. I. f. H. a. C. UK NICE Guidance. 2018
Di Colo G, Zambito Y, Zaino C. Polymeric enhancers of Fatahzadeh M, Schwartz RA. Human herpes simplex virus
mucosal epithelia permeability: synthesis, trans- infections: epidemiology, pathogenesis, symptomatol-
epithelial penetration-enhancing properties, mecha- ogy, diagnosis, and management. J Am Acad Dermatol.
nism of action, safety issues. J Pharm Sci. 2008; 2007;57(5):737–63; quiz 764–736
97(5):1652–80. Fedele S, Fung PP, Bamashmous N, Petrie A, Porter S.
Di Rienzo Businco L, Di Rienzo Businco A, D'Emilia M, Long-term effectiveness of intralesional triamcinolone
Lauriello M, Coen Tirelli G. Topical versus systemic acetonide therapy in orofacial granulomatosis: an
diclofenac in the treatment of temporo-mandibular joint observational cohort study. Br J Dermatol. 2014;
dysfunction symptoms. Acta Otorhinolaryngol Ital. 170(4):794–801.
2004;24(5):279–83. Fedorowicz Z, Aljufairi H, Nasser M, Outhouse TL,
Di Stefano G, Truini A. Pharmacological treatment of Pedrazzi V. Mouthrinses for the treatment of halitosis.
trigeminal neuralgia. Expert Rev Neurother. 2017; Cochrane Database Syst Rev. 2008;4:CD006701.
17(10):1003–11. Ficarra G, Carlos R. Syphilis: the renaissance of an old
Di Zenzo G, Carrozzo M, Chan LS. Urban legend series: disease with oral implications. Head Neck Pathol.
mucous membrane pemphigoid. Oral Dis. 2014; 2009;3(3):195–206.
20(1):35–54. Fleischmann RM, Caldwell JR, Roth SH, Tesser JRP,
Dib JG. Focus on topiramate in neuropathic pain. Curr Olson W, Kamin M. Tramadol for the treatment of
Med Res Opin. 2004;20(12):1857–61. joint pain associated with osteoarthritis: a randomized,
Dixon RB, Christy NP. On the various forms of corticoste- double-blind, placebo-controlled trial. Curr Ther Res.
roid withdrawal syndrome. Am J Med. 1980;68(2): 2001;62(2):113–28.
224–30. Forbes JA, Calderazzo JP, Bowser MW, Foor VM,
Dost F, Farah CS. Stimulating the discussion on saliva Shackleford RW, Beaver WT. A 12-hour evaluation of
substitutes: a clinical perspective. Aust Dent J. the analgesic efficacy of diflunisal, aspirin, and placebo
2013;58(1):11–7. in postoperative dental pain. J Clin Pharmacol. 1982;22
Dressler D, Adib Saberi F. Botulinum toxin: mechanisms (2–3):89–96.
of action. Eur Neurol. 2005;53(1):3–9. Fowler JA, Shen JY, Bettinger TL. Successful use of
Drugs.com Drugs.com. 2018https://www.drugs.com. topiramate in a patient with severe postherpetic neural-
Elion GB. Acyclovir: discovery, mechanism of action, and gia. Ann Pharmacother. 2009;43(1):139–42.
selectivity. J Med Virol Suppl. 1993;1:2–6. Fromm GH, Terrence CF, Chattha AS. Baclofen in the treat-
Elliott T, Campbell H, Escudier M, Poate T, Nunes C, ment of trigeminal neuralgia: double-blind study and
Lomer M, Mentzer A, Patel P, Shirlaw P, Brostoff J, long-term follow-up. Ann Neurol. 1984;15(3):240–4.
Challacombe S, Sanderson J. Experience with anti- Fromm GH, Terrence CF, Chattha AS, Glass JD. Baclofen
TNF-alpha therapy for orofacial granulomatosis. in trigeminal neuralgia: its effect on the spinal trigem-
J Oral Pathol Med. 2011;40(1):14–9. inal nucleus: a pilot study. Arch Neurol. 1980;37(12):
Elshibly A, Coulter WA, Millar BC, Prendergast BD, 768–71.
Thornhill M, Irwin C, Goldsmith CE, Moore JE. Furness S, Bryan G, McMillan R, Worthington HV.
Effective oral health in infective endocarditis: efficacy Interventions for the management of dry mouth:
of high-street mouthwashes against the viridans group non-pharmacological interventions. Cochrane Data-
streptococci. J Investig Clin Dent. 2014;5(2):151–3. base Syst Rev. 2013;8:CD009603.
Epstein JB, Epstein JD, Epstein MS, Oien H, Truelove EL. Furness S, Worthington HV, Bryan G, Birchenough S,
Doxepin rinse for management of mucositis pain in McMillan R. Interventions for the management of dry
patients with cancer: one week follow-up of topical mouth: topical therapies. Cochrane Database Syst Rev.
therapy. Spec Care Dentist. 2008;28(2):73–7. 2011;12:CD008934.
Galer BS, Rowbotham M, Perander J, Devers A, therapy in adolescents. Ann Pharmacother. 1996;30
Friedman E. Topical diclofenac patch relieves minor (5):481–3.
sports injury pain: results of a multicenter controlled Haviv Y, Rettman A, Aframian D, Sharav Y, Benoliel R.
clinical trial. J Pain Symptom Manag. 2000;19(4): Myofascial pain: an open study on the
287–94. pharmacotherapeutic response to stepped treatment
Gandhi A, Jana S, Sen KK. In-vitro release of acyclovir with tricyclic antidepressants and gabapentin. J Oral
loaded Eudragit RLPO((R)) nanoparticles for sustained Facial Pain Headache. 2015;29(2):144–51.
drug delivery. Int J Biol Macromol. 2014;67:478–82. Herman CR, Schiffman EL, Look JO, Rindal DB. The
Gandolfo S, Scully C, Carrozzo M. Oral medicine. Edin- effectiveness of adding pharmacologic treatment with
burgh: Churchill Livingstone; 2006. clonazepam or cyclobenzaprine to patient education
Georgakopoulou EA, Scully C. Systemic use of and self-care for the treatment of jaw pain upon awak-
non-biologic corticosteroids in orofacial diseases. ening: a randomized clinical trial. J Orofac Pain.
Oral Dis. 2014;20(2):127–35. 2002;16(1):64–70.
Georgakopoulou E, Scully C. Biological agents: what they Hiltunen K, Vehkalahti MM, Peltola JS, Ainamo A. A
are, how they affect oral health and how they can 5-year follow-up of occlusal status and radiographic
modulate oral healthcare. Br Dent J. 2015a;218(12): findings in mandibular condyles of the elderly. Int J
671–7. Prosthodont. 2002;15(6):539–43.
Georgakopoulou EA, Scully C. Orofacial adverse effects Hu Y, Guan X, Fan L, Li M, Liao Y, Nie Z, Jin L.
of biological agents. J Investig Clin Dent. 2015b; Therapeutic efficacy and safety of botulinum toxin
6(4):252–60. type A in trigeminal neuralgia: a systematic review.
Georgakopoulou EA, Scully C. Systemic use of J Headache Pain. 2013;14:72.
non-biologic agents in orofacial diseases: other immu- Hua F, Xie H, Worthington HV, Furness S, Zhang Q, Li C.
nomodulatory agents. Oral Dis. 2015c;21(3):273–82. Oral hygiene care for critically ill patients to prevent
Germanas J, Pandya AG. Alkylating agents. Dermatol ventilator-associated pneumonia. Cochrane Database
Ther. 2002;15:317–24. Syst Rev. 2016;10:CD008367.
Gomez-Arguelles JM, Dorado R, Sepulveda JM, Hullah EA, Blaker PA, Marinaki AM, Escudier MP,
Herrera A, Arrojo FG, Aragon E, Huete CR, Sanderson JD. A practical guide to the use of
Terron C, Anciones B. Oxcarbazepine monotherapy thiopurines in oral medicine. J Oral Pathol Med.
in carbamazepine-unresponsive trigeminal neuralgia. 2015;44(10):761–8.
J Clin Neurosci. 2008;15(5):516–9. Humphrey SP, Williamson RT. A review of saliva: normal
Gomez-Moreno G, Aguilar-Salvatierra A, Guardia J, composition, flow, and function. J Prosthet Dent.
Uribe-Marioni A, Cabrera-Ayala M, Delgado- 2001;85(2):162–9.
Ruiz RA, Calvo-Guirado JL. The efficacy of a topical Jackson JL, Kuriyama A, Hayashino Y. Botulinum toxin A
sialogogue spray containing 1% malic acid in patients for prophylactic treatment of migraine and tension
with antidepressant-induced dry mouth: a double-blind, headaches in adults: a meta-analysis. JAMA.
randomized clinical trial. Depress Anxiety. 2013; 2012;307(16):1736–45.
30(2):137–42. Jackson S, Gilchrist H, Nesbitt LT Jr. Update on the der-
Gonzalez-Moles MA, Scully C. HPA-suppressive effects matologic use of systemic glucocorticosteroids.
of aqueous clobetasol propionate in the treatment of Dermatol Ther. 2007;20(4):187–205.
patients with oral lichen planus. J Eur Acad Dermatol James P, Worthington HV, Parnell C, Harding M,
Venereol. 2010;24(9):1055–9. Lamont T, Cheung A, Whelton H, Riley
Gorsky M, Epstein J, Rabenstein S, Elishoov H, Yarom N. P. Chlorhexidine mouthrinse as an adjunctive treatment
Topical minocycline and tetracycline rinses in treat- for gingival health. Cochrane Database Syst Rev.
ment of recurrent aphthous stomatitis: a randomized 2017;3:CD008676.
cross-over study. Dermatol Online J. 2007;13(2):1. Jankovic J. Botulinum toxin in clinical practice. J Neurol
Gough A, Chapman S, Wagstaff K, Emery P, Elias E. Neurosurg Psychiatry. 2004;75(7):951–7.
Minocycline induced autoimmune hepatitis and sys- Jenkins S, Addy M, Wade W. The mechanism of action of
temic lupus erythematosus-like syndrome. BMJ. chlorhexidine. A study of plaque growth on enamel
1996;312(7024):169–72. inserts in vivo. J Clin Periodontol. 1988;15(7):415–24.
Grisius MM. Salivary gland dysfunction: a review of sys- Jiang YC, Feng H, Lin YC, Guo XR. New strategies
temic therapies. Oral Surg Oral Med Oral Pathol Oral against drug resistance to herpes simplex virus. Int J
Radiol Endod. 2001;92(2):156–62. Oral Sci. 2016;8(1):1–6.
Gurcan HM, Ahmed AR. Analysis of current data on the Jiyad Z, Olsen CM, Burke MT, Isbel NM, Green AC.
use of methotrexate in the treatment of pemphigus and Azathioprine and risk of skin cancer in organ transplant
pemphigoid. Br J Dermatol. 2009;161(4):723–31. recipients: systematic review and meta-analysis. Am J
Handbook AM. Australian medicines handbook. Adelaide: Transplant. 2016;16(12):3490–503.
Australian Medicines Handbook Pty Ltd; 2018. Joly P, Maho-Vaillant M, Prost-Squarcioni C, Hebert V,
Harel L, Amir J, Livni E, Straussberg R, Varsano I. Serum- Houivet E, Calbo S, Caillot F, Golinski ML, Labeille B,
sickness-like reaction associated with minocycline Picard-Dahan C, Paul C, Richard MA, Bouaziz JD,
Duvert-Lehembre S, Bernard P, Caux F, Alexandre M, Lee YC, Shin SY, Kim SW, Eun YG. Intralesional injection
Ingen-Housz-Oro S, Vabres P, Delaporte E, Quereux G, versus mouth rinse of triamcinolone acetonide in oral
Dupuy A, Debarbieux S, Avenel-Audran M, lichen planus: a randomized controlled study.
D'Incan M, Bedane C, Beneton N, Jullien D, Otolaryngol Head Neck Surg. 2013;148(3):443–9.
Dupin N, Misery L, Machet L, Beylot-Barry M, Lehner T, Lyne C. Adrenal function during topical oral
Dereure O, Sassolas B, Vermeulin T, Benichou J, corticosteroid treatment. Br Med J. 1969;4(5676):
Musette P, French study group on autoimmune bullous 138–41.
skin diseases. First-line rituximab combined with short- Lenz W. A short history of thalidomide embryopathy.
term prednisone versus prednisone alone for the treat- Teratology. 1988;38(3):203–15.
ment of pemphigus (Ritux 3): a prospective, multi- Levell NJ, Munro CS, Marks JM. Severe lichen planus
centre, parallel-group, open-label randomised trial. clears with very low-dose cyclosporin. Br J Dermatol.
Lancet. 2017;389(10083):2031–40. 1992;127(1):66–7.
Jovanovic M, Golusin Z. Nonsteroidal Topical Immuno- Levine MJ, Aguirre A, Hatton MN, Tabak LA. Artificial
modulators in Allergology and Dermatology. Biomed salivas: present and future. J Dent Res. 1987;66 Spec
Res Int. 2016;2016:5185303. No:693–8.
Kanwar AJ, De D. Methotrexate for treatment of lichen Limited TG. eTG complete [Internet]. Melbourne: Thera-
planus: old drug, new indication. J Eur Acad Dermatol peutic Guidelines Limited; 2018.
Venereol. 2013;27(3):e410–3. Liu D, Ahmet A, Ward L, Krishnamoorthy P, Mandelcorn
Karpinski TM, Szkaradkiewicz AK. Chlorhexidine – ED, Leigh R, Brown JP, Cohen A, Kim H. A practical
pharmaco-biological activity and application. Eur Rev guide to the monitoring and management of the com-
Med Pharmacol Sci. 2015;19(7):1321–6. plications of systemic corticosteroid therapy. Allergy
Kaur S, Pandhi P, Dutta P. Painful diabetic neuropathy: an Asthma Clin Immunol. 2013;9(1):30.
update. Ann Neurosci. 2011;18(4):168–75. Lynch ME, Clark AJ, Sawynok J. A pilot study examining
Kim J, Chan JJ. Cyclophosphamide in dermatology. topical amitriptyline, ketamine, and a combination of
Australas J Dermatol. 2017;58(1):5–17. both in the treatment of neuropathic pain. Clin J Pain.
Kirtschig G, Murrell D, Wojnarowska F, Khumalo N. 2003;19(5):323–8.
Interventions for mucous membrane pemphigoid and Lyu X, Zhao C, Yan ZM, Hua H. Efficacy of nystatin for
epidermolysis bullosa acquisita. Cochrane Database the treatment of oral candidiasis: a systematic review
Syst Rev. 2003;1:CD004056. and meta-analysis. Drug Des Devel Ther.
Knowles SR, Shapiro L, Shear NH. Serious adverse reactions 2016;10:1161–71.
induced by minocycline. Report of 13 patients and review Macura AB. The influence of some antifungal drugs on
of the literature. Arch Dermatol. 1996;132(8):934–9. in vitro adherence of Candida albicans to human buccal
Kopsky DJ, Liebregts R, Keppel Hesselink JM. Central epithelial cells. Mycoses. 1988;31(7):371–6.
neuropathic pain in a patient with multiple sclerosis Madan V, Griffiths CE. Systemic ciclosporin and
treated successfully with topical amitriptyline. Case tacrolimus in dermatology. Dermatol Ther. 2007;20
Rep Med. 2012;2012:471835. (4):239–50.
Kovac M, Mitic G, Kovac Z. Miconazole and nystatin used Mansh M, Binstock M, Williams K, Hafeez F, Kim J,
as topical antifungal drugs interact equally strongly Glidden D, Boettger R, Hays S, Kukreja J, Golden J,
with warfarin. J Clin Pharm Ther. 2012;37(1):45–8. Asgari MM, Chin-Hong P, Singer JP, Arron
Krishna MT, York M, Chin T, Gnanakumaran G, ST. Voriconazole Exposure and Risk of Cutaneous
Heslegrave J, Derbridge C, Huissoon A, Diwakar L, Squamous Cell Carcinoma, Aspergillus Colonization,
Eren E, Crossman RJ, Khan N, Williams AP. Multi- Invasive Aspergillosis and Death in Lung Transplant
centre retrospective analysis of anaphylaxis during Recipients. Am J Transplant. 2016;16(1):262–70.
general anaesthesia in the United Kingdom: aetiology Mariette X, Ravaud P, Steinfeld S, Baron G, Goetz J,
and diagnostic performance of acute serum tryptase. Hachulla E, Combe B, Puechal X, Pennec Y,
Clin Exp Immunol. 2014;178(2):399–404. Sauvezie B, Perdriger A, Hayem G, Janin A, Sibilia
Kuriyama A, Jackson JL, Doi A, Kamiya T. Metronida- J. Inefficacy of infliximab in primary Sjogren's syn-
zole-induced central nervous system toxicity: a system- drome: results of the randomized, controlled Trial of
atic review. Clin Neuropharmacol. 2011;34(6):241–7. Remicade in Primary Sjogren's Syndrome (TRIPSS).
Kurtoglu C, Gur OH, Kurkcu M, Sertdemir Y, Guler- Arthritis Rheum. 2004;50(4):1270–6.
Uysal F, Uysal H. Effect of botulinum toxin-A in Martin LK, Werth V, Villanueva E, Segall J, Murrell DF.
myofascial pain patients with or without functional Interventions for pemphigus vulgaris and pemphigus
disc displacement. J Oral Maxillofac Surg. 2008;66 foliaceus. Cochrane Database Syst Rev. 2009;(1):
(8):1644–51. CD006263.
Kuten-Shorrer M, Treister NS, Stock S, Kelley JM, Ji YD, Martini MZ, Galletta VC, Pereira EM, De Sousa SC, Lemos
Woo SB, Lerman MA, Palmason S, Sonis ST, Villa A. CA, Migliari DA. Orofacial granulomatosis of the lip: a
Topical Clonazepam Solution for the Management of report of 2 cases with histological and immunohisto-
Burning Mouth Syndrome: A Retrospective Study. chemical analyses and intralesional corticotherapy.
J Oral Facial Pain Headache. 2017;31(3):257–63. Minerva Stomatol. 2010;59(10):579–81.
Mattsson U, Magnusson B, Jontell M. Squamous cell in orofacial granulomatosis patients treated with
carcinoma in a patient with oral lichen planus treated intralesional triamcinolone acetonide injections alone
with topical application of tacrolimus. Oral Surg Oral or in combination with topical pimecrolimus 1%. J Oral
Med Oral Pathol Oral Radiol Endod. 2010;110(1): Pathol Med. 2013;42(1):73–81.
e19–25. Miki A, Ohtani H, Sawada Y. Warfarin and miconazole
Max MB, Culnane M, Schafer SC, Gracely RH, Walther oral gel interactions: analysis and therapy recommen-
DJ, Smoller B, Dubner R. Amitriptyline relieves dia- dations based on clinical data and a pharmacokinetic
betic neuropathy pain in patients with normal or model. J Clin Pharm Ther. 2011;36(6):642–50.
depressed mood. Neurology. 1987;37(4):589–96. Mimouni D, Nousari CH. Inhibitor of purine and
Mays JW, Fassil H, Edwards DA, Pavletic SZ, Bassim CW. pyirimidine synthesis: mycophenolate, azathioprine
Oral chronic graft-versus-host disease: current patho- and leflunomide. Dermatol Ther. 2002;15:311–6.
genesis, therapy, and research. Oral Dis. 2013;19 Molad Y. Update on colchicine and its mechanism of
(4):327–46. action. Curr Rheumatol Rep. 2002;4(3):252–6.
McCarty M, Fivenson D. Two decades of using the com- Moon C, Chae YK, Lee J. Targeting epidermal growth
bination of tetracycline derivatives and niacinamide as factor receptor in head and neck cancer: lessons learned
steroid-sparing agents in the management of pemphi- from cetuximab. Exp Biol Med (Maywood). 2010;235
gus: defining a niche for these low toxicity agents. J Am (8):907–20.
Acad Dermatol. 2014;71(3):475–9. Morra ME, Elgebaly A, Elmaraezy A, Khalil AM, Altibi
McDonald LC, Gerding DN, Johnson S, Bakken JS, Car- AM, Vu TL, Mostafa MR, Huy NT, Hirayama K.
roll KC, Coffin SE, Dubberke ER, Garey KW, Gould Therapeutic efficacy and safety of Botulinum Toxin A
CV, Kelly C, Loo V, Shaklee Sammons J, Sandora TJ, Therapy in Trigeminal Neuralgia: a systematic review
Wilcox MH. Clinical practice guidelines for Clostrid- and meta-analysis of randomized controlled trials.
ium difficile infection in adults and children: 2017 J Headache Pain. 2016;17(1):63.
update by the Infectious Diseases Society of America Nagashima W, Kimura H, Ito M, Tokura T, Arao M,
(IDSA) and Society for Healthcare Epidemiology of Aleksic B, Yoshida K, Kurita K, Ozaki N.
America (SHEA). Clin Infect Dis. 2018;66(7):987–94. Effectiveness of duloxetine for the treatment of chronic
McMillan R, Taylor J, Shephard M, Ahmed R, nonorganic orofacial pain. Clin Neuropharmacol.
Carrozzo M, Setterfield J, Grando S, Mignogna M, 2012;35(6):273–7.
Kuten-Shorrer M, Musbah T, Elia A, McGowan R, Naumann M, Albanese A, Heinen F, Molenaers G,
Kerr AR, Greenberg MS, Hodgson T, Sirois D. World Relja M. Safety and efficacy of botulinum toxin type
Workshop on Oral Medicine VI: a systematic review of A following long-term use. Eur J Neurol. 2006;
the treatment of mucocutaneous pemphigus vulgaris. 13 Suppl 4:35–40.
Oral Surg Oral Med Oral Pathol Oral Radiol. 2015; NHS England. Clinical commissioning policy: rituximab
120(2):132–142 e161. for immunobullous disease. https://www.england.nhs.
McQuay HJ, Carroll D, Glynn CJ. Dose-response for anal- uk/commissioning/wp-content/uploads/sites/12/2013/
gesic effect of amitriptyline in chronic pain. Anaesthe- 04/16035_FINAL.pdf. Last accessed July 2018.
sia. 1993;48(4):281–5. Niedner R. Cytotoxicity and sensitization of povidone-
Meijer JM, Pijpe J, Bootsma H, Vissink A, Kallenberg CG. iodine and other frequently used anti-infective agents.
The future of biologic agents in the treatment of Dermatology. 1997;195 Suppl 2:89–92.
Sjogren's syndrome. Clin Rev Allergy Immunol. Nielsen OH, Ainsworth MA. Tumor necrosis factor inhib-
2007;32(3):292–7. itors for inflammatory bowel disease. N Engl J Med.
Mejersjo C, Wenneberg B. Diclofenac sodium and occlusal 2013;369(8):754–62.
splint therapy in TMJ osteoarthritis: a randomized con- O'Neill ID, Scully C. Biologics in oral medicine: oral
trolled trial. J Oral Rehabil. 2008;35(10):729–38. Crohn's disease and orofacial granulomatosis. Oral
Mercadante V, Al Hamad A, Lodi G, Porter S, Fedele Dis. 2012;18(7):633–8.
S. Interventions for the management of radiotherapy- O'Neill ID, Scully C. Biologics in oral medicine: Sjogren
induced xerostomia and hyposalivation: A systematic syndrome. Oral Dis. 2013;19(2):121–7.
review and meta-analysis. Oral Oncol. 2017;66:64–74. Obermann M, Mueller D, Yoon MS, Pageler L, Diener H,
Merrill RL, Dionne RA. Medications for Management of Katsarava Z. Migraine with isolated facial pain: a diag-
Chronic, Non-Odontogenic Pain. In: Dowd F, nostic challenge. Cephalalgia. 2007;27(11):1278–82.
Johnson B, Mariotti A, editors. Pharmacology and Ondo WG, Simmons JH, Shahid MH, Hashem V,
Therapeutics for Dentistry. St. Louis: Elsevier; 2017. Hunter C, Jankovic J. Onabotulinum toxin-A injections
Mignogna MD, Fedele S, Lo Russo L, Adamo D, for sleep bruxism: A double-blind, placebo-controlled
Satriano RA. Effectiveness of small-volume, study. Neurology. 2018;90(7):e559–64.
intralesional, delayed-release triamcinolone injections Oray M, Abu Samra K, Ebrahimiadib N, Meese H, Foster
in orofacial granulomatosis: a pilot study. J Am Acad CS. Long-term side effects of glucocorticoids. Expert
Dermatol. 2004;51(2):265–8. Opin Drug Saf. 2016;15(4):457–65.
Mignogna MD, Pollio A, Leuci S, Ruoppo E, Fortuna G. O0 Reilly RA, Goulart DA, Kunze KL et al. Mechanisms of
Clinical behaviour and long-term therapeutic response the stereoselective interaction between miconazole and
racemic warfarin in human subjects. Clin Pharmacol Russell IJ, Kamin M, Bennett RM, Schnitzer TJ, Green JA,
Ther. 1992;51:656–667. Katz WA. Efficacy of tramadol in treatment of pain in
Overman RA, Toliver JC, Yeh JY, Gourlay ML, Deal fibromyalgia. J Clin Rheumatol. 2000;6(5):250–7.
CL. United States adults meeting 2010 American Col- Saenz A, Ausejo M, Shea B, Wells G, Welch V, Tugwell P.
lege of Rheumatology criteria for treatment and pre- Pharmacotherapy for Behcet's syndrome. Cochrane
vention of glucocorticoid-induced osteoporosis. Database Syst Rev. 2000;(2):CD001084.
Arthritis Care Res (Hoboken). 2014;66(11):1644–52. Samaranayake LP, Keung Leung W, Jin L. Oral mucosal
Palmberger TF, Hombach J, Bernkop-Schnurch fungal infections. Periodontol. 2009;49:39–59.
A. Thiolated chitosan: development and in vitro evalu- Sankar V, Brennan MT, Kok MR, Leakan RA, Smith JA,
ation of an oral delivery system for acyclovir. Int J Manny J, Baum BJ, Pillemer SR. Etanercept in
Pharm. 2008;348(1–2):54–60. Sjogren's syndrome: a twelve-week randomized,
Pamba A, Richardson ND, Carter N, Duparc S, Premji Z, double-blind, placebo-controlled pilot clinical trial.
Tiono AB, Luzzatto L. Clinical spectrum and severity Arthritis Rheum. 2004;50(7):2240–5.
of hemolytic anemia in glucose 6-phosphate dehydro- Schmader K. Herpes zoster and postherpetic neuralgia in
genase-deficient children receiving dapsone. Blood. older adults. Clin Geriatr Med. 2007;23(3):615–32,
2012;120(20):4123–33. vii–viii
Pemberton MN. Allergy to Chlorhexidine. Dent Update. Schreier H, Erdos G, Reimer K, Konig B, Konig W,
2016;43(3):272–4. Fleischer W. Molecular effects of povidone-iodine on
Perret LJ, Tait CP. Non-antibiotic properties of tetracy- relevant microorganisms: an electron-microscopic and
clines and their clinical application in dermatology. biochemical study. Dermatology. 1997;195 Suppl
Australas J Dermatol. 2014;55(2):111–8. 2:111–6.
Pijpe J, Meijer JM, Bootsma H, van der Wal JE, Spijkervet Scottish Dental Clinical Effectiveness Programme
FK, Kallenberg CG, Vissink A, Ihrler S. Clinical and (SDCEP). Drug prescribing for dentistry. 3rd ed.
histologic evidence of salivary gland restoration sup- 2016. http://www.sdcep.org.uk/wp-content/uploads/
ports the efficacy of rituximab treatment in Sjogren's 2016/03/SDCEP-Drug-Prescribing-for-Dentistry-3rd-
syndrome. Arthritis Rheum. 2009;60(11):3251–6. edition.pdf
Piret J, Boivin G. Resistance of herpes simplex viruses to Scully C, Bagan J. Oral mucosal diseases: erythema multi-
nucleoside analogues: mechanisms, prevalence, and forme. Br J Oral Maxillofac Surg. 2008;46(2):90–5.
management. Antimicrob Agents Chemother. 2011; Scully C, Felix DH. Oral medicine – update for the dental
55(2):459–72. practitioner. Aphthous and other common ulcers. Br
Preshaw PM. Host response modulation in periodontics. Dent J. 2005;199(5):259–64.
Periodontol. 2008;48:92–110. Selvaggi G, Monstrey S, Van Landuyt K, Hamdi M,
Preshaw PM, Grainger P, Bradshaw MH, Mohammad AR, Blondeel P. The role of iodine in antisepsis and
Powala CV, Nolan A. Subantimicrobial dose doxycy- wound management: a reappraisal. Acta Chir Belg.
cline in the treatment of recurrent oral aphthous ulcer- 2003;103(3):241–7.
ation: a pilot study. J Oral Pathol Med. 2007; Seymour RA, Hogg SD. Antibiotics and chemoprophy-
36(4):236–40. laxis. Periodontol. 2008;46:80–108.
Rains C, Bryson HM. Topical capsaicin. A review of its Sfikakis PP, Markomichelakis N, Alpsoy E, Assaad-
pharmacological properties and therapeutic potential in Khalil S, Bodaghi B, Gul A, Ohno S, Pipitone N,
post-herpetic neuralgia, diabetic neuropathy and osteo- Schirmer M, Stanford M, Wechsler B, Zouboulis C,
arthritis. Drugs Aging. 1995;7(4):317–28. Kaklamanis P, Yazici H. Anti-TNF therapy in the man-
Ranoux D, Attal N, Morain F, Bouhassira D. Botulinum agement of Behcet's disease–review and basis for rec-
toxin type A induces direct analgesic effects in chronic ommendations. Rheumatology (Oxford). 2007;46(5):
neuropathic pain. Ann Neurol. 2008;64(3):274–83. 736–41.
Razonable RR. Antiviral drugs for viruses other than Sharav Y, Singer E, Schmidt E, Dionne RA, Dubner R. The
human immunodeficiency virus. Mayo Clin Proc. analgesic effect of amitriptyline on chronic facial pain.
2011;86(10):1009–26. Pain. 1987;31(2):199–209.
Restivo DA, Lauria G, Marchese-Ragona R, Vigneri Shen S, O'Brien T, Yap LM, Prince HM, McCormack CJ.
R. Botulinum Toxin for Burning Mouth Syndrome. The use of methotrexate in dermatology: a review.
Ann Intern Med. 2017;166(10):762–3. Australas J Dermatol. 2012;53(1):1–18.
Restivo DA, Tinazzi M, Patti F, Palmeri A, Maimone D. Shorvon SD, Perucca E, Engel J. The treatment of epilepsy.
Botulinum toxin treatment of painful tonic spasms in Oxford: Wiley; 2015.
multiple sclerosis. Neurology. 2003;61(5):719–20. Sidebottom A, Maxwell S. The medical and surgical man-
Ring J, Möhrenschlager M, Henkel V. The US FDA ‘black agement of trigeminal neuralgia. J Clin Pharm Ther.
box’ warning for topical calcineurin inhibitors: an 1995;20(1):31–5.
ongoing controversy. Drug Saf. 2008;31(3):185–98. Silberstein SD. Topiramate in migraine prevention: a 2016
Robinson ND, Guitart J. Recalcitrant, recurrent aphthous perspective. Headache. 2017;57(1):165–78.
stomatitis treated with etanercept. Arch Dermatol. Sindrup SH, Andersen G, Madsen C, Smith T, Brosen K,
2003;139(10):1259–62. Jensen TS. Tramadol relieves pain and allodynia in
polyneuropathy: a randomised, double-blind, con- double blind controlled 3 month clinical trial.
trolled trial. Pain. 1999;83(1):85–90. J Rheumatol. 2001;28(6):1347–55.
Singer E, Dionne R. A controlled evaluation of ibuprofen Thompson DF, Brooks KG. Systematic review of topical
and diazepam for chronic orofacial muscle pain. amitriptyline for the treatment of neuropathic pain.
J Orofac Pain. 1997;11(2):139–46. J Clin Pharm Ther. 2015;40(5):496–503.
Slots J. Low-cost periodontal therapy. Periodontol. Thomson WM, Lawrence HP, Broadbent JM, Poulton
2012;60(1):110–37. R. The impact of xerostomia on oral-health-related
Smith MR, Cooper SC. Mycophenolate mofetil therapy in quality of life among younger adults. Health Qual
the management of inflammatory bowel disease – a Life Outcomes. 2006;4:86.
retrospective case series and review. J Crohns Colitis. Thongprasom K, Carrozzo M, Furness S, Lodi
2014;8(8):890–7. G. Interventions for treating oral lichen planus.
Sneader W. Drug discovery: the evolution of modern med- Cochrane Database Syst Rev. 2011;(7):CD001168.
icines. Chichester: Wiley; 1989. Ting PT, Freiman A. The story of Clostridium botulinum:
Sokumbi O, Wetter DA. Clinical features, diagnosis, and from food poisoning to Botox. Clin Med (Lond).
treatment of erythema multiforme: a review for the 2004;4(3):258–61.
practicing dermatologist. Int J Dermatol. 2012;51(8): Tofferi JK, Jackson JL, O'Malley PG. Treatment of fibro-
889–902. myalgia with cyclobenzaprine: A meta-analysis.
Stankus SJ, Dlugopolski M, Packer D. Management Arthritis Rheum. 2004;51(1):9–13.
of herpes zoster (shingles) and postherpetic Tomson T, Battino D, Perucca E. The remarkable story of
neuralgia. Am Fam Physician. 2000;61(8):2437–44, valproic acid. Lancet Neurol. 2016;15(2):141.
2447–2438 Toth PP, Urtis J. Commonly used muscle relaxant therapies
Stern RS. Clinical practice. Exanthematous drug eruptions. for acute low back pain: a review of carisoprodol,
N Engl J Med. 2012;366(26):2492–501. cyclobenzaprine hydrochloride, and metaxalone. Clin
Stow PJ, Glynn CJ, Minor B. EMLA cream in the treat- Ther. 2004;26(9):1355–67.
ment of post-herpetic neuralgia. Efficacy and pharma- Towheed TE, Maxwell L, Judd MG, Catton M, Hochberg
cokinetic profile. Pain. 1989;39(3):301–5. MC, Wells G. Acetaminophen for osteoarthritis.
Strathie Page SJ, Tait CP. Mycophenolic acid in dermatol- Cochrane Database Syst Rev. 2006;(1):Cd004257.
ogy a century after its discovery. Australas J Dermatol. Troullos ES, Hargreaves KM, Butler DP, Dionne RA.
2015;56(1):77–83. Comparison of nonsteroidal anti-inflammatory drugs,
Striano P, Striano S. Gabapentin: a Ca2+ channel alpha ibuprofen and flurbiprofen, with methylprednisolone
2-delta ligand far beyond epilepsy therapy. Drugs and placebo for acute pain, swelling, and trismus.
Today (Barc). 2008;44(5):353–68. J Oral Maxillofac Surg. 1990;48(9):945–52.
Svensson P, Wang K, Arendt-Nielsen L. Effect of muscle van den Berghe LI, de Boever JA, Schautteet H. Double-
relaxants on experimental jaw-muscle pain and blind clinical study of Piroxicam as adjuvant in the
jaw-stretch reflexes: a double-blind and placebo- treatment of the pain and dysfunction of the temporo-
controlled trial. Eur J Pain. 2003;7(5):449–56. mandibular joints. Cranio. 1986;4(4):351–6.
Ta LE, Dionne RA. Treatment of painful temporomandib- Veilleux MS, Shear NH. Biologics in patients with skin
ular joints with a cyclooxygenase-2 inhibitor: a ran- diseases. J Allergy Clin Immunol. 2017;139(5):1423–30.
domized placebo-controlled comparison of celecoxib Villa A, Wolff A, Aframian D, Vissink A, Ekstrom J,
to naproxen. Pain. 2004;111(1–2):13–21. Proctor G, McGowan R, Narayana N, Aliko A, Sia
Tan EK, Jankovic J. Botulinum toxin A in patients with YW, Joshi RK, Jensen SB, Kerr AR, Dawes C, Peder-
oromandibular dystonia: long-term follow-up. Neurol- sen AM. World Workshop on Oral Medicine VI: a
ogy. 1999;53(9):2102–7. systematic review of medication-induced salivary
Tan EK, Jankovic J. Tardive and idiopathic oromandibular gland dysfunction: prevalence, diagnosis, and treat-
dystonia: a clinical comparison. J Neurol Neurosurg ment. Clin Oral Investig. 2015;19(7):1563–80.
Psychiatry. 2000;68(2):186–90. Volcy M, Rapoport AM, Tepper SJ, Sheftell FD, Bigal ME.
Tan HH, Goh CL. Viral infections affecting the skin in Persistent idiopathic facial pain responsive to
organ transplant recipients: epidemiology and current topiramate. Cephalalgia. 2006;26(4):489–91.
management strategies. Am J Clin Dermatol. 2006; von Bultzingslowen I, Sollecito TP, Fox PC, Daniels T,
7(1):13–29. Jonsson R, Lockhart PB, Wray D, Brennan MT,
Tao Y, Lu Y, Sun Y, Gu B, Lu W, Pan J. Development of Carrozzo M, Gandera B, Fujibayashi T, Navazesh M,
mucoadhesive microspheres of acyclovir with Rhodus NL, Schiodt M. Salivary dysfunction associ-
enhanced bioavailability. Int J Pharm. 2009;378 ated with systemic diseases: systematic review and
(1–2):30–6. clinical management recommendations. Oral Surg
Tedesco D, Haragsim L. Cyclosporine: a review. J Transp Oral Med Oral Pathol Oral Radiol Endod. 2007;
Secur. 2012;2012:230386. 103 Suppl:S57 e51–15.
Thie NM, Prasad NG, Major PW. Evaluation of glucos- Vranken JH. Mechanisms and treatment of neuropathic
amine sulfate compared to ibuprofen for the treatment pain. Cent Nerv Syst Agents Med Chem. 2009;9(1):
of temporomandibular joint osteoarthritis: a randomized 71–8.
Vujevich J, Zirwas M. Treatment of severe, recalcitrant, Woo SB, Challacombe SJ. Management of recurrent oral
major aphthous stomatitis with adalimumab. Cutis. herpes simplex infections. Oral Surg Oral Med Oral
2005;76(2):129–32. Pathol Oral Radiol Endod. 2007;103 Suppl:S12
Waljee AK, Rogers MA, Lin P, Singal AG, Stein JD, Marks e11–8.
RM, Ayanian JZ, Nallamothu BK. Short term use of Wu JJ, Huang DB, Pang KR, Hsu S, Tyring SK.
oral corticosteroids and related harms among adults in Thalidomide: dermatological indications, mechanisms
the United States: population based cohort study. BMJ. of action and side-effects. Br J Dermatol. 2005;
2017;357:j1415. 153(2):254–73.
Wee JS, Shirlaw PJ, Challacombe SJ, Setterfield Wullaert A, van Loo G, Heyninck K, Beyaert R. Hepatic
JF. Efficacy of mycophenolate mofetil in severe muco- tumor necrosis factor signaling and nuclear factor-
cutaneous lichen planus: a retrospective review of kappaB: effects on liver homeostasis and beyond.
10 patients. Br J Dermatol. 2012;167(1):36–43. Endocr Rev. 2007;28(4):365–86.
Wiffen PJ, Derry S, Lunn MP, Moore RA. Topiramate for Xia J, Li C, Hong Y, Yang L, Huang Y, Cheng B. Short-
neuropathic pain and fibromyalgia in adults. Cochrane term clinical evaluation of intralesional triamcinolone
Database Syst Rev. 2013;(8):CD008314. acetonide injection for ulcerative oral lichen planus.
Williams K, Arron ST. Association of CYP2C19 *17/*17 J Oral Pathol Med. 2006;35(6):327–31.
Genotype With the Risk of Voriconazole-Associated Ylikontiola L, Sorsa T, Hayrinen-Immonen R, Salo T.
Squamous Cell Carcinoma. JAMA Dermatol. 2016; Doxymycine-cyanoacrylate treatment of recurrent
152(6):719–20. aphthous ulcers. Oral Surg Oral Med Oral Pathol Oral
Wise M, Callen JP. Azathioprine: a guide for the manage- Radiol Endod. 1997;83(3):329–33.
ment of dermatology patients. Dermatol Ther. 2007; Yuson CL, Katelaris CH, Smith WB. Cephalosporin
20(4):206–15. allergy’ label is misleading. Aust Prescr. 2018;41(2):
Wojenski DJ, Bartoo GT, Merten JA, Dierkhising RA, 37–41.
Barajas MR, El-Azhary RA, Wilson JW, Plevak MF, Zakrzewska JM, Chaudhry Z, Nurmikko TJ, Patton DW,
Hogan WJ, Litzow MR, Patnaik MM, Wolf RC, Mullens EL. Lamotrigine (lamictal) in refractory tri-
Hashmi SK. Voriconazole exposure and the risk of geminal neuralgia: results from a double-blind pla-
cutaneous squamous cell carcinoma in allogeneic cebo controlled crossover trial. Pain. 1997;73(2):
hematopoietic stem cell transplant patients. Transpl 223–30.
Infect Dis. 2015;17(2):250–8. Zhang LW, Fu JY, Hua H, Yan ZM. Efficacy and safety of
Wong SSW, Samaranayake LP, Seneviratne CJ. In pursuit miconazole for oral candidiasis: a systematic review
of the ideal antifungal agent for Candida infections: and meta-analysis. Oral Dis. 2016;22(3):185–95.
high-throughput screening of small molecules. Drug Zhao CY, Murrell DF. Pemphigus vulgaris: an evidence-
Discov Today. 2014;19(11):1721–30. based treatment update. Drugs. 2015;75(3):271–84.
Odontogenic Pathology
Takashi Takata, Mutsumi Miyauchi, Ikuko Ogawa, and

Alan Mighell
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472
Tooth Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473
Developmental Dental Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478
Anomalies of Tooth Number, Shape, and Mineralized Tissue Quality . . . . . . . . . . . . . . . . 481
Physical and Chemical Injuries of Teeth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 489
Attrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490
Abrasion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490
Erosion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491
Abfraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491
Dental Caries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496
Pit and Fissure Caries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
Smooth Surface Caries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
Root Caries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
Enamel Caries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
Dentin Caries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
Cementum Caries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502
Pulpitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502
Acute Pulpitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 504
T. Takata (*) · M. Miyauchi

Department of Oral and Maxillofacial Pathobiology,
Graduate School of Biomedical and Health Sciences,
Hiroshima University, Hiroshima, Japan
e-mail: ttakata@hiroshima-u.ac.jp; mmiya@hiroshima-u.
ac.jp
I. Ogawa
Center of Oral Clinical Examination, Hiroshima University
Hospital, Hiroshima, Japan
e-mail: dlabo@hiroshima-u.ac.jp
A. Mighell
Department of Oral Medicine, School of Dentistry,
University of Leeds, Leeds, UK
e-mail: A.J.Mighell@leeds.ac.uk

https://doi.org/10.1007/978-3-319-72303-7_22
472 T. Takata et al.
Chronic Pulpitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 504

Pulp Necrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 504
Periapical Periodontitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505
Periodontal Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508
Gingivitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509
Periodontitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512
Odontogenic Cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 516
Inflammatory Odontogenic Cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517
Developmental Odontogenic Cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 520
Odontogenic Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 530
Benign Epithelial Odontogenic Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 530
Benign Mixed Epithelial and Mesenchymal Odontogenic Tumors . . . . . . . . . . . . . . . . . . . . 537
Benign Mesenchymal Odontogenic Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541
Malignant Odontogenic Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 545
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 549
Abstract insults. Advances in molecular genetics are pro-

Various pathologies affect the tooth and tooth- viding new insights into these conditions and
forming apparatus such as developmental related healthcare delivery.
anomalies, bacterial and nonbacterial tooth Partial or entire loss of a tooth is caused by
injuries, inflammation, cysts, and neoplasms. bacterial and non-bacterial etiological factors. The
In this chapter, we describe representative disease caused by bacterial infection of a tooth is
odontogenic disorders, with a particular focus dental caries, and disorders of non-bacterial origin
on odontogenic cysts and tumors. To under- include attrition, abrasion, erosion, and abfraction
stand the pathogenesis of these conditions, cli- of teeth. Dental caries remains the most prevalent
nicians must have a basic understanding of chronic disease in adults, although it is largely
odontogenesis and the morphological and preventable. Dental caries is generally decreasing
functional characteristics of teeth and related in developed countries, but disparities remain in
structures. developing nations and among some population
groups (Sgan-Cohen et al. 2013). When infection,
Keywords mainly from dental caries, extends to the pulp and
Odontogenic pathology · Developmental periapical periodontal tissues, acute or chronic
dental anomalies · Injuries of teeth · Dental inflammation is evoked in these tissues as pulpitis
caries · Pulpitis · Apical periodontitis · and periapical periodontitis.
Periodontal disease · Odontogenic cysts · Gingivitis and periodontitis are inflammatory
Odontogenic tumors · Bone pathology conditions of the tooth-supporting tissues mainly
caused by periodontal pathogens. Periodontitis is
the most common cause of tooth loss among
Introduction adults. Cytokines such as TNF-alpha, IL-1beta,
and IL-8 produced from residential periodontal
Developmental anomalies of teeth affect tooth cells and immune cells contribute to progression
number, shape, and/or the quality of the dental of inflammation and tissue damage including
tissues. Tooth anomalies consequent to abnormal attachment loss and bone resorption. Accumula-
development are a heterogeneous, diverse group tion of information of the cytokine network in
arising as a result of genetic and/or environmental periodontal tissues provides a new therapeutic
Odontogenic Pathology 473
strategy for this disease. Recently, chronic dental and Feng 2017). This complexity is reflected in
infections such as periodontitis have been the embryonic origins of dental tissues. Under-
reported as a risk factor for various systemic standing the underpinning key molecular events
health problems. of tooth formation remains a research focus; this
Various cysts and tumors of odontogenic origin insight has translational benefit to patient care and
develop in the jaw bone. Odontogenic cysts the potential to inform development of new ther-
are subclassified as inflammatory or develop- apeutic approaches that include the goal of tissue
mental in origin. Odontogenic tumors are sub- regeneration. Tooth development requires epithe-
divided into three groups based on the types lium from the first pharyngeal arch and part of the
of odontogenic tissues involved. The majority of frontonasal process supported by ectodermal cra-
odontogenic tumors are benign and rarely exhibit nial neural crest-derived mesenchyme. The first
malignant behaviors. Recent studies support the histological indication of tooth development is
possibility for molecular-targeted therapy for thickening of the epithelium along the crest of
ameloblastomas and other odontogenic tumors the future alveolar ridge to form the dental lamina
with BRAF p.V600E variant. around 7 weeks post conception (Figs. 1, 2, and
3). Focal epithelial invaginations at the site of
tooth development soon follow to form individual
Tooth Formation dental placodes (Fig. 1). These morphological
changes represent early dental epithelial cell pro-
Human teeth are a complex composite of very liferation, differentiation, and migration, which
different hard and soft tissues that in health are are essential to tooth formation. The sequence
supported within bone by the periodontal liga- of required epithelial changes can only occur
ments with an associated hard and soft tissue through signaling from the mesenchymal tissues.
interface that includes the gingivae (Cobourne The molecular interplay between the two tissue
and Sharpe 2013; Juuri and Balic 2017; Wang types results in a sequence of morphological
Fig. 1 Stages of tooth development (odontogenesis). (Original drawing by Dr Hala Al Janaby, Perth WA, Australia)
Fig. 2 Head (coronal

plane; decalcified) of a
12-week human embryo
showing tooth germs (*) in
“cap” stage. Oral cavity
(OC) and tongue (T) are
noted. (Hematoxylin and
eosin stain). (Image
courtesy of Professor
Camile Farah, UWA Dental
School, University of
Western Australia, Perth
WA, Australia)
stages: bud, cap, and bell (Figs. 1, 2, 3, 4, and 5).

The same fundamental processes are attenuated to
reflect the heterodont nature of the human denti-
tion. Teeth of the secondary dentition that follow a
primary tooth arise from an extension of the dental
lamina around the time of the cap stage (Fig. 4). It
remains unclear if the secondary dentition molar
teeth are associated with primary molar tooth
development or are a consequence of independent
dental placodes arising directly from the dental
lamina. Failures of key early molecular events in
tooth formation result in tooth agenesis. This is
reflected not only in clinical presentations of
patients but also in the evolution of dentitions in
a wide range of living life-forms.
By the bell stage (Fig. 5), there is separation of
the developing tooth from the oral epithelium with
this separation continuing until the point of tooth
eruption (Figs. 1 and 5). The epithelial-derived
cells have differential rates of growth that form
the physical shape of the future dentin-enamel
junction (DEJ) (Fig. 6). Hard tissue formation is
Fig. 3 Hematoxylin and eosin stained section shows a tooth
initiated in the bell stage where the future cusps in the tooth “bud” stage (TB) including the dental lamina
will form. Reciprocally inductive signaling (DL) with surrounding mesenchymal cells (Mc). Inferior to
triggers the formation of pre-ameloblasts and the tooth bud is the developing bone of the jaw (B) and deep
pre-odontoblasts derived from the epithelial and to it is the successional lamina (SL) which will become a
permanent tooth. The immature oral cavity (OC) can be seen
mesenchymal tissues, respectively. Formation of at the top of the image. (Image courtesy of Dr Rita Hardiman,
odontoblasts leads to early deposition of predentin Melbourne Dental School, University of Melbourne, Carlton
matrix that mineralizes leading to induction of VIC, Australia)
Fig. 4 Hematoxylin and eosin stained histology section the image. The dental papilla, comprised of mesenchymal
shows a developing tooth in the “cap” stage. The inner and cells, is surrounded by the IEE, and the dental follicle
outer enamel epithelia (IEE and OEE) are present and (DF) surrounds the developing tooth structure. (Image
separated by the stellate reticulum (SR) and stratum courtesy of Dr Rita Hardiman, Melbourne Dental School,
intermedium (SI). The dental lamina (DL) is still present, University of Melbourne, Carlton VIC, Australia)
and the successional lamina (SL) can be seen to the right of
Fig. 5 Hematoxylin and eosin stained histology section epithelium (OEE) can be seen and will soon fuse with the
shows a developing tooth at the “bell” stage. Dentin stratum intermedium (SI) to become the reduced enamel
(D) can be seen (in its greatest quantity at this stage at the epithelium. Bone (B) can be seen forming around the
future cusp tip) being laid down by odontoblasts (Ob). developing tooth, and the oral mucosa (OM) is visible at
Ameloblasts (Ab) are also present. The stellate reticulum the top right corner of the image. (Image courtesy of
is still present (SR) as are parts of the stratum intermedium Dr Rita Hardiman, Melbourne Dental School, University
(SI). The pulp is more developed at this stage too, and of Melbourne, Carlton VIC, Australia)
blood vessels (BV) are infiltrating it. The outer enamel
Fig. 6 Hematoxylin and eosin stained histology section reticulum is still present (SR). The pulp (P) is more devel-
shows a developing tooth at the “matrix secretion” stage oped with prominent blood vessels (BV). Bone (B) can be
(28-week fetus; decalcified). Mature dentin (D) can be seen forming around the developing tooth, and the oral
seen, in addition to pre-dentin (PD) being laid down by mucosa epithelium (OM) is visible at the top right corner of
odontoblasts (Ob). Ameloblasts (Ab) are also present, the image. (Image courtesy of Professor Camile Farah,
secreting pre-enamel (PE). The enamel space (ES) is UWA Dental School, University of Western Australia,
caused by the demineralization process. The stellate Perth WA, Australia)
ameloblast formation and the initial enamel and the layer of odontoblasts at the dentin-pulp
matrix formation (Figs. 6 and 7). interface means that dentin can be deposited
Odontoblasts and ameloblasts are highly syn- throughout life, albeit typically at a very low
thetic cells expressing tissue-specific organic rate. Unlike bone, dentin does not include cells
matrices that mineralize to form the very differ- or have the capacity to completely remodel
ent hard tissues of dentin and enamel, respec- itself.
tively (Figs. 6, 7, and 8). Initiation of hard tissue Coronal dentin formation merges seamlessly
formation continues toward the point of the into root dentin formation. Epithelial-
eventual enamel crown cervical margin. Cohorts mesenchymal induction remains critical with
of ameloblasts continue to lay down enamel Hertwig’s epithelial root sheath proliferating
matrix that mineralizes as they move away from the cervical loop of the forming crown
from the DEJ to the eventual tooth surface (Luder 2015). The external surface of the dentin
where apoptosis occurs. Mature enamel is pri- is covered by a thin layer of cementoblast-derived
marily hydroxyapatite crystals organized into cementum that acts as the interface with the peri-
distinctive enamel prisms. Accordingly, enamel, odontal ligament (Hosoya et al. 2017). The dra-
which is the hardest substance in the body with matic slowing of odontoblast dentin synthesis
the capacity to last a lifetime, has no capacity for leaves space for the ectodermal, dental papilla-
cellular repair once formed. Odontoblasts move derived dental pulp with neurovascular connec-
away from the DEJ toward the future dental tions between the pulp and alveolar tissues
pulp. By contrast with enamel, the organic and typically at the root apices on completion of root
inorganic composition of dentin has similarities formation. The ability to isolate stem cells from
to bone. Dentin includes odontoblast processes, dental pulp is a focus of research activity. Tooth
Fig. 7 Matrix secretion stage of tooth development (odontogenesis). (Original drawing by Dr Hala Al Janaby, Perth WA,
Australia)
Fig. 8 Hematoxylin and eosin stained histology section reticulum is still present (SR). The pulp (P) is more devel-
shows a developing tooth at the “matrix secretion” stage oped. Bone (B) can be seen forming around the developing
at the level of the developing root. Mature dentin tooth root. (Image courtesy of Professor Camile Farah,
(D) can be seen, in addition to odontoblasts (Ob). Amelo- UWA Dental School, University of Western Australia,
blasts (Ab) are present secreting enamel (E). The stellate Perth WA, Australia)
eruption initiates before final formation of the have a variable impact on clinical decision-
dental apices and remains a poorly understood making.
process. More detail on tooth development can Odontogenesis, the formation of teeth, is
be found in the chapter on ▶ “Normal Variation a developmental process influenced by genetic
in the Anatomy, Biology, and Histology of the and environmental factors. Formation of the com-
Maxillofacial Region.” plete dentition (primary and permanent) is an
extended developmental process that starts
around 6 weeks into pregnancy with initiation of
Developmental Dental Anomalies the first primary tooth and extends into early
adulthood with eruption of the final permanent
Developmental dental anomalies (DDAs) are a tooth.
heterogeneous group of disorders that may Initiation of each tooth requires inductive molec-
involve any part of tooth formation or eruption ular signaling between odontogenic epithelium and
(Cobourne and Sharpe 2013; Klein et al. 2013) neural crest-derived ectomesenchyme in the dental
(Table 1). The spectrum covers major disparities lamina (Cobourne and Sharpe 2013; Klein et al.
from normal, such as tooth absence, through to 2013). For a given tooth, soft tissue patterning of
mild changes, such as variations in cusp mor- the crown shape leads on to hard tissue formation,
phology. These are encountered on a regular followed by root development and tooth eruption to
basis during delivery of oral healthcare and form the occlusion.
Table 1 Selected examples of developmental dental examples with a known genetic cause. Mendelian-
anomalies (DDAs). DDAs may occur in apparent isolation inherited conditions with multiple OMIM entries, for
or be part of wider health problems including syndromes. example, due to variants in more than one gene, are marked
More than one dental anomaly may be present. OMIM with an asterisk*. Not all dental anomalies are due to
six-digit numbers are given in brackets for selected genetic variants
Anomaly Occurrence in isolation Occurrence as part of a wider phenotype
Missing tooth/ Yes Cleft palate* (Twigg and Wilkie 2015)
teeth – selective Ectodermal dysplasia (Figs. 9 and 10)* (Trzeciak and
tooth agenesis Koczorowski 2016)
Supernumerary Yes Familial adenomatous polyposis [175100] (Almeida et al.
teeth (Figs. 11, 2016)
12, and 13) Cleidocranial dysplasia (Fig. 14) [119600]
Nance-Horan syndrome [301350] (Gjorup et al. 2017)
Exaggerations Isolated maxillary “peg laterals” are Odontodental dysplasia [166750] (enlarged canines)
of crown size common [150400] KBG syndrome [148050] (macrodontia)
(macro- or Deafness, congenital, with inner ear agenesis, microtia, and
microdontia) microdontia. [610706] (microdontia)
Enamel Amelogenesis imperfecta (Fig. 15)* Enamel renal syndrome [204690]
formation Molar incisor hypomineralization Jalili syndrome [217080]
(MIH) (Fig. 16) Kohlschutter-Tonz syndrome[226750]
Fluorosis
Dentin Dentinogenesis imperfecta (Fig. 17)* Osteogenesis imperfecta* (selected types)
formation (de La Dure-Molla et al. 2015) (Thomas and DiMeglio 2016)
Dentinal dysplasia*
(de La Dure-Molla et al. 2015)
Tooth eruption Yes Enamel renal syndrome [204690] – delayed eruption
Osteopetrosis* – delayed eruption and other dental
anomalies (Detailleur et al. 2016)
Hypophosphatasia* (selected types) – premature
exfoliation of primary teeth (Hollis et al. 2013)
Papillon-Lefevre syndrome [245000] – premature
exfoliation of primary teeth
Fig. 9 Ectodermal
dysplasia. Teeth are
congenitally missing from
the maxilla (a) and
mandible (b) in two
separate patients.
Mandibular teeth have a
peg-shaped pointed
morphology. (Images
courtesy of Associate
Professor Robert
Anthonappa, UWA Dental
WA, Australia)
Genetic variations that affect odontogenesis Accurate assessment of the dental phenotype can
reflect the genetic makeup of an individual from provide important information in reaching a unify-
conception. The role of a particular gene in ing diagnosis, particularly where there is a spectrum
odontogenesis and the degree to which normal of presentations outside the oral cavity (Table 1).
gene function is disrupted impact on the tooth Clinical evaluation of dental anomalies to
phenotype. Many genetic variations affecting inform clinical decision-making should:
tooth development occur in isolation of other
health problems, whereas some are markers • Characterize each anomaly
of a wider clinical phenotype that extends beyond • Consider the known medical history
the mouth (Bailleul-Forestier et al. 2008; • Consider any co-segregating phenotypic fea-
Cobourne and Sharpe 2013; Smith et al. 2017). tures (oral or elsewhere)
Classification into “non-syndromic” and “syn- • Involve a family history (pedigree) with
dromic” forms is associated with limitations with consideration of consanguinity in potentially
an increasing awareness from growing genotype- autosomal recessive conditions
phenotype insight that there is not always a clear • Recognize that the phenotypic descriptions for
distinction (Ratbi et al. 2015). The nature of states involving dental anomalies are incomplete
specific genetic variants within a single gene can • Recognize that recognition of dental anomalies
have a profound impact on the resultant pheno- can influence overall health and the care provided
types (Table 2). Genetic screening of cohorts with
DDAs confirms that even with recent advances, There is greater understanding of the monoge-
understanding of the causative genetic variants is netic basis to dental anomalies (http://omim.org/)
limited and far from complete (Prasad et al. 2016; compared to those affected by polygenetic events.
Yamaguchi et al. 2017). Ongoing advances in genetics are being translated
Fig. 10 Ectodermal dysplasia. Patient in the primary den- successors (b). (Images courtesy of Associate Professor
tition stage with several primary teeth missing and only Robert Anthonappa, UWA Dental School, University of
few permanent successors in formation (a). Patient with Western Australia, Perth WA, Australia)
only primary teeth and complete absence of permanent
to clinical care in a rapidly changing area of incisor hypomineralization (MIH) (Fig. 16)
healthcare. being an exemplar of a condition that has a wide-
By contrast, environmental factors are not spread impact on clinical services.
fixed in the same way as genetic factors, and While a single DNA base pair genetic variant
timing of the event will be an important determi- may be sufficient to cause a DDA, there is a
nant on the final tooth phenotype. Some environ- more complex interplay of genetic and environ-
mental factors are readily identifiable, such mental factors in many other instances (Fig. 18).
as living in areas of high fluoride content in drink- Clinical evaluation of DDAs, including a family
ing water, severe systemic illness, or iatrogenic history, can provide important diagnostic infor-
causes such as radiotherapy, chemotherapy, or mation about an individual’s current, past, and
tetracycline use (Gawade et al. 2014; Goodarzi future overall health. DDAs may affect tooth
et al. 2016). Other environmental factors are number, shape, and/or the quality of the dental
poorly defined with those that influence molar tissues.
Fig. 11 Examples of
supernumerary teeth in the
primary dentition. Teeth are
particularly conical and
pointed in example (a).
(Images courtesy of
Associate Professor Robert
WA, Australia)
Fig. 12 Multiple supernumerary teeth overlying the supernumerary overlying 21 is inverted. (Image courtesy of
unerupted permanent upper central incisors (11 and 21; Associate Professor Robert Anthonappa, UWA Dental
dashed white oval) in a patient in the mixed dentition. The School, University of Western Australia, Perth WA, Australia)
Anomalies of Tooth Number, Shape, Genes known to influence tooth number and
and Mineralized Tissue Quality shape play critical roles in signaling pathways
and include WNT10A, MSX1, PAX9, AXIN2,
Tooth initiation is programmed to occur at specific EDA, EDAR, EDARADD, and LRP6.
sites at specific developmental time points Failure of initiation for a given tooth, most
(Cobourne and Sharpe 2013; Klein et al. 2013). typically due to a genetic variation, will result in
Fig. 13 Supernumerary
tooth lying between the
upper central incisors
(11 and 21; white dashed
oval) consistent with a
mesiodens (which is
inverted in this example).
(Image courtesy of
WA, Australia)
Fig. 14 Patient with

cleidocranial dysplasia
showing multiple
supernumerary teeth in both
maxilla and mandible.
(Image courtesy of
WA, Australia)

amelogenesis imperfecta.
Teeth are discolored, pitted,
and grooved and prone to
rapid wear and breakage.
(Images courtesy of
WA, Australia)
Fig. 16 Patient with molar

incisor hypomineralization
demonstrating enamel
defects on permanent first
molars and incisors in both
Teeth appear yellow and
brown in comparison to
remainder of dentition and
are often descripted as
“cheese molars.” (Images
Professor Robert
WA, Australia)

dentinogenesis imperfecta.
Teeth are discolored
(yellow/brown) with a
translucent appearance
giving them an opalescent
hue (a, b, c). Teeth also
demonstrate significant loss
of enamel which is also
noticeable on intraoral
radiographs (d, e). (Images
Professor Robert
WA, Australia)
congenital absence of one or more teeth – selec- et al. 2017). The clinical consequences of tooth
tive tooth agenesis (Table 3). Tooth agenesis may agenesis will be determined by the situation of
be associated with other anomalies in teeth that each individual and may relate to esthetics and
have formed (Cobourne and Sharpe 2013; Choi function.
Table 2 Examples of developmental dental anomalies known genetic cause. Mendelian-inherited conditions
due to single genetic variants where the dental phenotype with multiple OMIM entries, for example, due to variants
gives important information to the patient’s overall health. in more than one gene, are marked with an asterisk*
OMIM six-digit numbers are given in brackets with a
Genetic
variants Syndrome/
(inheritance) disorder Oral phenotype Clinical relevance
FAM20A Enamel renal Hypoplastic amelogenesis AI as a developmental anomaly is evident from
(AR) syndrome imperfecta early childhood, whereas calcification of the
[204690] May include: kidneys and other tissues presents later in life.
- Gingival hyperplasia Oral phenotype recognition and onward referral
- Dental pulp stones for renal assessment allows early specialist input
- Delayed eruption (de la Dure-Molla et al. 2014)
- Eruption cysts
- Root dilaceration
PEX1 & Zellweger Hypoplastic amelogenesis Zellweger spectrum disorder encompasses a
PEX6 (AR) spectrum disorder* imperfecta wide variation in multisystem phenotypes that
can be confused with other syndromes. AI as a
developmental anomaly evident from early
childhood provides an important but easily
overlooked clinical feature (Ratbi et al. 2015)
STIM1 (AR) Immunodeficiency Hypomineralized There is a variable impact on immune
10 [612783] amelogenesis imperfecta dysfunction, whereas AI is a constant feature
(Parry et al. 2016)
APC (AD) Familial May include: Early recognition of the significance of the
adenomatous - Tooth agenesis dental features should prompt onward referral
polyposis [175100] - Delayed tooth for further investigation in this group who are at
eruption increased risk of colon cancer later in life
- Supernumerary teeth (Almeida et al. 2016)
- Complex odontomas
AR autosomal recessive, AD autosomal dominant
Fig. 18 Developmental defects of enamel result from imperfecta (AI) is a consequence of Mendelian-inherited
amelogenesis being influenced by genetic and environ- genetic variants with potential phenotype attenuation by
mental factors. Dental fluorosis (DF) reflects a single envi- environmental factors. It is highly plausible that MIH is a
ronmental factor as the predominant event, although there consequence of as yet poorly defined genetic susceptibility
is evidence for genetic susceptibility. Amelogenesis and environmental factors.
Tooth initiation at an additional site can give by impairing eruption or causing abnormal
rise to a supernumerary tooth (Figs. 11, 12, 13, spacing (e.g., median diastema), may cause
and 14) (Table 4). Unerupted supernumerary root resorption, be associated with cystic
teeth may affect the position of adjacent teeth change, or remain unerupted and undetected
Table 3 Selective tooth agenesis resulting in missing teeth until recognized as a coincidental finding on
as a consequence of genetic variants (Cobourne and Sharpe dental imaging. Erupted supernumerary teeth
2013; Choi et al. 2017). Tooth agenesis is more likely in the
permanent than primary dentition. An absent primary tooth may have poor esthetics and be situated outside
will typically be associated with an absent successor perma- the dental arch.
nent tooth. The most frequently absent permanent teeth in Double teeth (Fig. 25) are a rare anomaly of
decreasing order of prevalence are the mandibular second tooth number and shape (AlZamel et al. 2016)
premolar, maxillary lateral incisor, and maxillary second
premolar. Variations in prevalence vary between (Table 5). Exaggerations of normal tooth shape
populations; the prevalence rates given are guides are more commonly encountered as small (micro-
Guide prevalence dontia) rather than large teeth (macrodontia)
in permanent (Fig. 26). More localized crown anomalies may
Term Definition dentition (%) occur, for example, involving a cusp or invagina-
Hypodontia 1–5 teeth absent, 5 tion (Table 6).
(Figs. 19, 20, excluding third Anomalies of tooth number may occur in
and 21) molars
isolation or be part of conditions with more
Oligodontia 6 teeth absent, 0.2
(Figs. 22 and excluding third widespread clinical phenotypes. Genotype-phe-
23) molars notype correlations are incomplete but indicate
Anodontia Failure of one or 0.01 that specific clinical phenotypes can relate to
both dentitions to specific genetic variants. For example, specific
develop
WNT10A variants may cause selected tooth
Fig. 19 Hypodontia in
primary dentition. (Images
Professor Robert
WA, Australia)
Fig. 20 Hypodontia in
permanent dentition with
missing upper lateral
incisors (a). The remainder
of the permanent teeth is
present (b). There is an
over-retained upper right
primary canine still present.
(Images courtesy of
WA, Australia)
agenesis with delayed dental age in the teeth phenotypes from early enamel failure to persis-
present, which may or may not be associated tent, localized opacities. Mixed phenotypes are
with ectodermal abnormalities that characterize common.
ectodermal dysplasia (Fig. 10) (Bergendal et al. Amelogenesis imperfecta (AI) (Fig. 15) is a
2016). A small number of syndromes are asso- heterogeneous group of Mendelian-inherited
ciated with supernumerary teeth including developmental enamel defects affecting the pri-
familial adenomatous polyposis (Table 1) and mary and permanent teeth. The prevalence of AI
cleidocranial dysplasia (Fig. 14) (Lubinsky and varies (1/700 and 1/14,000) depending upon the
Kantaputra 2016). population studied (Smith et al. 2017). The diag-
The range of developmental enamel defects is nosis and classification of AI has been based on
broad. The enamel organ responds to a wide clinical presentation and inheritance pattern
spectrum of insults in a limited number of ways (Witkop 1988). However, clinical phenotyping
that are reflected in abnormalities of enamel can be complicated by posteruptive changes to
quantity and/or quality. Deficiencies in enamel the abnormal enamel, and increasingly genetic
matrix volume manifest as generalized or focal classification is being used. Variants in a large
enamel hypoplasia (reduced quantity). Hypo- number of genes are known to cause AI either in
mineralized enamel (reduced quality) can be gen- isolation or as part of syndromes (Tables 1
eralized or focal with a broad spectrum of and 7).
Fig. 21 Clinical (a + b) and radiographic (c) presentation (35 and 45). (Images courtesy of Associate Professor
of a patient with hypodontia of the mixed dentition dem- Robert Anthonappa, UWA Dental School, University of
onstrating absence of lower second premolar teeth Western Australia, Perth WA, Australia)
Molar incisor hypomineralization (MIH) anomalies affecting both structure and shape of
(Fig. 16) involves demarcated, qualitative devel- teeth such as Hutchinson’s incisors (Fig. 30) and
opmental defects of enamel, affecting one or Mulberry molars (Fig. 31) (Little 2005;
more first permanent molars, with or without Nissanka-Jayasuriya et al. 2016). Mild changes
involvement of the incisor teeth. The etiology is can mimic other more common causes of enamel
poorly understood (Serna et al. 2016; Silva et al. hypoplasia such as MIH (Nissanka-Jayasuriya
2016). Wide variations in prevalence have been et al. 2016).
reported (<5–40%) depending on the population Dental fluorosis is widely reported around
investigated with variations over time (Dietrich the world, but prevalence differs based on
et al. 2003; Kukleva et al. 2008; Soviero et al. geography. Nearly 90% of dental fluorosis in
2009). Although not commonly encountered in the United States, for example, is considered
modern western practice, enamel hypoplasia very mild or mild, often appearing as barely
resulting from congenital syphilis should be con- visible lacy white markings or spots on the
sidered in the differential diagnosis of dental enamel (Figs. 32, 33, and 34) (Health and
Fig. 22 Oligodontia.
Multiple permanent teeth
are missing from both the
Primary teeth are over-
retained with shortening of
the roots. (Images courtesy
of Associate Professor
Robert Anthonappa, UWA
Dental School, University
of Western Australia, Perth
WA, Australia)
Fig. 23 Oligodontia
presenting with absence of
several permanent teeth
from both the maxilla and
mandible including teeth
17, 12, 22, 35, 32, 31, and
42. (Image courtesy of
WA, Australia)
Human Services Federal Panel on Community although some have cautioned against this (Spen-
Water 2015). This has recently lead the US Pub- cer and Do 2016). The Environmental Protection
lic Health Service to recommend that the optimal Agency considers the severe form of dental fluo-
fluoride concentration in drinking water for rosis with staining and pitting of the tooth surface
prevention of dental caries in the United States (Figs. 32, 33, and 34) as an adverse health effect
be reduced to 0.7 mg/L, from the previous range that should be prevented (Health and Human
of 0.7–1.2 mg/L (Health and Human Services Services Federal Panel on Community Water
Federal Panel on Community Water 2015), 2015).
Table 4 Supernumerary teeth is the collective term for tuberculate, supplemental, and odontome (Fig. 24)), orien-
additional teeth, which can be simply divided into supple- tation (vertical or normal, inverted, horizontal) (Figs. 12
mental and rudimentary teeth. Classification can take con- and 13), and position (buccal, palatal, transverse)
sideration of location (mesiodens (Fig. 13), paramolar, (Mallineni et al. 2014). Supernumerary teeth are more
distomolar, parapremolar), morphology (conical (Fig. 11), likely in the permanent than primary dentition
Term Definition Comments
Supplemental teeth Additional teeth that resemble Erupted supplemental teeth are typically positioned
(Figs. 11, 12, 13, and 14) near-normal adjacent teeth outside of the dental arch due to lack of space
Rudimentary teeth Additional teeth that are small Examples include:
(Figs. 11 and 13) and have abnormal Mesiodens: the most common (0.5–2.0%) supernumerary
morphology tooth, which is a rudimentary tooth typically located
between the upper central maxillary incisors (Fig. 13)
Conical: peg-like rudimentary teeth that typically occur in
the anterior mouth (Fig. 11)
Tuberculate: A rare variant of a rudimentary tooth with
two or more tubercles/cusps
Fig. 24 Small odontome

associated with the crown
of the unerupted upper right
canine (13). (Image
Professor Robert
WA, Australia)
Dentin anomalies affect coronal and root den- abfraction of teeth (Wetselaar and Lobbezoo
tin (de La Dure-Molla et al. 2015). Development 2016).
of tooth roots (number, shape, and length) is under Dentin formed during normal tooth develop-
the control of Hertwig’s epithelial root sheath that ment is primary dentin, which constitutes the bulk
also contributes to cementum formation. A wide of a tooth. After complete tooth formation, dentin
range of dentin anomalies may occur in response formation proceeds slowly throughout life. This
to environmental factors, such as trauma to one or type of dentin is secondary dentin, which is
more teeth and when generalized due to rare caused by physiological factors including the
genetic variations (Luder 2015) (Table 8). functional force of occlusion. It is prominent at
the pulpal roof, floor, and root canal orifice. Sec-
ondary dentin increases with age and leads to
Physical and Chemical Injuries of Teeth decrease in pulpal size. Tertiary dentin also called
reparative dentin forms around the pulp chamber
Tooth wear, which is the loss of tooth structure as a pathological response to attrition, aberration,
after its formation by nonbacterial causes, erosion, caries, or tooth restoration (Bleicher
includes attrition, abrasion, erosion, and 2014).
Fig. 25 Examples of double teeth; both primary and permanent (a). Permanent premolar double tooth (b) and permanent
molar double tooth (c)
Attrition destruction of Tomes’ processes and sclerosis of

dentinal tubules as reactive changes (opaque den-
Attrition is the loss of tooth structure in tooth to tin). In ground sections, it is seen as a black
tooth contact during mastication by physiological bundle, so-called dead tract (Fig. 40) (Fish 1928)
and/or pathological causes, which include abnor- (Stanley et al. 1983). Attrition stimuli may acti-
mal occlusion, bruxism, and abnormal tooth struc- vate underlying odontoblasts through dentinal
ture such as amelogenesis imperfecta. It occurs tubules to deposit newly formed dentin as a
predominantly at the cuspal and incisal edges of defense reaction (tertiary dentin).
the anterior teeth, followed by the occlusal sur-
faces of the molars. Physiological attrition gener-
ally progresses slowly with age. The lesion is Abrasion
cup-shaped with an enamel rim and smooth sur-
face (Fig. 40). In progression stage, the reduction Abrasion is the abnormal loss of tooth structure by
of cusp height and flattening of the occlusal sur- mechanical friction independent of occlusion
face are seen (Bartlett and Shah 2006). The under- (Fig. 41). Toothbrush abrasion is the most common
lying exposed dentin shows degeneration/ type of abrasion caused by a combination of
abrasive dentifrice and horizontal brushing strokes soft drinks, and citrus fruits (d’Incau et al. 2012).
(Lussi and Schaffner 2000). It is most pronounced Smooth saucer-shaped cavitation on the labial
in the cervical region of the labial surface of inci- surface of the anterior incisors is a characteristic
sors to premolars in the maxilla and appears as finding (Fig. 41). Reduction in salivary flow
wedge-shaped grooves with sharp angles. In enhances the severity of the lesion (Imfeld
underlining dentin, sclerotic opaque dentin and 1996). Occupational erosion is seen in workers
tertiary dentin formation are seen. Habitual abra- chronically exposed to acid (atmospheric pollu-
sion in pipe smokers and occupational abrasion in tion) at their workplace. The labial surfaces of
hairdressers or carpenters are also evident. maxillary/mandibular incisors are affected. Peri-
molysis (decalcification of tooth enamel from
frequent exposure to gastric acid) is seen in peo-
Erosion ple with chronic vomiting such as pregnant
women with severe morning sickness. In this
Erosion is the loss of tooth structure by chemical condition, erosion is generally seen on the lin-
causes. Dietary erosion may be induced by gual surfaces of anterior teeth. Exposure of den-
excessive intake of acidic beverages, carbonated tal tubules by tooth injuries may cause dentin
hypersensitivity.
Table 5 Examples of double teeth, which are rare anom-
alies more likely to involve permanent than primary teeth
(AlZamel et al. 2016) Abfraction
Gemination A double tooth Identification of
Abfraction indicates the loss of cervical tooth
(conjoined) arising from the the type of double structure in the absence of caries. It is usually
(Figs. 25 and incomplete tooth can be observed in the buccal region at the
27) division of a tooth difficult. cementoenamel junction (CEJ) of the teeth. It is
bud Evaluation
should include
typically a wedge-shaped defect with sharp inter-
Fusion A double tooth
(twinned) arising from the assessment of nal and external line angles. The buccal surface of
(Figs. 25 and joining of two which adjacent premolars and canines is the most affected area.
27) adjacent tooth teeth are present Excessive cyclic forces caused by malocclusion
buds or bruxism induce pathological damage of enamel
Fig. 26 Macrodontia of
permanent upper incisor
teeth
Fig. 27 Clinical examples of gemination/fusion (*). Dis- adjacent teeth are present. (Images courtesy of Associate
crimination between germination and fusion can be diffi- Professor Robert Anthonappa, UWA Dental School, Uni-
cult. Evaluation should include assessment of which versity of Western Australia, Perth WA, Australia)
Table 6 Examples of localized anomalies of crown shape

Dens An abnormal pit resulting from inappropriate Also known as “dens-in-dente” (“tooth within a
invaginatus invagination of the dental hard tissues into the tooth”).
(Fig. 28) pulp Primarily involves the permanent second
maxillary incisor.
Restoration of the tooth may involve root canal
therapy (Zhu et al. 2017)
Dens Defined as a tubercle or protuberance from the
evaginatus involved surface of the affected tooth consisting
of an outer layer of enamel, a core of dentin, and
may contain a slender extension of pulp tissue
Talon cusp A cusp-like projection arising from the labial or A rare developmental anomaly that is more
(Fig. 29) lingual surface of an anterior tooth that includes prevalent in the permanent than primary dentition
enamel, dentin, and pulp and has a base that is at (Mallineni et al. 2014)
least half the distance between the incisal edge
and dentin-enamel junction
Cusp of Additional cusp of variable size arising from the A common variation that can be prominent in
Carabelli mesiopalatal aspect of the first permanent some individuals (Moormann et al. 2013)
maxillary molar tooth
Fig. 28 Dens invaginatus

(dens-in-dente) upper left
lateral incisor (22; white
dashed oval). There is a
periapical radiolucency
involving this tooth
consistent with an
inflammatory process.
(Image courtesy of
Professor Camile Farah,
Qscan Radiology Clinics,
Brisbane QLD, Australia)
Fig. 29 Talon cusp on

upper right lateral incisor
(12; white dashed oval).
(Image courtesy of
Table 7 Examples of genes where variants result in amelogenesis imperfecta (Fig. 15) in isolation (Smith et al. 2017).
See also Table 1 for syndromic examples and OMIM for further information
Gene Function Inheritance Comments
AMELX Predominant enamel matrix X-linked Affected females may exhibit clinically grooved
protein enamel due to lyonization that can contrast with the
more profound AI phenotype in affected males
MMP20 Enamel matrix protease that helps AR Hypomaturation subtype of hypomineralized AI
to remove enamel matrix proteins
in an ordered way to allow full
hydroxyapatite mineralization
ACPT Acid phosphatase AR Hypoplastic AI
C4orf26 Possible hydroxyapatite AR Hypomineralized AI
nucleation in enamel matrix
GPR68 Proton-sensor necessary for pH AR Hypomaturation subtype of hypomineralized AI
regulation
SLC24A4 Ion exchange: potassium- AR Hypomaturation subtype of hypomineralized AI
dependent sodium/calcium
exchanger family
WDR72 Vesicle transport in ameloblasts AR Hypomineralized AI
FAM83H Organization of the keratin AD Dominant mutations result in the hypocalcified
cytoskeleton subtype of hypomineralized AI
LAMB3 Hemidesmosome integrity AD Dominant mutations in the final exon result in
hypomineralized enamel with focal hypoplasia as a
form of isolated AI – note: other mutations in
LAMB3 cause junctional epidermolysis bullosa
Fig. 32 Mild fluorosis. (Image courtesy of Associate Pro-

Fig. 30 Hutchinson’s incisors with their characteristic fessor Robert Anthonappa, UWA Dental School, Univer-
tapering straightedge incisal edges, and maximal sity of Western Australia, Perth WA, Australia)
mesiodistal width at the middle third described as a barrel
shape. These also display enamel hypoplasia at the incisal
edge. (Image courtesy of Associate Professor Robert
Anthonappa, UWA Dental School, University of Western
Australia, Perth WA, Australia)
Fig. 33 Moderate fluorosis. (Image courtesy of Associate

Professor Robert Anthonappa, UWA Dental School, Uni-
versity of Western Australia, Perth WA, Australia)
Fig. 31 Mulberry molar (also known as Fournier’s molar

and misidentified as Moon’s molar) demonstrates an occlu-
sal anatomy with numerous disorganized globular projec-
tions that resemble the surface of a mulberry. (Image
courtesy of Associate Professor Robert Anthonappa, Fig. 34 Severe fluorosis. (Image courtesy of Associate
UWA Dental School, University of Western Australia, Professor Robert Anthonappa, UWA Dental School, Uni-
Perth WA, Australia) versity of Western Australia, Perth WA, Australia)
Table 8 Examples of dentin and root development disorders that illustrate the broad spectrum of anomalies (Luder 2015)
Root A sharp abnormal bend in the root Most typically a consequence of physical
dilacerations trauma during root development but can be a
(Figs. 35 and 36) consequence of genetic variation (e.g., enamel
renal syndrome due to FAM20A variants)
Taurodontism Elongation of the pulp chamber resulting in Multiple causes and may be associated with
(Fig. 37) apical displacement of the furcation, which is other DDAs (e.g., amelogenesis imperfecta and
most evident in the first permanent molar teeth taurodontism in tricho-dento-osseous syndrome
(Fig. 38) due to DLX3 variants)
Hereditary Generalized abnormal dentin and cementum A heterogeneous group of conditions due to
hypophosphatasia due to loss of function of tissue-nonspecific ALPL variants with incomplete root formation
alkaline phosphatase that may lead to early exfoliation of primary
teeth, often associated with bone abnormalities
Dentin dysplasia Generalized pulpal obliteration and very short A rare, dominant inherited due to SSUH2
type I (Fig. 39) roots and early exfoliation variants
Dentinogenesis Generalized abnormal dentin with variable Type I: associated with osteogenesis imperfecta
imperfecta morphological changes to the overall dentin due to COL1A1 or COL1A2 variants
(Fig. 17) morphology Type II: due to DSPP variants
Type III: “shell teeth” with large pulp chambers
due to DSPP variants
X-linked Hypomineralized dentin with abundant Due to variants in PHEX
hypophosphatasia interglobular dentin and large pulp chambers
Fig. 35 Root dilaceration

of permanent canine teeth
Fig. 36 Cropped
orthpantomogram showing
distal dilaceration of the
root of the upper left lateral
incisor (22; white dashed
oval). (Image courtesy of
Fig. 37 Taurodontism.
There is elongation of the
pulp chambers (*) of the
molar teeth in particular
resulting in apical
displacement of the
furcation, which is most
evident in the lower second
permanent molar teeth
(37 and 47) (a), and first
permanent molar teeth and
primary second molar teeth
(b + c) in a separate patient.
(Images courtesy of
WA, Australia)
and dentin at the CEJ, which is located away from different countries; it is decreasing in developed
the loading (Sarode and Sarode 2013). nations and increasing in developing nations.
The microbiology of dental caries and the role
of the human oral microbiome are explored in
Dental Caries more detail in the chapter on ▶ “Odontogenic
Bacterial Infections.” In this section, focus is
Dental caries (tooth decay) is one of the most placed on the clinical and histological presenta-
prevalent dental diseases in the world (Figs. 42 tion of dental caries and its resultant induction
and 43). The prevalence and severity vary in of other odontogenic pathologies including
Fig. 38 (continued)
Fig. 39 Dentin dysplasia (Type I; radicular form). The There is obliteration of the pulp chambers, mostly of the
roots are very short or nonexistent and abnormally shaped. anterior teeth. (Image courtesy of Professor Camile Farah,
The lower molar roots have the typical shallow “W” shape. Qscan Radiology Clinics, Brisbane QLD, Australia)
pulpitis, periodontal abscess, and periapical bone considered as a complex unique biofilm-mediated
pathology. disease affected by multiple factors involving die-
Dental caries is an infectious disease of cario- tary life (frequent ingestion of fermentable carbo-
genic bacterium in bacterial biofilm (dental hydrate), poor oral hygiene, inadequate fluoride
plaque). It constitutes the localized demineraliza- exposure, etc. The modified Keyes model of den-
tion and destruction of dental hard tissues by tal caries including cariogenic bacterium, host
acidic products resulting from bacterial fermenta- (susceptible tooth surface), food (substrate), and
tion of dietary carbohydrates. There is no single time is now well accepted (Fig. 44) (Selwitz et al.
bacterium related to the development of dental 2007). Moreover, it is well known that dental
caries. Streptococcus mutans, Streptococcus caries is a dynamic process showing repeated
sobrinus, and Lactobacillus species are key path- cycles of demineralization and remineralization.
ogens (Larsen and Fiehn 2017). Dental caries is The balance of the pathological and protective
Fig. 38 Tricho-dento-osseous syndrome. Orthopanto- density of the cranial bones. There is an overall impression
mogram (a) and lateral cephalogram (b) show that the of loss of mastoid pneumatization (associated with
wisdom teeth are missing. The upper second molars are Eustachian tube dysfunction). The features are consistent
in the crown formation stage and are unerupted. The lower with those noted in tricho-dento-osseous syndrome. Intra-
second molars are missing. There are multiple other teeth oral clinical photographs (c–f) show small, widely spaced
missing consistent with oligodontia. There is evidence of teeth with thin enamel. Oligodontia is confirmed clinically.
taurodontism and enlarged pulp chambers involving the Note the presence of a labial draining sinus associated with
first permanent molars. There is internal resorption of the tooth 53 (e). Extra-oral clinical photographs (g, h) demon-
upper left and right primary canines (53 and 63) with a strate dry, thin, kinky hair typical of patients with tricho-
periapical radiolucency associated with 53 suggestive of an dento-osseous syndrome. (Images courtesy of Professor
underlying inflammatory process. A similar but less appar- Camile Farah, Qscan Radiology Clinics, and Dr Steve
ent pattern can be seen apical to 63. There is evidence of Kazoullis, Lady Cilento Children’s Hospital, Brisbane
enamel hypoplasia, affecting all erupted teeth. There is QLD, Australia)
evidence of occipital bossing and overall increased bone
Fig. 41 Erosion and abrasion of dentition. (Image cour-

tesy of Dr Fujii, Hiroshima University, Japan)
easily induced. Chronic caries is commonly seen

in elderly persons. The amount of softened dentin
is less than that of acute caries because prominent
remineralization occurs in such lesions. Tertiary
dentin formation is commonly seen between
chronic caries and pulp tissue. On the other
hand, arrested caries is static and stationary caries
without any future progression. If a clinically
Fig. 40 Attrition. Cup-shaped lesions with an enamel rim plaque-free condition is obtained, arrested caries
and smooth surface (a) (Image courtesy of Dr Nagahara, can occur at any disease progression stages. In
Nippon Kokan Fukuyama Hospital, Japan). Ground spec- addition, caries is further classified as pit and
imen (b) shows dead tracts (*), tertiary dentin (D), and
pulp (P). fissure caries, smooth surface caries, and root
caries based on anatomical location.
factors, which influence the initiation and progres-

sion of dental caries, is important. Protective fac- Pit and Fissure Caries
tors such as healthy diet, appropriate tooth
brushing, fluoride application, and normal sali- Pit and fissure caries (Fig. 45) occurs on the
vary function result in promoting remineralization occlusal surface of molars and premolars. Pits
and lesion arrest. On the other hand, pathological and fissures, which are deep narrow spaces, pro-
factors, including frequent consumption of dietary vide mechanical habitats for cariogenic organisms
sugars, poor oral hygiene, and salivary dysfunc- like streptococci and lactobacilli (Juhl 1983). In
tion, induce initiation and progression of caries this area, enamel rods radiate from pit and fissure
(Pitts et al. 2017). toward dentin-enamel junction (DEJ). So, enamel
There are different classification systems for caries spreads as a cone shape inverted “V” with
dental caries based on numerous aspects. the apex at the pit or fissure and the wide base at
According to the caries progression model, there the DEJ. Dentin caries initially spreads laterally
is acute caries, chronic caries, and arrested caries along the DEJ and begins to penetrate the dentin
(Nyvad and Fejerskov 1997). Acute caries shows toward the pulp via the dentinal tubules. Con-
rapid progression and is prevalent in children to versely dentin caries spreads as a cone shape
young adults. In acute caries, bacterial invasion “V” with the tip on pulpal side. Under dentin
and softened dentin are prominent, but tertiary caries, dead tracts, which are empty tubules with
dentin formation is rare; therefore, pulpitis is sclerosis, are observed (Fig. 45).
Fig. 42 Dental caries in the primary dentition. Frontal (a), Anthonappa, UWA Dental School, University of Western
maxillary occlusal (b), mandibular occlusal (c) views. Australia, Perth WA, Australia)
(Images courtesy of Associate Professor Robert
Smooth Surface Caries Root Caries
Smooth surface caries (Fig. 46) occurs on the Root surface caries occurs on the cementum of
proximal surfaces of teeth or on the gingival denuded roots near the cementoenamel junction
third of the buccal and lingual surface with poor (CEJ) because of periodontitis, gingival reces-
self-cleaning function. It originates on the wide sion, and abfraction. It usually progresses as
enamel surface usually covered by plaque. In chronic caries without pain. Root surface caries
smooth surface caries, the enamel caries cone is often prevalent in the elderly population.
has its base on the enamel surface and the apex Recently, incidence of root caries is significantly
at the DEJ. At the DEJ, caries spreads laterally increasing, because the number of elderly per-
and penetrates deeply through the dentinal sons who have more teeth with denuded root
tubules in the same manner as pit and fissure surface caused by gingival recession and covered
caries (Fig. 46). Between smooth surface caries with cariogenic biofilm has increased (Ritter
and pulp, dead tracts are seen. et al. 2010).
about 40 μm of surface enamel remains. The

surface enamel is an active remineralization
area, in which mineral ions derived from
plaque/saliva or resulted from the demineraliza-
tion of the lesion redeposit again (Pitts et al.
2017). The intact surface enamel inhibits
bacterial invasion into the lesion. Therefore,
careful follow-up observation of early enamel
caries is recommended because both processes
of demineralization-remineralization simulta-
neously occur in early enamel caries. This
stage of the lesion can be arrested or reversed
by modifying the causative factors or applying
preventive intervention, while an imbalance of
demineralization-remineralization can result in
formation of an enamel defect.
Dentin Caries
When enamel caries reaches the dentin-enamel

junction, lateral spread occurs and leads to the
involvement of numerous dentinal tubules and
undermining of the enamel. The undermining
of the enamel suddenly results in a wide-open
cavity. Dentin caries progresses along the
Fig. 43 Dental caries. Clinical (a + b) and associated
radiographic (c + d) changes in the same patient. (Images
dentinal tubules. In ground sections, dentin
courtesy of Associate Professor Robert Anthonappa, UWA caries shows a layered structure inclusive of a
Dental School, University of Western Australia, Perth WA, translucent zone, demineralization zone, bacte-
Australia) rial invasion zone, and destruction zone
(Fig. 46). In infected dentin, destructive struc-
tures such as beaded expansion, transverse
Histopathological findings also differ clefting, and hollow formation packed with
among affected areas, be they enamel, dentin, numerous bacteria are observed (Fig. 48). A
or cementum. protective layer of tertiary dentin is often
formed at the surface of the pulp chamber
under dentin caries (Kidd and Fejerskov
Enamel Caries 2004).
Removal of softened dentin and restoration
The first visible sign of enamel caries is a whitish of the tooth substance defect is required. In case
spot, chalky-white opacity of enamel without an of large caries with pulpal infection, dental
enamel defect (so-called white spot lesion) pulp capping, pulpotomy, and pulpectomy
(Kudiyirickal and Ivancakova 2008). Histologi- may be required depending on the degree
cally four zones are seen in ground sections of of pulp damage. Untreated dental caries
early enamel caries: surface enamel, body of may sequentially result in pulp inflammation
lesion, dark, and translucent zones (Fig. 47). (pulpitis) and periapical periodontitis and even-
Despite loss of mineral in the subsurface area, tually spread into the bone causing
Fig. 44 The modified

Keyes model of dental
caries. (Modified from
Selwitz et al. 2007)
Fig. 45 Pit and fissure

caries. Enamel caries cone
(a), dentin caries cone (b),
and dead tract (c)
osteomyelitis due to the imbalance of host resis- spreads along the cementum lamella and finally
tance/bacterial virulence. leads to stripping of cementum.
Cementum Caries Pulpitis
Cementum caries starts at the exposed root surface Pulpitis is inflammation of the pulp, which is a
cementum and progresses through Sharpey’s viable structure of the tooth consisting of pulpal
fibers inserting into cementum and laterally cells, nerves, and blood vessels enclosed by dental
Fig. 46 Smooth surface

caries. Enamel caries cone
(a), dentin caries cone (b),
and dead tract (c)
Fig. 47 Low-power view

of early enamel caries.
Surface enamel (a) appears
to be intact. Body of lesion
(b) is subsurface decalcified
lesion showing
enhancement of striae of
Retzius and surrounded by
dark zone (c) and
translucent zone (d)
hard structures. The main cause of pulpitis is changes that are seen in the pulp are pulpal hyper-
bacterial infection. Mechanical, thermal, and emia, which induces excessive blood flow,
chemical causes also contribute to the develop- followed by serous exudation and inflammatory
ment of pulpitis. Dental caries is the main infec- cell infiltration. It is a precursor condition of
tious cause of pulpitis (carious pulpitis). Pulpitis pulpitis, which can be resolved by removal of
may occasionally occur without caries because of stimulation (reversible pulpitis). However, pro-
an infection from the root apex or accessory root longed stimulation induces frank pulp inflamma-
canals, which are involved by deep periodontitis, tion (irreversible pulpitis).
periapical periodontitis of adjacent teeth, or The pulp has special anatomical properties; it
widely extended osteomyelitis (ascending is almost surrounded by dental hard tissues and
pulpitis). Severe sepsis may also induce pulpitis receives its blood supply only through the apical
in intact teeth (hematogenous pulpitis) through foramen. Therefore, elevation of internal pres-
circulation. sure associated with an inflammatory exudate
Carious pulpitis starts as a localized inflamma- easily occurs in the pulp. In addition, it may
tion associated with infected dentin. The first also lead to local pulp necrosis through tissue
elevation of internal pressure in the pulp. Acute

suppurative pulpitis is marked by significant neu-
trophil infiltration. The pulp is covered by soft-
ened dentin. A clinically important diagnostic
symptom is severe spontaneous pain. After pus
discharge by opening of the pulp chamber, the
severe pain rapidly disappears.
Chronic Pulpitis
Chronic pulpitis histopathologically shows prolif-

eration of granulation tissue with infiltration of
lymphocytes and plasma cells. It presents with a
long disease course. Pus is discharged by loss of
carious softened dentin changing acute suppura-
tive pulpitis to chronic ulcerative pulpitis. Clini-
Fig. 48 Histology of dentin caries. Reactionary dentin cally, the affected tooth presents with a large
(arrows) and inflammatory cell infiltration in pulp (*) (a).
Destructive structures in dentin caries (b); Transverse cleft
cavity with wide exposure of the pulp. Although
and liquefaction focus (L) the pulp is exposed, pain is usually absent. Food
impaction within the large cavity may rapidly
hypoxia. Inflammatory mediators released from induce pain, but it can be resolved by removing
necrotic pulpal tissue may induce further inflam- impacted food. Scraping of the ulcerative surface
mation and edema. The cyclic episode may with dental instruments induces severe pain and
eventually result in extension to total pulp bleeding.
necrosis. Continuous slight stimuli may induce polypoid
The most obvious clinical symptom of pulpitis proliferation of granulation tissue resulting in
is pain that is easily induced by elevated internal chronic hyperplastic pulpitis (also known as
pressure in the pulp. In pulp hyperemia (reversible “pulp polyp”) in deciduous teeth or permanent
pulpitis), transient pain is particularly caused by teeth of young adults with high tissue viability
cold stimulus. According to the progression of and good blood supply from a wide apical fora-
inflammation, hot, sweet, and acidic stimuli also men (Fig. 49). The pulp polyp consists of surface
induce pain, which may be more spontaneous or fibrinopurulent exudate, immature granulation tis-
continuous. In acute suppurative pulpitis, the pain sue, and fibrous connective tissue at deeper por-
increases in intensity, and a strong throbbing and tions. It may be covered by squamous epithelium
radiating pain is felt. Pulpitis is explored in greater of oral mucosal origin (Fig. 49).
detail in the chapter on ▶ “Odontogenic Bacterial Mild serous or suppurative inflammation
Infections.” occurs in pulpal tissue covered by healthy dentin
resulting in chronic closed pulpitis. Pain and other
symptoms are milder than acute pulpitis.
Acute Pulpitis
Acute pulpitis shows prominent exudative inflam- Pulp Necrosis

mation with clinically acute symptoms. Acute
serous pulpitis shows serous inflammation in Total pulp necrosis (gangrene) is the result of an
pulpal tissue. The affected tooth is covered by untreated pulpitis. Pulp necrosis with bacterial
intact dentin. Intense hyperemia and exudation infection (Proteus infection) constitutes pulp gan-
lead to spontaneous pain at night through grene. It is associated with a foul odor when the
Fig. 49 Pulp polyp. Radiograph (a) showing large radio- Proliferation of granulation tissue covered by squamous
lucency (*) corresponding to the carious lesion involving epithelium is in connection with pulp (c). (Hematoxylin
the crown of the upper second molar (b). Hyperplastic and eosin) (Images (a) and (b) courtesy of Dr Nagahara,
pulpal tissue (white arrow) is located in the large cavity. Nippon Kokan Fukuyama Hospital, Japan)
pulp is opened for endodontic treatment. Conser- in greater detail in the chapter on ▶ “Odontogenic
vative treatment for pulpitis such as application of Bacterial Infections.”
anti-inflammatory agents or pulp capping is indi-
cated for early stage of pulpitis. Advanced pulpitis Acute Periapical Periodontitis
requires vital pulpotomy or pulpectomy. Pulpitis Stimulation from pulpitis induces hyperemia and
frequently spreads to surrounding periapical peri- edema in periodontal tissues at the root apex
odontal tissues and results in periapical resulting in acute serous periapical periodontitis.
periodontitis. Clinical symptoms are not clear, and there are no
changes noted on radiographs. Acute suppurative
periapical periodontitis manifests clinically as a
Periapical Periodontitis severe pain including continuous throbbing pain
and strong occlusal and percussion pain. Tooth
Periapical periodontitis is an inflammatory lesion extrusion, loosening, and mobility are prominent.
around the apex of a tooth root. Bacterial infection Enlargement of regional lymph nodes and sys-
from the pulp is the major cause of periapical temic symptoms such as fever and shivering are
periodontitis. The intense bacterial challenge experienced. Radiographs may show diffuse
leads to acute suppurative periapical periodontitis. radiolucency at the apical zone. Histopathologi-
Moreover, if the level of bacterial challenge is in cally, marked neutrophil infiltration with abscess
equilibrium with the host defense response, a formation is seen. Periodontal ligament destruc-
transition from acute to chronic periapical peri- tion and bone resorption with osteoclasts are seen.
odontitis is evident. Chronic periapical periodon-
titis includes chronic periapical abscess, chronic Chronic Periapical Periodontitis
periapical granuloma, and radicular cyst. The Persistent stimulation by bacteria and their prod-
chronicity of acute periapical periodontitis leads ucts from the root apex leads to chronic peri-
to chronic periapical abscess, which is encapsu- apical periodontitis (chronic suppurative
lated by granulation tissue, and the continuous periapical periodontitis; chronic periapical
organization of abscess results in periapical gran- abscess). Clinical symptoms are mild. Slight
uloma. Eventually, proliferation of the epithelial tooth loosening and mobility are seen. On radio-
cell rests of Malassez in periapical granuloma graphs, widening of the periodontal ligament and
associated with inflammation may lead to the bone destruction at the root apex area are evident
development of radicular cyst. These lesions can (Fig. 50). Histologically, an abscess at the root
remain quiescent for long periods of time without apex area is seen that is associated with bone
any symptoms. Periapical pathology is explored resorption. Chronic periapical abscess is
Fig. 50 Chronic periapical abscess associated with 47; new bone formation (black arrows in d). An inflammatory
cropped panoramic radiograph (a), oblique sagittal (b) phlegmon lingual to the perforation involving the attach-
maximum intensity CT coronal soft-tissue window recon- ment of mylohyoid extends inferiorly and buccally into the
struction (c), and cropped, axial, bone window CT recon- submandibular space (white dotted arrows in c). Eventu-
struction (d) of the 46–48 region. There is an ovoid lucent ally, this extended peripherally through subcutaneous fat
lesion (white arrows in a and b) around the distal root and forming a skin sinus. (Images courtesy of Clinical Associ-
apex of the non-vital 47 which is much more clearly seen ate Professor Andy Whyte, Perth Radiological Clinic,
on CT (b). Perforation of the lingual cortex overlying the Perth WA, Australia)
lesion (white dashed arrow in d) with adjacent periosteal
histologically encapsulated by granulation tissue cells (lipid-laden macrophages) are frequently

(abscess membrane). seen in granulation tissue. Occasionally periapical
granuloma contains proliferation of anastomosing
Periapical Granuloma squamous epithelium, which is derived from the
The replacement of chronic periapical abscess by epithelial cell rests of Malassez (Nair 2000; Nair
chronic inflammatory granulation tissue results in 2004) (Fig. 51).
formation of periapical granuloma. Clinically,
there are no subjective symptoms. Radiographic Radicular Cyst
examination reveals a radiolucent lesion with Radicular cyst is the most common inflamma-
well-demarcated margin at the root apex tory cyst of the jaws. It is mainly formed by
(Fig. 51). Histologically, the lesion consists cystic change in proliferated squamous epithe-
of immature granulation tissue with infiltration lium in a periapical granuloma. Clinically it is
of lymphocytes, plasma cells, and macrophages asymptomatic. Radiographic examination
surrounded by mature fibrous connective tissue shows a well-demarcated oval radiolucent
(Fig. 51). As collagen fibers in connective tissue lesion surrounded by a radiopaque line, which
are firmly attached to the root apex surface, peri- contains the non-vital tooth apex (Figs. 52 and
apical granuloma may be removed together with 53). Histologically, the cyst wall consists of
the extracted tooth. Cholesterol slits and foam inner granulation tissue with various degrees
Fig. 51 Periapical granuloma. A radiolucent area is seen power histopathological view (c) showing numerous foam
in association with the apex of a non-vital tooth (a). cells and chronic inflammatory cells observed in granula-
Low-power histopathological view of periapical granu- tion tissue. (Hematoxylin and eosin stain) (Image (a) cour-
loma at apex of tooth root (b). Proliferation of epithelial tesy of Professor Kakimoto, Hiroshima University, Japan)
rests of Malassez (arrows) are seen in the lesion. High-
Fig. 52 Radicular cyst associated with a carious tooth (a). (a) courtesy of Professor Camile Farah, UWA Dental
Cyst wall (b) consists of (1) non-keratinizing squamous School, University of Western Australia, Perth WA,
epithelium, (2) granulation tissue and (3) fibrous connec- Australia)
tive tissue. (Hematoxylin and eosin stain) (Image
of inflammatory cell infiltration and an outer producing cells and/or ciliated columnar cells.
fibrous connective tissue. The cyst wall is Radicular cyst, which may remain after extrac-
lined by nonkeratinizing squamous epithelium tion of the offending tooth, is termed a residual
(Fig. 52), which occasionally includes mucous- cyst (Fig. 52).
Fig. 53 Radicular cyst: Case 1 - sagittal (a) and soft-tissue uniloculate lesion associated with the apices of the rotated
axial reconstruction (b) in the right mandible. Associated 25 and the restored 26 and 27. This represents an apical
with the apex of a carious tooth 44 root remnant, there is an radicular cyst in association with a non-vital tooth 26.
18mm uniloculate, fluid-filled lesion which extends to the Advanced periodontitis is present around the roots of 27
apices of 43 and 45 (white dotted arrows in a and b). Case 2 (white dotted arrows in c and d) with an oro-antral com-
- cropped panoramic radiograph (c) and coronal CT (d) in munication (OAC) palatal to the apices (as seen in d).
the left maxilla. Elevating the floor of the left maxillary (Images courtesy of Clinical Associate Professor Andy
sinus (white arrows in c and d), there is a 27mm expansile, Whyte, Perth Radiological Clinic, Perth WA, Australia)
To remove infection, root canal treatment is when there is mucosal thickening in a sinus adjacent
mainly performed. Sometimes, removal of the to an infected tooth with periapical radiolucency
offending tooth with the periapical lesion is suggestive of a periapical abscess (Fig. 54).
required. Acute exacerbation of periapical peri- A narrow drainage route formed by disease
odontitis associated with the increase of bacterial connecting an abscess to a free surface results in
virulence and/or decrease of host resistance leads formation of a dental fistula. A fistula opening
to the continuous enlargement of periapical peri- toward the oral cavity is an internal dental fistula,
odontitis. Sequelae can include osteomyelitis, while a fistula opening toward facial skin is an
odontogenic sinusitis, or dental fistula. external dental fistula (Fig. 55).
Infection may spread into the bone marrow and
cause bone inflammation (osteomyelitis). Inflamma-
tion can spread into the surrounding soft tissue and Periodontal Diseases
produce additional suppurative inflammation such
as a gingival abscess and phlegmon of oral floor. Periodontal diseases and conditions are classified
Bone tissue between the root apex of upper first according to the International Workshop for a
molars and the lining of the maxillary sinus is very Classification of Periodontal Disease and Con-
thin. Acute periapical abscess can easily destroy this ditions (Table 9) (Wiebe and Putnins 2000;
thin bony tissue and expand into the maxillary sinus Armitage 1999), and which has recently been
wall. Odontogenic sinusitis is relatively common updated (Caton et al. 2018). Plaque-induced peri-
and is diagnosed by radiographic examination odontal diseases are divided into two categories:
Fig. 54 Odontogenic
sinusitis. The left maxillary
sinus lining demonstrates
thickening (white arrow).
(Image courtesy of
Professor Kakimoto,
Hiroshima University,
Japan)
gingivitis and periodontitis. Plaque-induced gingivi- represents chronic inflammation localized to the
tis is modified by several factors including systemic gingiva. Clinically, redness, edema, bleeding, and
conditions, mucocutaneous disorders, and/or medi- swelling at the gingival margin are prominent, and
cations. On the other hand, periodontal lesions are there is loss of gingival stippling (Fig. 56). No
classified into seven categories: chronic periodonti- radiographic changes are seen and there is no clin-
tis, aggressive periodontitis, periodontitis associated ical evidence of tooth mobility. Histologically, dila-
with systemic diseases, necrotizing periodontal tation and hyperemia of capillaries and severe
diseases, abscesses of periodontium, combined infiltration with lymphocytes and plasma cells are
periodontic-endodontic lesions, and developmental observed in the subjunctional epithelium and the
or acquired deformities and conditions. Periodontitis underlying connective tissue. In widely dilated
is a chronic inflammatory disease of the tooth- intercellular spaces of junctional epithelium cells,
supporting tissues including the gingiva, cementum, numerous neutrophils are seen (Fig. 56).
periodontal ligament, and alveolar bone. The world-
wide prevalence of periodontitis makes it one of the Gingivitis Modified by Systemic
most common infectious diseases of human beings. Conditions
Periodontal bacterial diseases are explored in greater Puberty-associated gingivitis is an inflammatory
detail in the chapter on ▶ “Odontogenic Bacterial enlargement of the gingiva resulting from a hor-
Infections”, while gingival and periodontal condi- monal imbalance during puberty (Fig. 57). With
tions are explored in more detail in separate chapters a similar amount of dental plaque, the severity of
on ▶ “Gingival Pathology,” ▶ “Oral Vesicular and gingival inflammation in 9–14-year-old children
Bullous Lesions,” ▶ “Oral Lichen Planus, (puberty period) is greater than adult because of
▶ Odontogenic Bacterial Infections”, and ▶ “Non- hormonal imbalance.
odontogenic Bacterial Infections”. Readers are also Pregnancy-associated gingivitis occurs in
directed to the 2017 new classification scheme for females whereby they show greater susceptibility
periodontal and peri-implant diseases and conditions to gingivitis caused by accumulation of dental
for more detail (Caton et al. 2018). plaque when they are exposed to high levels of
progesterone associated with pregnancy (Fig. 58).
Gingivitis
Gingivitis Modified by Mucocutaneous
Plaque-Induced Gingivitis Diseases
Plaque-induced gingivitis and periodontitis are the The clinical term “desquamative gingivitis”
most representative periodontal diseases. Gingivitis is applied to the gingival manifestation of
various mucocutaneous diseases with vesicle

formation such as oral lichen planus, mucous
membrane pemphigoid, and pemphigus
vulgaris (Sugerman and Savage 2002; Endo
et al. 2008; Gagari and Damoulis 2011; Hasan
2014). The majority of patients are women in
middle and advanced age (Leao et al. 2008;
Suresh and Neiders 2012). The Nikolsky’s sign
in which gingival mucosal epithelium easily
separates or peels away from gingival tissue by
rubbing, can be a useful test to confirm the
presence of oral mucocutaneous diseases, but
this should not be used routinely. More exten-
sive discussion of this topic can be found in
separate chapters on ▶ “Gingival Pathology,”
▶ “Oral Vesicular and Bullous Lesions” and
▶ “Oral Lichen Planus.”
Drug-Induced Gingival Overgrowth

Some medications may induce gingival hyper-
plasia through excessive production of colla-
gen in gingival connective tissue (Seymour
et al. 1996; Trackman and Kantarci 2015).
Clinically, gingival enlargement is character-
ized by lobulated proliferation. After surgical
resection of the lesion, it easily recurs if the
medication is not altered or ceased. Removal
of dental plaque alone cannot suppress gingi-
val overgrowth due to medication. The most
Fig. 55 Dental fistula/draining sinus (a) associated with common drugs that cause this condition
dens in dente on the upper left second premolar in a include the anticonvulsant drug (phenytoin)
14-year-old female. Orthopantomogram (b) demonstrating
a 7 mm oval radiolucency present between the roots of the (Arya and Gulati 2012), the calcium channel
upper left first (24) and second (25) premolars (white arrow blocking agent (nifedipine) (Nery et al. 1995;
in b). No appreciable abnormality is noted associated with Ponnaiyan and Jegadeesan 2015), and the
either tooth; however, the lucency appears to overlie and immunosuppressive drug (cyclosporine). Fifty
involve the root of 25. Cone Beam CT (c) demonstrating a
dens in dente deformity (white arrow in c) on the mesial percent of patients on long-term phenytoin
aspect of the crown of the upper left second premolar develop gingival hyperplasia, while gingival
(25) with an elongated tract lined by low density enamel hyperplasia occurs in 20% of patients on
extending superiorly and slightly mesially where it drains nifedipine and 25–30% of those taking cyclo-
into a large accessory, mesial root canal. This widened
accessory root canal communicates with a 7 5 mm radio- sporine after transplant surgery. More detailed
lucency between the roots of 24 and 25 which demineral- description of these conditions can be found in
izes the overlying buccal cortex (white open arrow). separate chapters on ▶ “Gingival Pathology”,
(Images courtesy of Professor Camile Farah, Perth Oral and ▶ “Oral Manifestations of Systemic Dis-
Medicine & Dental Sleep Centre, Perth WA, Australia)
eases and Their Treatments.”
Table 9 Classification of periodontal diseases and condi- Table 9 (continued)

tions (Armitage 1999)
1. Gingival diseases of b. Mouthrinses/
I. Gingival diseases 3. Gingival diseases of specific bacterial origin mouthwashes
fungal origin a. Neisseria gonorrhea- c. Chewing gum additives
A. Dental plaque-induced a. Candida species associated lesions
gingival diseasesa infections b. Treponema pallidum- 3. Other
1. Gingivitis associated with 1. Generalized gingival associated lesions
dental plaque only candidiasis c. Streptococcal species- 6. Traumatic lesions
a. Without other local b. Linear gingival associated lesions (factitious, iatrogenic,
contributing factors erythema accidental)
b. With local contributing c. Histoplasmosis d. Other a. Chemical injury
factors (see VIII A) 2. Gingival diseases of b. Physical injury
2. Gingival diseases d. Other viral origin
modified by systemic a. Herpesvirus infections c. Thermal injury
factors 1. Primary herpetic 7. Foreign body reactions
a. Associated with the 4. Gingival lesions of gingivostomatitis
endocrine system genetic origin 2. Recurrent oral herpes 8. Not otherwise specified
1. Puberty-associated a. Hereditary gingival (NOS)
gingivitis fibromatosis 3. Varicella zoster infections
2. Menstrual cycle- b. Other b. Other
associated gingivitis
II. Chronic periodontitisb VII. Periodontitis
3. Pregnancy associated 5. Gingival associated with
manifestations of endodontic lesions
systemic conditions
A. Localized A. Combined periodontic-
a. Gingivitis a. Mucocutaneous endodontic lesions
disorders
B. Generalized VIII. Developmental or
b. Pyogenic granuloma 1. Lichen planus acquired deformities
4. Diabetes mellitus- 2. Pemphigoid and conditions
associated gingivitis III. Aggressive A. Localized tooth-related
b. Associated with blood 3. Pemphigus vulgaris periodontitisb factors that modify or
dyscrasias predispose to plaque-
1. Leukemia-associated 4. Erythema multiforme induced gingival diseases/
gingivitis periodontitis
2. Other 5. Lupus erythematosus A. Localized 1. Tooth anatomic factors
3. Gingival diseases 6. Drug induced B. Generalized 2. Dental restorations/
modified by medications appliances
a. Drug-influenced gingival 7. Other IV. Periodontitis as a 3. Root fractures
diseases manifestation of systemic
1. Drug-influenced gingival b. Allergic reactions diseases
enlargements A. Associated with 4. Cervical root resorption
2. Drug-influenced 1. Dental restorative hematological disorders and cemental tears
gingivitis materials 1. Acquired neutropenia B. Mucogingival
a. Oral contraceptive- a. Mercury deformities and conditions
associated gingivitis around teeth
b. Other b. Nickel 2. Leukemias 1. Gingival/soft tissue
4. Gingival diseases c. Acrylic recession
modified by malnutrition 3. Other a. Facial or lingual surfaces
a. Ascorbic acid-deficiency d. Other B. Associated with genetic b. Interproximal (papillary)
gingivitis disorders
b. Other 2. Reactions attributable to 1. Familial and cyclic 2. Lack of keratinized
B. Non-plaque-induced a. Toothpastes/dentifrices neutropenia gingiva
gingival lesions 2. Down syndrome 3. Decreased vestibular
(continued) (continued)
Table 9 (continued) adolescence, while early periodontitis occurs in the

3. Leukocyte adhesion 4. Aberrant frenum/muscle majority of adults. Prevalence and proportion of
deficiency syndromes position periodontitis increase with age. The main cause of
4. Papillon-Lefèvre 5. Gingival excess periodontal disease is periodontal pathogens such
syndrome as Porphyromonas gingivalis, Tannerella for-
5. Chediak-Higashi a. Pseudopocket
sythia, Treponema denticola, and Aggregatibacter
syndrome
6. Histiocytosis syndromes b. Inconsistent gingival
actinomycetemcomitans coexisting in biofilm (den-
margin tal plaque). Local factors, which affect accumula-
7. Glycogen storage c. Excessive gingival tion and growth of plaque or interfere with self-
disease display cleaning action, include calculus, inadequate
8. Infantile genetic d. Gingival enlargement dental restorations, dry mouth, and malalignment
agranulocytosis (see I.A.3 and I.B.4) of teeth. Other risk factors such as smoking,
9. Cohen syndrome 6. Abnormal color
occlusal trauma, nutritional deficiency, emo-
10. Ehlers-Danlos C. Mucogingival
syndrome (types IV and deformities and conditions
tional/physical stress, and genetic factors can
VIII) on edentulous ridges affect the status of periodontal disease. The
11. Hypophosphatasia 1. Vertical and/or development and progression of periodontal dis-
horizontal ridge deficiency ease are associated with the imbalance of the qual-
12. Other 2. Lack of gingiva/ ity/quantity of periodontal pathogens and host
keratinized tissue defense responses. Periodontal tissue destruction
C. Not otherwise specified 3. Gingival/soft tissue
is not continuous but is episodic in nature.
(NOS) enlargement
V. Necrotizing periodontal 4. Aberrant frenum/muscle
Periodontal diseases associated with plaque
diseases position are progressive diseases although gingivitis
A. Necrotizing ulcerative 5. Decreased vestibular does not necessarily progress to periodontitis.
gingivitis (NUG) depth Periodontal disease progression is divided into
B. Necrotizing ulcerative 6. Abnormal color four stages: initial, early, established, and
periodontitis (NUP)
advanced lesion (Page and Schroeder 1976;
VI. Abscesses of the D. Occlusal trauma
Wolf et al. 2004).
periodontium
A. Gingival abscess 1. Primary occlusal trauma
B. Periodontal abscess 2. Secondary occlusal Acute Periodontitis
trauma Immediately after accumulation of dental plaque,
C. Pericoronal abscess an initial periodontal lesion cannot be clini-
cally detected. Periodontal pathogens and their
Readers are directed to the 2017 new classification
scheme for periodontal and peri-implant diseases and con- products such as lipopolysaccharide (LPS)
ditions for more detail (Caton et al. 2018) injure junctional epithelium (JE) and lead to
a
Can occur on a periodontium with no attachment loss or on
a periodontium with attachment loss that is not progressing increased permeability of JE. LPS induces
b
Can be further classified on the basis of extent and sever- pro-inflammatory cytokine production from JE,
ity. As a general guide, extent can be characterized as resulting in capillary dilatation, edema, and neu-
localized = 30% of sites involved and generalized = trophil infiltration in the sub-JE area (induction of
>30% of sites involved. Severity can be characterized on
the basis of the amount of clinical attachment loss (CAL) as acute exudative inflammation).
follows: slight = 1 or 2 mm CAL, moderate = 3 or 4 mm Eight to 14 days after plaque accumulation, an
CAL, and severe = 5 mm CAL early lesion is clinically detected as gingivitis. It is
associated with macrophage activation and a pre-
Periodontitis dominant infiltration of T lymphocytes. In gingi-
val tissues, transition from innate immunity to
Periodontitis demonstrates deeply spreading acquired immunity is observed. Inflammation
chronic inflammation with connective tissue expands laterally and apically. Neutrophils infil-
attachment loss and alveolar bone destruction. Gin- trated in JE injure epithelial attachment resulting
givitis is common in children and more severe in in early gingival pocket formation.
Fig. 56 Gingivitis. Gingival swelling with bleeding is widely dilated intercellular space of epithelial cells (b).
seen associated with lower incisors (a). Inflammatory cell Cemento-enamel junction (CEJ), enamel space (ES), and
infiltration is limited to subepithelial gingival connective dental plaque (white asterisk) (c). (Hematoxylin and eosin
tissue (b). In the connective tissue, lymphocytes and stain)
plasma cells are mainly seen. Neutrophils infiltrate into
Fig. 57 Puberty-associated gingivitis. (Image courtesy of

Associate Professor Alessandro Quaranta, UWA Dental Fig. 58 Pregnancy-associated gingivitis. (Image courtesy
School, University of Western Australia, Perth WA, of Associate Professor Alessandro Quaranta, UWA Dental
Australia) School, University of Western Australia, Perth WA,
Australia)
Two to three weeks after plaque accumulation, JE and swelling of the gingiva and is reversible
a characteristic shift in the inflammatory cell pop- with proper oral hygiene. The three stages includ-
ulation, from T lymphocytes to B lymphocytes/ ing initial, early, and established lesions comprise
plasma cells, is evident, with the establishment of the clinical entity of gingivitis.
a B-cell lesion in the gingiva. The gingival pocket More than 4 weeks after plaque accumula-
(reversible pocket) is deepened by destruction of tion, acute exudative inflammation still exists
in the JE and sub-JE area. Chronic inflammation lymphocytes and plasma cells are also seen in
continuously extends deeper into the periodontal gingival connective tissue. Hyperemia, edema,
tissues. This signals the establishment of chronic and destruction of collagen fibers are prominent.
periodontitis, which is characterized by the loss In advanced cases, marked attachment loss and
of connective tissue attachment, alveolar bone bone resorption with many osteoclasts are evident.
destruction, and apical migration of JE followed Periodontitis can be associated with hematological
by formation of a periodontal pocket (irrevers- disorders and genetic disorders including Down
ible pocket). In periodontitis, cytokines such as syndrome, Papillon-Lefévre syndrome, and
TNF-alpha, IL-1beta and IL-8, PGE2, and Chediak-Higashi syndrome.
MMPs produced from tissue constitutive cells Periodontitis is a silent disease and symptoms
and/or immune cells contribute to progressive may not appear until an advanced stage. Accumu-
inflammation and promote attachment loss and lating evidence indicates that low-grade long-
bone destruction. IL-8 induces neutrophil standing inflammation due to dental infection
recruitment in the pocket wall and causes loss such as periapical and marginal periodontitis is a
of epithelial attachment, whereas TNF-alpha, potential risk factor for various systemic health
IL-1beta, and PGE2 activate fibroblasts and conditions including cardiovascular disease, dia-
macrophages to produce MMPs, which degrade betes mellitus, and preterm birth/low birth weight
collagen fibers in the periodontium. These (Offenbacher et al. 1996; Pihlstrom et al. 2005;
molecules also induce osteoclastic bone Seymour et al. 2007; Jeftha and Holmes 2013).
resorption. The possible biological mechanisms linking
dental infection and systemic health problems
Chronic Periodontitis include translocation of periodontal pathogens,
Chronic periodontitis is the most common peri- challenge of bacterial products like lipopolysac-
odontal disease in adults. The main causative path- charide through blood circulation, and effects of
ogen is Porphyromonas gingivalis. The condition pro-inflammatory cytokine upregulation in serum,
is characterized by loss of connective tissue attach- namely, TNF-alpha, IL-1beta, and IL-6, which are
ment, destruction of alveolar bone, and true pocket produced in the oral lesion.
formation caused by bacterial challenge. In the Initial treatment for periodontitis includes
periodontal pocket, deposition of plaque and cal- oral hygiene instruction, scaling and root plan-
culus is seen on the root surface. Clinically, alveo- ning that may improve the disease, and/or pre-
lar bone resorption and tooth movement due to venting disease progression for patients with
periodontal tissue destruction occur in addition to mild periodontitis (less than 4 mm of periodon-
signs of gingivitis. Due to alveolar bone loss, gin- tal pocket depth). Surgical periodontal treatment
gival recession and exposure of the root gradually may be required for moderate to severe peri-
occur, resulting in tooth mobility and movement odontitis, indicated by pocket depth of more
(Fig. 59). Untreated periodontitis finally leads to than 6 mm.
tooth loss. The histologic findings in gingival tis-
sues are similar to those in gingivitis. Inflammation Aggressive Periodontitis
however extends beyond the alveolar crest fibers Aggressive periodontitis is a rare form of peri-
and spreads into the periodontal ligament and alve- odontitis often seen in adolescence. Familial
olar bone, leading to attachment loss and bone occurrence is reported. It is characterized by
destruction, respectively. JE grows along the rapid destruction of alveolar bone with vertical
denuded root surface (Fig. 59). The detachment bone resorption. There are two types of lesions:
of the coronal portion of JE gives rise to pocket localized and generalized (more than 30% sites
epithelium. Pocket epithelium is erosive or ulcera- are included). Aggregatibacter actinomycetem-
tive and associated with lateral elongation of rete comitans (A.a.), Prevotella intermedia, and
ridges. In wide intercellular spaces of JE, numerous Porphyromonas gingivalis are considered the
neutrophils are observed. Dense infiltration of suspected pathogens responsible for this
Fig. 59 Periodontitis. Loss

of periodontal connective
tissues and attachment is
demonstrated in (a) and (b).
There is radiographic
evidence of horizontal bone
loss (b). Down growth of
junctional epithelium
(JE) and deep pocket
formation are observed.
Bone resorption of alveolar
bone is evident. Cemento-
enamel junction (CEJ),
enamel space (ES), pocket
epithelium (PE), calculus
and plaque (black asterisk)
(c). (Hematoxylin and eosin
stain)
condition. Aggressive periodontitis is closely females younger than 30 years. In comparison

related to a demonstrable neutrophil/macrophage with the localized variant, heavy plaque, calculus,
dysfunction including reduction of phagocytosis, and severe gingival inflammation are present.
abnormal chemotaxis, and increased cytokine Moreover, the pathogen in the generalized variant
production. Recently, a special clone of is more complex, and Porphyromonas gingivalis
A.a. (JP2), having high ability for leukotoxin pro- is more prominent.
duction, was isolated from an 8-year-old patient
with aggressive periodontitis. It is accepted that Necrotizing Ulcerative Gingivitis
the highly leukotoxic JP2 clone is associated with Necrotizing ulcerative gingivitis (acute necrotizing
initiation and progression of aggressive periodon- ulcerative gingivitis, ANUG) is characterized by
titis (Haubek and Johansson 2014; Nibali 2015). gingival necrosis and ulcer formation (Cobb et al.
Localized aggressive periodontitis typically 2003). Histological observation shows three layers
occurs in females 11–13 years of age and has of a surface bacterial zone, polymorphonuclear
a strong familial tendency. This type is localized leucocyte aggregation zone, and necrotic zone.
to the first molars and incisors. Vertical bone Although the opportunistic gingival infection
destruction with deep infrabony pockets is rapidly caused by Spirochetes and Fusobacteria plays a
formed, leading to tooth migration and mobility. key role in pathogenesis, some predisposing host
A.a. is the main pathogen in dental plaque. Gen- factors may be required, including poor oral
eralized aggressive periodontitis occurs mainly in hygiene, viral infection, immunocompromised
status, and malnutrition. It is also known as

“Vincent infection.” Clinically it starts as severe
inflammation of the interdental papilla followed
by “punched out” necrosis and ulceration. The
ulcers are covered with a yellow-white pseudo-
membrane (Fig. 60). A foul odor, hemorrhage,
and spontaneous pain are noted. Occasionally the
patient presents with lymphadenopathy, fever, and
malaise. The lesion can progress into necrotizing
ulcerative periodontitis (NUP) with attachment
loss and can spread to adjacent soft tissue (necro-
tizing ulcerative stomatitis). NUG and NUP more
frequently occur among patients with HIV infec-
tion and AIDS, in whom disease condition is more Fig. 60 Necrotizing ulcerative gingivitis. Ulcers are cov-
ered by a yellow-white pseudomembrane involving the
severe and destructive (Fowler et al. 2011).
interdental papilla. (Image courtesy of Dr Matsuda, Hiro-
shima University, Japan)
Periodontal Abscesses
A gingival abscess is localized to the gingival
tissues without involvement of the adjacent peri- compression necrosis. On the surface of alveolar
odontal ligament or alveolar bone. It is caused by bone margin, numerous osteoclasts appear and
bacterial infection from adjacent periodontal actively resorb the bone, resulting in widening of
pockets, external irritation, injury, or infection periodontal ligament space. On the other hand, in
to the gingival tissues. A periodontal abscess the tension zone, widening of periodontal space
is a localized suppurative inflammation of the and extension of ligament fibers are evident. Both
gingiva, which is associated with loss of peri- the root and bone surfaces show spikelike deposi-
odontal ligament and alveolar bone. A periodontal tion of cementum and the bone, respectively
abscess often arises in a preexisting periodontitis. (Roberts-Harry and Sandy 2004).
The closure of the entrance into a periodontal
pocket induces a periodontal abscess. Gingival Epulides
Epulis is a clinical term indicating a localized
Occlusal Trauma “tumorlike pedunculated enlargement” of the gin-
Occlusal trauma to the periodontal tissues as a giva. It is generally applied to reactive hyperplasia
result of excessive occlusal force is known as a of gingival or periodontal connective tissue and
traumatic occlusion. This is divided into two not to neoplastic lesions. Gingival epulides arise
groups: primary occlusal trauma and secondary from the interdental papillae, as a result of trauma
occlusal trauma. Primary occlusal trauma is injury or irritation from subgingival plaque and calculus.
resulting from excessive occlusal forces applied to Epulis is histologically divided into several types
a tooth or teeth with normal periodontal support. such as granulomatous epulis, fibrous epulis, vas-
Excessive occlusal forces include high restora- cular epulis, ossifying fibrous epulis, and giant
tions, bruxism, and orthodontic movement. Sec- cell epulis. These are described in more detail in
ondary occlusal trauma is injury resulting from the chapter on ▶ “Gingival Pathology”.
normal occlusal forces applied to a tooth or teeth
with reduction of support by periodontal diseases.
During orthodontic tooth movement process, lat- Odontogenic Cysts
eral excessive force applied to a tooth induces
pressure and tension in the periodontal ligaments. In the jaws, a high frequency of various cysts is a
In the pressure zone, narrowing of the periodontal unique characteristic not observed in other
ligament causes hyalinization as a result of bones. One of the reasons for this is the presence
of epithelium involved in odontogenesis. Cysts sclerotic margin in association with the apex of
lined by epithelium derived from odontogenic a non-vital tooth (Fig. 61). A lateral radicular cyst
epithelium are referred to as odontogenic cysts. is present at the opening of lateral accessory root
Odontogenic cysts are encountered relatively canals. Root resorption is common. Histologi-
commonly in the clinical practice. They are sub- cally, the cyst is composed of inflammatory gran-
classified as inflammatory or developmental in ulation tissue and lining epithelium (Fig. 62). In
origin. Recently, significant modifications have the inflammatory granulation tissue, infiltration of
occurred in the classification of these lesions foamy macrophages, deposition of cholesterol
with a certain amount of controversy and dis- clefts (Fig. 62) with foreign body giant cells, and
agreement, so it is prudent that the clinician hemosiderin pigmentation are common. The lin-
maintains an awareness of the changing nomen- ing epithelium is non-keratinized stratified squa-
clature, classification, and underpinning mous epithelium with irregularly elongated rete
research that contribute to these changes. In ridges. The epithelial rests of Malassez in the
this text, the classification followed is that of periodontal ligament are thought to be the origin
the most recent WHO Classification of Head of lining epithelium in most cases. Mucous cell
and Neck Tumors (2017). metaplasia is rarely observed. Rushton bodies
(Fig. 63), eosinophilic, linear or arched, glassy
structures, are occasionally found in the epithelial
Inflammatory Odontogenic Cysts lining. Rarely, the epithelium may be derived
from the maxillary sinus in cases of maxillary
Inflammatory odontogenic cysts include radicular teeth that have extended into the sinus wall. Treat-
cyst, residual cyst, and inflammatory collateral ment options depend on clinical and radiographic
cyst. Radicular and residual cysts are the result features. Some cases resolve with endodontic
of infection extending from the pulp of a tooth therapy. If the initial endodontic therapy appears
into the periapical tissues. On the other hand, to be non-effective, the lesions are surgically
inflammatory collateral cysts are associated with treated by apicectomy or extraction of the tooth
inflammation in pericoronal tissues. with the cyst.
Radicular Cyst Residual Cyst

The radicular cyst is the most common cyst of The residual cyst is defined as a radicular cyst
the jaws and accounts for more than half of that remains in the bone, following tooth extrac-
odontogenic cysts. It results from an infected tion. Radiographically, a residual cyst is a well-
and necrotic pulp caused by dental caries or demarcated, unilocular radiolucency with
tooth fracture, leading to periapical inflammation. a corticated margin at a site of previous tooth
As such, radicular cysts are associated with roots extraction (Fig. 64). It is usually asymptomatic,
of a non-vital tooth, and this is an important cri- but the continuous inflammation can cause mild
terion for diagnosis (Fig. 61). It occurs at a wide symptoms. Histopathologic features of a residual
age range but is quite rare in primary teeth. Clin- cyst are almost the same as those of a radicular
ically, the radicular cyst is frequently symptom- cyst. Inflammatory granulation tissue surrounds
less, because of its small size that is about 1–2 cm a cystic cavity lined by nonkeratinized stratified
in diameter, and chronic inflammation, and often squamous epithelium (Fig. 65). Because inflam-
detected only on radiographic examination. If the mation is usually milder than that in radicular
cyst grows to large dimensions, the expansion of cysts, inflammatory cell infiltration is not promi-
the jaw and mild sensitivity may be noted. When nent, and fibrosis progresses. Treatment of
acute exacerbation occurs, a drainage tract (fistula the lesions is by enucleation. Because other
tract) may be present in the oral mucosa overlying odontogenic and non-odontogenic cysts and
the cyst. Radiographically, a radicular cyst is tumors may mimic the clinical and radiographic
a well-defined, unilocular radiolucency with a features of residual cysts, the surgically removed
Fig. 61 Radicular cyst. Low power histological view (a) and lined by non-keratinized squamous epithelium with
and radiographic view (b) of a radicular cyst. A well- irregularly elongated rete ridges (c). (Hematoxylin and
defined, unilocular radiolucency with a sclerotic margin eosin stain) (Images a and b courtesy of Professor
is seen in association with the apex of a non-vital tooth. Kakimoto, Hiroshima University, Japan)
The cyst is composed of inflammatory granulation tissue
tissues should be submitted for histopathological roots of a partially or recently erupted tooth as a
examination. consequence of an inflammatory process in the
pericoronal tissues. Paradental cyst and mandibu-
Inflammatory Collateral Cyst lar buccal bifurcation cyst are included under the
The inflammatory collateral cyst (Philipsen et al. heading of inflammatory collateral cyst (Fig. 66).
2004) is defined as a cyst on the lateral aspect of The incidence of inflammatory collateral cysts is
Fig. 62 Radicular cyst. Cholesterol clefts (arrow).

(Hematoxylin and eosin stain) (Image courtesy of Profes-
Fig. 64 Radiograph demonstrating a residual cyst. Awell-
sor Camile Farah, UWA Dental School, University of
demarcated radiolucency with a corticated margin at the
Western Australia, Perth WA, Australia)
site of a previous tooth extraction. (Image courtesy of
Professor Kakimoto, Hiroshima University, Japan)
Fig. 63 Rushton bodies. Eosinophilic, linear or arched,

glassy structures are occasionally found in the epithelial
lining. (Hematoxylin and eosin stain) (Image courtesy of Fig. 65 Residual cyst. Cystic cavity lined by non-
Professor Camile Farah, UWA Dental School, University keratinized stratified squamous epithelium (arrow).
of Western Australia, Perth WA, Australia) (Hematoxylin and eosin stain) (Image courtesy of Profes-
about 5% of all odontogenic cysts. Most patients
are under the age of 40 years, and males are more painless swelling of the gingiva and vestibular
often affected. mucosa buccal to the furcation of an associated
Paradental cyst localizes to the distal, buccal, mandibular first or second molar. Radiographi-
or, rarely, mesial region of partially erupted molar cally, paradental cyst presents as a well-
teeth. The cyst that develops in a specific location, demarcated radiolucency with corticated margin
the buccal bifurcation region of the mandibular associated with the crown of a partially erupted
first molar and less frequently second molar, usu- molar (Fig. 66). The radiolucency sometimes
ally in the second half of the first decade, is called extends apically, but the periodontal ligament
mandibular buccal bifurcation cyst. Most patients space is intact. The mandibular buccal bifurcation
suffering from paradental cyst have a history of cyst presents as a well-demarcated radiolucency
long-standing pericoronitis with symptoms of with a corticated margin at the furcation and
pain and swelling. On the other hand, mandibular buccal aspect of a mandibular molar with a
buccal bifurcation cyst usually presents with a deep periodontal pocket. Cervical enamel
Fig. 66 Radiograph demonstrating a paradental cyst. A

well-demarcated radiolucency is associated with the crown
of partially erupted third molar (arrow). (Image courtesy of Fig. 67 Radiographic view of a dentigerous cyst. A well-
Professor Kakimoto, Hiroshima University, Japan) defined radiolucency with corticated border is associated
with the crown of an unerupted third molar. (Image cour-
extension is associated with the development of tesy of Professor Kakimoto, Hiroshima University, Japan)
the cyst. Histologically, the inflammatory collat-
eral cyst is indistinguishable from a radicular common odontogenic cyst, comprising up to 20%
cyst, but the involved tooth is vital. The cystic of all odontogenic cysts. It develops around the
cavity is lined by nonkeratinized stratified crown of unerupted tooth and is attached at the
squamous epithelium of varying thickness. The cementoenamel junction (Fig. 67). Dentigerous
lining epithelium may be attached at the cysts originate by the accumulation of fluid between
cementoenamel junction or be continuous with reduced enamel epithelium and a completed tooth
the epithelium of the pericoronal tissues. The crown. Because the mandibular third molars are the
lining epithelium is surrounded by inflammatory most frequently impacted teeth, about 75% of
granulation tissue. The paradental cyst is treated dentigerous cysts are associated with these teeth,
by excision with or without extraction of the followed by maxillary canines. Dentigerous cysts
involved tooth depending on clinical features. may be encountered in patients over a wide age
Mandibular buccal bifurcation cysts are success- range, with peak incidence in the second to fourth
fully treated by simple enucleation without tooth decades. There is a slight male prediction.
extraction in most cases. Clinically, the cyst is asymptomatic, unless it
is secondarily infected. Therefore, it is often
identified on radiographs undertaken for other
Developmental Odontogenic Cysts reasons or the failure of a tooth to erupt. Large
cysts result in the painless expansion of bone.
Developmental odontogenic cysts are of unknown Secondary infection by extension from a peri-
etiology and not a result of inflammation. They apical or periodontal lesion of an adjacent tooth
include dentigerous cyst, odontogenic keratocyst, may cause pain and swelling. Radiographically,
lateral periodontal cyst/botryoid odontogenic the dentigerous cyst typically appears as a
cyst, gingival cyst, glandular odontogenic cyst, well-defined, unilocular radiolucency with a
calcifying odontogenic cyst, and orthokeratinized corticated border associated with the crown of
odontogenic cyst. unerupted tooth (Fig. 68). The radiographic dif-
ference between a dentigerous cyst and a dental
Dentigerous Cyst follicle is based on the size of the radiolucent
The dentigerous cyst is the most common develop- space. The involved tooth is occasionally
mental odontogenic cyst and the second most displaced for a considerable distance.
Fig. 68 Dentigerous cyst. Cropped panoramic radiograph demonstrates a uniloculate, mildly expansile lesion in a
(a) showing a uniloculate lesion in a follicular relationship follicular relationship (black arrows) to the unerupted and
to the unerupted 18 which protrudes into the lumen of impacted 38. There is no resorption of the roots of 37.
the right maxillary sinus (white arrows). Oblique sagittal (Images courtesy of Clinical Associate Professor Andy
reconstruction from a multidetector CT scan (b) Whyte, Perth Radiological Clinic, Perth WA, Australia)
Radiographic findings are useful to detect

dentigerous cyst, but final diagnosis requires
histopathological assessment as other
odontogenic cysts and tumors may have radio-
graphic features identical to those of a
dentigerous cyst. Histologically, a dentigerous
cyst is composed of a thin connective tissue wall
lined by cuboidal or nonkeratinizing, stratified
squamous epithelial cells (Figs. 69 and 70). The
epithelial-connective tissue interface is flat.
Small islands or cords of inactive-appearing
odontogenic epithelial rests may be scattered
in the connective tissue. In the inflamed cyst,
the lining epithelium may elongate rete ridges
into the fibrous wall with infiltration of inflam-
matory cells. Treatment of dentigerous cysts is
fenestration or decompression, followed by
enucleation together with the unerupted tooth,
if cysts are large. Rarely, ameloblastoma and
squamous cell carcinoma may arise in the lining
epithelium. Fig. 69 Low-power histological view of a dentigerous
cyst. The cyst surrounds the crown and is attached at the
An eruption cyst is a variant of dentigerous
neck (cementoenamel junction; CEJ) of the tooth. Enamel
cyst in the soft tissues overlying the alveolar space (ES). (Hematoxylin and eosin stain)
bone in children (Fig. 71). It develops as a result
of separation of the dental follicle from around the
crown of an erupting tooth. clinical behavior and histopathologic features.
Up until 2005, it was classified as an odontogenic
Odontogenic Keratocyst cyst, but the World Health Organization (WHO)
Odontogenic keratocyst (OKC) (Shear and classification in 2005 (Barnes et al. 2005) desig-
Speight 2007) is a distinctive type of developmen- nated it as a benign odontogenic tumor known as
tal odontogenic cyst characterized by specific the keratocystic odontogenic tumor (KCOT),
because its behavior was noted to be more aggres- and are found incidentally by radiographical
sive than other odontogenic cysts (Li 2011). In the examination for other reasons, unless secondarily
2017 WHO classification (2017), this decision infected. Even in large cysts, bone expansion is
was reversed, and it is once again designated as relatively minor, because of a tendency to grow in
an odontogenic cyst. OKC is the third most com- a posteroanterior direction (Fig. 72). Multiple
mon cyst affecting the jaws, accounting for OKCs may be present, and nearly half of these
10–20% of all odontogenic cysts. OKCs arise in occur in the setting of nevoid basal-cell carcinoma
a wide age range but most frequently in the second syndrome (NBCCS). Radiographically, OKCs
to third decade, with a definite male predilection. demonstrate well-demarcated, unilocular to multi-
The mandible is involved in 60–80% of cases, locular radiolucencies with or without a scalloped
with a marked tendency to occur in the posterior margin similar to ameloblastoma (Figs. 72, 73, 74,
body and ramus. OKCs are usually asymptomatic and 75).
Recurrence rate is 10–20% of cases. OKC is
potentially aggressive (Fig. 76), especially when
it is associated with NBCCS. Histologically, OKC
is a cystic lesion lined by parakeratinized squa-
mous epithelium. The epithelium is usually thin
and lacks rete ridges. Cuboidal to columnar basal
cells show palisading of nuclei, and the para-
keratinized surface is often corrugated (Fig. 77).
Frequent desquamation of lining epithelium from
the subjacent connective tissue, mitotic figures in
suprabasal layer, epithelial budding, and small
daughter cysts in the connective tissue (Fig. 78)
may be related to the relatively high recurrence
rate of OKC. Recent genetic studies have reported
Fig. 70 Dentigerous cyst. The cyst is composed of con- allelic loss of PTCH gene and overexpression of
nective tissue wall without inflammation lined by a thin, bcl-1 and TP53 in both NBCCS and sporadic
flat layer of cuboidal epithelial cells. (Hematoxylin and
eosin stain) OKC.
Fig. 71 Eruption cyst

demonstrating both cyst
lining on the inner aspect of
the lumen (E) and
squamous oral mucosal
epithelium (OE) separated
by connective tissue.
stain) (Image courtesy of
UWA Dental School,
University of Western
Australia, Perth WA,
Australia)
Treatment is by decompression and enucle-

ation either alone or with removal of associated
tooth (Fig. 79).
Lateral Periodontal Cyst and Botryoid

Odontogenic Cyst
Lateral periodontal cyst is a rare type of devel-
opmental odontogenic cyst found in association
with the lateral root surface or in the interprox-
imal area of erupted teeth (Fig. 80) (Shear and
Speight 2007). Botryoid odontogenic cyst
(BOC) is a multilocular variant of lateral peri-
odontal cyst. These cysts account for less than
Fig. 72 Radiograph of odontogenic keratocyst showing a
well-demarcated, multilocular radiolucency in the right
2% of odontogenic cysts (Ramer and Valauri
mandible. (Image courtesy of Professor Kakimoto, Hiro- 2005). The peak incidence is in the sixth and
shima University, Japan) seventh decades. There is a slight male
Fig. 73 Odontogenic keratocyst of the right mandibular hyperdense debris (white dotted arrow in c), typical of
body. Axial bone window CT (a), oblique sagittal bone these lesions. Fourteen months after decompression and
window reconstruction (b), axial soft tissue reconstruction enucleation, the lesion has healed and is replaced by scle-
(c), and axial cone beam CT 14 months after surgery (d). A rotic medullary bone (d). (Images courtesy of Clinical
large multilobulate, elongated lesion is expansile towards Associate Professor Andy Whyte, Perth Radiological
its mesial margin. It is associated with apical resorption of Clinic, Perth WA, Australia)
46 and 47 (white arrows in a and b) and contains
Fig. 74 Odontogenic keratocyst in the maxilla. Axial CT a). The lesion is of fluid attenuation with hyperdense
scan with bone window (a) and soft-tissue window (b) keratin debris as seen on the soft-tissue window image
reconstructions. Expansile lesion with a multilobulate mar- (white arrow in b). (Images courtesy of Clinical Associate
gin extending from the upper right second molar (17) to the Professor Andy Whyte, Perth Radiological Clinic, Perth
upper left lateral incisor (22) region (white dotted arrows in WA, Australia)
Fig. 75 Odontogenic keratocyst in a follicular relationship (black arrow) peripheral to the lesion and also the hyper-
to the unerupted upper right third molar (18) which is intense mucosa of the right inferior turbinate (IT) secondary
displaced into the right maxillary sinus. Coronal CT scan to the water-rich nature of these tissues. Diffusion-weighted
reconstruction (a), T1 coronal MRI (b) demonstrating that imaging (DWI) (d) in the axial plane demonstrates hyper-
the contents of the OKC are hyperintense Axial T2 weighted intensity (white dashed oval) indicating restricted diffusion
MRI (c), the keratin debris responsible for the hyperintensity secondary to the keratin-rich contents of the lesion. (Images
on T1 leads to reduction in signal on T2. Note the hyper- courtesy of Clinical Associate Professor Andy Whyte, Perth
intense mucosal thickening in the right maxillary sinus Radiological Clinic, Perth WA, Australia)
Fig. 76 Recurrent odontogenic keratocyst. Soft-tissue situated in the inferior aspect of the right maxillary sinus
axial CT (a), T1 axial MRI (b), fat saturation T2 MRI (c), (orange dotted arrows in b and c) with a smaller lesion
and diffusion weighted imaging (DWI) (d). There has been immediately anterior to the right pterygoid plates (white
a previous right posterior maxillectomy and Caldwell-Luc dotted arrows in b and c) which contains proteinaceous
procedure for removal of an OKC in the right posterior fluid (white dotted arrows in b and c). All three lesions
maxillary alveolus and sinus. CT shows recurrent OKC demonstrate restricted diffusion (image d), they are hyper-
(white arrow in a) in the retro-antral fat which represents intense secondary to the keratin rich content. (Images
the inferior infra-temporal fossa. Two additional foci of courtesy of Clinical Associate Professor Andy Whyte,
recurrent OKC are seen on MRI; the larger lesion is Perth Radiological Clinic, Perth WA, Australia)
Fig. 77 Histology of odontogenic keratocyst. The cyst is

lined by a parakeratinized stratified squamous epithelium Fig. 78 Satellite microcysts within fibrous wall of
without rete ridges. There is palisading and reverse polari- odontogenic keratocyst. (Hematoxylin and eosin stain)
zation of the columnar cells of the basal layer of corrugation (Image courtesy of Professor Camile Farah, UWA Dental
of the surface epithelium. (Hematoxylin and eosin stain) School, University of Western Australia, Perth WA, Australia)
Fig. 79 Odontogenic keratocyst of the right mandibular pathology. (Images courtesy of Professor Camile Farah,
ramus at diagnosis (a) and 2.5 years later following decom- Perth Oral Medicine & Dental Sleep Centre, and Dr Nathan
pression and enucleation (b) demonstrating full bony Vujcich, West Perth Oral & Maxillofacial Surgery, Perth
recovery and no evidence of any residual or recurrent WA, Australia)
Fig. 81 Lateral periodontal cyst. The cyst wall is com-

posed of a non-inflamed, fibrous connective tissue lined by
thin, non-keratinized, cuboidal epithelium approximately
6 cells thick. (Hematoxylin and eosin stain) (Image cour-
tesy of Professor Camile Farah, UWA Dental School, Uni-
versity of Western Australia, Perth WA, Australia)
appearance. Macroscopically, BOC may show a

grape-like appearance. Histologically, the lateral
periodontal cyst wall is composed of a
Fig. 80 Lateral periodontal cyst. (Image courtesy of Pro- non-inflamed, fibrous connective tissue lined
fessor Camile Farah, UWA Dental School, University of by thin, nonkeratinized, cuboidal epithelium
(Fig. 81), which may present with focal nodular
or plaque-like thickening (Fig. 82). Plaques may
predilection. About two thirds occur in the man- have whorled epithelial cell aggregates with
dibular canine-premolar region. Most cases are glycogen-rich clear cells. In BOCs, multiple
less than 1cm in size and asymptomatic. Radio- cystic cavities are seen at low power (Fig. 83).
graphically, lateral periodontal cyst presents as a The lining epithelium is similar to that of lateral
well-defined, unilocular radiolucency associated periodontal cyst. BOC can be successfully
with the lateral periodontal ligament space of an treated by simple enucleation without extraction
erupted tooth. BOC may exhibit a multilocular of adjacent tooth. Recurrence is rare, but is
Fig. 84 Histology of gingival cyst of infancy. Cyst

containing keratin is lined by a thin, flat, parakeratinizing
Fig. 82 Histology of lateral periodontal cyst. The cyst stratified squamous epithelium. (Hematoxylin and eosin
wall is a fibrous connective tissue lined by a thin, stain)
non-keratinized, cuboidal epithelium with focal nodular
or plaque-like thickening (arrow). (Hematoxylin and
eosin stain)
Gingival Cyst of Infant
Gingival cyst of infant is a fairly common super-
ficial cyst of alveolar mucosa. It appears as white,
single or multiple, small (less than 2mm in diam-
eter) papules. It usually disappears spontaneously,
because of rupture. Histologically, the cyst con-
tains keratin or desquamated epithelium and is
lined by a thin, flat, parakeratinizing stratified
squamous epithelium without palisading of the
basal cell layer and corrugation of the superficial
layer (Fig. 84).
Gingival Cyst of Adult

Gingival cyst of adult is rare and considered to
represent the soft tissue counterpart of the lateral
periodontal cyst. Most cases are identified in the
buccal gingiva of the mandibular canine-
Fig. 83 Histology of botryoid odontogenic cyst. Multiple premolar region like lateral periodontal cyst.
cystic cavities are seen at low-power. The lining epithelium Maxillary adult gingival cysts show predilection
is similar to that of lateral periodontal cyst. (Hematoxylin to occur in the incisor to premolar region. The
and eosin stain)
cysts appear as painless, dome-like elevations in
the gingiva or alveolar mucosa, usually less than
reported in BOCs, especially in large, multi- 5mm in diameter. Histologically, the cysts lying
cystic lesions. below the oral epithelium are lined by thin cuboi-
dal to squamous epithelium without rete ridges
Gingival Cyst (Fig. 85). Plaque-like epithelial thickening with
Gingival cyst is a small cyst in the alveolar clear cells, similar to those of the lateral peri-
mucosa without involvement of alveolar bone odontal cyst, is sometimes present. Simple, con-
that may arise from remnants of the dental lamina. servative excision is the treatment for choice.
Gingival cysts are of two types, infant and adult. The prognosis is excellent.
Glandular Odontogenic Cyst is common. Histologically, GOC is lined by squa-

Glandular odontogenic cyst (GOC) is an mous or cuboidal epithelium of varying thickness.
extremely rare, developmental cyst, accounting In addition, they are characterized by glandular
for less than 0.5% of all odontogenic cysts that differentiation of lining epithelium, including
have features of ductal and mucous cell differen- intraepithelial microcysts, apocrine metaplasia,
tiation. The term, sialo-odontogenic cyst, has been mucous cells, and ciliated cells (Fig. 86). Apo-
also used as a synonym. GOC occurs in the sec- crine metaplasia of luminal cells, clear cells in
ond to the ninth decade with a peak in the fifth to basal and parabasal layers, papillary projection
eighth decade. There is no gender predilection. into the lumen, and plaque-like epithelial thicken-
The mandible is involved in about 75% of cases. ing similar to those in lateral periodontal cyst are
Painless swelling or expansion with thinning and also observed in some cases. Formation of multi-
perforation of cortical bone is the common symp- ple cysts similar to botryoid odontogenic cyst is
tom. Size varies from small to large. Radiograph- sometimes present (Fowler et al. 2011). The dis-
ically, the lesion presents as a well-defined, tinction from central low-grade mucoepidermoid
unilocular or multilocular radiolucency with a carcinoma is most important, because of some
sclerotic border. Scalloping is occasionally overlap of histologic features between the two
observed. Tooth displacement or root resorption lesions. Compared to GOCs, mucoepidermoid
carcinoma has a tendency to form cystic nests
composed of larger thickenings of squamous,
mucous, and intermediate cells. Examination of
multiple sections may permit distinction. Fusion
genes specific for mucoepidermoid carcinoma,
CRTC1/3-MAML2, have been found to be nega-
tive in GOCs (Bishop et al. 2014).
Enucleation is the most common treatment;
however, resection has been suggested as a treat-
ment option, particularly for large or multilocular
lesions, because of the high recurrence rate
(20–50%) that has been reported after conserva-
tive enucleation or curettage. Long-time follow-
up is essential.
Fig. 85 Histology of gingival cyst of adult. Cyst lying
below the oral epithelium (OE) is lined by a thin cuboidal Calcifying Odontogenic Cyst
to squamous epithelium without rete ridges (arrow). Calcifying odontogenic cyst (COC) is an
(Hematoxylin and eosin stain) uncommon developmental odontogenic cyst
Fig. 86 Histology of
glandular odontogenic cyst.
Cyst is lined by a cuboidal
epithelium of varying
thickness with glandular
differentiation, including
intraepithelial microcysts
(white arrow) and mucous
cells. (Hematoxylin and
eosin stain)
characterized by ameloblastoma-like lining epi-

thelium with a variable number of ghost cells. In
the 2005 WHO classification (Barnes et al.
2005), it was classified as a benign odontogenic
tumor, known as calcifying cystic odontogenic
tumor (CCOT). However, most cases behave
clinically as nonneoplastic lesions; therefore,
in the 2017 WHO classification, it has been
reclassified as a cyst (2017). COC may occa-
sionally be associated with odontogenic tumors,
most commonly odontomas. COCs occur with
about equal frequency in the maxilla and man-
dible and a predilection for the anterior region.
About 10% of cases are extraosseous (periph-
eral). The lesions may be encountered in patients
over a wide age range, but they are most fre-
quently diagnosed in the second to fourth decade.
Intraosseous COC present as a painless expansion
of the jaws, with perforation of the cortical bone in
some cases. Radiographically, the lesion presents Fig. 87 Calcifying odontogenic cyst. A well-defined, uni-
as a well-defined, unilocular or multilocular radio- locular radiolucency with radiopaque irregular structures.
Root resorption is seen in this example. (Image courtesy of
lucency (Figs. 87 and 88). Radiopaque irregular or Professor Kakimoto, Hiroshima University, Japan)
tooth-like structures are present in about half of the
cases. Root resorption or tooth displacement is
seen. Extraosseous COC present as a localized
gingival swelling. Histologically, COC is a cyst account for about 10% of keratinizing cysts of the
lined by odontogenic epithelium of varying thick- jaws. The peak incidence is the third to fifth
ness. The essential feature for diagnosis as COC is decade, with a male predilection. OOCs are
a lining epithelium composed of a cuboidal or most frequently found in the mandibular third
columnar, palisaded basal cell layer, and the over- molar region. About 75% of cases are associated
lying stellate reticulum-like layer shows resem- with an unerupted tooth. Most are asymptomatic
blance to that of ameloblastoma, with the and incidentally found on radiographic examina-
presence of ghost cells (Fig. 89). Calcification in tion. Radiographically, OOC shows a well-
ghost cells is common. Band-like eosinophilic defined, unilocular radiolucency with a corticated
matrices that are considered to represent dysplas- margin. OOC with an unerupted tooth is indistin-
tic dentin (dentinoid) may also be present in the guishable from a dentigerous cyst. Histologically,
fibrous cyst wall adjacent to the epithelial lining. the lining epithelium of OOC is a uniformly thin,
Prognosis is good after enucleation and only a few orthokeratinized stratified squamous epithelium
recurrences have been reported. with a prominent granular cell layer without rete
ridges (Fig. 90). Focal areas of parakeratosis are
Orthokeratinized Odontogenic Cyst rarely observed in OOCs, but corrugated appear-
The orthokeratinized odontogenic cyst (OOC) is a ance of the parakeratinized layer and prominent
rare developmental odontogenic cyst almost palisading arrangement of nuclei of cuboidal or
entirely lined by orthokeratinized, stratified squa- columnar basal cells are absent. OOCs are treated
mous epithelium. The separation of OOC from by simple enucleation. Recurrence is very low
odontogenic keratocyst is important because of and has been reported to be less than 2%. OOCs
the difference in recurrence rates after conserva- are not associated with nevoid basal cell carci-
tive enucleation (Dong et al. 2010). OOCs may noma syndrome.
Fig. 89 Histology of calcifying odontogenic cyst. Lining

epithelium is composed of a cuboidal, palisaded basal cell
layer and the overlying stellate reticulum-like layer shows
resemblance to that of ameloblastoma, with the presence of
ghost cells (black arrow), and calcification (black open
arrow). (Hematoxylin and eosin stain)
Fig. 88 Calcifying odontogenic cyst. A radiolucent uni-

locular lesion (white dashed oval) involving the posterior
mandible and ascending ramus. (Image courtesy of Profes-
Odontogenic Tumors
Fig. 90 Histology of orthokeratinized odontogenic cyst.
Lining epithelium is a uniformly thin, orthokeratinized
Odontogenic tumors are neoplasms or tumorlike stratified squamous epithelium with a prominent granular
malformations derived from the tooth-forming cell layer, without rete ridges, and without a palisading
apparatus or its remnants. As teeth develop in arrangement of basal cells. (Hematoxylin and eosin stain)
the jawbones, odontogenic tumors are found
mostly within the maxillofacial skeleton
intraosseously. Some tumors can be seen in gin- odontoma are the most common among
giva or alveolar mucosa overlying tooth-bearing odontogenic tumors (Buchner et al. 2006).
areas. These tumors are called peripheral
odontogenic tumors. The majority of odontogenic
tumors are benign and rarely exhibit malignant Benign Epithelial Odontogenic Tumors
behavior (Sekerci et al. 2015). Odontogenic
tumors are subdivided into three groups based Ameloblastoma
on the types of odontogenic tissues involved: Ameloblastoma is the most representative
1. epithelial tumors, 2. mixed epithelial and mes- odontogenic tumor (Buchner et al. 2006). It is
enchymal tumors, and 3. mesenchymal tumors a slow-growing but locally aggressive benign
(Table 10). Odontogenic tumors are rare, tumor with a high rate of recurrence.
representing less than 1% of all oral tumors Ameloblastomas are subclassified into four
(Buchner et al. 2006). Ameloblastoma and types: conventional type, unicystic type,
Table 10 WHO classification of tumors of odontogenic Table 10 (continued)

and maxillofacial bone tumors (El-Naggar et al. 2017)
Low-grade central osteosarcoma
Odontogenic carcinomas Chondroblastic osteosarcoma
Ameloblastic carcinoma Parosteal osteosarcoma
Primary intraosseous carcinoma, NOS Periosteal osteosarcoma
Sclerosing odontogenic carcinoma Benign maxillofacial bone and cartilage tumors
Clear cell odontogenic carcinoma Chondroma
Ghost cell odontogenic carcinoma Osteoma
Odontogenic carcinosarcoma Melanotic neuroectodermal tumor of infancy
Odontogenic sarcomas Chondroblastoma
Benign epithelial odontogenic tumors Chondromyxoid fibroma
Ameloblastoma Osteoid osteoma
Ameloblastoma, unicystic type Osteoblastoma
Ameloblastoma, extraosseous/peripheral type Desmoplastic fibroma
Metastasizing ameloblastoma Fibro-osseous and osteochondromatous lesions
Squamous odontogenic tumor Ossifying fibroma
Calcifying epithelial odontogenic tumor Familial gigantiform cementoma
Adenomatoid odontogenic tumor Fibrous dysplasia
Benign mixed epithelial and mesenchymal Cemento-osseous dysplasia
odontogenic tumors Osteochondroma
Ameloblastic fibroma Giant cell lesions and bone cysts
Primordial odontogenic tumor Central giant cell granuloma
Odontoma Peripheral giant cell granuloma
Odontoma, compound type Cherubism
Odontoma, complex type Aneurysmal bone cyst
Dentinogenic ghost cell tumor Simple bone cyst
Benign mesenchymal odontogenic tumors Hematolymphoid tumors
Odontogenic fibroma Solitary plasmacytoma of bone
Odontogenic myxoma/myxofibroma
Cementoblastoma
Cemento-ossifying fibroma
Odontogenic cysts of inflammatory origin
extraosseous/peripheral type, and metastasizing
Radicular cyst ameloblastoma. Among these types, the conven-
Inflammatory collateral cysts tional type represents more than 80% of all
Odontogenic and non-odontogenic developmental cases.
cysts About 80% of conventional ameloblastoma
Dentigerous cyst occur in the mandible, usually in the molar region
Odontogenic keratocyst and ramus (Hertog et al. 2012). Most conventional
Lateral periodontal cyst and botryoid odontogenic cyst ameloblastoma cases are diagnosed between the
Gingival cyst third to seventh decade (average age is 37 years).
Glandular odontogenic cyst There is no gender predilection. A painless expan-
Calcifying odontogenic cyst sion of the jaw is a common clinical presentation
Orthokeratinized odontogenic cyst of conventional ameloblastomas. Conventional
Nasopalatine duct cyst
ameloblastomas present as multilocular or uniloc-
Malignant maxillofacial bone and cartilage tumors
ular radiolucencies (Figs. 91, 92, 93, and 94). An
Chondrosarcoma
unerupted tooth, most often a mandibular third
Chondrosarcoma, grade 1
molar, is associated with about 40% of conven-
Chondrosarcoma, grade 2/3
Mesenchymal chondrosarcoma
tional ameloblastomas. The clear cut resorption of
Osteosarcoma, NOS margins of the radiolucency often show irregular
(continued) scalloping. Conventional ameloblastomas may
Fig. 91 Radiograph of ameloblastoma showing a multi- toward the inferior border of the mandible. Clear cut root
locular radiolucent lesion extending from the lower left resorption is observed at mandibular second molar. (Image
second molar to ramus of mandible. The margin of the courtesy of Professor Kakimoto, Hiroshima University,
lesion shows irregular scalloping. An unerupted third Japan).
molar is observed at the periphery of the lesion displaced
invade into surrounding soft tissue with perfora- Unicystic ameloblastoma is found in younger
tion of the cortical bone (Apajalahti et al. 2015). patients than conventional ameloblastoma with
Histologically, conventional ameloblastomas a mean age of about 20 years. Unicystic
show two basic patterns: follicular and plexiform ameloblastoma typically presents as a well-
patterns. The follicular pattern is the most com- circumscribed pericoronal radiolucency associ-
mon and shows enamel organ-like nests ated with an unerupted mandibular third molar,
consisting of peripheral columnar ameloblast- often resembling a dentigerous cyst (Figs. 98 and
like cells and central loosely arranged cells resem- 99). There are two histological patterns: luminal
bling the stellate reticulum (Fig. 95). Squamous unicystic ameloblastoma and intraluminal
metaplasia and cystic degeneration of nests are unicystic ameloblastoma. The luminal type
often observed. The plexiform pattern shows shows a simple cyst lined by ameloblastomatous
anastomosing strands of dental lamina-like epi- epithelium (Fig. 100). The intraluminal type
thelium or sheets of odontogenic epithelium is characterized by intraluminal protrusion of
(Fig. 96). BRAF V600E has been reported as the the ameloblastomatous epithelium, usually in
most common mutation in conventional a plexiform pattern. Simple enucleation is
ameloblastoma (Brown et al. 2014). Marginal indicated for both luminal and intraluminal
resection is the most widely accepted treatment unicystic ameloblastomas. Prognosis of unicystic
modality. Recurrence rates of 50–90% have been ameloblastomas is good.
reported in various studies after curettage and up Peripheral ameloblastoma is a rare type of
to 15% even after marginal or block resection ameloblastoma (about 1% of all ameloblastomas)
(Fig. 97) (Pogrel and Montes 2009). occurring on the gingiva or alveolar mucosa
Unicystic ameloblastomas account for (Philipsen et al. 2001). The mean age of patients
10–15% of all ameloblastomas (Li et al. 1998). with peripheral ameloblastoma is about
Fig. 92 Ameloblastoma. CT, oblique sagittal of the right the majority of these lesions contain more cystic (white
(a) and left (b) mandible; axial postcontrast soft-tissue arrows in c) than solid tissue (white dotted arrow in c)
window (c) and comparison bone window image (d). presumably representing macrocystic degeneration of
There is a multiloculate, expansile lesion projecting from solid components. (Images courtesy of Clinical Associate
the alveolus of the mandibular symphysis in this edentu- Professor Andy Whyte, Perth Radiological Clinic, Perth
lous patient. Despite the designation of the “solid” subtype, WA, Australia)
50 and significantly higher than that of conven- islands of well-differentiated squamous epithe-
tional ameloblastoma, although histological lium in a fibrous stroma. There is a wide age
features are similar to those of conventional range with a mean age of 38 years at diagno-
ameloblastoma. Conservative excision is the sis. The male to female ratio is 1.8:1 (Badni
treatment of choice, because peripheral et al. 2012). Squamous odontogenic tumors
ameloblastoma generally shows an innocuous mostly arise intraosseously around the alveolar
clinical behavior (Philipsen et al. 2001). Very processes between the roots of vital erupted
rare cases of ameloblastomas showing distant teeth. Affected teeth may become mobile.
metastasis in spite of a benign histologic appear- Radiographically, SOT often show triangular
ance are known as metastasizing ameloblastoma unilocular or multilocular radiolucencies lat-
(Dissanayake et al. 2011). eral to the teeth roots (Jones et al. 2011).
Histopathologically, squamous odontogenic
Squamous Odontogenic Tumor tumors consist of islands of terminally differ-
Squamous odontogenic tumor is a rare benign entiated squamous epithelium. There is no
epithelial odontogenic tumor consisting of peripheral palisading or cytological atypia.
Fig. 93 Coexistent conventional and desmoplastic (white arrows in b) with a midline component of mixed
ameloblastoma. OPG (a), postcontrast T1 axial (b), and radiopacity and soft-tissue representing the desmoplastic
coronal bone window (c) CT reconstructions. There is a component (white dotted arrow in b). (Images courtesy of
large expansile, multiloculate mandibular lesion extending Clinical Associate Professor Andy Whyte, Perth Radiolog-
from teeth 36 to 45 causing aggressive root resorption ical Clinic, Perth WA, Australia)
(a and c). The majority of the lesion is of fluid attenuation
Conservative surgical treatment is applied and (Kaplan et al. 2001), and most are unilocular,
recurrences are rare. but about one quarter are multilocular
(Fig. 101). In about half of the cases, an
Calcifying Epithelial Odontogenic Tumor unerupted tooth, most often a mandibular third
The calcifying epithelial odontogenic tumor molar, is associated with the lesion. Histopatho-
(CEOT), also known as Pindborg tumor, is logically, CEOT is composed of sheets or islands
a locally invasive epithelial odontogenic neo- of odontogenic epithelial cells close to eosino-
plasm, characterized by the presence of amyloid philic material in a fibrous connective tissue
material that tends to calcify. CEOT occurs in stroma (Fig. 102). Well-developed intercellular
patients between 20 and 60 years of age with bridges can be noted between cells. Cellular
a mean about 40 years (Philipsen and Reichart pleomorphism of the tumor cells is observed,
2000). There is no gender predilection. Most but mitosis is rare. Differential diagnosis from
cases are intraosseous. CEOT affects the mandi- intraosseous squamous cell carcinoma is
ble more often than the maxilla with a ratio of required to avoid overtreatment. A clear cell var-
2:1. Intraosseous CEOTs present as slow- iant of CEOT is well documented that requires
growing painless expansions of the jawbones. differential diagnosis from clear cell
Radiographically, most CEOTs present as odontogenic carcinoma or metastatic clear cell
mixed radiolucent and radiopaque lesions carcinoma. Positive staining with Congo red and
Fig. 94 Ameloblastoma right maxilla. An axial CT scan multiple tiny nodular non-enhancing foci on a T1,
(a) through the mid-maxilla shows a round, uniloculate, fat-saturated image (white circle in c). It was not associated
expansile lesion (white arrows) which is of soft-tissue with an unerupted tooth. (Images courtesy of Clinical
attenuation (black dotted circle in b). Following contrast, Associate Professor Andy Whyte, Perth Radiological
the lesion shows diffuse contrast enhancement with Clinic, Perth WA, Australia)
Fig. 96 Histology of ameloblastoma, plexiform type.

Fig. 95 Histology of ameloblastoma, follicular type. Anastomosing strands of dental lamina-like epithelium or
Tumor nests show enamel organ-like nests consisting of sheets of odontogenic epithelium proliferate in a loose
peripheral columnar ameloblast-like cells and central connective tissue stroma. Central stellate reticulum is
loosely arranged cells resembling the stellate reticulum. inconspicuous. (Hematoxylin and eosin stain) (Image
Cystic degeneration of nests is observed (*). (Hematoxylin courtesy of Professor Camile Farah, UWA Dental School,
and eosin stain) University of Western Australia, Perth WA, Australia)
Fig. 97 Recurrent ameloblastoma that originally arose in the right ramus and condyle (black dotted arrow in c) but
the right mandible: CT axial bone window (a), postcontrast also the right temporal fossa (white dotted arrow in b).
coronal (b), and sagittal (c) soft-tissue window images. (Images courtesy of Clinical Associate Professor Andy
Tumor involves not only the right mandible but has spread Whyte, Perth Radiological Clinic, Perth WA, Australia)
to a costo-chondral graft replacing the superior aspect of
fluorescence with thioflavine T show the eosino- Adenomatoid Odontogenic Tumor

philic material to be amyloid. Recently, the amy- Adenomatoid odontogenic tumor (AOT) is a
loid material has been reported to be positive slow-growing benign epithelial tumor with duct-
for odontogenic ameloblast-associated protein like structures. AOTs account for 3–7% of all
(Murphy et al. 2008). Dystrophic calcification odontogenic tumors (Philipsen et al. 2007).
is often seen in the amyloid-like material and More than two thirds are diagnosed in the second
fuses together to form large masses. Most cases decade of life. Females are affected about twice as
are treated with local surgical removal, and the often as males. More than 95% of cases are
overall recurrence rate is about 15% (Franklin intraosseous. The tumors are twice as common
and Pindborg 1976). in the maxilla as in the mandible. About 60% of
odontomas (Philipsen et al. 1991). Recurrences

are extremely rare after enucleation.
Benign Mixed Epithelial

and Mesenchymal Odontogenic
Tumors
Ameloblastic Fibroma
Ameloblastic fibroma is a rare odontogenic tumor
in which the epithelial and mesenchymal tissues
are both neoplastic. Most tumors (80%) occur in
the first two decades of life with a mean age of
15 years (Buchner and Vered 2013). The male to
female ratio is 1.4:1. The most common location
is the posterior region of the mandible.
Ameloblastic fibromas are usually slow-growing,
painless tumors. Radiographically, ameloblastic
Fig. 98 Radiograph of unicystic ameloblastoma. A well- fibroma is a well-defined unilocular or multi-
defined unicystic radiolucency with cortical bone destruc-
tion is observed in the right mandible associated with an
locular radiolucent lesion. An unerupted tooth,
impacted lower right third molar (48). Clear cut root usually a first or second premolar, is associated
resorption is observed (Figs. 91, 93). (Image courtesy of with the lesion in about 80% of cases (Fig. 105).
Professor Kakimoto, Hiroshima University, Japan) Histopathologically, ameloblastic fibroma is com-
posed of a cell-rich mesenchymal tissue resem-
bling the dental papilla admixed with proliferating
cases occur in the anterior segments, especially odontogenic epithelium (Fig. 106). The epithelial
the canine region. AOT usually presents radio- component is arranged in strands or islands of
graphically as a well-defined unilocular radiolu- odontogenic epithelium. The former resembles
cency surrounding the crown of an unerupted the dental lamina, and the latter resembles the
tooth, most often a canine, resembling a follicular stage of the enamel organ. Conservative
dentigerous cyst. Fine snowflake calcifications surgical removal is recommended for
are often present in the radiolucent lesion, helping ameloblastic fibromas in patients younger than
differential diagnosis of AOT from a dentigerous 22 years, because the lesion may be an early
cyst (Fig. 103). Microscopically, AOT is well stage of a developing odontoma, often known as
encapsulated by a fibrous capsule. Tumor shows an ameloblastic fibro-odontoma. As to patients
various-sized solid nodules of cuboidal or older than 22 years, radical surgery should be
spindle-shaped odontogenic epithelium with min- considered when the tumor is massive in size or
imal stroma. Within these nodules, there are char- when the tumor recurs more than once. Long-term
acteristic rosette- or duct-like spaces that are the follow-up is recommended for ameloblastic
most characteristic features of AOT (Fig. 104). fibroma lesions, due to the risk of recurrence or
Duct-like spaces are lined by a columnar or cuboi- malignant transformation into ameloblastic fibro-
dal epithelium. There is often eosinophilic amor- sarcoma (Chen et al. 2007).
phous material, tumor droplets, within the nodule.
Small foci to large areas of calcification are fre- Primordial Odontogenic Tumor
quently seen. At the periphery of the tumor, a Primordial odontogenic tumor (POT) is a new
plexiform pattern of tumor cells may present. entity in odontogenic tumors first reported in
AOT and AOT-like areas have been recognized 2014 (Mosqueda-Taylor et al. 2014). Primordial
with calcifying epithelial odontogenic tumor and odontogenic tumor is a benign mixed epithelial
Fig. 99 Unicystic ameloblastoma in a 17-year-old female right third molar (48) (a and b). The lesion is associated
of Asian extraction. Multidetector CT: oblique sagittal CT with apical resorption of the apices of the lower right
reconstruction (a), coronal reconstruction (b), axial recon- second molar (47) and lower right first molar (46) (white
struction (c), and soft tissue axial reconstruction following arrows in a) and is of fluid attenuation (d). (Images cour-
contrast (d). Uniloculate, expansile lesion in a follicular tesy of Clinical Associate Professor Andy Whyte, Perth
relationship to the unerupted and inferiorly displaced lower Radiological Clinic, Perth WA, Australia)
Fig. 100 Histology of unicystic ameloblastoma, luminal Fig. 101 Calcifying epithelial odontogenic tumor pre-
type. The luminal type of unicystic ameloblastoma shows a senting as a mixed radiolucent-radiopaque multilocular
simple cyst lined by ameloblastomatous epithelium. lesion involving the posterior mandible with thin opaque
(Hematoxylin and eosin stain) trabeculae crossing the radiolucent region. (Image courtesy
of Professor Camile Farah, UWA Dental School, Univer-
sity of Western Australia, Perth WA, Australia)
and mesenchymal odontogenic tumor. All Odontoma

reported cases exhibit early age of presentation Odontomas are tumorlike developmental anoma-
(3–19 years; mean 12.5 years) (Ando et al. lies (hamartoma). Odontoma is one of the most
2017). There is no sex predilection. The mandible common odontogenic tumors (Soluk Tekkesin
is predominantly affected (maxilla: mandi- et al. 2012). Odontomas are painless slow-growing
ble = 1:6). Most POT cases were asymptomatic. lesions, often detected during routine radiographic
Radiologically, POT shows a “dentigerous cyst- examination. They are primarily diagnosed in chil-
like” radiolucency. Histologically, POT is com- dren and young adults. There is no gender predi-
posed of a mass of dental papilla-like loose fibrous lection. Odontomas are subdivided into compound
tissue covered by ameloblastic epithelium, odontoma and complex odontoma. Many of com-
mimicking the early (primordial) stages of pound odontomas are located in the anterior region
tooth development. Enucleation results in no of the maxilla, while complex odontomas tend to
recurrence. be located in the mandibular premolar and molar
region. Radiographically, odontomas usually pre-
sent as well-demarcated radiopacities surrounded
Fig. 102 Histology of calcifying epithelial odontogenic

tumor. Tumor is composed of sheets or islands of
odontogenic epithelial cells close to eosinophilic material Fig. 104 Histology of adenomatoid odontogenic tumor.
in a fibrous connective tissue. Cellular pleomorphism of There are characteristic rosette-like structures (*) or duct-
the tumor cells is observed but mitosis is not seen. Dystro- like spaces lined by columnar or cuboidal epithelial cells.
phic calcification is seen in the amyloid-like material. Small foci of calcification are seen at the left edge (white
(Hematoxylin and eosin stain) arrow). (Hematoxylin and eosin stain)
Fig. 103 Radiograph of

adenomatoid odontogenic
tumor showing a well-
defined unilocular
radiolucency surrounding
the crown of an unerupted
upper left canine (black
dashed oval). Fine
snowflake calcifications are
present in the radiolucent
lesion. (Image courtesy of
Professor Kakimoto,
Hiroshima University,
Japan)
Fig. 106 Histology of ameloblastic fibroma. Tumor is

composed of a cell rich mesenchymal tissue resembling
the dental papilla admixed with proliferating odontogenic
epithelium arranged in strands or islands. (Hematoxylin
and eosin stain) (Image courtesy of Professor Camile
Farah, UWA Dental School, University of Western
focal areas of calcification. Microscopically, the

compound odontoma consists of various numbers
of small tooth-like structures (odontoids)
(Fig. 107), while the complex odontoma is com-
posed of haphazard mass of dental tissues
(Fig. 108). Odontomas are treated by local excision
(Boffano et al. 2012).
Dentinogenic Ghost Cell Tumor

Dentinogenic ghost cell tumor (DGCT) is
a benign but locally infiltrating neoplasm charac-
terized by ameloblastoma-like islands of epithe-
Fig. 105 Amelobastic fibroma in an 8 year old boy. Cone
Beam CT with oblique sagittal (a and b) reconstructions lial cells in a mature connective tissue stroma
through the right mandibular body (image b being buccal (Buchner et al. 2016). DGCT contains aberrant
to a) with an axial reconstruction (c). A multiloculate keratinization, with a variable number of ghost
lesion situated superior to the inferiorly displaced and
cells and dentinoid material. DGCT is more com-
distally angulated 45 (white arrows in b and c) thins the
cortices, including the follicles overlying 45 and 46, the mon in males than in females. There is a wide age
eruption of the first molar being impeded. There is aggres- range with a mean age of 40 years at diagnosis.
sive resorption of the distal root of 85. (Images courtesy of DGCT usually occur as an intraosseous lesion
Clinical Associate Professor Andy Whyte, Perth Radiolog-
(83%) and less commonly as a peripheral lesion
ical Clinic, Perth WA, Australia)
in the gingiva (17%). Intraosseous DGCT com-
monly occurs in the posterior maxilla and mandi-
by a thin radiolucent zone of a soft tissue capsule ble and presents as an asymptomatic bony
(Figs. 107 and 108). The compound odontoma expansion. Radiographically, DGCT presents as
appears as a collection of tooth-like structures of a unilocular (80%) or multilocular (20%) lesion.
varying size and shape (Fig. 107), while the com- Images show a radiolucent to mixed radiolucent/
plex odontoma appears as a radiopaque amorphous radiopaque appearance depending on the amount
calcified mass (Fig. 108). In the early stage, an of calcification. DGCT shows sheets and islands
odontoma may appear as a radiolucency with of odontogenic epithelial cells in a mature
Fig. 107 Compound

odontoma in the anterior
mandible. Cone Beam CT:
panoramic reconstruction
(a), axial reconstruction (b),
and radial reconstruction (c)
in the lower right canine
(43) region. There is a
cluster of “denticles”
between lower right lateral
incisor (42) and lower right
canine (43) focally
expanding the thinning the
junction the lingual and
crestal cortices (white
arrows). Histology of
compound odontoma (d).
Dental hard tissues are
arranged in a more
organized fashion
resembling smaller tooth-
like structures.
stain). (Images a, b,
c courtesy of Clinical
Associate Professor Andy
Whyte, Perth Radiological
Clinic, and image
d courtesy of Professor
WA, Australia)
connective tissue. The epithelial component material. Wide local resection is recommended for
resembles that of an ameloblastoma. Some intraosseous DGCT, particularly, if the tumor is
DGCTs have tumor nests of hyperchromatic radiologically ill-defined (Buchner et al. 2016).
basaloid cells. Mitotic figures are rare. A charac-
teristic feature of DGCT is the transformation of
epithelial cells into ghost cells. Some ghost cells Benign Mesenchymal Odontogenic
undergo calcification. DGCT forms dysplastic Tumors
dentin although in minute amounts. Dentinoid
material is formed at the interface between the Odontogenic Fibroma
epithelial cells and the adjacent connective tis- Odontogenic fibroma is a rare neoplasm of mature
sues. Ghost cells may be trapped in the dentinoid fibrous connective tissue in which various
Fig. 108 Cropped orthpantomogram of complex odontoma (b). Tumor is composed of a haphazard mass
odontoma (a). There is an odontome in the left mandibular of dental tissues, some of which look like small teeth.
molar region showing a well-demarcated radiopacity (Hematoxylin and eosin stain) (Image a courtesy of Prof.
surrounded by a thin radiolucency at the coronal aspect Kakimoto, Hiroshima University, Japan).
of the impacted first molar. Histology of complex
Fig. 109 Odontogenic fibroma. A well-demarcated radio- odontogenic epithelial islands (black arrowheads) (b).
lucent lesion (white arrows) is seen in left maxilla (a). (Hematoxylin and eosin stain) (Image a courtesy of Pro-
Tumor is composed of fibrous connective tissue with fessor Kakimoto, Hiroshima University, Japan)
amounts of nonneoplastic odontogenic epithelium be present. Sclerosing odontogenic carcinoma

are embedded (Eversole 2011). Odontogenic shares some histological features with odontogenic
fibroma has a wide patient age range and a slight fibroma and should be considered in the differential
female predilection. Odontogenic fibroma usually diagnosis (Speight and Takata 2017). Odontogenic
forms a well-circumscribed unilocular radiolu- fibroma is usually treated by enucleation and curet-
cency (Fig. 109). Histologically, odontogenic tage. Recurrence is uncommon (Eversole 2011).
fibroma is composed of fibrous connective tissue
with odontogenic epithelial islands or strands Odontogenic Myxoma
(Fig. 109). The amount of epithelial elements Odontogenic myxoma is a benign mesenchymal
varies from being totally absent (epithelium-poor odontogenic neoplasm characterized by stellate
type) to being a conspicuous feature (epithelium- cells in an abundant myxoid matrix (Martinez-
rich type). Cementum-like calcifications may Mata et al. 2008). When collagenous fiber
formation is evident, the odontogenic myxoma is

designated as odontogenic myxofibroma. Most
cases of odontogenic myxoma are diagnosed in
the second to fourth decades of life and are more
common in females. Two thirds of odontogenic
myxomas are located in the mandible and most
commonly in the molar regions. Odontogenic
myxomas may cause painless expansion of jaw-
bones. Radiographically, odontogenic myxomas
appear as unilocular or multilocular radiolu-
cencies showing a soap bubble or honeycomb
configuration. Odontogenic myxomas are com-
posed of a gelatinous translucent tissue. Micro-
Fig. 110 Histology of odontogenic myxoma. Tumor
scopically, odontogenic myxoma shows shows haphazardly arranged stellate and spindle-shaped
haphazardly arranged stellate and spindle- cells in an abundant loose myxoid stroma. Islands of
shaped cells in an abundant loose myxoid stroma odontogenic epithelial cells are seen at the lower right
resembling the dental papilla of a developing corner. (Hematoxylin and eosin stain)
tooth (Fig. 110). There may be islands of
odontogenic epithelial cells in the tumor.
Odontogenic myxomas are benign but infiltra-
tive. The recurrence rate is about 25%. Larger
lesions require complete excision with free mar-
gins (Boffano et al. 2011).
Cementoblastoma
Cementoblastoma is a rare odontogenic tumor
characterized by formation of cementum-like
tissue in connection with the tooth root
(Brannon et al. 2002). Cementoblastoma mostly
occurs in patients less than 30 years of age.
There is no distinct gender predilection. The
majority of cementoblastomas are slow-growing
swellings located in the mandible, particularly Fig. 111 Cementoblastoma. A well-defined radiopaque
related to the first molar. A characteristic feature mass (white arrows) is fused with the root of the left
of cementoblastoma is pain similar to toothache. upper second premolar. The opaque mass is surrounded
Radiographic findings are almost pathogno- by a thin radiolucent zone (black arrow). (Image courtesy
of Professor Kakimoto, Hiroshima University, Japan)
monic. Cementoblastoma appears as a well-
defined radiopaque mass fused with one or several
roots of affected teeth (Figs. 111 and 112). The
is usually excised surgically with extraction of the
opaque mass is surrounded by a thin radiolucent
affected tooth.
zone. Cementoblastoma consists of dense masses
of basophilic cementum-like hard tissue with irreg-
ular reversal lines. Cellular fibrovascular tissue is Ossifying Fibroma
present between the mineralized trabeculae that are Ossifying fibroma (OF) is a benign fibro-osseous
lined by plump cementoblast-like cells. Multi- neoplasm of the jaws. There are three clinicopatho-
nucleated giant cells are often present. At the logical variants: cemento-ossifying fibroma (COF),
periphery of the tumor, radiating columns of juvenile trabecular ossifying fibroma (JTOF), and
unmineralized tissue are seen. Cementoblastoma juvenile psammomatoid ossifying fibroma (JPOF).
Fig. 112 Cementoblastoma of the right mandible in a lucent margin (white arrows) and demineralizes the buccal
young adult male: Cone Beam CT with oblique sagittal cortex (black open arrow). (Images courtesy of Clinical
(a) and coronal (b) reconstructions. A round, expansile Associate Professor Andy Whyte, Perth Radiological
sclerotic opacity is fused to the mesial root of the lower Clinic, Perth WA, Australia)
right first molar (46) (black dotted arrows). It has a thin
Fig. 113 Ossifying

fibroma (cemento-ossifying
fibroma). Small well-
localized radiodensity with
a thin radiolucent rim is
limited to the tooth bearing
area (a). Large lesion
presenting with mixed
radiolucent-radiopaque
composition and causing
significant expansion
buccolingually (b). (Images
WA, Australia)
COF is a rare odontogenic tumor (El-Mofty or bone and cementum-like tissue (Fig. 115). Oste-
2002; El-Mofty 2009). COF most commonly oblastic rimming of bone trabeculae is evident.
occurs in the second to fourth decade and JTOF also affects the jaws, with the maxilla
shows a predilection for females. COF occurs being a more common site. JTOF consists of
exclusively in the tooth-bearing areas of the cellular fibrous tissue with cellular osteoid with-
jaws. The mandibular premolar and molar out osteoblastic rimming and bone trabeculae
regions are the most common site. COF presents with rimming of osteoblasts. Aneurysmal bone
as a painless expansion of the affected bone. cyst showing multinucleated giant cells and hem-
Radiographically, early lesions are typically orrhages may be present.
radiolucent, but they become more radiopaque JPOF predominantly occurs in the extragnathic
with time (Figs. 113 and 114). Histologically, craniofacial bones, particularly the periorbital
COF is composed of hypercellular fibroblastic frontal and ethmoid bones. JPOF is characterized
stroma containing variable amounts of osteoid by a fibroblastic stroma containing small spherical
Fig. 114 Ossifying fibroma (cemento-ossifying fibroma) peripheral corticated rim (white dotted arrows in (b). It is
in the left posterior mandible of a male aged 15 years. Axial not related to a tooth and is superior to the left inferior
Cone Beam CT (a), and oblique sagittal reconstruction (b). alveolar canal (IAC). (Images courtesy of Clinical Associ-
The lesion exhibits centrifugal growth at 90 to the long ate Professor Andy Whyte, Perth Radiological Clinic,
axis of the mandible (white double headed arrow in (a); it is Perth WA, Australia)
homogeneously sclerotic and has a lucent margin with a
Fig. 115 Histology of cemento-ossifying fibroma. Tumor Fig. 116 Juvenile psammomatoid ossifying fibroma is
is composed of fibroblastic stroma containing variable characterized by a fibroblastic stroma containing small
amounts of osteoid or bone (eosinophilic trabecular hard spherical ossicles resembling psammoma bodies. (Hema-
tissue) and cementum-like tissue (basophilic blue hard toxylin and eosin stain) (Image courtesy of Professor
tissue). (Hematoxylin and eosin stain) Toyosawa, Osaka University, Japan)
ossicles resembling psammoma bodies (Fig. 116). Malignant Odontogenic Tumors

The ossicles may fuse to form larger aggregates.
JPOF may show trabeculae of woven bone in a Odontogenic Carcinomas
loose stromal tissue. COF is surgically excised,
and there is no recurrence in most cases. Higher Ameloblastic Carcinoma
recurrence rates (30–60%) have been reported for Ameloblastic carcinoma is a rare epithelial malig-
JTOF and JPOF compared to COF (Sun et al. nant odontogenic neoplasm (Kar et al. 2014).
2007). Ameloblastic carcinoma is the malignant
Fig. 117 Histology of secondary ameloblastic carcinoma. Fig. 118 Primary intraosseous carcinoma NOS. Histolog-
Secondary undifferentiated cancer arises in a preexisting ically, this demonstrates features of a squamous cell carci-
benign ameloblastoma (right upper edge of the Figure). noma but also shows features of peripheral palisading and a
(Hematoxylin and eosin stain) plexiform pattern suggesting its odontogenic origin.
(Hematoxylin and eosin stain) (Image courtesy of Profes-
counterpart of ameloblastoma. Ameloblastic car- Western Australia, Perth WA, Australia)
cinomas frequently occur in the mandibular molar
region of older individuals, in their seventh
decade or more. Most cases arise de novo features of a squamous cell carcinoma. Some
(primary ameloblastic carcinoma) but some cases show features of peripheral palisading and
arise in preexisting ameloblastomas (secondary a plexiform pattern suggesting their odontogenic
ameloblastic carcinoma). Both primary and sec- origin (Fig. 118). PIOC is locally aggressive and
ondary ameloblastic carcinomas show the histo- metastasize to lymph nodes. Prognosis is poor,
logical pattern of an ameloblastoma with cellular and 5-year survival rates are ranging from 30%
atypia (Fig. 117). Multiple recurrences of a prior to 40% (Thomas et al. 2001).
ameloblastoma may precede malignant transfor-
mation. Vascular or perineural invasion and Sclerozing Odontogenic Carcinoma
necrotic foci within nests may help differential Sclerozing odontogenic carcinoma is a very rare
diagnosis. Approximately one third of patients primary intraosseous carcinoma of the jaws char-
develop pulmonary metastases. A local recur- acterized by thin cords and strands of epithelium in
rence rate is 28% and the median overall survival a densely sclerotic stromal connective tissue
is 17.6 years (Yoon et al. 2009). (Fig. 119) (Koutlas et al. 2008). Sclerozing
odontogenic carcinoma frequently locates in pre-
Primary Intraosseous Carcinoma NOS molar and molar regions of the mandible. There is
Primary intraosseous carcinoma (PIOC) NOS is a no sex predilection. Radiographically, sclerozing
rare central carcinoma of the jawbones that cannot odontogenic carcinoma presents as a poorly
be categorized as any other type of carcinoma defined radiolucency with frequent cortical bone
(Thomas et al. 2001). Some PIOC arise de novo destruction. Microscopically cancer cells invade
and some arise in odontogenic cysts or benign nerves and surrounding tissues. Sclerozing
odontogenic tumors. PIOC shows a male predi- odontogenic carcinoma is a low-grade carcinoma,
lection with a mean age of 52.3 years (age range and no metastasis is reported. Resection is the main
from 4 to 81 years). The most common site for treatment for sclerozing odontogenic carcinoma.
PIOC is the retromolar to ramus area of the man-
dible. Radiographically, these tumors present as Clear Cell Odontogenic Carcinoma
an ill-defined osteolytic lesion often with cortical Clear cell odontogenic carcinoma (CCOC) is an
perforation. Histologically, PIOC demonstrates odontogenic carcinoma characterized by sheets
Fig. 119 Histology of sclerozing odontogenic carcinoma. Fig. 120 Histology of clear cell odontogenic carcinoma.
Small islands and strands (arrowheads) of cancer cells are Cancer cells are entirely composed of clear cells with a
seen in a densely sclerotic stromal connective tissue. hyalinized stroma. (Hematoxylin and eosin stain)
(Hematoxylin and eosin stain)
and islands of clear cells (Loyola et al. 2015). 2008). Males are more commonly affected with
CCOC arises predominantly in the posterior a male to female ratio of 4:1. Incidence peaks in
mandible during the fifth to eighth decade with the fourth decade of life. GCOC is twice as com-
a female predilection (male to female ratio is mon in the maxilla as in the mandible. GCOC
1:1.6). CCOC is usually slow growing but arises as a de novo tumor or in a preexisting
locally invasive. Recurrence and metastasis benign precursor lesion such as a calcifying
may develop after many years. Radiographi- odontogenic cyst (COC) or a dentinogenic ghost
cally, most CCOC show an ill-defined radiolu- cell tumor (DGCT). GCOC causes a slow-
cency. Histologically, CCOC exhibits two growing swelling of the jawbones. Imaging
patterns: monophasic and biphasic. The mono- shows a poorly defined osteolytic radiolucency
phasic pattern shows epithelial nests entirely with radiopaque materials. Microscopically
composed of clear cells (Fig. 120). Some GCOC shows malignant epithelial components
show peripheral columnar cells with reverse with ghost cells in isolation or in clusters. The
nuclear polarity like ameloblastoma. A malignant component consists of rounded epithe-
biphasic pattern is most frequent and tumor lial cells with atypical features (Fig. 121). Depo-
nests consist of clear cells and small basaloid sition of dysplastic dentin may be present.
cells with eosinophilic cytoplasm. The clear Secondary cases show evidence of a COC or
cells are positive for cytokeratins but negative DGCT precursor. Most are relatively low grade
for mucin. Dentinoid formation is reported in but recurrences are common. The overall 5-year
some cases. Recently, EWSR1 rearrangements survival rate is 73% (Lu et al. 1999).
have been reported in more than 80% of
CCOC. Surgical resection is recommended. Odontogenic Carcinosarcoma
Forty-three percent of patients treated with Odontogenic carcinosarcoma is an extremely
resection alone experience a recurrence (Ebert rare tumor in which both the epithelial and the
et al. 2005). mesenchymal components are cytologically
malignant (DeLair et al. 2007). Most of the
Ghost Cell Odontogenic Carcinoma reported odontogenic carcinosarcomas arise in
Ghost cell odontogenic carcinoma (GCOC) is the mandible. Radiographically, lesions are
a very rare variant of odontogenic carcinoma radiolucent with poorly defined borders. Corti-
characterized by ghost cells with or without cal perforation and root resorption have been
dentinoid deposition (Ledesma-Montes et al. reported. The overall architecture resembles
Fig. 121 Histology of ghost cell odontogenic carcinoma. Fig. 122 Ameloblastic fibrosaroma. Histologically, there
Clusters of ghost cells are seen in the solid sheets of are lamina or follicular-like epithelial components without
rounded epithelial cells with atypical features. (Hematox- atypical features. The stromal component shows hyper-
ylin and eosin stain) cellularity and variable degrees of cytological atypia.
Deposition of dentinoid and/or enameloid material is
noted. (Hematoxylin and eosin stain) (Image courtesy of
Professor Camile Farah, UWA Dental School, University
that of ameloblastic fibroma. Odontogenic car- of Western Australia, Perth WA, Australia)
cinosarcoma is clinically very aggressive with
high rates of recurrence and metastasis. Progno-
sis of reported cases is poor, but adequate sur- Conclusions and Future Directions
gical treatment may lead to good outcomes
(Kim et al. 2015). Tooth anomalies consequent to abnormal devel-
opment are a heterogeneous, diverse group arising
Odontogenic Sarcomas as a result of genetic and/or environmental insults.
Odontogenic sarcomas are a group of mixed Developmental dental anomalies may occur in
odontogenic tumors in which the epithelial isolation or be associated with other health prob-
component is bland and cytologically benign lems (e.g., as part of syndromes), and clinical
and the mesenchymal component is malignant evaluation should always take account of this.
(Muller et al. 1995). Ameloblastic fibrosarcoma Advances in molecular genetics are providing
is the most common type of odontogenic sar- new insights that will inform understanding and
coma (Fig. 122). Ameloblastic fibrosarcoma related healthcare delivery.
occurs more commonly in men than women Dental caries and periodontal diseases are still
(male/female = 1.5:1). There is a wide age the most common chronic diseases, even though
range with a mean age of 27.5 years at diagnosis. they are preventable. They cause problems not only
Most cases arise in the mandible. Typically, to oral function but also to systemic health. Dental
ameloblastic fibrosarcoma presents as a radiolu- infection is not the primary cause of systemic dis-
cency with ill-defined borders. Histologically, ease but plays a significant role in progression of
there is a various amount of lamina- or systemic diseases as a source of bacteria, their
follicular-like epithelial component without products, and inflammatory cytokines. Elucidation
atypical features. The stromal component shows of the oral-systemic health connection is an impor-
hypercellularity and variable degrees of cytolog- tant issue for both medical and dental care.
ical atypia. Deposition of dentinoid and/or A high frequency of cysts in the jawbones is
enameloid material is reported in some cases. a characteristic not observed in other bones. Most
Radical surgery is recommended. Odontogenic of these are nonneoplastic cysts; however, the dis-
sarcomas are locally aggressive but generally tinction between nonneoplastic and neoplastic
low grade. cystic lesions remains controversial, especially
concerning the odontogenic keratocyst (OKC)/ References

keratocystic odontogenic tumor (KCOT) and the
calcifying cystic odontogenic tumor (CCOT)/calci- Almeida FT, Pacheco-Pereira C, Porporatti AL, Flores-
Mir C, Leite AF, De Luca Canto G, Guerra EN. Oral
fying odontogenic cyst (COC). The WHO classifi-
manifestations in patients with familial adenomatous
cation of odontogenic tumors in 2017 (El-Naggar polyposis: a systematic review and meta-analysis.
et al. 2017) proposed that they should be classified J Gastroenterol Hepatol. 2016;31(3):527–40.
as OKC and COC, respectively, because most cases AlZamel G, Odell S, Mupparapu M. Developmental
disorders affecting jaws. Dent Clin N Am. 2016;
of KCOT and CCOT behave clinically as non-
60(1):39–90.
neoplastic lesions and are treated as cysts mainly American Academy of Periodontology. International
with marsupialization and decompression. Future Workshop for a classification of periodontal diseases
treatment strategies may focus on molecular and conditions. Ann Periodontol. 1999;4(1): i, 1–112.
Ando T, Shrestha M, Nakamoto T, Uchisako K,
approaches and eventually reduce or eliminate the
Yamasaki S, Koizumi K, Ogawa I, Miyauchi M, Takata
need for aggressive surgeries (Li 2011). T. A case of primordial odontogenic tumor: a new
The majority of odontogenic tumors are benign, entity in the latest WHO classification. Pathol Int.
with ameloblastoma and odontoma being the most 2017;67(7):365–9.
Apajalahti S, Kelppe J, Kontio R, Hagstrom J. Imaging
common among odontogenic tumors. Recent
characteristics of ameloblastomas and diagnostic
research shows different kinds of mutations asso- value of computed tomography and magnetic reso-
ciated with odontogenic tumors, especially nance imaging in a series of 26 patients. Oral Surg
ameloblastomas. BRAF V600E is the most com- Oral Med Oral Pathol Oral Radiol. 2015;120(2):
e118–30.
mon mutation in ameloblastoma. Understanding
Armitage GC. Development of a classification system for
how molecular and genetic alterations affect the periodontal diseases and conditions. Ann Periodontol.
development and progression of odontogenic 1999;4(1):1–6.
tumors will bring new molecular-targeted treat- Arya R, Gulati S. Phenytoin-induced gingival overgrowth.
Acta Neurol Scand. 2012;125(3):149–55.
ment for odontogenic tumors (Heikinheimo et al.
Badni M, Nagaraja A, Kamath V. Squamous odontogenic
2015; Nagi et al. 2016). tumor: a case report and review of literature. J Oral
Maxillofac Pathol. 2012;16(1):113–7.
Bailleul-Forestier I, Molla M, Verloes A, Berdal A. The
genetic basis of inherited anomalies of the teeth. Part
Cross-References 1: clinical and molecular aspects of non-syndromic
dental disorders. Eur J Med Genet. 2008;51
(4):273–91.
▶ Clinical Evaluation of Oral Diseases Barnes L, Eveson JW, Reichart PA, Sidransky D, editors.
▶ Diagnostic Imaging Principles and Applica- Pathology and genetics of head and neck tumours,
tions in Head and Neck Pathology World Health Organization classification of tumours.
Lyon: IARC Press; 2005.
▶ Gingival Pathology Bartlett DW, Shah P. A critical review of non-carious
▶ Head and Neck Tumors cervical (wear) lesions and the role of abfraction, ero-
▶ Interface between Oral and Systemic Disease sion, and abrasion. J Dent Res. 2006;85(4):306–12.
▶ Laboratory Medicine and Diagnostic Pathology Bergendal B, Norderyd J, Zhou X, Klar J, Dahl N. Abnor-
mal primary and permanent dentitions with ectodermal
▶ Non-odontogenic Bone Pathology symptoms predict WNT10A deficiency. BMC Med
▶ Normal Variation in the Anatomy, Biology, and Genet. 2016;17(1):88.
Histology of the Maxillofacial Region Bishop JA, Yonescu R, Batista D, Warnock GR,
▶ Odontogenic Bacterial Infections Westra WH. Glandular odontogenic cysts (GOCs)
lack MAML2 rearrangements: a finding to discredit
▶ Oral Manifestations of Systemic Diseases and the putative nature of GOC as a precursor to central
Their Treatments mucoepidermoid carcinoma. Head Neck Pathol.
▶ Oral Mucosal Malignancies 2014;8(3):287–90.
▶ Pediatric Oral Medicine Bleicher F. Odontoblast physiology. Exp Cell Res.
2014;325(2):65–71.
▶ Salivary Gland Disorders and Diseases Boffano P, Gallesio C, Barreca A, Bianchi FA, Garzino-
▶ Soft and Hard Tissue Operative Investigations Demo P, Roccia F. Surgical treatment of odontogenic
in the Diagnosis and Treatment of Oral Disease myxoma. J Craniofac Surg. 2011;22(3):982–7.
Boffano P, Zavattero E, Roccia F, Gallesio C. Complex Berdal A, Bloch-Zupan A. Pathognomonic oral pro-
and compound odontomas. J Craniofac Surg. file of Enamel Renal Syndrome (ERS) caused by
2012;23(3):685–8. recessive FAM20A mutations. Orphanet J Rare Dis.
Brannon RB, Fowler CB, Carpenter WM, Corio RL. 2014;9:84.
Cementoblastoma: an innocuous neoplasm? A clinico- DeLair D, Bejarano PA, Peleg M, El-Mofty SK.
pathologic study of 44 cases and review of the literature Ameloblastic carcinosarcoma of the mandible arising
with special emphasis on recurrence. Oral Surg in ameloblastic fibroma: a case report and review of the
Oral Med Oral Pathol Oral Radiol Endod. literature. Oral Surg Oral Med Oral Pathol Oral Radiol
2002;93(3):311–20. Endod. 2007;103(4):516–20.
Brown NA, Rolland D, McHugh JB, Weigelin HC, Zhao L, Detailleur V, Vansteenkiste G, Renard M, Verdonck A.
Lim MS, Elenitoba-Johnson KS, Betz BL. Activating Dental care approach in patients with osteopetrosis.
FGFR2-RAS-BRAF mutations in ameloblastoma. Clin Eur Arch Paediatr Dent. 2016;17(6):435–43.
Cancer Res. 2014;20(21):5517–26. Dietrich G, Sperling S, Hetzer G. Molar incisor hypo-
Buchner A, Vered M. Ameloblastic fibroma: a stage in the mineralisation in a group of children and adolescents
development of a hamartomatous odontoma or a true living in Dresden (Germany). Eur J Paediatr Dent.
neoplasm? Critical analysis of 162 previously reported 2003;4(3):133–7.
cases plus 10 new cases. Oral Surg Oral Med Oral Dissanayake RK, Jayasooriya PR, Siriwardena DJ,
Pathol Oral Radiol. 2013;116(5):598–606. Tilakaratne WM. Review of metastasizing (malignant)
Buchner A, Merrell PW, Carpenter WM. Relative fre- ameloblastoma (METAM): pattern of metastasis and
quency of central odontogenic tumors: a study of treatment. Oral Surg Oral Med Oral Pathol Oral Radiol
1,088 cases from Northern California and comparison Endod. 2011;111(6):734–41.
to studies from other parts of the world. J Oral Dong Q, Pan S, Sun LS, Li TJ. Orthokeratinized
Maxillofac Surg. 2006;64(9):1343–52. odontogenic cyst: a clinicopathologic study of
Buchner A, Akrish SJ, Vered M. Central dentinogenic 61 cases. Arch Pathol Lab Med. 2010;134(2):271–5.
ghost cell tumor: an update on a rare aggressive Ebert CS Jr, Dubin MG, Hart CF, Chalian AA,
odontogenic tumor. J Oral Maxillofac Surg. 2016; Shockley WW. Clear cell odontogenic carcinoma:
74(2):307–14. a comprehensive analysis of treatment strategies.
Caton JG, Armitage G, Berglundh T, Chapple ILC, Head Neck. 2005;27(6):536–42.
Jepsen S, Kornman KS, Mealey BL, Papapanou PN, El-Mofty S. Psammomatoid and trabecular juvenile ossi-
Sanz M, Tonetti MS. A new classification scheme for fying fibroma of the craniofacial skeleton: two dis-
periodontal and peri-implant diseases and conditions - tinct clinicopathologic entities. Oral Surg Oral Med
Introduction and key changes from the 1999 classifica- Oral Pathol Oral Radiol Endod. 2002;93(3):
tion. J Periodontol. 2018;89 (1 Suppl):S1-S8. https:// 296–304.
doi.org/10.1002/JPER.18-0157. El-Mofty S. Bone lesions. In: Gnepp DR, editor. Diagnos-
Chen Y, Wang JM, Li TJ. Ameloblastic fibroma: a review tic surgical pathology of the head and neck. Philadel-
of published studies with special reference to its phia: Saunders Elsevier; 2009.
nature and biological behavior. Oral Oncol. El-Naggar A, Chan JKC, Grandis JR, Takata T,
2007;43(10):960–9. Slootweg PJ, editors. WHO classification of head and
Choi SJ, Lee JW, Song JH. Dental anomaly patterns asso- neck tumours. Lyon: IARC; 2017.
ciated with tooth agenesis. Acta Odontol Scand. Endo H, Rees TD, Hallmon WW, Kuyama K, Nakadai M,
2017;75(3):161–5. Kato T, Kono Y, Yamamoto H. Disease progression from
Cobb CM, Ferguson BL, Keselyak NT, Holt LA, mucosal to mucocutaneous involvement in a patient with
MacNeill SR, Rapley JW. A TEM/SEM study of the desquamative gingivitis associated with pemphigus
microbial plaque overlying the necrotic gingival papil- vulgaris. J Periodontol. 2008;79(2):369–75.
lae of HIV-seropositive, necrotizing ulcerative peri- Eversole LR. Odontogenic fibroma, including amyloid
odontitis. J Periodontal Res. 2003;38(2):147–55. and ossifying variants. Head Neck Pathol. 2011;
Cobourne MT, Sharpe PT. Diseases of the tooth: the 5(4):335–43.
genetic and molecular basis of inherited anomalies Fish EW. Dead tracts in dentine. Proc R Soc Med.
affecting the dentition. Wiley Interdiscip Rev Dev 1928;22(2):227–36.
Biol. 2013;2(2):183–212. Fowler CB, Brannon RB, Kessler HP, Castle JT, Kahn MA.
d’Incau E, Couture C, Maureille B. Human tooth wear in Glandular odontogenic cyst: analysis of 46 cases with
the past and the present: tribological mechanisms, scor- special emphasis on microscopic criteria for diagnosis.
ing systems, dental and skeletal compensations. Arch Head Neck Pathol. 2011;5(4):364–75.
Oral Biol. 2012;57(3):214–29. Franklin CD, Pindborg JJ. The calcifying epithelial
de La Dure-Molla M, Philippe Fournier B, Berdal A. odontogenic tumor. A review and analysis of
Isolated dentinogenesis imperfecta and dentin dyspla- 113 cases. Oral Surg Oral Med Oral Pathol. 1976;
sia: revision of the classification. Eur J Hum Genet. 42(6):753–65.
2015;23(4):445–51. Gagari E, Damoulis PD. Desquamative gingivitis as
de la Dure-Molla M, Quentric M, Yamaguti PM, a manifestation of chronic mucocutaneous disease.
Acevedo AC, Mighell AJ, Vikkula M, Huckert M, J Dtsch Dermatol Ges. 2011;9(3):184–8.
Gawade PL, Hudson MM, Kaste SC, Neglia JP, Kim IK, Pae SP, Cho HY, Cho HW, Seo JH, Lee DH,
Constine LS, Robison LL, Ness KK. A systematic Park IS. Odontogenic carcinosarcoma of the mandible:
review of dental late effects in survivors of child- a case report and review. J Korean Assoc Oral
hood cancer. Pediatr Blood Cancer. 2014;61(3): Maxillofac Surg. 2015;41(3):139–44.
407–16. Klein OD, Oberoi S, Huysseune A, Hovorakova M,
Gjorup H, Haubek D, Jacobsen P, Ostergaard JR. Nance- Peterka M, Peterkova R. Developmental disorders of
Horan syndrome-The oral perspective on a rare disease. the dentition: an update. Am J Med Genet C Semin
Am J Med Genet A. 2017;173(1):88–98. Med Genet. 2013;163C(4):318–32.
Goodarzi F, Mahvi AH, Hosseini M, Nedjat S, Koutlas IG, Allen CM, Warnock GR, Manivel JC. Scle-
Nabizadeh Nodehi R, Kharazifard MJ, rosing odontogenic carcinoma: a previously unreported
Parvizishad M, Cheraghi Z. The prevalence of dental variant of a locally aggressive odontogenic neoplasm
fluorosis and exposure to fluoride in drinking water: a without apparent metastatic potential. Am J Surg
systematic review. J Dent Res Dent Clin Dent Pros- Pathol. 2008;32(11):1613–9.
pect. 2016;10(3):127–35. Kudiyirickal MG, Ivancakova R. Early enamel lesion part
Hasan S. Desquamative gingivitis – a clinical sign in mucous II. Histo-morphology and prevention. Acta Medica.
membrane pemphigoid: report of a case and review of 2008;51(3):151–6.
literature. J Pharm Bioallied Sci. 2014;6(2):122–6. Kukleva MP, Petrova SG, Kondeva VK, Nihtyanova TI.
Haubek D, Johansson A. Pathogenicity of the highly Molar incisor hypomineralisation in 7-to-14-year old
leukotoxic JP2 clone of Aggregatibacter actinomyce- children in Plovdiv, Bulgaria – an epidemiologic study.
temcomitans and its geographic dissemination and role Folia Med (Plovdiv). 2008;50(3):71–5.
in aggressive periodontitis. J Oral Microbiol. 2014;6: Larsen T, Fiehn NE. Dental biofilm infections – an update.
e23980. APMIS. 2017;125(4):376–84.
Heikinheimo K, Kurppa KJ, Elenius K. Novel targets Leao JC, Ingafou M, Khan A, Scully C, Porter S.
for the treatment of ameloblastoma. J Dent Res. Desquamative gingivitis: retrospective analysis of
2015;94(2):237–40. disease associations of a large cohort. Oral Dis.
Hertog D, Bloemena E, Aartman IH, van-der-Waal I. His- 2008;14(6):556–60.
topathology of ameloblastoma of the jaws; some Ledesma-Montes C, Gorlin RJ, Shear M, Prae Torius F,
critical observations based on a 40 years single institu- Mosqueda-Taylor A, Altini M, Unni K, Paes de
tion experience. Med Oral Patol Oral Cir Bucal. Almeida O, Carlos-Bregni R, Romero de Leon E,
2012;17(1):e76–82. Phillips V, Delgado-Azanero W, Meneses-Garcia A.
Hollis A, Arundel P, High A, Balmer R. Current concepts International collaborative study on ghost cell
in hypophosphatasia: case report and literature review. odontogenic tumours: calcifying cystic odontogenic
Int J Paediatr Dent. 2013;23(3):153–9. tumour, dentinogenic ghost cell tumour and ghost
Hosoya A, Takahama A, Nakamura H. Localization of cell odontogenic carcinoma. J Oral Pathol Med.
RELM-beta/FIZZ2 is associated with cementum for- 2008;37(5):302–8.
mation. Anat Rec (Hoboken). 2017;300(10):1865–74. Li TJ. The odontogenic keratocyst: a cyst, or a cystic
Imfeld T. Dental erosion. Definition, classification and neoplasm? J Dent Res. 2011;90(2):133–42.
links. Eur J Oral Sci. 1996;104(2 (Pt 2)):151–5. Li TJ, Kitano M, Arimura K, Sugihara K. Recurrence
Jeftha A, Holmes H. Periodontitis and cardiovascular dis- of unicystic ameloblastoma: a case report and review
ease. SADJ. 2013;68(2):60. 62–63 of the literature. Arch Pathol Lab Med. 1998;122(4):
Jones BE, Sarathy AP, Ramos MB, Foss RD. Squamous 371–4.
odontogenic tumor. Head Neck Pathol. 2011;5(1):17–9. Little JW. Syphilis: an update. Oral Surg Oral Med Oral
Juhl M. Three-dimensional replicas of pit and fissure Pathol Oral Radiol Endod. 2005;100(1):3–9.
morphology in human teeth. Scand J Dent Res. Loyola AM, Cardoso SV, de Faria PR, Servato JP, Barbosa
1983;91(2):90–5. de Paulo LF, Eisenberg AL, Dias FL, Gomes CC,
Juuri E, Balic A. The biology underlying abnormalities Gomez RS. Clear cell odontogenic carcinoma: report
of tooth number in humans. J Dent Res. of 7 new cases and systematic review of the current
2017;96(11):1248–56. knowledge. Oral Surg Oral Med Oral Pathol Oral
Kaplan I, Buchner A, Calderon S, Kaffe I. Radiological Radiol. 2015;120(4):483–96.
and clinical features of calcifying epithelial Lu Y, Mock D, Takata T, Jordan RC. Odontogenic ghost
odontogenic tumour. Dentomaxillofac Radiol. 2001; cell carcinoma: report of four new cases and review of
30(1):22–8. the literature. J Oral Pathol Med. 1999;28(7):323–9.
Kar IB, Subramanyam RV, Mishra N, Singh AK. Lubinsky M, Kantaputra PN. Syndromes with
Ameloblastic carcinoma: a clinicopathologic dilemma supernumerary teeth. Am J Med Genet
– report of two cases with total review of literature from A. 2016;170(10):2611–6.
1984 to 2012. Ann Maxillofac Surg. 2014;4(1):70–7. Luder HU. Malformations of the tooth root in humans.
Kidd EA, Fejerskov O. What constitutes dental caries? Front Physiol. 2015;6:307.
Histopathology of carious enamel and dentin related Lussi A, Schaffner M. Progression of and risk factors for
to the action of cariogenic biofilms. J Dent Res. dental erosion and wedge-shaped defects over a 6-year
2004;83:C35–8. period. Caries Res. 2000;34(2):182–7.
Mallineni SK, Panampally GK, Chen Y, Tian T. Mandib- Page RC, Schroeder HE. Pathogenesis of inflammatory
ular talon cusps: a systematic review and data analysis. periodontal disease. A summary of current work. Lab
J Clin Exp Dent. 2014;6(4):e408–13. Invest. 1976;34(3):235–49.
Martinez-Mata G, Mosqueda-Taylor A, Carlos-Bregni R, Parry DA, Holmes TD, Gamper N, El-Sayed W,
de Almeida OP, Contreras-Vidaurre E, Vargas PA, Hettiarachchi NT, Ahmed M, Cook GP, Logan CV,
Cano-Valdez AM, Dominguez-Malagon H. Johnson CA, Joss S, Peers C, Prescott K, Savic S,
Odontogenic myxoma: clinico-pathological, immuno- Inglehearn CF, Mighell AJ. A homozygous STIM1
histochemical and ultrastructural findings of a multi- mutation impairs store-operated calcium entry and
centric series. Oral Oncol. 2008;44(6):601–7. natural killer cell effector function without clinical
Moormann S, Guatelli-Steinberg D, Hunter J. Metamer- immunodeficiency. J Allergy Clin Immunol.
ism, morphogenesis, and the expression of Carabelli 2016;137(3):955–7. e958
and other dental traits in humans. Am J Phys Philipsen HP, Reichart PA. Calcifying epithelial odontogenic
Anthropol. 2013;150(3):400–8. tumour: biological profile based on 181 cases from the
Mosqueda-Taylor A, Pires FR, Aguirre-Urizar JM, Carlos- literature. Oral Oncol. 2000;36(1):17–26.
Bregni R, de la Piedra-Garza JM, Martinez-Conde R, Philipsen HP, Reichart PA, Zhang KH, Nikai H, Yu QX.
Martinez-Mata G, Carreno-Alvarez SJ, da Silveira HM, Adenomatoid odontogenic tumor: biologic profile
de Barros Dias BS, de Almeida OP. Primordial based on 499 cases. J Oral Pathol Med.
odontogenic tumour: clinicopathological analysis 1991;20(4):149–58.
of six cases of a previously undescribed entity. Philipsen HP, Reichart PA, Nikai H, Takata T, Kudo Y.
Histopathology. 2014;65(5):606–12. Peripheral ameloblastoma: biological profile based on
Muller S, Parker DC, Kapadia SB, Budnick SD, 160 cases from the literature. Oral Oncol.
Barnes EL. Ameloblastic fibrosarcoma of the jaws. 2001;37(1):17–27.
A clinicopathologic and DNA analysis of five cases Philipsen HP, Reichart PA, Ogawa I, Suei Y, Takata T. The
and review of the literature with discussion of its inflammatory paradental cyst: a critical review of
relationship to ameloblastic fibroma. Oral Surg Oral 342 cases from a literature survey, including 17 new
Med Oral Pathol Oral Radiol Endod. 1995;79 cases from the author’s files. J Oral Pathol Med.
(4):469–77. 2004;33(3):147–55.
Murphy CL, Kestler DP, Foster JS, Wang S, Macy SD, Philipsen HP, Reichart PA, Siar CH, Ng KH, Lau SH,
Kennel SJ, Carlson ER, Hudson J, Weiss DT, Zhang X, Dhanuthai K, Swasdison S, Jainkittivong A,
Solomon A. Odontogenic ameloblast-associated pro- Meer S, Jivan V, Altini M, Hazarey V, Ogawa I,
tein nature of the amyloid found in calcifying epithelial Takata T, Taylor AA, Godoy H, Delgado WA, Carlos-
odontogenic tumors and unerupted tooth follicles. Bregni R, Macias JF, Matsuzaka K, Sato D, Vargas PA,
Amyloid. 2008;15(2):89–95. Adebayo ET. An updated clinical and epidemiological
Nagi R, Sahu S, Rakesh N. Molecular and genetic aspects profile of the adenomatoid odontogenic tumour: a col-
in the etiopathogenesis of ameloblastoma: an update. laborative retrospective study. J Oral Pathol Med.
J Oral Maxillofac Pathol. 2016;20(3):497–504. 2007;36(7):383–93.
Nair PN. Apical periodontitis: a dynamic encounter Pihlstrom BL, Michalowicz BS, Johnson NW. Periodontal
between root canal infection and host response. diseases. Lancet. 2005;366(9499):1809–20.
Periodontol 2000. 2000;13:121–48. Pitts NB, Zero DT, Marsh PD, Ekstrand K, Weintraub JA,
Nair PN. Pathogenesis of apical periodontitis and the Ramos-Gomez F, Tagami J, Twetman S, Tsakos G,
causes of endodontic failures. Crit Rev Oral Biol Ismail A. Dental caries. Nat Rev Dis Prim.
Med. 2004;15(6):348–81. 2017;3(17030):30.
Nery EB, Edson RG, Lee KK, Pruthi VK, Watson J. Pogrel MA, Montes DM. Is there a role for enucleation in
Prevalence of nifedipine-induced gingival hyperplasia. the management of ameloblastoma? Int J Oral
J Periodontol. 1995;66(7):572–8. Maxillofac Surg. 2009;38(8):807–12.
Nibali L. Aggressive periodontitis: microbes and host Ponnaiyan D, Jegadeesan V. Cyclosporine A: novel con-
response, who to blame? Virulence. 2015;6(3):223–8. cepts in its role in drug-induced gingival overgrowth.
Nissanka-Jayasuriya EH, Odell EW, Phillips C. Dental Dent Res J. 2015;12(6):499–506.
stigmata of congenital syphilis: a historic review Prasad MK, Geoffroy V, Vicaire S, Jost B, Dumas M, Le
with present day relevance. Head Neck Pathol. Gras S, Switala M, Gasse B, Laugel-Haushalter V,
2016;10(3):327–31. Paschaki M, Leheup B, Droz D, Dalstein A, Loing A,
Nyvad B, Fejerskov O. Assessing the stage of caries lesion Grollemund B, Muller-Bolla M, Lopez-Cazaux S,
activity on the basis of clinical and microbiological Minoux M, Jung S, Obry F, Vogt V, Davideau JL,
examination. Community Dent Oral Epidemiol. Davit-Beal T, Kaiser AS, Moog U, Richard B,
1997;25(1):69–75. Morrier JJ, Duprez JP, Odent S, Bailleul-Forestier I,
Offenbacher S, Katz V, Fertik G, Collins J, Boyd D, Rousset MM, Merametdijan L, Toutain A, Joseph C,
Maynor G, McKaig R, Beck J. Periodontal infection Giuliano F, Dahlet JC, Courval A, El Alloussi M,
as a possible risk factor for preterm low birth weight. Laouina S, Soskin S, Guffon N, Dieux A, Doray B,
J Periodontol. 1996;67(10 Suppl):1103–13. Feierabend S, Ginglinger E, Fournier B, de la Dure
Molla M, Alembik Y, Tardieu C, Clauss F, Berdal A, Soluk Tekkesin M, Pehlivan S, Olgac V, Aksakalli N,
Stoetzel C, Maniere MC, Dollfus H, Bloch-Zupan A. Alatli C. Clinical and histopathological investigation
A targeted next-generation sequencing assay for the of odontomas: review of the literature and presen-
molecular diagnosis of genetic disorders with orodental tation of 160 cases. J Oral Maxillofac Surg.
involvement. J Med Genet. 2016;53(2):98–110. 2012;70(6):1358–61.
Ramer M, Valauri D. Multicystic lateral periodontal cyst Soviero V, Haubek D, Trindade C, Da Matta T, Poulsen S.
and botryoid odontogenic cyst. Multifactorial analysis Prevalence and distribution of demarcated opacities
of previously unreported series and review of literature. and their sequelae in permanent 1st molars and incisors
N Y State Dent J. 2005;71(4):47–51. in 7 to 13-year-old Brazilian children. Acta Odontol
Ratbi I, Falkenberg KD, Sommen M, Al-Sheqaih N, Scand. 2009;67(3):170–5.
Guaoua S, Vandeweyer G, Urquhart JE, Chandler KE, Speight PM, Takata T. New tumour entities in the 4th
Williams SG, Roberts NA, El Alloussi M, Black GC, edition of the World Health Organization Classification
Ferdinandusse S, Ramdi H, Heimler A, Fryer A, Lynch of Head and Neck tumours: odontogenic and maxillo-
SA, Cooper N, Ong KR, Smith CE, Inglehearn CF, facial bone tumours. Virchows Arch. 2017. https://doi.
Mighell AJ, Elcock C, Poulter JA, Tischkowitz M, Davies org/10.1007/s00428-017-2182-3
SJ, Sefiani A, Mironov AA, Newman WG, Waterham Spencer AJ, Do LG. Caution needed in altering the ‘opti-
HR, Van Camp G. Heimler syndrome is caused by hypo- mum’ fluoride concentration in drinking water.
morphic mutations in the peroxisome-biogenesis genes Community Dent Oral Epidemiol. 2016;44(2):101–8.
PEX1 and PEX6. Am J Hum Genet. 2015;97(4):535–45. Stanley HR, Pereira JC, Spiegel E, Broom C, Schultz M.
Ritter AV, Shugars DA, Bader JD. Root caries risk indica- The detection and prevalence of reactive and physiologic
tors: a systematic review of risk models. Community sclerotic dentin, reparative dentin and dead tracts
Dent Oral Epidemiol. 2010;38(5):383–97. beneath various types of dental lesions according to tooth
Roberts-Harry D, Sandy J. Orthodontics. Part 11: ortho- surface and age. J Oral Pathol. 1983;12(4):257–89.
dontic tooth movement. Br Dent J. 2004;196(7):391–4. Sugerman PB, Savage NW. Oral lichen planus: causes, diag-
Sarode GS, Sarode SC. Abfraction: a review. J Oral nosis and management. Aust Dent J. 2002;47(4):290–7.
Maxillofac Pathol. 2013;17(2):222–7. Sun G, Chen X, Tang E, Li Z, Li J. Juvenile ossifying
Sekerci AE, Nazlim S, Etoz M, Deniz K, Yasa Y. fibroma of the maxilla. Int J Oral Maxillofac Surg.
Odontogenic tumors: a collaborative study of 2007;36(1):82–5.
218 cases diagnosed over 12 years and comprehensive Suresh L, Neiders ME. Definitive and differential
review of the literature. Med Oral Patol Oral Cir Bucal. diagnosis of desquamative gingivitis through direct
2015;20(1):e34–44. immunofluorescence studies. J Periodontol.
Selwitz RH, Ismail AI, Pitts NB. Dental caries. Lancet. 2012;83(10):1270–8.
2007;369(9555):51–9. Thomas IH, DiMeglio LA. Advances in the classification
Serna C, Vicente A, Finke C, Ortiz AJ. Drugs related to the and treatment of osteogenesis imperfecta. Curr
etiology of molar incisor hypomineralization: a system- Osteoporos Rep. 2016;14(1):1–9.
atic review. J Am Dent Assoc. 2016;147(2):120–30. Thomas G, Pandey M, Mathew A, Abraham EK, Francis A,
Seymour RA, Thomason JM, Ellis JS. The pathogenesis of Somanathan T, Iype M, Sebastian P, Nair MK. Primary
drug-induced gingival overgrowth. J Clin Periodontol. intraosseous carcinoma of the jaw: pooled analysis of
1996;23(3 Pt 1):165–75. world literature and report of two new cases. Int J Oral
Seymour GJ, Ford PJ, Cullinan MP, Leishman S, Maxillofac Surg. 2001;30(4):349–55.
Yamazaki K. Relationship between periodontal infec- Trackman PC, Kantarci A. Molecular and clinical aspects
tions and systemic disease. Clin Microbiol Infect. of drug-induced gingival overgrowth. J Dent Res.
2007;13(Suppl 4):3–10. 2015;94(4):540–6.
Sgan-Cohen HD, Evans RW, Whelton H, Villena RS, Trzeciak WH, Koczorowski R. Molecular basis of hypo-
MacDougall M, Williams DM, Steering I-G, Task G. hidrotic ectodermal dysplasia: an update. J Appl Genet.
IADR global oral health inequalities research agenda 2016;57(1):51–61.
(IADR-GOHIRA(R)): a call to action. J Dent Res. Twigg SR, Wilkie AO. New insights into craniofacial
2013;92(3):209–11. malformations. Hum Mol Genet. 2015;24(R1):R50–9.
Shear M, Speight P. Odontogenic keratocyst. In: Cysts of U.S. Department of Health and Human Services Federal
the oral and maxillofacial regions. Oxford: Blackwell Panel on Community Water Fluoridation. U.S. public
Munksgaard; 2007. p. 6–58. health service recommendation for fluoride concentra-
Silva MJ, Scurrah KJ, Craig JM, Manton DJ, Kilpatrick N. tion in drinking water for the prevention of dental
Etiology of molar incisor hypomineralization – a sys- caries. Public Health Rep. 2015;130(4):318–31.
tematic review. Community Dent Oral Epidemiol. Wang J, Feng JQ. Signaling pathways critical for tooth root
2016;44(4):342–53. formation. J Dent Res. 2017;96(11):1221–8.
Smith CEL, Poulter JA, Antanaviciute A, Kirkham J, Wetselaar P, Lobbezoo F. The tooth wear evaluation sys-
Brookes SJ, Inglehearn CF, Mighell AJ. Amelogenesis tem: a modular clinical guideline for the diagnosis and
imperfecta; Genes, proteins, and pathways. Front management planning of worn dentitions. J Oral
Physiol. 2017;8:435. Rehabil. 2016;43(1):69–80.
Wiebe CB, Putnins EE. The periodontal disease classifica- Shirota T, Kikkawa Y, Yamada A, Kamijo R, Park SB,
tion system of the American Academy of Perio- Nakamura M, Maki K, Inoue I. Comprehensive genetic
dontology – an update. J Can Dent Assoc. 2000; exploration of selective tooth agenesis of mandibular
66(11):594–7. incisors by exome sequencing. Hum Genome Var.
Witkop CJ Jr. Amelogenesis imperfecta, dentinogenesis 2017;4:17005.
imperfecta and dentin dysplasia revisited: problems in Yoon HJ, Hong SP, Lee JI, Lee SS, Hong SD. Ameloblastic
classification. J Oral Pathol. 1988;17(9–10):547–53. carcinoma: an analysis of 6 cases with review of the
Wolf HF, Rateitschak KH, Rateitschak EM, Hassell TM. literature. Oral Surg Oral Med Oral Pathol Oral Radiol
Color atlas of dental medicine: periodontology. Endod. 2009;108(6):904–13.
New York: Thieme; 2004. Zhu J, Wang X, Fang Y, Von den Hoff JW, Meng L. An
Yamaguchi T, Hosomichi K, Yano K, Kim YI, Nakaoka H, update on the diagnosis and treatment of dens
Kimura R, Otsuka H, Nonaka N, Haga S, Takahashi M, invaginatus. Aust Dent J. 2017;62:261.
Non-odontogenic Bone Pathology
Hedley Coleman, Jos Hille, Willie van Heerden, Sonja Boy, and
Annabelle Mahar
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 556
Primary Benign Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 558
Chondroma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 558
Osteochondroma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 558
Synovial Chondromatosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 559
Osteoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 561
Osteoid Osteoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562
Osteoblastoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 564
Desmoplastic Fibroma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568
H. Coleman (*)
Department of Tissue Pathology and Diagnostic Oncology,
Pathology West, Westmead Hospital, ICPMR, Sydney,
NSW, Australia
e-mail: hedley.coleman@health.nsw.gov.au
J. Hille
Department Oral and Maxillofacial Pathology, University
of the Western Cape/National Health Laboratory Service,
Cape Town, South Africa
Oral/Head and Neck Pathology, University of the Western
Cape, Cape Town, South Africa
e-mail: oral.path@iafrica.com
W. van Heerden
Department of Oral Pathology & Oral Biology, University
of Pretoria, Pretoria, South Africa
e-mail: willie.vanheerden@up.ac.za
S. Boy
Department of Oral Pathology, Sefako Makgatho Health
Sciences University, Pretoria, South Africa
e-mail: Sonja.Boy@smu.ac.za
A. Mahar
Department of Tissue Pathology and Diagnostic, Royal
Prince Alfred Hospital, Camperdown, NSW, Australia
e-mail: annabelle.mahar@sswahs.nsw.gov.au

https://doi.org/10.1007/978-3-319-72303-7_23
556 H. Coleman et al.
Chondromyxoid Fibroma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570

Schwannoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571
Neurofibroma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574
Hemangioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575
Langerhans Cell Histiocytosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 578
Primary Malignant Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 580
Chondrosarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 580
Osteosarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 582
Ewing Sarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584
Lymphoma of the Jaw Bone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 587
Multiple Myeloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 590
Plasmacytoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 592
Secondary Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 596
Metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 596
Cysts/Cyst-Like Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 596
Nasopalatine Duct Cyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 596
Aneurysmal Bone Cyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599
Simple Bone Cyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601
Giant Cell Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603
Cherubism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603
Central Giant Cell Granuloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605
Hyperparathyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608
Paget’s Disease of Bone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 610
Fibro-osseous Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 612
Fibrous Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 612
Osseous Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620
Abstract Keywords
This chapter describes the more common Bone pathology · Non-odontogenic
lesions encountered in bones of the maxillofa- pathology · Benign bone lesions · Malignant
cial skeleton, which are not derived from the bone tumors · Fibro-osseous lesions ·
odontogenic or tooth-forming apparatus. The Metastatic bone disease · Non-odontogenic
entities include both non-neoplastic and neo- cysts · Giant cell lesions · Osteosarcoma ·
plastic conditions with some conditions being Bone metastases · Nasopalatine duct cyst ·
unique to these bones. Entities that involve the Incisive canal cyst · Aneurysmal bone cyst ·
maxillofacial bones secondarily by direct exten- Simple bone cyst · Solitary bone cyst ·
sion from adjacent structures are not discussed. Cemento-osseous dysplasia · Fibrous
Management of patients with bone tumors dysplasia · Paget’s disease of bone
and tumor-like lesions requires a team approach.
Good communication between clinician, radiol-
ogist, surgeon, and pathologist is imperative for Introduction
accurate interpretation and diagnosis of these
neoplasms. Pathologists who attempt to make a This chapter describes non-odontogenic bone
diagnosis of bony lesions without the clinical and pathology encountered in the maxillofacial skele-
radiographic information are at a distinct disad- ton that are not derived from the odontogenic or
vantage, and this is to be strongly discouraged. tooth-forming apparatus (Table 1). The entities
Non-odontogenic Bone Pathology 557
Table 1 Non-odontogenic bone lesions arising in the maxillofacial region

Category Tissue Benign Malignant
Primary Cartilage Chondroma Chondrosarcoma
neoplasms Osteochondroma
Synovial chondromatosis
Bone Osteoma Osteosarcoma
Osteoid osteoma
Osteoblastoma
Fibrous Desmoplastic fibroma
Chondromyxoid fibroma
Neural Schwannoma
Neurofibroma
Vascular Malformations/
hemangioma
Hematolymphoid Langerhans cell Lymphomas
histiocytosis Plasmacytoma
Multiple myeloma
Neuroectodermal Ewing’s sarcoma
Secondary Epithelial Breast, prostate, kidney, testis,
neoplasms colon, liver, lung
Cysts Epithelial – developmental Nasopalatine duct cyst
Cyst-like Bone – primary/secondary Aneurysmal bone cyst
lesions Bone – developmental Simple/solitary/traumatic
bone cyst
Giant cell Osteoclasts Central giant cell
lesions granuloma
Cherubism
Hyperparathyroidism
Fibro-osseous Bone, fibrous tissue, and/or Paget’s disease of bone
lesions cementum Fibrous dysplasia
Osseous dysplasia
include both non-neoplastic and neoplastic condi- those that occur in the remainder of the skeleton.
tions that present within the maxillofacial bones, Giant cell granulomas are also unique to the jaws,
with some conditions being unique to these bones demonstrating similar features to the solid aneurys-
and that are not encountered elsewhere in the mal bone cysts.
appendicular or axial skeleton. Neoplastic conditions discussed include pri-
Non-neoplastic conditions that are covered mary benign and malignant neoplasms as well as
include cysts and cyst-like lesions, the so-called secondary, metastatic neoplasms. Primary bone
giant cell lesions of the jaws as well as some fibro- neoplasms, in general, are among the least com-
osseous lesions. The group of fibro-osseous lesions mon neoplasms in contrast to metastatic disease of
would also encompass lesions deemed to be of the bones and hematopoietic neoplasms, which
odontogenic origin and which for completeness, are relatively more common. Benign neoplasms
are also discussed in the chapter on ▶ “Odontogenic are more common than their malignant counter-
Pathology.” Non-odontogenic cysts and pseudo- parts (3:1). Bone tumors involving the head
cysts occur within the jaws and maxillofacial skele- and neck primarily, are even less frequently
ton, with the nasopalatine duct cyst being unique to encountered.
the anterior maxilla. Solitary bone cysts and aneu- With molecular advances in diagnostics in var-
rysmal bone cysts demonstrate similar features to ious fields of pathology, especially lymphomas
and soft tissue neoplasms, extrapolation of Patient Management

targeted management strategies has been devel- Prior to making a definitive diagnosis, correla-
oped, and this progress is most likely to con- tion with the radiographic features is mandatory.
tinue in the years ahead with pathologists being Complete surgical curettage is the recommended
called upon to assist in the identification of the treatment with or without bone grafting (Unni
various genetic episodes that will improve the et al. 2005; Unni and Inwards 2010). Recurrence
management and outcomes for the patients is uncommon and the prognosis is good. Since
involved. Where current knowledge exists in chondromas are exceedingly rare in the
this regard, this information is highlighted craniofacial skeleton, the presence of any carti-
within the chapter. laginous lesion should raise the suspicion of
malignancy, such as a chondrosarcoma or more
commonly a chondroblastic osteosarcoma (Unni
Primary Benign Neoplasms et al. 2005; Inwards 2007; Unni and Inwards
2010).
Chondroma
Epidemiology Osteochondroma
Chondroma is a benign neoplasm composed of
mature hyaline cartilage. Most are located cen- Epidemiology
trally within the medullary cavity of the bone Osteochondroma is a benign bony outgrowth of
and are called enchondromas. A large proportion the cortex composed of cortical and medullary
of these neoplasms are located in the small bones bone with a cartilaginous cap (Fig. 1) (Unni
of the hands and feet, and are extremely rare in the et al. 2005; Unni and Inwards 2010). It is a com-
head and neck region with only occasional cases mon lesion of the axial skeleton; however, it is
being described in the condylar region and ante- rarely associated with the maxillofacial bones and
rior maxilla (Unni et al. 2005; Inwards 2007; Unni mandibular condyle (Warner et al. 2000; Unni
and Inwards 2010). et al. 2005; Franklin 2006; Unni and Inwards
2010; Roychoudhury et al. 2011). Most patients
Etiology would present before 20 years of age with a male
The etiology is not known, although somatic predominance; however, in the maxillofacial
mutations in the IDH1 gene (isocitrate dehydro- bones, the age at presentation is later (Warner
genase 1) have been reported (Amary et al. 2011). et al. 2000; Unni and Inwards 2010;
Roychoudhury et al. 2011).
Clinical-Pathologic Features
These tumors are generally slow growing and usu- Etiology
ally asymptomatic, but symptoms may be noted The etiology is uncertain, but trauma may be an
following pathologic fracture. There is no gender etiological factor (Roychoudhury et al. 2011).
predilection. Multiple lesions may occur in Ollier’s Osteochondroma may represent a misplaced
disease and Maffucci’s syndrome (Unni et al. 2005; epiphyseal plate on the bone surface (Unni et al.
Unni and Inwards 2010). They usually present as a 2005); however, the demonstration of clonal chro-
radiolucency with central areas of opacification. mosomal abnormalities of the EXT1 and EXT2
The endosteal aspect of the bony cortex maybe genes provides some evidence that it may repre-
scalloped (Unni et al. 2005; Unni and Inwards sent a neoplastic process (Unni et al. 2005;
2010). The tumor is composed of mature hyaline Roychoudhury et al. 2011).
cartilage with a well-defined, lobulated margin.
There is no evidence of cytologic atypia or hyper- Clinical-Pathologic Features
cellularity (Unni et al. 2005; Unni and Inwards Grossly lesions are usually pedunculated and
2010). mushroom-like with a thin cartilaginous surface
Fig. 1 Osteochondroma of
the right condyle. Axial soft
tissue CT reconstruction
(a), axial bone window of
the right condyle (b), and
lateral, bone window,
sagittal reconstruction of
the right condyle (c). An
exostosis of cortical and
medullary bone projects
anteriorly and laterally from
the right condyle (white
arrows in b and c).
Overlying the bony
component, there is a
nonossified cartilage cap
(curvilinear white dotted
line in a) (Images courtesy
of Clinical Associate
Professor Andy Whyte,
Perth Radiological Clinic,
that measures less than 2 cm. Radiographically, it Patient Management

has a radiopaque appearance, while the cortex If the lesion causes symptoms and disability,
and medullary cavity of the lesion merge with becomes a cosmetic concern, or shows an increase
the underlying bone (Fig. 2) (Warner et al. 2000). in size, then complete surgical excision at the base
Microscopically, the lesion consists of central of the lesion, flush with the cortex, is necessary to
cancellous bone with outer compact lamellar prevent recurrence (Warner et al. 2000; Unni et al.
bone that is continuous with the cap of hyaline 2005; Unni and Inwards 2010). Malignant trans-
cartilage. The bony trabeculae are separated by formation of an osteochondroma is very rare
fatty marrow with possible associated hemato- (Unni et al. 2005; Unni and Inwards 2010).
poietic elements. The cartilage resembles the
growth plate and demonstrates columns of
chondrocytes that undergo ossification with mat- Synovial Chondromatosis
uration into cancellous bone (Fig. 3) (Warner
et al. 2000; Unni et al. 2005; Unni and Inwards Epidemiology
2010). Synovial chondromatosis, or chondrometaplasia,
Symptoms would depend upon location and has always been considered to be a benign, non-
size of the lesion. Pain is rarely attributed to the neoplastic monoarticular process (Warner et al.
lesion itself but is due to impingement upon other 2000; Unni et al. 2005; Franklin 2006; Unni and
surrounding structures (Unni and Inwards 2010). Inwards 2010). It has however been suggested
Involvement of the mandibular condyle would that it may be a benign neoplasm that presents as
result in enlargement of the condyle with associ- multiple hyaline cartilage nodules typically within
ated facial asymmetry, deviation of the chin on the sub-synovial tissues (Sciot and Bridge 2013).
opening, as well as limited mouth opening It is an uncommon condition that usually affects
(Roychoudhury et al. 2011). adults, with males being affected more frequently
Fig. 2 Osteochondroma of
the right mandible. Cone
Beam CT axial (a) and
coronal (b) reconstructions.
A pedunculated exostosis
consisting of cortical and
medullary bone protrudes
lingually from the junction
of the crestal and lingual
margin of the 48 region
(Images courtesy of Clinical
Associate Professor Andy
Whyte, Perth Radiological
Clinic, Perth WA, Australia)
temporomandibular joint is infrequently involved

(Warner et al. 2000; Franklin 2006).
Etiology
In the primary form of the disease, the etiology is
not known; however, a response to repetitive,
low-grade trauma has been proposed. Secondary
synovial chondromatosis is more common and
arises as a result of either an inflammatory or
non-inflammatory arthropathy.
Generally presenting symptoms would include
Fig. 3 Osteochondroma. The cartilage resembles the pain and swelling with locking of the joint or
growth plate and demonstrates columns of chondrocytes
that undergo ossification with maturation into cancellous
stiffness; however, the lesion maybe painless
bone (Image courtesy of Dr Chris Angel, Australian Clin- (Unni et al. 2005; Unni and Inwards 2010).
ical Labs, Melbourne VIC, Australia) There may be erosion of the adjacent bone (Unni
et al. 2005; Unni and Inwards 2010).
than females, except for when the temporoman- Plain radiographs are of little assistance
dibular joint is involved, when it occurs more unless there is calcification or ossification. Addi-
commonly in females than males (Warner et al. tional imaging including MRI demonstrates
2000). The most frequent sites for this condition synovial chondroid nodules (Fig. 4) (Unni et al.
are the knee, followed by the hip. The 2005).
Microscopically, the lesion is composed of features of articular hyaline cartilage without the
variably sized nodules of hyaline cartilage irregular arrangement and cytologic atypia (Unni
exhibiting clustering of chondrocytes within the et al. 2005; Unni and Inwards 2010).
sub-synovial tissue (Fig. 5). The chondrocytes are Synovial chondrosarcoma is a rare com-
mildly atypical with occasional binucleate forms plication of synovial chondromatosis (Ichikawa
(Fig. 6). Calcification of the nodules may occur et al. 1998; Unni et al. 2005; Unni and Inwards
with ossification (Warner et al. 2000; Unni et al. 2010; Coleman et al. 2013). Histologic differenti-
2005; Unni and Inwards 2010). The differential ation from synovial chondromatosis is extremely
diagnosis includes osteocartilaginous loose bod- difficult. The histologic features that suggest
ies that occur in the joint secondary to degenera- malignancy include variable architecture,
tive joint disease. The fragments are single or increased cellularity, spindling of cells with prom-
fewer than the chondroid nodules observed in inent nuclear atypia, mitoses, myxoid matrix, and
synovial chondromatosis, while the cartilage has necrosis (Ichikawa et al. 1998; Unni and Inwards
2010; Coleman et al. 2013).
Patient Management
Management of synovial chondromatosis is by
local excision with associated synovectomy (War-
ner et al. 2000). Recurrences commonly occur,
and this may predispose the patient to degenera-
tive joint disease (Unni and Inwards 2010).
Malignant transformation is very rare with only
three reported cases involving the temporoman-
dibular joint (Ichikawa et al. 1998; Coleman et al.
2013).
Osteoma
Epidemiology
Fig. 4 Synovial chondromatosis. Axial MRI view dem- Osteoma is a benign neoplasm that is composed of
onstrating the lobulated chondroid lesion surrounding the
mature compact or cancellous bone. Most involve
left mandibular condylar head (arrow)
Fig. 5 Synovial
chondromatosis.
Low-power magnification
demonstrating multiple
nodules of hyaline cartilage
surrounding the condylar
neck with adjacent parotid
gland (Hematoxylin and
eosin stain)
Fig. 6 Synovial
chondromatosis. High-
power magnification of
hyaline cartilage nodules
containing clusters of
chondrocytes with enlarged
hyperchromatic nuclei
stain)
the craniofacial bones (Nielsen and Rosenberg adenomatous polyposis coli gene (Lee et al.
2007; Larrea-Oyarbide et al. 2008; Unni and 2009).
Inwards 2010) with a male predominance and Microscopically, osteomas are composed of
peak incidence in the third to fifth decades vital compact lamellar bone (compact osteoma)
(Larrea-Oyarbide et al. 2008). Osteomas may pre- (Fig. 8), trabecular bone (cancellous/spongy oste-
sent either centrally or peripherally involving the oma) (Fig. 9), or combination thereof (Nielsen
surface of the bone. The mandible is affected more and Rosenberg 2007). Sino-orbital osteomas
commonly than the maxilla, and the condylar may contain osteoblastoma-like areas; however
region is a common site. Central osteomas may this is not associated with a more aggressive clin-
also involve the sino-orbital region, specifically ical behavior (Larrea-Oyarbide et al. 2008).
the nasal cavity, paranasal sinuses particularly the
frontal sinuses, and orbit (Nielsen and Rosenberg Patient Management
2007; Larrea-Oyarbide et al. 2008; McHugh et al. Definitive treatment of osteoma includes surgical
2009). excision. Recurrence is rare, and there is no evi-
dence of malignant transformation.
Etiology
The etiology of osteoma is unknown.
Osteoid Osteoma
Peripheral or surface lesions generally present as Epidemiology
painless swellings. Central lesions on the other Osteoid osteoma is a benign bone-forming neo-
hand are often asymptomatic. Sino-orbital oste- plasm that is characterized by limited growth
omas may present with pain including headache potential and is usually less than 1–2 cm in
or visual disturbances (Nielsen and Rosenberg greatest dimension. It predominantly affects chil-
2007; McHugh et al. 2009). Radiographically dren and young adults and has a peak incidence in
osteomas present as well-defined radiopaque the second decade. Males are affected more com-
lesions usually measuring less than 2 cm in diam- monly than females (Unni et al. 2005; Unni and
eter (Fig. 7). Inwards 2010).
The presence of multiple osteomas raises the
possibility of Gardner’s syndrome (familial ade- Etiology
nomatous polyposis). This is a manifestation in It has been proposed that this condition is a benign
the maxillofacial skeleton of an autosomal domi- osteoblastic neoplasm arising in the jaws and that
nant condition characterized by a mutation of the both osteoid osteoma and osteoblastoma should
Fig. 7 Osteoma involving

the right ramus presenting
as a well-defined
radiopaque lesion (Image
Camile Farah, Queensland
Oral Medicine & Pathology,
Fig. 8 Osteoma.
Low-power
photomicrograph of
osteoma showing vital
compact lamellar bone
stain) (Image courtesy of
UWA Dental School,
Australia)
Fig. 9 Peripheral osteoma.

Low-power
photomicrograph showing
trabecular bone (cancellous/
spongy osteoma). Surface
epithelium is to the left of
the image (Hematoxylin
and eosin stain) (Image
WA, Australia)
be considered as a single entity, namely, an 2014). Another possible therapeutic option

osteoblastoma (Jones et al. 2006). includes medical management with long-term
nonsteroidal anti-inflammatory drugs (Unni
Clinical-Pathologic Features et al. 2005).
Patients with osteoid osteoma typically present
with pain, which is frequently worse at night
and which is relieved by aspirin or other non- Osteoblastoma
steroidal anti-inflammatory drugs. Localized
swelling or tenderness may be associated with Epidemiology
the lesion. The long bones, particularly the Osteoblastoma is a rare benign bone-forming
femur and tibia, are the most commonly tumor usually greater than 2 cm in diameter and
involved sites. Involvement of the maxillofacial accounts for less than 1% of primary bone tumors
bones is very uncommon, with the mandible with approximately 10–15% of lesions arising in
being affected more frequently than the maxilla the craniofacial skeleton (Nielsen and Rosenberg
(Unni et al. 2005; Nielsen and Rosenberg 2007; 2007). It most frequently affects the mandible of
Jalil and Hin-Lau 2009; Unni and Inwards 2010; young adults, occurring in the second and third
Stewart et al. 2014). decades with a male predominance (Unni et al.
Radiographically, lesions may involve the cor- 2005; Nielsen and Rosenberg 2007; Unni and
tex, medulla, or bone surface. They usually pre- Inwards 2010).
sent as a small, well-defined cortical radiolucency
less than 1 cm in size with a central nidus which Etiology
may be calcified (Fig. 10) (Unni et al. 2005; Unni The etiology of osteoblastoma is unknown.
and Inwards 2010; Stewart et al. 2014). Surround-
ing sclerosis is usually prominent. There may be Clinical-Pathologic Features
associated periostitis. MRI scans show reactive Patients frequently present with a localized swell-
changes in the marrow and soft tissues. Bone ing that is painful and which may mimic toothache
scans are almost always positive (Unni et al. (Unni et al. 2005; Nielsen and Rosenberg 2007;
2005; Unni and Inwards 2010). Unni and Inwards 2010; Stewart et al. 2014),
Grossly the nidus is usually red-tan and gritty although the lesion maybe asymptomatic. Radio-
measuring less than 1 cm (Unni et al. 2005; Unni graphically osteoblastomas may occur in the med-
and Inwards 2010). The surrounding bone is ullary cavity or on the surface of the bone and
densely sclerotic. Microscopically, the nidus is present as a circumscribed mixed radiopaque
an interlacing network of bony trabeculae of radiolucent lesion that may be associated with
woven bone and osteoid. Osteoblastic rimming bony expansion with a well-defined sclerotic mar-
of the osteoid trabeculae is observed. Sclerotic gin (Fig. 12) (Unni et al. 2005; Nielsen and
cortical or medullary bone usually surrounds the Rosenberg 2007; Unni and Inwards 2010; Stewart
nidus (Fig. 11). The bone matrix is surrounded by et al. 2014).
vascularized fibrovascular connective tissue Grossly the lesion is greater than 2 cm and it
(Unni et al. 2005; Unni and Inwards 2010; Stewart exhibits a dark-red appearance (Unni et al. 2005;
et al. 2014). Nielsen and Rosenberg 2007; Unni and Inwards
2010). Microscopically it is composed of irregu-
Patient Management larly arranged trabeculae of osteoid and woven
Treatment is by complete surgical resection or bone which is rimmed by plump osteoblasts with
ablation of the nidus. This may be carried out by scattered osteoclasts (Figs. 13 and 14). The inter-
block excision of the nidus and some of the vening stroma is cellular containing prominent
surrounding bone or radiofrequency ablation vascular spaces with associated extravasated
(Unni et al. 2005; Nielsen and Rosenberg blood (Fig. 15) (Capodiferro et al. 2005; Unni
2007; Unni and Inwards 2010; Stewart et al. et al. 2005; Jones et al. 2006; Rawal et al. 2006;
Fig. 10 Osteoid osteoma of the left glenoid fossa and hyperintense marrow and soft-tissue edema is present
articular eminence; presentation with pain and trismus in within the nidus of osteoid osteoma, adjacent sclerotic
a young adult patient. Sagittal bone window CT recon- bone, the condyle, joint and lateral pterygoid muscle
struction (a), coronal bone window reconstruction (b), fat (orange dashed outline in c). Following gadolinium (con-
saturation T2 sagittal MRI of the left TMJ (c), and post trast), the nidus and its lucent margin, joint, surrounding
gadolinium, fat saturation T1 coronal MRI (d). There is a soft tissues and condylar marrow show diffuse enhance-
round sclerotic nidus representing an osteoid osteoma with ment (orange dotted oval in d). Faint enhancement is
a lucent margin measuring 10 mm in diameter in the roof of present in marrow surrounding the nidus in the glenoid
the glenoid fossa (orange arrows). There is diffuse sclerosis fossa with subtle meningeal thickening in the overlying left
of the articular eminence, root of the zygoma, remainder of middle cranial fossa (white arrows in d) (Images courtesy
the glenoid fossa, and to a lesser extent the condyle (white of Clinical Associate Professor Andy Whyte, Perth Radio-
dotted oval in a, white dotted square in b). Extensive, logical Clinic, Perth WA, Australia)
Fig. 11 Osteoid osteoma.

Sclerotic nidus with thick
bony trabeculae that have
prominent cement lines
resulting in a mosaic or
pagetoid appearance
stain)
Fig. 12 Osteoblastoma of the right glenoid fossa super- sequence. The condylar marrow edema has resolved; the
imposed on internal derangement, remodeling and early soft-tissue edema posterior to the condyle (white dotted
arthropathy of the right TMJ in a 17-year-old female. Initial arrows in b) is unchanged. The external auditory canal
fat saturation T2 sagittal of the right TMJ demonstrates an (eac) is indicated. Sagittal (c) and coronal (d) CT bone
attenuated, anteriorly displaced disc (Disc) and marrow window reconstructions demonstrate the large, sclerotic
edema in the right condylar head and neck (white dotted nidus (orange arrows), an irregular thin relatively lucent
oval in a) and retro-condylar soft-tissue edema (white margin and marked adjacent sclerosis and thickening of the
dotted arrows). There is a subtle band of edema in the temporal bone. There is joint space narrowing, articular
roof of the glenoid fossa (orange dotted arrow in a). Four- surface flattening, and subarticular sclerosis in the TMJ
teen months later, there is now a 16 mm, edematous round (black arrows in c) due to remodeling and early degenera-
nidus in the expanded postero-superior aspect of the tive arthropathy (Images courtesy of Clinical Associate
glenoid fossa demarcated by more marked marginal Professor Andy Whyte, Perth Radiological Clinic, Perth
edema (orange arrows in b) on a similar fat saturation T2 WA, Australia)
Nielsen and Rosenberg 2007; Unni and Inwards (Nielsen and Rosenberg 2007; Unni and Inwards
2010; Stewart et al. 2014). Occasionally the oste- 2010).
oblasts have an “epithelioid” appearance with
interspersed immature bone, and these neoplasms Patient Management
have been termed epithelioid or aggressive These tumors are treated by surgical excision
osteoblastomas (Unni et al. 2005; Nielsen and (Capodiferro et al. 2005; Jones et al. 2006; Rawal
Rosenberg 2007; Unni and Inwards 2010). The et al. 2006). Curettage alone may result in incom-
lack of atypical mitoses and a permeative growth plete removal with ensuing recurrences in approx-
pattern distinguishes it from an osteosarcoma imately 20% of cases. Malignant transformation is
Fig. 13 Osteoblastoma.
Low-power
photomicrograph
demonstrating a well-
circumscribed,
encapsulated tumor. Central
nidus with vascular fibrous
tissue (Hematoxylin and
eosin stain)
High-power
photomicrograph of tumor
comprising trabeculae of
osteoid with osteoblastic
rimming by plump
osteoblasts (Hematoxylin
and eosin stain)
High-power
photomicrograph of tumor
nidus exhibiting vascular
fibrous connective tissue
with interspersed bony
trabeculae and surrounding
osteoclasts (Hematoxylin
and eosin stain)
very rare (Unni and Inwards 2010; Stewart et al. Radiographically, the features of desmoplastic
2014). The tumor must be differentiated from a fibroma are generally non-specific osteolytic
cementoblastoma that is a neoplasm derived from changes consisting of well- or ill-demarcated
cementoblasts and that is fused to the roots of the uni-/multilocular radiolucencies with varying
involved tooth resulting in root resorption degrees of marginal sclerosis (Fig. 16). Cortical
(Slootweg 1992; Rawal et al. 2006). expansion and thinning are often observed, with
aggressive tumors producing cortical erosion
and perforation (Said-Al-Naief et al. 2006;
Desmoplastic Fibroma Nedopil et al. 2013; Woods et al. 2015)
(Fig. 17). Hence, desmoplastic fibroma can often
Epidemiology resemble other common as well as unusual tumors
Desmoplastic fibroma (fibromatosis of bone, or pathosis of the jaws including ameloblastoma,
extra-abdominal desmoid tumor of bone) mainly odontogenic myxoma, aneurysmal bone cyst,
affects the maxillofacial bones and the metaphysis chondromyxoid fibroma, central hemangioma,
of long bones. Of the jaw bones, the mandible is and eosinophilic granuloma (Hopkins et al.
the most commonly affected (86%) with over 1996). Tumors with rapid expansion may occa-
150 cases reported; the maxilla is less frequently sionally induce a new bone-forming periosteal
(14%) involved. The majority of the jaw tumors reaction mimicking the “sunburst” appearance of
are located posteriorly (Said-Al-Naief et al. 2006; an osteosarcoma (Kang et al. 2014). CT (Fig. 17)
Woods et al. 2015), with a slight female predilec- and MRI are the preferred imaging techniques for
tion (56%) observed. Although a wide age distri- the diagnosis and assessment of intraosseous
bution has been reported, it mainly occurs in the tumor extension and cortex involvement.
first three decades of life. Histologically, desmoplastic fibromas are low to
moderately cellular spindle-cell tumors composed
Etiology of fibroblasts/myofibroblasts in an abundant col-
Desmoplastic fibroma is a rare, locally aggres- lagenous stroma (Fig. 18). The elongated, uniform
sive, densely fibrous tumor of unknown etiol- tumor cells are typically organized in fascicles or
ogy and represents less than 1% of all bone bundles that can be long or short, and usually some
tumors (Bohm et al. 1996). It is considered to swirling is noted (Fig. 19). Noticeable pleomor-
represent the osseous counterpart of the soft phism is generally lacking and the mitotic activity
tissue aggressive fibromatosis (Woods et al.
2015).
Clinically, these tumors usually grow relatively
slowly as either a painless or painful swelling,
often with buccal expansion, mandibular canal
involvement, mobility, and/or displacement of
teeth within the affected jaw with malocclusion.
Rapid growth (6%), trismus, and odontogenic
infection-like symptoms are also described.
Other presenting symptoms include temporoman-
dibular disorders, dental root resorption and
delayed tooth eruption, spontaneous bleeding,
paresthesia, and pathologic fracture. Maxillary
Fig. 16 Desmoplastic fibroma. Cropped panoramic radio-
lesions can result in proptosis, palatal swelling,
graph demonstrating a large radiolucent, expansile lesion
nasal obstruction, and sinusitis (Woods et al. occupying the greater part of the posterior mandible and
2015). ramus (arrows)
Fig. 19 Desmoplastic fibroma. Medium power demon-

Fig. 17 Desmoplastic fibroma. Coronal CT scan of the strating the relative sparse population of elongated fibro-
lesion in the right ramus (Fig. 16) showing the apparent blasts/myofibroblasts in an abundant collagenous stroma
multilocularity with cortical expansion, thinning, and (Hematoxylin and eosin stain)
resorption
Fig. 18 Desmoplastic fibroma. Low-power microscopy Fig. 20 Desmoplastic fibroma. Typical small blood ves-
demonstrating the low cellularity in a densely collagenous sels with periadventitial space are located in the tumor
stroma (Hematoxylin and eosin stain) stroma (Hematoxylin and eosin stain)
is sparse. Typical small blood vessels with peri- The MIB-1 (Ki67) index is usually very low (Said-
adventitial space are located in the stroma (Fig. 20). Al-Naief et al. 2006; Woods et al. 2015).
There is no capsule and the microscopic borders are
usually ill-defined. In particularly aggressive cases, Patient Management
the proliferations infiltrate the cortical bone and can Regarding treatment, there is some controversy
invade surrounding soft tissues (Ferri et al. 2013). over the surgical management of desmoplastic
It is important to distinguish highly cellular fibroma. However segmental, en bloc, or wide
variants from fibrosarcoma since the latter has a surgical excision with thorough curettage of the
high metastatic potential. The tumor cells are surrounding bone is the preferred treatment as
immunoreactive to anti-vimentin and specifically these tumors are destructive and have a high pro-
to anti-smooth muscle actin; they are non-reactive pensity for recurrence if removed with close mar-
for S-100 and muscle-specific actin. Immunoreac- gins. Patients with positive or inadequate surgical
tivity to β-catenin is variable and thus not specific. margins are managed with adjuvant radiation or
chemotherapy; however, such patients are in the Fomete et al. (2014) describe a very large man-
minority (Said-Al-Naief et al. 2006). dibular tumor protruding out of the mouth causing
deranged occlusion and an inability to eat with
body mass wasting.
Chondromyxoid Fibroma Radiographically, the lesion is a circumscribed
radiolucent defect with septa and well-defined
Epidemiology sclerotic or scalloped/lobulated margins
Chondromyxoid fibroma of the maxillofacial (Fig. 21). On initial presentation, the size of
bones is an exceedingly rare, benign cartilaginous reported chondromyxoid fibromas in the jaws
neoplasm which has to be distinguished from varies from 5 to 9 cm in greatest diameter. Cortical
other cartilage-forming tumors, in particular expansion, usually with thinning and partial ero-
chondrosarcoma. It accounts for less than 1% of sion or destruction (50%), can be observed, and
bone tumors. The tumor can be found in the long soft tissue infiltration (30%) has been described in
and flat bones where it is prevalent in males; advanced cases. The majority of tumors show a
however, the incidence in women prevails in a purely lucent matrix, but central radiopacities are
2:1 ratio when the craniofacial bones are involved. sometimes (13%) noticed within the lesion. CT
Very few case reports of chondromyxoid fibroma scans of chondromyxoid fibromas almost always
of the jaws are reported. It mostly occurs between suggest a benign nature but are diagnostically
the second and third decades, but it has a wide age non-specific. The tumor returns a low, non-
range. The tumor is less frequently reported in the homogeneous signal intensity on T2-weighted
mandible than in the maxilla; however, according imaging due to the chondroid and myxoid tissue
to Wenig (2016) the mandible is the most common components. The main radiological differential
site (symphysis or molar-retromolar area). The diagnosis is chondrosarcoma that also shows lob-
tumor even less frequently affects the sphenoid ular outlines and may have myxoid areas. The
and ethmoid sinuses (Hammad et al. 1998). chondromyxoid fibroma differs from a
chondrosarcoma by its fibroid elements separat-
Etiology ing the lobes and also has sharper margins
As for most bone tumors, no specific cause is between the tumor and the normal tissue (Razek
known for chondromyxoid fibroma. However, a 2011; Fomete et al. 2014).
clonal rearrangement of chromosome 6 has been Histologically, chondromyxoid fibromas are
reported in four patients (Granter et al. 1998). In encapsulated masses composed of lobulated or
addition, the glutamate receptor gene GRM1 pseudolobulated sheets of spindle-shaped or
expression levels have been shown to be notice- plump, stellate cells with abundant interspersed
ably (100- to 1400-fold) increased through gene chondroid, and fibromyxoid substance resem-
fusion and promoter swapping in 90% of a series bling different stages of chondrogenesis (Romeo
of 20 patients (Nord et al. 2014). et al. 2009). The myxoid elements are the hall-
mark characteristics of this neoplasm. The
Clinical-Pathologic Features chondroid macrolobules are typically separated
The clinical characteristics of the chondromyxoid by zones of a more cellular tissue composed of
fibroma vary depending on the anatomical area spindle-shaped or round cells (Figs. 22 and 23)
involved. Usually the tumor is slow growing and with the presence of varying numbers of
often incidentally discovered on routine radio- osteoclastic-type multinucleated giant cells
graphic examination. Chronic non-specific local mainly toward the periphery; the nuclei are
pain (85%), swelling (65%), and edema (65%) are round to oval shaped. Mitotic activity is rare.
frequently reported first, perhaps followed by a The cartilage-like tissue does not exceed 75% of
palpable hard and/or soft-tissue mass causing jaw the tumor mass. A microlobular pattern, a combi-
movement restriction and more rarely a patholog- nation of both, or no pattern at all has also been
ical fracture (Hammad et al. 1998; Razek 2011). described (Wu et al. 1998).
Fig. 21 Panoramic
radiograph of a
chondromyxoid fibroma
involving the posterior left
mandible and ramus
showing well-defined
sclerotic margins (Image
courtesy of Professor CJ
Nortje, University of the
Western Cape, Cape Town,
South Africa)
Fig. 22 Low-power microscopy of chondromyxoid Fig. 23 Medium-power microscopy of chondromyxoid

fibroma showing sheets of spindled and plump cells in a fibroma demonstrating the lobulated nature of the
chondromyxoid background (Hematoxylin and eosin stain) chondromyxoid stroma (Hematoxylin and eosin stain)
Focal areas of calcification and spicules of the recurrence rate following curettage has been
residual bone can also be present within the reported to be close to 25%. In the maxillofacial
tumor stroma. Large pleomorphic cells that could area, excision is preferred over resection because
cause confusion with chondrosarcoma may be of functional and cosmetic restraints (Razek 2011).
seen (Fig. 24); however, the distinctly lobulated Radiation therapy is not advocated unless the tumor
appearance of the chondroid and fibromyxoid is surgically inaccessible (Rahimi et al. 1972;
stromal elements in a chondromyxoid fibroma is Isenberg 1995). Metastases of chondromyxoid
different from the malignant chondromatous fibroma have not been reported (Armah et al. 2007).
islands in a chondrosarcoma. The myxoid areas
may become fibrotic as the lesion matures. Immu-
nohistochemical staining shows that S-100 protein Schwannoma
is found in the cell of cartilaginous origin and is not
detected in the stromal fibroblasts (Zillmer and Epidemiology
Dorfman 1989). Maxillofacial intraosseous schwannomas (also
referred to as neurilemmomas) are very rare but
Patient Management arise fairly commonly in the head and head soft
Curettage or excision followed by diligent follow- tissues. The most common intraosseous site of
up seems the preferred method of treatment overall; incidence is the mandible, and often there is a
associated with clinical swelling, and 16 patients

complained of pain or tenderness. Tooth mobility
or displacement was reported in eight occur-
rences, and paresthesia was recorded in seven
cases. Radiographically, most schwannomas
have a non-specific, benign appearance and are
characterized by well-circumscribed, unilocular
radiolucencies with cortical expansion (15%)
and a thin sclerotic border, suggesting a benign
odontogenic cyst or tumor (Fig. 25). About 13%
appear multilocular and about 8% show periph-
eral scalloping. Root resorption and cortical ero-
sion may be each observed in about 18% of cases
Fig. 24 Medium-high power view of chondromyxoid (Fig. 26). A periosteal reaction is occasionally
fibroma demonstrating pleomorphic spindled and stellate-
shaped stromal cells (Hematoxylin and eosin stain) noted. Interestingly, distention of the mandibular
canal has been infrequently reported (9%), and a
direct association with a neurovascular bundle
clear relationship between the lesion and the infe- was intraoperatively noted in 16 cases. In five
rior alveolar nerve (Murphy and Giunta 1985; cases, an intimate association of nerve and tumor
Belli et al. 1997; Chi et al. 2003). A comprehen- was seen, yet a direct connection was not
sive literature review (Zhang et al. 2012) yielded a documented (Zhang et al. 2012).
series of 60 jaw cases, 55 in the mandible and 5 in Histologically, the features of the intraosseous
the maxilla. Forty of the mandibular cases were and soft tissue schwannomas are indistinguish-
located in the posterior body and ramus, and able from each other. The frequently encapsulated
15 cases arose in the anterior body including the lesions are composed of spindle-shaped tumor
symphysis. The mean age of patients with man- cells with an often wavy, eosinophilic cytoplasm
dibular tumors was 35 years (with a very wide age containing an oval-shaped nucleus. Typically,
range of 3–72), and the mean age for maxillary there are two separate, alternating morphological
lesions was 25.6, also with a wide age range configurations recognizable within classic
(11–64). The peak prevalence is in the second schwannomas referred to as Antoni type A and
and third decades. The male-to-female ratio for Antoni type B areas (Fig. 27). These alternating
mandibular versus maxillary tumors is 1.3:1 and areas of Antoni type A and type B occur in vari-
for maxillary cases 4:1. able proportions. The relatively more cellular
Antoni type A fields display a unique pattern
Etiology with more differentiated foci where the whirling
The schwannoma is a benign neoplasm that tumor cells and nuclei form palisading rows and
derives from the neural sheath. The cells of origin fairly pathognomonic “Verocay bodies.” Antoni
are the Schwann cells that cover myelinated nerve type B tissue is composed of less organized or less
fibers. These tumors typically grow on the periph- differentiated but more vascularized neural tissue
eral nerve surfaces. with thickened blood vessels. S-100
immunostaining is stronger in Antoni type A tis-
Clinical-Pathologic Features sues than in Antoni type B areas. Several histo-
The most typical presentation is that of an asymp- pathological variants of the schwannoma are
tomatic swelling of the posterior mandible. recognized that include cellular, plexiform, epi-
In the same comprehensive review (Zhang thelioid (psammomatous), melanotic, and ancient
et al. 2012), 13 patients with mandibular types. The cellular variants are predominantly or
schwannoma did not report any symptoms, exclusively composed of Antoni type A tissues
31 cases of the mandible and maxilla were without formation of Verocay bodies. The
Fig. 25 Schwannoma of the left inferior alveolar nerve. canal (d) (Images courtesy of Clinical Associate Professor
CT axial bone reconstruction (a), coronal bone reconstruc- Andy Whyte, Perth Radiological Clinic, Perth WA,
tion (b), axial soft-tissue reconstruction (c), oblique sagittal Australia)
soft-tissue reconstruction along the left inferior alveolar
Fig. 27 Medium-power histological view of a schwannoma

showing the Antoni Type A tissue composed of typical
palisading rows of the tumor nuclei embedded in an eosin-
ophilic hyalinized stroma (A) and less-organized Antoni
Type B tissue (B) (Hematoxylin and eosin stain)
neoplastic cells are arranged in a combination of

Fig. 26 A lateral-oblique view of a mandibular schwannoma short, intersecting fascicles, whirling pattern and
showing marked expansion of the mandibular canal and
long sweeping and interdigitating fascicles. Low
some root resorption of the posterior teeth (Image courtesy
of Professor CJ Nortje, University of the Western Cape, mitotic activity may be observed and necrosis is
Cape Town, South Africa) less than 10% of the cases (Chi et al. 2003; Zhang
et al. 2012). The psammomatous melanotic Etiology

schwannomas differ considerably from the The neurofibroma is an equally uncommon
classic-type schwannoma and consist of polygo- benign oral neuronal tumor that is derived from
nal to spindle-shaped cells in a syncytium-like peripheral nerve cells. The tumor consists of a
pattern with heavy melanin deposits and mixture of nerve sheath cells comprising
psammoma bodies in the stroma. More than half Schwann cells, perineural hybrid cells, and
of the patients with this lesion have evidence of intraneural fibroblasts (Bruce 1954; Jangam
Carney complex (Chi et al. 2003), an autosomal et al. 2014). Neurofibromas incorporate axons as
dominant syndrome associated with spotty pig- these tumors grow, in contrast to schwannomas
mentation of the skin, endocrinopathy, and endo- which originate in the nerve sheath and displace
crine and non-endocrine tumors. Malignant axons. Neurofibroma is usually considered to be
schwannomas are rare; these tumors are usually an essential characteristic of a generalized syn-
well-defined and pseudoencapsulated, with infil- drome known as neurofibromatosis (NF), a
trative growth, located inside or beside the nerve neurocutaneous systemic disease that arises from
stem. Malignant schwannomas have not been an autosomal dominant mutation of the NF1 or
reported in intraosseous cases (Zhang et al. 2012). NF2 gene. NF includes a heterogeneous spectrum
of disorders. NF-1 is the generalized, most com-
Patient Management mon form and is characterized by a range of
The preferred treatment of schwannomas is total neurocutaneous and subcutaneous/soft-tissue
surgical enucleation with regular follow-up. lesions as well as hyperpigmentation (café au lait
Recurrences are rare and have been reported in spots) in most patients (Friedman 1999). NF type
five of the mandibular cases from the above 2 (a central form) is characterized by the develop-
review of cases; there were no recurrences of the ment of bilateral acoustic neuromas (Pastores
maxillary cases in the case reports analyzed et al. 1991). The risk of transformation of soft
(Zhang et al. 2012). tissue neurofibromas into malignant peripheral
nerve sheath tumors in patients with neurofibro-
matosis is about 2.7 times higher than in the
Neurofibroma general population with a cumulative risk of
20% by age 50 (Walker et al. 2006).
Epidemiology
The majority of the neurofibromas of the head and Clinical-Pathologic Features
neck regions affect the soft tissues (Deichler et al. Most intraosseous neurofibromas are asymptom-
2011). The maxillofacial intraosseous variants atic, especially in the early stages, but in later stages
occur even more rarely. Less than 50 cases have some can present with pain and paresthesia of the
been reported in the literature with a predilection lower lip when there is bone destruction (Deichler
for the mandible (Dalili and Adham 2012; Jangam et al. 2011). Radiologically, intraosseous neurofi-
et al. 2014). The rarity of intraosseous neurofibroma are usually radiolucent accompanied by
bromas, like for schwannomas, can be attributed fusiform, sometimes destructive enlargement of
to the fact that bone marrow spaces do not have the inferior alveolar nerve canal (Fig. 28) in the
nerve sheaths or myelinated nerves except for part posterior part of the mandible or mental foramen, a
of the body of mandible. Neurofibroma affects branched mandibular canal, a deep sigmoid notch,
patients between 14 and 45 years old; the average a decreased mandibular angle, a deformed condyle,
age is 27.5 (Deichler et al. 2011). The tumors arise non-eruption of teeth, and a cyst-like lesion. Inter-
in females twice as much as in males (Vivek et al. estingly, a homogenous radiopacity with a radiolu-
2006). A case of intraosseous neurofibroma and cent border has been reported (Gujjar et al. 2015).
simultaneous involvement of the mandible, max- Hypo- or hyperplasia of the mandible, maxilla,
illa, and orbit has been reported (Dalili and zygoma, and the temporomandibular joints has
Adham 2012). also been reported (Kaplan et al. 1994; Lee et al.
Fig. 29 Medium-power histological view of a typical

neurofibroma composed of spindle-shaped cells in a deli-
cate fibrillar eosinophilic stroma; many of the nuclei have a
fusiform and wavy shape (Hematoxylin and eosin stain)
Fig. 28 Mandibular neurofibroma in neurofibromatosis.

Note the destructive radiolucency both above and below such as schwannomas and traumatic neuromas.
the mandibular canal (Image courtesy of Professor CJ The presence of mast cells and a fine fibrillar
Nortje, University of the Western Cape, Cape Town, matrix in neurofibromas will differentiate it from
South Africa) schwannomas.
1996; Hisatomi et al. 2005; Dalili and Adham Patient Management

2012). Primary intraosseous malignant peripheral Since neurofibromas are not usually encapsulated,
nerve sheath tumors have been documented; a wide excision margin may be necessary. The
11 case reports in the mandible and 2 case reports lack of encapsulation may lead to recurrences.
in the maxilla were identified (Terry et al. 1998). Thus, a more radical resection would have to be
Histologically neurofibromas consist of a considered if the tumor occurs in bone (Gujjar
mixture of cell types, including Schwann et al. 2015). Patients with neurofibromatosis
cells, perineurial-like cells, fibroblastic cells, and should as a routine be radiographically examined,
entrapped axons. Intraosseous and soft tissue neu- and, vice versa, patients with intraosseous neuro-
rofibromas are unencapsulated; however, the fibromas should be investigated for other cutane-
lesions may be well-demarcated if intraneural or ous or subcutaneous neurofibromas.
cutaneous but are diffusely infiltrative if located in
extraneural soft tissue. Intraosseous lesions can
either be well-demarcated or infiltrative/locally Hemangioma
destructive (Fig. 28). Neurofibromas usually
exhibit a diffuse, irregular pattern with interlacing Epidemiology
bundles of spindle-shaped cells with round, Intraosseous hemangiomas of the jaw bones are rare
ovoid, or fusiform (often wavy) nuclei and eosin- benign vasoformative neoplasms or developmental
ophilic cytoplasm within a loose matrix of fibrillar conditions, and only a few recent case reports and
collagen (Fig. 29); there can be areas with small literature reviews exist. Intraosseous variants, or
plexiform elements (Fig. 30). Neurofibromas with cavernous hemangiomas, are relatively rare and
a predominant plexiform pattern are usually asso- comprise 0.5–1% of all intraosseous tumors (Beziat
ciated with neurofibromatosis-1. Neurofibromas et al. 1997). An extensive review of 74 cases
are usually S-100 positive confirming the neural (Barnes 1985) reported 22 histologically proven
origin. Neurofibromas have to be carefully distin- intraosseous hemangiomas of the jaws (Heckl
guished from other neural spindle cell lesions et al. 2002). The majority present during the second
from central spongiosa) or peripheral type (arising

from periosteum). Hemangiomas may occur as a
part of a variety of syndromes such as Osler-Weber-
Rendu syndrome, Klippel-Trenaunay syndrome,
Kasabach-Merritt syndrome, Sturge-Weber syn-
drome, Parkes Weber syndrome, CLOVES syn-
drome, Maffucci syndrome, Cobb syndrome,
PHACES syndrome, and Blue rubber bleb nevus
syndrome (Nosher et al. 2014).
Hemangiomas are usually asymptomatic, and it
Fig. 30 Medium-power histological view of a neurofi- may take months or years before patients become
broma with a more plexiform arrangement of the cellular aware of these lesions and seek treatment. The
elements (Hematoxylin and eosin stain) lesions tend to grow very slowly and remain clin-
ically undetectable and painless until the tumors
decade of life, and the female-to-male ratio varies become large. Later these lesions can show signs of
from 2:1 to 3:2. When encountered, the majority of bony hard swelling, bluish discoloration of gingiva
these lesions present during the second decade but and mobile teeth, discomfort, and oozing or pulsa-
can be diagnosed until the fifth decade in life (Beziat tile bleeding from the gingiva around the teeth in
et al. 1997; Adler and Wold 2002). The mandibular the area of the lesion. Pain is usually of the throb-
body (including the inferior alveolar canal) and bing type. Some tumors can be compressible or
ramus are more commonly affected than the max- pulsate with a bruit detectable auscultation. Aspi-
illa; 65% are found in the molar and premolar ration of the tumors will easily yield blood as they
regions (Alves et al. 2006; Cheng et al. 2006). may be under pressure (White and Pharaoh 2004).
Radiological studies should include conventional
Etiology radiography, computer tomography (CT) or cone
Hemangiomas are vasoproliferative tumors and beam computed tomography (CBCT), and mag-
part of the group of benign vascular anomalies. netic resonance imaging (MRI).
This group also includes vascular malformations. Radiologically, centrally located hemangiomas
These lesions can occur in the skin, soft tissues, and are not pathognomonic and often have a multi-
bone. The diagnosis and management of vascular locular appearance; small osteolytic locules may
lesions continue to present diagnostic and therapeu- mimic enlarged marrow spaces surrounded by
tic challenges, partly because of a lack of agreement coarse, dense, and well-defined trabeculae
regarding the nosology and classifications of the (Fig. 31). This pattern may result in a honeycomb
lesion (Handa et al. 2014). Hemangiomas are best or soap-bubble pattern (Dhiman et al. 2015). The
classified as benign vascular neoplasms composed periphery is usually corticated and well-defined,
of an abnormal proliferation of blood vessels but in some cases, it can be ill-defined through
resulting from growth of endothelial cells. Many bone erosion simulating a malignant lesion.
hemangiomas are self-involuting (Sundine and Involvement of the inferior alveolar canal
Wirth 2007; Jain et al. 2016), and several are actu- increases the width of the whole canal, and often
ally considered as hamartomas. The pathogenesis the canal assumes a serpiginous shape (Fig. 32).
of intraosseous hemangiomas remains unknown. Occasionally lesions may be completely radiolu-
Nonetheless, local trauma may be a cause, because cent. Displacement and root resorption of the
many patients with intraosseous hemangiomas have regional teeth is often observed. Associated devel-
experienced local trauma (Akiner et al. 2011). Hem- oping teeth may be larger and could erupt earlier
angioma of bone has in the past occasionally been (White and Pharaoh 2004). Phleboliths may
classified as central or intraosseous type (arising occur in hemangiomas which extend into the
Fig. 31 A relatively well-circumscribed hemangioma in

the posterior mandible demonstrating a typical honeycomb
appearance due to the radiolucencies surrounded by the
thick trabeculae (Image courtesy of Professor CJ Nortje,
University of the Western Cape, Cape Town, South Africa)
Fig. 33 Sagittal MRI image of the same patient showing

the well-visualized tortuous nature of the flow-voids
(arrows), indicative of the vascular nature of the lesion
(Image courtesy of Professor CJ Nortje, University of the
Western Cape, Cape Town, South Africa)
sunray-like pattern of a malignant tumor like an

osteosarcoma (White and Pharaoh 2004).
Histologically, hemangiomas are classified into
capillary, cavernous, and mixed variants (Thoma
and Goldman 1971). The capillary types are com-
posed of aggregates, lobules, and sheets of prolif-
erating capillary-sized blood vessels lined by
endothelial cells; in the cavernous type, the vari-
ably sized, sometimes cystically dilated and
irregular-shaped vascular spaces, are thin-walled;
these spaces are lined by a single layer of endothe-
lial cells and contain a large number of red blood
Fig. 32 A well-circumscribed hemangioma in the posterior cells. The endothelial cells are CD31 and CD34
mandible and ramus with serpigenous widening of the infe- positive. The blood vessels in the cavernous type
rior alveolar canal (Image courtesy of Professor CJ Nortje,
are arranged in a plexiform pattern and are dis-
University of the Western Cape, Cape Town, South Africa)
persed in the edematous fibrous stroma among the
bony trabeculae (Figs. 34 and 35). Emboli and
surrounding soft tissues. MRI can demonstrate the thrombi with intravascular papillary endothelial
tortuous nature of the vascular structures hyperplasia are occasionally observed in older
(Fig. 33). When a central hemangioma breaks hemangiomas. As mentioned above, a hemangi-
through the outer cortex, occlusal radiographic oma can have both features of the capillary and
films may reveal perpendicular linear bony spec- cavernous types. Strong osteolytic activity by oste-
ulations of the periosteum which can resemble the oclasts of the surrounding bony trabeculae can
Fig. 34 Medium-power microscopic view of a cavernous Fig. 35 High-power microscopic view of the irregularly
hemangioma infiltrating the marrow spaces of the cortical dilated blood vessels filled with red blood cells in the
and cancellous bone (Hematoxylin and eosin stain) (Image marrow spaces between the bony trabeculae (Hematoxylin
courtesy of Dr P Sadow, Head & Neck Pathology, Massa- and eosin stain) (Image courtesy of Dr P Sadow, Head &
chusetts General Hospital, Boston, MA, USA) Neck Pathology, Massachusetts General Hospital, Boston,
MA, USA)
result in bone degradation which may lead to a with a range of clinical presentations unified by
pathological fracture (Hansen et al. 2009). granulomatous lesions composed of clonal
CD207+ and CD1a+ histiocyte-like cells. The
Patient Management pathology may affect a single organ but may
An incisional biopsy is contraindicated because of also occur as disseminated multi-organ disease
the high risk of bleeding; a fine needle aspiration is with 10–20% mortality among those diagnosed
better suited, and the blood obtained immediately with the disease. Both children and adults are
in the syringe is diagnostic. The ideal and most affected, usually with slightly different clinical
effective treatment of intraosseous hemangiomas presentations. Most patients are however under
is to remove the tumor completely without any 20 years of age, and males are affected at least
functional deficit, cosmetic deformity, or signifi- twice as frequently as females.
cant tissue loss. However, the feasibility thereof
depends on the size and location of lesion and age Etiology
of the patient. The location of the feeder vessels of The question whether LCH is primarily an immune
hemangiomas should be obtained by angiography; deregulatory disorder or a neoplasm remains unan-
these feeder vessels should be ligated (Lamberg swered. Clonality of LCH cells, in association with
et al. 1979; Yih et al. 1989) or embolized BRAF mutations in up to 55% of patients, and
(Sadowsky et al. 1981), especially prior to surgery. activation of the RAS-RAF-MEK-ERK pathway
A vascular bone graft may be necessary in case of (where MEK and ERK are mitogen-activated pro-
an en bloc bony resection. Other treatment modal- tein kinase and extracellular signal-regulated
ities include steroid therapy, use of sclerosing kinase, respectively) in nearly 100% of patients
agents, laser therapy, and irradiation. with LCH (Egeler et al. 2016) provide further
evidence to the long-standing hypothesis of a
neoplastic background. The cell of origin is also
Langerhans Cell Histiocytosis unanswered, although molecular studies have dem-
onstrated lesional cells to be genetically more
Epidemiology closely associated with myeloid-derived precursor
Langerhans cell histiocytosis (LCH) is an uncom- dendritic cells than to terminally differentiated epi-
mon but poorly understood hematologic disorder dermal Langerhans cells (Allen et al. 2010).
Clinical-Pathologic Features with or without diabetes insipidus, adjacent lymph

The range of symptoms and clinical overlap with node involvement, or skin rash. Disseminated LCH
other conditions make the initial diagnosis of LCH a presents with involvement of (i) the internal organs,
clinical challenge. However, once a biopsy is under- with or without diabetes insipidus, adjacent lymph
taken, the diagnosis is straightforward in most cases node involvement, or a skin rash, but without dys-
with a cellular heterogeneous lesion consisting of function of the lung, liver, or hematopoietic system;
langerin-positive (CD207+) dendritic cells admixed and (ii) all of the above, but with dysfunction of the
with inflammatory cells, including lymphocytes, lung, liver, or hematopoietic systems (Zinn et al.
eosinophils, and macrophages (Fig. 36). LCH is 2016).
generally subdivided into localized and dissemi- Of all the clinical presentations of LCH, the
nated types. Localized LCH presents as either bone and skin are the most commonly involved
(i) a simple skin rash without affecting organs; organs, with bone lesions seen in more than 70%
(ii) simple bone involvement, with or without dia- of patients and skin involvement in more than
betes insipidus, adjacent lymph node involvement, 30% (Stalemark et al. 2008). In the head and
or a skin rash; and (iii) multiple bone involvement, neck specifically, the most common clinical
Fig. 36 Langerhans cell

histiocytosis.
Orthopantomogram shows
significant bone loss around
lower right first and second
molar teeth (46 and 47)
giving 47 the so called
“floating teeth” appearance
(a). Lesion consists of
dendritic cells admixed with
inflammatory cells
including lymphocytes,
eosinophils and
macrophages (b)
stain). (Images courtesy of
Queensland Oral Medicine
& Pathology, Brisbane
QLD, Australia)
presentation of LCH is a localized variant known Primary Malignant Neoplasms

as eosinophilic granuloma (EG) of bone that
most commonly affects the skull; however, any Chondrosarcoma
of the craniofacial bones may be involved with or
without systemic involvement. In a number of Epidemiology
small case series published over the years, the Chondrosarcoma (CS) is a malignant tumor of
mandible has been affected more commonly than bone producing exclusively cartilage. Although
the maxilla (Eckardt and Schultze 2003; Li et al. it is the second most common primary malignancy
2006; Jalil and Hin-Lau 2009), although the age of bone following osteosarcoma, it is not common
ranges varied in different studies. A painful or in the head and neck region (Koch et al. 2000). CS
painless, punched-out radiolucency without cal- affects primarily the pelvis, ribs, and extremities.
cification or peripheral sclerosis, or in severe When present in the head and neck, the larynx and
cases a floating teeth appearance with or without jaws are almost always involved. CS of the jaws
an associated soft-tissue mass, is the most com- may affect patients of any age, although a peak
mon clinical presentation in the jaws. Bone pain, incidence is found in the sixth and seventh decade.
tooth mobility, and necrotic ulcers of adjacent Mesenchymal chondrosarcomas (MC) are very
soft tissue (Golai et al. 2015; Goncalves et al. rare and account for less than 1% and up to 10% of
2016) may be misdiagnosed as dental infection chondrosarcomas with a peak incidence in the
or osteomyelitis, resulting in unnecessary dental second and third decade of life (Xu et al. 2015).
extractions. MC have a widespread distribution in bone but
also occur in extraskeletal sites.
Patient Management
Due to the generally non-specific clinical appear- Etiology
ance of LCH of the jaw bones, the differential The majority of CS and MC develop spontaneously.
diagnosis includes an array of reactive, benign, CS harbors IDH1 and IDH2 mutations in about half
and malignant neoplastic diseases. As soon as the of cases (Amary et al. 2011), while MC show a
diagnosis is established by microscopic examina- recurrent HEY1-NCOA2 fusion (Nakayama et al.
tion, however, further clinical workup is mandatory 2012). This fusion is not present in conventional
to determine the extent of the disease. For staging, CS, and similarly the IDH1 and IDH2 mutations are
clinical workup should include a thorough physical not found in MC (Damato et al. 2012).
examination, including complete evaluation of the
skin and oral mucosa, lungs, liver function, spleen, Clinical-Pathologic Features
blood cell counts, bone marrow biopsy, and aspi- The anterior maxilla and sinonasal structures are
ration cytology, especially in patients under the preferred sites for CS (Hong et al. 2009). Most
2 years, and a radiologic workup for skeletal survey patients with CS of the head and neck are in the
and magnetic resonance imaging (MRI) of the fourth decade and present with a painless swelling
brain and spine if central nervous system (CNS) (Pontes et al. 2012). MC are seen at a younger age,
involvement is suspected (Zinn et al. 2016). Treat- between the second and third decade with the
ment of LCH is beyond the scope of this text but anterior maxilla as the most frequent site (Jaetli
has historically depended on the extent and loca- and Gupta 2011). Most patients with MC present
tion of disease ranging from management of local- with a painless swelling followed by nasal
ized pathology to extensive systemic involvement obstruction and epistaxis (Kumar et al. 2014).
and treatment. Prognosis of patients with LCH CS has a great variability regarding the matu-
depends on the extent of the disease as well as rity of the cartilage produced. It may vary from
response to treatment. Identification of mutations well-differentiated to high-grade consisting of
in specific genes could contribute to target therapy atypical chondrocytes in the chondroid stroma.
becoming the main therapeutic choice for patients Binucleate chondrocytes are often found in single
with LCH (Arico 2016). lacunae (Figs. 37 and 38). Calcification of the
Fig. 37 Chondrosarcoma.
Low-power
photomicrograph of a
chondrosarcoma showing
lobular cartilage production
with atypical chondrocytes
and areas of infiltration
(arrow) (Hematoxylin and
eosin stain)
Fig. 38 Chondrosarcoma.
Binucleate chondrocytes
(arrows) are clearly visible
in the higher magnification
of a chondrosarcoma
stain)
chondroid tissue is sometimes found. Most CS of with a well-differentiated CS. No malignant oste-
the jaws are low-grade tumors. Several histologi- oid (osteoid produced by malignant osteoblasts)
cal variants of CS exist with conventional CS should be present. This is important to distinguish
accounting for almost 90% of cases (Pontes et al. CS from chondroblastic osteosarcomas, the most
2012). A dedifferentiated CS shows the presence common type of osteosarcoma in the jaws. MC is
of a poorly differentiated sarcoma, often with composed of poorly differentiated small blue cells
none of the chondroblastic features associated associated with cartilaginous islands. The small
cells have hyperchromatic nuclei and little cyto- Etiology

plasm and may have a spindle-shaped growth Osteosarcoma of the jaw usually arises without
pattern. Mitotic figures are common. obvious predisposing factors. Potential pre-
CS and MC present as poorly demarcated disposing factors include tumor syndromes such
radiolucent lesions. Expansion of bone is comas Li-Fraumeni syndrome, retinoblastoma syn-
monly observed (Pontes et al. 2012). The presence drome (germline mutation of RB gene), and
of radiopacities depends on the amount of calcifi- Rothmund-Thomson syndrome (rare autosomal
cation present in the tumor. Widening of the peri- recessive genodermatosis), in which osteosar-
odontal ligament space is also a common finding, coma usually presents at a young age.
and root resorption may be present. Li-Fraumeni syndrome is an autosomal domi-
nant syndrome that in most cases is associated
Patient Management with a germline mutation in TP53. By definition,
The diagnosis of CS and MC is made on histol- the proband is diagnosed with a sarcoma before the
ogy. The clinical and radiological features are age 45 and has a first-degree relative with any cancer
used to support the histological diagnosis. Wide diagnosed before 45 years and another first- or
surgical excision with clear margins is the treat- second-degree relative with a sarcoma (any age) or
ment of choice. Chemotherapy and radiotherapy a cancer before the age of 45 (Malkin 2013). Other
are of minor value for CS. The prognosis of jaw predisposing factors include Paget’s disease (Paget’s
CS is worse compared to other sites as it is diffi- sarcoma), prior irradiation, bone infarction, and
cult to obtain adequately wide surgical margins. (rarely) transformation of a benign tumor (e.g.,
Recurrences are therefore not uncommon, while fibrous dysplasia). In these situations, osteosarcoma
metastasis is rare. MC of the jaws appears to have usually presents at a later age (e.g., >40–50 years).
a more favorable prognosis although long-term High-grade osteosarcoma has no characteristic
follow-up is necessary due to the possibility of molecular signature. Low-grade osteosarcoma
delayed metastases (Nakashima et al. 1986). shows MDM2 amplification (Duhamel et al. 2012).
Osteosarcoma Osteosarcoma usually presents as a painless or
painful swelling. It can present due to tooth loos-
Epidemiology ening or toothache (Nielsen and Rosenberg 2007).
Osteosarcoma is a malignant tumor character- Other symptoms can include paresthesia and nasal
ized by the production of osteoid matrix by blockage.
malignant cells (Unni et al. 2005; Green and Radiology can assist in determining the loca-
Mills 2014). Osteosarcoma is the most common tion and extent of the tumor and the type of
primary bone malignancy in children, adoles- matrix present (chondroid or osteoid). Conven-
cents, and young adults and most commonly tional osteosarcoma is usually ill-defined, scle-
arises in the metaphysis of long bones (Unni rotic, and/or lucent and often has an aggressive
et al. 2005; Green and Mills 2014). Osteosarcoma periosteal reaction. There may be an associated
involving the maxilla and mandible (gnathic oste- soft-tissue mass (Fig. 39). An aggressive tumor
osarcoma) accounts for 6% of all osteosarcomas, with chondroid matrix in the jaw is more likely
occurs at an older age (peak incidence in fourth to be a chondroblastic osteosarcoma than a
decade), and is commonly chondroblastic (Rosen- chondrosarcoma, especially in a young patient,
berg et al. 2013). and radiological correlation can be useful in this
Low-grade osteosarcoma (low-grade central distinction.
osteosarcoma and parosteal osteosarcoma) is Osteosarcoma can be classified according to
much less common than conventional high-grade location (intramedullary vs surface, periosteal or
osteosarcoma at all locations, including the jaw, parosteal), by grade, and by histology (e.g., osteo-
but has been reported at this location. blastic, chondroblastic, fibroblastic, giant cell rich).
Fig. 39 Osteosarcoma (chondrogenic). Axial bone win- arrows). Ill-defined medullary sclerosis is present in alve-
dow CT (a), and coronal reconstruction through the first olar bone (white arrow) extending inferiorly to partially
molar regions (b). Ill-defined and bizarre new bone forma- surround the left inferior alveolar canal (IAC) (Images
tion is present at the crestal margin of the eroded buccal courtesy of Clinical Associate Professor Andy Whyte,
cortex in the lower left first molar (36) region (white dotted Perth Radiological Clinic, Perth WA, Australia)
Most osteosarcomas of the jaw are conven- low-grade osteosarcoma show amplification of
tional intramedullary osteosarcomas. While the MDM2 (Duhamel et al. 2012), most reproducibly
pathological hallmark of osteosarcoma is the pro- demonstrated by fluorescent in situ hybridization,
duction of osteoid matrix by malignant cells, in and this can be useful if present in distinguishing a
the jaw approximately 50% of osteosarcomas are low-grade osteosarcoma from benign differential
chondroblastic, and osteoid can be sparse. In diagnoses such as fibrous dysplasia (for
chondroblastic osteosarcoma there are lobules of intramedullary lesions) and osteochondroma (for
atypical hyaline or myxoid cartilage with spin- surface lesions). For this reason, bone biopsies
dling and increased cellularity at the periphery of should receive adequate formalin fixation, and at
the lobules (Figs. 40, 41, and 42). The tumor has a least a sample of the biopsy should receive gentle
permeative and destructive pattern of growth. (e.g., EDTA-based) decalcification. Routine
Osteoid matrix in osteosarcoma can show a vari- decalcification damages DNA and precludes
ety of patterns including lace-like and filigree most molecular investigations including FISH.
patterns or broad trabeculae (Fig. 43).
Osteoid can be focal, may not be the predom- Patient Management
inant histological subtype, and may not be present Prior to making a definitive diagnosis, correlation
in a biopsy of chondroblastic osteosarcoma. with the radiographic features is mandatory, and
Radiological and clinical correlation are impera- discussion in the context of a multidisciplinary
tive. SATB2 immunostain can be useful as it specialist sarcoma unit is ideal.
highlights osteoid matrix and often stains the High-grade osteosarcoma is usually treated with
undifferentiated and chondroid components of chemotherapy followed by surgery (complete exci-
osteosarcoma (Conner and Hornick 2013). sion), with subsequent further chemotherapy. The
Low-grade osteosarcoma is less common but latter may be modified depending on the percent-
occasionally seen, and can be intramedullary age of necrosis determined by histological evalua-
(low-grade central) or surface (parosteal). Radio- tion of the surgical resection specimen.
logical correlation is critical. The pathology There is some evidence that gnathic osteosar-
resembles a fibro-osseous lesion with parallel coma has a better prognosis and a lower likelihood
seams of osteoid with intervening fibrous stroma of distant metastasis than extra-gnathic osteosar-
(Fig. 44). The cellularity of the latter is variable. coma (Bertoni et al. 1991). For this reason, some
Atypia is usually seen in the spindle-cell compo- suggest a primarily surgical approach. The main
nent but can be mild and subtle (Fig. 45). Most cause of death is uncontrolled local disease.
Fig. 40 Low-power photomicrograph of chondroblastic Fig. 42 Chondroblastic osteosarcoma with focal osteoid
osteosarcoma (Hematoxylin and eosin stain) and a peripheral increase in cellularity and spindling of the
chondroid matrix (Hematoxylin and eosin stain)
Fig. 41 Lobule of atypical chondroid matrix with a Fig. 43 Irregular pattern of osteoid produced by malig-
peripheral increase in cellularity in chondroblastic osteo- nant cells in an osteoblastic osteosarcoma (Hematoxylin
sarcoma (Hematoxylin and eosin stain) and eosin stain)
Tumors of the mandible appear to have a better is required in interpretation of a chondroid-

prognosis than tumors of the maxilla (likely containing lesion of the jaw (Stewart et al. 2014).
related to ability to obtain clear margins), and Radiological correlation can be critical at arriving at
tumors of the extra-gnathic craniofacial bones do a correct diagnosis of chondroblastic osteosarcoma.
worse than gnathic osteosarcomas. In some cases, Clinical features such as patient age should also be
there is a role for postoperative radiotherapy. taken into consideration.
Low-grade osteosarcoma (low-grade central
osteosarcoma or parosteal osteosarcoma) is treated
by surgery (complete excision with clear margins). Ewing Sarcoma
If histological examination of the excised specimen
demonstrates high-grade transformation, chemo- Epidemiology
therapy can be given postoperatively. As most Ewing sarcoma (ES) is a type of small round blue
gnathic osteosarcomas are chondroblastic, caution cell malignant neoplasm. It can arise in bone
Fig. 44 Parallel trabeculae of osteoid and focal cartilage Fig. 45 Mild atypia in the spindle cell component in a
in a low-grade osteosarcoma (Hematoxylin and eosin stain) low-grade central osteosarcoma (Hematoxylin and eosin
stain)
(80–90%) or soft tissue (10–20%). The term Clinical-Pathologic Features

“PNET” denoting primitive neural ectodermal Most patients present with a painful enlarging
tumor has been dropped from the current WHO mass. Toothache or tooth loosening can be the
classification of bone and soft tissue tumors and is presenting feature. There may be systemic symp-
now encompassed by the term ES (De Alava et al. toms (e.g., fever or anemia) (Khoury 2005). ES of
2013). bone has a permeative, destructive appearance on
ES is characterized by small round blue cell imaging and is usually lytic but occasionally scle-
morphology, a characteristic but non-specific rotic. An aggressive periosteal reaction is com-
immunophenotype, and in most cases a transloca- mon (e.g., onion skinning), and most have an
tion involving rearrangement of EWSR1 gene. It is associated large soft-tissue mass, best demon-
an uncommon tumor (6–8% of primary malignant strated on MRI. The main radiological differential
bone tumors) but is the second most common diagnosis for an aggressive, lytic, permeative
malignant bone tumor in young people, following bone lesion with a large soft-tissue mass is lym-
osteosarcoma. ES usually occurs at a young age phoma. Other radiological differential diagnoses
(peak incidence in the second decade) but can be can include infection and Langerhans’ cell
seen in adults. It is slightly more common in men. histiocytosis.
It is most common in Caucasians and is rare in Grossly the tumor has a fleshy white-tan
other racial groups. It can arise in any part of the appearance. On microscopy, Ewing sarcoma is
skeleton or soft tissues but most commonly characterized by sheets of uniform small round
develops in the diaphysis or metadiaphysis of blue cells with hyperchromatic nuclei, inconspic-
the long bones and in the flat bones of the pelvis. uous nucleoli, and minimal, ill-defined cytoplasm
The head and neck region is an uncommon loca- (Fig. 46). Intracytoplasmic glycogen can often be
tion for Ewing sarcoma (<5%) (Siegal et al. demonstrated in a PAS stain.
1987). The differential diagnosis on morphology
alone is broad and depends on the age of the
Etiology patient and the location of the tumor (bone or
Ewing sarcoma is characterized in most cases by soft tissue). In bone, the main differential diagno-
fusion of EWSR1 gene (or less commonly FUS) sis is non-Hodgkin lymphoma. Other differential
with a gene from the ETS family (e.g., FLI-1, diagnoses include melanoma (S-100, SOX-10),
ERG, ETV, or FEV) (Stewart et al. 2014). small cell osteosarcoma (osteoid, SATB2), and
Fig. 46 Low-power
photomicrograph of a
Ewing sarcoma showing
uniform small round blue
tumor cells
small cell carcinoma (diffuse CK, CD56, TTF-1).

In soft tissue, the differential diagnosis includes
rhabdomyosarcoma (desmin, myogenin), poorly
differentiated synovial sarcoma (TLE-1, FISH for
SS18), lymphoma (TdT, CD20, CD45), mela-
noma, and mesenchymal chondrosarcoma
(chondroid matrix; FISH for NCOA2). Ewing sar-
coma occurring in the sinonasal tract has a wider
differential diagnosis than ES occurring else-
where due to a number of small round blue cell
tumors that occur at that location (e.g., olfactory
neuroblastoma, sinonasal undifferentiated carci-
noma, NUT midline carcinoma). Histological
and atypical variants of Ewing sarcoma are Fig. 47 CD99 immunostain with membranous pattern of
described, including an adamantinoma-like vari- staining in Ewing sarcoma
ant (Folpe et al. 2005).
Immunohistochemistry is useful mainly in
excluding differential diagnoses. The should always be given to processing part of
immunoprofile of Ewing sarcoma is not specific. any bone biopsy performed for tumor diagnosis
The most sensitive immunostain for ES is CD99. with either no decalcification (if lesional soft
The staining for CD99 must be membranous in tissue can be separated from bone) or by gentle
pattern (“Olympic rings”) and should be diffuse (EDTA-based) decalcification if the biopsy is
(Fig. 47). If the tumor is negative for CD99, other entirely bony. Treatment by most routine forms
diagnoses should be entertained. Positive staining of tissue decalcification will preclude molecular
for FLI-1 (nuclear) is usually present. Focal analysis.
staining for cytokeratin is not uncommon in
ES. It is important to include TdT immunostain Patient Management
for lymphoblastic lymphoma as the latter is often While the diagnosis of ES is made on histology
CD99 and FLI-1 positive and can be negative for aided by ancillary investigations (immunohisto-
CD45, CD20, and CD3. chemistry and molecular confirmation), the
EWSR1 rearrangement can be detected by clinical and radiological features are used to
FISH or RT-PCR (Fig. 48). Consideration support the histological diagnosis. Diagnosis
involvement of the underlying bone. Non-Hodg-

kin lymphomas (NHL) (Fig. 49) affect the oral
and maxillofacial complex more than Hodgkin
lymphoma which is usually a nodal lymphoma
predominantly affecting the neck and mediasti-
num, and the latter will not be discussed here
further.
Primary bone lymphoma is defined as a malig-
nant lymphoproliferative neoplasm, usually NHL,
of only the bone without involvement of the
lymph nodes or adjacent soft tissue. This is a
distinctly rare entity accounting for less than
1–2% of all adult lymphomas diagnosed annually,
Fig. 48 Break apart FISH probe demonstrating and less than 5% of malignant bone tumors, usu-
rearrangement of EWSR1 in Ewing sarcoma ally involving the femur, spine, and pelvic bones
(Murphey and Kransdorf 2016). Primary lympho-
and management are ideally performed in the mas of bone are most commonly of diffuse large
context of a multidisciplinary sarcoma unit. B-cell type (DLBCL) (Mendonca et al. 2013). In
Treatment of ES is chemotherapy followed by the jaws, primary lymphoma of bone is extremely
surgery with wide excision with clear margins, rare, reported by some to involve the maxilla more
with subsequent further chemotherapy. The latter than the mandible (Agrawal et al. 2011) and reg-
may be modified after surgery depending on the istered mostly as single case reports (Agrawal
outcome of the histological evaluation of the et al. 2011; Zadik et al. 2012; Jessri et al. 2013;
response to therapy. Mendonca et al. 2013).
Local treatment (surgery and radiotherapy) is a More commonly encountered is secondary jaw
particular challenge in the head and neck region bone involvement by systemic lymphomas or
due to the proximity to vital structures and the even more frequently, by direct infiltration of the
cosmetic effects of surgery or radiotherapy on a bone by soft tissue lymphomas of the head and
growing child or adolescent. Adjuvant radiother- neck. The latter is the second most common
apy is commonly used in the head and neck region. region to be affected by extranodal lymphomas
Prognosis for ES has improved but remains after the gastrointestinal track and involves lym-
poor for patients with metastatic disease at pre- phomas of the sinonasal tract, ocular adnexa, sal-
sentation or early relapse (Bacci et al. 2000). A ivary glands, Waldeyer ring, oral cavity, and skin
recent small series reports that Ewing sarcoma of of the face (Thakral et al. 2015). Any type of low-
the jaw has a better prognosis than extra-gnathic or high-grade, B- or T-cell lymphoma may affect
tumors (Owosho et al. 2016). Deeper knowledge the maxillofacial complex, but those of B-cell
of the molecular abnormalities found in Ewing origin are generally most commonly seen such
sarcoma obtained via newer technologies might as mucosa-associated lymphoid tissue (MALT)
lead to novel therapies. lymphomas, variations of follicular and mantle
cell lymphoma, as well as a variety of high-
grade lymphomas. NHL was included as an
Lymphoma of the Jaw Bone AIDS-defining illness in 1985 and the incidence
of all subtypes thereof shown to increase more
Epidemiology than 60 times in the presence of HIV-related
Lymphoma, a diverse group of malignant neo- immunosuppression (Raphael et al. 2008). Coun-
plasms of the lymphoreticular system, may affect tries affected by human immunodeficiency virus
the jaw bones in two scenarios, either as a primary (HIV)-associated pathology are therefore more
neoplasm of bone or as a result of secondary likely to see lymphomas associated with this
Fig. 49 Non-Hodgkin lymphoma (NHL). A T1 axial weighting indicating cellular tumor (c). There is a patho-
sequence (a) shows abnormal intermediate signal in the logically enlarged left submental (level 1a) node of identi-
right ramus (white arrow) as compared with normal hyper- cal signal (white ovals in b and c) which was confirmed to
intense signal of fatty marrow in the left ramus. Coronal T1 represent NHL on ultrasound guided FNAC with flow
(b) and T2 (c) weighted MRI demonstrate additional foci cytometry (Images courtesy of Clinical Associate Profes-
of abnormal marrow signal in the right maxillary tuberosity sor Andy Whyte, Perth Radiological Clinic, Perth WA,
and both mandibular bodies (white arrows in b and dotted Australia)
arrows in c) which become moderately hyperintense on T2
kind of immunodeficiency such as aggressive, less commonly. The incidence of T-cell lymphomas
high-grade variants of diffuse large B-cell lym- increases with age and have higher incidences in
phoma (DLBCL), Burkitt lymphoma (BL), pri- East Asian, Latin American, and Native American
mary effusion lymphoma, and plasmablastic populations. Of special note are extranodal natural
lymphoma (PBL). In these cases, diagnosis of killer (NK)/T-cell lymphomas frequently presenting
the lymphoma may give an important clue to the as ulcerative or even midpalatal destructive lesions.
diagnosis of HIV infection (Diamond et al. 2006; These clinical features are the result of the
Engels et al. 2006). angioinvasive and angiodestructive properties of
Various types of T-cell lymphomas may also these neoplasms, usually originating from the nasal
involve the oral cavity and jaw bones albeit much mucosa (Kwong and Khong 2011).
Etiology Table 2 2016 WHO classification of mature lymphoid,

To discuss the etiology and pathophysiology of histiocytic, and dendritic neoplasms (Swerdlow et al. 2016)
lymphomas is beyond the scope of this text as it Mature B-cell neoplasms
varies between different types of lymphomas. A Chronic lymphocytic leukemia/small lymphocytic
combination of viral and complex genetic pathol- lymphoma
Monoclonal B-cell lymphocytosis
ogy is accepted as the most common, general
B-cell prolymphocytic leukemia
etiological pathways for the development of lym-
Splenic marginal zone lymphoma
phoma. The World Health Organization (WHO)
Hairy cell leukemia
classification of tumors of hematopoietic and lym-
Splenic B-cell lymphoma/leukemia, unclassifiable
phoid tissues includes a combination of cellular Splenic diffuse red pulp small B-cell lymphoma
morphology, immunophenotype, genetic, molec- Hairy cell leukemia-variant
ular, and clinical features in the diagnostic criteria Lymphoplasmacytic lymphoma
and classification of these neoplasms. Since the Waldenström macroglobulinemia
2008 WHO classification, major advances with Monoclonal gammopathy of undetermined
significant clinical and biologic implications significance (MGUS), IgM
have been made. Following a Clinical Advisory μ heavy-chain disease
Committee meeting in 2014 aimed at multi- γ heavy-chain disease
disciplinary consultation and agreement critical α heavy-chain disease
to the revision, a revision of the classification Monoclonal gammopathy of undetermined
significance (MGUS), IgG/A
was published in 2016 (Table 2) highlighting sev-
Plasma cell myeloma
eral new entities (Swerdlow et al. 2016).
Solitary plasmacytoma of bone
Extraosseous plasmacytoma
Clinical-Pathologic Features Monoclonal immunoglobulin deposition diseases
The clinical features of a patient with jaw bone Extranodal marginal zone lymphoma of mucosa-
involvement by lymphoma will generally depend associated lymphoid tissue (MALT lymphoma)
on the type of lymphoma, the anatomical location Nodal marginal zone lymphoma
of jaw bone involvement, immune status of the Pediatric nodal marginal zone lymphoma
patient involved, as well as whether it is a primary Follicular lymphoma
or secondary jaw bone lymphoma. Primary jaw In situ follicular neoplasia
bone lymphomas reported in the literature usually Duodenal-type follicular lymphoma
present as a well- or poorly circumscribed lytic Pediatric-type follicular lymphoma
bone lesion with or without resorption of the Large B-cell lymphoma with IRF4 rearrangement
adjacent tooth roots. These lesions may be con- Primary cutaneous follicle center lymphoma
Mantle cell lymphoma
fused with periapical bone pathology or even
In situ mantle cell neoplasia
gnathic osteomyelitis (Jessri et al. 2013)
Diffuse large B-cell lymphoma (DLBCL), NOS
(Fig. 50). Cases of hematolymphoid neoplasms
Germinal center B-cell type
mimicking bisphosphonate-related osteonecrosis
Activated B-cell type
of the jaw have also been reported (Gander et al. T-cell/histiocyte-rich large B-cell lymphoma
2014). Primary DLBCL of the central nervous system (CNS)
Intermittent pain of various degrees, swelling, Primary cutaneous DLBCL, leg type
palpable masses, and sometimes even systemic EBV+ DLBCL, NOS
signs such as weight loss and pyrexia may all EBV+ mucocutaneous ulcer
signify lymphomatous involvement of the jaw DLBCL associated with chronic inflammation
bone, either primary or secondary. In the case of Lymphomatoid granulomatosis
secondary involvement due to infiltration from Primary mediastinal (thymic) large B-cell lymphoma
adjacent tissue, boggy, soft, hemorrhagic, or Intravascular large B-cell lymphoma
even ulcerated soft-tissue masses may overlie ALK+ large B-cell lymphoma
jaw bone destruction. The latter may be clinically Plasmablastic lymphoma
(continued)
Table 2 (continued) Table 2 (continued)

Primary effusion lymphoma Nodular sclerosis classical Hodgkin lymphoma
HHV8+ DLBCL, NOS Lymphocyte-rich classical Hodgkin lymphoma
Burkitt lymphoma Mixed cellularity classical Hodgkin lymphoma
Burkitt-like lymphoma with 11q aberration Lymphocyte-depleted classical Hodgkin lymphoma
High-grade B-cell lymphoma, with MYC and BCL2 Posttransplant lymphoproliferative disorders (PTLD)
and/or BCL6 rearrangements Plasmacytic hyperplasia PTLD
High-grade B-cell lymphoma, NOS Infectious mononucleosis PTLD
B-cell lymphoma, unclassifiable, with features Florid follicular hyperplasia PTLD
intermediate between DLBCL and classical Hodgkin Polymorphic PTLD
lymphoma
Monomorphic PTLD (B- and T-/NK-cell types)
Mature T and NK neoplasms
Classical Hodgkin lymphoma PTLD
T-cell prolymphocytic leukemia
Histiocytic and dendritic cell neoplasms
T-cell large granular lymphocytic leukemia
Histiocytic sarcoma
Chronic lymphoproliferative disorder of NK cells
Langerhans cell histiocytosis
Aggressive NK-cell leukemia
Langerhans cell sarcoma
Systemic EBV+ T-cell lymphoma of childhood
Indeterminate dendritic cell tumor
Hydroa vacciniforme-like lymphoproliferative
Interdigitating dendritic cell sarcoma
disorder
Follicular dendritic cell sarcoma
Adult T-cell leukemia/lymphoma
Fibroblastic reticular cell tumor
Extranodal NK-/T-cell lymphoma, nasal type
Disseminated juvenile xanthogranuloma
Enteropathy-associated T-cell lymphoma
Monomorphic epitheliotropic intestinal T-cell
lymphoma
Indolent T-cell lymphoproliferative disorder of the GI visible as mobile teeth due to direct periodontal
tract destruction or as extensive bone destruction visu-
Hepatosplenic T-cell lymphoma alized on radiographic imaging.
Subcutaneous panniculitis-like T-cell lymphoma
Mycosis fungoides Patient Management
Sézary syndrome The diagnosis of lymphoma is always made on
Primary cutaneous CD30+ T-cell lymphoproliferative histological diagnosis of a biopsy from the suspi-
disorders
cious area or lesion. The diagnostic criteria of
Lymphomatoid papulosis
lymphomas currently include a wide array of
Primary cutaneous anaplastic large-cell lymphoma
Primary cutaneous γδ T-cell lymphoma
highly specialized immunohistochemical and
Primary cutaneous CD8+ aggressive epidermotropic genetic investigations undertaken by a specialist
cytotoxic T-cell lymphoma hematopathologist after which treatment is fully
Primary cutaneous acral CD8+ T-cell lymphoma the responsibility of an oncologist. The spectrum
Primary cutaneous CD4+ small/medium T-cell of treatment options employed for the manage-
lymphoproliferative disorder ment of these neoplasms is beyond the scope of
Peripheral T-cell lymphoma, NOS this text and may, depending on the type of lym-
Angioimmunoblastic T-cell lymphoma phoma, include chemotherapy, immunotherapy,
Follicular T-cell lymphoma
radiation oncology, targeted therapy, stem cell
Nodal peripheral T-cell lymphoma with TFH
transplants, and in rare cases surgery.
phenotype
Anaplastic large-cell lymphoma, ALK+
Anaplastic large-cell lymphoma, ALK
Breast implant-associated anaplastic large-cell Multiple Myeloma
lymphoma
Hodgkin lymphoma Epidemiology
Nodular lymphocyte predominant Hodgkin lymphoma Multiple myeloma (MM) is a systemic malignant
Classical Hodgkin lymphoma lymphoproliferative disease of cytogenetically
(continued)
Fig. 50 (a) Primary diffuse large B-cell Non-Hodgkin premolar, and first and second molars which have been
lymphoma presenting intra-orally as a 1cm swelling on endodontically treated. There is loss of crestal bone
the labial aspect of the lower left molars (36 and 37). (b) between these teeth (black arrow) (Images courtesy of
Cropped orthopantomograph showing a diffuse radiolu- Professor Camile Farah, Queensland Oral Medicine &
cency (white oval) involving the mandibular second Pathology, Brisbane QLD, Australia)
Fig. 51 Multiple myeloma

demonstrating clonal
plasma cells (Hematoxylin
courtesy of Dr Chris Angel,
Australian Clinical Labs,
Melbourne VIC, Australia)
heterogeneous clonal plasma cells (Fig. 51) which MGUS and MM that precedes development of the
may also include pathological involvement of the malignant disease. Prognostic models to predict
jaw bones. MM is preceded by a premalignant progression rates of either MGUS or smoldering
condition termed monoclonal gammopathy of MM to full blown MM have been proposed but
undetermined significance (MGUS). In a small lack concordance (Cherry et al. 2013). The rate of
percentage of patients, MGUS is followed by smol- MGUS progression to MM is currently accepted as
dering MM, an intermediate clinical stage between 05–1% per year, influenced by the concentration
and type of the monoclonal protein, serum free least 5 mm or more are required, which may include
light-chain ratio, bone marrow plasmacytosis, pro- any of the jaw bones. Increased uptake on PET-CT,
portion of phenotypically clonal plasma cells, and the presence of osteoporosis, vertebral compression
the presence of immunoparesis (Rajkumar et al. fractures, or bone densitometric changes alone are
2014). In the case of smoldering MM, the progres- not adequate, and evidence of actual osteolytic bone
sion to MM is much higher. A population-based destruction is necessary. The three biomarkers now
study from Scandinavia recently determined smol- included in the diagnostic criteria are (i) clonal bone
dering MM to account for about 14% of all patients marrow plasma cells greater than or equal to 60%;
with MM (Kristinsson et al. 2013). (ii) serum free light-chain (FLC) ratio of 100 or
higher, provided involved FLC level is 100 mg/L
Etiology or higher; or (iii) more than one focal lesion on MRI
MM is the result of a multistep transformation pro- (Fig. 53) (Rajkumar et al. 2014). Inclusion of these
cess which includes the MGUS as a premalig- changes enables earlier diagnosis with quicker initi-
nant state. Translocations, somatic mutations, copy ation of therapy and more effective prevention of
number, and/or epigenetic changes in MGUS define end-organ damage in high-risk patients. Earlier
early pathways in MM oncogenesis. MGUS pro- intervention reduces the incidence of acute renal
gress to one of two main groups of MM. The first, failure and pathological fractures frequently encoun-
also known as the hyperdiploid myeloma subgroup, tered in these individuals, both leading to substan-
is characterized by odd-number chromosome tive long-term morbidity for affected patients.
trisomies. The second, or the non-hyperdiploid mye- Disease biology of MM is reflected by the
loma subgroup, exhibits recurrent chromosomal molecular subtype as defined by the specific cyto-
translocations involving the IgH locus (14q32). genetic abnormalities (Kumar et al. 2012). The
Irrespective of the pathway followed, over- newly proposed staging system incorporates
expression of cyclin D follows. Certain genomic high-risk cytogenetic abnormalities in addition
variants are known to carry prognostic significance to standard laboratory markers of prognosis
and form the basis for the development of novel (Rajkumar 2016).
targeted therapy regimes (Smith and Yong 2016;
Weaver and Tariman 2017). Patient Management
The survival rate of patients diagnosed with MM
Clinical-Pathologic Features varies widely and depends on a variety of host
MM is diagnosed according to a set list of criteria factors, tumor burden (disease stage), biology
determined by the International Myeloma Working (cytogenetic abnormalities), and response to ther-
Group. The group revised their diagnostic criteria apy (Russell and Rajkumar 2011). Although the
and staging system for MM in 2014 allowing the treatment of patients with MM is beyond the
use of specific biomarkers in addition to the scope of this text, it is worth noting that the last
established CRAB features (calcium elevation, decade has seen emergence of numerous new drug
renal insufficiency, anemia, and bone abnormalities) therapies including immunomodulating agents
as well as the inclusion of computerized tomogra- and proteasome inhibitors changing the previous
phy (CT) (Fig. 52) and F-fluorodeoxyglucose approaches utilizing high-dose chemotherapy and
positron emission tomography with computed stem cell transplantation (Cartier et al. 2015;
tomography (PET-CT) to diagnose MM-related Shank et al. 2015; Armoiry et al. 2017).
bone disease (Rajkumar et al. 2014). These addi-
tions followed on from a systematic review which
compared various imaging techniques for the detec- Plasmacytoma
tion of skeletal lesions in MM. The study proved a
greater sensitivity with detection of 80% more Epidemiology
lesions by CT and PET-CT (Regelink et al. 2013). Plasmacytoma is an uncommon neoplastic prolif-
One or more sites of osteolytic bone destruction of at erations of monoclonal plasma cells, the last
Fig. 52 Multiple myeloma of the left mandibular body. cortical bone of the edentulous posterior segment of the
CT oblique sagittal bone window (a), axial soft-tissue post left mandibular body (white dotted arrows in a and c)
contrast (b), and axial bone window (c). A large soft-tissue (Images courtesy of Clinical Associate Professor Andy
mass causes (white arrows in b) protrudes into the buccal Whyte, Perth Radiological Clinic, Perth WA, Australia)
sulcus and causes permeative erosion of medullary and
differentiation stage of B-lymphocytes, which many similarities, medullary (SBP) and extra-
may occur either as solitary bone lesions (solitary medullary plasmacytomas are considered distinct
plasmacytoma of bone) (SBP) or as soft-tissue clinical entities with SBP showing a much higher
lesions (extramedullary plasmacytoma). predisposition to evolve into multiple myeloma
Plasmacytoma of bone represents 5–10% of all (MM) (Kilciksiz et al. 2012).
plasma cell neoplasms in which case it mostly
occurs in the bones of the axial skeleton, such as Etiology
the vertebra and skull (Dimopoulos et al. 2000). Solitary plasmacytomas are rare lesions, and no
SBP in the jaw bones is very rare and mostly studies relating to the etiology or genetic abnor-
reported as single case reports (Kanazawa et al. malities of plasmacytoma series are available.
1993; Di Micco et al. 2002; Anil 2007; Marotta Population-based studies on these neoplasms did
and Di Micco 2010; Ghazizadeh et al. 2015; not evaluate the genetic aberrations compared to
Allegra et al. 2016). MM (de Waal et al. 2016; Nahi et al. 2017). The
Extramedullary plasmacytoma (EMP) occur- high transformation probability of SBP to MM
ring in the soft tissue of the head and neck is proves a need to find predictive factors for trans-
extremely rare, although more than 80% affects formation including genetic features that may pre-
this region (Galieni et al. 2000). Irrespective of dict a higher transformation rate.
Fig. 53 Multiple myeloma involving the mandibular with a further small enhancing deposit in the right condyle
symphysis and right condyle. MRI T1 axial (a), T1 coronal (dashed white arrow in d) (Images courtesy of Clinical
(b), and post gadolinium T1 coronal (c and d). There is a Associate Professor Andy Whyte, Perth Radiological
homogeneously enhancing, solid mass replacing marrow Clinic, Perth WA, Australia)
of the mandibular symphysis (white arrows in a, b, and c)
Clinical-Pathologic Features The diagnosis is based on the presence of a

The median age of a patient with any form of solitary bone lesion confirmed by thorough skel-
plasmacytoma is 55 years with a male-to-female etal survey, plasma cell infiltration proven by
ratio of approximately 2:1 and a slightly higher biopsy, <10% plasma cells on bone marrow
incidence in black patients (Dores et al. 2009). biopsy, and lack of CRAB (calcium elevation,
Although the incidence rate rises with age; it is renal insufficiency, anemia, and bone abnormal-
less common than MM at old age. SBP involv- ities apart from the localized lesion in the jaw) to
ing only the head and neck is very rare and is exclude MM.
then usually situated in the sinonasal tract as On microscopic examination of a biopsy from
extramedullary lesions more than the jaw bones the bone lesion, monomorphic collections of
(Marotta and Di Micco 2010). Progressive plasma cells are seen (Fig. 54). The lineage of
swelling with eventual involvement of the over- the plasma cells may be confirmed by immuno-
lying mucosa is sometimes encountered in jaw histochemical markers, especially in cases with
cases (Di Micco et al. 2002). SBP of the jaw less mature plasma cell morphology such as
follows the same age and gender predilection plasmablastic or even anaplastic plasmacytomas,
as those affecting other bones, presenting as a variants seen with higher frequency in HIV
localized lesion commonly associated with pain, infected individuals (Lorsbach et al. 2011).
bone destruction, and pathological fractures. Kappa or Lambda light-chain restriction is
Fig. 54 Plasmacytoma of
bone demonstrating
monomorphic collections of
plasma cells (Hematoxylin
courtesy of Dr Chris Angel,
Australian Clinical Labs,
Melbourne VIC, Australia)
usually confirmed by special investigations that were demonstrated to be the only two independent
include immunohistochemistry and in situ poor prognostic factors for overall survival and
hybridization (preferred) showing intra- disease-free survival in these patients (Zhu et al.
cytoplasmic monoclonal immunoglobulin pro- 2016).
duction. Secretory plasmacytoma produces Plasmacytoma may recur after treatment, pro-
immunoglobulins; may be associated with gress to MM, or develop new bone lesions with-
blood calcium level alterations, kidney dysfunc- out progression to MM. Literature with respect to
tion, and elevated serum β-2-microglobulin the factors that influence the risk and frequency of
levels; and may be associated with POEMS syn- progression to MM is controversial. The risk of
drome (polyneuropathy, organomegaly, endo- recurrence or progression to myeloma within
crinopathy, MM, and skin changes) (Di Micco 3 years is approximately 10% for patients with
and Di Micco 2005). Plasmacytomas of bone solitary plasmacytoma (Rajkumar et al. 2014).
most commonly give an isointense signal on Localized radiation therapy at 40–50 Gy to the
T1-weighted images and an iso- to hyperintense involved site remains the treatment of choice, and
signal on T2-weighted images with contrast there is no role for systemic chemotherapy in the
enhancement on CT or MRI (Ooi et al. 2006). management of these lesions (Kilciksiz et al.
The inclusion of CT, and PET-CT, in the diag- 2012; Rajkumar et al. 2014). The risk for local
nostic armamentarium of MM was recently con- recurrence after optimal radiation therapy is less
firmed by the International Myeloma Working than 5%. Approximately 20% of patients remain
Group (Rajkumar et al. 2014). disease-free for several years; some may even be
cured (Bachar et al. 2008). Those patients in
Patient Management whom the monoclonal or M protein disappears
A clinical staging system to predict the survival of by 1 year after radiotherapy have the best disease
patients with extramedullary plasmacytomas was prognosis (Dimopoulos and Hamilos 2002).
only recently proposed, and up to now clinicians These cases are best managed by a combined
relied on MM staging systems. Lymph node team of hematologists, radiotherapists, and sur-
metastasis and a larger primary tumor (5 cm) geons and referral therefore mandatory.
Secondary Neoplasms ulceration may be seen in advanced cases with

cortical bone destruction (Fig. 57). Patients are
Metastases usually older due to the higher prevalence of
malignancies in older persons. The first sign of
Epidemiology jaw metastases may be tumor proliferation from a
Adenocarcinomas are the most common type of recent extraction socket.
malignancy metastasizing to the jaws (McClure Metastases to the jaws usually present as a
et al. 2013). The most common sites of origin poorly demarcated radiolucent lesion. A moth-
include the breast (Fig. 55), lung, kidney eaten appearance is frequently observed. Metasta-
(Fig. 56), thyroid (Fig. 57), and prostate ses affect the mandible more often than the max-
(Fig. 58) (Hirshberg et al. 2014). Any malignancy illa. Some tumor metastases, especially prostate
however has the potential to metastasize to the carcinoma, have a tendency to induce new
jaws. Metastases to the jaws are usually hematog- bone formation (Fig. 58). This will result in a
enous in nature. mixed radiolucent-radiopaque lesion (Fig. 55).
Advanced techniques such as a PET scan can be
Etiology used as an additional aid to detect metastatic
Metastasis is the process whereby malignant cells lesions.
from a primary site spread to another site in the The histological features will be dependent on
body. Metastasis to the oral cavity is not common the origin of the primary tumor (Fig. 59). Metas-
and accounts for about 1% of all oral malignancies tases are often poorly differentiated, and it may be
(Beena et al. 2011). difficult for the pathologist to determine the pre-
cise site of origin.
Many bony metastatic lesions are initially asymp- Patient Management
tomatic, although non-specific complaints like Any suspicious soft tissue or bony lesion should
pain, loosening of teeth, nerve fallout, or patho- be biopsied. Metastases may be the first sign
logical fracture may be present. Non-specific of an underlying primary tumor (Hirshberg
et al. 2014). It is critical that all tissue removed
during routine surgical procedures, including
apicectomies, is submitted for pathological
evaluation so as to identify these cases
(Raubenheimer et al. 2012). The presence of
any bone metastasis classifies the patient with
stage IV disease with obvious prognostic impli-
cations. The treatment modality available will
depend on the tumor itself.
Cysts/Cyst-Like Lesions
Nasopalatine Duct Cyst
Epidemiology
Nasopalatine duct cyst is an epithelial lined cyst
Fig. 55 CT scan of patient with metastatic breast carci-
noma to the left maxilla showing the presence of a mixed of non-odontogenic origin that is thought to be
radiopaque-radiolucent lesion due to reactive bone forma- derived from epithelial remnants within the
tion (arrow) nasopalatine (incisive) canal. The cyst may
Fig. 56 Metastatic renal cell carcinoma. CT coronal (a), and axial (f) images show additional metastases (white
sagittal (b), and axial of the left condyle and ramus (c) dotted arrows) in the clivus and the left articular eminence
demonstrate permeative radiolucency of cortical and med- as well as the lesion seen on CT in the left ramus (Images
ullary bone of the left ramus with buccal periosteal new courtesy of Clinical Associate Professor Andy Whyte,
bone formation (white arrows and white oval). Combined Perth Radiological Clinic, Perth WA, Australia)
low-dose CT isotope bone scan coronal (d), sagittal (e),
occur within the nasopalatine canal or within the

soft tissue of the incisive papilla, where the cyst
is termed a cyst of the palatine papilla (Shear and
Speight 2007; Nelson and Linfesty 2010). It is
the most common of the non-odontogenic cysts
of the maxillofacial tissues with the majority
occurring in male patients between the third and
sixth decades of life (Shear and Speight 2007).
Etiology
The etiology of these cysts is unknown, although
they are thought to be developmental in nature,
Fig. 57 Patient with a metastatic thyroid carcinoma to the being derived from epithelial remnants within the
mandible presented with an ulcerated lesion following
nasopalatine canal. The mucous glands in the
cortical destruction
fibrous wall have been implicated to possibly
Fig. 58 (a) Eighty-six-year-old male with a history of associated periosteal bone formation (yellow arrow). The
prostate cancer complained of paresthesia in left anterior sclerosis is predominantly in the inferior and buccal side of
mandible along the path of the mental nerve. The posterior the mandible displacing the left inferior alveolar nerve
mandible is edentulous and the premolar teeth are canal medially with a small defect in the lingual cortex of
uninvolved. Note a subtle radiodense area at inferior bor- the mandible anteriorly (white arrow), explaining the
der of left mandible in molar region (white arrow). (b) patient’s complaint of paresthesia (Images courtesy of Pro-
Metastatic prostate cancer to the mandible demonstrating fessor Camile Farah, Perth Oral Medicine & Dental Sleep
sclerosis of the body of the left hemimandible with Centre, Perth WA, Australia)
play a role in the pathogenesis with speculation of Radiographically, the features are highly sug-
retention of mucinous secretion. gestive presenting as a well-circumscribed,
often corticated radiolucency measuring 6 mm
Clinical-Pathologic Features or more in diameter in the midline of the anterior
Patients may be asymptomatic; however, the most hard palate (Figs. 60 and 61) (Nelson and
common symptom is a swelling in the anterior Linfesty 2010). Occasionally the lesion extends
region of the midline of the hard palate posterior between the roots of the central incisors and may
to the incisor teeth (Shear and Speight 2007; Nel- result in displacement of the roots of these teeth
son and Linfesty 2010). Cysts arising deeper within (Fig. 62). Rarely is there evidence of root
the canal may bulge into the floor of the nose. resorption.
Fig. 59 Histological
specimen of patient with
metastatic breast carcinoma
shows the presence of
metastatic adenocarcinoma
islands between bone
trabeculae (Hematoxylin
and eosin stain)
Fig. 60 Panoramic
radiograph demonstrating
pear-shaped radiolucency in
the anterior maxilla with
displacement of the roots of
the maxillary central incisor
teeth consistent with a
nasopalatine duct cyst
Most nasopalatine duct cysts are lined by non- not recur (Shear and Speight 2007; Nelson and
keratinizing stratified squamous epithelium that Linfesty 2010).
may be continuous with low cuboidal, columnar,
and pseudostratified ciliated respiratory-type epi-
thelium (Fig. 63). The cyst wall is composed of Aneurysmal Bone Cyst
fibrovascular connective tissue with interspersed
large neurovascular bundles (Fig. 64), occasional Epidemiology
lobules of mucous glands, and isolated nodules of Aneurysmal bone cyst (ABC) is a multiloculated,
benign hyaline cartilage (Shear and Speight 2007; expansile cystic lesion. Primary ABC is charac-
Nelson and Linfesty 2010). terized by rearrangement of USP6 in 70–75% of
cases (Oliveira et al. 2004; Amary et al. 2013)
Patient Management and is now regarded as a benign neoplasm rather
Complete surgical enucleation is the treatment of than a reactive process. Secondary ABC shows
choice for such lesions, and lesions generally do identical histological features but lacks USP6
Fig. 61 CT showing well-demarcated corticated enlarge-

ment of the incisive foramen consistent with a nasopalatine
duct cyst (Image courtesy of Professor Camile Farah, Fig. 62 Large well-corticated radiolucent lesion in the
Queensland Oral Medicine & Pathology, Brisbane QLD, anterior maxilla with displacement of the roots of the
Australia) maxillary central incisor teeth and superimposition of the
nasal septum
rearrangement (Oliveira et al. 2004; Flanagan Histologically, ABC consists of blood-filled

and Speight 2014) and, by definition, is associated spaces with intervening septa that contain
with another lesion that is usually benign, osteoclast-type giant cells, linear osteoid, woven
such as an osteoblastoma, fibrous dysplasia, bone, and bland spindle cells (fibroblasts)
chondroblastoma, giant cell tumor, or chon- (Figs. 67 and 68). Solid areas and solid variants
dromyxoid fibroma. ABC can occur at any age, of ABC can be seen. Some contain “blue bone” or
but most occur in the first two decades of life. Any “blue reticulated chondroid type material”
bone can be affected, but the most common sites (Fig. 69) (Bahk and Mirra 2015). Typically mito-
are the metaphysis of long bones (femur, tibia, ses can be frequent.
humerus) or the posterior elements of the vertebral The presence of an associated lesion distin-
bodies. The craniofacial bones can be affected, guishes secondary ABC from primary ABC and
usually by secondary ABC (Czerniak 2016). from central giant cell reparative granuloma. In
the absence of an associated lesion, FISH for
Etiology evidence of USP6 can be performed to distinguish
Primary ABC shows rearrangement of USP6. The between primary and secondary ABC.
etiology of secondary ABC is unknown. Telangiectatic osteosarcoma (tOS) may
mimic ABC at low magnification; however, on
Clinical-Pathologic Features high power, the mononuclear cells of tOS exhibit
Patients usually present with pain and or a mass anaplasia, atypical mitoses, and a permeative
but can present due to facial asymmetry pattern of growth (all three should be absent in
(Motamedi et al. 2014). Some present following ABC).
pathological fracture. Solid ABC shows many similarities to central
The radiological features of ABCs are often giant cell reparative granuloma. The presence of
distinctive. They are well-defined, expansile, USP6 rearrangement may be useful in
lucent, intramedullary cystic lesions that can distinguishing primary ABC from central giant
appear destructive and aggressive (Fig. 65). The cell reparative granuloma (Agaram et al. 2014).
affected bone appears “ballooned,” and the lesion It is always prudent to exclude hyperparathy-
has a thin shell of subperiosteal bone (Fig. 66). roidism when a biopsy demonstrates a giant cell
Multiple fluid-fluid levels are seen on MRI, a rich lesion. Recognition of USP6 rearrangement
characteristic feature. in primary ABC and peripheral giant cell
Fig. 63 Photomicrograph
showing nasopalatine duct
cyst epithelial lining
comprising pseudostratified
columnar epithelium
stain)
showing nasopalatine duct
cyst epithelial lined cyst
with a small mucous gland
within the fibrous wall
stain)
reparative granuloma, but not central giant cell Simple Bone Cyst
reparative granuloma, has refined our understand-
ing of these giant cell rich lesions, but further Epidemiology
study is required to determine the incidence of Simple bone cyst (SBC) is also known as solitary
primary ABC in the head and neck region. bone cyst or unicameral bone cyst. It is a uniloc-
ular cystic lesion filled with serous fluid. SBC can
Patient Management occur at any site but are most commonly seen in
Radiological findings are useful (especially MRI), the proximal humerus, proximal femur, or proxi-
but a biopsy is required for diagnosis. Thorough mal tibia (Kalil and Santini Araujo 2013). They
sampling and correlation with the radiological have been described at other sites, including the
findings may be necessary to identify the associ- facial bones, in which the mandible is the most
ated lesion in secondary ABC. common location. There is a male predominance
Treatment of ABC includes curettage, locally (3:1). In the mandible an association has been
applied adjuvants such as liquid nitrogen, and reported between simple bone cyst and cemento-
grafting. Primary ABC has a significant risk of osseous dysplasia (COD) (Horner and Forman
local recurrence (20–70%), and recurrent lesions 1988; Mahomed et al. 2005). Most occur in the
can be treated with repeat curettage, liquid nitro- first two decades, although those reported in asso-
gen, and grafting. ciation with COD occurred at an older age.
Fig. 65 Cropped orthopantomograph (a) showing demonstrates labial expansion and a well-defined margin
ill-defined radiolucency in anterior mandible apical to (c) (Images courtesy of Professor Camile Farah, Queens-
vital teeth. CT of same lesion shows well-defined radiolu- land Oral Medicine & Pathology, Brisbane QLD,
cency associated with lower incisors (b) which Australia)
Etiology The microscopic features include the presence

The etiology is unknown, but SBC is probably a of flocculent, eosinophilic amorphous material
developmentally derived tumor-like lesion. resembling cementum or fibrin (Fig. 72). This has
been shown to consist of collagen and decorin
Clinical-Pathologic Features (Baumhoer et al. 2011). Other microscopic features
SBC is usually asymptomatic and may be an include loose or fibrous connective tissue, hemo-
incidental finding or may present following path- siderin pigment, cholesterol clefts, osteoclast-type
ological fracture. On occasion, presentation may giant cells, and reactive woven bone (Fig. 73). The
be due to pain. fibrinous-/cementum-like material is characteristic.
On imaging, the characteristic feature is a In the absence of this, the differential diagnosis can
well-defined intramedullary lucency with a include an aneurysmal bone cyst (usually multi-
thin sclerotic margin (Figs. 70 and 71). Cortical loculated with blood-filled spaces and more cellu-
thinning can be present. Fluid content can be lar) and a post-traumatic cyst.
confirmed on MRI. In the mandible, the cyst can
be associated with root resorption. The macro- Patient Management
scopic appearance is that of a unilocular cavity If asymptomatic, SBC can be followed by imag-
containing serous or serosanguinous fluid. A ing without intervention. If there has been a path-
thin smooth membrane may be seen lining the ological fracture, if fracture is incipient, or if the
cyst. patient presents with pain, the cyst can undergo
Fig. 68 Medium-power photomicrograph of aneurysmal

bone cyst showing osteoclast-type giant cells, spindle cells,
and osteoid (Hematoxylin and eosin stain)
Fig. 66 Aneurysmal bone cyst showing affected bone

with “ballooned” appearance and thin bone shell (Image
courtesy of Professor Camile Farah, UWA Dental School,
University of Western Australia, Perth WA, Australia)
Fig. 69 High-power photomicrograph of aneurysmal

bone cyst showing so-called blue bone (Hematoxylin and
eosin stain)
Giant Cell Lesions
Fig. 67 Low-power photomicrograph of aneurysmal Cherubism

bone cyst showing blood-filled spaces with intervening
septa (Hematoxylin and eosin stain)
Epidemiology
Cherubism is a very rare disorder with only about
drainage and curettage and be packed with bone 300 cases reported, making it difficult to deter-
graft or cement. An alternative treatment involves mine a disease frequency (Chacon et al. 2007).
instillation of methylprednisolone into the cyst.
Recurrence can occur (10–20%) and is more Etiology
likely in younger patients or larger cysts (Neer Cherubism is an autosomal dominant disease with
et al. 1966). high (100%) penetrance in males and 50–70%
Fig. 70 Simple bone cyst. Axial CT, bone windows (a) root resorption (white arrows) (Images courtesy of Clinical
and oblique sagittal reconstruction from the CT scan (b). Associate Professor Andy Whyte, Perth Radiological
The margin of simple bone cysts is usually ill-defined and Clinic, Perth WA, Australia)
they insinuate between tooth roots without expansion or
Fig. 71 Plain film presentation of simple bone cyst show-

ing characteristic well-defined intramedullary lucency with
a thin sclerotic margin (Image courtesy of Professor Fig. 72 Photomicrograph of fibrin/cementum-like material
Camile Farah, UWA Dental School, University of Western in simple/solitary bone cyst (Hematoxylin and eosin stain)
penetrance in females. Variable expression of the Clinical-Pathologic Features

condition is found. Mutation of the SH3BP2 gene Cherubism is only found in the jaws and usually
on chromosome 4 has been implicated in familial occurs between the ages of 2 and 5 years. Younger
cases (Prescott et al. 2013). This mutation is prob- patients have been described (Kaugars et al.
ably associated with Msx-1 activation linked to 1992). Patients present with symmetrical, painless
increased bone formation together with abnormal swelling of the posterior region of the mandible
osteoclastic activity (Levaot et al. 2011). Cases that may interfere with mastication and speech.
presenting without an autosomal dominant inher- Lesions enlarge until puberty when they stabilize
itance pattern most likely represent spontaneous or even reduce in size. Bilateral involvement is
mutations. Cases of cherubism associated with usually present, and the maxilla is involved in the
several syndromes, including genetic disorders majority of cases.
including Noonan syndrome, Ramon syndrome, The name of the disease arises from the plump
and Fragile X syndrome, have been reported (van face appearance of young patients when all four
Capelle et al. 2007). quadrants are affected with associated pressure on
the floors of the orbits pushing the eyes upward, histological differential diagnosis of giant cell
exposing the sclera below the eye pupils. Missing lesions of the jaws (Hamner 1969; Kaugars
teeth, multiple diastemas, and misplaced teeth et al. 1992).
may be present. Mild cases may only be noticed
early in the second decade of life. Patient Management
Large areas of multilocular radiolucent lesions This diagnosis is based on the clinical features and
are present associated with thin and expanded a biopsy is not indicated. Because spontaneous
cortices and displaced teeth (Fig. 74). These are regression usually starts at puberty, it is
more prominent in the mandibular angle area recommended to allow for natural involution. If
extending into the ramus and coronoid processes cosmetic surgery (contouring) is considered, it
(Redfors et al. 2013). The condyles are usually not should be performed after puberty when regres-
affected. The radiological features are diagnostic sion and remodeling have taken place (Redfors
of this condition. et al. 2013). Early surgical intervention often leads
The histology of cherubism is basically that of to rapid regrowth of the lesions.
a giant cell lesion in a cellular vascular stroma
and is non-specific. Perivascular eosinophilic
cuffing has been reported and may aid in the Central Giant Cell Granuloma
Epidemiology
The majority of central giant cell granulomas
(CGCGs) are found in patients younger than
30 years of age with the mandible most often
involved. It is more common in females than
males and accounts for about 10% of benign jaw
tumors (Flanagan and Speight 2014).
Etiology
Various theories exist about the origin of the giant
cells in a CGCG. It is possible that CGCG repre-
sents the less aggressive counterpart of a giant cell
tumor (GCT) of bone usually found in long bones.
GCT occurs in older patients and has a higher
Fig. 73 Photomicrograph of cholesterol clefts in simple/ recurrence rate. The presence of mutations in his-
solitary bone cyst (Hematoxylin and eosin stain) tone 3.3 in the majority of GCTs further supports
Fig. 74 The multilocular

nature and thinning of
cortices are clearly visible
in this case of cherubism
this distinction (Behjati et al. 2013). It is also (Chuong et al. 1986). Distinguishing between
postulated that CGCG represents an abnormal these two forms is mostly done retrospectively as
response to intra-bony hemorrhage secondary to studies have failed to demonstrate any histological
trauma. or biochemical difference (Vered et al. 2007).
CGCGs present as well-demarcated multi-
Clinical-Pathologic Features locular radiolucencies, while unilocular lesions
Patients usually present with a painless buccal and are more frequently associated with smaller
lingual bone expansion, although cortical perfora- lesions. Cortical expansion and teeth displace-
tion can be present (Fig. 75). CGCGs are divided ment are common findings, and root resorption
into aggressive and nonaggressive forms based on may be present (Figs. 76, 77, and 78). A predilec-
clinical and radiological features. About 70% are tion for the anterior part of the jaws exists.
slow growing and asymptomatic, while the Histologically, this lesion consists of giant
remaining 30% have an aggressive and more cells, closely associated with vascular vessels
destructive behavior (Vered et al. 2008). The aggres- and areas of hemorrhage, in a cellular stroma
sive form affects patients at an earlier age, is larger at containing uniform fibroblasts. Hemosiderin pig-
time of diagnosis, and recurs more frequently ment, on its own or within histiocytes, is often
Fig. 75 Central giant cell granuloma. Painless expansile lump distal and buccal to the lower right second molar (47)
palatal swelling in a female teenager causing some displace- in a 28 year old male patient (c). On Cone Beam CT, there is
ment of teeth (a). CT of lesion (b) demonstrates a large a bony defect distal to the 47 which is approximately 13 mm
radiolucency associated with the upper right canine (13). in mesiodistal dimension and 6 mm in depth causing erosion
There is expansion bucco-palatally with evidence of fenes- of the lingual cortical plate (d). (Images a and b courtesy of
tration of the labial cortical plate. The lesion extends to the Professor Camile Farah, Queensland Oral Medicine &
distal aspect of the upper right lateral incisor (12) root and Pathology, Brisbane QLD, and images c and d courtesy of
the mesial of the upper right first premolar (14). There is Professor Camile Farah, Perth Oral Medicine & Dental
displacement of the 14 disto-buccally. Soft tissue gingival Sleep Centre, Perth WA, Australia)
Fig. 76 Central giant cell granuloma. Expansile lesion in calcification/septa; there is no root resorption. T1 (c) and
the left mandibular body as shown on oblique sagittal (a) post contrast T1 fat–saturation (d) axial MRI images dem-
and axial CT (b) reconstructions. Expansion leads to diver- onstrate that the lesion is of intermediate signal (c) and
gence of the lower left second premolar (35) and lower left shows diffuse enhancement (d) indicating a solid tumor
first molar (36) and elevation of the buccal cortex. The (Images courtesy of Clinical Associate Professor Andy
lesion has a corticated margin and contains internal foci of Whyte, Perth Radiological Clinic, Perth WA, Australia)
Fig. 77 Panoramic radiograph of an aggressive central giant cell granuloma in a young female with a multilocular
appearance and cortical destruction (arrow)
Fig. 79 Low-power photomicrograph of a central giant

cell granuloma showing the numerous giant cells in a
cellular stroma associated with extravasated red blood
cells (Hematoxylin and eosin stain)
investigations. Both cherubism and hyperparathy-

roidism can present as giant cell lesions. The
clinician must be cautious, especially when diag-
nosing multifocal CGCGs. Giant cell osteosarco-
mas will demonstrate features of malignancy such
as pleomorphism and atypical mitotic figures.
Fig. 78 Radiograph of an aggressive central giant cell Curettage is the treatment of choice. Recurring
granuloma demonstrating extensive bone destruction and lesions should be curetted again. Tumor regression
advanced root resorption of incisor teeth (Image courtesy with intralesional calcitonin, interferon, or steroids
of Professor Camile Farah, UWA Dental School, Univer- has recently been reported and should be consid-
sity of Western Australia, Perth WA, Australia)
ered in cases where the lesions are large prior to
performing a resection. An anti-osteolytic agent,
seen (Fig. 79). Osteoid and bone production may imatinib, was recently suggested as an option for
be present. Normal mitotic figures are frequently the treatment of CGCG (de Lange et al. 2009).
present. The giant cells usually vary in size and
shape. Although it is not possible to distinguish
between the aggressive and nonaggressive types Hyperparathyroidism
on histology, it has been suggested that tumors
where the giant cells are of uniform size and Epidemiology
distribution are more likely to behave in an Hyperparathyroidism is a condition that occurs as a
aggressive manner. These giant cells are more result of over production of parathyroid hormone
reminiscent of those seen in giant cell tumors. (PTH) by the parathyroid glands (Silverman et al.
1968; Triantafillidou et al. 2006; Jebasingh et al.
Patient Management 2008; Unni and Inwards 2010). It most commonly
These lesions cannot be diagnosed on clinical occurs in women in the third to fifth decades of life.
criteria alone, and a biopsy is compulsory.
Small, unilocular lesions may represent a variety Etiology
of cysts, depending on location, while multi- Primary hyperparathyroidism occurs as a result of
locular lesions may mimic ameloblastoma. Other uncontrolled production of PTH due to a parathy-
causes of central giant cell lesions must always be roid adenoma, hyperplasia, or, uncommonly, an
eliminated through clinical evidence or special adenocarcinoma. It may be associated with the
rare hyperparathyroid-jaw tumor syndrome radiolucencies that frequently involve the jaws
(Schmidt et al. 2009). Secondary hyperparathy- (Fig. 80). These lesions may be solitary or multi-
roidism presents as a response to hypocalcaemia ple often involving the small bones of the hand.
usually due to chronic renal failure and resultant Grossly, the lesion has a brown appearance at
excessive excretion of calcium and phosphate. time of operation as a result of hemosiderin depo-
In both types of hyperparathyroidism, the sition within the lesion. Microscopically, the
excess PTH levels results in expression of lesion is indistinguishable from a giant cell gran-
RANKL and induction of osteoclast-mediated uloma (Fig. 81). It is composed of variable num-
bone resorption resulting in generalized deminer- bers of multinucleated osteoclast-like giant cells
alization of the skeleton and focal bony lesions with surrounding spindle-shaped fibroblasts and
known as “brown tumors of hyperparathyroid- interspersed collagen. In addition, it also demon-
ism” (osteitis fibrosa cystica). strates resorption of bony trabeculae by osteo-
clasts with scattered chronic inflammatory cells
Clinical-Pathologic Features being observed including lymphocytes and mac-
Radiographically, these bony lesions present rophages. Extravasated blood with associated
as well-defined unilocular or multilocular hemosiderin-laden macrophages is present within
Fig. 80 Brown tumor of hyperparathyroidism involving metastasis, or less likely, a solid ameloblastoma (Images
the anterior maxilla in an elderly male patient. An ovoid, courtesy of Clinical Associate Professor Andy Whyte,
expansile lesion in the edentulous, anterior maxilla (white Perth Radiological Clinic, and Professor Camile Farah,
arrows in a and c) contains solid tissue (black arrows in d) Perth Oral Medicine & Dental Sleep Centre, Perth WA,
which enhances with contrast (white dotted arrows in b). Australia)
The differential diagnosis would include myeloma, a
Fig. 81 Hyperparathyroidism. Microscopically the lesion fibroblasts and interspersed collagen (Hematoxylin and
is indistinguishable from a giant cell granuloma and is eosin stain) (Image courtesy of Dr Chris Angel,
composed of variable numbers of multinucleated Australian Clinical Labs, Melbourne VIC, Australia)
osteoclast-like giant cells with surrounding spindle-shaped
the lesion which accounts for its clinical Paget’s Disease of Bone
red-brown appearance (Unni and Inwards 2010).
Epidemiology
Patient Management Paget’s disease of bone is an osseous dysplasia
Both forms of the disease are associated with that is characterized by areas of rapid turnover and
elevated levels of PTH; however, in primary remodeling with excessive bone resorption
hyperparathyroidism, patients are hypercalcemic followed by bony deposition and eventual sclero-
with the associated clinical signs and symptoms sis (Eversole et al. 2008; Unni and Inwards 2010).
(“stones, bones, and abdominal groans”), while It usually occurs in patients who are over 50 years
those with secondary hyperparathyroidism are of age with a slight male predilection and is rare
hypocalcemic. Laboratory investigations reveal under the age of 40 years. The disease may
raised serum alkaline phosphatase, calcium, and involve a single bone (monostotic) or multiple
PTH with low to normal phosphate levels. bones (polyostotic), and all bones of the craniofa-
Treatment of the patients is aimed at the cause cial complex may be affected with the maxilla
of the condition, and the bony lesions would then being affected twice as frequently as the mandible
usually resolve and require no further treatment. (Eversole et al. 2008; Unni and Inwards 2010).
For primary hyperparathyroidism, surgical resec-
tion of the involved parathyroid gland is required, Etiology
while for the secondary form, medical manage- The cause of Paget’s disease is unknown. In some
ment is undertaken including the use of vitamin D, parts of the world, such as Asia, the disease is
bisphosphonates, or calcimimetics, and in certain extremely uncommon, whereas it is relatively
cases a renal transplant may be indicated (Lessa more common in parts of the British Isles and
et al. 2005; Wuthrich et al. 2007; Resendiz- New Zealand (Eversole et al. 2008; Unni and
Colosia et al. 2008). Inwards 2010). A viral etiology has long been
considered since osteoclastic inclusions that There are several histological features which
resemble paramyxovirus have been identified as suggest a diagnosis of Paget’s disease. The fea-
well as antigens for canine distemper and respira- tures are those of a fibro-osseous lesion with bony
tory syncytial virus; however, no direct cause and trabeculae that appear thickened and irregular.
effect has been established (Eversole et al. 2008; These thickened trabeculae have irregular resting
Unni and Inwards 2010). Recently, genetic muta- and reversal (cement) lines giving rise to a mosaic
tions that affect the regulation of osteoclas- pattern (Fig. 82). Osteoblasts and osteoclasts are
togenesis have been identified in some cases prominent. The marrow is usually highly vascular
(Eversole et al. 2008). and may be replaced by fibrosis. Although these
features are typical of Paget’s disease, they are not
Clinical-Pathologic Features diagnostic. Pagetoid bone can be seen in a variety
Patients may have no symptoms; however, may of other conditions including neoplasms such as
present with bone pain that is often of long dura- osteoblastoma and osteoid osteoma.
tion. Narrowing of foramina in the skull may Laboratory investigations reveal raised serum
result in neuropathies with associated deafness, alkaline phosphatase (SAP) with normal calcium
dizziness, and headache (Eversole et al. 2008). and phosphate levels (Eversole et al. 2008). Bio-
The affected bones are enlarged, and involvement chemical markers of bone remodeling are raised.
of the maxillary alveolus results in spaces The markers of resorption include urinary
appearing between teeth or dentures that no longer hydroxyproline, serum deoxypyridinoline cross-
fit. Pathological fractures of the long bones are links, as well as N- and C-telopeptide of type
very common in Paget’s disease. 1 collagen, while elevated markers for bone depo-
Plain radiographs show a mixed radiopaque sition in addition to SAP include osteocalcin and
radiolucent lesion with thickening of the cortex N-terminal propeptide of type 1 collagen
resulting in a ground-glass pattern. With pro- (Roodman and Windle 2005).
gression of Paget’s disease, areas of patchy scle- Before making a diagnosis of Paget’s disease,
rosis and radiolucency may be noted resulting in it is important to correlate these findings with the
a so-called “cotton wool” appearance with loss radiographic appearance to ensure the features are
of the lamina dura around the associated teeth consistent with this diagnosis.
may also show evidence of hypercementosis
(Eversole et al. 2008; Unni and Inwards 2010). Patient Management
Radioisotope bone scans appear hot in Paget’s Cosmetic issues with attention to dental problems
disease. may need to be addressed, and extractions could
Fig. 82 High-power
photomicrograph of Paget’s
disease of bone
demonstrating sclerotic
bone with a mosaic
appearance as a result of
prominent basophilic
“cement lines”
stain)
result in prolonged bleeding due to the vascularity

of the involved bone. Sclerotic bone is susceptible
to infection. Calcitonin and more recently
bisphosphonates have shown prominence in
arresting the progress of this disease process.
Pain management is usually with analgesics
when indicated.
A complication of Paget’s disease of bone may
be the development of a neoplastic process such as
a giant cell tumor or sarcoma, particularly osteo-
sarcoma which may occur in less than 1% of cases
(Cheng et al. 2002; Eversole et al. 2008).
Fig. 83 Café au lait pigmentation on the skin (Image
courtesy of Clinical Associate Professor Kurt Gebauer,
Dermatology West, Perth WA, Australia)
Fibro-osseous Lesions
The fact that only a single bone is affected in
Fibrous Dysplasia monostotic fibrous dysplasia is an indication that
the mutation of the GNAS gene occurred in post-
Epidemiology natal life. This is in contrast to the McCune-
Fibrous dysplasia (FD) accounts for about 7% of Albright syndrome where the mutation occurs
all benign bone tumors (DiCaprio and Enneking early during embryonic development in the
2005). Monostotic FD is more common than poly- undifferentiated cells with the result that several
ostotic FD with a typical onset in adolescence or tissue types carry the mutation with subsequent
late childhood (Lustig et al. 2001). The gender abnormalities as seen in the syndrome. A single
prevalence is equal. FD lesion of the maxilla usually affects more than
one bone but is still considered to be monostotic in
Etiology nature. This is termed craniofacial FD (Waldron
FD is a developmental lesion resulting from a spo- 1993).
radic post-zygotic mutation in the guanine Monostotic fibrous dysplasia is the most com-
nucleotide-binding protein and alpha-stimulating mon form of FD and is usually seen in young
activity polypeptide I (GNAS1) gene located at adults as a painless swelling of the jaws, espe-
chromosome 20q, leading to abnormal bone forma- cially the maxilla, resulting in an asymmetric
tion (Shenker et al. 1994; Riminucci et al. 2010). appearance (Figs. 84 and 85). The clinical symp-
toms are linked to the area affected. Malocclusion
Clinical-Pathologic Features and tooth displacement are commonly present if
The clinical spectrum of FD depends on the time the the alveolar bone is involved, while visual distur-
mutation of the GNAS1 gene takes place (Weinstein bance is reported when the orbit is involved. Dis-
et al. 2002). FD is divided into monostotic FD placement of adjacent structures is seen in large
(occurring in one bone) and polyostotic FD (affect- lesions. FD usually stops enlarging with matura-
ing more than one bone). If multiple bones are tion of the skeleton.
affected together with café au lait pigmentation on Polyostotic fibrous dysplasia is often seen in
the skin (Fig. 83), it has been referred to as Jaffe- young persons and is usually associated with
Lichtenstein syndrome, while the McCune- gross deformities. The café au lait pigmentations
Albright’s syndrome consists of polyostotic FD, have irregular borders, which is in contrast to the
skin pigmentations, and endocrine abnormalities, pigmented lesions seen in neurofibromatosis with
notably sexual precocity. Mazabraud syndrome is smooth borders (DiCaprio and Enneking 2005).
a rare syndrome characterized by polyostotic FD The radiographic appearance of FD is as a
and soft tissue myxomas (Gaumetou et al. 2012). “ground-glass” or “smoke screen” appearance
Fig. 84 Fibrous dysplasia right maxilla and maxillary of the maxillary sinus and encasement and constriction of
sinus. CT axial (a) and coronal (b) views. Diffuse expan- the infra-orbital neurovascular canal (white arrow) (Images
sion and “ground glass” sclerosis of the right maxilla courtesy of Clinical Associate Professor Andy Whyte,
including the alveolar process and palate with obliteration Perth Radiological Clinic, Perth WA, Australia)
(Figs. 86 and 87). The lesion is poorly contraindicated because of well-documented sar-
circumscribed with no distinct borders. Cortical comatous change in these cases.
expansion is frequently observed (Fig. 88). The
lesion blends with normal surrounding bone.
The histological features of all types of FD Osseous Dysplasia
are similar and consist of irregular bone trabec-
ulae of woven bone in a loose cellular fibrous Epidemiology
stroma (Fig. 89). The bone has been described as Osseous dysplasia (OD) is only found in the
“Chinese characters.” The bone is thought to be tooth-bearing areas and is the most common
the result of metaplasia and is therefore seldom fibro-osseous lesion in the jaws. This group of
lined by osteoblasts. Peritrabecular clefting is lesions is divided into periapical, focal, and florid
postulated as a histological feature to distinguish OD (Speight and Carlos 2006). Florid OD is con-
FD from ossifying fibromas (Prado Ribeiro et al. sidered to be a more extensive form of focal and
2012). Aneurysmal bone cyst changes may periapical OD. Both periapical and florid OD
occur as a secondary phenomenon (Lustig et al. affect mainly middle-aged black women (Neville
2001). The bone trabeculae in craniofacial FD and Albenesius 1986). Focal OD is the most com-
often have a more lamellar appearance and are mon form of OD encountered.
often lined by osteoblasts; this is often in long-
standing cases and probably represents a “mat- Etiology
uration” phase (Waldron 1993). No capsule or OD is only found in the tooth-bearing areas of the
line of demarcation is present, and the lesion jaws and is not neoplastic in nature. The precise
merges with the surrounding bone. nature is uncertain although there is some evi-
dence to suggest a periodontal ligament origin
Patient Management (Kawai et al. 1999).
Clinical and radiological features are essential to
distinguish this from other fibro-osseous lesions Clinical-Pathologic Features
of the jaws. Treatment should be postponed until Periapical osseous dysplasia is commonly found
the patient has reached early adulthood if possible, below the apices of the mandibular incisor teeth
then surgery can be considered for cosmetic and presents as discreet lesions less than 1 cm in
improvement. Radiation therapy at any stage is size. The density of the lesions varies from a
Fig. 85 Fibrous dysplasia. Cropped panoramic radio- glass attenuation with loss of normal corticomedullary
graph of the left mandible (a), and axial bone reconstruc- differentiation which measures 18 x 9 x 8 mm (d). The
tion from a CT scan (b). Poorly defined, ground glass appearance is typical of a small focus of fibrous dysplasia.
opacity (white dotted arrows). Classically, arises within No adjacent soft tissue abnormality is demonstrated. No
basal bone and is expansile along the length of the bone, other focus of fibrous dysplasia is shown in the maxillofa-
elevating the inferior alveolar canal (white arrows). In a cial region and no significant bone lesion is demonstrated.
separate patient, a cropped panoramic radiograph shows (Images a and b courtesy of Clinical Associate Professor
very subtle radiolucent changes involving the right angle Andy Whyte, Perth Radiological Clinic, and images c and
of the mandible (white dotted oval) (c). CT of this patient d courtesy of Professor Camile Farah, Perth Oral Medicine
shows a mildly expansile focus of predominantly ground- & Dental Sleep Centre, Perth WA, Australia)
purely radiolucent lesion (osteolytic stage) OD. The lesions may be associated with teeth but
(Fig. 90), through a mixed lucent-opaque stage are also present in edentulous areas (Fig. 93).
(osteoblastic stage) to a solidly opaque lesion Florid osseous dysplasia presents as multiple
(mature stage) (Fig. 91). The opacity develops lucent-opaque lobulated masses affecting more
from the center of the lesion. The associated than one quadrant (Figs. 94 and 95). These masses
teeth are vital. These lesions are asymptomatic are usually present in the alveolar bone areas. The
and usually discovered accidentally on routine mandibular teeth are almost always affected. A
radiographs. similar pattern of maturation can be observed if
Focal osseous dysplasia is asymptomatic and patients are identified in the early osteolytic phase.
usually presents as a mixed lucent-opaque lesion Florid OD is also asymptomatic, although patients
less than 2 cm in size that are fairly well-demarcated may complain of secondary infection in these
(Fig. 92). Other features resemble periapical areas resulting in pain or bone sequestrum in
Fig. 86 Fibrous dysplasia affecting the posterior maxillary patient with ground glass appearance in both the maxilla and
alveolar ridge with typical ground glass appearance (white mandible (b). (Images courtesy of Professor Camile Farah,
dotted oval) (a). Widespread changes are noted in a separate Qscan Radiology Clinics, Brisbane QLD, Australia)
Fig. 87 Ground-glass appearance of fibrous dysplasia in

the mandible (arrow). Note the absence of demarcation
between the lesion and surrounding bone
Fig. 88 CT scan of a patient with polyostotic fibrous

dysplasia (arrows)
of fibrous dysplasia
demonstrating irregular
bony trabeculae in a cellular
fibrous stroma
stain)
Fig. 91 Periapical osseous dysplasia presenting as peri-

apical radiodense areas (Image courtesy of Professor
Camile Farah, UWA Dental School, University of Western
advance cases (Fig. 96). Simple bone cysts have

been reported in these lesions (Fig. 97) (Melrose
et al. 1976).
Histological features of all forms of OD resem-
ble those of cemento-ossifying fibroma and
changes with the stage of maturation. The stroma
Fig. 90 Periapical osseous dysplasia presenting as peri-
apical radiolucent areas with some degree of mineraliza- is usually very cellular, and the calcifications vary
tion. The teeth are vital from small foci of mineralization in the osteolytic
Fig. 92 Focal osseous dysplasia in the anterior mandible arrows in a). The periodontal ligament spaces are pre-
in a 42 year old female. Panoramic (a) and coronal recon- served and the lesions are not fused to the apices. Focal
structions (b) from a CT mandibular Dentascan. There is cemento-osseous dysplasia is defined as one or more peri-
an 8 mm dense, sclerotic opacity directly with a thin lucent apical sclerotic lesions in a single quadrant (Images cour-
margin inferior to the apex of 43 with additional smaller tesy of Clinical Associate Professor Andy Whyte, Perth
sclerotic foci associated with the apices of 42 and 32 (white Radiological Clinic, Perth WA, Australia)
Periapical OD should be differentiated from

periapical granulomas or early radicular cysts
associated with non-vital anterior teeth. Vitality
tests and associated symptoms are important to
differentiate between the two groups of lesions
and should aid the clinician in making the correct
diagnosis and prevent unnecessary endodontic
treatment.
Focal OD may be difficult (sometimes impossi-
ble) to distinguish from idiopathic osteosclerosis or
focal sclerosing osteomyelitis that has remained
after extraction of the associated tooth.
Fig. 93 Radiograph shows an area of focal osseous dys-
plasia (arrow) A biopsy to confirm the diagnosis, especially
in the florid form of OD, is not indicated because
stage to dense sclerotic bone in the mature stage of the risk of infection in the dense relative avas-
(Fig. 98). cular bony masses. Extraction of teeth associated
with the sclerotic masses should be avoided as
Patient Management far as possible. With infection, sequestration of
Clinical and radiological features are usually the involved areas is frequently seen. Almost
pathognomonic. all cases of the entity “diffuse sclerosing
Fig. 94 Florid osseous dysplasia: panoramic (superior) 33 are sclerotic, the lesions associated with 32–41 and
and radial (inferior row of images) reconstructions from 43 are lucent. The lesions around the intact apices and
CBCT. There are multiple lucent, sclerotic, and mixed roots of 37 and 46 are of mixed attenuation (Images cour-
density lesions associated with the apices of virtually all tesy of Clinical Associate Professor Andy Whyte, Perth
mandibular teeth. The lesions associated with teeth 47 and Radiological Clinic, Perth WA, Australia)
Fig. 95 Panoramic view of florid osseous dysplasia with radiopaque areas in the mandible
osteomyelitis” are cases of florid OD with sec-

ondary infection.
Conclusions and Future Directions
Management of patients with bone tumors and

tumor-like lesions requires a team approach.
Good communication between radiologist,
attending maxillofacial or head and neck surgeon,
and pathologist is imperative for accurate inter-
Fig. 96 Necrotic bone sequestrum (arrow) of the right pretation and diagnosis of these lesions. Patholo-
mandible in a patient with florid cemento-osseous dysplasia gists who attempt to make a diagnosis of bony
Fig. 97 Simple bone cyst developing in florid osseous there is interval expansion, and increased radiolucency
dysplasia. CBCT axial views (a + c) and cropped and apical resorption, of the similar process in the right
reconstructed panoramic views of the right mandible (b + mandibular body extending from teeth 44 to 47. There is
d) of a 34 year old female with florid cemento-osseous thinning of the buccal and lingual cortices and inferior
dysplasia. (a) and (b) show initial presentation at age 34 of extension to involve the superior cortical margin of the
multiple foci of altered bone pattern in the left and right inferior alveolar canal both in the 2nd and 3rd molar
mandible consistent with osseous dysplasia undergoing regions. This is considered to represent increase in size of
various stages of maturity. There is expansion and thinning associated simple bone cysts (c + d). (Images courtesy of
of the buccal cortical plate in the 45 and 46 positions (a). Dr Marie Anne Matias and Clinical Associate Professor
There are radiopaque (black arrows) and radiolucent Andy Whyte, Perth Radiological Clinic, Perth WA,
(white arrows) areas seen in (b) at initial presentation Australia)
associated with teeth 45, 46 and 47. 10 months later,
References
Adler CP, Wold L. Hemangioma and related lesions. In:
Fletcher CDM, Unni KK, Mertens F, editors. Pathology
and genetics of tumours of soft tissue and bone. Lyon:
IARC; 2002. p. 320–1.
Agaram NP, LeLoarer FV, Zhang L, Hwang S, Athanasian
EA, Hameed M, Antonescu CR. USP6 gene
rearrangements occur preferentially in giant cell repar-
ative granulomas of the hands and feet but not in
gnathic location. Hum Pathol. 2014;45(6):1147–52.
Agrawal MG, Agrawal SM, Kambalimath
DH. Non-Hodgkins lymphoma of maxilla: a rare entity.
Natl J Maxillofac Surg. 2011;2(2):210–3.
Akiner MN, Akturk MT, Demirtas M, Atmis
EO. Intraosseous cavernous hemangioma of inferior
Fig. 98 Higher magnification of osseous dysplasia shows turbinate: a rare case report. Case Rep Otolaryngol.
the prominent irregular bone trabeculae (arrows) in a cel- 2011;2011:431365.
lular, vascular stroma in the osteoblastic phase (Hematoxy- Allegra A, Nastro Siniscalchi E, Cicciu M, Bacci F,
lin and eosin stain) Catalfamo L, Innao V, De Ponte FS, Musolino
C. Extramedullary plasmacytoma of the maxilla simu-
lating a maxillary radicular cyst: quick diagnosis and
management. J Craniofac Surg. 2016;27(3):e296–7.
lesions without the clinical and radiographic Allen CE, Li L, Peters TL, Leung HC, Yu A, Man TK,
information are at a distinct disadvantage, and Gurusiddappa S, Phillips MT, Hicks MJ, Gaikwad A,
Merad M, McClain KL. Cell-specific gene expression
this is to be strongly discouraged.
in Langerhans cell histiocytosis lesions reveals a dis-
Continued progress and advances in molec- tinct profile compared with epidermal Langerhans
ular diagnostic techniques are improving cells. J Immunol. 2010;184(8):4557–67.
our understanding of the etiology of the Alves S, Junqueira JL, de Oliveira EM, Pieri SS, de
Magalhaes MH, Dos Santos Pinto D Jr, Mantesso
various lesions, and the resultant development
A. Condylar hemangioma: report of a case and review
of personalized management strategies. The of the literature. Oral Surg Oral Med Oral Pathol Oral
current gold standards of histopathology and Radiol Endod. 2006;102(5):e23–7.
immunohistochemistry will be accompanied by Amary MF, Bacsi K, Maggiani F, Damato S, Halai D,
Berisha F, Pollock R, O’Donnell P, Grigoriadis A,
techniques such as fluorescence in situ hybridi-
Diss T, Eskandarpour M, Presneau N, Hogendoorn
zation, next-generation sequencing, and proteo- PC, Futreal A, Tirabosco R, Flanagan AM. IDH1 and
mics resulting in the diagnosis and management IDH2 mutations are frequent events in central
of these diseases involving bones to be based chondrosarcoma and central and periosteal
chondromas but not in other mesenchymal tumours.
upon their specific genetic footprints.
J Pathol. 2011;224(3):334–43.
Amary MF, Ye H, Berisha F, Tirabosco R, Presneau N,
Flanagan AM. Detection of USP6 gene rearrangement
Cross-References in nodular fasciitis: an important diagnostic tool.
Virchows Arch. 2013;463(1):97–8.
Anil S. Solitary plasmacytoma of the maxilla – a case
▶ Clinical Evaluation of Oral Diseases report and review of the literature. Gen Dent. 2007;55
▶ Diagnostic Imaging Principles and Applica- (1):39–43.
tions in Head and Neck Pathology Arico M. Langerhans cell histiocytosis in children: from
the bench to bedside for an updated therapy. Br J
▶ Head and Neck Tumors
Haematol. 2016;173(5):663–70.
▶ Laboratory Medicine and Diagnostic Pathology Armah HB, McGough RL, Goodman MA, Gollin SM,
▶ Odontogenic Pathology Surti U, Parwani AV, Rao UN. Chondromyxoid
▶ Oral and Maxillofacial Viral Infections fibroma of rib with a novel chromosomal translocation:
a report of four additional cases at unusual sites. Diagn
▶ Pediatric Oral Medicine
Pathol. 2007;2:44.
▶ Soft and Hard Tissue Operative Investigations Armoiry X, Tsertsvadze A, Connock M, Melendez-Torres
in the Diagnosis and Treatment of Oral Disease GJ, Clarke A. Systematic review and network meta-
analysis of treatment outcomes for multiple myeloma. review and meta-analysis of published clinical trial
J Clin Oncol. 2017;35:2975–6. data. Oncol Res Treat. 2015;38(3):88–94.
Bacci G, Ferrari S, Bertoni F, Rimondini S, Longhi A, Chacon GE, Ugalde CM, Jabero MF. Genetic disorders and
Bacchini P, Forni C, Manfrini M, Donati D, Picci bone affecting the craniofacial skeleton. Oral
P. Prognostic factors in nonmetastatic Ewing’s sarcoma Maxillofac Surg Clin North Am. 2007;19(4):467–74, v
of bone treated with adjuvant chemotherapy: analysis Cheng YS, Wright JM, Walstad WR, Finn
of 359 patients at the Istituto Ortopedico Rizzoli. J Clin MD. Osteosarcoma arising in Paget’s disease of the
Oncol. 2000;18(1):4–11. mandible. Oral Oncol. 2002;38(8):785–92.
Bachar G, Goldstein D, Brown D, Tsang R, Lockwood G, Cheng NC, Lai DM, Hsie MH, Liao SL, Chen
Perez-Ordonez B, Irish J. Solitary extramedullary YB. Intraosseous hemangiomas of the facial bone.
plasmacytoma of the head and neck – long-term outcome Plast Reconstr Surg. 2006;117(7):2366–72.
analysis of 68 cases. Head Neck. 2008;30(8):1012–9. Cherry BM, Korde N, Kwok M, Manasanch EE,
Bahk WJ, Mirra JM. Differential diagnostic value of “blue Bhutani M, Mulquin M, Zuchlinski D, Yancey MA,
reticulated chondroid-like material” in aneurysmal Maric I, Calvo KR, Braylan R, Stetler-Stevenson M,
bone cysts: a classic histopathologic analysis of Yuan C, Tembhare P, Zingone A, Costello R,
215 cases. Am J Clin Pathol. 2015;143(6):823–9. Roschewski MJ, Landgren O. Modeling progression
Barnes L. Solitary hemangioma of bone. In: Barnes L, risk for smoldering multiple myeloma: results from a
editor. Surgical pathology of the head and neck, vol. prospective clinical study. Leuk Lymphoma. 2013;54
1. New York: Dekker; 1985. p. 932–6. (10):2215–8.
Baumhoer D, Smida J, Nathrath M, Jundt G. The nature of Chi AC, Carey J, Muller S. Intraosseous schwannoma of
the characteristic cementum-like matrix deposits in the the mandible: a case report and review of the literature.
walls of simple bone cysts. Histopathology. 2011;59 Oral Surg Oral Med Oral Pathol Oral Radiol Endod.
(3):390–6. 2003;96(1):54–65.
Beena V, Panda S, Heera R, Rajeev R. Multiple metastatic Chuong R, Kaban LB, Kozakewich H, Perez-Atayde
tumors in the oral cavity. J Oral Maxillofac Pathol. A. Central giant cell lesions of the jaws: a clinicopath-
2011;15(2):214–8. ologic study. J Oral Maxillofac Surg. 1986;44
Behjati S, Tarpey PS, Presneau N, Scheipl S, Pillay N, Van (9):708–13.
Loo P, Wedge DC, Cooke SL, Gundem G, Davies H, Coleman H, Chandraratnam E, Morgan G, Gomes L,
Nik-Zainal S, Martin S, McLaren S, Goody V, Bonar F. Synovial chondrosarcoma arising in synovial
Robinson B, Butler A, Teague JW, Halai D, Khatri B, chondromatosis of the temporomandibular joint. Head
Myklebost O, Baumhoer D, Jundt G, Hamoudi R, Neck Pathol. 2013;7(3):304–9.
Tirabosco R, Amary MF, Futreal PA, Stratton MR, Conner JR, Hornick JL. SATB2 is a novel marker of
Campbell PJ, Flanagan AM. Distinct H3F3A and osteoblastic differentiation in bone and soft tissue
H3F3B driver mutations define chondroblastoma and tumours. Histopathology. 2013;63(1):36–49.
giant cell tumor of bone. Nat Genet. 2013;45 Czerniak B. Dorfman and Czerniak’s bone tumors. Phila-
(12):1479–82. delphia: Elsevier Saunders; 2016.
Belli E, Becelli R, Matteini C, Iannetti G. Schwannoma of Dalili Z, Adham G. Intraosseous neurofibroma and con-
the mandible. J Craniofac Surg. 1997;8(5):413–6. current involvement of the mandible, maxilla and orbit:
Bertoni F, Dallera P, Bacchini P, Marchetti C, Campobassi report of a case. Iran J Radiol. 2012;9(1):45–9.
A. The Istituto Rizzoli-Beretta experience with osteo- Damato S, Alorjani M, Bonar F, McCarthy SW, Cannon
sarcoma of the jaw. Cancer. 1991;68(7):1555–63. SR, O’Donnell P, Tirabosco R, Amary MF, Flanagan
Beziat JL, Marcelino JP, Bascoulergue Y, Vitrey D. Central AM. IDH1 mutations are not found in cartilaginous
vascular malformation of the mandible: a case report. tumours other than central and periosteal
J Oral Maxillofac Surg. 1997;55(4):415–9. chondrosarcomas and enchondromas. Histopathology.
Bohm P, Krober S, Greschniok A, Laniado M, Kaiserling 2012;60(2):363–5.
E. Desmoplastic fibroma of the bone. A report of two De Alava E, Lessnick SL, Sorensen PH. Ewing sarcoma.
patients, review of the literature, and therapeutic impli- Lyon: IARC Press; 2013.
cations. Cancer. 1996;78(5):1011–23. de Lange J, van Rijn RR, van den Berg H, van den Akker
Bruce KW. Solitary neurofibroma (neurilemmoma, HP. Regression of central giant cell granuloma by a
schwannoma) of the oral cavity. Oral Surg Oral Med combination of imatinib and interferon: a case report.
Oral Pathol. 1954;7(11):1150–9. Br J Oral Maxillofac Surg. 2009;47(1):59–61.
Capodiferro S, Maiorano E, Giardina C, Lacaita MG, Lo de Waal EG, Leene M, Veeger N, Vos HJ, Ong F, Smit WG,
Muzio L, Favia G. Osteoblastoma of the mandible: Hovenga S, Hoogendoorn M, Hogenes M, Beijert M,
clinicopathologic study of four cases and literature Diepstra A, Vellenga E. Progression of a solitary
review. Head Neck. 2005;27(7):616–21. plasmacytoma to multiple myeloma. A population-
Cartier S, Zhang B, Rosen VM, Zarotsky V, Bartlett JB, based registry of the northern Netherlands. Br J
Mukhopadhyay P, Wagner S, Davis C. Relationship Haematol. 2016;175(4):661–7.
between treatment effects on progression-free survival Deichler J, Martinez R, Niklander S, Seguel H,
and overall survival in multiple myeloma: a systematic Marshall M, Esguep A. Solitary intraosseous
neurofibroma of the mandible. Apropos of a case. Med surgical considerations and follow-up in three cases.
Oral Patol Oral Cir Bucal. 2011;16(6):e704–7. J Craniomaxillofac Surg. 2013;41(5):367–70.
Dhiman NK, Jaiswara C, Kumar N, Patne SC, Pandey A, Flanagan AM, Speight PM. Giant cell lesions of the
Verma V. Central cavernous hemangioma of mandible: craniofacial bones. Head Neck Pathol. 2014;8
case report and review of literature. Natl J Maxillofac (4):445–53.
Surg. 2015;6(2):209–13. Folpe AL, Goldblum JR, Rubin BP, Shehata BM, Liu W,
Di Micco P, Di Micco B. Up-date on solitary Dei Tos AP, Weiss SW. Morphologic and
plasmacytoma and its main differences with multiple immunophenotypic diversity in Ewing family tumors:
myeloma. Exp Oncol. 2005;27(1):7–12. a study of 66 genetically confirmed cases. Am J Surg
Di Micco P, Niglio A, Torella R, Di Micco B. Solitary Pathol. 2005;29(8):1025–33.
plasmacytoma of the jaw occurring in an elderly Fomete B, Adeosun OO, Awelimobor DI, Olayemi
woman affected by hepatitis C virus infection: a case L. Chondromyxoid fibroma of the mandible: case
report. Tumori. 2002;88(5):420–3. report and review of the literature. Ann Maxillofac
Diamond C, Taylor TH, Im T, Anton-Culver Surg. 2014;4(1):78–80.
H. Presentation and outcomes of systemic non-- Franklin CD. Pathology of the temporomandibular joint.
Hodgkin’s lymphoma: a comparison between patients Curr Diagn Pathol. 2006;12:31–9.
with acquired immunodeficiency syndrome (AIDS) Friedman JM. Epidemiology of neurofibromatosis type 1.
treated with highly active antiretroviral therapy and Am J Med Genet. 1999;89(1):1–6.
patients without AIDS. Leuk Lymphoma. 2006;47 Galieni P, Cavo M, Pulsoni A, Avvisati G, Bigazzi C,
(9):1822–9. Neri S, Caliceti U, Benni M, Ronconi S, Lauria F.
DiCaprio MR, Enneking WF. Fibrous dysplasia. Patho- Clinical outcome of extramedullary plasmacytoma.
physiology, evaluation, and treatment. J Bone Joint Haematologica. 2000;85(1):47–51.
Surg Am. 2005;87(8):1848–64. Gander T, Obwegeser JA, Zemann W, Gratz KW, Jacobsen
Dimopoulos MA, Hamilos G. Solitary bone plasmacytoma C. Malignancy mimicking bisphosphonate-associated
and extramedullary plasmacytoma. Curr Treat Options osteonecrosis of the jaw: a case series and literature
in Oncol. 2002;3(3):255–9. review. Oral Surg Oral Med Oral Pathol Oral Radiol.
Dimopoulos MA, Moulopoulos LA, Maniatis A, 2014;117(1):32–6.
Alexanian R. Solitary plasmacytoma of bone and Gaumetou E, Tomeno B, Anract P. Mazabraud’s syndrome.
asymptomatic multiple myeloma. Blood. 2000;96 A case with multiple myxomas. Orthop Traumatol Surg
(6):2037–44. Res. 2012;98(4):455–60.
Dores GM, Landgren O, McGlynn KA, Curtis RE, Linet Ghazizadeh M, Alavi Amlashi H, Mehrparvar G. Radio-
MS, Devesa SS. Plasmacytoma of bone, extra- resistant extramedullary plasmacytoma of the maxil-
medullary plasmacytoma, and multiple myeloma: inci- lary sinus: a case report and review article. Iran J
dence and survival in the United States, 1992–2004. Br Otorhinolaryngol. 2015;27(81):313–8.
J Haematol. 2009;144(1):86–94. Golai S, Nimbeni B, Patil SD, Kakanur M, Paul S.
Duhamel LA, Ye H, Halai D, Idowu BD, Presneau N, Langerhans histiocytosis in a child – diagnosed by
Tirabosco R, Flanagan AM. Frequency of mouse double oral manifestations. J Clin Diagn Res. 2015;9(4):
minute 2 (MDM2) and mouse double minute 4 (MDM4) ZD09–11.
amplification in parosteal and conventional osteosar- Goncalves CF, Morais MO, de Cassia Goncalves Alencar R,
coma subtypes. Histopathology. 2012;60(2):357–9. Batista AC, Mendonca EF. Solitary Langerhans cell
Eckardt A, Schultze A. Maxillofacial manifestations of histiocytosis in an adult: case report and literature review.
Langerhans cell histiocytosis: a clinical and therapeutic BMC Res Notes. 2016;9:19.
analysis of 10 patients. Oral Oncol. 2003;39(7):687–94. Granter SR, Renshaw AA, Kozakewich HP, Fletcher JA.
Egeler RM, Katewa S, Leenen PJ, Beverley P, Collin M, The pericentromeric inversion, inv (6)(p25q13), is a
Ginhoux F, Arceci RJ, Rollins BJ, Steering Committee novel diagnostic marker in chondromyxoid fibroma.
of the Nikolas Symposium. Langerhans cell Mod Pathol. 1998;11(11):1071–4.
histiocytosis is a neoplasm and consequently its recur- Green JT, Mills AM. Osteogenic tumors of bone. Semin
rence is a relapse: in memory of Bob Arceci. Pediatr Diagn Pathol. 2014;31(1):21–9.
Blood Cancer. 2016;63(10):1704–12. Gujjar PK, Hallur JM, Patil ST, Dakshinamurthy SM,
Engels EA, Pfeiffer RM, Goedert JJ, Virgo P, McNeel Chande M, Pereira T, Zingade J. The solitary variant
TS, Scoppa SM, Biggar RJ, H. A. C. M. Study. of mandibular intraosseous neurofibroma: report of a
Trends in cancer risk among people with AIDS in rare entity. Case Rep Dent. 2015;2015:520261.
the United States 1980–2002. AIDS. 2006;20 Hammad HM, Hammond HL, Kurago ZB, Frank JA.
(12):1645–54. Chondromyxoid fibroma of the jaws. Case report and
Eversole R, Su L, ElMofty S. Benign fibro-osseous lesions review of the literature. Oral Surg Oral Med Oral Pathol
of the craniofacial complex. A review. Head Neck Oral Radiol Endod. 1998;85(3):293–300.
Pathol. 2008;2(3):177–202. Hamner JE 3rd. The demonstration of perivascular colla-
Ferri A, Leporati M, Corradi D, Ferri T, Sesenna E. Huge gen deposition IN CHERUBISM. Oral Surg Oral Med
desmoplastic fibroma of the paediatric mandible: Oral Pathol. 1969;27(1):129–41.
Handa H, Naidu GS, Dara BG, Deshpande A, Jones AC, Prihoda TJ, Kacher JE, Odingo NA, Freedman
Raghavendra R. Diverse imaging characteristics of a PD. Osteoblastoma of the maxilla and mandible: a
mandibular intraosseous vascular lesion. Imaging Sci report of 24 cases, review of the literature, and discus-
Dent. 2014;44(1):67–73. sion of its relationship to osteoid osteoma of the jaws.
Hansen T, Kunkel M, Katenkamp D, Eletr S, Wagner Oral Surg Oral Med Oral Pathol Oral Radiol Endod.
W. Hemangioma of the mandible: case report with 2006;102(5):639–50.
special emphasis on bone degradation. Oral Maxillofac Kalil RK, Santini Araujo E. Simple bone cyst. Lyon: IARC
Surg. 2009;13(4):239–42. Press; 2013.
Heckl S, Aschoff A, Kunze S. Cavernomas of the skull: Kanazawa H, Shoji A, Yokoe H, Midorikawa S,
review of the literature 1975–2000. Neurosurg Rev. Takamiya Y, Sato K. Solitary plasmacytoma of the
2002;25(1–2):56–62; discussion 66–57 mandible. Case report and review of the literature.
Hirshberg A, Berger R, Allon I, Kaplan I. Metastatic J Craniomaxillofac Surg. 1993;21(5):202–6.
tumors to the jaws and mouth. Head Neck Pathol. Kang DM, Juhng SK, Sohn YJ, Kim HS. Imaging
2014;8(4):463–74. findings of desmoplastic fibroma rarely involving the
Hisatomi M, Asaumi J, Konouchi H, Yanagi Y, Kishi clavicle: case report. Korean J Radiol. 2014;15(1):
K. Bone deformity showing a deep coronoid notch of 130–3.
the mandible in a patient with neurofibromatosis type 1. Kaplan I, Calderon S, Kaffe I. Radiological findings in
Dentomaxillofac Radiol. 2005;34(6):380–3. jaws and skull of neurofibromatosis type 1 patients.
Hong P, Taylor SM, Trites JR, Bullock M, Nasser JG, Hart Dentomaxillofac Radiol. 1994;23(4):216–20.
RD. Chondrosarcoma of the head and neck: report of Kaugars GE, Niamtu J 3rd, Svirsky JA. Cherubism: diag-
11 cases and literature review. J Otolaryngol Head nosis, treatment, and comparison with central giant cell
Neck Surg. 2009;38(2):279–85. granulomas and giant cell tumors. Oral Surg Oral Med
Hopkins KM, Huttula CS, Kahn MA, Albright JE. Oral Pathol. 1992;73(3):369–74.
Desmoplastic fibroma of the mandible: review and Kawai T, Hiranuma H, Kishino M, Jikko A, Sakuda M.
report of two cases. J Oral Maxillofac Surg. 1996;54 Cemento-osseous dysplasia of the jaws in 54 Japanese
(10):1249–54. patients: a radiographic study. Oral Surg Oral Med Oral
Horner K, Forman GH. Atypical simple bone cysts of the Pathol Oral Radiol Endod. 1999;87(1):107–14.
jaws. II: a possible association with benign fibro- Khoury JD. Ewing sarcoma family of tumors. Adv Anat
osseous (cemental) lesions of the jaws. Clin Radiol. Pathol. 2005;12(4):212–20.
1988;39(1):59–63. Kilciksiz S, Karakoyun-Celik O, Agaoglu FY, Haydaroglu
Ichikawa T, Miyauchi M, Nikai H, Yoshiga K. Synovial A. A review for solitary plasmacytoma of bone and
chondrosarcoma arising in the temporomandibular extramedullary plasmacytoma. Sci World
joint. J Oral Maxillofac Surg. 1998;56(7):890–4. J. 2012;2012:895765.
Inwards CY. Update on cartilage forming tumors of Koch BB, Karnell LH, Hoffman HT, Apostolakis LW,
the head and neck. Head Neck Pathol. 2007;1(1): Robinson RA, Zhen W, Menck HR. National cancer
67–74. database report on chondrosarcoma of the head and
Isenberg SF. Endoscopic removal of chondromyxoid neck. Head Neck. 2000;22(4):408–25.
fibroma of the ethmoid sinus. Am J Otolaryngol. Kristinsson SY, Holmberg E, Blimark C. Treatment for
1995;16(3):205–8. high-risk smoldering myeloma. N Engl J Med.
Jaetli V, Gupta S. Mesenchymal chondrosarcoma of max- 2013;369(18):1762–3.
illa: a rare case report. Med Oral Patol Oral Cir Bucal. Kumar S, Fonseca R, Ketterling RP, Dispenzieri A, Lacy
2011;16(4):e493–6. MQ, Gertz MA, Hayman SR, Buadi FK, Dingli D,
Jain S, Singaraju S, Singaraju M. Central hemangioma: a Knudson RA, Greenberg A, Russell SJ, Zeldenrust
case report and review of literature. J Indian Soc Pedod SR, Lust JA, Kyle RA, Bergsagel L, Rajkumar SV.
Prev Dent. 2016;34(1):87–91. Trisomies in multiple myeloma: impact on survival in
Jalil A, Hin-Lau S. Oral Langerhans cell histiocytosis in patients with high-risk cytogenetics. Blood. 2012;119
Malaysian children: a 40-year experience. Int J Paediatr (9):2100–5.
Dent. 2009;19(5):349–53. Kumar M, Suresh K, Patil M, Pramod R, Yusuf R, Bilahari
Jangam SS, Ingole SN, Deshpande MD, Ranadive PA. N. Mesenchymal chondrosarcoma of posterior maxilla:
Solitary intraosseous neurofibroma: report of a unique report of a case with brief literature review. Ann Med
case. Contemp Clin Dent. 2014;5(4):561–3. Health Sci Res. 2014;4(Suppl 1):S49–52.
Jebasingh F, Jacob JJ, Shah A, Paul TV, Seshadri MS. Kwong YL, Khong PL. Central palatal perforation in nasal
Bilateral maxillary brown tumours as the first presen- natural killer cell lymphoma. Br J Haematol. 2011;152
tation of primary hyperparathyroidism. Oral Maxillofac (1):2.
Surg. 2008;12(2):97–100. Lamberg MA, Tasanen A, Jaaskelainen J. Fatality from
Jessri M, AbdulMajeed AA, Matias MA, Farah CS. A case central hemangioma of the mandible. J Oral Surg.
of primary diffuse large B-cell non-Hodgkin’s lym- 1979;37(8):578–84.
phoma misdiagnosed as chronic periapical periodonti- Larrea-Oyarbide N, Valmaseda-Castellon E, Berini-Aytes-
tis. Aust Dent J. 2013;58(2):250–5. L, Gay-Escoda C. Osteomas of the craniofacial region.
Review of 106 cases. J Oral Pathol Med. 2008;37 Murphy J, Giunta JL. Atypical central neurilemmoma of
(1):38–42. the mandible. Oral Surg Oral Med Oral Pathol. 1985;59
Lee L, Yan YH, Pharoah MJ. Radiographic features of the (3):275–8.
mandible in neurofibromatosis: a report of 10 cases and Nahi H, Genell A, Walinder G, Uttervall K, Juliusson G,
review of the literature. Oral Surg Oral Med Oral Pathol Karin F, Hansson M, Svensson R, Linder O, Carlson K,
Oral Radiol Endod. 1996;81(3):361–7. Bjorkstrand B, Kristinsson SY, Mellqvist UH,
Lee BD, Lee W, Oh SH, Min SK, Kim EC. A case report of Blimark C, Turesson I. Incidence, characteristics, and
Gardner syndrome with hereditary widespread outcome of solitary plasmacytoma and plasma cell leu-
osteomatous jaw lesions. Oral Surg Oral Med Oral kemia. Population-based data from the Swedish Mye-
Pathol Oral Radiol Endod. 2009;107(3):e68–72. loma Register. Eur J Haematol. 2017;99(3):216–22.
Lessa MM, Sakae FA, Tsuji RK, Filho BC, Voegels RL, Nakashima Y, Unni KK, Shives TC, Swee RG, Dahlin
Butugan O. Brown tumor of the facial bones: case DC. Mesenchymal chondrosarcoma of bone and soft
report and literature review. Ear Nose Throat tissue. A review of 111 cases. Cancer. 1986;57
J. 2005;84(7):432–4. (12):2444–53.
Levaot N, Voytyuk O, Dimitriou I, Sircoulomb F, Nakayama R, Miura Y, Ogino J, Susa M, Watanabe I,
Chandrakumar A, Deckert M, Krzyzanowski PM, Horiuchi K, Anazawa U, Toyama Y, Morioka H,
Scotter A, Gu S, Janmohamed S, Cong F, Simoncic Mukai M, Hasegawa T. Detection of HEY1-NCOA2
PD, Ueki Y, La Rose J, Rottapel R. Loss of Tankyrase- fusion by fluorescence in-situ hybridization in
mediated destruction of 3BP2 is the underlying patho- formalin-fixed paraffin-embedded tissues as a possible
genic mechanism of cherubism. Cell. 2011;147 diagnostic tool for mesenchymal chondrosarcoma.
(6):1324–39. Pathol Int. 2012;62(12):823–6.
Li Z, Li ZB, Zhang W, Li JR, Wang SP, Cheng Y, Wei Nedopil A, Raab P, Rudert M. Desmoplastic fibroma: a
MX. Eosinophilic granuloma of the jaws: an analysis of case report with three years of clinical and radiographic
clinical and radiographic presentation. Oral Oncol. observation and review of the literature. Open Orthop
2006;42(6):574–80. J. 2013;8:40–6.
Lorsbach RB, Hsi ED, Dogan A, Fend F. Plasma cell Neer CS 2nd, Francis KC, Marcove RC, Terz J, Carbonara
myeloma and related neoplasms. Am J Clin Pathol. PN. Treatment of unicameral bone cyst. A follow-up
2011;136(2):168–82. study of one hundred seventy-five cases. J Bone Joint
Lustig LR, Holliday MJ, McCarthy EF, Nager GT. Fibrous Surg Am. 1966;48(4):731–45.
dysplasia involving the skull base and temporal bone. Nelson BL, Linfesty RL. Nasopalatine duct cyst. Head
Arch Otolaryngol Head Neck Surg. 2001;127 Neck Pathol. 2010;4(2):121–2.
(10):1239–47. Neville BW, Albenesius RJ. The prevalence of benign
Mahomed F, Altini M, Meer S, Coleman H. Cemento- fibro-osseous lesions of periodontal ligament origin in
osseous dysplasia with associated simple bone cysts. black women: a radiographic survey. Oral Surg Oral
J Oral Maxillofac Surg. 2005;63(10):1549–54. Med Oral Pathol. 1986;62(3):340–4.
Malkin D. Li-Fraumeni syndrome. Lyon: IARC Press; 2013. Nielsen GP, Rosenberg AE. Update on bone forming
Marotta S, Di Micco P. Solitary plasmacytoma of the jaw. tumors of the head and neck. Head Neck Pathol.
J Blood Med. 2010;1:33–6. 2007;1(1):87–93.
McClure SA, Movahed R, Salama A, Ord Nord KH, Lilljebjorn H, Vezzi F, Nilsson J, Magnusson L,
RA. Maxillofacial metastases: a retrospective review Tayebwa J, de Jong D, Bovee JV, Hogendoorn PC,
of one institution’s 15-year experience. J Oral Szuhai K. GRM1 is upregulated through gene fusion
Maxillofac Surg. 2013;71(1):178–88. and promoter swapping in chondromyxoid fibroma.
McHugh JB, Mukherji SK, Lucas DR. Sino-orbital osteoma: Nat Genet. 2014;46(5):474–7.
a clinicopathologic study of 45 surgically treated cases Nosher JL, Murillo PG, Liszewski M, Gendel V, Gribbin
with emphasis on tumors with osteoblastoma-like fea- CE. Vascular anomalies: a pictorial review of nomen-
tures. Arch Pathol Lab Med. 2009;133(10):1587–93. clature, diagnosis and treatment. World J Radiol.
Melrose RJ, Abrams AM, Mills BG. Florid osseous dys- 2014;6(9):677–92.
plasia. A clinical-pathologic study of thirty-four cases. Oliveira AM, Perez-Atayde AR, Inwards CY, Medeiros F,
Oral Surg Oral Med Oral Pathol. 1976;41(1):62–82. Derr V, Hsi BL, Gebhardt MC, Rosenberg AE, Fletcher
Mendonca EF, Sousa TO, Estrela C. Non-Hodgkin lym- JA. USP6 and CDH11 oncogenes identify the neoplas-
phoma in the periapical region of a mandibular canine. tic cell in primary aneurysmal bone cysts and are absent
J Endod. 2013;39(6):839–42. in so-called secondary aneurysmal bone cysts. Am J
Motamedi MH, Behroozian A, Azizi T, Nazhvani AD, Pathol. 2004;165(5):1773–80.
Motahary P, Lotfi A. Assessment of 120 maxillofacial Ooi GC, Chim JC, Au WY, Khong PL. Radiologic mani-
aneurysmal bone cysts: a nationwide quest to under- festations of primary solitary extramedullary and mul-
stand this enigma. J Oral Maxillofac Surg. 2014;72 tiple solitary plasmacytomas. AJR Am J Roentgenol.
(8):1523–30. 2006;186(3):821–7.
Murphey MD, Kransdorf MJ. Primary musculoskeletal Owosho AA, Ko E, Rosenberg HI, Yom SK, Antonescu
lymphoma. Radiol Clin N Am. 2016;54(4):785–95. CR, Huryn JM, Estilo CL. Primary Ewing family of
tumors of the jaw has a better prognosis compared to Venema D, Zijlstra JM, Arens AI, de Rooy JW,
tumors of extragnathic sites. J Oral Maxillofac Surg. Hoekstra OS, Raymakers R, Sonneveld P, Ostelo RW,
2016;74(5):973–81. Zweegman S. Comparison of modern and conventional
Pastores GM, Michels VV, Jack CR Jr. Early childhood imaging techniques in establishing multiple myeloma-
diagnosis of acoustic neuromas in presymptomatic related bone disease: a systematic review. Br J
individuals at risk for neurofibromatosis 2. Am J Med Haematol. 2013;162(1):50–61.
Genet. 1991;41(3):325–9. Resendiz-Colosia JA, Rodriguez-Cuevas SA, Flores-
Pontes HA, Pontes FS, de Abreu MC, de Carvalho PL, de Diaz R, Juan MH, Gallegos-Hernandez JF, Barroso-
Brito Kato AM, Fonseca FP, de Freitas Silva BS, Neto Bravo S, Gomez-Acosta F. Evolution of maxillofacial
NC. Clinicopathological analysis of head and neck brown tumors after parathyroidectomy in primary
chondrosarcoma: three case reports and literature hyperparathyroidism. Head Neck. 2008;30
review. Int J Oral Maxillofac Surg. 2012;41(2):203–10. (11):1497–504.
Prado Ribeiro AC, Carlos R, Speight PM, Hunter KD, Riminucci M, Robey PG, Saggio I, Bianco P. Skeletal
Santos-Silva AR, de Almeida OP, Vargas PA. Peri- progenitors and the GNAS gene: fibrous dysplasia of
trabecular clefting in fibrous dysplasia of the jaws: an bone read through stem cells. J Mol Endocrinol.
important histopathologic feature for differentiating 2010;45(6):355–64.
fibrous dysplasia from central ossifying fibroma. Oral Romeo S, Hogendoorn PC, Dei Tos AP. Benign cartilagi-
Surg Oral Med Oral Pathol Oral Radiol. 2012;114 nous tumors of bone: from morphology to somatic and
(4):503–8. germ-line genetics. Adv Anat Pathol. 2009;16
Prescott T, Redfors M, Rustad CF, Eiklid KL, Geirdal AO, (5):307–15.
Storhaug K, Jensen JL. Characterization of a Norwe- Roodman GD, Windle JJ. Paget disease of bone. J Clin
gian cherubism cohort; molecular genetic findings, oral Invest. 2005;115(2):200–8.
manifestations and quality of life. Eur J Med Genet. Rosenberg AE, Cleton-Jansen AM, de Pinieux G, Deyrup
2013;56(3):131–7. AT, Hauben E, Squire J. Conventional osteosarcoma.
Rahimi A, Beabout JW, Ivins JC, Dahlin Lyon: IARC Press; 2013.
DC. Chondromyxoid fibroma: a clinicopathologic Roychoudhury A, Bhatt K, Yadav R, Bhutia O,
study of 76 cases. Cancer. 1972;30(3):726–36. Roychoudhury S. Review of osteochondroma of man-
Rajkumar SV. Updated diagnostic criteria and staging sys- dibular condyle and report of a case series. J Oral
tem for multiple myeloma. Am Soc Clin Oncol Educ Maxillofac Surg. 2011;69(11):2815–23.
Book. 2016;35:e418–23. Russell SJ, Rajkumar SV. Multiple myeloma and the road
Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, to personalised medicine. Lancet Oncol. 2011;12
Merlini G, Mateos MV, Kumar S, Hillengass J, (7):617–9.
Kastritis E, Richardson P, Landgren O, Paiva B, Sadowsky D, Rosenberg RD, Kaufman J, Levine BC,
Dispenzieri A, Weiss B, LeLeu X, Zweegman S, Friedman JM. Central hemangioma of the mandible.
Lonial S, Rosinol L, Zamagni E, Jagannath S, Literature review, case report, and discussion. Oral
Sezer O, Kristinsson SY, Caers J, Usmani SZ, Lahuerta Surg Oral Med Oral Pathol. 1981;52(5):471–7.
JJ, Johnsen HE, Beksac M, Cavo M, Goldschmidt H, Said-Al-Naief N, Fernandes R, Louis P, Bell W, Siegal
Terpos E, Kyle RA, Anderson KC, Durie BG, Miguel GP. Desmoplastic fibroma of the jaw: a case report
JF. International Myeloma Working Group updated and review of literature. Oral Surg Oral Med Oral
criteria for the diagnosis of multiple myeloma. Lancet Pathol Oral Radiol Endod. 2006;101(1):82–94.
Oncol. 2014;15(12):e538–48. Schmidt BP, Bradrick JP, Gabali A. Hyperparathyroidism-
Raphael M, Said J, Borisch B, Cesarman E, Harris jaw tumor syndrome: a case report. J Oral Maxillofac
NL. Lymphomas associated with HIV infection. Surg. 2009;67(2):423–7.
Lyons: IARC Press; 2008. Sciot R, Bridge JA. Synovial chondromatosis. Lyon: IARC
Raubenheimer EJ, Noffke CE, Hendrik HD. Metastases to Press; 2013.
the oral cavity. SADJ. 2012;67(10):586–8. Shank BR, Brown VT, Schwartz RN. Multiple mye-
Rawal YB, Angiero F, Allen CM, Kalmar JR, Sedghizadeh loma maintenance therapy: a review of the pharma-
PP, Steinhilber AM. Gnathic osteoblastoma: clinico- cologic treatment. J Oncol Pharm Pract. 2015;21
pathologic review of seven cases with long-term fol- (1):36–51.
low-up. Oral Oncol. 2006;42(2):123–30. Shear M, Speight PM. Cysts of the oral and maxillofacial
Razek AA. Imaging appearance of bone tumors of the regions. Oxford: Blackwell Munksgaard; 2007.
maxillofacial region. World J Radiol. 2011;3 Shenker A, Weinstein LS, Sweet DE, Spiegel AM. An
(5):125–34. activating Gs alpha mutation is present in fibrous dys-
Redfors M, Jensen JL, Storhaug K, Prescott T, Larheim plasia of bone in the McCune-Albright syndrome.
TA. Cherubism: panoramic and CT features in adults. J Clin Endocrinol Metab. 1994;79(3):750–5.
Dentomaxillofac Radiol. 2013;42(10):20130034. Siegal GP, Oliver WR, Reinus WR, Gilula LA, Foulkes
Regelink JC, Minnema MC, Terpos E, Kamphuis MH, MA, Kissane JM, Askin FB. Primary Ewing’s sarcoma
Raijmakers PG, Pieters-van den Bos IC, Heggelman involving the bones of the head and neck. Cancer.
BG, Nievelstein RJ, Otten RH, van Lammeren- 1987;60(11):2829–40.
Silverman S Jr, Ware WH, Gillooly C Jr. Dental aspects of Vivek N, Manikandhan R, James PC, Rajeev R. Solitary
hyperparathyroidism. Oral Surg Oral Med Oral Pathol. intraosseous neurofibroma of mandible. Indian J Dent
1968;26(2):184–9. Res. 2006;17(3):135–8.
Slootweg PJ. Cementoblastoma and osteoblastoma: a com- Waldron CA. Fibro-osseous lesions of the jaws. J Oral
parison of histologic features. J Oral Pathol Med. Maxillofac Surg. 1993;51(8):828–35.
1992;21(9):385–9. Walker L, Thompson D, Easton D, Ponder B, Ponder M,
Smith D, Yong K. Advances in understanding prognosis in Frayling I, Baralle D. A prospective study of neurofi-
myeloma. Br J Haematol. 2016;175(3):367–80. bromatosis type 1 cancer incidence in the UK. Br J
Speight PM, Carlos R. Maxillofacial fibro-osseous lesions. Cancer. 2006;95(2):233–8.
Curr Diagn Pathol. 2006;12(1):1–10. Warner BF, Luna MA, Robert Newland T. Temporoman-
Stalemark H, Laurencikas E, Karis J, Gavhed D, Fadeel B, dibular joint neoplasms and pseudotumors. Adv Anat
Henter JI. Incidence of Langerhans cell histiocytosis in Pathol. 2000;7(6):365–81.
children: a population-based study. Pediatr Blood Can- Weaver CJ, Tariman JD. Multiple myeloma genomics: a
cer. 2008;51(1):76–81. systematic review. Semin Oncol Nurs. 2017;33:237–53.
Stewart BD, Reith JD, Knapik JA, Chi AC. Bone- and Weinstein LS, Chen M, Liu J. Gs(alpha) mutations and
cartilage-forming tumors and Ewing sarcoma: an imprinting defects in human disease. Ann N Y Acad
update with a gnathic emphasis. Head Neck Pathol. Sci. 2002;968:173–97.
2014;8(4):454–62. Wenig B. Atlas of head and neck pathology. Philadelphia:
Sundine MJ, Wirth GA. Hemangiomas: an overview. Clin Elsevier; 2016.
Pediatr (Phila). 2007;46(3):206–21. White SC, Pharaoh MJ. Oral radiology: principles and
Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, interpretation. St Louis: Mosby; 2004.
Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz Woods TR, Cohen DM, Islam MN, Rawal Y,
AD, Jaffe ES. The 2016 revision of the World Health Bhattacharyya I. Desmoplastic fibroma of the mandi-
Organization classification of lymphoid neoplasms. ble: a series of three cases and review of literature. Head
Blood. 2016;127(20):2375–90. Neck Pathol. 2015;9(2):196–204.
Terry DG, Sauser DD, Gordon MD. Intraosseous malig- Wu CT, Inwards CY, O’Laughlin S, Rock MG, Beabout
nant peripheral nerve sheath tumor in a patient with JW, Unni KK. Chondromyxoid fibroma of bone: a
neurofibromatosis. Skelet Radiol. 1998;27(6):346–9. clinicopathologic review of 278 cases. Hum Pathol.
Thakral B, Zhou J, Medeiros LJ. Extranodal hematopoietic 1998;29(5):438–46.
neoplasms and mimics in the head and neck: an update. Wuthrich RP, Martin D, Bilezikian JP. The role of
Hum Pathol. 2015;46(8):1079–100. calcimimetics in the treatment of hyperparathyroidism.
Thoma KH, Goldman HM. Bone tumors of the jaws. In: Eur J Clin Investig. 2007;37(12):915–22.
Gorlin RJ, Goldman HM, editors. Thoma’s oral pathol- Xu J, Li D, Xie L, Tang S, Guo W. Mesenchymal
ogy. St Louis: CV Mosby Company; 1971. p. 564–6. chondrosarcoma of bone and soft tissue: a systematic
Triantafillidou K, Zouloumis L, Karakinaris G, review of 107 patients in the past 20 years. PLoS One.
Kalimeras E, Iordanidis F. Brown tumors of the jaws 2015;10(4):e0122216.
associated with primary or secondary hyperparathy- Yih WY, Ma GS, Merrill RG, Sperry DW. Central heman-
roidism. A clinical study and review of the literature. gioma of the jaws. J Oral Maxillofac Surg. 1989;47
Am J Otolaryngol. 2006;27(4):281–6. (11):1154–60.
Unni KK, Inwards CY. Dahlin’s bone tumors. Philadel- Zadik Y, Lehman H, Neuman T, Benoliel R. Primary
phia: Lippincott Williams & Wilkins; 2010. lymphoma of the mandible masquerading as
Unni KK, Inwards CY, Bridge JA, Kindblom L-G, Wold bisphosphonate-related osteonecrosis of jaws. Quintes-
LE. Tumors of the bones and joints. Washington, DC: sence Int. 2012;43(9):769–75.
AFIP; 2005. Zhang L, Xia BQ, Sun H, Wang LZ, Zhao ZL, Li B, Wang
van Capelle CI, Hogeman PH, van der Sijs-Bos CJ, XD. Intraosseous schwannomas of the jaws: 2 case
Heggelman BG, Idowu B, Slootweg PJ, Wittkampf AR, reports and review of the literature. Oral Surg Oral
Flanagan AM. Neurofibromatosis presenting with a Med Oral Pathol Oral Radiol. 2012;114(6):e13–7.
cherubism phenotype. Eur J Pediatr. 2007;166(9):905–9. Zhu Q, Zou X, You R, Jiang R, Zhang MX, Liu YP, Qian CN,
Vered M, Nasrallah W, Buchner A, Dayan D. Stromal Mai HQ, Hong MH, Guo L, Chen MY. Establishment of
myofibroblasts in central giant cell granuloma of the an innovative staging system for extramedullary
jaws cannot distinguish between non-aggressive and plasmacytoma. BMC Cancer. 2016;16(1):777.
aggressive lesions. J Oral Pathol Med. 2007;36 Zillmer DA, Dorfman HD. Chondromyxoid fibroma of
(8):495–500. bone: thirty-six cases with clinicopathologic correla-
Vered M, Buchner A, Dayan D. Central giant cell granu- tion. Hum Pathol. 1989;20(10):952–64.
loma of the jawbones – new insights into molecular Zinn DJ, Chakraborty R, Allen CE. Langerhans cell
biology with clinical implications on treatment histiocytosis: emerging insights and clinical implications.
approaches. Histol Histopathol. 2008;23(9):1151–60. Oncology (Williston Park). 2016;30(2):122–32, 139.
Head and Neck Tumors
Moni A. Kuriakose, Swagnik Chakrabarti, Sok Ching Cheong,

Luiz P. Kowalski, Tiago Novaes Pinheiro, and Camile S. Farah
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 629
Developmental Lesions of the Head and Neck . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 629
Dermoid Cyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 631
Epidermoid Cyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633
Thyroglossal Duct Cyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 634
Branchial Cleft Cyst/Lymphoepithelial Cyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637
M. A. Kuriakose
Department of Head and Neck Surgery/Plastic and
Reconstructive Surgery, Roswell Park Cancer Institute,
Buffalo, NY, USA
e-mail: Moni.Kuriakose@RoswellPark.org
S. Chakrabarti
Head and Neck Oncology Services, Tata Memorial
Hospital, Mumbai, India
e-mail: dr.swagnik@gmail.com
S. C. Cheong
Cancer Research Malaysia, CARIF Oral Cancer Research
Team, Subang Jaya, Malaysia
e-mail: sokching.cheong@cancerresearch.my
L. P. Kowalski
Head and Neck Surgery and Otorhinolaryngology
Department, A.C. Camargo Cancer Center, São Paulo,
Brazil
e-mail: lp_kowalski@uol.com.br
T. Novaes Pinheiro
Anatomic Pathology Service, Amazonas State University,
Manaus, Brazil
e-mail: tpinheiro@uea.edu.br
C. S. Farah (*)
UWA Dental School and Oral Health Centre of Western
Australia, Faculty of Health and Medical Sciences,
University of Western Australia, Perth, WA, Australia

https://doi.org/10.1007/978-3-319-72303-7_20
628 M. A. Kuriakose et al.
Vascular Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 639

Lymphangioma Including Cystic Hygroma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 648
Benign Tumors of the Head and Neck . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651
Fibroma/Traumatic Fibroma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651
Myofibroma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 653
Lipoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 655
Neuroma Including Multiple Endocrine Neoplasia Type 2B (MEN2B) . . . . . . . . . . . . . . . 658
Neurilemoma/Schwannoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663
Neurofibroma Including Neurofibromatosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 665
Granular Cell Tumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668
Rhabdomyoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 670
Hemangioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671
Sinonasal Papilloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 674
Malignant Epithelial Tumors of the Head and Neck . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675
Oropharyngeal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 679
Hypopharyngeal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 692
Laryngeal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696
Nasopharyngeal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702
Tumors of the Nasal Cavity and Paranasal Sinuses (Skull Base Tumors) . . . . . . . . . . . . . 705
Thyroid Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 712
Malignant Soft Tissue Tumors of the Head and Neck . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 721
Fibrosarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 726
Liposarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 729
Malignant Peripheral Nerve Sheath Tumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 731
Kaposi Sarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 732
Angiosarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 734
Leiomyosarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 735
Rhabdomyosarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 736
Tumors of the Temporomandibular Joints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 737
Molecular Aspects of Head and Neck Squamous Cell Carcinoma . . . . . . . . . . . . . . . . . 740
Genome-Wide Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 743
Copy Number Alterations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 744
Mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 746
Gene Expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 748
Targeting Key Signaling Pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 748
Immune Markers and Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 749
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 751
Abstract Therefore, these lesions can appear at any time

The head and neck region is a complex part of the during life, usually caused by the interaction of
human body. The diagnosis of soft tissue lesions factors such as the environment and genetics.
of the head and neck comprises a wide variety of This chapter highlights and discusses the most
pathologic entities. These lesions may originate significant features for the diagnosis of epithelial
from developmental problems or from benign or and mesenchymal soft tissue tumors of the head
malignant neoplastic transformation of normal and neck region, in addition to tumors of the
tissue. Developmental problems arise from dis- temporomandibular joint. Tumors are divided
turbances of organogenesis, histogenesis, or into developmental tumors/tumorlike lesions,
functional maturation of the involved structures. benign tumors, and malignant tumors and may
Head and Neck Tumors 629
have non-odontogenic, reactive, or neoplastic aspiration, core biopsy, image-guided biopsy, and
etiology. incisional or excisional biopsy.
The varying tissues and structures of this com-
Keywords plex region of the human body also predispose to
Head and neck tumors · Head and neck a varying array of pathologies ranging from devel-
malignancies · Benign tumors · Neck masses · opmental lesions to neoplastic ones. Tissues
Oropharyngeal cancer · Nasopharyngeal include mucosal epithelium, lymphoid tissues,
cancer · Hypopharyngeal cancer · Laryngeal salivary glands, thyroid tissue, and sinonasal
cancer · Human papilloma virus · structures. These varying pathologies also call
Nasopharyngeal carcinoma · Tumors of the for differing treatment approaches which include
nasal cavity · Tumors of paranasal sinuses · surgery, radiation therapy, and chemotherapy.
Thyroid cancer · Treatment guidelines · More recently, this has included immunotherapy
Tumors of the temporomandibular joint · particularly for head and neck squamous cell car-
Temporomandibular joint neoplasms cinomas. As our understanding of the molecular
basis of these diseases increases, so will the suc-
cess in managing these devastating cancers.
In this chapter, developmental tumors, benign
Introduction and malignant epithelial tumors, soft tissue tumors,
and tumors of the thyroid gland and temporoman-
Tumors and tumorlike lesions of the head and neck dibular joint are explored in detail expected of a
are commonly encountered in contemporary oral contemporary oral medicine practitioner, particu-
medicine practice. Presentation of a mass in the larly as this relates to their involvement in multi-
head or neck should be evaluated with care and disciplinary head and neck teams and tumor boards.
examined in detail. These masses may present as The content of this chapter is not exhaustive, and
lumps with no associated symptoms noted inciden- certain tumors are covered in other dedicated chap-
tally by the patient, or may present as painful lesion ters such as ▶ “Oral Mucosal Malignancies,”
attracting the patient’s attention. On presentation to ▶ “Salivary Gland Disorders and Diseases,”
the clinician, a comprehensive head and neck cancer ▶ “Odontogenic Pathology,” and ▶ “Non-odo-
examination should be undertaken in addition to a ntogenic Bone Pathology.” In this chapter, we
detailed risk assessment. Detailed information from focus on those parts of the anatomy not typically
the patient about their history, risk factors, habits, directly dealt with by the oral medicine specialist but
mass location, mass characteristics, mass growth for which they must have a comprehensive knowl-
pattern, and signs and symptoms are all useful pieces edge base. In addition, tumors not covered elsewhere
of information for establishing an accurate diagno- in this book are also included here for completeness,
sis. In addition to visual examination and palpation with some minor overlap. It is expected that the oral
of the lesion, imaging studies and diagnostic studies medicine clinician will avail themselves of more
are often undertaken to better ascertain the exact comprehensive texts on the topics covered here for
nature of a tumor in the head and neck region. a more detailed appreciation of the complexity and
Indeed many tumors of the laryngopharyngeal sites scope of head and neck tumors (WHO Classification
are not easily assessed clinically, and diagnostic of Head and Neck Tumours 2017).
imaging is often the first modality used to better
understand the extent of the mass in question. A
detailed understanding of the complex anatomy of Developmental Lesions of the Head
the head and neck region is required for any clinician and Neck
attempting to manage such conditions. The intricate
and complicated structures of the head and neck The most significant transformation of the
region also require care and finesse when diagnostic human body takes place during intrauterine life.
investigations are undertaken, such as fine needle The head and neck region has a significant role in
all stages of in utero development, which makes Benign developmental tumors/tumorlike

it a key point for the diagnosis of developmental lesions of the head and neck comprise
diseases. After birth, the developmental transfor- choristomas, teratomas, and hamartomas.
mations are grouped in infancy, adulthood, and Although developmental cysts have different
old age, each one related to its particular com- explanations relating to their etiology, they are
mon diseases. This section will focus only on usually related to persistent, ectopic, or hetero-
cysts and tumors that may rise in the head and plastic epithelium proliferation.
neck region, but consideration should be given to Although developmental lesions may appear
the fact that some lesions are part of systemic at any time during life, 2–3% of these are diag-
developmental disorders, such as syndromes, nosed before birth, and this number rises to
sequences, and syntropy. 4–6% until the fifth year of life. There is no
In order to fully understand the etiology of gender predilection, and some lesions may be
these lesions, a review of the basic nosology of influenced by or influence hormonal activity, so
these disorders is necessary. Problems during other key periods of manifestation are puberty
organogenesis lead to anomalies and and old age.
malformations. These groups of lesions comprise These lesions usually have a multifactorial ori-
incomplete formation diseases: such as agenesis, gin, but trauma, infections, carcinogenic agents,
aplasia, hypoplasia, persistency, atresia, and ste- and spontaneous genetic mutations comprise
nosis. Also there are redundant lesions, called the major causes of such lesions. These agents
supernumerary, and the aberrant ones, known as are also called dysontogenetic factors or
ectopias, choristomas, and teratomas. Problems in teratogenic agents. Table 2 highlights different
histogenesis may lead to hamartomas or hetero- dysontogenetic factors and diseases directly
plasias. Finally, problems in functional maturation related to them.
are known as deformities. Table 1 outlines devel- In order to improve the understanding of these
opmental terms and their definitions and common different kinds of lesions, this chapter has grouped
examples. the developmental cysts and tumorlike lesions.
Table 1 Correlation of terminology applied to developmental disturbances with their definition and some clinical
examples
Developmental
problems Definition Examples
Agenesis Absence of organ formation Teeth, glands
Aplasia Absence of organ growth Tooth germ, aplastic bone marrow, limbs
Hypoplasia Insufficient organ growth Microdens, hypoplastic heart, lung,
kidneys
Persistency Persistent structure from the developmental process Thymus, tail, stapedial artery, vomeronasal
organ
Atresia Incomplete formation of a luminal organ Esophageal, pharyngeal, aural, choanal
Stenosis Pathologic narrowing of a luminal organ Salivary duct, arteries, cardiac valves
Supernumerary Excessive number of a determined organ Teeth, glands, fingers
Ectopia Formation of an organ in a different anatomic place Teeth, glands, limbs, heart
Choristoma and Benign neoplastic proliferation of tissue from Osseous, cartilaginous, head and neck
teratoma different embryonal origins teratoma
Hamartoma Benign neoplastic or neoplastic-like proliferation of Odontoma, lymphangioma, hemangioma,
a tissue in its natural anatomic position lipoma
Heteroplasia Proliferation of a tissue beyond its natural anatomic Foregut cysts, dens in dens, lymphoid,
position glandular
Deformity Alteration of anatomic form that may compromise Radicular dilaceration, congenital club
normal function foot, septum deviation, micrognathia
Table 2 Potential dysontogenetic factors and associated diseases

Dysontogenetic
factors Pathogens Process Diseases
Physical Trauma Production of growth factors, Vascular malformations, traumatic
persistence of the agent impairing fibroma
complete recovery of injuries
Radiation Free radical formation, genetic damage, Carcinomas, sarcomas,
thermal tissue damage hematolymphoid tumors
Chemical Heavy Direct – alters the cellular genome Cancers, osteomalacia, cirrhosis, blood
metals Indirect – depends on dosage, disorders, neurotoxicity, kidney
absorption, transport, distribution, diseases, tooth pigmentation,
storage, biotransformation, and gingivostomatitis, alopecia
Organic excretion. It can cause its effects in any Leukemia, carcinomas
compounds phase of exposition
Halogens Burns, poisoning, mineralized tissue
disorders, cancer
Biological Viruses Genetic integration with the cellular HPV-carcinomas
genome altering its expression EBV-Burkitt’s lymphoma,
nasopharyngeal carcinomas
HHV8-Kaposi sarcoma
HBV and HCV-hepatic carcinoma
Bacteria Immunosuppressive action, bacterial Congenital defects, deafness, blindness,
endotoxins, and exotoxins craniofacial anomalies, neural and brain
problems
Fungi Carcinogenic mycotoxins Liver cancer, subcutaneous sarcomas,
leukemia, pulmonary tumors
Dermoid Cyst of a teratoma. Cysts found in the head and neck do

not show such complexity.
Epidemiology, Etiology, and Pathology Considered a rare lesion, it has no gender pre-
Dermoid cysts originate from cystic formation dilection and is usually diagnosed in intraoral
resulting from sudden proliferation of ectopic epi- sites. Affected patients are generally young and
thelium associated with adnexal structures such as there are even congenital lesions described. The
hair follicles and sebaceous and sudoriferous differential diagnosis of a dermoid cyst includes
glands. The most accepted theory of the origin the epidermoid cyst. Lesions that occur close to
of these epithelial remnants is that they probably the skin are more likely to contain adnexal struc-
are derived from the fusion of developmental pro- tures nearby, so there is doubt if the latter form
cesses. This presumption is based on the usual part of the lesion in biopsied specimens or just
clinical location of such lesions, in the midline represent characteristics of the anatomic position,
of the floor of the mouth and the soft palatal being usually diagnosed as epidermoid cysts.
pillars. Other theories suggest that these lesions Dermoid and epidermoid cysts represent together
could represent a cystic manifestation of a tera- about 7% of cysts found in the head and neck
toma. These cysts are not restricted to the head region, and only 1.6% are located within the oral
and neck region and are commonly found in the cavity.
ovary and uterus. In these regions, it is usual to
find the muscle and even neural tissue in the Clinical Presentation
surrounding tissues of the cystic cavity. The pres- Intraoral lesions present as a yellowish or nor-
ence of components of all embryonic tissues in mally colored fluctuating nodule, with soft
these cases is compatible with the characteristics resilient consistency on palpation (Fig. 1).
Fig. 1 Dermoid cyst

involving the floor of mouth
(a) and MRI sagittal view
(b) shows a well-defined
large cyst-like lesion
positioned medially within
the floor of the mouth
extending inferolaterally
above the hyoid bone
Early clinical identification of these lesions can of the lesion but is less frequently used due to
mimic a ranula or mucocele, mostly due to the higher technical complexity. MRI has the best
coloration which is similar to the adjacent soft tissue quality of imaging, showing soft tissue
mucosa. Lesions vary in size, most of which structures and providing different sonographic
measure 2–5 cm, but very large cysts (over appearances with different frequencies, providing
10 cm) have been described. a good view of the cystic content and its surround-
ing structures (Fig. 1) (Rumboldt 2015).
FNAC is useful for surgical planning. Keratin
Investigations
is normally found within the cystic cavity. The
Investigations include ultrasound, computerized
quick result from cytopathology also helps differ-
tomography (CT), and magnetic resonance imag-
entiate the lesion from a ranula for lesions located
ing (MRI) exams (Fig. 1), in addition to fine
close to the midline of the floor of the mouth. This
needle aspiration cytology (FNAC). Ultrasound
simple procedure may prevent unnecessary dis-
examination is low cost and has the advantage
section of salivary glands which could give rise to
that it can be used in real time with other clinical
a postsurgical mucocele.
procedures such as FNAC. High-frequency pro-
Cytopathological examination reveals
bes (10–15 MHz) and mid-range frequency pro-
desquamative epithelial cells, mostly from the ker-
bes (5–10 MHz) provide better resolution but
atin layer. Some of these cells also present a clear
have less penetration. High-frequency probes are
cytoplasm with hydropic degeneration or signs of
preferred for ultrasound images of superficial
karyolysis giving a ghost cell-like appearance.
lesions (2–4 cm) deep such as dermoid cysts of
Gross specimen evaluation of the dermoid cyst
the head and neck region. The echogenicity of the
usually shows a white-to-brown pasty to granular
dermoid cyst is predominantly a hypoechoic
material. The characteristic keratin odor is usually
circumscribed mass, indistinguishable from other
not affected by tissue fixation. In empty
mass lesions such as lipomas. Low-contrast CT
specimens, the cystic internal lining presents as
imaging usually shows a circumscribed mass with
a smooth brilliant surface. Microscopic examina-
low density, sometimes presenting scattered
tion shows a stratified squamous cell ortho-
hyperdense structures, when calcified keratin
keratinized epithelium, without projections to
material is present within the cystic content.
the connective tissue capsule, with five to ten
High-contrast CT imaging provides a better view
cells thick. The difference with epidermoid,
trichilemmal, and pillar cysts is the marked hyper- Due to its superficial position, secondary infection
granulation layer and abrupt transition to the ker- is common, also related to patients’ attempt to
atin layer. The differential diagnosis with squeeze the lesion. In these cases, pain, hyper-
epidermoid cyst is based on the presence of epi- emia, and edema will be noted. Lesions that suffer
thelial appendices like glands or hair follicles. repetitive drainage attempts also show peripheral
fibrosis and inflammatory reactions to keratin and
Treatment require the removal of at least part of the skin
Cyst enucleation is the treatment of choice for related to the lesion. Similar to the dermoid cyst,
dermoid cyst. During dissection of the lesion, it it has a particular odor related to keratin.
can rupture. If this occurs, it is important to per-
form meticulous cleaning of the surgical site with Investigations
saline solution to minimize the inflammatory The clinical manifestations of the epidermoid cyst
potential of keratin, providing better immediate are quite typical, making the presumptive diagnosis
postsurgical recovery. Recurrence of such lesions highly convergent with histopathological exam.
is low. If chronic trauma or previous infection has Most cases are located subcutaneously, which
occurred, adherence of the cystic capsule could makes direct access through the skin very practical.
increase the chance of surgical rupture of the cyst Only unusual site manifestations demand more
and elevate the chances of recurrence, when part meticulous investigations. Although less common,
of the lesion is left behind at the surgical site. it is possible to reach lesions from an intraoral
surgical access site. This may be required for
esthetic reasons or after deep skin inclusions due
Epidermoid Cyst to trauma. In this more complex clinical manifes-
tation, the same methods used in dermoid cyst
Epidemiology, Etiology, and Pathology investigation can be applied here.
The epidermoid cyst is considered an infundibular Ultrasound imaging of epidermoid cysts is
cyst. The infundibular region of the hair follicle similar to dermoid cysts, presenting with a well-
represents a major interface zone of mammalian circumscribed hypoechoic appearance. Second-
skin epithelium with the environment. A common ary inflammation can contribute to liquid accumu-
manifestation, lesions in the head and neck region lation in the cystic cavity. These cases are reported
are usually related to trauma. This cause-effect to show hypoechoic mixed with round anechoic
relationship supports other conditions such as regions giving the cyst a “sack-of-marbles”
inclusion cysts and pillar cysts. Epidermoid cyst appearance. Dystrophic calcifications in the kera-
has a male gender predilection, mostly on areas tin close to the epithelium can generate hyper-
related to razoring of the beard. These lesions are echoic areas. For more complex cases, MRI and
usually mislabeled sebaceous cysts, since its cys- CT scans can provide more detail for surgical
tic content is mostly filled with keratin. The planning (Fig. 2).
microscopic characteristics of epidermoid and
dermoid cysts are similar, although epidermoid Treatment
cysts are usually more superficial and more often Cyst enucleation is the treatment of choice for
related to the skin than oral mucosa. The most epidermoid cysts (Fig. 3). During dissection of
essential difference of the epidermoid cyst to the the lesion, it may rupture. If this occurs, it is
dermoid cyst is the hypergranular layer that is important to perform a meticulous cleaning of
usually absent in dermoid cysts and the absence the surgical site with saline solution to reduce
of adnexal structures in the cystic capsule. the inflammatory potential of keratin, providing
better immediate postsurgical recovery. Recur-
Clinical Presentation rence of such lesions is low. If chronic trauma,
Epidermoid cysts manifest as well-circumscribed previous infection, or other changes have
fluctuating nodules, resilient on palpation (Fig. 2). occurred, adherence of the cystic capsule could
Fig. 2 Epidermoid cyst presenting as a soft tissue fluctu- craniocaudal 22 mm transverse 28 mm AP (b). This
ant mass in the anterior floor of mouth with no symptoms is T1 hypointense, T2 mildly hyperintense, does not
(a). MRI T1 coronal (b) and post-gadolinium coronal (c) enhance with the administration of contrast (c + d) and
and sagittal (d) views show a well-defined ovoid lesion does demonstrate diffusion restriction. It suppresses on fat
within the floor of the mouth splaying the geniohyoid and suppression techniques
genioglossus muscles and which measures 27 mm
increase the chance of surgical rupture of the cyst their maturation over the newly formed hyoid
and elevate the chances for recurrence. bone. The duct has a tortuous path similar to
major salivary ducts and blood vessels and is
situated mostly in the para-medial region, starting
Thyroglossal Duct Cyst on the tongue surface and ending up in the
hyoid bone.
Epidemiology, Etiology, and Pathology Usually, the cells of the thyroglossal duct enter
The tongue, the hyoid bone, and the thyroid and apoptosis and the duct begins an involution phase.
the parathyroid glands have their embryologic The usual anatomic vestige of its presence is the
origin in the fusion of third, fourth, and fifth foramen cecum on the tongue. The thyroglossal
branchial arches. During the first 10–12 weeks cyst origins from remnant epithelial ductal cells
of pregnancy, organogenesis of the thyroid and that persist after its involution. These develop-
parathyroid glands begins inside the oral cavity, mental problems can also affect the thyroid
along with the posterior third of the developing gland. In some cases, the duct involutes before
tongue. During histodifferentiation, these glands completion of the gland descent, leading to
descend through the thyroglossal duct and end ectopic positioning. The most extreme cases
Fig. 3 (continued)
Fig. 4 Thyroglossal duct cyst. Axial (a) and coronal (b) CT shows a 19 mm ovoid lesion in the position of an infrahyoid
thyroglossal duct cyst (dashed orange oval)
show the so-called lingual thyroid, when the in the midline that are most visible during deglu-
gland, or part of it, fully develops on the tongue tition, with variable anteroposterior location from
surface or in some part of the ductal pathway the base of the tongue to the hyoid bone. Intraoral
through the neck. lesions develop inside the muscle in the base of
The lesions have a broad spectrum of age inci- the tongue. In these cases, it is normal for the
dence, varying from congenital lesions to lesions patient to expect symptoms such as dysphagia
in older patients. There is a small predilection of and dyslalia. Sometimes more than one cyst is
male-to-female incidence, according to most stud- present not necessarily close to each other. The
ies. These lesions are the most common middle usual presentation is a non-tender, mobile neck
neck mass (Adelchi et al. 2014). Although mass, which is painful on swallowing. Secondary
unusual, malignant transformation of the lesion infection is also possible, enhancing the painful
to a thyroglossal duct carcinoma and the combi- sensation and interfering with surrounding tis-
nation of thyroglossal duct cyst with thyroid car- sues, sometimes giving the impression of a
cinoma have been reported. non-fluctuating mass on palpation.
Clinical Presentation Investigations

Since the pathway of the duct is long, the lesions Most primary investigations comprise imaging
can appear at any part of its trajectory (Fig. 4). procedures. Clinical access of the lesion is one
Most lesions present as a painless nodule located of the major problems. FNAC is an option for
ä
Fig. 3 Epidermoid cyst. Clinical aspect of a fluctuating surgical site with abundant irrigation with saline solution
nodule on the cheek. FNAC was performed at the first visit. (e). Cystic cavity filled with keratin with thin epithelial
During the procedure, a characteristic odor was noticed (a). lining of five to eight layers of stratified squamous epithe-
Microscopic findings of the FNAC revealing cornified lium with hypergranulosis and absence of epithelial pro-
epithelial cells without evident nuclei forming agglomer- jections and sudoriparous or sebaceous glands in the
ates of orthokeratin. The cytopathological diagnosis was capsule confirming the diagnosis of epidermoid cyst (f).
suggestive of dermoid/epidermoid cyst (b). Surgical exci- Differential diagnosis of the pillar inclusion cyst, revealing
sion in the lip commissure was undertaken for esthetic melanosis at the parabasal layers, areas of epithelial thick-
reasons, and access to the cyst (c). During enucleation of ening with a marked granular layer. In this cyst, it is
the cyst, the cystic capsule ruptured revealing its yellow possible to see adnexal glands due to the proximity to the
granular content (d). Sutures were placed after cleaning the skin (g, h) (Hematoxylin and eosin stain)
preoperative diagnosis of thyroglossal duct cyst. branchial arches, entrapped and persistent after
Ultrasound guidance for this type of procedure fusion of the branchial arches. These cysts are
prevents unsatisfactory sampling and trans- usually lined by pavemented squamous cell epi-
fixation damage of important anatomical struc- thelium and found on the surrounding capsular
tures, such as nerves and major blood vessels. connective tissue, with lymphoid structures,
The lesion usually has an anechoic echogenicity. not always well arranged but sometimes
The cytomorphologic features of thyroglossal exhibiting germinative centers and maturation
duct cyst include colloid (thick and fragmented, zones. Another etiological hypothesis for the
thin and watery, or mucinous), macrophages, lym- lymphoepithelial cyst suggests the reactive prolif-
phocytes, and predominantly neutrophils. The eration of the epithelium from the tonsillar crypts,
epithelium is ciliated columnar, metaplastic squa- which may enclose a cystic cavity (Fitzpatrick and
mous, or of mature squamous type. Thyroid epi- Gordon 2013).
thelium is rarely present. Identification of possible These lesions have no gender predilection
ectopic thyroid tissue can be also verified through reported in most epidemiological studies. The
scintillography. most common of the two is the branchial cleft
Microscopic examination confirms cyst, but both lesions are considered rare manifes-
cytomorphologic investigations. Cysts located tations in the head and neck. Lesions are usually
adjacent to the tongue base are lined with stratified diagnosed in young patients, but there is a
squamous epithelium, while those adjacent to the broad spectrum of age incidence, varying from
thyroid gland are lined with cells resembling the congenital lesions to lesions in older patients.
thyroidal acinar epithelium. More than half of all The branchial cleft cyst is usually diagnosed in
thyroglossal duct cyst walls contain ectopic rests the para-medial region of the neck and even
of thyroid tissue. Hormonal alterations should within major salivary glands such as the parotid.
also be investigated. Patients with ectopic thyroid Lymphoepithelial cysts are found close to
tissue may have no other functional glands or intraoral areas of lymphoid tissue from the
present with hypofunctional problems. Waldeyer’s ring, which also comprise branchial
cleft-derived regions. Therefore, the posterior
Treatment border of the tongue and the soft palate pillars
Enucleation with the Sistrunk technique is the are the main intraoral sites of occurrence. These
treatment of choice for most cases. This tech- lesions can also develop inside major salivary
nique dissects the region of the possible remnant glands such as the parotid, given it also has an
of the duct and removes it along with the cyst, ectomesenchymal origin (Luna and Pineda-
including part of the hyoid bone. Although this Daboin 2006).
procedure reduces the chance of recurrence, due
to the inconstant, irregular, and thin macroscopic
appearance of the ductal remnants, recurrence is Clinical Presentation
still possible. Branchial cleft cysts are usually painless, fluctu-
ating, flexible nodules on palpation, located in the
para-medial line of the neck (Fitzpatrick and Gor-
Branchial Cleft Cyst/ don 2013) (Fig. 5). Movements of deglutition can
Lymphoepithelial Cyst help their detection on physical examination. The
median size of these lesions varies from 1 to 3 cm.
Epidemiology, Etiology, and Pathology Larger lesions may give the impression of a dou-
The branchial cleft cyst and the lymphoepithelial ble chin, suggesting other cysts such as the
cyst share the same probable etiology despite thyroglossal duct cyst or dermoid cysts. Some-
different clinical locations (Figs. 5, 6, and 7). times these lesions can be associated with further
The most accepted hypothesis for their etiology defects of branchial arch fusion, such as the ana-
is based on epithelial rests from the clefts of the tomic continuity of the cyst with a fistula or a
Fig. 5 Post-contrast CT showing a second branchial cleft the sternocleidomastoid muscle (red arrows). (Images
cyst presenting as a fluid-filled lobular mass on the lateral courtesy of Dr Chady Sader, Western ENT, Perth WA,
aspect of the left neck, posterolateral to the submandibular Australia)
salivary gland, lateral to the carotid space, and anterior to
Fig. 6 Lymphoepithelial cyst at the posterior border of the squamous epithelium. The most characteristic feature of
tongue, presenting as a painless firm yellow nodule (a). lymphoepithelial and branchial cysts is the presence of
Microscopic view of the cyst (b) revealing a deep lingual organized and disorganized foci of lymphocytic infiltrate,
crypt that entrapped the mucosal epithelium forming a sometimes assuming a follicular pattern, localized close to
parakeratin and serofibrinous exudate-filled cavity. The the cystic epithelium (Hematoxylin and eosin stain)
epithelial lining is hyperplastic stratified pavementous
Fig. 7 Lymphoepithelial cysts involving the floor of the mouth (a) and palatal mucosa (b)
sinus tract. In such cases, secondary infection hybridization for HPV 16/18, which is positive
could alter normal clinical presentation, adding in cystic metastasis but not in branchial cyst
pain and swelling and decreasing the lesion’s fluc- (Zidar 2016). On ultrasound examination, the
tuation on palpation. branchial cleft cyst presents as a subcutaneous
Lymphoepithelial cysts are usually smaller sub- hypoechoic fluctuating mass. Hypercontrast
mucosal yellowish, resilient nodules, ranging from computerized tomographic images reveal a
0.5 to 2 cm, located on the posterior border of the hyperdense nodule. On MRI T2, they present
tongue and in the soft palate pillars (Figs. 6 and 7). with an intense signal.
Clinical differential diagnosis comprises salivary Oral lymphoepithelial cysts are usually easier
duct cysts, mucous extravasation cysts, lipomas, to access and do not demand further imaging
and dermoid cysts. Accessory lingual tonsils also (Figs. 6 and 7). Lesions developing inside
have been related to lymphoepithelial cysts at the major salivary gland tissue may require ultra-
posterior border of the tongue. Usually superficial, sound, CT, or MRI imaging.
these lesions can be easily emptied of their contents
during puncture. Treatment
Both branchial cleft cysts and lymphoepithelial
Investigations cysts have low recurrence rates once enucleated
Fine needle aspiration cytology is a good starting or excised. Treatment of branchial cleft cysts can
point for diagnosing branchial cleft cysts. This be more complex if the cyst is in continuity with a
procedure has better results when it is performed fistula or a sinus tract.
along with ultrasound guidance. Cytopathologic
smears usually comprise squamous epithelial
cells, lymphocytes, and histiocytes along with Vascular Malformations
keratinous eosinophilic content. The most com-
mon differential diagnoses of branchial cleft Epidemiology, Etiology, and Pathology
cysts are dermoid cysts and thyroglossal duct Vascular malformations comprise a set of differ-
cysts. The most important differential diagnosis ent types of lesions all related to vascular non-
is cystic metastasis of a squamous cell carci- neoplastic development. There are some
noma, which often originates from the orophar- controversial perspectives to their classification,
ynx and is positive for HPV 16/18 and p16. as it is difficult to determine if the process is
Immunohistochemistry for cytokeratins may be neoplastic or not on clinical examination alone.
useful to demonstrate islands of invasive squa- In fact, this group of lesions is poorly understood.
mous cell carcinoma in the wall of the cystic The diagnosis of these lesions demands periodical
lesion, as well as staining for p16 and in situ follow-up prior to any intervention in order to
observe progression and decide on whether the and subsequently revised (ISSVA Classification
lesion is self-limiting or nonneoplastic. of Vascular Anomalies 2018).
Vascular malformations are appropriately Vascular malfunctions have variable etiologi-
named by their predominant vessel type. The cal factors such as genetic mutations or molecular
International Society for the Study of Vascular changes related to syndromes, trauma, blood flow,
Anomalies (ISSVA) convenes the official system and vascular wall resistance and may form part of
for classification of congenital disorders of vascu- other systemic diseases. These lesions can
lar development. Table 3 represents the latest develop in any part of the body, and the most
ISSVA classification of vascular malformations common intraoral sites are the tongue and lips.
approved at the 20th ISSVA Workshop in 2014 With a wide range of age manifestations,
Table 3 ISSVA classification of vascular malformations approved at the 2014 ISSVA workshop (ISSVA Classification of
Vascular Anomalies 2018)
Of major named
Simple Combined vessels Associated with other anomalies
Capillary CM + VM= CVM capillary venous Affect: Klippel-Trenaunay syndrome: CM
malformations malformation Lymphatics + VM +/ LM + limb overgrowth
Veins Parkes Weber syndrome: CM +
Arteries AVF + limb overgrowth
Lymphatic CM + LM = CLM capillary Anomalies of: Servelle-Martorell syndrome: limb
malformations lymphatic malformation Origin VM + bone undergrowth
Venous LM + VM = LVM lymphatic Course Sturge-Weber syndrome: facial +
malformations venous malformation Number leptomeningeal CM + eye
Length anomalies
Diameter (aplasia, +/ bone and/or soft tissue
hypoplasia, stenosis, overgrowth
ectasia/aneurysm)
Arteriovenous CM + LM + VM = CLVM capillary Limb CM + congenital
Valves
malformations lymphatic venous malformation nonprogressive limb hypertrophy
Communication
Arteriovenous CM + AVM = CAVM capillary (arteriovenous fistula) Maffucci syndrome: VM +/
fistula arteriovenous malformation Persistence spindle cell hemangioma +
CM + LM + AVM = CLAVM (of embryonal vessel) enchondroma
capillary lymphatic arteriovenous Macrocephaly: CM (M-CM/
malformation MCAP)
CM + VM + AVM = CVAVM Microcephaly: CM (MICCAP)
capillary venous arteriovenous CLOVES syndrome: LM + VM +
malformation CM +/ AVM + lipomatous
overgrowth
CM + LM + VM + AVM = Proteus syndrome: CM, VM
CLVAVM capillary lymphatic and/or LM + asymmetrical
venous arteriovenous malformation somatic overgrowth
Bannayan-Riley-Ruvalcaba
syndrome: AVM + VM
+macrocephaly, lipomatous
overgrowth
AVF arteriovenous fistula, AVM arteriovenous malformation, CAT cutaneovisceral angiomatosis with thrombocytopenia,
CAVM capillary arteriovenous malformation, CCM cerebral cavernous malformation, CLAVM capillary lymphatic
arteriovenous malformation, CLOVES congenital lipomatous overgrowth, vascular malformations, epidermal nevi,
skeletal/scoliosis and spinal abnormalities, CLM capillary lymphatic malformation, CLVAVM capillary lymphatic venous
arteriovenous malformation, CLVM capillary lymphatic venous malformation, CM capillary malformation, CM-AVM
capillary malformation-arteriovenous malformation, CMTC cutis marmorata telangiectatica congenita, CNS central
nervous system, CVAVM capillary venous arteriovenous malformation, CVM capillary venous malformation, DIC
disseminated intravascular coagulopathy, GLA generalized lymphatic anomaly, GSD Gorham-Stout disease, GVM
glomuvenous malformation, HHT hereditary hemorrhagic telangiectasia
Table 4 Most common vascular malformations of the head and neck region according to blood flow pattern
Slow flow High flow
Sturge-Weber syndrome Arteriovenous malformations
Venous malformations Arteriovenous fistula
Capillary malformations Capillary arteriovenous malformation
Capillary venous malformation Capillary lymphatic venous arteriovenous malformation
Capillary lymphatic malformation
Lymphatic venous malformation
Capillary lymphatic venous malformation
congenital lesions are usually labeled “birth- (port-wine stains), seizures, and glaucoma (Fried-
marks.” Intraosseous lesions are not as readily man et al. 2013) (Fig. 8).
detected, usually incidentally found during other Slow-flow vascular malformations are usually
imaging procedures and routine examinations, but detected at birth. Venous malformations vary in
can cause asymmetry and even bone expansion. color depending on depth, from normal coloration
This group of lesions comprises aneurysms, to deep purple (Fig. 9). The major differential
vascular stenosis, and tumorlike vascular lesions, diagnosis for these lesions is the hemangioma
such as hamartomatous proliferations. It is postu- but differs from it due to the continuous growth
lated that vascular malformations do not contain to significant proportions during puberty, under
hyperplastic cells but consist of progressively hormonal influence.
enlarging aberrant and ectatic vessels composed High-flow vascular malformations usually
of a particular vascular architecture such as veins, appear before the third decade of life, appearing
lymphatic vessels, venules, capillaries, arteries, or during childhood as a bluish coloration, some-
mixed vessel types (Buckmiller et al. 2010). times resembling port-wine stains. Arteriove-
These lesions can also be classified according to nous malformations (AVM) also commonly
blood flow as either slow flow or high flow. present at birth but commence with significant
Table 4 shows the most common vascular clinical changes during puberty (Figs. 10 and
malformations of the head and neck region 11). Swelling, pain, and bleeding are the most
according to their blood flow pattern. Congenital reported events. The lesion is not fluctuant on
vascular malformations are often visible vascular palpation; sometimes the affected area becomes
lesions known to affect 4–10% of newborn chil- thickened and even pulsatile. Combined lesions
dren (Friedman et al. 2013). with capillary, venous, and lymphatic vessels
behave as high flow due to arterial supply.
Clinical Presentation Lesions should be distinguished from those of
Clinically vascular malformations vary according conditions such as hereditary hemorrhagic telan-
to the extension of the lesion and location and giectasia (Fig. 12).
neighboring tissue displacement. The so-called
port-wine stain is one of the most common vascu-
lar malformations, found on the skin, in the oral Investigations
mucosa, and even in the sclera (Fig. 8). They can The correct diagnosis of vascular malformations
be isolated or multiple and can be part of other has an important role in appropriate treatment
systemic diseases. Sturge-Weber syndrome planning. The choice of a surgical removal, vas-
(SWS, encephalofacial angiomatosis, craniofacial cular sclerosis, embolization, or immunotherapy
angiomatosis, OMIM 185300) is characterized by is linked to the classification of the lesion, if they
intracranial vascular abnormality and can present with similar clinical features. Investi-
leptomeningeal angiomatosis, usually involving gations commence with imaging, but microscopic
the occipital and posterior parietal lobes, associ- evaluation provides the best impression of the
ated with facial cutaneous vascular malformations vascular alterations present in the lesion.
Fig. 8 Sturge-Weber syndrome. Clinical presentation of port-wine stain affecting the head and neck, respecting the
midline (a). The right sclera (b) and oral mucosa (c) also present with port-wine stain angiomatosis (white arrows)
Sometimes biopsy procedures represent a high Microscopic features such as the presence of
risk for the patient, so whenever microscopic arteries or arterioles as an integral part of the
evaluation is possible, correct characterization of lesion are determined not only by morphology of
the lesion is essential. the blood vessel but also by identification of spe-
Hypercontrast CT examination along with cific structures with the aid of specific stains such
MRI is the best imaging tool for the diagnosis as elastic tissue stains (Figs. 9 and 11). Further
and treatment planning of vascular differences can be evaluated through immunohis-
malformations. Venous malformations have a pro- tochemical examination such as S-100, to study
pensity to occur in muscle groups but can also the various tissue components present in these
involve skin and mucosa. Areas frequently lesions. The first important differential diagnosis
involved in the head and neck are masseter, is to determine whether the lesion is a hemangi-
temporalis, tongue musculature, and oral and air- oma or vascular malformation. Nerve bundles are
way mucosa. MRI remains the diagnostic modal- consistently present in vascular malformations
ity of choice to assess the extent and plan and absent in hemangiomas, serving as a diagnos-
treatment for these lesions. Regarding high-flow tic clue to differentiate between the lesions and
lesions such as AVM, MRI with T2-weighted also confirming the hamartomatous nature of
processing will typically reveal a hyperintense, these lesions (Adegboyega and Qiu 2005).
irregular lesion with numerous flow voids. A Investigation of a series of genetic mutations is
magnetic resonance arteriogram (MRA) and a essential to diagnose syndromic conditions and
computed tomography arteriogram (CTA) can other systemic diseases. Simple and combined
give excellent images of the AVM (Ziyeh et al. vascular malformations may have altered genetic
2005) (Figs. 11 and 13). expression. Table 5 shows the known causal gene
Fig. 9 Vascular malformation at the apex of the tongue compression (b). Low power magnification of venous-
presenting clinically as a red patch (a). Diascopy capillary malformation showing multiple blood vessels of
(blanching procedure) reveals whitish appearance after variable width (c + d) (Hematoxylin and eosin stain)
Fig. 10 Arteriovenous
malformation involving
right dorsal and lateral
tongue in an elderly female
Fig. 11 (continued)
Fig. 12 Patient with hereditary hemorrhagic telangiectasia presenting with multiple red colored lesions on the oral
mucosa (a) and skin (b). (Images courtesy of Dr Sue-Ching Yeoh, Sydney Oral Medicine, Sydney NSW, Australia)
mutations correlated with various vascular Treatment

malfunctions according to 2014 ISSVA Multiple treatment options exist for vascular
classification. malformations, including conservative measures
Intraosseous vascular malformations can pre- such as head-of-bed elevation and compression
sent variable imaging patterns. Lesions can present for venous malformations, laser therapy, sclero-
with poorly defined borders or a well- therapy, embolization, and surgery. Decisions
circumscribed halo, ranging from unilocular to regarding which treatment course to follow vary
multilocular and from unicystic bubble-shaped for- widely with various specialties and institutions.
mations to a honeycomb appearance (Fig. 13). Because of the wide variety of management
Bone expansion can also produce subperiosteal options and patient presentations, it is strongly
ossification assuming patterns resembling malig- recommended that patients with vascular
nancies or reactive lesions. Differential diagnosis malformations undergo treatment at a multi-
includes odontogenic cysts or tumors. It is difficult disciplinary center for treating vascular anomalies
to establish immediate correlation of the lesion with (Buckmiller et al. 2010). Treatment effectiveness
the major vessels of the affected region. If the of vascular malformations and its prognosis is
patient does not show asymmetry, pain, or bone linked with the correct diagnosis of the lesion.
expansion, it is extremely uncommon for the clini- Conservative measures are only effective for
cian to consider vascular malformations as a differ- venous malformations. These vascular
ential diagnosis. malformations have a tendency to expand instead
Fig. 11 High-flow arteriovenous malformation. The mental vein (e–g). Microscopic aspect of the arteriovenous
patient presents with a pinkish non-fluctuating nodule malformation (h), revealing the close relationship of arter-
extending from the midline of the lower lip to the left labial ies with thick walls and narrow lumen, and veins with
commissure (a + b). The mucosal aspect of the lesion (c) dilated blood-filled lumen and thin vascular walls. The
and clinical compression exam (d) reveals the pulsating lesion infiltrates the surrounding tissue. In this specimen,
behavior of the lesion indicating its flow pattern. MRA adipose tissue is seen with striated skeletal muscle as well
exam reveals the arterial origin from the facial artery and as neural fibers in the original connective tissue from the
the appearance of an arteriovenous fistula forming a plex- affected area (Hematoxylin and eosin stain)
iform arrangement with dilated vessels and the effluent
Fig. 13 Orthopantomogram showing deformity of the projection (b) and 3D CT angiography (c) of same patient
anterior right mandible demonstrating asymmetry and show feeding vessels to the right mandible and demon-
expansion of the inferior border (a). Maximum intensity strate arteriovenous malformation
of proliferate; the resistance of the vascular wall periodontal disease, and dental extractions will
and blood pressure in the area are the main causes require patient hospitalization prior to performing
of this undesirable development. Therefore, head- these procedures. Blood loss control during these
of-bed elevation is an important measure to pre- procedures is better achieved with aids of a
vent increase of local blood pressure while the 1.064 nm 10 W Nd:YAG laser, which allows
patient is in bed. Compression is a good adjunc- deeper coagulation compared to 10,600 nm wave-
tive conservative measure, effective in body length CO2 laser (Bradley 1997). Electrocautery,
extremities such as limbs, with aids of compres- presurgical embolization, and splinting of the
sive sleeves, socks, and gloves, but not readily region are also widely applied in these situations,
amenable in the head and neck region. but reported complications such as postoperative
Systemic diseases such as syndromes will pre- bleeding, infection, and scar formation are more
sent with specific alterations that call for profes- frequent.
sional management. In cases of Sturge-Weber Laser therapy is the treatment modality most
syndrome, for instance, gingival overgrowth, widely applied for vascular malformations,
Table 5 Known causal gene mutations correlated with the different conditions according to 2014 ISSVA classification
(ISSVA Classification of Vascular Anomalies 2018)
Condition Gene
Capillary malformation of CM-AVM RASA1
Telangiectasia ENG, ACVRL1, SMAD4
Common and familial venous malformation TIE2 and TIE2 somatic
Glomuvenous malformation Glomulin
Cerebral cavernous malformation types 1–3 KRIT1, Malcavernin, and PDCD10
Arteriovenous malformations and arteriovenous fistulas ENG, ACVRL1, SMAD4, and RASA1
Parkes Weber syndrome RASA1
Sturge-Weber syndrome GNAQ
Macrocephaly syndrome PIK3CA
Microcephaly syndrome STAMBP
CLOVES syndrome PIK3CA
Proteus syndrome AKT1
Bannayan-Riley-Ruvalcaba syndrome PTEN
Table 6 Most common sclerozing agents along with complication and effectiveness rates based on Horbach et al. (2016)
Number of Reported Effectiveness rates (weighted
Sclerozing agent patients complications mean)
Pingyangmycin 698 2% 79–100% (98%)
Absolute ethanol 306 18% 84–100% (92%)
OK-432 (Picibanil) 205 6% 50–100% (71%)
Ethanolamine oleate 188 3% 88–100% (98%)
Bleomycin 82 6% 68–100% (82%)
Polidocanol 39 3% 100%
Doxycycline 22 0% 100%
Sodium tetradecyl 12 0% 83%
sulfate
promoting thermocoagulation. Capillary effectiveness rates. The complications related to

malformations present good esthetic results with the use of these substances can be systemic or at
lasers, while superficial venous malformations the site of application including hemoglobinuria,
have better results than deep and infiltrative infection, nausea, swelling, pain, ulceration,
lesions. Pulsed dye lasers ranging from 580 to necrosis, and cellulitis.
575 nm CO2 lasers and Nd:YAG laser tunable to Surgical excision offers the best chance for cure
1064 nm applying 30–70 W/cm2 per session com- of vascular malformations. Excision of extensive
bined with simultaneous cooling offer good treat- lesions remains a challenge, as these lesions are
ment outcomes (Zheng et al. 2010). rarely well defined and intraoperative bleeding can
Arteriovenous malformations are the exception make identification and preservation of important
for this treatment modality as these cases demand structures difficult. Preoperative sclerotherapy can
embolotherapy combined with surgical excision. be beneficial not only to decrease bleeding, which
A recent systematic review of the literature has improves visibility and eases dissection, but also to
identified the most common sclerozing agents decrease blood loss and operative time (Buckmiller
used for treating vascular malfunctions and eval- et al. 2010). High-flow lesions demand MRA or
uated their performance (Horbach et al. 2016). CTA prior to the procedure, as well as adjunctive
Table 6 summarizes the most common sclerozing embolization. Regardless of approach, attention
agents along with their complication rates and must be made to eradicate the nidus. If the nidus
is left untreated, recruitment and collateralization all-encompassing term is lymphatic

of new vessels, along with early recurrence, are malformations (LM), also applied by the ISSVA.
common (Friedman et al. 2013). Traditionally, vascular malformations involving
Embolization is usually achieved with cyanoac- the lymphatic vessels were known by a variety
rylate, onyx, or absolute alcohol injection. Just like of terms including cystic hygroma,
in sclerotherapy, alcohol is more often associated lymphangioma, and hemolymphangioma
with complications such as nerve paralysis, signifi- (Fig. 14) (Wall et al. 2016). They can potentially
cant swelling, necrosis, ulceration, scaring, and develop in any part of the body, and most of the
even cardiovascular collapse. Onyx is also very lesions are identified during childhood.
expensive and requires increased fluoroscopy time. Usually lesions consist of collections of
Arteriovenous malformations usually recur, and ectatic lymph vessels that form endothelial
treatment of very extensive lesions is always life- lined cystic spaces, classified as macrocystic
threatening. In bony lesions, the result of emboliza- (single or multiple cysts >2 cm3), microcystic
tion is confirmed with new bone formation inside (single or multiple cysts >2 cm3), or mixed
radiolucent spaces during imaging follow-up. (Friedman et al. 2013). They can also be classi-
fied as simple, cavernous, or cystic, according to
the diameter and number of lymphatic vessels in
Lymphangioma Including Cystic the lesion.
Hygroma The etiology of these lesions is still an area of
constant investigation. Lymphangiogenic
Epidemiology, Etiology, and Pathology growth factors (such as VEGF-C and transcrip-
Lymphangiomas are uncommon, benign, tion factor Prox-1) have been reported to be
hamartomatous proliferation of lymphatic vessels. involved in the process through upregulation of
Given the benign nature of these anomalies and VEGFR-3 (Itakura et al. 2009; Pavlov et al.
their wide-ranging manifestations, the preferred 2009).
Fig. 14 Facial asymmetry caused by lymphangiomas (a + b). Note the difference of a microcytic lymphangioma in (a)
with more diffuse asymmetry and a macrocystic/cystic hygroma with more localized appearance (b)
component of these lesions continues to involve

an increased amount of area with age.
Large lymphatic malformations involving the
head and neck identified in utero have the poten-
tial to create airway obstruction upon delivery.
The morbidity of such cases is usually related to
the size and location of the lesions; therefore it is
important to assess the extent of the lesion. In
patients with more diffuse lesions, the airway
must be examined. Macrocystic lymphatic
malformations present as a lump beneath normal
or slightly bluish skin. These are soft but not
compressible (Fig. 14). The mass can undergo
Fig. 15 Intraoral view of a microcystic lymphangioma sudden enlargement secondary to intracystic
showing multiple vesicles
bleeding or infection. When affecting the
tongue, large lesions may cause airway obstruc-
tion and impair feeding and speech. Over time,
Clinical Presentation cystic lymphatic lesions can develop bleeding,
Small individual intraoral lymphangiomas are dif- infection, and cutaneous vesicles. Recurrent
ficult to differentiate from mucoceles and ranulas infections and chronic wounds are common
(de Carvalho et al. 2015). Oral lymphangiomas are with superficial lesions.
usually superficial lesions formed by a cluster of Secondary bony overgrowth can cause cranio-
transparent vesicles resembling the appearance of facial disfigurement. These can be asymptomatic
tapioca pudding or frog eggs (Fig. 15). These or lead to pathologic fractures. When lymphatic
lesions show slow growth, normal to red-purple malformations involve the cervicofacial skeleton
coloration, and size varying from 1 to 5 cm in or the surrounding soft tissues, they can lead to
diameter. Differential diagnoses include hemangi- osseous hypertrophy resulting in maxillary or
omas, dermoid cysts, thyroglossal duct cysts, mandibular deformities, malocclusion, or open
angiogranulomas, and granular cell tumors. Diag- bite (Friedman et al. 2013).
nosis is usually made in childhood, and if not
obvious from birth, it may become apparent with Investigations
infections such as upper respiratory infection or Lymphatic malformations are frequently diag-
otitis media, which can cause swelling of the mal- nosed on prenatal ultrasound and may require
formation caused by increased lymph flow. Lesions special preparations for delivery if perinatal air-
typically grow slowly but may rapidly swell with way compromise is suspected. The best imaging
infections or with hormonal changes such as modalities for lymphatic malformations are ultra-
puberty (Buckmiller et al. 2010). sonography, MRI, and contrast lymphography.
On palpation, lesions usually feel fluid filled and Ultrasound is valuable in differentiating lym-
are non-compressible, which can help in phatic malformations from other vascular lesions
distinguishing them from venous malformations. that contain blood flow (e.g., hemangioma). Ultra-
Mucosal and skin surfaces can be affected with sound is further able to characterize the size and
vesicle formation, which represents small external extent of superficially localized lesions.
fluid-filled cysts. Vesicle formation causes prob- MRI remains the visualization method of
lems with bleeding, weeping of lymph fluid, and choice for delineating the extent of the malforma-
pain. Microcystic lymphatic malformations present tion, planning intervention, predicting outcome
as soft non-compressible masses with an overlying (macrocystic vs microcystic), and verifying diag-
ill-defined area of clear, yellow, or red (secondary nosis. MRI offers an additional advantage of axial
to intracystic bleeding) vesicles. The external imaging that can further identify the extent of
Fig. 16 Cavernous microcystic lymphangioma of the oral amorphous eosinophilic material (b) (Hematoxylin and
submucosa. Numerous vascular spaces with thin endothe- eosin stain)
lial walls (a), sometimes filled with plasma/lymph
large diffuse lesions and highlight the precise including extent of functional deficit and cosmetic
relationship between malformations and adjacent deformity as well as the possible negative impact
anatomical structures (Wall et al. 2016). For the of progression of the lesion. Life-threatening lym-
fetus whose airway may be in jeopardy, it is phatic malformations require early intervention
important to try to differentiate, by prenatal (Friedman et al. 2013).
MRI, between the soft and usually The preferred approach to sclerotherapy uti-
non-compressive lymphatic malformation from lizes ultrasound guidance with cyst aspiration
the firm and often airway compressing teratoma followed by injection of a sclerozing agent. Etha-
(Steigman et al. 2009). nol and sotradecol have traditionally been used to
If these lesions are biopsied, they show numer- treat lymphatic malformations with good results
ous vascular spaces with thin endothelial walls preferentially in macrocystic lesions. Multiple
sometimes filled with plasma/lymph amorphous treatment sessions may be required, and there are
eosinophilic material (Fig. 16). sometimes weight-limited dose concerns with
these toxic agents in small children. Complica-
Treatment tions can include skin breakdown, prolonged
There are sporadic reports of spontaneous resolu- swelling, pain, and airway compromise. Lym-
tion of a small percentage of lymphatic phatic malformations tend to recur and can do so
malformations, although this is quite rare several years after reporting a cure with sclero-
(Buckmiller et al. 2010). It has been proposed that therapy, so the literature must be analyzed care-
the lesions that are most likely to resolve are small, fully. Other sclerosants have been reported in an
macrocystic, and within the posterior triangle of the attempt to find an effective treatment while max-
neck. Infected and inflamed lesions can show some imizing safety. These include doxycycline,
regression after antibiotics and anti-inflammatory OK-432, and bleomycin. Concerns still remain
therapy with corticosteroids (Friedman et al. 2013). regarding complications with each treatment.
Indications for definitive treatment of lym- Doxycycline can cause neural damage, OK-432
phatic malformations include esthetic consider- can be associated with sepsis, shock, myalgia, and
ations and functional compromise. Treatments bleomycin still carries a warning of pulmonary
include surgery, sclerotherapy, and laser therapy. fibrosis, although this is related to total lifetime
Often, a combination of therapies is utilized. The dose and doses received for treatment of lym-
timing of treatment depends on several variables phatic malformation usually do not approach
that level. All of these sclerozants can still cause inches before being detected. Most small and
severe swelling with airway compromise, skin superficial benign soft tissue tumors are diag-
breakdown, and other toxic side effects. It must nosed after surgical excision. Complete excision
be emphasized that treatment outcomes are based of such tumors should be considered diagnostic as
on multiple treatments, sometimes in excess of well as therapeutic. These lesions can be well
five to ten treatments, and long-term follow-up circumscribed by a fibrous capsule or present an
data is lacking (Buckmiller et al. 2010). infiltrative pattern demanding careful dissection
Surgery is important not only for removing and from the surrounding structures in order to pre-
hopefully eliminating the malformation but also vent unnecessary surgical sequelae.
for correcting the secondary deformities caused
by the malformation. Surgical resection is typi-
cally required for the treatment of microcystic Fibroma/Traumatic Fibroma
lesions. These lesions can encase major structures,
and great care must be taken to avoid significant Epidemiology, Etiology, and Pathology
vascular and nerve damage. It is often stated that Fibroma is the most frequent soft tissue tumor of
large microcystic lesions in the neck can be the the oral cavity (Castellanos and Diaz-Guzman
most challenging benign lesions to safely resect. 2008). These lesions are characterized by collagen
Some lesions can be well vascularized and trans- rich, hypovascularized connective tissue, lined by
fusion may be required. Recurrence is reported the oral mucosa. The true neoplastic nature of
from 15% to 50% after surgical resection. Recur- these lesions has always been questioned, since
rence is associated with incomplete resection, it can also be a reactive excess of collagen depo-
which is often due to the need to preserve critical sition by an inflammatory process, caused by
structures that the cyst is adherent to, such as chronic trauma or irritation (traumatic fibroma/
nerve tissue. Resection and particularly recur- fibroepithelial polyp). Low mitotic activity of the
rences are associated with fat hypertrophy possi- fibroblasts is also a characteristic of these lesions.
bly due to excess lymph fluid and leaking that The presence of inflammation is minimal except
exits post resection (Wall et al. 2016). in scattered submucosal areas. It has a 2:1 male-
to-female gender predilection and can appear at
any part of the oral mucosa, although most lesions
Benign Tumors of the Head and Neck are found in the vestibular mucosa or areas related
to masticatory function. Although fibromas can
Benign neoplastic proliferations of soft tissues of occur at any time of life, patients usually notice
the head and neck are slow-growing masses, usu- these tissue growths during the fourth to sixth
ally painless, that promote asymmetry. Although decades.
most benign soft tissue tumors are asymptomatic The main difference of a fibroma from a trau-
and present in the form of a painless nodule or matic fibroma and fibroepithelial polyp is the
mass, schwannomas and neurofibromas may be cause-effect clinical correlation and the intensity
tender and painful. Some of these lesions can also of the inflammatory process. While traumatic
form characteristic parts of syndromes. With few fibromas and fibroepithelial polyps exhibit areas
exceptions, benign soft tissue tumors are diseases of intense chronic inflammation, even ulcerated
of young and middle-aged adults. Most of these mucosa and epithelial hyperplasia, fibromas
lesions are considered uncommon findings in clin- appear more mature and almost free from inflam-
ical practice but represent one of the most com- mation. In addition, a mature angiogranuloma is
mon benign neoplasms diagnosed in oral and microscopically indistinguishable from a fibroma.
maxillofacial pathology services.
The average size of benign soft tissue tumors at Clinical Presentation
a superficial location is seldom more than 2 cm. These present as sessile or pedunculated, normal
Deep tumors, however, may grow to several colored, soft-to-tender nodules, with slow
Fig. 17 Fibroma/traumatic fibroma presenting as a nodule due to local irritation (a). Cause-effect relationship
pedunculated, normal colored, soft nodule, with slow proof a traumatic fibroma, with the patient reporting frequent
gression. In this case, there is hyperkeratinization incidental biting since beginning orthodontic treatment (b)
appearing as white patches at the inferior aspect of the
Fig. 18 Large traumatic fibromas caused by overworn Fig. 19 Leaflike traumatic fibroma related to overworn,
upper complete denture in the vestibular sulcus uncleaned, complete upper denture
progression (Fig. 17). Lesions can present with collagenized with fibroblasts that can be fusiform,
hyperkeratinization appearing white if local irrita- elongated, round or oval, and sometimes stellate
tion is present. Fibromas are small lesions, with an shaped (Fig. 20) (Villa et al. 2016). Chronically
average size of 7–8 mm, but can be larger inflamed areas are more likely to show epithelial
(1–2 cm). Traumatic fibromas and fibroepithelial hyperplasia, with typical features of acanthosis,
polyps can progress to more extensive lesions, hydropic degeneration, and pseudo-
mostly when related to old, ill-fitting complete epitheliomatous hyperplasia (Fig. 21).
prosthesis (Figs. 18 and 19) (van der Waal 2016).
Treatment
Investigations Conservative surgical excision is the treatment of
Microscopic investigations of this lesion show choice for these lesions. Recurrence is low if no
large areas of atrophic squamous cell epithelium further irritation or trauma persists in the affected
almost without any projections into the underly- region. Lesions related to prostheses require new,
ing connective tissue. The connective tissue is perfectly fitting replacements. Prosthetic hygiene
is also necessary, so the clinician should educate Myofibromatosis affects infants and young adults
and train the patient on how to take good care of almost exclusively and is known as infantile
prostheses. myofibroma. There are various types of fibroblas-
tic/myofibroblastic lesions, with different behav-
iors presenting as benign, intermediate with
Myofibroma malignant potential, or malignant lesions.
Myofibroma is part of the spectrum of these
Epidemiology, Etiology, and Pathology lesions that may also include nasopharyngeal
Myofibroma is a rare benign mesenchymal tumor angiofibroma, fibrosarcoma, nodular fasciitis,
mostly found in the head and neck region and fibromyxoma, and fibrous hamartoma.
characterized by the proliferation of fibroblasts,
myofibroblasts, or both. Sometimes it manifests
as a multifocal lesion called myofibromatosis. Clinical Presentation
Clinically, myofibromas present as single or mul-
tiple, hard, reddish-purple nodules in the skin,
muscles, bones, viscera, or central nervous system
(Fig. 22). Localized fibromatosis is the most com-
mon presentation, seen mainly in the soft tissues
of the head and neck. Infantile fibromatosis
should be included in the differential diagnosis
of multiple bony, soft tissue, and central nervous
system lesions in a child, along with Langerhans
cell histiocytosis, multiple metastases from neu-
roblastoma, or sarcomas. Definitive diagnosis is
established by means of biopsy (Hourani et al.
2015). Ulceration is a tumor characteristic that
may be suggestive of a more aggressive biologic
potential and should increase the clinician’s sus-
Fig. 20 Collagen rich, hypovascularized connective tis-
picion for malignancy. Microscopic evaluation of
sue, lined by thin oral mucosa, without epithelial projec-
tions and without a significant inflammatory process the lesion with appropriate use of immunohisto-
(Hematoxylin and eosin stain) chemical stains can provide the correct diagnosis.
Fig. 21 Chronically inflamed areas of traumatic fibroma degeneration, and pseudoepitheliomatous hyperplasia.
(a) and fibroepithelial polyp (b) show epithelial hyperpla- The connective tissue presents with an intense diffusely
sia, with typical features of acanthosis, hydropic spread lymphocytic exudate (Hematoxylin and eosin stain)
Fig. 22 Myofibroma. Rapid growing solitary lesion reconstruction (b + c). Proliferation of fusiform cells
involving the left mandible (a). Lytic expansile pattern of arranged in interlaced bundles (d) and fascicles (e) (Hema-
growth in the posterior mandible noted on CT toxylin and eosin stain)
Investigations soft tissue mass best viewed with post-contrast

The most appropriate imaging exam to identify enhancement on T1 scans with fat suppression.
myofibromas is MRI, which reveals an ill-defined Computerized tomographic scanning of lesions
involving bone structures reveals an expansive represent 0.1–5% of all benign tumors of the oral
lytic behavior sometimes resembling malignancy cavity (Fregnani et al. 2003). Lesions can be sol-
but also mimicking odontogenic tumors such as itary manifestations or multiple. Patients with
myxoma and ameloblastoma (Fig. 22) multiple lesions in the body should be investi-
(Nabavizadeh et al. 2017). On ultrasound, gated for syndromes and rare obesity disorders.
myofibroma presents as a hyperechoic mass with A retrospective study of 46 cases of lipomas of the
an anechoic or hypoechoic center traversed by oral cavity found the mean age of patients was
thick septa and surrounded by a thick hypoechoic 52 years, ranging from 8 to 80 years, with 57.8%
rim with rare flow on power Doppler (Koujok of female prevalence. The most common site was
et al. 2005). the buccal mucosa (45.7%), followed by the
The histopathological examination of tongue and lips (13% each) and floor of the
myofibroma usually reveals biphasic plexiform mouth (10.9%) (Fregnani et al. 2003). The size
paucicellular regions and spindle cell and vascular of lesions varied from 0.3 to 5 cm, with an average
regions (Fig. 22). Immunohistochemical panels of 2 cm.
show positive marking for muscle markers such
as SMA, muscle-specific actin, HHF35, and Clinical Presentation
vimentin and negativity to neural markers such Head and neck lipomas are usually found in the
as CD56, GFAP, and S100. posterior neck subcutaneous tissue and in the
scalp (Fig. 23). Lesions have soft-to-tender con-
Treatment sistency on palpation and present mostly as a
Solitary lesions are amenable to conservative sur- loose mobile fluctuating nodule with normal skin
gical resection. In the generalized form, lesions coloration.
often regress spontaneously over 6–18 months. In Oral cavity lipomas are slowly enlarging, with
multicentric life-threatening forms, chemotherapy a soft, smooth surface mass of submucosal tissues.
with vinblastine and methotrexate promotes When superficial, there is a yellow surface
tumor regression (Hourani et al. 2015).
Lipoma
Epidemiology, Etiology, and Pathology

Lipomas are characterized by well-circumscribed
benign neoplastic proliferations of adipose tissue
and are usually found as long-standing soft nodu-
lar asymptomatic swellings covered by normal
mucosa or skin. The size of the lesions does not
follow the adipose tissue variation, increasing
even when patients go through weight loss. Lipo-
mas are more common in men and are one of the
most frequent benign mesenchymal tumors, with
15–20% of them seen in the head and neck
(Harnsberger and Osborn 2006; Harnsberger
et al. 2006). There is a bimodal peak of presenta-
tion in children and during the fifth/sixth decades Fig. 23 Axial T1 MRI showing 23 mm lipoma superficial
of life, often seen in overweight individuals. to the right zygomatic arch and the adjacent superior por-
tion of the masseter muscle, immediately deep to the super-
Intraoral lesions on the other hand are less fre-
ficial muscular aponeurotic system (SMAS) and temporalis
quent than lesions of the head and neck, fascia and closely related to the superficial parotid tissue
representing only 1–4% of these tumors. These and the zygomaticus major muscle
Fig. 24 Lipoma. Patient presenting with extraoral asym- material with a wet appearance with formation of lobules
metry involving the left lower lip (a). On palpation, a soft after fixation spay was applied. The surgical presentation
well-circumscribed fluctuating nodule was noticed (b). of the dissected lesion, with a thin fibrous capsule and
FNAC was performed at the first visit (c), which showed yellow coloration (d)
coloration. Lesions may be pedunculated or ses-

sile, and occasional cases show surface
bosselation (Figs. 24, 25, and 26). Puncture of
these lesions for FNAC reveals a wet, shiny, trans-
parent or hyaline, gelatinous material. When fix-
ation solution is sprayed over the surface of the
slide, it forms a small goticular pattern (Fig. 27).
Although lipomas are well circumscribed, intra-
muscular lesions require careful dissection and
reconstitution of the muscular plane after surgical
removal. Grossly, lipomas are of variable size.
They tend to appear as smooth or lobulated, often
well demarcated or encapsulated, with a yellow
color. One distinctive behavior of lipomas is that
Fig. 25 Lipoma. A small lesion on the posterior border of they float when immersed in formalin solution.
the tongue that resembles a lymphoepithelial cyst. These The main differential diagnosis of lipoma
lesions float when placed in formalin solution includes fibroma, which is composed of fibrous
Fig. 26 Lipoma in the floor of the mouth (a) appearing as a yellow colored mass under the mucosal surface. Lump was
completely excised (b)
Fig. 27 Microscopic features of FNAC cytologic smear pattern of the adipocytes is noted, not all of which show
from a lipoma. Hematoxylin and eosin stain (a), preservation of the cytoplasmic membrane. The fat lobules
Papanicolaou stain (b), and Sudan red stain (c). A globular are best visualized with Sudan red stain
tissue and is much more firm than lipoma. Other

differential diagnoses include tumors such as granu-
lar cell tumor, liposarcoma, neurofibroma, tumor
pleomorphic adenoma, traumatic fibroma, mucocele,
and other salivary gland tumors (Fig. 28). Histopath-
ological examination is therefore essential for diag-
nostic conclusion in cases of lipoma.
Investigations
Lipomas demonstrate characteristic low attenua-
tion on CT and signal intensity similar to that of fat
on all MRI sequences with minimal internal archi-
tecture and mass effect with displacement of the
surrounding structures (Fig. 23). The margins
may not be easily distinguishable from normal Fig. 28 Lump in the buccal sulcus suggestive of a lipoma
fat. There is no contrast enhancement on CT but proven histopathologically to be a salivary
examinations (Nagornaya and Bhatia 2013). plasmacytoid myoepithelioma
Fig. 29 Microscopic characteristics of lipoma. In (a) the the lesion is termed a fibrolipoma. In (b), the lipoma was
lesion was dissected and a thin fibrous capsule circum- submucosal and was excised along with the surrounding
scribes the well-organized adipose tissue, with loose con- tissue. There is still a thin fibrous capsule circumscribing
nective tissue forming bands through the lesion. If the the adipose tissue from the mucosal epithelium (Hematox-
amount of adipose tissue and connective tissue is similar, ylin and eosin stain)
Three different microscopic variations of lipo- Fine needle aspiration cytopathologic smears
mas are noted including typical lipomas, are good investigative tools for treatment plan-
fibrolipomas, and spindle cell lipomas. Typical lipo- ning, and when the clinical suspicion of lipoma
mas are by far the most common feature, exhibiting is present, enough smears should be obtained to
a delicate connective tissue capsule circumscribing perform hematoxylin and eosin or Papanicolau
lobules of hexagonal cells with transparent cyto- and Sudan red stains (Fig. 27).
plasm, with peripherally placed nucleus, resembling Several syndromes include lipomas or
normal adipose tissue (Fig. 29). Larger lesions show lipomatosis as their most significant features includ-
connective tissue vascularized septa. Fibrolipomas ing Bannayan-Riley-Ruvalcaba syndrome, multiple
are similar to lipomas by gross examination but symmetric lipomatosis, encephalocraniocutaneous
microscopically present proportional amounts of lipomatosis, Proteus syndrome, Cowden syndrome,
connective tissue mixed with agglomerates of adi- phosphatase and tensin homolog, and familial par-
pocytes, mature adipose tissue interspersed by broad tial lipodystrophy type 2 (Fregnani et al. 2003).
bands, or fascicles of dense connective tissue; the
capsule is less evident than typical lipomas or even Treatment
absent. The histologic features of spindle cell lipoma Surgical excision is the main treatment for lipoma,
comprise spindle cells, mature adipose tissue, colla- and recurrence is not likely to occur. For large and
gen bundles, and myxoid interstitial matrix. Histo- difficult-to-access lesions, it is of paramount
chemical and immunohistochemical study of the importance to perform adequate imaging, diag-
lesion highlights numerous mast cells and immuno- nostic biopsy, and careful assessment before sur-
histochemical expression of CD34 and vimentin in gery is planned.
the spindle cells (Fregnani et al. 2003).
Other microscopic features described in the
literature include angiolipomas where there is a Neuroma Including Multiple Endocrine
well-vascularized lesion, pleomorphic lipomas Neoplasia Type 2B (MEN2B)
when the lesion presents pleomorphic lipoblasts
and adipocytes, intramuscular/infiltrating lipo- Epidemiology, Etiology, and Pathology
mas, and salivary gland lipomas according to the Neuroma is an abnormal proliferation of hyperplas-
site of lipomatous proliferation. tic axons well delimited by fibrous perineurium.
Fig. 30 Traumatic neuroma. Clinical features of a trau- there is mild chronic inflammation (b), accentuated fibro-
matic neuroma after laceration of the right upper lip which sis, and disorganized axons with fibrous perineurium (c)
healed without professional intervention, causing asymme- (Hematoxylin and eosin stain)
try and esthetic concern for the patient (a). Microscopically
Different pathologic entities use the term neuroma, after tooth extraction, due to local chronic masti-
such as traumatic/amputation neuroma, encapsu- catory trauma caused by a total prosthesis to the
lated palisaded (solitary circumscribed) neuroma, mental nerve of patients with advanced stage alve-
and mucosal neuroma in multiple endocrine neo- olar ridge resorption. The most common sites for a
plasia type 2B (MEN 2B). traumatic neuroma in the head and neck are the
A traumatic neuroma (Fig. 30) is a hyperplastic inferior alveolar nerve, lingual nerve, and great
lesion caused by trauma or surgery that involves auricular nerve.
the peripheral nerves and is not considered to be a Neuroma was first described by Reed et al. in
true neoplasm. Traumatic neuromas, also called 1972 as a palisaded, encapsulated, solitary, benign
amputation neuromas, are reactive proliferations cutaneous tumor. It was classified as a primary
of neural tissue that occur after transection or hyperplasia of nerve fibers (axons and their sheath
damage to a nerve bundle. These lesions can cells) with equal frequency in both sexes and
start after any surgical treatment, such as proce- limited anatomic distribution to areas bordering
dures that need tissue dissection such as biopsy, mucocutaneous junctions, predominantly on the
face, with rare exceptions (Reed et al. 1972). The procedure, it can be difficult to determine the
alternate designation solitary circumscribed neu- exact extension of the lesion. Differential diagno-
roma was proposed based on the fact that most sis comprises traumatic fibromas, granular cell
lesions were not fully encapsulated and showed tumor, schwannoma, and neurofibroma.
only focal palisading (Fletcher 1989). A review of Clinically palisaded encapsulated neuromas
55 cases of palisaded encapsulated neuromas (Fig. 31) are usually small, rarely ulcerated nod-
found that tumors were located on the palate ules, the size of which never exceeds 1.0 cm in
(31), maxillary or palatal gingiva (8) (including greatest dimension. Lesion duration can vary from
one example on an edentulous maxillary alveolar months up to 20 years, but asymptomatic lesion
ridge), tongue (4), mandibular gingiva (3), upper may be reported by the patient as unknown dura-
lip vermillion border (3), mucosal part of the tion. Symptoms are unusual findings, but some
lower lip (3), lower lip vermillion border (2), and patients report pain upon “drinking hot bever-
buccal mucosa (1). Patient age ranged from 20 to ages” or “after irritation” (Koutlas and
73 years, with 70.3% being men and 29.7% Scheithauer 2010).
women (Koutlas and Scheithauer 2010). MEN2B has a characteristic phenotype with
Multiple endocrine neoplasia type 2 is a syn- medullary thyroid carcinoma (MTC) and pheo-
drome of inherited susceptibility to tumors of chromocytoma. The face may have a wide-eyed
endocrine cell types including the thyroid “C” expression with thickening and eversion of the
cells, the adrenal medulla, and the parathyroid upper eyelid margins and visible tarsal plates.
glands. In some disease subtypes, developmental Neuromas may be present on the eyelids and
abnormalities may also be present. MEN2 is conjunctiva, and prominent thickened corneal
caused by inherited mutations of the gene that nerves that extend to the pupillary area may be
encodes the RET receptor tyrosine kinase which seen on slit lamp examination. The eyebrows are
leads to its unregulated activation and is transmit- large and prominent. The face is elongated with
ted in an autosomal dominant fashion. Subtypes prominent “blubbery” lips, and submucosal nod-
of MEN2 are MEN2A, MEN2B, and FMTC ules present on the vermilion border, often later-
(familial medullary thyroid carcinoma) (Castinetti ally. Oral manifestations, which are often the first
et al. 2018). Because of its low point prevalence clue to the syndrome in infancy or early child-
(0.9–1.65 per million) and incidence (1.4–2.6 per hood, include mucosal neuromas on the anterior
million live births per year), MEN2B (OMIM dorsal surface of the tongue. Mucosal neuromas
#162300) remains poorly described in the of the tongue are almost pathognomonic in the
literature. presence of medullary thyroid carcinoma. Other
oral features include palatal and pharyngeal neu-
Clinical Presentation romas, a high-arched palate, and a prominent jaw
Traumatic neuromas present clinically as nodules (Morrison and Nevin 1996). MEN2A accounts for
or masses, less than 2 cm in diameter that can be about 75% of all MEN2 cases and expresses
related to altered sensation on palpation, such as MTC, pheochromocytoma, and parathyroid
local pain, numbness, or shock (Fig. 30). The gland hyperplasia. FMTC is another variant
mucosa will present normal coloration. Some- which accounts for about 20% of MEN2 cases
times patients do not remember the cause of and has a particularly benign course of MTC and
trauma, for instance, lesions on the anterior border a low incidence of other clinical manifestations.
of the tongue are very common due to masticatory MEN2B accounts for only 5% of MEN2 cases;
accidental biting. Long-lasting lesions do not however, its clinical course is the most aggressive.
show any sign of inflammation. Sometimes reac- The American Thyroid Association has
tive fibrous hyperplasia or vascular malformations recommended preventive thyroidectomy before
can be associated with the lesion. Lesions are not the age of 1 in cases of MEN2B. Patients with
well circumscribed or encapsulated, so if the dam- MEN2B usually present with very early-onset
aged nerve bundle is not visible during the biopsy MTC, a 50% lifetime risk of pheochromocytoma,
Fig. 31 Palisaded encapsulated neuroma. Firm peduncu- fascicles of fusiform Schwann cells with elongated prom-
lated nodule on the anterior border of the tongue (a). inent nuclei, in an oriented formation (c). Higher magnifi-
Nodular arrangement of well-circumscribed neural tissue cation showing wavy fusiform nuclei (d) (Hematoxylin
of the palisaded encapsulated neuroma (b). Interlaced and eosin stain)
and universal extra-endocrine features, mainly arrangement (Figs. 30, 31, and 32). Inflammation
bowel problems due to diffuse intestinal has been mentioned as an important morphologic
ganglioneuromatosis (constipation, feeding diffi- feature for diagnosis of traumatic neuromas, but
culties in infancy, megacolon) and alacrima, both long-lasting traumatic neuromas can present with
of which can be the earliest presenting features, in almost an absence of inflammatory cells.
addition to mucosal neuromas and a marfanoid Palisaded encapsulated neuromas, mucosal
body habitus, both of which may not become MEN2B neuromas, as well as other benign neu-
clinically apparent until several years of age rogenic tumors can also present with secondary
(Castinetti et al. 2018). inflammation caused by secondary trauma or
infection (Woodruff 1993; Koutlas and
Investigations Scheithauer 2010; Lee et al. 2017). Table 7 com-
Microscopic differential diagnosis of the different pares the most important features in the differen-
types of neuromas includes other benign neuro- tial diagnosis of neuromas.
genic tumors such as schwannoma and neurofi- MEN2B is caused by a germline missense
broma. Key points of morphologic observations mutation in the RET proto-oncogene. The RET
include perineural encapsulation, presence of gene which is located on chromosome 10q11.2
mast cells, pattern of Schwann cell proliferation, encodes a receptor tyrosine kinase. It is expressed
presence of Verocay bodies, axons, and stromal in neuroendocrine cells including thyroid C cells,
Fig. 32 MEN 2B neuroma showing abnormal hyperplas- magnification showing multiple well-delimited anaxonic
tic axons well delimited by fibrous perineurium, without bundles with perineural cells in the surrounding fibrous
inflammation or cause-effect correlation (a). Higher stroma (b) (Hematoxylin and eosin stain)
Table 7 Important features in differential diagnosis of neuromas

Palisaded
Traumatic encapsulated MEN2B mucosal
Characteristics neuroma neuroma neuroma Neurofibroma Schwannoma
Perineural Absent Variable Complete Absent Complete
encapsulation
Schwann cell Microfascicular Cellular Microfascicular Hypocellular Antoni A and
proliferation compartmentalized microfascicles compartmentalized sheets Antoni B
and haphazard coursing in and haphazard patterns
various
directions,
superficial
fascicles blend
with
connective
tissue
Imumuno- S100 (+), EMA (+ S100 (+), S100 (+), EMA (+ S100 (+), S100 (+),
histochemical in perineurium), EMA in perineurium), EMA ( ), EMA (+),
profile NFP (+) (variable), NFP (+) factor XIIIa factor XIIIa
NFP (+) (+), NFP ( ) ( ), NFP ( )
Verocay bodies Absent Uncommon Absent Absent Present in
Antoni A
Axons Regenerated, Multiple with Clusters of separate Residual In the
parallel and haphazard tortuous bundles periphery of
proportional to arrangement the tumor
proliferating
Schwann cells
Stroma Mucoid to Limited Loose connective Mucoid/ Collagenous
fibrocollagenous collagenous tissue myxoid in Antoni A,
depending on the with myxoid in
“age” of the lesions occasional Antoni B
myxoid areas
in the
periphery
Mast cells Few eventual Few eventual Few eventual Present Present in
Antoni B
urogenital system cells, adrenal glands, and para- manifest with facial hypoesthesia, paresthesia, or
sympathetic and sympathetic ganglia. More than pain (Fig. 34). Obstructive symptoms may occur if
90% of MEN2B cases are caused by a single point the tumor gains enough size to compress the upper
mutation of M918T at 918 codon on exon 16 of aerodigestive tract (Liu et al. 2011).
the RET gene. Bilateral schwannomas are usually related to
neurofibromatosis type 2 syndrome (NF2). The
Treatment etiology of NF2 centers on unregulated growth
The treatment of traumatic neuromas and of neural crest-derived tissues, including
circumscribed/encapsulated palisaded neuromas Schwann cells. This manifests as lesions involv-
is surgical excision with low recurrence rates ing cutaneous structures and the central and
(Woodruff 1993). Mucosal neuromas of MEN2B peripheral nervous system. The hallmark of NF2
have insignificant repercussion on the quality of is hearing loss secondary to bilateral vestibular
life of these patients. In such cases, all attention schwannomas. Neurofibromatosis 2 (NF2) is
must be focused on prevention or treatment of associated with a rare, potentially treatable type
MTC and pheochromocytoma which are life- of deafness. Hearing loss usually begins in the
threatening. third decade and is most often an adult disease.
NF2 is the result of inactivation of a classical
tumor suppressor gene, NF2, on chromosome
Neurilemoma/Schwannoma 22. Mutations in NF2 are causative, and molecular
genetic testing of at-risk family members facili-
Epidemiology, Etiology, and Pathology tates early diagnosis and treatment (Gallo et al.
Schwannomas are the most common benign 1977; Kluwe et al. 2003).
neurogenic neoplasms and have propensity to
affect sensory nerves more than motor nerves. Investigations
They are a neoplastic proliferation comprised Ultrasound images of schwannoma are character-
exclusively of cells that have ultrastructural ized by a round or elliptical cross section with a
characteristics closely resembling Schwann clear border with the internal echo reflective of
cells and have the antigenic phenotype of histology. Patterns may be homogeneous to het-
Schwann cells (WHO Classification of Head erogeneous and cystic change may be seen. Ultra-
and Neck Tumours 2017). Some 25–45% of sound has greater diagnostic utility when the
schwannomas are located in the head, and these diameter of the nerve of origin is large and is
often present as diagnostic and management connected to a well-delineated nerve.
challenges, mainly arising on the tongue, Computed tomography usually shows well-
followed by the palate, mouth floor, buccal defined homologous lesions. When a heteroge-
mucosa, gingiva, lips, and vestibule. It shows neous lesion is observed on CT, malignant
no gender predisposition, being more likely to change may be suspected (Cohen et al. 1986).
affect middle-aged adults (Das Gupta et al. 1969; MRI with contrast is the primary diagnostic test
Colreavy et al. 2000). used for schwannomas. These lesions are hypo-
intense on T1-weighted images with post-
Clinical Presentation contrast enhancement with gadolinium.
The majority of head and neck schwannomas are Schwannomas are iso- to hypointense on
non-vestibular and extracranial. Clinically, T2-weighted imaging. MRI is superior to CT at
schwannomas are benign, usually solitary, encap- depicting schwannomas, as it is not degraded by
sulated masses of long duration at the time of dental artifact that plagues CT in the intraoral
presentation and rarely show a rapid growth course region. MRI also allows mass size to be accu-
(Fig. 33). Usually schwannomas are painless and rately measured and mass localization in relation
not ulcerated but, depending on location and to other structures. Characteristically, these
whether a major nerve is involved, could initially tumors usually appear to be smooth and well
Fig. 33 Neurilemoma/schwannoma. Large firm nodule to a speech pathologist and recovered from the dyslalia (g).
involving the right tongue. The patient complained about Antoni A pattern of schwannoma showing Verocay bodies,
difficulty with speech but no pain or paresthesia (a). Sur- eosinophilic hyalinized matrix delimited by fusiform
gical access to the lesion choosing the border of the tongue palisading Schwann cells (h). In contrast, Antoni B pattern
as election point because it is less vascularized (b). Gross of schwannoma is characterized by storiform arrangement
specimen, a 5-cm-wide nodule (c). Surgical site after exci- of fusiform cells with pleomorphic nuclei. This pattern
sion (d). Internal suture (e) aims to eliminate pathologic varies between areas of more cellularized and vacuolated
spaces and external continuous sutures (f) close the wound. cells with myxoid areas (i) (Hematoxylin and eosin stain)
Postsurgical follow-up at 3 weeks, the patient was referred
Fig. 34 Palatal oral schwannoma (a) with plexiform cutaneous schwannomas (b) in the same patient
demarcated and do not invade surrounding Neurofibroma Including

structures. Neurofibromatosis
Fine needle aspiration cytology (FNAC) can
be performed for tumors located in the superficial Epidemiology, Etiology, and Pathology
part of the neck, although the histological diagno- Neurofibroma is a benign peripheral nerve sheath
sis and its clearance should be confirmed on tumor composed of a variable mixture of
paraffin-embedded sections. Smears are expected Schwann, perineural-like, and fibroblastic cells,
to contain blood, degenerate cells, and spindle as well as ones with features intermediate between
cells. The diagnostic accuracy of FNAC depends these various cells, contained in a collagenous or
strongly on specimen quality and the experience myxoid matrix. Neurofibromas may present either
of the cytopathologist. as solitary lesions or as part of the generalized
Histologically, all schwannomas are encapsu- syndrome of neurofibromatosis. Approximately,
lated, and beneath the capsules, there are two 25% of all neurofibromas are found in the head
main patterns observed, called Antoni A and and neck region, and 6.5% occur in the oral cavity
Antoni B types (Fig. 33). The Antoni type A is as solitary or multiple lesions associated with
highly cellular and is composed of elongated neurofibromatosis type 1 (Marocchio et al. 2007).
Schwann cells, exhibiting areas of organized Neurofibromatosis type 1 (NF1) was described
spindle-shaped cells in a palisading arrangement in 1882 by von Recklinghausen who gave the
around acellular, eosinophilic areas, forming disease its first full description, including recog-
Verocay bodies. The Antoni type B is also com- nition that the tumors arose from the fibrous tissue
posed of elongated Schwann cells, but cells surrounding small nerves, leading to his designa-
are arranged in a less dense myxoid manner and tion of these tumors as “neurofibromas.” The dis-
are more disorganized compared to Antoni ease also known as von Recklinghausen disease is
type A (Fig. 33) (Table 7). Cystic change one of the most common dominantly inherited
becomes more prominent as the tumor genetic disorders affecting about 1 in 3000 new-
enlarges and is associated with mucinous degen- borns. NF1 is an autosomal dominant condition
eration, hemorrhage, necrosis, and microcyst caused by mutations of a gene cloned on chromo-
formation. some 17q11.2. The gene acts as a tumor suppres-
sor gene, and its mutation leads to the
Treatment development of benign and malignant tumors.
Complete resection is curative in cases of More than 500 different mutations of the NF1
schwannomas and is not likely to recur. Malig- gene have been identified which result in disease
nant transformation has not been reported. phenotype.
Depending on the location of the lesion, and
possible risk to a major nerve or other vital struc- Clinical Presentation
tures, it is possible to opt for close follow-up Solitary neurofibromas are normal colored sessile
observation (Lee et al. 2017). For tumors arising or pedunculated lesions, a smooth, firm swelling
from major cranial nerves, excision of the tumor on palpation, usually painless with an
with the division of the nerve of origin renders unpredictable growth pattern leading to local
lifelong morbidity to the patients. On the other asymmetry (Fig. 35). Other possible clinical
hand, other nerve-preserving excision methods, signs less commonly found comprise paresthesia
e.g., intracapsular enucleation, do not guarantee and pain, mostly attributed to nerve compression
intact nerve function after surgery. Because of produced by the lesion. These lesions range from
the substantial chance of nerve palsy after sur- small 1 to 2 cm to disfiguring proportions.
gery, obtaining an accurate preoperative diagno- Intraosseous lesions are considered to be
sis, and preferably with the identification of the extremely rare and are described as well-
nerve of origin, is crucial to the management of circumscribed non-encapsulated usually on the
the disease. periphery of a nerve. In the maxilla, there are
Fig. 35 Neurofibromatosis type I. Soft nodular subcuta- cells with pleomorphic nuclei varying from fusiform to
neous lesions of neurofibromatosis (a + b). Café au lait round, ovoid, or stellate (g) (Hematoxylin and eosin
spot on the arm (c). Enlarged fungiform papillae (d). Lisch stain). Toluidine blue stain reveals numerous mast cells
nodules are seen in the iris of both eyes (e + f). Nodular within the tumor (h)
neurofibroma revealing interlaced bundles of fusiform
reports of lesions affecting the nasal sinus, and in serious conditions including malignant peripheral
the mandible, lesions are usually related to the nerve sheath tumor, plexiform neurofibromas, and
mandibular nerve. Gross specimen evaluation of central nervous system gliomas (Hirsch and
the mass shows a whitish to light brown color Moskowitz 2013).
with a soft, friable consistency. Clinical differen- Cutaneous neurofibromas develop in 99% of
tial diagnosis comprises other nerve sheath NF1 patients but do not undergo malignant
benign neurogenic tumors such as neuromas and change. They are soft and fleshy, ranging in
schwannomas. color from blue to tan. They can be sessile or
NF1 is typically characterized by multiple café pedunculated and range in size from less than
au lait spots, multiple cutaneous neurofibromas, 1 mm to large and disfiguring masses. Subcuta-
axillary and inguinal freckling, and Lisch nodules neous neurofibromas frequently cause pain and
(Fig. 35). The underlying predisposition to tumor neurological symptoms and are occasionally vis-
formation can manifest in a number of other ible just beneath the skin. These are palpable firm
and tender nodules. Plexiform neurofibromas are greatest diameter in postpubertal individuals
found in 50–60% of patients and can cause sig- (Fig. 35)
nificant neurological deficits and disfigurement. • Axillary or groin freckling, two or more neu-
Most plexiform neurofibromas are internal and rofibromas, or one plexiform neurofibroma
not suspected clinically. They represent discrete • Two or more Lisch nodules in the iris (Fig. 35)
tumors that arise in nerves within organs or tis- • Optic pathway glioma
sues beneath the dermis, frequently clustering • A distinctive osseous lesion, including
around proximal nerve roots. They vary in size bony dysplasia of the sphenoid
and can extend along significant lengths of wing, or pseudoarthrosis of the long bones
nerves (Chen 2012). (Fig. 36)
The average life expectancy of individuals
with NF1 is reduced by approximately 15 years
(Rasmussen et al. 2001). The appearance of
malignant peripheral nerve sheath tumors Investigations
(MPNSTs) and vasculopathy is the important Neurofibromas may appear as soft tissue
cause of early death in patients with NF1, but the opacities on standard radiographs. On ultra-
most common cause of death in patients with NF1 sonography, these lesions appear as well-
is malignancy. MPNSTs usually arise from demarcated fusiform, hypoechogenic struc-
pre-existing subcutaneous neurofibromas or plex- tures, in close relation to the native nerve. On
iform neurofibromas but can develop de novo CT, the lesions have low density. MRI is
(Tucker et al. 2005). These are the most frequent the imaging technique of choice for detection
malignant neoplasms associated with NF1. These and characterization of tumors of peripheral
tumors are very aggressive and are often fatal. nerves. On MRI, neurogenic tumors are of
MPNSTs are difficult to diagnose because they low to intermediate signal intensity on
develop in patients who are generally habituated T1-weighted images and of variably increased
to develop other lumps and skin changes. Warning signal intensity on T2-weighted MR images
signs associated with the development of MPNST (Baert 2008).
in a patient with pre-existing neurofibroma Neurofibromas have a variable morphological
include persistent or nocturnal pain, rapid increase pattern on histopathological examination. They
in size, asymmetric growth, new neurological def- are composed of fusiform cells in a mucoid/
icit, or change to a more firm texture and consis- myxoid matrix. The tumor is composed of an
tency. The lifetime risk of developing an MPNST irregular pattern of proliferative fibers and
in a patient with NF1 is 5–13%. MPNSTs that mucoid masses, with a variable mixture of
develop in children and adolescents are rare but Schwann, perineural-like, and fibroblastic cells
tend to be low grade. In contrast, MPNSTs that (Fig. 35). Two major variants are described, a
develop in patients in their 20s and 30s tend to be well-circumscribed nodular variant and the plex-
high-grade tumors. iform variant which produces poorly
Clinical diagnosis of NF1 is based on the circumscribed tumors. The later carries risk of
criteria set forth by a National Institutes of Health malignant transformation. Neurofibromas form
Consensus Conference in 1987 and is still tortuous cords along the segments and branches
accepted for routine clinical use. The diagnostic of a nerve with a tendency to develop centripe-
criteria are met in a patient with the presence of at tally along a nerve course. Inflammation is found
least two major disease features out of the in 44% of specimens (Marocchio et al. 2007),
following: which is important when differentiating these
from other neurogenic tumors such as traumatic
• A first-degree relative with NF1, six or more neuromas. Other comparative morphologic
cafe´ au lait patches >5 mm in greatest diam- characteristics of the tumor are displayed on
eter in prepubertal individuals, and >15 mm in Table 7.
Fig. 36 Neurofibromatosis 1 in a 25-year-old female. The mandibular rami. There appears to be discontinuity of the
left condylar head is significantly hypoplastic, and there is infraorbital rim and hypoplasia of the paranasal sinuses.
elongation of the left condylar neck and flattening of the There is enlargement of the mandibular foramina. These
right condylar head with osteophyte formation. There is changes are consistent with features of neurofibromatosis
deformity of the left sigmoid notch. There is thinning of the type 1. Other findings not described
Treatment Granular Cell Tumor

The gold standard treatment for neurofibromas is
surgical excision. Easy-to-access lesions such as on Epidemiology, Etiology, and Pathology
the skin do not demand further precautions, Granular cell tumor (GCT) was described in 1926
but some head and neck lesions can show by Abrikossoff, and the etiology of this disease is
some complications related to anatomy, sacrifice controversial and much discussed in the literature.
of cranial nerves that can result in functional prob- Schwann cells, fibroblasts, histiocytes, myoblasts,
lems such as permanent anesthesia or loss of motor and undifferentiated mesenchymal cells have been
function, and even significant deformity. The clin- identified in the histogenesis of GCT. It is a rare
ical behavior of neurofibromas is characterized by a benign neoplasm of soft tissues, characterized by
benign course with a low frequency of recurrence poorly demarcated proliferation of round or spindle
after surgical excision. plump cells with granular cytoplasm. The granular
Other therapies such as photodynamic therapy appearance is a result of increased accumulation of
have been proposed for large and difficult-to- lysosomes in the cytosol of the cells.
access lesions, with promising results, but still Considered a rare lesion, the most common
lack long-term research of its effectiveness sites for this lesion are in the head and neck region
(Hamdoon et al. 2012). accounting for 50% of cases, although it can
Neurofibromatosis type 1 raises the need for appear in any area of the body. In the oral cavity,
periodic clinical follow-up of patients in order to the most affected site is the tongue, but other sites
prevent malignant neoplasms. The survival rate of such as the hard palate, buccal mucosa, lips,
most patients with NF1 exceeds 50 years. Once uvula, parotid gland, and gingiva have been
diagnosed with NF1, it is important to provide reported. The peak age of incidence of GCT is
genetic counseling to the patient and their 40–60 years, but it can affect all ages. Most
relatives. reports describe a female-to-male ratio of 2:1,
and higher incidence in black populations has inflammatory process usually adds symptoms
been noticed. such as pain and discomfort as well as cause-
effect correlation.
Clinical Features
GCT presents as a firm, polypoid, or sessile tumor Investigations
that forms a “lump” on the surface of the affected Microscopic analysis shows a lesion mainly
site (Fig. 37). It is superficial, poorly consisting of large polygonal or elongated
circumscribed, and slow-growing involving the cells with clear, granular cytoplasm and an
subcutaneous or submucosal tissues. Most lesions oval or round nucleus with loose chromatin
are small, do not exceed 3 cm in diameter, and are (Fig. 37). Periodic acid-Schiff (PAS)-stain-posi-
covered by mucosa that can be normal colored, tive granules are detected in the cytoplasm. The
yellow colored, or with pale to leukoplakic tumor cells are strongly positive for S-100,
appearance. On palpation, the tumor often appears vimentin, and CD68 and are negative for GFAP
demarcated but not encapsulated. and NFP. Intraoral lesions present frequently
The differential diagnosis for these lesions with pseudoepitheliomatous epithelial hyperpla-
comprises other benign soft tissue neoplasms sia in the overlying mucosa; therefore, care
such as fibromas, lipomas, neurofibromas, neuro- should be taken to avoid an erroneous diagnosis
mas, and schwannomas. Reactive lesions such as of squamous cell carcinoma (Ferreira et al.
traumatic fibroma can also resemble GCT, but the 2017).
Fig. 37 Granular cell tumor. Sessile nodule forming a hyperplasia of the mucosa (c) and a poorly circumscribed
lump of pale coloration on the dorsum of the tongue (a), lesion consisting of large polygonal or elongated cells with
and raised hard lump with yellow coloration on dorsal clear, granular cytoplasm and an oval or round nucleus
tongue in a separate patient (b). Microscopic features of with loose chromatin (d) (Hematoxylin and eosin stain)
granular cell tumor of the tongue show epithelial
Multiple GCT may be familial and associated the cardiac rhabdomyoma occurs almost exclu-
with syndromes such as LEOPARD, NF1, or sively in the heart of infants and young children,
Noonan, all related to the Ras/MAP kinase path- is the most prevalent, and is related to tuberous
way probably caused by mutation in PTPN11. sclerosis. Extracardiac rhabdomyomas are sub-
Rare examples of malignant GCT characterized divided into fetal, adult, and genital. Extracardiac
by pleomorphism, mitotic activity, and necrosis rhabdomyomas are true neoplasms, with a recip-
have also been described (van der Wal 2016). rocal translocation between chromosomes 15 and
17 (Gibas and Miettinen 1992). Because
Treatment rhabdomyomas are more commonly found in the
Surgical excision with a safe margin of tissue is the neck and preauricular region, it is speculated that
treatment of choice for GCT, although this is not the etiology of these neoplastic cells is based on
always possible because the tumor lacks a capsule, branchial musculature of the third and fourth
as histologically demonstrated by an undefined branchial arches. The median age is 60 years
cellular margin. Recurrence is low, although it has with 3:1 male-female predominance.
been reported in incompletely removed lesions and
in patients with multiple GCT. Clinical Features
In the head and neck region, only the fetal and adult
forms are likely to occur; the genital form is exclu-
Rhabdomyoma sive to the female gender affecting the vagina and
vulva of middle-aged women. Although usually
Epidemiology, Etiology, and Pathology solitary, adult-type rhabdomyoma can occasionally
Rhabdomyoma is a rare benign proliferation of be multinodular and rarely multifocal. Multifocal
mesenchymal cells with skeletal striated muscle adult-type rhabdomyoma usually presents as slow-
differentiation (Fig. 38). It is estimated that growing lumps in the parapharyngeal region. Large
rhabdomyomas represent less than 2% of soft or multilobulated lesions may be first identified due
tissue tumors and are considerably less common to complaints of progressive dysphagia, hoarse-
than its malignant counterpart the rhabdomyosar- ness, and snoring.
coma. Rhabdomyoma is classified into cardiac
and extracardiac, based on anatomic location. It Investigations
can manifest as a local or multifocal lesion. Contrast-enhanced CT and MRI are the best imag-
Among the different types of rhabdomyomas, ing examinations to identify rhabdomyomas.
Fig. 38 Rhabdomyoma. Large normal colored mass in the floor of the mouth (a). Intermediate magnification showing a
uniform tumor formed by polyhedral granular cells with focal vacuolization (b) (Hematoxylin and eosin stain)
Usually the tumors develop close to other skeletal Hemangioma

muscles, as a well-circumscribed mass with homo-
genously similar intensity. Aspiration of these Epidemiology, Etiology, and Pathology
tumors contains diluted blood without agglutina- Hemangiomas are true neoplasms of blood ves-
tion; therefore schwannoma is included as the pri- sels formed by endothelial proliferation assuming
mary differential diagnosis (Lu et al. 2017). variable width. The lesion is usually present at
Radiologically rhabdomyoma presents as a well- birth and can regress spontaneously. They are
circumscribed mass without invasion of surround- distinct from vascular malformations due to a
ing soft tissues. In addition, the characteristically higher mitotic activity. Reactive lesions such as
increased 18 F-fluoro-2-deoxy-D-glucose (18 F- angiogranuloma, which are ulcerated and have a
FDG) uptake on positron-emission tomographic clear cause-effect relationship, have similar
CT is vitally useful for the detection of multifocal mitotic activity and microscopic appearance and
adult rhabdomyoma, especially in the case of very frequently cause discussions as to whether it rep-
small lesions, which are easily missed with tradi- resents a true hemangioma, also named lobular
tional examination (de Trey et al. 2013). capillary hemangioma.
Adult-type rhabdomyoma is the most common The origin of hemangiomas, although still under
subtype of extracardiac rhabdomyoma, character- debate, has been narrowed to embryonic placental
ized by mature skeletal muscle differentiation angioblasts or intrinsic endothelial progenitor cells
forming homogeneous masses of polygonal cells with the ability to clonally duplicate in a precise
sometimes with more than one nucleus, with eosin- environment of cytokines and estrogen concentra-
ophilic granular cytoplasm resulting in a “spider tion (Yu et al. 2004). It is even possible that both
web” appearance (Fig. 38). In contrast, fetal-type theories regarding the origin of hemangiomas coex-
rhabdomyoma exhibits immature muscle differen- ist. Hemangiomas likely arise from progenitor cells
tiation, characterized by bland spindle cells associ- with directional preponderance to become
ated with fetal myotubules haphazardly arranged in placental-like tissue in specific organs such as
abundant myxoid stroma (Fig. 38). Microscopic skin and liver (Barnes et al. 2007).
differential diagnosis of rhabdomyoma comprises The role of molecular signaling involved in
granular cell tumor, hibernoma, oncocytoma, para- vascularization is better understood in hemangioma
ganglioma, or crystal-storing histiocytosis. The development. Increased levels of common molec-
lesion is PAS positive, and immunohistochemical ular contributions to endothelial cell migration and
panels show positivity for desmin, MSA, SMA, new vessel development have been discovered dur-
and myoglobin and negativity for S100, EMA, ing the proliferative phase of hemangioma growth
and cytokeratin. such as vascular endothelial growth factor (VEGF),
basic fibroblast growth factor (b-FGF), insulin-like
Treatment growth factor (IGF), and matrix metalloprotease-9
Surgical resection of the tumor performed through (MMP-9). Similarly, and as would be expected, the
a transcervical approach and transoral incision levels of angiogenic markers also wane during the
under general anesthesia applies to most involution phase of hemangiomas (Buckmiller
lesions due to its regular site manifestation. et al. 2010).
Rhabdomyomas are removed easily with blunt dis- Hemangiomas proliferate during the first
section. These tumors appear as a soft, tissue- 9–12 months of life and subsequently involute at
encapsulated mass with a smooth shiny surface. a variable course over many years. The tumor has
Cut sections present with a pink and smooth texture a female predominance, occurring commonly in
that is similar to muscle tissue. Rhabdomyomas are the head and neck region but rarely in the oral
not likely to recur if removed completely; however, cavity. These lesions are subdivided into two cat-
when small lesions are located in vital structures, egories based on their clinical behavior and his-
the risk-to-benefit ratio of complete excision should tology. The more common infantile hemangioma
be carefully weighed. (IH) develops shortly after birth and follows the
expected course of proliferation with prolonged of the overlying skin. No two hemangiomas are
involution. Infantile hemangiomas are vascular the same, and the rate of growth is variable in the
tumors comprised of rapidly dividing endothelial proliferative phase. Involution may occur as early
cells affecting up to 10% of the population with a as 6 months of age in isolated lesions or much
greater incidence in Caucasians and premature later when deep or segmentally distributed hem-
and low-birth-weight infants. Approximately angiomas are present.
60% occur in the head and neck region. Congen- Infantile hemangiomas are usually superficial
ital hemangioma is rare, is present at birth, and lesions, but their depth can vary, altering its clin-
does not follow the natural growth phase of its ical presentation. Depth can be expressed as
infantile counterpart. superficial, deep, or mixed/compound which indi-
cates the amount of tissue involvement. Superfi-
Clinical Features cial IH will typically have a deep red appearance
These lesions present a smooth reddish purple, on the skin or mucosa. Deep IH often will be
sessile, polypoid, or pedunculated masses, often visualized to have a bluish hue under the
with increasing size and occasional bleeding normal-appearing skin. Compound IH possess
(Fig. 39). Most infantile hemangiomas are not attributes of both (Friedman et al. 2013).
apparent at birth or may appear to be a small
“scratch” or “bruise.” Infantile hemangiomas Investigations
become evident shortly after birth as well- Since most hemangiomas are superficial lesions
demarcated, red, vertically expansive lesions. and respond to objective tests such as diascopy,
They can be overlooked during the first month there is limited use for imaging exams, only
of life as they are difficult to differentiate from applied for differential diagnosis or in deep or
other common skin blushes seen in the newborn. difficult-to-access lesions. For that matter, ultra-
During this period, they are flat, pink, and some- sound and MRI are helpful tools. These can be
times more pale or bluish than their surrounding used to distinguish between IH and vascular
tissue. Slower but continuous growth occurs up to malformations if the diagnosis is in question.
9 months in most patients. Rapid expansion can Color Doppler ultrasound will demonstrate either
lead to adjacent skin and soft tissue ischemia, fast-flow or slow-flow lesions. The best diagnostic
necrosis, and ulceration. The bright red discolor- radiologic clue for IH is the presence of a
ation is persistent until the onset of involution high-flow soft tissue mass. On ultrasound, hyper-
when resurfacing is observed as variable graying echoic and/or hypoechoic lesions can be seen with
Fig. 39 Infantile hemangioma in a 4-year-old female, sclerotherapy with four periodical local infiltrations of
presenting as a growing blue sessile mass, first noticed monoethanolamine oleate, with complete remission of the
during her first year of life (a). Patient received lesion after 8 months from initial diagnosis (b)
variable presence of vessels. MRI for IH typically The most difficult microscopic differential
shows a well-defined, non-infiltrating lesion. diagnosis of hemangiomas is the angiogranuloma.
Intermediate signal intensity is seen on Good clinical information is essential to avoid
T1-weighted images and increased signal inten- confusion between these lesions without
sity of T2-weighted sequences. After gadolinium molecular investigation; loss of integrity of skin/
injection, strong enhancement is observed. mucosal lining also favors the diagnosis of
MRI is especially important in the evaluation angiogranuloma. Other important differential
of patients with large facial hemangiomas to diagnoses of vascular tumors include congenital
rule out neurocutaneous PHACES syndrome hemangiomas, tufted angiomas, and a variety of
[OMIM #606519]. This syndrome is character- hemangioendotheliomas. Final diagnosis of this
ized by posterior cranial fossa anomalies lesion can demand the use of an immunohisto-
(P), facial hemangiomas (H), and one or more chemical panel.
major cervical and arterial cerebral vascular (A), Immunohistochemical panels for the diagno-
cardiovascular (C), eye (E), and sternal or supra- sis of hemangiomas show CD34, CD31, and
umbilical (S) anomalies/defects (Heyer et al. ERG positive. Infantile hemangiomas have a
2008). specific marker (GLUT1) which is negative for
Microscopically hemangiomas are classified angiogranuloma and congenital hemangioma
according to the lumina of the capillary vessels (2017).
that are predominant in the lesion. Capillary
hemangiomas consist of multilobular arrange- Treatment
ments of proliferating endothelial cells and cap- The treatment of hemangiomas comprises a vari-
illaries of various shapes and sizes surrounded ety of modalities that are best suited for each case.
by pericytes (Fig. 40). The capillary type Infantile hemangiomas include observational
appears more cellularly rich, but mitotic activity follow-up, since up to 50% of lesions completely
is similar to the cavernous type. The lumina resolve by 5 years of age, 70% by 7 years, and
may be subtle or dilated, especially in 90% by 9 years. Bleeding, ulceration, functional
IH. Cavernous hemangiomas are named due to risk, and esthetic concerns usually require profes-
the similarity to the capillaries found in the sional intervention. Historically corticosteroid
penial cavernous body and show larger dilated therapy was used in IHs. This therapy can be
vascular spaces lined by endothelial cells systemic or local infiltration. Systemic adminis-
(Fig. 40). tration has important side effects in children,
Fig. 40 Low magnification of infantile hemangioma pre- hemangioma with flattened endothelial cells and more
senting as a cellular well-circumscribed lesion with endo- evident vascular spaces in a more fibrous stroma (b)
thelial cells in a lobular arrangement (a). Mature lesion of (Hematoxylin and eosin stain)
mostly related to long-term use. Steroids are effec- type with estimated prevalence of 0.74–2.3 new
tive in retarding the growth phase of IH, but if cases per 100,000 population, affecting patients
discontinued, the lesion returns to its normal ranging from 6 to 84 years, 2.5–3 times as com-
growth. mon in males as in females. The oncocytic papil-
Flash lamp dye laser therapy has also produced loma has no gender predilection, and most
good results, promoting regression in the size of patients are over 50 years of age. This type lacks
the lesions. This treatment modality offers the best correlation with HPV infection, which is distinct
results in superficial lesions. Such lesions require from the other two types. Sinonasal exophytic
future excision of residual scar. Adjunctive anti- papilloma is most related to HPV infection with
biotic ointment before and after flash lamp dye up to 63.5% of cases, affecting two to ten times
laser therapy improves healing and prevents infec- more males than females, typically in patients
tion of ulcerated lesions. aged 20–50 years. Malignant transformation
In the past decade, propranolol has become and/or other malignant lesions arising from
first-line treatment for IH (Leaute-Labreze et al. sinonasal papillomas are exceptions worth careful
2008). Since the serendipitous discovery of the attention (Maitra et al. 2001).
favorable results of beta-blockers in these lesions,
many studies have shown good outcomes, ini- Clinical Presentation
tially with small case series, but lately larger sam- Patients with sinonasal papillomas first present
ple size studies have reinforced its safe use with with non-specific symptoms such as nasal
96.9% effectiveness and low complications obstruction, polyps, epistaxis, rhinorrhea, hypo-
(3.8%). Complications include sleep disturbance, smia, and headache. Unilateral nasal obstruction
diarrhea, and bronchospasm. In one study, only and the presence of an asymptomatic mass can
22.6% of cases had incomplete involution of IH also represent sinus papilloma progression. Exo-
and needed further assistance with other adjunc- phytic sinonasal papillomas usually arise on the
tive therapies including timolol maleate or pulsed lower anterior nasal septum and present warty
dye laser (Zhang et al. 2017). The mechanism of appearance.
action of propranolol on reducing or curing hem-
angiomas remains unclear although the most Investigations
likely mechanism is the pharmacologic stimula- Because of its non-specific symptoms, delay in
tion of programmed endothelial cell death (apo- diagnosis is sometimes reported, as unsuccessful
ptosis). A dose of 1–2 mg/kg/day for the treatment treatments of “recurrent sinusitis” or “chronic rhi-
of infantile hemangiomas is currently being nitis.” Diagnostic imaging is important for diag-
applied. The treatment may last for up to 6 months, nosis with CT and MRI offering the best
demands close monitoring, and is terminated information about the site of origin of the tumor.
when the infant reaches 1 year of age. Endoscopy is also a valuable complementary
exam for lesions affecting the nasal cavity.
Inverted growth is the hallmark of the inverted
Sinonasal Papilloma sinonasal papilloma, forming islands or nests of
stratified squamous epithelium and/or columnar
Epidemiology, Etiology, and Pathology respiratory cells. The basement membrane is
Sinonasal papillomas are surface mucosal lesions intact, with eventual mitotic figures only in the
of the sinonasal tract related to HPV infection, as basal layer. Dysplastic features may cause con-
well as exposure to solvents, smoking, and alco- cern about malignant transformation. The Ameri-
hol consumption. They manifest in three different can Joint Committee on Cancer (AJCC) staging
forms: inverted type, oncocytic type, and exo- system is commonly used for staging these
phytic type. This differentiation is based on the lesions. The oncocytic type presents both exo-
pattern of proliferation that these lesions can pro- phytic and endophytic growth patterns, and the
duce. The inverted papilloma is the most frequent oncocytic appearance of the epithelium is due to
the hyperchromatic nuclei and the abundant gran- C oxidase (Levine et al. 1987) and for
ular eosinophilic cytoplasm. Cilia in various cytokeratins (Maitra et al. 2001). Oncocytic pap-
stages of regression are occasionally found in the illoma may be confused with low-grade sinonasal
superficial layers. Finally, the exophytic type adenocarcinoma, which often shows a papillary
resembles the endophytic epithelial lining chang- growth pattern but presents an epithelial growth
ing only the direction of growth. Keratinization of characterized by a single-layered, non-oncocytic
the epithelial surface is possible, mostly in lesions epithelium with some degree of atypia, occasional
exposed to trauma or drying effects of the air, mitotic figures, and invasive growth. Due to the
and malignant transformation is less likely to presence of several microcysts within the epithe-
occur. The main differential diagnosis of this lial layer, oncocytic papilloma may also be con-
lesion is the cutaneous squamous cell papilloma, fused with rhinosporidiosis. In this infectious
which is more keratinized and does not present disease, however, organisms are found both in
signs of respiratory epithelium and submucous the epithelium and the stroma, and the epithelium
glands in the specimen. does not show oncocytic changes (Franchi 2016).
HPV is detected more frequently in exophytic
papillomas than in endophytic ones, with a Treatment
weighted prevalence of 65.3% (Lawson et al. Complete surgical excision is the treatment of
2008). Types 6/11 are found in most cases. HPV choice, and these lesions are not likely to recur,
has been detected with variable frequency in but surgical access to the lesions can be difficult
inverted sinonasal papilloma, with a mean rate of and incomplete removal may lead to recurrence. If
16% (Lawson et al. 2008). A preponderance of high-risk HPV infection and/or dysplasia is
HPV 6/11 has been reported as compared to HPV detected, clean surgical margins should be pur-
16/18, with a ratio of low-risk to high-risk HPV sued during surgical excision (Levine et al. 1987;
types of 2.8:1 (Lawson et al. 2008). The frequency Karligkiotis et al. 2014).
of HPV detection increases in inverted papillomas
with dysplasia and in lesions with malignant
progression to carcinoma, with a shift toward a Malignant Epithelial Tumors
higher frequency of high-risk subtypes (Lawson of the Head and Neck
et al. 2008).
Inverted papillomas present monoclonal pro- Laryngopharyngeal cancers constitute about 40%
liferations, as shown by X chromosome analysis. of all head and neck cancers. The pharynx is
However, the chromosomal loss of heterozygos- divided into three subsites: the nasopharynx
ities (LOHs) at arms 3p, 9p21, 11q13, 13q11, and which extends from the posterior choana to the
17p13 have not been detected (Califano et al. level of free border of the soft palate, the orophar-
2000). The main differential diagnosis of the ynx which consists of the soft palate, tonsils,
inverted type is with sinonasal cylindrical cell lateral pharyngeal wall, and the base of the
carcinoma and squamous cell carcinoma, which tongue. It extends from the level of the soft palate
can be distinguished by the presence of significant to the level along the superior surface of the hyoid
nuclear pleomorphism, atypical mitoses, and stro- bone. The hypopharynx is the region of the phar-
mal invasion. Respiratory epithelial adenomatoid ynx from the plane along the superior level of the
hamartoma can be separated from inverted hyoid bone to the plane along the inferior border
sinonasal papilloma because it contains numerous of the cricoid bone. This region consists of the
gland-like structures lined by respiratory epithe- pyriform sinuses, the postcricoid region, and the
lium, surrounded by thick hyalinized basement posterior pharyngeal wall.
membrane, which is not present in sinonasal The larynx is subdivided into the supraglottis,
papilloma. glottis, and subglottis. The supraglottis extends
The epithelial cells of oncocytic papillomas from the superior level of the hyoid bone to the
stain for the mitochondrial enzyme cytochrome laryngeal ventricles and consists of the epiglottis,
aryepiglottic folds, arytenoids, and false cord. The Imaging is complementary to clinical exami-
glottis includes the vocal cords and extends from nation in treatment planning. While endoscopic
the ventricles inferiorly by 1 cm. The subglottis evaluation maps the mucosal extent of the disease,
extends from the level of the glottis to the inferior involvement of the soft tissues, bone, and carti-
level of the cricoid cartilage (Fig. 41). lage can be determined by imaging. Pretreatment
In contrast to cancers of the oral cavity which staging is done based on both clinical and radio-
mostly draw early attention due to a visible lesion, logical findings. Contrast-enhanced CT of both
tumors originating in the oropharynx and hypo- the head and neck and chest are the most com-
pharynx usually present late due to their location monly employed imaging modalities. MRI with
in apparently hidden areas and non-specific symp- contrast is an alternate approach. If an organ pres-
toms masquerading as many benign conditions. ervation strategy using chemotherapy and radio-
Apart from the routine blood investigations, therapy is planned, PET/CT may be considered
which include complete blood count, renal function, for response evaluation (Fig. 43). The advantages
and coagulation profile, tissue diagnosis and imag- of each are depicted in Table 9 and are outlined in
ing are required for treatment planning. Diagnostic more detail in the chapter on ▶ “Diagnostic Imag-
evaluation for HPV status is mandatory (Table 8). ing Principles and Applications in Head and Neck
A biopsy from the primary lesion is needed to Pathology.” The imaging modality of choice
establish the primary diagnosis. A deep biopsy varies with the subsite and the disease extent.
(to include the basement membrane) from the most The same modality used to image the primary
“representative” part of the lesion should be taken. lesion is used to image the neck. Metastatic neck
Large ulcers tend to have a necrotic center, and nodes on imaging appear enlarged and rounded
biopsy from the necrotic area should be avoided. and show necrosis, extracapsular spread, and
In cases of infiltrative disease which spreads sub- invasion of adjacent structures. Necrosis is the
mucosally, a wedge biopsy is required to target the most reliable criteria for metastasis. The sensitiv-
most indurated area. Such lesions are common in the ity and specificity of CT for assessing neck nodal
base of tongue (BOT) region (Fig. 42). metastasis vary from 55% to 95% and 39–96%,
Fig. 41 Anatomy of the pharynx including the laryngopharyngeal subsites

Table 8 Principles, merits, and demerits of validated laboratory methods of HPV detection
PCR for HPV detection
Principle
HPV DNA or RNA sequence is amplified several orders of magnitude through several rounds of denaturing,
annealing, and DNA replication using a DNA polymerase
Merits
Highly sensitive cost-effective method for HPV detection
Demerits
Low specificity
Does not differentiate between HPV that is present in neoplastic cells and surrounding nonneoplastic epithelium
Does not distinguish between episomal and integrated HPV DNA
Technically cumbersome to perform
HPV-16 DNA in situ hybridization
Principle
Only molecular method allowing reliable detection and identification of HPV in topographical relationship to
pathological lesions
Whole HPV detection occurs within the nuclei of infected cell
Merits
Detection of clinically significant HPV infection within tumor specimen
Evidence of active oncogenic transcription
High specificity (100%)
Demerits
Poor sensitivity (80–85%) due to inability to detect HPV oncogenic strains other than HPV-16
Technically difficult to perform
p16 immunohistochemistry
Principle
Overexpression of p16 is a result of inactivation of pRb by the HR-HPV E7 oncoprotein and consequent release of
pRb-mediated negative regulation of p16
Surrogate marker
Merits
High sensitivity
Accessible to most laboratories
Demerits
Surrogate marker
Lacks specificity due to non-HPV-related causes of p16 overexpression resulting in high false positives
Lack of standardization and interpretation of results
respectively, while those for MRI are 64–92% and Comprehensive Cancer Network (NCCN) guide-
40–81%, respectively (de Bondt et al. 2007). lines recommend FDG-PET/CT for the initial
Distant metastasis (DM) from head and neck work-up of patients with stage III and IV head
squamous cell carcinomas most commonly spread and neck cancers. Taking into consideration the
to the lungs followed by the liver and bone lack of availability and cost of FDG-PET/CT, a
(Mamelle et al. 1994). Factors associated with multi-slice CT (MSCT) of the chest is an equally
distant metastatic disease include histologic good alternative in advanced cancers as the most
tumor type, T stage, N stage, extranodal tumor common sites for DM are the lungs and mediasti-
spread, and number and level of neck nal nodes (Fig. 44).
nodes. FDG-PET in head and neck SCC alters Treatment protocols are determined primarily
TNM stage in 43% and management in 13.7% of by the oncologic outcome followed by the func-
cases (Lonneux et al. 2010). The National tional and cosmetic outcome. Cost-effectiveness,
Table 9 Commonly used imaging modalities

Advantages of CT
Imaging modality of choice for assessing bone erosion
Easy availability
Less time-consuming
Less costly
Advantages of MRI
Better soft tissue delineation
Better delineation of perineural invasion
No radiation exposure
No iodinated contrast
Quality of image not affected by dental artifacts
Fig. 42 Contrast-enhanced T1 MRI image showing an

infiltrative tumor over the left base of tongue (arrow)
Fig. 44 Contrast-enhanced CT thorax axial sections

showing multiple metastatic lung nodules (some shown
by red arrows)
patient preferences, and quality of life (QoL)

should also be taken into account. Early-stage
cancers (stages I and II) are usually treated with
single modality (surgery or radiation), while
advanced stages (stages III and IV) are treated
with multimodality treatment which includes sur-
gery, radiation, and/or chemotherapy.
Posttreatment surveillance (Table 10) is an
elaborate part of patient management. Identifying
early recurrence improves the oncologic outcome.
Functional and cosmetic issues can also be
addressed through surveillance which improves
the QoL for cancer survivors. There is no fixed
protocol for frequency and duration of follow-up,
Fig. 43 PET/CT fusion axial image showing an enhanc-
ing lesion involving the right base of tongue suggestive of but several guidelines exist such as the NCCN
neoplastic etiology guidelines. Patient compliance, place of stay,
Table 10 Posttreatment surveillance Shoulder function should be assessed in patients

3 monthly follow-up for 2 years, 6 monthly follow-up for undergoing neck dissection and encouraged for
next 5 years, yearly follow-up thereafter active shoulder exercises. Tobacco cessation and
Post-treatment baseline imaging within 6 months of alcohol counseling should be carried out with
treatment completion patients continuing these habits. Patients suffering
Yearly chest imaging especially in smokers
from depression and psychosocial and end-of-life
Thyroid function tests six monthly in patients receiving
radiation to the head and neck
issues require proper psychiatric consultation and
Voice and swallowing evaluation and appropriate social support.
rehabilitation
Habit cessation counseling and rehabilitation
Nutritional evaluation and rehabilitation Oropharyngeal Cancer
Psychiatric evaluation if required
Squamous cell carcinoma (SCC) constitutes more
nature of work, and commitment of caregivers than 90% of malignant tumors of the oropharynx.
decide how frequently the patient is followed Oropharyngeal tumors are now distinctly divided
up. Generally, patients are followed three monthly into two subtypes, namely, HPV-positive SCC
for the first 2 years, six monthly for the next and HPV-negative SCC. HPV-negative tumors
5 years, and yearly thereafter. All patients undergo tend to behave like their counterparts in the oral
a routine head and neck clinical examination to cavity and appear to be associated with increased
detect early recurrences or second primary can- risk of exposure to tobacco and alcohol.
cers. Patients of oropharyngeal, hypopharyngeal, Human papillomavirus (HPV) infection is now
and laryngeal cancers should also undergo a flex- clearly associated with a subset of head and neck
ible endoscopy with air insufflation (for pyriform cancers. Among all subsites of head and neck
sinus and postcricoid cancers) or rigid endoscopic SCC (HNSCC), HPV prevalence is the highest
examination. First posttreatment imaging (MSCT in oropharyngeal cancers where 40–80% are pos-
or contrast-enhanced MRI) should be done within itive for the virus, and the number continues to
6 months of treatment completion. For patients increase (D’Souza et al. 2007; Adelstein et al.
undergoing nonsurgical treatment, contrast- 2009; Dayyani et al. 2010; Chaturvedi et al.
enhanced FDG-PET/CT is recommended for 2011). HPV is an epitheliotropic small double-
response assessment. PET/CT should not be car- stranded DNA virus with more than 200 identified
ried out before 8 weeks and preferably after subtypes (Oguejiofor et al. 2013). Of these, about
12 weeks posttreatment completion to allow for 15 types are thought to have high-risk oncogenic
the inflammatory response to subside. If residual potential. HPV strains 16, 18, 31, 33, and 35 are
disease, recurrence, or a synchronous second pri- associated with oropharyngeal SCC (OPSCC)
mary is suspected within 8 weeks, a MSCT or with strain HPV-16 being responsible for more
MRI is recommended. Yearly imaging of the than 90% of HPV-induced cancers (Marur et al.
chest is recommended especially in patients with 2010).
a history of smoking. All patients undergoing HPV has a predilection for the basal cells of the
radiation to the head and neck need to undergo a epithelium. Initially the viral genome remains as
thyroid function test six monthly. As radiation an episome expressing early replicative protein
adversely affects the constrictors, swallowing E2. Subsequently integration into the host
functions should be evaluated during follow-up. genome occurs following which E2 protein is
Voice evaluation is required in patients undergo- suppressed and E6 and E7 proteins become acti-
ing total laryngectomy. On each follow-up, vated. The main aim of E6 is to abrogate p53
patients need to undergo detailed nutritional function to facilitate its own replication and
assessment as they are prone to nutritional depri- results in allowing genetic mutations in the
vation as a result of impaired swallowing. absence of p53 function. E6 inhibits p53 directly
as well as via E6-associated protein (ubiquitin basis in the follow-up period. As metastatic
ligase). The function of E7 is degradation of the lesions usually have an indolent behavior, treat-
Rb gene complex resulting in activation of E2F ment of the primary lesion is undertaken even in
protein and subsequent progression of the cell the presence of metastatic disease.
cycle beyond the G1S checkpoint. Apart from Mucoepidermoid carcinomas are most common
the oncogenic proteins E6 and E7, E5 plays a minor salivary gland malignancies and account for
significant role in oncogenesis by enhancing the 9–23% of all salivary gland tumors (Eveson and
transforming activity of E6 and E7, upregulating Cawson 1985; Waldron et al. 1988; Ellis et al.
epidermal growth factor receptor (EGFR), and 1991). In the oropharynx, they have a propensity
inhibiting major histocompatibility complex to involve the palate. Treatment is essentially sur-
(MHC). More detailed discussion about gical resection with neck dissection being indicated
HPV-associated tumors and molecular under- in high-grade, high-stage tumors and those with
standing of head and neck squamous cell carci- evidence of neck nodal metastasis. Adjuvant radi-
noma can be found in a later section of this ation is indicated in high-grade, high-stage tumors,
chapter. positive/close resection margins, perineural inva-
The oropharynx is also rich in minor salivary sion, and lymphovascular spread.
glands and lymphoid tissue and is the site for Hematolymphoid malignancies, most com-
salivary gland neoplasms and hematolymphoid monly non-Hodgkin’s lymphoma, present with
malignancies. Oropharyngeal salivary gland an exophytic mass, submucosal bulge, or an ulcer-
tumors constitute about 1.1–3.3% of all minor ated lesion commonly involving the palatine ton-
salivary gland tumors (Spiro et al. 1973; Eveson sils or the base of tongue. Rarely, mucosal
and Cawson 1985; Ellis et al. 1991). Nearly half melanomas can present in the oropharynx as a
of these salivary neoplasms are malignant adenoid blackish, gray, or reddish pigmented (rarely
cystic carcinoma (ACC) and mucoepidermoid amelanotic) lesion. These are very aggressive
carcinoma (MEC) (Eveson and Cawson 1985). tumors, and the mainstay of treatment is surgery
Adenoid cystic carcinomas are relatively com- with multimodality adjuvant therapy.
mon, and 42.5% of these occur in the minor sali- An increasing number of oropharyngeal can-
vary glands (Gnepp 2001). About 20% of these cers are associated with HPV. HPV has emerged
minor salivary gland ACCs occur in the oral cav- as a mutagen for head and neck cancers with the
ity and oropharynx (Gnepp 2001). They usually oropharynx being the most common site and
present as a slow-growing submucosal mass with being associated with about 60–70% of oropha-
ulceration in advanced cases. The most common ryngeal cancers (D’Souza et al. 2007). The prev-
histologic subtype is the cribriform variant alence of HPV-associated oropharyngeal cancers
although tubular and solid patterns can also be is low in the Asia-Pacific region in comparison to
seen (Waldron et al. 1988). The cribriform variant Western developed countries.
carries a favorable prognosis as compared to other Presence of HPV is now considered a distinct
variants. Perineural invasion is common and clinical, pathological, and prognostic entity in the
symptoms like pain raise the suspicion of such etiology of head and neck cancers, especially those
spread. These tumors commonly spread through of the oropharynx. Epidemiological studies have
the hematogenous route with the lungs being the shown that the incidence of HPV-induced oropha-
most common site for metastatic disease. Neck ryngeal cancers is increasing worldwide over the
nodal metastasis occurs in 10–15% of patients. last decades, while the overall incidence of head-
Surgery remains the main treatment for ACCs neck SCC has declined in the developed countries
with neck dissection being reserved for clinically (Benson et al. 2014). Although HPV-positive
metastatic neck disease. As these tumors are rela- OPSCC presents at a relatively advanced stage as
tively radiosensitive, adjuvant radiation is compared to HPV-negative OPSCC, they have a
warranted in most cases. Imaging of the chest is significantly better prognosis with 60–80% reduced
mandatory in the initial work-up and on a yearly risk of death as compared to the HPV-negative
Table 11 Treatment outcome of HPV-positive and HPV-negative tumors in multiinstitutional trials

Follow-
Study Author (year) N Primary end point up HPV +ve vs ve tumors
ECOG 2399 Fakhry et al. 96 Tumor progression 2 years 2-year survival (95% vs 62%)
(2008)
RTOG 0129 Ang et al. (2010) 323 Overall survival 4.8 years 3-year survival (82.4% vs
Progression-free 57.1%)
survival
TROG 02.02 Rischin (2010) 185 Overall survival 5 years 2-year survival (91% vs 74%)
Failure-free survival
DHANCA 6 and 7 Lassen (2011) 794 Overall survival 5 years (62% vs 47%) conventional
RT
Disease-free survival (52% vs 48%) accelerated RT
TAX 324 Posner (2011) 111 Disease-specific 5 years 5-year survival (82% vs 35%)
survival
Overall survival
counterpart (Gildener-Leapman et al. 2014). Mul- Increased lifetime number of oral and genital sex-
tiple multiinstitutional trials have shown better ual partners, younger age at the time of first sexual
prognosis of HPV-positive OPSCCs (Table 11). intercourse, infrequent use of condoms, and his-
Compared to matched staged HPV-negative tory of previous sexually transmitted infection has
tumors, patients with HPV-positive tumors have found to be associated with HPV-induced OPSCC
better overall survival (Ang et al. 2010), and (Heck et al. 2010). Patients with HPV-positive
while this is not completely understood, these OPSCC commonly present with small primary
could be attributed to several factors including the tumors with large cystic lymph nodes (Fakhry
fact that HPV-positive tumors respond better to et al. 2008). Tonsils, followed by the base of
chemotherapy and radiotherapy (perhaps due to tongue, are the most common sites for primary
the presence of non-mutated tumor suppressor OPSCC tumors (2017). Patients presenting with
genes, TP53 and RB), have higher immunogenic HPV-negative OPSCC typically present with sore
response to viral-specific tumor antigens, have throat or difficulty swallowing (2017).
lower risk of developing secondary tumors (per- Symptoms vary as per the subsite of origin
haps due to less field cancerization), are less likely (Table 12). The base of tongue, tonsillar fossa,
to express biomarkers of poor prognosis such as the and pyriform sinus are rich in lymphatics, and
epidermal growth factor receptor (EGFR), and are cancers of these subsites commonly present with
found in younger patients with fewer comorbidities metastatic neck nodes as the initial sign. Any
and good performance status (Westra et al. 2008; patient presenting with neck nodal metastatic
Adelstein et al. 2009; Hong et al. 2010). Based on squamous cell carcinoma (SCC) without any
the evidence of better prognosis of HPV-positive obviously visible primary lesion should be metic-
OPSCC, the American Joint Committee on Cancer ulously evaluated for a hidden lesion in these
(AJCC) has staged HPV-positive OPSCC as an subsites. Cancers arising from the base of tongue
entity separate from HPV-negative OPSCC in the (BOT) usually present late. Early symptoms of a
most recent AJCC 8th Edition Cancer Staging Sys- sore throat, feeling of a lump in the throat, and
tem (Lydiatt et al. 2017). slight discomfort on swallowing are non-specific
and often ignored by the patient as well as by the
Clinical Presentation primary care physician. In most cases, metastatic
Clinically, HPV-positive OPSCC is seen in youn- neck nodes draw attention to the primary lesion.
ger subjects with less exposure to tobacco and Late symptoms include dysphagia, referred
alcohol. White men with higher socioeconomic otalgia, change in quality of speech (hot potato
status are more commonly affected (2017). voice), and hemoptysis. Early tonsillar cancers
Table 12 Common symptoms of oropharyngeal, hypo- Layfield 2007). However, for large cystic nodes
pharyngeal, and laryngeal cancers (commonly seen in HPV-positive cancers), the
Symptoms of oropharyngeal cancers sensitivity of FNAB drops to 33–50% (Pisharodi
Throat discomfort 1997) due to high false-negative results.
Metastatic neck nodes (most commonly level II nodes) Ultrasound-guided FNAB is useful in this sce-
Dysphagia nario to guide the needle to the wall of the node
Odynophagia for obtaining cellular material. A p16 IHC, HPV
Referred otalgia DNA ISH, and Epstein-Barr-encoded RNA on
Hot potato voice
ISH can help to localize the site of primary tumor.
Symptoms of hypopharyngeal cancers
The presence of HPV can be detected by HPV
Metastatic neck nodes (levels II–IV)
in situ hybridization which detects the presence of
Dysphagia
HPV genetic material in tissue sections of the
Pain
Earache
tumor and could simultaneously detect several
Change in voice high-risk HPV genotypes including HPV-16 and
Aspiration HPV-18. In addition, the expression of p16 which
Dyspnea increases in HPV-positive tumors is a surrogate
Symptoms of laryngeal cancers marker and can be detected by immunohisto-
Dyspnea chemistry which can be performed routinely in
Hoarseness of voice most pathology laboratories. HPV detection in
Metastatic cervical neck nodes (levels II and III) tumor cells can also be undertaken by polymerase
chain reaction (PCR) for detection of HPV DNA
(or reverse transcription PCR for detection of
remain hidden within the tonsil or the tonsillar bed HPV mRNA). HPV classification is made when
and are rarely diagnosed at this stage, and meta- the sample is positive for HPV ISH and p16
static level II neck nodes are the earliest pre- immunohistochemistry (Westra 2009; Robinson
senting symptoms. Advanced tumors present et al. 2010). The principles, merits, and demerits
with bleeding, pain, voice change, and trismus of each are outlined in Table 8.
(due to masticatory muscle involvement). Imaging for early oropharynx cancers is a diag-
nostic challenge as abundant lymphoid tissue fills
Investigations the oropharynx which enhances on contrast admin-
Carcinomas of the oropharynx, hypopharynx, and istration. An additional challenge with CT is dis-
nasopharynx are notorious for their presentation tortion of image quality due to dental artifact
with metastatic neck nodes without any obviously (Figs. 45 and 46). Tongue and swallowing move-
discernible primary lesion. In these circum- ments can hamper the quality of MRI images;
stances, a fine needle aspiration biopsy (FNAB) however, for better delineation of tumor from adja-
from the clinically suspicious neck nodes helps in cent soft tissues, MRI remains the investigation of
establishing the tissue diagnosis as well as identi- choice for oropharyngeal cancers (Figs. 47 and 48).
fying the putative site of the primary tumor. It is an Staging of oropharyngeal tumors is outlined in
effective, minimally invasive, and cost-effective Table 13. Lymph node compartments are separated
diagnostic tool with negligible risk of complica- into levels and sublevels as shown in Fig. 49.
tions such as tumor seeding along the needle tract,
bleeding, infection, and fistula formation. FNAB Treatment
usually yields representative cellular samples both The current preferred therapy for oropharyngeal
for routine histological staining and immunohis- cancer is radiation or concurrent chemoradiation
tochemistry (IHC). With an experienced histopa- (depending on the stage of disease), and while
thologist, FNAB achieves a diagnostic sensitivity these could result in good patient outcomes, they
of 83–97% and a specificity of 91–100% for met- nevertheless are often linked with worrying side
astatic lesions (Gourin and Johnson 2000; effects, such as damage to the larynx and throat
Fig. 45 T1N2b squamous cell carcinoma of the palatine cervical lymph nodes were present including a predomi-
tonsil. CT (a) shows a heterogeneously enhancing cen- nantly cystic 32 mm left level II node. On PET/CT (b) there
trally necrotic mass within the superior aspect of the left is intense asymmetric activity at the left palatine tonsil
palatine tonsil, measuring up to 17 mm consistent with a corresponding to the lesion seen on CT
left tonsillar SCC. Multiple centrally necrotic/cystic left
Fig. 46 Squamous cell carcinoma of the palatine tonsil. inferiorly it involves the anterior tonsillar pillar and fills
CT (a) shows an expansile enhancing mass lesion centered the glossotonsillar sulcus. It approximately measures
in the left palatine tonsil. The lesion has an unusual mor- 44 mm craniocaudal 35 mm transverse oblique
phology, and it involves the entire left palatine tonsil and 26 mm AP oblique. PET/CT (b) shows intense uptake
extends superiorly to the junction of the upper oropharynx centered on the left palatine tonsil with quite extensive
with the lower nasopharynx. Anteriorly at the upper pole involvement of the soft palate extending across the midline
region, it crosses the midline and involves the posterior to the right side and superiorly to the junction of the
aspect of the soft palate and the uvula, and further oropharynx with the nasopharynx
Fig. 47 Base of tongue squamous cell carcinoma. MRI tumor extends to the midline including the median
(a) shows a well-defined, left-sided tongue base mass glossoepiglottic fold. The tumor is of identical signal to
measuring 26 mm in its superoinferior dimension with a lymphoid tissue. PET/CT before surgery (b). Patient
mediolateral width of 21 mm and a depth of 13 mm. The received TORS (c), neck dissection, and postoperative
lesion fills the left vallecula and has a peripheral enhancing radiation, with excellent functional outcomes and
margin merging with the normal oropharyngeal and tongue disease-free at 54 months posttreatment (d) (Images cour-
base mucosa. There is no overt invasion of the remainder of tesy of Dr Chady Sader, Western ENT, Perth WA,
the tongue base, the oral tongue, or the oropharynx. The Australia)
which could affect speech and swallowing, likelihood of cure with a single modality treat-
respectively. ment – either surgery or radiation therapy (RT).
The preferred treatment modality is RT in most
Early Oropharyngeal Cancers patients as it comprehensively addresses both the
For early-stage oropharyngeal cancers (Fig. 50), primary site and the neck nodes and has excellent
the fundamental principle is to maximize the functional outcome. A major advantage of RT is
Advanced Oropharyngeal Cancers

Concurrent chemoradiation is the preferred treat-
ment modality for stage III and IV oropharyngeal
cancers (Fig. 55). RT alone can be considered for
low bulk stage III disease (T1, 2 N1). Primary
surgery can also be considered for selected
low-volume stage III cancers (T3 N0) (Hurtuk
et al. 2012). If the margins of resection are nega-
tive with no pathological metastatic nodes or other
adverse risk factors like perineural invasion (PNI)
or lymphovascular spread (LVS), surgery alone
may be adequate thus reducing the cost and treat-
ment morbidity. On the contrary for other stage III
diseases, patients require adjuvant radiation or
even chemoradiation (if positive margins or extra-
capsular spread) resulting in significant morbidity.
For stage IV cancers, concurrent chemoradiation
is the treatment modality of choice. In general, it
involves concomitant cisplatin chemotherapy
Fig. 48 Contrast-enhanced T1 MRI image showing thick- with full-dose RT (70 Gy, 35#) to the primary
ening of the tonsillar fossa (arrow) suggestive of an early
tumor
site and the neck. Chemotherapy can be given
either in three weekly or weekly doses.
HPV-Associated Oropharyngeal Cancers

that it addresses the retropharyngeal nodes HPV-associated oropharyngeal cancers have a rel-
which carry a high chance of metastasis in oro- atively better prognosis as compared to
pharyngeal cancers and are not usually HPV-negative counterparts. Selected HPV-positive
addressed in routine neck dissection. With patients (T1-3, N0-2a) treated by RT alone have
improved radiation techniques such as inten- low locoregional failure and distant metastasis
sity-modulated radiation therapy (IMRT), there (O’Sullivan et al. 2013). Based on these results,
has been significant improvement of function the concept of de-intensification of treatment in
compared with conventional radiation treatment HPV-positive oropharyngeal cancers to reduce the
(Garden et al. 2007; Nutting et al. 2011). treatment-related morbidities has been proposed
The major drawback of surgery is the associated (O’Sullivan et al. 2013). While this may be ideal,
morbidity and the high rate of occult implementation has not been straightforward as
neck metastasis which results in addition of clinical observation suggests that even within
adjuvant RT and its toxicities. However, propo- HPV-positive patients, there is a significant
nents of surgery argue that the overall dose of minority who still respond poorly to treatment
radiation to the pharynx is less in the adjuvant and have a poor prognosis (Ang et al. 2010).
setting compared to the definitive setting, Currently there are no clinically relevant
thus reducing toxicities (Figs. 51 and 52). markers to distinguish these individuals, making
Minimally invasive surgery in the form of the possibility of selecting patients who may ben-
transoral laser surgery (TOLS) or transoral efit from treatment de-escalation rather challeng-
robotic surgery (TORS) is the treatment of ing. Notwithstanding, based on features of these
choice in patients where it can be carried out patients which include heavy smoking (>10 pack-
with minimal functional morbidity and in years smoking) and advanced nodal disease (N2b
appropriately selected salvage cases (Figs. 53 and above), patients who match these criteria have
and 54). been excluded from treatment de-escalation trials
Table 13 Staging of pharyngeal tumors. TNM clinical classification and staging of pharyngeal malignant tumors
(Adapted from Brierley et al. 2017)
Primary tumor (T)
p16-negative cancers of the oropharynx
TX Primary tumor cannot be assessed
T1 Tumor 2 cm or less in greatest dimension
T2 Tumor more than 2 cm but not more than 4 cm in greatest dimension
T3 Tumor more than 4 cm in greatest dimension or extension to lingual surface of epiglottis
T4a Tumor invades any of the following: larynxa, deep/extrinsic muscle of the tongue (genioglossus, hyoglossus,
palatoglossus, and styloglossus), medial pterygoid, hard palate, or mandible
T4b Tumor invades any of the following: lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, skull
base, or encases carotid artery
p16-positive cancers of the oropharynx
T1 Tumor 2 cm or less in greatest dimension
T2 Tumor more than 2 cm but not more than 4 cm in greatest dimension
T3 Tumor more than 4 cm in greatest dimension or extension to the lingual surface of the epiglottis
T4 Tumor invades any of the following: larynxa, deep/extrinsic muscle of the tongue (genioglossus, hyoglossus,
palatoglossus, and styloglossus), medial pterygoid, hard palate, mandiblea, lateral pterygoid muscle, pterygoid
plates, lateral nasopharynx, skull base, or encases carotid artery
Hypopharynx
T1 Tumor limited to one subsite of the hypopharynx (see page 23) and/or 2 cm or less in greatest dimension
T2 Tumor invades more than one subsite of hypopharynx or an adjacent site or measures more than 2 cm but not
more than 4 cm in greatest dimension, without fixation of the hemilarynx
T3 Tumor more than 4 cm in greatest dimension or with fixation of the hemilarynx or extension to the esophagus
T4a Tumor invades any of the following: thyroid/cricoid cartilage, hyoid bone, thyroid gland, esophagus, and
central compartment soft tissueb
T4b Tumor invades prevertebral fascia, encases carotid artery, or invades mediastinal structures
Nasopharynx
T1 Tumor confined to the nasopharynx or extends to the oropharynx and/or the nasal cavity without
parapharyngeal involvement
T2 Tumor with extension to parapharyngeal space and/or infiltration of the medial pterygoid, lateral pterygoid,
and/or prevertebral muscles
T3 Tumor invades bony structures of skull base cervical vertebra, pterygoid structures, and/or paranasal sinuses
T4a Tumor with intracranial extension and/or involvement of cranial nerves, hypopharynx, orbit, and parotid gland
and/or infiltration beyond the lateral surface of the lateral pterygoid muscle
Regional lymph nodes (N)
Oropharynx (p16-negative) and hypopharynx
NX Regional nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension without extranodal extension
N2a Metastasis in a single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dimension
N2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension, without extranodal
extension
(continued)
N2c Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension, without
N3a Metastasis in a lymph node more than 6 cm in greatest dimension without extranodal extension
N3b Metastasis in a single or multiple lymph nodes with clinical extranodal extensionc
Oropharynx (p-16 positive)
N1 Unilateral metastasis, in lymph node(s), all 6 cm or less in greatest dimension
N2 Contralateral or bilateral metastasis in lymph node(s), all 6 cm or less in greatest dimension
N3 Metastasis in lymph node(s) greater than 6 cm in dimension
Nasopharynx
N1 Unilateral metastasis, in cervical lymph node(s), and/or unilateral or bilateral metastasis in retropharyngeal
lymph nodes, 6 cm or less in greatest dimension, above the caudal border of the cricoid cartilage
N2 Bilateral metastasis in cervical lymph node(s), 6 cm or less in greatest dimension, above the caudal border of
the cricoid cartilage
N3 Metastasis in cervical lymph node(s) greater than 6 cm in dimension and/or extension below the caudal border
of the cricoid cartilage
Distant metastasis (M)
M0 No distant metastasis
Staging
Stage TNM classification
Oropharynx (p16-negative) and hypopharynx
0 Tis N0 M0
I T1 N0 M0
II T2 N0 M0
III T3 N0 M0
T1, T2, T3 N1 M0
IVA T1, T2, T3 N2 M0
T4a N0, N1, N2 M0
IVB T4b Any N M0
Any T N3 M0
IVC Any T Any N M1
Oropharynx (p-16 positive)
0 Tis N0 M0
I T1, T2 N0, N1 M0
II T1, T2 N2 M0
T3 N0, N1, N2 M0
III T1, T2, T3 N3 M0
T4 Any N M0
IV Any T Any N M1
Nasopharynx
0 Tis N0 M0
I T1 N0 M0
II T1 N1 M0
T2 N0, N1 M0
(continued)
III T1, T2 N2 M0
T3 N0, N1, N2 M0
IVA T4 N0, N1, N2 M0
Any T N3 M0
IVB Any T Any N M1
a
Mucosal extension to the lingual surface of the epiglottis from primary tumors of the base of the tongue and vallecula
does not constitute invasion of the larynx
b
Central compartment soft tissue includes prelaryngeal strap muscles and subcutaneous fat
c
structures or clinical signs of nerve involvement is classified as clinical extranodal extension. Midline nodes are
considered ipsilateral nodes
Fig. 49 Lymph node compartments separated into levels and VB. The level V nodes are in the posterior triangle,
and sublevels. The level I node compartment includes the lateral to the lateral edge of the sternocleidomastoid mus-
submental and submandibular nodes, above the hyoid bone cle. Level VI contains the thyroid gland, and the adjacent
and anterior to the posterior edge of the submandibular nodes bordered superiorly by the hyoid bone, inferiorly by
gland. The level II, III, and IV nodes are arrayed along the the innominate (brachiocephalic) artery, and laterally on
jugular veins on each side, bordered anteromedially by each side by the carotid sheaths. The inferior extent of level
level VI and laterally by the posterior border of the VI is defined as the suprasternal notch. Many authors also
sternocleidomastoid muscle. The level III nodes are include the pretracheal and paratracheal superior mediasti-
bounded superiorly by the level of the hyoid bone and nal lymph nodes above the level of the innominate artery
inferiorly by the cricoid cartilage; levels II and IV are (sometimes referred to as level VII) in central neck
above and below level III, respectively. Levels I, II, and dissection
V can be further subdivided as noted IA, IB, IIA, IIB, VA,
Stage I, II Oropharyngeal Cancers
Definive RT TORS with neck dissecon Open Surgery with neck dissecon
Preferred treatment • Small primaries Least preferred treatment
• Selected salvage cases
No adverse factors • pT3, pT4 • Positive margins

Observe • PNI • ECS
• LVS Adjuvant CT+RT
• N+ without ECS
Adjuvant RT
Fig. 50 Treatment algorithm of early oropharyngeal cancers
Fig. 51 Extensive osteoradionecrosis in a 71-year-old reconstruction with a free fibula flap (c + d). The patient
female post chemoradiation for oropharyngeal squamous had significant functional and quality of life improvement
cell carcinoma (a and b). Significant symptoms of pain, (e) (Images courtesy of Dr Chady Sader, Western ENT,
trismus, and an orocutaneous fistula were present. The Perth WA, Australia)
patient underwent oromandibular resection and
Fig. 52 Clinical (a) and CT radiological (b) appearance of generated model of the mandible (c) aided the free tissue
osteoradionecrosis with a pathological mandibular fracture reconstruction of the jaw (d). The skin paddle of the
and orocutaneous fistula in a 50-year-old male who had pedicle was used to reconstruct the cutaneous defect of
previously undergone neck dissection and radiation for a the neck (e) (Images courtesy of Dr Chady Sader, Western
left tonsillar squamous cell carcinoma. The 3D computer- ENT, Perth WA, Australia)
(Ang et al. 2010; Granata et al. 2012). Patients

whose tumors have evident tumor-infiltrating
lymphocytes have superior survival suggesting
that the immune infiltrate could identify the subset
of HPV-positive patients who have poor progno-
sis (Ward et al. 2014). While such biomarkers
could impact on patient selection and have the
potential to change clinical practice, the evalua-
tion of tumor-infiltrating lymphocytes is still at an
early stage and not yet in mainstream clinical use.
Trials for de-escalation of treatment in
HPV-positive OPSCC are underway (ADEPT,
ECOG 3311, PATHOS).
Fig. 53 Oropharyngeal cancer removed with transoral The role of HPV vaccines in preventing oropha-
robotic surgery (TORS) (Image courtesy of Dr Chady
ryngeal cancers is an area of active discussion. As
Sader, Western ENT, Perth WA, Australia)
the majority of oropharyngeal cancers are caused
Fig. 54 TORS setup showing the surgical assistant at the secretions. The surgeon is seated in the surgeon’s console
bedside (a) ensuring patient safety, facilitating any adjust- (b) and operating the robot (Images courtesy of Dr Chady
ments to the robotic arms, communicating with the sur- Sader, Western ENT, Perth WA, Australia)
geon, and ensuring smoke evacuation and suction of blood/
Fig. 55 Treatment Stage III, IV Oropharyngeal Cancer

algorithm of advanced
oropharyngeal cancers
Concurrent chemoradiaon Surgery

Preferred treatment Transoral or open resection
RT alone can be considered for with neck dissection
selected HPV +ve tumors (Less Preferred)
Positive margins Other risk factors

• ECS Adjuvant RT
Adjuvant CT+RT
primarily by HPV-16, a particularly dangerous 6, 11, 16, 18, 31, 33, 45, 52, and 58 (Gardasil 9)
strain of the virus, it is conceivable that the two have been approved by the US FDA for routine
vaccines that protect against HPV-16 that are cur- vaccination of adolescents (girls and boys) at age
rently approved to prevent cervical cancer could 11 or 12 years and can be started as early as 9 years
also do the same for oropharyngeal cancer. The of age. While it is theoretically possible, studies to
quadrivalent HPV vaccine types 6, 11, 16, and determine if HPV vaccine will prevent oropharyn-
18 (Gardasil/Gardisil/Silgard) are effective in pre- geal cancers are hampered by the need for invasive
venting anal, cervical, vaginal, and vulvar pre- sampling deep in the tonsillar area where the cancer
cancers and cancers, while the bivalent HPV arises, and therefore, the vaccine is currently not
vaccine types 16 and 18 (Cervarix) have been indicated for the prevention of head and neck can-
demonstrated to be effective in cervical precancers cers, but it is likely that population-based observa-
and cancers (Garland and Smith 2010; Lu et al. tion studies in vaccinated cohorts will reveal a
2011). More recently 9-valent HPV vaccine types positive benefit in the future (Scudellari 2013).
Hypopharyngeal Cancer dysphagia, hoarseness of voice (due to laryngeal

involvement), symptoms of aspiration, pain, ear-
Epidemiology, Etiology, and Pathology ache (referred otalgia), and dyspnea.
Although 95% of hypopharyngeal cancers are Endoscopic evaluation of the upper
SCCs, rarely lymphomas, sarcomas, and adeno- aerodigestive tract is undertaken to map the extent
carcinomas can arise from the hypopharynx. of the disease as well as to take a biopsy from the
While tobacco smoking is the primary etiologic primary lesion. Disease mapping includes assess-
factor of laryngeal cancers, hypopharyngeal ment of the adequacy of the airway, evaluation of
cancers are associated with alcohol abuse (Spitz the mucosal extent of disease, and mobility of
1994). Ethyl alcohol during metabolism is first the vocal cords and arytenoids and signs of aspira-
converted into acetaldehyde (a carcinogenic tion. All cases of hypopharyngeal cancers should
by-product) which is further metabolized into undergo a rigid esophagoscopy to delineate
acetate (excretory end product) by an enzyme the lower extent of tumor and for evaluation of a
acetaldehyde dehydrogenase. Inability to con- potential second primary lesion in the esophagus.
vert acetaldehyde to acetate due to mutations in
acetaldehyde dehydrogenase gene results
Investigations
in accumulation of carcinogenic metabolic inter-
Cross-sectional imaging with CT and MRI
mediate acetaldehyde. The carcinogenic effect
plays an indispensable complementary role to
of acetaldehyde is exerted by generation of
endoscopy in the pre-therapeutic work-up of
free radicals, direct DNA damage, and
hypopharyngeal cancer and is very valuable for
upregulation of enzymes of the cytochrome
the detection of tumor recurrence after surgery or
P450 system which results in activation of
radiation treatment as well. CT is the preferred
certain procarcinogens to carcinogens. Addition-
imaging method for staging of hypopharyngeal
ally, alcohol acts as a solvent for tobacco
cancer. The primary tumor typically appears as a
increasing the cellular permeability of tobacco
solid soft tissue nodule or region of superficial
carcinogens through the mucosa of the upper
thickening with increased enhancement. When it
aerodigestive tract. Alcohol also impairs
extends beyond the confines of the pharynx, the
immunity and causes nutritional deficiencies
surrounding fat planes are obliterated. Careful
thus lowering the resistance to cancer. Alcohol
assessment of cervical lymph nodes is essential
is believed to act synergistically to tobacco in
as up to 75% of patients with hypopharyngeal
the etiology of head and neck cancers.
SCCs have nodal metastases at the time of diag-
Dietary risk factors have also been implicated
nosis (Fig. 56). MRI has the ability to be superior
as a risk factor for hypopharyngeal cancers.
to CT in local staging and assessing perineural
Plummer-Vinson syndrome is characterized by
spread; however, relatively long acquisition
iron deficiency anemia, hypopharyngeal webs,
times and degradation by motion artifact are
koilonychias, weight loss, and dysphagia. This
sometimes challenging. Both CT and MRI are
syndrome is accompanied by an increased risk of
routinely used for detection of subtle cartilage
postcricoid SCC. Treatment of iron deficiency
invasion (Fig. 57), but there is still controversy
anemia has been found to decrease the risk of
about which modality can most accurately detect
malignancy.
cartilage invasion, and both modalities have
shortcomings (2003). As is the case with other
Clinical Presentation metabolically active tumors, FDG PET/CT has
Pyriform fossa and postcricoid tumors of the an increasing role in the diagnosis, staging, and
hypopharynx initially present with non-specific follow-up of hypopharyngeal tumors (Fig. 58).
throat symptoms and metastatic cervical Staging of hypopharyngeal tumors is outlined in
nodes. However, advanced tumors present with Table 13.
Fig. 56 Hypopharyngeal carcinoma. Post-contrast CT into the extra-laryngeal space where it infiltrates the under-
sagittal (a), axial (b), and coronal (c) views show an surface of the strap muscles and extends inferiorly to
extremely large heterogeneous and partially necrotic left- infiltrate the superior aspect of the left lobe of the thyroid.
sided mass lesion (arrows). This measures approximately There is associated extensive left-sided necrotic and obvi-
10 cm craniocaudal 6.8 cm transverse 4.5 cm ously metastatic lymphadenopathy within the left IIA,
AP. Cranially, the lesion is centered in the hypopharynx IIIA, and IVA levels (d + e). PET/CT(F-18 FDG) fusion
and aryepiglottic fold on the left extending anterior to sagittal (f), coronal (g), and axial (h) views. There is a large
involve the pre-epiglottic space but spreads into the left invasive left neck mass centered on the hypopharynx
paralaryngeal space markedly narrowing and displacing which is intensely FDG-avid and appears to cross the
the supraglottic airway to the right. It crosses posteriorly midline to the right hypopharynx. There are enlarged left
into the right side of the hypopharynx and involves both level IIa and III lymph nodes with central photopenia and
left and right false cords. It spreads laterally to erode the peripheral intense FDG uptake, consistent with necrotic
posterior aspect of the left thyroid cartilage and extends nodes
Stage I and II Hypopharyngeal Cancers
Definitive RT Surgery TOLS or OPL

Preferred Treatment with B/L neck
Chemo RT dissection
For bulky lesions Patients with good
pulmonary function
Adjuvant treatment
depending on
histopathology
Fig. 57 Contrast-enhanced CT neck (bone window)
showing a pyriform fossa tumor showing erosion of the Fig. 59 Treatment algorithm for early hypopharyngeal
inner lamina of the thyroid cartilage without exolaryngeal cancer
spread (arrow)
tracheostomy and a shorter hospital stay. How-

ever, the neck must be addressed in all patients.
If TOLS is the primary treatment modality, neck
dissection can be carried out either simulta-
neously or after an interval of 7–10 days. The
advantages of interval neck dissection include a
second look into the operated cavity under gen-
eral anesthesia and for margin revision if
required based on the final histopathology,
avoid acute edema of the larynx which can
occur if bilateral neck dissection is undertaken
simultaneously with the primary resection, and
address transit lymphatics (not a universally
Fig. 58 PET/CT fusion axial image showing an enhanc- accepted concept). The major drawback of inter-
ing lesion involving hypopharynx with gross exolaryngeal val neck dissection is the need for a second
extension
surgery under general anesthesia.
Treatment Advanced Hypopharyngeal Cancers

In advanced lesions which require total laryngec-
Early Hypopharyngeal Cancer tomy with pharyngectomy, induction chemother-
Radiotherapy is the preferred treatment modal- apy can be utilized to facilitate organ preservation
ity for early hypopharyngeal cancers as surgery (Fig. 60). An EORTC phase III RCT has shown
in this region results in high odds of aspiration that in the group randomized to the nonsurgical
(Fig. 59). Moreover, due to the high propensity arm (induction chemotherapy with cisplatin and
of occult nodal metastasis, surgery frequently fluorouracil followed by radiation in responders),
upstages the neck resulting in administration of more than half of patients who survived preserved
multimodality treatment. Surgical procedures, if their larynx (Lefebvre et al. 1996, 2012). There
planned, are either TOLS or open partial was no difference in 5- and 10-year overall or
laryngopharyngectomy. The morbidity of progression-free survival between the surgical
TOLS is significantly less than open surgery (surgery followed by adjuvant treatment) and
including the avoidance of a temporary nonsurgical arms (Lefebvre et al. 1996, 2012).
Stage III, IV Hypopharyngeal Cancers
T3 T4a T4b
Functional larynx Non functional larynx Palliative treatment
NACT and response Chemoradiation

assessment
Total or near total
laryngo-pharengectomy
with B/L ND with
Complete response Partial response Less than adjuvant treatment
partial response
Concurrent
chemoradiotherapy
Fig. 60 Treatment algorithm for advanced hypopharyngeal cancers
To further facilitate organ preservation with loss), hyper-fractioned radiation can be consid-
induction chemotherapy, docetaxel has been ered. Similar to concurrent chemotherapy, no ben-
used in combination with cisplatin and fluoroura- efit of hyper-fractioned radiation has been
cil (5FU) in a triple therapy regimen commonly demonstrated in patients >70 years old (Baujat
known as TPF (Taxotere, Platinol, Fluorouracil). et al. 2010). Alternatively, biological targeting
Although overall survival was the same in the TPF agents can be used in patients not fit for concur-
and PF (cisplatin/5FU) arms, a higher tumor rent chemotherapy. In a phase III RCT of
response rate (80% vs 59%) and laryngeal preser- advanced head and neck cancer patients compar-
vation rate (70% vs 57%) was seen in the TPF arm ing radiation alone with radiation plus weekly
compared to PF arm (Pointreau et al. 2009). cetuximab, a 10% overall survival benefit was
Concurrent chemoradiation remains a treat- found in patients treated with concurrent
ment option for advanced hypopharyngeal can- cetuximab (Bonner et al. 2006). Cisplatin poten-
cers, although there is no conclusive evidence tiates radiation-induced toxicities and causes its
for its role in exclusive hypopharyngeal cancer own toxicities limiting its doses and thus efficacy,
patients. Data is extrapolated from studies on whereas cetuximab on the other hand does not
laryngeal and general head and neck cancers. A enhance radiation-induced toxicities and thus is
meta-analysis of 17,346 patients of head and neck better tolerated than concurrent cisplatin.
cancers demonstrated an absolute benefit of 6.5% Advanced hypopharyngeal cancers with
and 2.4% in overall survival with concurrent nonfunctional larynx or extra-laryngeal spread
chemoradiotherapy and induction chemotherapy are candidates for total laryngectomy with partial
with radiotherapy, respectively. The benefit of or circumferential pharyngectomy with appro-
concurrent chemotherapy was predominantly priate reconstruction followed by adjuvant
seen in younger patients with no benefit seen in treatment depending on final histopathology.
patients >70 years of age (Pignon et al. 2009). Patients with positive resection margins or
In patients who are not candidates for concur- extracapsular nodal spread receive adjuvant
rent chemotherapy (poor performance status, chemoradiation, while others receive adjuvant
renal insufficiency, or sensorineural hearing radiation alone.
Laryngeal Cancer

Laryngeal cancers are primarily squamous cell
carcinomas with minor salivary gland cancers,
sarcomas, neuroendocrine tumors, and hematoly-
mphoid tumors forming a minority of the cases.
Tobacco and alcohol are the two major risk
factors of laryngopharyngeal cancers, with
tobacco smoking representing the primary etio-
logic factor for laryngeal cancers. Tobacco is con-
sumed in the smoked and the smokeless form.
Tobacco smoke contains about 60 carcinogens of
which polycyclic aromatic hydrocarbons consti-
tute the main carcinogen followed by aromatic
amines. Smokeless tobacco contains about 16 car-
cinogens, nitrosamines being the major constitu-
ent. Metabolism of tobacco products results in the
formation of electrophilic intermediates which
bind to normal DNA resulting in the formation
of DNA adducts. These adducts are either repaired
Fig. 61 Contrast-enhanced CT neck axial image showing
or undergo apoptosis. Persistence of miscoding tumor involvement of the pre-epiglottic space (yellow
leads to mutation of crucial genes regulating the arrow) and necrotic level II lymph node (red arrow)
cell cycle (e.g., RAS, MYC, p53, p16, RB)
resulting in carcinogenesis.
Clinical Presentation
Laryngeal cancers as opposed to pharyngeal can-
cers present relatively early due to symptoms
related to airway obstruction and voice change.
Supraglottic cancers present initially with neck
nodes and dyspnea. Hoarseness of voice appears
relatively late. Glottis cancers on the other hand
present at early stage with hoarseness of voice.
Due to the paucity of lymphatics in the glottic
region, neck nodes appear late when the tumor
has spread to the adjacent subsites of supraglottis
or the pyriform sinus.
Investigations
The pre-epiglottic space is best evaluated in axial Fig. 62 Contrast-enhanced CT neck sagittal image show-
and sagittal images (Figs. 61, 62, and 63). The ing a base of tongue tumor infiltrating into the
sensitivities of CT and MRI are 100%, with spec- pre-epiglottic space (yellow arrow)
ificity for CT being 93% and MRI being 84–90%
(Becker 1998). Radiological invasion of the para- while the specificity varies between 50% and
glottic space is best seen in axial and coronal 76%. Reduced specificity is due to disease over-
sections (Figs. 64 and 65). The sensitivities for estimation because of peritumoral inflammation
CT and MRI are 93% and 97%, respectively, (Becker 1998). Overall, contrast-enhanced CT is
Fig. 65 Contrast-enhanced CT showing a glottic tumor

Fig. 63 Contrast-enhanced CT neck sagittal image show- involving the paraglottic space (yellow line)
ing a supraglottic tumor almost completely filling the
pre-epiglottic space (yellow arrow)
Fig. 64 Contrast-enhanced CT neck (soft tissue window) Fig. 66 Contrast-enhanced CT neck showing a laryngeal
showing a pyriform fossa tumor with paraglottic extension tumor with sclerosis of the thyroid cartilage indicating
(red arrow), erosion of the inner lamina of the thyroid early cartilage invasion
cartilage without exolaryngeal spread (yellow arrow)
the investigation of choice for laryngeal cancers determinants in upstaging the disease and man-
(Fig. 66) with MRI reserved for cases with doubt- agement of laryngeal and hypopharyngeal can-
ful erosion on CT and in patients with allergy to cers. Radiologically, cartilage invasion can be
iodinated contrast or compromised renal function. divided into three stages (Becker et al. 1997):
Videostroboscopy helps determine the location (1) sclerosis, (2) erosion/lysis, and (3) extra-
and size of a tumor, as well as how the tumor laryngeal tumor spread.
has affected the function of the larynx and hypo- Sclerosis histologically corresponds to early
pharynx. Histopathology shows squamous differ- perichondral involvement or microscopic intra-
entiation and invasion on biopsy. Cartilage cartilaginous spread. CT is sensitive in detecting
invasion and extra-laryngeal spread are major sclerosis but specificity varies between cartilages
preservation is higher in patients treated with

TOLS (100%) compared to those treated with
definitive RT (93%) (Remmelts et al. 2013).
No prospective study has been performed com-
paring the oncologic and voice outcomes of TOLS
versus definitive RT for T1a glottic cancers.
Available data from multiple retrospective series
have not found any significant difference in onco-
logic or voice outcomes between the two treat-
ment modalities although larynx preservation has
been found to be better in TOLS patients. In a
meta-analysis based on over 7600 patients, there
Fig. 67 Contrast-enhanced CT neck showing a supra- was no difference in local control or
glottic tumor with cartilage erosion and exolaryngeal
spread (yellow arrow)
laryngectomy-free survival between TOLS and
RT (Higgins et al. 2009). Although there was a
trend toward improved overall survival in patients
being lowest for thyroid cartilage (40%) and treated with TOLS, and improved voice outcome
higher for cricoid (76%) and arytenoid cartilages in definitive RT patients, the difference did not
(79%). Erosion or lysis corresponds to osteolysis reach statistical significance (Higgins et al. 2009).
without through and through cartilage disruption, Another meta-analysis of 1729 patients compar-
with/without new bone formation. Contrast- ing the oncologic and functional outcomes of
enhanced CT has a high specificity for erosion TOLS and RT found no difference in local con-
detection (93%), but the sensitivity is poor trol, overall survival, disease-specific survival, or
(Fig. 67) (Becker et al. 1997). Extension of the posttreatment voice quality between the two
tumor outside the laryngeal framework is termed groups; however, larynx preservation was signif-
as extra-laryngeal spread. Similarly, for extra- icantly higher in the TOLS group compared to the
laryngeal spread multi-slice CT (MSCT) has RT group (Abdurehim et al. 2012). Due to the lack
high specificity (95%) with a poor sensitivity of prospective data, the treatment modality for T1
(Becker et al. 1997). MRI has higher sensitivity glottic cancers should be individualized. Young
(89–95%) but lower specificity (74–84%) as com- patients with mid-cord lesions and a good endo-
pared to CT in detecting cartilage invasion. The scopic exposure are preferably treated with
negative predictive value of MRI is very high TOLS. Patients with lesions involving anterior
(94–96%) (Mukherji and Bradford 2006). Tumor commissure or involving both cords and patients
infiltration of the marrow is best identified in T1 who are voice professionals are preferably treated
contrast images with fat suppression. Staging of with definitive RT. Pros and cons of each treat-
laryngeal tumors is outlined in Table 14. ment option should be discussed with the patient
before choosing a treatment modality.
Treatment
T2 Glottic Cancers
T1 Glottic Cancers Similar to T1 glottic cancers, the treatment of T2
The primary goal of treatment is to maximize cure glottic cancers with mobile cords is TOLS or
and minimize treatment-related morbidity. T1a definitive RT (Fig. 69). The treatment should be
glottic cancers can be treated either by definitive individualized depending on institutional exper-
RT or transoral laser surgery (TOLS) (Table 15) tise and patient preference. Tumors with restricted
(Fig. 68). Both treatment modalities have similar cord mobility indicate infiltrative disease which
locoregional control and disease-specific survival responds poorly to RT alone. These patients are
(Khan et al. 2012; Canis et al. 2015). Although the preferably treated with chemoradiation. TOLS has
oncologic outcomes are comparable, larynx a limited role in these lesions as resection is
Table 14 Staging of laryngeal tumors. TNM clinical classification and staging of laryngeal malignant tumors (Adapted
from Brierley et al. 2017)
Primary tumor (T)
Supraglottis
T1 Tumor limited to one subsite of supraglottis with normal vocal cord mobility
T2 Tumor invades mucosa of more than one adjacent subsite of supraglottis or glottis or region outside the
supraglottis (e.g., mucosa of base of the tongue, vallecula, medial wall of the piriform sinus) without fixation of
the larynx
T3 Tumor limited to the larynx with vocal cord fixation and/or invades any of the following: postcricoid area,
pre-epiglottic space, paraglottic space, and/or inner cortex of the thyroid cartilage
T4a Tumor invades through the thyroid cartilage and/or invades tissues beyond the larynx, e.g., trachea, soft tissues
of the neck including deep/extrinsic muscle of the tongue (genioglossus, hyoglossus, palatoglossus, and
styloglossus), strap muscles, thyroid, or esophagus
T4b Tumor invades prevertebral space, encases the carotid artery, or mediastinal structures
Glottis
T1 Tumor limited to vocal cord(s) (which may involve anterior or posterior commissure) with normal mobility
T1a Tumor limited to one vocal cord
T1b Tumor involves both vocal cords
T2 Tumor extends to supraglottis and/or subglottis, and/or with impaired vocal cord mobility
T3 Tumor limited to the larynx with vocal cord fixation and/or invades paraglottic space and/or the inner cortex of
the thyroid cartilage
T4a Tumor invades through the outer cortex of the thyroid cartilage and/or invades tissues beyond the larynx, e.g.,
trachea, soft tissues of the neck including deep/extrinsic muscle of the tongue (genioglossus, hyoglossus,
palatoglossus, and styloglossus), strap muscles, thyroid, the esophagus
T4b Tumor invades prevertebral space and encases the carotid artery or mediastinal structures
Subglottis
T1 Tumor limited to subglottis
T2 Tumor extends to vocal cord(s) with normal or impaired mobility
T3 Tumor limited to the larynx with vocal cord fixation
T4a Tumor invades the cricoid or thyroid cartilage and/or invades tissues beyond the larynx, e.g., trachea, soft
tissues of the neck including deep/extrinsic muscle of the tongue (genioglossus, hyoglossus, palatoglossus,
and styloglossus), strap muscle, thyroid, and esophagus
T4b Tumor invades prevertebral space and encases the carotid artery or mediastinal structures
N1 Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension without extranodal extension
N2a Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension
N2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension, without extranodal
extension
(continued)
N2c Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension, without
N3a Metastasis in a lymph node more than 6 cm in greatest dimension without extranodal extension
N3b Metastasis in a single or multiple lymph nodes with clinical extranodal extensiona
Staging
0 Tis N0 M0
I T1 N0 M0
II T2 N0 M0
III T3 N0 M0
T1, T2, T3 N1 M0
IVA T1, T2, T3, T4a N2 M0
T4a N0, N1 M0
IVB T4b Any N M0
Any T N3 M0
IVC Any T Any N M1
a
structures or clinical signs of nerve involvement is classified as clinical extra nodal extension. Midline nodes are
considered ipsilateral nodes
Table 15 Benefits of different treatment modalities for early glottis cancers

Advantages of TOLS
Single-stage procedure reduces treatment time
No RT-induced toxicities
Cost-effective
Better larynx preservation rates
Reserves other treatment options like redo surgery and RT for recurrence or second primary
Advantages of RT
No surgical expertise required
Possibly improved voice quality
T1 Glottic Cancers
T1a T1b
TOLS Definitive RT Definitive RT TOLS Open partial

Preferred treatment • Endoscopic exposure Preferred treatment Staged to prevent laryngectomy (OPL)
is unsatisfactory web formation In salvage settings
• Voice professional
• Sometimes anterior
commissure lesions
Fig. 68 Treatment algorithm for T1 glottic cancers

extensive (a type III or IV cordectomy) rendering control with surgery (TOLS or open surgery) and
the patient with poor voice quality and significant radiation are comparable in T1 cancers (90–100%
chances of aspiration. for surgery and 77–100% for radiation), while
surgery has slightly better local control for T2
Early Supraglottic Cancers lesions (80–97% for surgery and 62–83% for
Early supraglottic cancers can be treated either RT) (Ambrosch 2007).
with definitive RT or surgery (Fig. 70). In view
of the high propensity of occult neck nodal metas- Advanced Laryngeal Cancers
tasis, surgery when used as the primary treatment Patients with advanced laryngeal cancers with a
modality frequently upstages the neck resulting in functional larynx and no extra-laryngeal spread
administration of adjuvant RT, converting a single are preferably treated on an organ preservation
modality into a multimodality treatment. Thus, protocol (Fig. 71). Concurrent chemoradiotherapy
definitive RT remains the treatment of choice for is the treatment of choice, although recent evi-
early supraglottic cancers. In patients with bulky dence suggests a higher morbidity and mortality
tumors, concurrent chemoradiation may be con- as compared to neoadjuvant chemotherapy
sidered as lesions >6 cm3 do not respond well to followed by radiation. The VA trial published in
RT alone (Mancuso et al. 1999). Surgery, mostly 1991 was the first RCT comparing neoadjuvant
TOLS or open partial laryngectomy, is usually chemotherapy followed by RT with the standard
considered in the salvage setting. Five-year local practice of total laryngectomy followed by
T2 Glottic Cancers
Freely mobile vocal cords Impaired cord mobility
TOLS Definitive RT Chemoradiation OPL TOLS

Preferred treatment If endoscopic Preferred treatment If patient not Only in expert hands
exposure is suitable for
unsatisfactory chemoradiation
Chemoradiation
For bulky disease
Fig. 69 Treatment algorithm for T2 glottic cancers
Fig. 70 Treatment Stage I, II Supraglottic Cancers

algorithm for early
supraglottic cancers
Definitive RT Surgery
Preferred treatment TOLS or OPL with B/L Neck dissection
Chemoradiation Good pulmonary reserve
For bulky lesions Resection not morbid
Salvage cases
Adjuvant treatment as indicated

Stage III, IV Laryngeal Cancers
T3 T4a T4b
Functional larynx Non functional larynx
Chemoradiaon NACT followed by RT Total/ near total Palliative treatment

Preferred treatment Less toxic than CT RT laryngectomy followed
by adjuvant treatment
Fig. 71 Treatment algorithm for advanced laryngeal cancer
adjuvant treatment in advanced laryngeal cancers CT RT patients; however, fistula formation fol-
(Department of Veterans Affairs Laryngeal Can- lowing salvage surgery was most commonly seen
cer Study et al. 1991). The estimated 2-year sur- in these patients.
vival was 68% in both groups. In the nonsurgical Patients with nonfunctional larynx (tracheos-
arm, the larynx could be preserved in 64% of tomy tube or Ryles tube in situ) and extra-
patients. The pattern of recurrence differed signif- laryngeal disease respond poorly to organ preser-
icantly with more local recurrences and few dis- vation and are treated with surgery (total/near-
tant failures in the nonsurgical arm. Patients with total laryngectomy with neck dissection) followed
stage IV tumors as compared to stage III tumors, by appropriate adjuvant treatment (Fig. 72).
and T4 disease as compared to smaller primaries,
had significantly increased rates of salvage
laryngectomies. Nasopharyngeal Cancer
Concurrent chemoradiotherapy (CT RT) and
neoadjuvant chemotherapy (NACT) followed by Epidemiology, Etiology, and Pathology
RT and RT alone have been used as treatment The nasopharynx forms the superior most part of
modalities in advanced laryngeal cancers (large- the pharynx and is a cuboidal cavity located
volume T4 lesions excluded) (Forastiere et al. beyond the choanae or the posterior nares. It com-
2003). Follow-up of patients with advanced laryn- prises two lateral walls and a roof which slopes
geal cancers treated with one of these modalities down till the level of the uvula thereby making the
showed that larynx preservation was significantly soft plate as its floor. Nasopharyngeal carcinoma
higher in the CT RT group compared to the two (NPC) is a squamous cell carcinoma arising from
other groups at 3.8 years posttreatment. Ten-year the surface epithelium of this region (Wenig 1999).
follow-up data revealed no difference in overall NPC is endemic to Southeast Asia (Southern
survival and laryngectomy-free survival between China) and also includes the first-generation emi-
NACT followed by RT and concurrent grated Chinese population in the West. Alaskan
chemoradiotherapy CT RT (Forastiere et al. Eskimos and Mediterraneans also report incidence
2013). Although local control and larynx preser- of NPC. In the Indian subcontinent, it is more
vation continued to be significantly better in the prevalent in the northeastern states which have a
CT RT arm, there were significantly more substantial mongoloid population. There are rare
noncancer-related deaths in the CT RT arm com- incidences of NPC in the rest of the world. In terms
pared to NACT arm (Forastiere et al. 2013). Least of age standardized ratio, the highest incidence is in
number of salvage surgeries were required in the Southern China ranging from 15 to 50 per 100,000.
Fig. 72 Macroscopic appearance of the larynx sectioned tumor abuts the thyroid cartilage and crosses the midline
transversely from superior to inferior (left to right) showing anteriorly. The tumor does not involve overlying strap
a left glottic squamous cell carcinoma which invades left muscles or left hemithyroid (Image courtesy of Dr Chris
paraglottic soft tissue and extends into subglottis. The Van Vliet, Pathwest, Perth WA, Australia)
There is a high male preponderance with a male-to- arising from oropharyngeal subsites (Marur et al.
female ratio of 3:1 and an usual age of presentation 2010).
between 20 and 60 years of age (Marks et al. 1998; The World Health Organization (WHO) clas-
Harrison 2014). sifies NPC into either keratinizing squamous cell
NPC has a multifactorial etiology which is carcinoma (WHO type I), non-keratinizing squa-
markedly different from other sites in the head mous cell carcinoma (WHO type II), or basaloid
and neck like tobacco and alcohol. Viral, genetic, squamous cell carcinoma (Chan et al. 2005).
and environmental factors contribute to NPC eti-
ology. Salted fish with high content of nitrosa- Clinical Presentation
mine, poor hygiene, improper ventilation, Initially NPC involves the fossa of Rosenmuller in
smoking, and the use of nasal balms have been the majority of cases, and as it advances, it
attributed as environmental factors. There has involves the nasal cavity, sphenoid sinus, poste-
been an increased genetic susceptibility associ- rior ethmoids, orbit, parapharyngeal space
ated with HLA-A2, B-17, B246, and BW58 geno- sphenopalatine fossa, foramen lacerum, and mid-
types, and reduced risk is associated with A11, dle cranial fossa. Symptoms of NPC include
B13, and B22 loci. There has been a drop in the breathing difficulty and nasal blockage, painless
incidence of NPC in the last 40 years which sug- neck mass, hearing loss, ear discharge, epistaxis,
gests the role of environmental factors2. The viral cranial nerve deficits, proptosis, and trismus. Nine
etiology is mainly attributed to Epstein-Barr virus out of ten patients usually present with at least
(EBV) for the endemic WHO type II/III. EBV is a unilateral metastatic neck nodes either in para-
B-lymphotropic herpes virus. It has a consistent pharyngeal or the jugular digastric nodal stations
role in the etiopathogenesis which can be seen (Marks et al. 1998; Chan et al. 2005).
from the early stages of the disease. EBV is absent
in normal nasopharyngeal mucosa. Clonal viral Investigations
genomes and latent membrane proteins (LMP-1) The nasopharynx can be clinically examined with
of EBV have been detected in NPC. Human pap- a flexible fiber-optic endoscope or a rigid rod
illoma virus (HPV) is associated with some NPC endoscope 0-degree or 70 . Neck examination
by palpation is imperative. Imaging can be done radiotherapy (Harrison 2014). Radiotherapy can
by means of contrast-enhanced CT (CECT) which cover all the areas of the nasopharynx and the
provides excellent information regarding the pri- potential sites of its spread without extensive mor-
mary site, nodal burden, and bone invasion, bidity or toxicity. Single modality treatment is
whereas an MRI can be complementary for better advised in the early stages. In advanced stages,
soft tissue extent of the tumor, to differentiate multiple trials have shown the advantage of using
between mucus and tumor and perineural spread
of the tumor (Sakata et al. 1999) (Figs. 73, 74, and
75). More than 20% of NPC can present with
distant metastasis to the bone, lung, and liver in
increasing frequency. Hence a PET/CT is
recommended in stage III/IV cases (Vikram et al.
1985). Biopsy can be either taken from the pri-
mary site using a punch forceps with the help of an
endoscope under topical local anesthesia. FNAC
from the nodes can also demonstrate NPC cells
and can be used for tissue diagnosis. Serological
markers like IgA antibody against viral capsid
antigen of EBV can be used for screening which
has a sensitivity upward of 80%. Plasma EBV
DNA using PCR also is used as a serological
marker with a sensitivity up to 96% and can be
used in early detection (Leung et al. 2006).
Treatment
NPC are distinct in regard to other cancers of the
head and neck as they are extremely radiosensi- Fig. 73 Shows an axial image of T2 MRI showing a right-
tive; therefore, they can be effectively treated with side nasopharyngeal carcinoma
Fig. 74 T1N2M0 nasopharyngeal carcinoma. On MRI invasion. The lesion is confined within the nasopharyngeal
there is a polypoid carcinoma in the right central aspect mucosal space with no convincing evidence of submucosal
of the nasopharyngeal mucosal space. The tumor demon- extension. There are no pathological retropharyngeal
strates T1 isointensity (a) and T2 hyperintensity (b) with enlarged lymph nodes and no evidence of perineural
mild to moderate enhancement. The lesion measures tumor spread along the trigeminal nerve. PET/CT (c)
26 mm transverse 9 22 mm AP and 8 mm shows intense abnormal FDG activity related to a soft
craniocaudal. There is preservation of the normal marrow tissue mass of the posterosuperior right nasopharynx.
signal of the clivus with no evidence of central skull base Activity appears well localized with no bone erosion
Fig. 75 T4N0M0 nasopharyngeal carcinoma. MRI shows abnormal soft tissue in the central superior and nasophar-
an aggressive strongly enhancing lobular mass within the ynx. The extent of the lesion is up to 36 mm superoinferior
central skull base, occupying most of the basisphenoid and 29 mm transverse 21 mm anteroposterior (a). The
the anterosuperior aspects of the basiocciput, protruding lesion is markedly T2 hypointense (b) and shows signifi-
minimally into the pre-pontine cistern, where it abuts the cant diffusion restriction, both features implying a densely
basilar artery, involving the posteromedial aspects of both cellular tumor consistent with a nasopharyngeal carcinoma
sphenoid sinuses and extending in continuity with
concurrent chemoradiation, with or without respectively, for response assessment. Routine

altered fractionation. An overview of the manage- follow-up should occur 1–3 months in the first
ment is shown in Fig. 76. In cases of residual year, 2–6 months in second year, and 4–8 months
disease or recurrent cases, various modalities from 3 to 5 years with imaging every 6 months.
have been attempted in the salvage setting. Routine thyroid function test and speech and
These include salvage re-irradiation, nasophar- swallowing evaluation every 6 months have
yngectomy, salvage neck dissection, stereotactic been recommended. Plasma EBV DNA in
radiosurgery, and intracavitary brachytherapy. endemic patients can be used for surveillance
Traditionally 2D techniques were used and and has been recommended by the NCCN guide-
they are still used at present in certain centers lines (Adelstein et al. 2017).
around the world. Two-dimensional techniques
can be effectively used for early lesions. Shielding
of the brainstem areas and the spinal cord is done Tumors of the Nasal Cavity
to prevent toxicities. Three-dimensional confor- and Paranasal Sinuses (Skull Base
mal therapy (3DCRT) and IMRT are currently Tumors)
used and have improved dose homogeneity and
permit dose escalation to high-risk areas with less Etiology, Epidemiology, and Pathology
toxicities to normal adjacent structures. Brachy- Tumors of the nasal cavity and paranasal sinuses
therapy and stereotactic radiosurgery boost esca- generally referred to as skull base tumors consti-
lating doses to the primary site alone in early tute a heterogeneous group of tumors with varied
stages of NPC (Harrison 2014). characteristics. Management of these tumors is
The NCCN guidelines have recommended relatively challenging owing to the intricate anat-
repeat of the baseline imaging or PET/CECT omy and the presence of vital structures in the
after at least 8–12 weeks and 12 weeks, vicinity.
Nasopharyngeal
carcinoma
T1-2a T any N+ M1
T2b-4
Definitive Radiotherapy of 66-70 Radiotherapy ≥ 70 Gy with Cisplatin based Chemotherapy

Gy to Nasopharynx and elective RT concurrent Chemotherapy with
of 50 Gy to neck cisplatin 100mg/m2 q 3wks x 3
Intracavity brachytherapy boost if Adjuvant Chemotherapy with 3 Definitive Radiotherapy to

required cycles of cisplatin and 5-FU Nasopharynx if complete response.
Palliative radiotherapy if partial
response
Fig. 76 Overview of management of nasopharyngeal carcinoma
Tumors of the nose and paranasal sinuses vascular component and are essentially benign.
(PNS) encompass a wide spectrum of clinicopath- The vascular component ranges from capillaries
ologically distinct tumors (Table 16). Benign to compressed slit-like spaces to ecstatic capil-
sinonasal tumors are relatively common as com- laries. Biopsy is not usually indicated as the clin-
pared to their malignant counterparts. Benign ical and radiological profile is adequate for
tumors can be classified into soft tissue tumors diagnosis.
and fibro-osseous lesions. Sinonasal papillomas Fibrous dysplasias are slow-growing fibro-osse-
(also called Schneiderian papillomas) are benign ous lesions. They result from a defect in osteoblastic
epithelial neoplasms of the nose and PNS. They differentiation and maturation that leads to replace-
are divided into three pathological subtypes – ment of the bone by fibrous tissue of variable cel-
inverted, fungiform, and oncocytic papillomas. lularity and immature woven bone. They usually
Inverted papillomas are the most common. present at a young age. Clinically, fibro-osseous
These tumors are more commonly seen in males dysplasias are monostotic (80%) or polyostotic
usually in the fifth and sixth decades of life and (20%). Monostotic lesions affect both genders
mostly originate from the lateral nasal wall. They equally, but polyostotic lesions have a female pre-
are mostly unilateral (bilateral in 2–4% cases) and ponderance. Polyostotic fibrous dysplasia can be
present as a pink nontranslucent polypoidal mass associated with McCune-Albright syndrome; the
with a convoluted surface protruding from the additional clinical features being cafe-au-lait spots,
nasal cavity. Microscopically, they are character- endocrine anomalies, and precocious puberty.
ized by an endophytic growth pattern into the Malignant neoplasms of the nasal cavity and
underlying stroma but with an intact basement paranasal sinuses are relatively rare and constitute
membrane. Common differentials include nasal about 2–3% of upper aerodigestive tract cancers
polyps and mucoceles. (Ali et al. 1986; Osguthorpe 1994). Squamous cell
Juvenile angiofibromas (Fig. 77) are highly carcinoma is the most common subtype with a
vascular tumors occurring in young males usually male preponderance and a peak incidence in the
in the second decade of life (Neel et al. 1973; fifth and sixth decades of life although other age
Bremer et al. 1986). They originate in the region groups can be affected (Robin et al. 1979; Roush
of the sphenopalatine foramen and usually present 1979; Grau et al. 2001; Myers et al. 2002;
with profuse epistaxis. As the name suggests, Bhattacharyya 2003). Increased incidence of
these tumors are composed of a fibrous and SCC has been reported in nickel-refining workers
Table 16 Common tumors of the nasal cavity and paranasal sinus

Benign tumors Malignant tumors
Soft tissue tumors Epithelial
Schneiderian papillomas Squamous cell carcinoma
Inverted Adenocarcinoma
Fungiform Adenoid cystic carcinoma
Oncocyte Sinonasal undifferentiated carcinoma
Juvenile angiofibromas Mesenchymal
Lobular capillary hemangiomas Sarcomas (with notable exceptions)
Schwannomas Hemangiopericytoma
Meningiomas Neuroendocrine tumors
Esthesioneuroblastoma
Ewing sarcoma
Melanoma
Fibro-osseous lesions Hematolymphoid
Fibrous dysplasia Lymphoma
Ossifying fibroma Metastatic deposits from head, neck, kidney, lung, or breast primaries
Osteoma
associated with nasal and PNS SCC. Furthermore,

smoking has been found to be a multiplicative risk
factor for SCC in nickel-refining workers (Ander-
sen et al. 1996). Squamous cell cancers can occur
after radiation exposure to the PNS after a long
latent period. Thorotrast (thorium dioxide) is a
radiopaque contrast agent injected into the maxil-
lary sinus and was used in the past for imaging of
the maxillary sinus. The dye gets retained in the
maxillary sinus lifelong and decays into meso-
thorium which emits radioactivity which reaches
its peak in 15 years. Squamous cell carcinoma is
found to occur in patients who have undergone
thorotrast injection after a period of 10–21 years
(Wingo et al. 1998). Similarly SCC has been
found in patients in radium dial painting industry
after a long latent period of 30–40 years
(Holmstrom and Lund 1991; Wingo et al. 1998).
Fig. 77 Holman-Miller sign – anterior bowing of the It is assumed that radium gets absorbed from the
posterior maxillary sinus wall (red arrow) (pathognomonic oral mucosa in workers who used to lick the
of juvenile angiofibroma) paintbrushes during painting of the watch dials.
Inverted papillomas have a 5–26% chance of
with the risk directly proportional to the duration being associated with a SCC – either synchronous
of exposure and inversely proportional to the age or metachronous (Szabo 1954; Zak and Lawson
of exposure. Although smoking has traditionally 1974; Cove 1979; Hofbauer et al. 2002; Mannone
not been associated as a major risk factor for et al. 2004; Bradley 2006).
sinonasal SCC (Fig. 78), there is substantial evi- Adenocarcinomas and adenoid cystic carcino-
dence that heavy smoking and snuff use are mas are other epithelial malignancies arising in
Fig. 78 T2N2M0 sinonasal carcinoma. On CT there is a dorsum and nasal bridge. Inferiorly it extends virtually to
lobular irregular enhancing mass occupying most of the the philtrum, and there is erosion of the anterior nasal
dorsa of the external nose with sparing of the nasal tip (a) spine. Superiorly, it causes subtle erosion of both nasal
and extending into and partially destroying the anterior bones. The tumor is slightly bulkier on the right. There is
aspect of the nasal septum (b). The mass measures up to no evidence of extension to the anterior skull base. The
47 mm superoinferior 38 mm anteroposterior 22 mm posterosuperior margin of the tumor involves the septum
transverse. Anteriorly it extends into the skin over the nasal about 4 mm below the anterior cribriform plate
the nasal cavity and PNS. They tend to account for mucosa. No definite etiologic factor is identified
10–15% of the PNS malignancies in the United in its causation. It has a slight male preponderance
States and as high as 40% in Europe. This dispar- with bimodal peak at the second to third and the
ity is primarily because of widespread of hard- sixth to seventh decades of life. They occur most
wood in Europe exposure to which has been found commonly in the cribriform area and can spread
to be an etiology for adenocarcinoma early into the anterior cranial fossa through the
(Klintenberg et al. 1984; Hanna 2009). The olfactory fibers. Macroscopically, they present as
latency period from the exposure to the tumor a reddish gray polypoidal mass that bleeds easily.
development is long (about 40 years). The most Microscopically they present as “small round
common site for adenocarcinoma in the PNS is the cell tumors” with immunohistochemistry positive
ethmoids (Fig. 79). These tumors are pathologi- for general neuroendocrine tumors (NSE,
cally divided into intestinal and subtypes. The SNP, S100).
intestinal type resemble adenocarcinomas arising Skull base sarcomas are anatomically and his-
in the intestinal tract; the non-intestinal type has a tologically distinct neoplasms arising from the
predominant seromucinous appearance. mesenchymal tissue and constitute only 10% of
Adenoid cystic carcinomas constitute about sarcomas and 1% of head and neck tumors (Weber
10–15% of the PNS malignancies. The most com- et al. 1986; Kraus et al. 1994; Landis et al. 1999;
mon subsites are the maxillary sinus and the eth- Jemal et al. 2002). Although most of them share a
moids. Three histologic subtypes have been common embryonal origin, notable exceptions are
described – tubular, cribriform, and solid. The malignant peripheral nerve sheath tumors and
peak incidence is in the fifth and sixth decades Ewing sarcoma which arise from the neuroendo-
of life. No known etiologic factors are associated crine tissue. The skull base and the neck are the
with ACCs. commonest sites for head-neck sarcomas. Unlike
Esthesioneuroblastomas are malignant neuro- extremity sarcomas where distant metastasis is a
endocrine neoplasms arising from the olfactory major cause of death, skull base sarcomas are
prone to local recurrence involving vital structures melanomas. Macroscopically, these tumors are
(brain, internal carotid artery, cavernous sinus, brown to black polypoidal lesions that tend to
orbital apex) which is the leading cause of death ulcerate. Microscopically, they display morpho-
in these patients. logical diversity with undifferentiated small
Sinonasal mucosal melanomas are extremely round cell being most common. Melanin pig-
rare and account for 1% of all melanomas and ment is found in two-thirds of cases. These
0.6–4% of all tumors of the nasal cavity and the tumors are positive for vimentin, HMB 45,
PNS. They tend to occur in elderly individuals and S100.
(60–70 years) with a slight male preponderance.
In the head and neck, the nasal cavity is the most Clinical Presentation
common site (55–79%) followed by the oral cav- Presenting symptoms depend on the biologic
ity. The lateral nasal wall and the inferior turbi- behavior and the anatomical location of the
nate are most common sites for origin of tumor. Common symptoms of skull base tumors
are outlined in Table 17. Most patients initially
present with unilateral nasal obstruction. Recur-
rent profuse epistaxis especially in young adult
may be due to a juvenile angiofibroma, although
malignant tumors like esthesioneuroblastoma and
sarcomas cannot be ruled out. Anosmia as a pre-
senting symptom can be due to a pathology
located at the region of the cribriform plate; a
common etiology being esthesioneuroblastoma.
Tumors compressing or invading the orbit, the
optic nerve, or the cavernous sinus can result in
diplopia, proptosis, or loss of vision. Tumors
located in the anteromedial aspect of the maxilla
can infiltrate or obstruct the lacrimal duct causing
epiphora. Tumors of the maxilla with erosion of
the bone can result in facial swelling and asym-
metry. Involvement of the branches of the trigem-
inal nerve can result in facial numbness or pain.
Nasopharyngeal tumors or those involving the
nasopharynx can cause blockage of the
Eustachian tube resulting in conductive hearing
Fig. 79 Contrast-enhanced CT of paranasal sinuses axial
image showing a heterogeneously enhancing lesion (oval) loss. Malignant tumors can present with meta-
involving the ethmoids with erosion of the nasal septum static neck nodes, although not very common in
and medial wall of right orbit nasal and PNS cancers.
Table 17 Common Symptoms Signs

symptoms and signs of skull
Unilateral/bilateral nasal obstruction Nasal mass
base tumors
Epistaxis Cranial nerve deficit
Hyposmia/anosmia Proptosis
Diplopia Middle ear effusion
Vision loss Cervical adenopathy
Facial swelling
Hearing loss
Investigations
The goals of preoperative imaging are to study
the anatomical relationship of the lesion with the
normal structures and thus to map the extent of
the disease. Furthermore, imaging can provide an
insight to the differential diagnosis. Contrast-
enhanced CT scan and MRI are complementary
in imaging of the skull base. CT scan is the
modality of choice for evaluating bony structures,
skull base foramina, calcifications, and bony
reactions to the tumor. High-resolution images
with thin sections (<3 mm) with 1 mm overlap
scans are ideal for imaging of the skull base. MRI
on the other hand is the preferred modality for
soft tissue delineation. Unenhanced axial T1-W
images are used for anatomical relationships and
to detect highly cellular lesions (e.g., malignant
tumors). Water-rich tissues enhance on T2-W
Fig. 80 Axial T2 MRI image of paranasal sinuses show-
images, and these images are very important to ing tumor originating in the nasopharynx with extension
differentiate tumors from retained secretions into the nasal cavity with retained secretions in the left
(Figs. 80, 81, and 82) and post-therapy fibrosis. maxillary sinus (yellow arrow)
Gadolinium enhancement with fat suppression
(short tau inversion recovery, STIR) images is
ideal for evaluation of malignant lesions, as the
lesions become clearer with contrast and the mar-
gins better delineated due to fat suppression. MR
angiography has replaced conventional angiogra-
phy as it is noninvasive and nonionizing. MRI is
contraindicated in patients with cardiac pace-
makers and ferromagnetic intracranial aneurysm
clips. Table 18 depicts the salient radiological
findings of common skull base tumors.
Treatment
Benign tumors of the skull base are essentially
treated by surgery. The treatment of most malig-
nant tumors is a multimodality treatment approach
which includes surgery, radiotherapy, and chemo-
therapy. Excepting for hematolymphoid malig-
nancies, surgery plays a key role in the
management of skull base malignancies. The Fig. 81 Coronal T2 MRI image of paranasal sinuses
showing tumor in the right nasal cavity with retained
basic principles of surgery are gross total resection
secretions in the right maxillary sinus (yellow arrow)
and maximum preservation of function. Surgical
approaches to the skull base are either open or
endoscopic (Fig. 83). expertise available. The major advantages of
The choice of the surgical approach depends endoscopic approaches include direct access to
on multiple factors: the site of origin, the extent the tumor, no brain retraction and edema, lesser
and pathology of the tumor, and the surgical morbidity, and reduced hospital stay. However,
the concept of “en bloc” tumor resection is vio-

lated by the endoscopic approaches, and it
requires a steep learning curve. The indications
and contraindications of endoscopic approaches
are depicted in Table 19.
Although no randomized controlled trial has
been conducted comparing endoscopic and open
surgical approaches to the skull base, data from
different studies reveal similar oncologic results
with reduced morbidity in patients undergoing
endoscopic resection (Howard et al. 2006; Ganly
et al. 2011; Abergel et al. 2012; Meccariello et al.
2016). However, proper patient selection and sur-
gical expertise is a key to endoscopic approaches.
Endoscopic resection has several advantages
over open surgery which include better cosmesis,
better quality of life, less CSF leakage, less cranial
Fig. 82 Sagittal T2 MRI image of paranasal sinuses morbidity, and better illumination. Radiotherapy is
showing tumor occupying the entire nasal cavity and eth- usually used as an adjuvant to surgery. Definitive
moid sinuses with gross bone destruction and intracranial
extension with retained secretions in the sphenoid sinus radiation is usually not used for resectable skull
Table 18 Salient radiological findings of common skull base tumors

Tumor Salient radiologic findings
Inverted papilloma Located in the lateral nasal wall/medial wall of the maxillary sinus
Unilateral
Bone remodeling/erosion
Slight contrast enhancement
Calcifications
Juvenile angiofibroma Bright contrast enhancement
Erosion of the upper medial pterygoid plate (early sign)
Anterior bowing of the posterolateral wall of the maxilla (Holman-Miller sign)
(pathognomonic)
Meningioma Isointense on T1 and T2 images, marked post-contrast enhancement
“Dural tail” and “CSF cleft” signs on MRI
Meningocele, Hypointense on T1 and hyperintense on T2-W images
meningomyelocele CSF leak on cisternography
Squamous cell carcinoma Bone erosion
Post-contrast enhancement
Adenoid cystic carcinoma Nerve thickening with irregular enhancement (perineural invasion)
Widening of the skull base foramina
Esthesioneuroblastoma Origin near the cribriform area
Focal calcifications
Marked post-contrast enhancement
Bone destruction
Sarcoma Marked post-contrast enhancement “onion skin” appearance on CT - Ewing sarcoma
Chondroid matrix, ringlike calcifications – chondrosarcoma
Chordoma Origin at the region of the clivus
Intratumoral calcifications
Honeycomb appearance
Site and extent of tumor

pathology expertise
Subcranial Transcranial
Open procedures Endonasal Expanded endoscopic Endo assisted CFR Open CFR
endoscopic approach approach
Transfacial approaches Midfacial degloving
Fig. 83 Treatment algorithm for nasal and paranasal cancers
Table 19 Indications and contraindications for endoscopic approach to skull base tumors
Indications Contraindications
Tumor confined to the sinonasal cavity or with “limited” Extensive involvement of brain parenchyma
dural or brain involvement Involvement of dura lateral to mid pupillary line
Expertise for endoscopic resection Involvement of the anterior wall of the frontal sinus
Involvement of orbital contents
Skin involvement
Lacrimal apparatus involvement
Palatal involvement
base cancers for two reasons: poor oncologic out- requiring multimodality therapy, and chemother-
come as compared to surgery with adjuvant radia- apy has a role in their management, although the
tion and toxicities (Choussy et al. 2008). Serious optimal strategy is not yet determined. Tumor and
visual complications occur in 16–66% of patients patient characteristics need to be evaluated before
with conventional radiation. Unilateral blindness planning the optimal regimen of systemic therapy.
occurs in 20–35% of patients and bilateral blind-
ness in 6–10% of patients. Complications of skull
base radiation include blindness, diplopia, painful Thyroid Cancer
red eye, brain necrosis, meningitis, hearing loss,
memory loss, hypopituitarism, skin fistula, trismus, Epidemiology, Etiology, and Pathology
bone/cartilage necrosis, and saddle nose deformity. More than 95% of thyroid tumors are benign.
The most common cause of ipsilateral blindness is Thyroid carcinoma has an excellent prognosis
retinopathy and contralateral blindness is optic when detected early and treated appropriately
neuropathy. However, in unresectable tumors, (Howlader et al. 2016). Thyroid cancer represents
radiotherapy alone has been found to have a mod- 1% of all cancers and is the most common endo-
est local control (Jansen et al. 2000). crine malignancy (Reiners et al. 2004). It is the
The objectives of systemic therapy in skull fifth most common cancer among women in the
base cancers are to improve tumor control as United States. There has been a significant and
well as organ preservation. The role of chemo- steady increase in the incidence of thyroid cancers
therapy is well established in “small round cell in the last decade which is partly due to detection
tumors” which include Ewing sarcoma, rhabdo- bias in developed countries, particularly South
myosarcoma, and hematolymphoid malignancies. Korea. Thyroid malignancies encompass a wide
Sinonasal undifferentiated carcinoma and neuro- spectrum of diseases ranging from well-
endocrine carcinoma are aggressive tumors differentiated thyroid cancers with excellent
prognosis at one extreme to anaplastic thyroid use is ceased (La Vecchia et al. 1999). Genetic
cancers carrying an equally dismal prognosis at causes for thyroid cancers are well known for med-
the other (Cabanillas et al. 2016) (Table 20). ullary thyroid carcinoma (MTC) with 25% of them
Ionizing radiation has long been noted as an being associated with MEN2 syndromes (Fig. 84
etiological factor for thyroid cancer. Its association and Table 21). Five to ten percent of papillary
was first described in the 1950s. Subclinical doses thyroid cancers also have a known genetic predi-
of radiotherapy have shown a dose-response rela- lection and are also associated with syndromes like
tionship particularly when exposed during young familial adenomatous polyposis (FAP), Gardner’s
age. Historical treatments of pediatric diseases like syndrome, Cowden syndrome, and Carney com-
acne, impetigo, sinusitis, adenoid enlargements, plex (Richards 2010).
keloids, and lymphomas with radiotherapy were
associated with increased incidence of thyroid can- Clinical Presentation
cers in adulthood. The risk ratio (RR) in such The thyroid gland is an endocrine gland located in
individuals ranges from 4.6 to 14.6 times and has the anterior aspect of the neck. It consists of two
a dose-dependent increase in risk till 20 Gy (Favus lobes connected by a thin isthmus which lies over
et al. 1976). Risk of environmental exposure of the second to fourth tracheal rings (Harrison 2014).
radiation after the Chernobyl nuclear disaster of In about 50–75% of patients, an additional pyrami-
1986 resulted in a significant increase in incidence dal lobe is present usually on the left side which is a
of thyroid malignancy among individuals who remnant of the thyroglossal duct. The term “goiter”
were either fetuses or children till the age of 15 at is used to describe any enlargement of the thyroid
the time of the radiation exposure. Geographic gland (Figs. 85 and 86). The enlargement can pre-
areas with high background radiation hold sent either in the form of a solitary nodule (50%),
increased risk of thyroid carcinoma (Baverstock multiple nodules, or smooth or diffuse enlargement
et al. 1992). Thyroid cancer is more common (Reiners et al. 2004). Endemic goiter is the most
among females, and hence multiple studies have common form and is defined when it is prevalent in
been carried out to investigate the association of 10% of the population in a particular geographic
female reproductive history and thyroid cancer; area or community.
however, no conclusive trends have been found
(Negri et al. 1999). The relationship between oral Investigations
contraceptive use and thyroid cancer has also Thyroid function tests (TFT) are the initial inves-
yielded variable results. Pooled analysis suggests tigation for evaluation of a thyroid nodule. Most
oral contraceptives to be a promoter of thyroid thyroid cancers are euthyroid at presentation. An
cancer; however, the risk is eliminated once its elevated or normal thyroid-stimulating hormone
Table 20 Classification of thyroid malignancies

Neuroendocrine C-cell-derived
Follicular cell-derived thyroid cancer thyroid cancer
Differentiated thyroid cancer Anaplastic thyroid cancer Medullary thyroid carcinoma
Papillary carcinoma Rare approx. 1% of thyroid 1–2% of thyroid malignancies
Most common (85%) malignancies
Follicular carcinoma Rapidly growing and aggressive MEN 2 syndrome, RET proto-
oncogene mutation
Have higher risk of hematogenous Patients with hereditary mutations to
metastasis undergo prophylactic thyroidectomies
Hurthle cell carcinoma Early compressive symptoms like
hoarseness, dyspnea, and dysphagia
Poorly differentiated thyroid cancer Poor prognosis
Poorer prognosis when compared to
other differentiated thyroid cancers
Fig. 84 MEN syndromes

MTC
and medullary thyroid
cancers
GENETIC SPORADIC
(25%) (75%)
MEN 2A MEN 2B FMTC

(85%) (5%) (15%)
Table 21 Multiple endocrine neoplasia syndrome

Inheritance
Syndrome pattern Clinical findings Genetics Remarks
MEN 2A Autosomal MTC (100%) Most commonly mutation Age of onset –
(85%) dominant Pheochromocytoma (50%) in codon 634 of exon 10 or second to third
11 decade
Hyperparathyroidism (10–20%) Other mutations are in
Cutaneous lichen amyloidosis codons 609, 611, 618, 620,
Hirchprung disease and 630
MEN 2B Autosomal MTC (100%) Most commonly mutation Age of onset –
(5%) dominant in codons 918 and 883 first to second
decade
Pheochromocytoma (50%) Most aggressive
Marfanoid habitus (>95%) form of the
Mucosal neuromas (>95%) disease
Familial Autosomal Four or more members of a Common mutations are Age of onset –
MTC dominant kindred without other endocrine 768, 790, 791, 804, and 891 fourth to fifth
(FMTC) tumors decade
(15%) Mildest form of
the disease
(TSH) harbors increased risk of malignancy, and (a) Suspected retrosternal extension of the thyroid
further investigations are directed toward the nodule (clinically lower limit of the nodule is
diagnosis of malignancy. Conversely, chances of not felt above the thoracic inlet) (Fig. 90)
malignancy are low if TSH is subnormal, and (b) Suspected infiltration into adjacent structures
further investigations are directed toward diagno- like the trachea and esophagus (history of
sis of a toxic nodule (Fig. 87). Ultrasound is hoarseness of voice, aspiration, dyspnea and
complementary to TFT in the diagnosis of thyroid dysphagia, clinical finding of vocal cord
malignancies. paralysis) (Figs. 91 and 92)
High-resolution ultrasound of the thyroid and (c) Metastatic nodes at lower neck (level VI, IV,
the neck (7.5–12 MHz) is the next step in the or V) which harbors high chance of mediasti-
work-up of a thyroid nodule. Ultrasound features nal adenopathy (Fig. 93)
suggestive of malignancy are depicted in
Table 22 (Figs. 88 and 89). Although ultrasound There has been a concern that contrast would
is a simple, cost-effective, widely available, non- interfere with postsurgery radioactive iodine
ionizing, and recommended diagnostic tool for (RAI) therapy making it less effective; however,
evaluation of thyroid nodule, a contrast- RAI therapy is usually performed at least
enhanced CT scan of the neck and thorax is 4–6 weeks after surgery, and the contrast agent
indicated in certain situations. These include: used for preoperative scanning is eliminated from
Work-up of a thyroid nodule with FNAC

reported as medullary thyroid carcinoma includes
serum calcitonin, urinary or plasma meta-
nephrines, serum calcium, RET mutation analy-
sis, locoregional and distant imaging, and
assessment of vocal cord mobility. Staging of
thyroid cancer is outlined in Table 25.
Treatment
The management of patients with thyroid nodules
is guided by thyroid function test, imaging, and
FNAC. The goals of treatment are to:
(a) Improve overall and disease-specific survival.

(b) Reduce the risk of persistent/recurrent/meta-
static disease.
(c) Minimize the risk of treatment-related
morbidity.
Surgery plays the major role in the manage-

ment of thyroid malignancies. Adjuvant radio-
iodine treatment and radiotherapy are indicated
Fig. 85 Benign thyroid nodule of the neck in a female
patient (black dashed oval) histopathologically confirmed
in high-risk patients.
as colloid nodular goiter (Image courtesy of Dr Chady The Bethesda reporting system provides a uni-
Sader, Western ENT, Perth WA, Australia) form baseline for treatment of thyroid nodules.
Bethesda I
the body by that time. PET/CT is usually not used An US-guided FNAC is preferred and, if
in the preoperative work-up of thyroid cancers available, on-site cytologic evaluation is done.
(Harrison 2014). Repeatedly nondiagnostic nodules without a
Fine needle aspiration cytology (FNAC) is used high-suspicion sonographic pattern require close
to investigate thyroid nodules. Ultrasound-guided observation or surgical excision for histopatho-
FNAC improves the diagnostic yield and accuracy logic diagnosis. Diagnostic surgery should be
but may not be routinely performed due to logistic considered if there is high suspicion on US fea-
purposes. Ultrasound guidance is recommended to tures, growth of the nodule (>20% in two dimen-
target the solid portion in a solid-cystic nodule, sions) is detected during US surveillance, or
when nodules are located in the posterior aspect clinical risk factors for malignancy are present.
of the thyroid, in case of multinodular goiter to
target the most suspicious nodule(s), for repeating Bethesda II
nondiagnostic cytology on blind FNAC, and when No further diagnostic or therapeutic intervention
non-palpable nodules are picked up on other imag- is required. Dietary iodine supplementation can be
ing. The indications of FNAC in a thyroid nodule given in patients from iodine-deficient areas.
based on sonographic features have been outlined There is no role of TSH suppression therapy in
in the American Thyroid Association (ATA) 2015 these patients.
guidelines (Table 23) (Haugen et al. 2016). In order
to maintain uniformity in the reporting of thyroid Bethesda III
FNAC, the Bethesda system is used (Table 24) Repeat FNA or molecular testing may be used to
(Crippa et al. 2010). supplement malignancy risk assessment. If repeat
Fig. 86 Large thyroid nodule in male patient (a), exposed (Images courtesy of Dr Chady Sader, Western ENT, Perth
during surgery (b), and final macroscopic specimen (c) WA, Australia)
confirmed histopathologically as benign nodular goiter
FNA cytology, molecular testing, or both are not consideration of clinical and sonographic fea-
performed or inconclusive, either surveillance or tures, molecular testing may be used to supple-
diagnostic surgical excision (hemithyroidectomy) ment malignancy risk assessment data, although
may be performed based on clinical risk assess- there is no robust evidence for molecular testing
ment, sonographic features, and patient as an alternative to diagnostic hemithyroidectomy
preference. in Bethesda IV lesions. The protocol for manage-
ment of Bethesda IV tumors is depicted in Fig. 94.
Bethesda IV
Follicular neoplasm encompasses three types Bethesda V and VI
of histology: follicular adenoma, follicular
carcinoma, and follicular variant of papillary car- Treatment of Differentiated Thyroid Cancer
cinoma. Diagnostic surgical excision is the long- The mainstay of treatment of thyroid cancers is
established standard of care for the management surgery (Haugen et al. 2016). The extent of sur-
of follicular neoplasm. However, after gery (hemi- or total thyroidectomy) has been a
Fig 87 Initial work-up of a Serum TSH measurement

thyroid nodule
TSH subnormal TSH normal/high
RAI scan Increased risk of

malignancy
Hot nodule Cold nodule

Ultrasound neck
FNAC
No cytological
evaluation required
Table 22 Ultrasound features suggestive of malignancy in a thyroid nodule

Solid nodules
Microcalcifications
Hypoechogenicity
Irregular (infiltrative) margins
Taller than wider shape
Extracapsular extension
Suspicious metastatic neck nodes
Fig. 88 Ultrasound of
thyroid nodule
demonstrating intrinsic
vascularity suspicious for
thyroid carcinoma (Image
courtesy of Dr Chady Sader,
Western ENT, Perth WA,
Australia)
matter of considerable discussion and evolution (Fig. 96). Intrathyroid unifocal <1 cm tumors
over the years. The indications of total and without any nodal or distant metastasis and no
hemithyroidectomy for differentiated thyroid family history of thyroid cancer or history of radi-
cancers are depicted in Fig. 95. Tumors >4 cm, ation exposure are indications for hemithyr-
those with extrathyroid extension, and metastatic oidectomy. Tumors between these two extremes
(nodal or distant) disease at presentation are can be managed either with total or hemithyr-
absolute indications for total thyroidectomy oidectomy; the decision of which needs to be
Fig. 89 Papillary thyroid carcinoma. Left thyroid nodule (Images courtesy of Dr Chady Sader, Western ENT, Perth
with microcalcifications (a) and FNA of a partially cystic WA, Australia)
left neck node with metastatic lymphadenopathy (b)
Fig. 90 Contrast-enhanced
CT axial section showing
retrosternal extension of
thyroid tumor
taken unanimously by the physician and the hemithyroidectomy is very similar to total thyroid-
patient. Based on retrospective studies, total ectomy in properly selected patients. Furthermore,
thyroidectomy improves survival and decreases follow-up regimen has moved away from diagnos-
recurrence rates as compared to hemithyr- tic RAI scanning to serial ultrasound and detection
oidectomy. It also allows routine use of RAI of changing Tg levels. Most physicians are
remnant ablation and facilitates detection of adopting a conservative approach to the relatively
remnant or persistent disease during follow-up. indolent cancer, and there is a shifting paradigm
The major drawback of total thyroidectomy is from total to hemithyroidectomy. However, careful
the need for lifelong exogenous thyroid patient selection is the key factor in the decision-
hormone therapy. The clinical outcome of making.
Fig 91 Axial contrast-

enhanced CT image of a
thyroid tumor of the left
lobe with extrathyroidal
extension and loss of fat
plane with the strap
muscles, trachea, and
carotid artery
Fig. 92 Papillary carcinoma in a thyroglossal duct cyst. strap muscles with mural solid nodule containing
Ultrasound of mass in the superior midline of the anterior microcalcifications (yellow arrows) (b). (Images
neck showing cystic lesion with solid nodule containing courtesy of Dr Chady Sader, Western ENT, Perth WA,
microcalcifications (red arrow) (a). CT sagittal recon- Australia)
struction shows midline anterior neck cyst elevating
The central compartment of the neck (levels VI compartment nodes. Care should be taken to pre-
and VII) is the first echelon nodal station from vent injury to the parathyroids and their blood
thyroid cancers. Therapeutic central compartment supply and the recurrent laryngeal nerves during
clearance is indicated in clinical or radiological central compartment clearance. If there is
evidence of metastatic nodes in central compart- devascularization injury to the parathyroids, auto-
ment. Prophylactic central compartment clearance transplantation should be considered. Lateral
is indicated in T3 or T4 primary tumors with N0 compartment nodal dissection (levels II–V) is
neck or in presence of metastatic lateral indicated in cases of metastatic lateral
Fig. 93 Papillary thyroid carcinoma in a 21-year-old specimen (c), and surgical bed demonstrating the trachea,
female. CT shows a large left thyroid mass biopsied and both laryngeal nerves and right common carotid (d).
shown to be papillary carcinoma (a). This is associated (Images courtesy of Dr Chady Sader, Western ENT, Perth
with extensive left level II, III, and IV adenopathy on the WA, Australia)
left (b). Total thyroidectomy and central neck dissection
compartment nodes, in metastatic central com- Treatment of Medullary Thyroid Cancer

partment nodes, or in tumors located in the region Treatment of choice of medullary thyroid cancer
of the upper pole of the thyroid gland. (MTC) is surgery. There is no role for RAI in the
Postsurgery patients of differentiated thyroid management of MTC. Tumors 1 cm in size or
cancer are stratified into low, intermediate, and with bilateral thyroid disease are treated with total
high risk based on clinical and histopathological thyroidectomy with bilateral central compartment
criteria (Table 26). Based on these criteria, the clearance. Tumors <1 cm can be treated with total
need and extent of adjuvant treatment are planned. thyroidectomy, but central compartment clearance
The details of adjuvant RAI treatment are depicted should preferably be considered. The role of adju-
in Figs. 97, 98, 99, and 100. vant radiation is not clear (Harrison 2014)
Table 23 Indications of fine needle aspiration cytology in a thyroid nodule (ATA guidelines 2015) (Haugen et al. 2016)
Level of Risk of
suspicion on malignancy Recommendation
ultrasonography Ultrasound features in percentage by the ATA
High suspicion Solid hypoechoic nodule or solid hypoechoic >70–90 FNA at 1 cm
component of a partially cystic nodule with one or more
of the following features: irregular margins (infiltrative,
microlobulated), microcalcifications, taller than wide
shape, rim calcifications with small extrusive soft tissue
component, and evidence of ETE
Intermediate Hypoechoic solid nodule with smooth margins without 10–20 FNA at 1 cm
suspicion microcalcifications and ETE or taller than wide shape
Low suspicion Isoechoic or hyperechoic solid nodule or partially 5–10 FNA at 1.5 cm
cystic nodule with eccentric solid areas, without
microcalcification, irregular margin or ETE, or taller
than wide shape
Very low Spongiform or partially cystic nodules without any of <3 To consider FNA at
suspicion the sonographic features described in low- 2 cm/observation
intermediate-, or high-suspicion patterns
Benign Purely cystic nodules (no solid component) <1 FNA not indicated
Table 24 Bethesda system of reporting of thyroid fine needle aspiration cytology (Crippa et al. 2010)
Bethesda Estimated risk of
system Diagnostic category malignancy (%)
I Nondiagnostic/unsatisfactory 1–4
II Benign 0–3
III Atypia of undetermined significance/follicular lesion of 5–15
undetermined significance
IV Follicular neoplasm or suspicious for follicular neoplasm 15–30
V Suspicious of malignancy 60–75
VI Malignancy 97–99
although it is recommended for tumors with extra- risk (Durante et al. 2013; Haugen et al. 2016).
thyroid extension (T4 tumors), gross residual dis- Patients are re-risk stratified as low, intermediate,
ease where attempts of surgical re-excision have and high based on the criteria depicted in patients,
been ruled out, and in metastatic nodes with extra- and further treatment is planned as required. The
capsular spread (Adelstein et al. 2017). Prophy- follow-up protocol for MTC relies on calcitonin
lactic thyroidectomy is carried out in patients with levels carried out 2–3 months postsurgery. MTC
MEN syndrome as depicted in Figs. 101 and 102. patients are started on thyroxine supplementation
Differentiated thyroid carcinomas have a good immediately after surgery.
overall survival upward of 90% (Society 2015).
The 5-year survival and 10-year survival for both
papillary and follicular carcinomas are approxima- Malignant Soft Tissue Tumors
tely equal at almost 90% for age group <45 years. of the Head and Neck
Above 45 years of age with increasing age, there is
a significant decrease in the overall survival seen up Malignant neoplasms of the soft tissues display a
to 50% in the group of 60–69 years at 10 years. diverse array of lesions and a wide spectrum of
Follow-up is usually done every 6 months with clinical activity ranging from relatively slow-
serum thyroglobulin, US, RAI scan, and thyroid growing lesions to aggressive local and regionally
function test with TSH suppression in cases of high destructive lesions with the potential for systemic
Table 25 Staging of thyroid cancer. TNM clinical classification and staging of thyroid malignant tumors (Adapted from
Brierley et al. 2017)
Primary tumor (T)a
T1 Tumor 2 cm or less in greatest dimension, limited to the thyroid
T1a Tumor 1 cm or less in greatest dimension, limited to the thyroid
T1b Tumor more than 1 cm but not more than 2 cm in greatest dimension, limited to the thyroid
T2 Tumor more than 2 cm but not more than 4 cm in greatest dimension, limited to the thyroid
T3 Tumor more than 4 cm in greatest dimension, limited to the thyroid or with gross extrathyroidal extension
invading only strap muscles (sternohyoid, sternothyroid, or omohyoid muscles)
T3a Tumor more than 4 cm in greatest dimension, limited to the thyroid
T3b Tumor of any size with gross extrathyroidal extension invading strap muscles (sternohyoid, sternothyroid, or
omohyoid muscles)
T4a Tumor extends beyond the thyroid capsule and invades any of the following: subcutaneous soft tissues, larynx,
trachea, esophagus, and recurrent laryngeal nerve
T4b Tumor invades prevertebral fascia and mediastinal vessels or encases the carotid artery
N1 Regional lymph node metastasis
N1a Metastasis in level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph nodes) or upper/superior
mediastinum
N1b Metastasis in other unilateral, bilateral, or contralateral cervical (levels I, II, III, IV, and V) or retropharyngeal
Stagingb
Papillary and follicularc under 55 years
I Any T Any N M0
II Any T Any N M1
Papillary and follicular 55 years and older
I T1a, T1b, T2 N0 M0
II T3 N0 M0
T1, T2, T3 N1 M0
III T4a Any N M0
IVA T4b Any N M0
IVB Any T Any N M1
Medullary
I T1a, T1b N0 M0
II T2, T3 N0 M0
III T1, T2, T3 N1a M0
IVA T1, T2, T3 N1b M0
T4a Any N M0
IVB T4b Any N M0
IVC Any T Any N M1
Anaplastic
IVA T1, T2, T3a N0 M0
(continued)
IVB T1, T2, T3a N1 M0
T3b, T4a, T4b N0, N1 M0
IVC Any T Any N M1
a
Including papillary, follicular, poorly differentiated, Hurthle cell, and anaplastic carcinomas
b
Separate stage groupings are recommended for papillary and follicular (differentiated), medullary, and anaplastic
(undifferentiated) carcinomas
c
Including papillary, follicular, poorly differentiated, Hurthle cell carcinoma
Bethesda IV – follicular neoplasm
Diagnostic hemithyroidectomy
Frozen section of specimen Frozen section of any clinically

suspicious node
Follicular variant of Papillary Follicular neoplasm

Carcinoma
Treat based on clinico- Final histopathology

pathological risk assessment
Follicular adenoma Follicular carcinoma
Observe Treat based on clinico-

pathological risk assessment
Fig. 94 Management protocol for follicular neoplasm
metastasis (Pellitteri et al. 2003). Sarcomas of the Since they can possibly initiate at any part of the
head and neck most commonly present as painless body, it is also important to investigate if lesions
submucosal or subcutaneous masses of uncertain of the head and neck region are in fact primary
duration. tumors or metastatic ones. Occurrence in the head
The success of treating these lesions has a strong and neck is rare, accounting for less than 1% of all
correlation between how early and how quickly the malignant tumors in this site. These lesions may
diagnosis is made. The resemblance between some attain a great size before symptoms occur and are
of these lesions is not restricted to their clinical often noted on routine dental, head, neck, or pha-
behavior, most of which have microscopic features ryngeal examination.
that make immunohistochemical investigation Sarcoma growth and local advancement employ
essential for conclusive diagnosis. Before molecu- a compressive mechanism, whereby tissue adjacent
lar investigations, these lesions were collectively to the tumor together with a local inflammatory
known as sarcomas, not otherwise specified. response contributes to the formation of a pseudo-
Most of these lesions are independent new capsule composed of normal tissue and both
neoplasms, but 10–20% have a history of malig- inflammatory and malignant neoplastic cells.
nant transformation from a benign counterpart. Despite the advances in oncology, the treatment
Fig. 95 Extent of surgery Total thyroidectomy Hemithyroidectomy

in differentiated thyroid
cancers
Unifocal tumor <1cm

Tumor >4cm Tumor 1-4 cms Intrathyroid tumor
Gross extrathyroid extension Microscopic ETE No nodal/distant metastases
Metastatic – nodal or distant Aggressive histology No past h/o RT
No family history
Fig. 96 Papillary thyroid carcinoma surgery in a 19-year- shows the sternomastoid (white arrow) and omohyoid
old female. Intraoperative photo (a) shows the appearance (black arrow) muscles as well as the internal jugular vein
after thyroidectomy illustrating the trachea (peanut swab), (red arrow). Appearance of postoperative wound (c)
the left recurrent laryngeal nerve (green arrow), and the (Images courtesy of Dr Chady Sader, Western ENT, Perth
superior left parathyroid gland (yellow arrow). WA, Australia)
Intraoperative view at completion of neck dissection (b)
Table 26 ATA risk stratification system with proposed modifications according to ATA guidelines 2015 (Haugen et al.
2016)
ATA low risk Papillary thyroid cancer (with all of the following):
No local or distant metastases
All macroscopic tumor has been resected
No tumor invasion of locoregional tissues or structures
The tumor does not have aggressive histology (e.g., tall cell, hobnail, variant, columnar cell
carcinoma)
If 131I is given, there are no RAI-avid metastatic foci outside the thyroid bed on the first
posttreatment whole-body RAI scan
No vascular invasion
Clinical N0 or 5 pathologic N1 micrometastases (<0.2 cm in largest dimension)a
Intrathyroidal, encapsulated follicular variant of papillary thyroid cancera
Intrathyroidal, well-differentiated follicular thyroid cancer with capsular invasion and no or
minimal (<4 foci) vascular invasiona
Intrathyroidal, papillary microcarcinoma, unifocal or multifocal, including BRAFV600E
mutated (if known)a
ATA intermediate Microscopic invasion of tumor into the perithyroidal soft tissues
risk RAI-avid metastatic foci in the neck on the first posttreatment whole-body RAI scan
Aggressive histology (e.g., tall cell, hobnail, variant, columnar cell carcinoma)
Papillary thyroid cancer with vascular invasion
Clinical N1 or >5 pathologic N1 with all involved lymph nodes <3 cm in largest dimensiona
Multifocal papillary microcarcinoma with ETE and BRAFV600E mutated (if known)a
ATA high risk Macroscopic invasion of tumor into the perithyroidal soft tissues (gross ETE)
Incomplete tumor section
Distant metastases
Postoperative serum thyroglobulin suggestive of distant metastases
Pathologic N1 with any metastatic lymph node 3 cm in the largest dimensiona
Follicular thyroid cancer with extensive vascular invasion (>4 foci of vascular invasion)a
a
Proposed modifications, not present in the original 2009 initial risk stratification system
Fig. 97 Postsurgery Initial Management of Low Risk Patients

management of low-risk
patients treated with total
Initial Therapy
thyroidectomy
(if total thyroidectomy)
Follow up in 6 months with s. Tg and USG neck

RAI diagnostic scan/ remnant ablation not recommended
Initial TSH goal
If non stimulated Tg is <0.2 ng/ml, maintain TSH between

0.5-2 mU/L
If non stimulated Tg is ≥0.2 ng/ml, maintain TSH between
0.1-0.5 mU/L
Response evaluation and re risk stratification

Initial Management of Low Risk Patients Initial Management of High Risk Patients
Initial therapy Initial therapy

(if hemithyroidectomy) Total thyroidectomy +/-neck dissection
Follow up with s.Tgand RAI diagnostic scan

USG may be considered along with RAI scan
Follow up in 6 months with s. Tgand USG neck
Remnant RAI ablation not recommended
RAI remnant ablation
For adjuvant therapy up to 150 mCirecommended
For known structural disease, empiric dose of 100-200 mCi
Maintain TSH between 0.5-2 mU/L recommended (lower in elderly) / dosimetry guided dosage
Maintain TSH < 0.1 mU/L


Fig. 98 Postsurgery management of low-risk patients
treated with hemithyroidectomy
Fig. 100 Postsurgery management of high-risk patients
Initial Management of Intermediate Risk Patients

unfavorably impacting both local control and sur-
Initial therapy vival. The rapidity of growth is variable
Total thyroidectomy +/-neck dissection depending on the biologic behavior and grade of
the tumor. Symptoms attributable to growth vary
Follow up with s. Tgand RAI diagnostic scan according to location; those involving the
USG may be considered along RAI scan aerodigestive tract generally become symptom-
atic earlier in the course of disease as compared
RAI remnant ablation with tumors involving the neck.
30mCi for remnant thyroid ablation Tumor grade significantly impacts the biologic
For adjuvant therapy up to 150 mCi recommended
(non metastatic) and clinical behavior of sarcomas and has impli-
cations with respect to treatment, control, and
long-term survival. Metastatic potential is higher
Maintain TSH at 0.1-0.5 mU/L
in higher-grade sarcomas. Lymph node metastasis
occurs rarely and almost exclusively in high-
Responsive evaluation and re risk stratification grade tumors. Distant metastases occur early
with high-grade sarcomas, but unfortunately
Fig. 99 Postsurgery management of intermediate-risk
even low-grade tumors can metastasize.
patients
of these lesions consists of en bloc resection with Fibrosarcoma

normal tissue removal a considerable distance
away from the identifiable tumor. This is due to Epidemiology, Etiology, and Pathology
the extension of the tumor along anatomic planes Fibrosarcoma is a malignant neoplasm of mesen-
formed by the fascia, muscle, and bone. chymal origin, with possible occurrence in the
Surgical treatment of these lesions is therefore head and neck region (Fig. 103). Before the era
frequently devastating, making the treatment itself of immunohistochemistry, fibrosarcoma was a
just as harmful as the neoplasm itself. Size very frequent diagnosis and represented one of
as related to the involvement of critical the most common types of soft tissue sarcoma.
neurovascular structures, thus limiting en bloc With the development of immunohistochemical
resection, has obvious implications for and molecular techniques, it is now rare for a
Prophylactic
thyroidectomy before
5 yrs of age
Level VI and lateral ND
depending on
suspicious nodes
Codon 634 mutation
Pheo screening by 8 yrs
No nodes
s. Ct if ≥ 3 yrs All thyroid nodules
MEN 2A/
USG neck if <5mm
FMTC
age > 3-5 yrs s. Calcitonin <40pg/ml
Other mutations Pheo
screening by 20 yrs
Thyroidectomy may be
delayed beyond
5 yrs of age
Annual neck USG and
s. Calcitonin to be done
Fig. 101 Prophylactic thyroidectomy in MEN 2A/FMTC patients
Total thyroidectomy
Age 0-1 yr old Level VV dissection if suspicious
Lateral neck dissection if suspicious
s. Calcitonin if age >6 months No nodes

Skilled neck USG in all pts All thyroid nodules
MEN 2B
Pheo screening by the <5mm
age of 8 yrs s. Calcitonin <40pg/ ml
Total thyroidectomy
Age >1 yr old To consider prophylactic level VI
dissection
Lateral neck dissection if suspicious
Fig. 102 Prophylactic thyroidectomy in MEN 2B patients
sarcoma to be termed fibrosarcoma, which by its characterized by a high local recurrence rate
name implies fibroblasts as the cell of origin. and a low incidence of locoregional lymph
Fibrosarcoma can arise in soft tissues or node and/or distant hematogenous metastases.
within the bone. Intraosseous fibrosarcomas However, hematogenous metastasis may involve
may develop endosteally or possibly peri- the lungs, mediastinum, abdominal cavity,
osteally, the latter affecting the bone by spread and bone.
from adjacent soft tissue. The mean age for Fibrosarcoma of the oral cavity most
occurrence of fibrosarcoma is between the sec- often manifests as a clinically innocuous,
ond and sixth decades with equal gender lobulated, sessile, painless, and nonhemorrhagic
distribution. submucosal mass of normal coloration. On
the other hand, aggressive fibrosarcomas
Clinical Features tend to be a rapidly enlarging (Fig. 103),
Clinically, the lesion can cause pain, swelling, hemorrhagic mass similar in clinical appearance
paresthesia, and occasionally loss of teeth to an ulcerated angiogranuloma, peripheral
and ulceration of the overlying mucosa. giant cell granuloma, or peripheral ossifying
The clinical behavior of fibrosarcoma is fibroma.
Investigations tissue. MRI, especially with gadolinium contrast,

Before therapy, the local extent of the neoplasm may be used as a supplement or alternative to CT
and the presence or absence of local and distant scanning. It has a distinct soft tissue advantage
metastases must be determined. Evaluation con- and is superior in delineating vascular involve-
tinues with directed imaging to determine the ment, especially with magnetic resonance angiog-
extent of tumor and involvement of critical raphy (MRA). CT offers an improved evaluation
adjacent structures which may influence biopsy for bony structure involvement of the paranasal
technique. Metastatic surveys should include sinuses, orbit, and cranial base. Formal cranial
chest radiography, scintigraphic bone scanning, angiography may be necessary to eliminate the
and abdominal ultrasound and/or computed possibility of carotid or vertebral artery involve-
tomography. ment and for the assessment of the feasibility of
Either CT or MRI represent forms of imaging performing angioinvasive techniques such as
which may be used individually or in combina- embolization and selective intra-arterial chemo-
tion. Contrast-enhanced head and neck CT has therapy. Positron-emission tomography (PET) is
proven to be a valuable tool for delineating the of value in the staging of malignancy to determine
size of the tumor and infiltration of neighboring distant disease.
Fig. 103 Fibrosarcoma. CT of large soft tissue mass and high magnification (d) of the lesion characterized by
extending from the floor of the mouth, affecting the right fusiform cells with nuclear atypia, numerous atypical
side of the tongue, altering the air spaces, and invading the mitotic figures forming whorls, in a storiform pattern
right mandibular bone (a) causing irregular osteolytic (Hematoxylin and eosin stain)
destruction affecting dental support (b). Intermediate (c)
The histological appearance of high-grade phenotype (2017). According to its grading and
fibrosarcoma may be similar to other tumors, differentiation, the neoplastic cells show variable
such as malignant fibrous histiocytoma, capability of lipid storage, generally assuming a
liposarcoma, or synovial sarcoma (Fig. 103). multivacuolated form. Factors considered to be
Fibrosarcoma can be graded as low- or high- important in the etiology of liposarcoma include
grade malignancy. Low-grade fibrosarcoma genetics, trauma, and irradiation.
shows spindle cells arranged in fascicles with Three biologic categories of liposarcomas are
low to moderate cellularity with a herringbone distinguished: well-differentiated/dedifferentiated,
appearance. There is a mild degree of nuclear myxoid, and pleomorphic. The most common
pleomorphism and rare mitosis, with a collage- type is the well-differentiated/dedifferentiated
nous stroma. High-grade lesions show intense type, and the most affected sites in the head and
nuclear pleomorphism, greater cellularity, and neck region are the pharynx, mouth (usually
atypical mitosis. The nuclei can be spindle related to the tongue), larynx, and neck.
shaped, oval, or round. Positive immunostaining Liposarcoma of the head and neck region rep-
for vimentin, together with negativity for muscu- resents approximately 1% of head and neck sar-
lar immune markers, helps to diagnose fibrosarcomas. Although considered a rare tumor of the
coma (Soares et al. 2006). head and neck region, liposarcomas usually affect
older males, ranging from 40 to 60 years of age
Treatment (Golledge et al. 1995).
Wide local excision remains the treatment of
choice, with at least 1 cm of margin confirmed Clinical Features
by histopathologic clearance. Unfortunately, it is Despite its malignant nature, the tumor has a slow
often difficult to achieve complete resection of the growth pattern, as a painless submucosal fatty-
tumor, and high recurrence rates have been fibrous texture that can sometimes ulcerate.
observed with surgery alone. Depending on the location of the tumor, other
Radiotherapy is mandatory when adequate symptoms can also be noted such as airway
safety margins cannot be obtained and salvage obstruction or dysphagia.
surgery is not possible. On the other hand, there
is a significant number of radiotherapy-induced Investigations
sarcomas of the head and neck region. The microscopic appearance of the most common
Adjuvant chemotherapy for sarcomas has been type of liposarcoma is characterized by adipocytes
applied in tumors of the trunk and extremities, as of variable size, with hyperchromatic and enlarged
well as in the head and neck. Although some nuclei. The surrounding fibrous tissue also presents
reports have raised the possibility of some benefit atypical features. Non-lipogenic areas of dediffer-
in certain types of sarcomas, the benefit of adju- entiation present with pleomorphic cells such as
vant chemotherapy with regard to prolonged sur- spindle cells, round cells, and giant cells or even
vival remains controversial. Chemotherapy is fibroblast-like appearance in a myxoid matrix.
most commonly employed in the setting of Immunohistochemical panels include MDM2 and
attempted control of metastatic disease. Its role CDK4 positivity in 90% of tumors.
in adjuvant therapy aimed at cure is not
established (Eeles et al. 1993). Treatment
Surgical excision is the treatment of choice for
liposarcomas. The lesion has a high recurrence
Liposarcoma rate, up to 50%. There is a direct relationship
with tumor site and grading with the prognosis
Epidemiology, Etiology, and Pathology of treatment. Oral liposarcoma is associated with a
Liposarcomas are malignant neoplastic prolifera- poor outcome despite the high proportion of
tions of mesenchymal cells with adipocyte low-grade tumors.
Fig. 104 (continued)

Malignant Peripheral Nerve Sheath Investigations

Tumor Microscopic investigation of MPNST reveals an
unencapsulated lesion, with highly infiltrative
Epidemiology, Etiology, and Pathology cells with different morphotypes such as epitheli-
The malignant peripheral nerve sheath tumor oid, pleomorphic, small round cells and spindle-
(MPNST) also known as malignant schwannoma, shaped cells. The lesion is composed of interlacing
neurofibrosarcoma, and malignant neurilemmo- fascicular arrangements, forming variable patterns,
ma is characterized by malignant proliferation of with highly cellularized areas of vacuolated cells
the soft tissues by peripheral nerves or benign with a myxoid matrix, alternating to whorls of
nerve sheath tumors, with variable differentiation storiform formations, with palisaded cells, some-
toward one of the cellular components of the times assuming a rosette formation. The nuclei are
nerve sheath, such as Schwann cells, fibroblasts, large and hyperchromatic, sometimes small, and
or perineural cells (Fig. 104) (Anghileri et al. other times fusiform with eventual atypical mitosis
2006). or binucleated cells. The tumors are graded low
About 20% of all MPNSTs develop in the head grade and high grade according to their mitotic
and neck, representing 5% of all soft tissue sarco- index, number of atypical mitosis, pleomorphism,
mas. As mentioned above, MPNST has a strong and necrosis (Fig. 104).
correlation with NF type 1 syndrome, affecting up Immunohistochemical investigation of the
to 25–30% of the patients with this particular lesion is frequently necessary, as other sarcomas
syndrome. The peak occurrence of this lesion is can present similar morphological features. This
during adulthood, during the third and fourth is essential for small incisional biopsies. The
decades of life. immunohistochemical panel should include
S-100, SOX10, and nestin strong positivity, and
Clinical Features cytokeratins, EMA, and CD34 may be positive,
MPNST can arise de novo or from a pre-existing but their expression has not been described in the
neurofibroma. The most affected nerves of the head epithelioid variant. Genetic investigation of NF1
and neck region are the vagal and vestibular nerves. is also recommended if the patient has no other
Malignant transformation of a pre-existing evident signs. There is loss of NF1 on 17q11 and
schwannoma is possible but considered to be rare. TP53 on 17q13 (2017).
Symptoms include pain associated with a rapid
growing mass, which may also compromise motor Treatment
or sensory neural function (Eeles et al. 1993). MPNSTs are treated with radical surgical exci-
Tumors may present as a white, solid, firm sion. The aggressive behavior of the lesion is
consistency within or attached to a nerve trunk frequently associated with large lesions. It is the
or neurofibroma. Sometimes the development of main cause of death of NF1 patients representing
tumors in intraosseous neural branches can pro- up to 25% of deaths of NF1-affected patients.
duce local enlargement of the nerve canal with or Therefore, to discover these tumors as early as
without bone destruction of the surrounding bone. possible, patients with NF1 syndrome should be
Pseudocystic spaces originating from hemorrhage followed carefully, because of the likelihood that
or focal necrosis may be observed during surgical they may develop MPNSTs. Presentation with
incision of the tumor. either primary or recurrent disease, tumor size,
Fig. 104 Malignant peripheral nerve sheath tumor. CT (c). Fascicles of atypical fusiform cells with irregular
scan of an irregular osteolytic lesion of the left maxilla (a). nuclei forming variable patterns with highly cellularized
T2-weighted MRI revealing the extension of the lesion in areas of vacuolated cells with a myxoid matrix (d), alter-
the maxilla (b). Bone scintillography imaging showing nating with whorls of storiform formations and palisaded
increased radiotracer accumulation in the affected area cells (e) (Hematoxylin and eosin stain)
and tumor location have major importance with among elderly men of Mediterranean or Jewish
regard to prognosis. Complete tumor resection ancestry), African-endemic KS, and immunosup-
with negative margins should be the objective of pressive drug-related KS. All these forms of KS
surgery (Minovi et al. 2007). share a similar histopathology that has been
The recurrence rate is as high as 40%, and divided into different progressive stages correlat-
adjunctive radiotherapy and chemotherapy are ing with both clinical appearance and progression
often required, but the lesion usually metastasizes of lesions. AIDS-associated KS is the most fre-
to the lungs and bone. Adjuvant radiation therapy quent tumor of human immunodeficiency virus
should be delivered to improve local control and type I (HIV-l) infection and the most aggressive
may also be beneficial for survival. High-grade and rapidly growing form of KS in AIDS, with
and large MPNSTs have particularly aggressive early dissemination in the skin and viscera. In
behavior, and thus patients with these tumors spite of the clear clinical differences, the histopa-
should be considered for new adjuvant medical thology of the various KS forms is essentially the
treatments. same, with characteristic changes related to stage
in the development of the KS tumor. Only the
AIDS-related type is associated with oral mani-
Kaposi Sarcoma festations. As many as 20% of individuals with
HIV-1 infection develop oral KS, usually in the
Epidemiology, Etiology, and Pathology fourth to fifth decades of life.
Kaposi sarcoma (KS) is an angioproliferative The incidence of KS has dramatically
malignant neoplasia of endothelial cells forming decreased in both the United States and Europe
an infiltrative capillary-rich lesion that eventually in the era of highly active antiretroviral therapy
disseminates to multiple cutaneous sites, viscera, (HAART). However, KS remains the second most
and lymph nodes. Kaposi sarcoma was first frequent tumor in HIV-infected patients world-
described by Moritz Kaposi in 1872 as “idiopathic wide and has become the most common cancer
multiple pigmented sarcomas of the skin.” Until in sub-Saharan Africa. Since the beginning of the
the HIV pandemic in the 1970s and 1980s, KS AIDS pandemic, AIDS-related KS has been more
was considered a rare and usually nonaggressive prevalent in homosexual and bisexual men.
lesion. After the pandemic infection with HIV
virus, lesion incidence arose as one of the diseases Clinical Features
related to acquired immunodeficiency syndrome The most affected oral location of KS is the hard
(AIDS) with aggressive behavior becoming one palate, followed by the gingiva and tongue (Figs.
of the major causes of death among AIDS 105-108). Up to 70% of patients with cutaneous
patients. AIDS-related KS also have oral lesions. Multiple
Today KS is known to be caused by HHV8 patches and papules with bluish to purple color are
infection of endothelial cells. HHV8 is found in the most common skin and mucosal presentations
immunocompetent people and is active in immu- (Fig. 105). With the progression of the disease,
nosuppression. In fact in the beginning of the the patched lesions develop to a nodular stage
twenty-first century, it was discovered that Tat (Fig. 108). Intraoral advanced lesions may present
protein produced by lymphoid cells infected with hemorrhage, pain, ulceration, and secondary
with HIV promoted the infection of HHV8, con- infections. Highly aggressive lesions are infiltra-
tributing to the highly aggressive nature of AIDS- tive, involving soft tissue and bone (Chen et al.
KS by inducing inflammatory cytokines and 2014). These lesions may disseminate compromis-
angiogenesis (Moore and Chang 1995; Gallo ing visceral organs and lymphatic nodes.
1998; Aoki and Tosato 2004).
Until the AIDS epidemic, this tumor was iden- Investigations
tified in three different settings: classic KS Early “patch-stage” KS lesions are histologically
(a slowly growing tumor particularly prevalent characterized by the proliferation of small and
Fig. 105 Multifocal macular AIDS-related Kaposi sar- Fig. 107 Extensive diffuse AIDS-related Kaposi sarcoma
coma and aggressive periodontal disease in 29 years old and tooth wear in a 45 year old Malawian male. (Image
Zambian male. (Image courtesy of Dr Tim Hodgson, East- courtesy of Dr Tim Hodgson, Eastman Dental Institute,
man Dental Institute, University College London, UK) University College London, UK)
Fig. 106 Gingival AIDS-related Kaposi sarcoma in 9 Fig. 108 Nodular palatal AIDS-related Kaposi sarcoma
year old Malawian female. (Image courtesy of Dr Tim in 28 years old Zambian female. (Image courtesy of Dr Tim
Hodgson, Eastman Dental Institute, University College Hodgson, Eastman Dental Institute, University College
London, UK) London, UK)
jagged endothelial-lined spaces surrounding nor- to exclude these differential diagnoses. Immuno-
mal dermal vessels and irregularly shaped, slit- histochemical investigation of KS targets HHV8
like vascular spaces dissecting collagen bundles, primarily, but podoplanin (D2-40), LYVE1,
often parallel to the epithelium, with extravasated VEGFR3, PROX1, CD34, CD31, and ERG are
erythrocytes and lymphocytes. The more also positive.
advanced stages of KS consist of the accumula-
tion of spindle-shaped cells, which are considered Treatment
to be the tumor cells of KS, showing intra- and The behavior and thus the treatment of KS depend
extracellular hyaline globules and increased on a number of factors such as the form of the
mitotic activity. disease, the symptoms, the location and extent of
The histologic differential diagnoses of Kaposi the lesion, the immunocompetence of the patient,
sarcoma include angiosarcoma, fibrosarcoma, and the general medical condition of the patient.
arteriovenous malformations, and spindle cell Local excision, radiation therapy, chemotherapy,
hemangioendothelioma. Clinicopathological fea- and the adjustment of immunosuppressive medica-
tures, mainly immunohistochemical studies, help tions can all be considered (La Ferla et al. 2013).
Local recurrence is common in AIDS-KS associated angiosarcoma (Stewart-Treves syn-

patients, but survival is more related to the immu- drome), and postirradiation angiosarcoma.
nological status of these patients; the mortality Besides an association with persistent chronic
rate can reach 20–25%. In patients with iatrogenic lymphoedema, previous irradiation, and
KS associated with immunosuppressants for rheu- pre-existing vascular malformation, little is
matic disease, tumor regression occurs in known regarding the causative factors of this dis-
response to treatment in about two-thirds of ease. With respect to pathogenesis, among others,
cases. Primary mucosal KS appears to have a upregulation of the glycopeptide VEGF-D, a vas-
similar prognosis to that of the typical cutaneous cular endothelial growth factor, seems to be
form presenting on the extremities. Localized responsible for endothelial cell proliferation.
nodular KS has the best prognosis, with few
deaths directly attributable to KS. Clinical Features
Clinical classification of KS may be the best Clinically the appearance of an angiosarcoma of
prognosticator, comparing localized nodular dis- the head and neck region can be variable. Early
ease, locally aggressive disease, and generalized lesions most commonly present as single or multi-
KS. The association between the aggressive clini- focal ill-defined, bruise-like erythematous-
cal course of classic KS and immunosuppression purplish areas with indurated borders. Sometimes
has previously been suggested. The immunological it may resemble hematoma-like lesions, being
dysfunction underlying classic KS is unknown and misinterpreted as benign inflammatory or allergic
may result from advanced age or chronic infection. hyperemias. More advanced lesions can present as
Its induction by immunosuppressive therapy and dark bluish, sometimes keratotic papules or nod-
its subsequent regression on removal of immuno- ules with ulceration and bleeding, mimicking
suppression provided early clinical recognition of other malignancies like squamous cell carcinoma,
the reversibility of classic KS (Gallo 1998). basal cell carcinoma, malignant melanoma, lym-
phoma, and metastases. Tumors usually extend
transdermally for far wider distances than their
Angiosarcoma clinical appearance suggests (Ettl et al. 2008;
Trevino-Gonzalez et al. 2009).
Angiosarcoma, also referred to as Investigations
hemangiosarcoma and lymphangiosarcoma, is a Microscopically a cutaneous angiosarcoma is typ-
rare malignant tumor of vascular endothelial cells, ically characterized by numerous, irregular, and
representing 2% of all sarcomas. They appear anastomosing vascular channels. These are lined
during middle age, and their prognosis depends by pleomorphic, hyperchromatic endothelial cells
on location, size, and degree of tissue invasion. with variable mitotic activity (Fig. 109). Immuno-
Angiosarcoma occurs predominantly in the histochemical positivity for the endothelial
elderly and is confined to the face and the scalp markers CD31 and factor VIII-related antigen as
region in more than 50% of cases but has been well as for the transcription factor Fli-1 may help
described in the spleen, bone, liver, and breast. to establish diagnosis. The differential diagnosis
Most angiosarcomas of the head and neck arise in includes hemangioma, especially tufted, cavern-
the dermis of the scalp and upper half of the face. ous, and epithelioid hemangioma on the one hand
Oral and salivary gland angiosarcomas are rare and acantholytic carcinoma on the other hand.
tumors in adults that generally behave more favor- Especially in immunocompromised patients,
ably than do angiosarcomas in other locations, Kaposi sarcoma might be a further differential
regardless of grade. diagnosis. Lack of cytoplasmic hyaline globules,
There are three main types of angiosarcoma of spindled cells with distinctive cytoplasmic bor-
the head and neck: idiopathic angiosarcoma of the ders, and scattered plasma cells distinguish
head and neck in elderly patients, lymphoedema- angiosarcoma from Kaposi sarcoma.
Fig. 109 Angiosarcoma.

Vascular spaces delimited
by pleomorphic
hyperchromatic endothelial
cells in a cellular stroma
with fusiform and
vacuolated cells
stain)
Morphologically, oral and salivary gland Angiosarcoma of the skin or soft tissue of the
angiosarcoma differs from that of angiosarcoma head and neck is associated with a 50% mortality
elsewhere (Fanburg-Smith et al. 2003). Although rate within the first 25 months and a 12% survival
the most common angiosarcoma morphology in rate at 5 years, compared to nasal cavity or paranasal
the oral and salivary gland location is spindled sinus angiosarcoma, which have a 22% survival rate
vasoformative and solid, one-third of oral and at 5 years according to grade of differentiation and
salivary gland angiosarcomas in the literature are early diagnosis. Because of this pattern of diffuse,
the unusual epithelioid angiosarcoma variant. The clinically undetectable spread, the disease is very
epithelioid subtype is composed of plump atypical difficult to treat surgically, and long-term results
round cells with prominent nucleoli and definite using surgery alone have been very poor.
intracytoplasmic lumina containing red blood
cells (i.e., epithelioid endothelial cells).
Leiomyosarcoma
Treatment
Radical surgery with ample margins is the treat- Epidemiology, Etiology, and Pathology
ment of choice in patients with head and neck Leiomyosarcoma is a malignant smooth muscle
angiosarcoma. Generally, the treatment of tumor, considered a rare lesion of the head and
angiosarcoma is based on radical surgery and neck, with mostly case reports published in the
postoperative radiation therapy. Surgery is postu- literature. In the head and neck, smooth muscle is
lated to attain a wide excision of the tumor with sparse and found mainly in the walls of blood ves-
histologically negative margins. Unfortunately sels and in the erector pili musculature of the skin. It
achieving negative margins is difficult, as multi- is presumed that these are the cells of origin of such
focal and extensive microscopic spread is com- tumors. These tumors are more likely to be found in
mon in this disease. Intraoperative frozen sections adults ranging from third to seventh decades, with
are often performed to assist in determining sec- little predominance in men. Pediatric cases are
tion margins (Morrison et al. 1995). described to represent the most aggressive forms.
Radiation-induced angiosarcomas of the oral
cavity, like non-oral primary angiosarcomas, are Clinical Features
reported to behave poorly, with early onset of The lesion is poorly circumscribed, with firm con-
metastases and death within 2 years after treatment. sistency on palpation, usually measuring more
than 2.5 cm, and can sometimes present with rhabdomyosarcoma. The latter is of the most
hemorrhage and necrosis. The lesions may affect clinical importance. Distinction among the others
the skin, scalp, neck, nose, tongue, gingiva, max- is less important than assigning a histological
illary sinus, and hard and soft palate. Due to the grade.
rarity of the lesion, a preferred site in the head and
neck region is inconclusive (Mindell et al. 1975; Treatment
Montgomery et al. 2002). Radical surgical excision with clear margins
is always the preferred treatment for
Investigations leiomyosarcomas. These tumors are likely to
Microscopically, typical features of recur if incompletely excised, and morbidity
leiomyosarcoma consist of perpendicularly relates to adequacy of surgical excision. How-
arranged fascicles of spindle cells with eosino- ever, the majority of leiomyosarcomas in the
philic delicately fibrillary cytoplasm, hyper- head and neck are aggressive intermediate- or
chromatic blunt-ended nuclei, and scattered high-grade tumors with little response to adju-
paranuclear vacuoles growing in interlacing vant therapy.
cords of cells with tapered nuclei and delicate
tiny nucleoli. Nuclear palisading and myofibrils
could also be noticed in well-differentiated Rhabdomyosarcoma
lesions, but high-grade tumors exhibit more ana-
plastic features such as large, bizarre, pyknotic Epidemiology, Etiology, and Pathology
nuclei and a large number of mitotic figures. Rhabdomyosarcomas (RMS) are malignant neo-
The lesions are mostly well circumscribed, plasms of skeletal striated muscle cells. The head
although infiltrative areas may be noted at and neck are the most common anatomic sites for
the periphery. Leiomyosarcomas in the head rhabdomyosarcoma, with an incidence currently
and neck tend to be more inflamed than placed at 0.104 cases per 100,000. Rhabdomyo-
leiomyosarcomas elsewhere. sarcomas are the most common soft tissue sarco-
Immunohistochemistry panels for mas in children and adolescents, accounting for
leiomyosarcoma include smooth muscle actin (+), 5–8% of all childhood malignancies. In contrast,
muscle-specific actin (+), desmin (+), cytokeratin it is rare in adults, occurs more frequently in the
( ), S100 protein (focally), myogenin (eventually extremities, and is not as well characterized clin-
+), CD34 ( ), and Ki67 (5–50% nuclear ically and pathologically in the head and neck
staining). The differential diagnosis of adult spin- region.
dle cell tumors in this site includes primarily spin- The WHO classification divides rhabdomyo-
dled carcinoma and melanoma, other sarcoma sarcomas into four clinicopathologic variants:
types, and various benign fibrous tumors and embryonal (ERMS), alveolar (ARMS), spindle
pseudotumors. Spindle cell carcinomas in the cell-sclerosing (SRMS-ScRMS) RMS, and pleo-
head and neck are frequently polypoid mucosal- morphic RMS. ERMS is the most common vari-
based tumors. Adequate sampling can sometimes ant and occurs in younger patients. ARMS is the
detect an in situ or obviously epithelial infiltrating second most common variant and has a predilec-
component, if one is present, and focal cytokeratin tion for older children and young adults. Pleomor-
expression. However, the surface component phic RMS is a rare variant, usually diagnosed in
can be lost by ulceration, and many spindle patients over the age of 45.
cell carcinomas are cytokeratin-negative yet Although most RMS have a sporadic presenta-
can occasionally express immunoreactivity for tion, in a small subset of patients, RMS is part of a
actin. Sarcomas that should be distinguished genetic syndrome, such as Beckwith-Wiedemann,
from leiomyosarcoma in this area include Von Recklinghausen disease, Costello, Noonan,
myofibrosarcoma, fibrosarcoma, malignant nerve Gorlin, Rubinstein-Taybi, and Li-Fraumeni
sheath tumor, malignant fibrous histiocytoma, and syndromes.
Clinical Features recurrent NCOA2 and VGLL2 related fusions in

The clinical presentation of head and neck RMS is congenital/infantile setting, which are associated
divided into three subsites based on its anatomic with a favorable outcome, or MYOD1-mutations
location and local relapse: parameningeal (PM), in older children and adults which are associated
including the paranasal sinuses, nasopharynx, with a poor prognosis (Kohsaka et al. 2014;
nasal cavity, middle ear, mastoid, parapharyngeal Szuhai et al. 2014; Rekhi et al. 2016).
region, pterygopalatine, and infratemporal
fossa; orbital; and non-PM/non-orbital site, Treatment
encompassing the neck, face, oral cavity, cheek, The management of head and neck RMS remains
external ear, scalp, and larynx. PM subsite is the challenging due to an increased failure of local
most common presentation and is associated with control as well as a high rate of early metastases
the least favorable outcome compared to other and high stage and recurrence rates, with often
locations (Chen et al. 2017). limited benefit from surgical management due to
its proximity to vital structures. In the last three
Investigations decades, RMS outcomes have improved signifi-
Head and neck rhabdomyosarcoma in adults can cantly due to evolving multidisciplinary therapy
manifest both classic and unique histologic fea- paradigms, such as improved surgical techniques,
tures for each subtype. ERMS shows a morpho- aggressive chemotherapy regimens, and more
logic resemblance to fetal skeletal muscle. effective conformal intensity-modulated radio-
ARMS, having a histological appearance of therapy. In adults, RMS presents an aggressive
undifferentiated small blue round cells, is clinical behavior regardless of subtype. The prog-
arranged in a variable alveolar or solid pattern. nostic factors in head and neck RMS have been
Spindle cell RMS (SRMS) is composed of mono- multifactorial, such as age, tumor site, overall
morphic spindle cells arranged in intersecting stage, distant metastases, histologic variant,
fascicles, lacking overt rhabdomyoblastic differ- nodal status, and status of primary surgical site
entiation (Fig. 110). A subset of SRMS display (Agaram et al. 2014).
areas of hyaline sclerosis suggesting a morpho- In children, RMS occurring in the head and
logic overlap with the even less common scle- neck tends to have favorable outcomes except
rosing RMS (ScRMS). ScRMS may show an for tumors arising in parameningeal sites such as
undifferentiated round cell component arranged the nasal cavity, paranasal sinuses, infratemporal
in a pseudovascular or pseudoalveolar pattern in fossa, and mastoid. Poorer outcomes for tumors in
a prominent hyalinized stroma. SRMS-ScRMS these sites are due in part to difficulty in achieving
represent a rare and recently recognized stand- complete resection from these areas. Embryonal
alone pathologic entity, separated from the broad RMS is associated with the most favorable out-
spectrum of ERMS. Pleomorphic RMS has a come compared to other variants. Alveolar RMS
morphologic appearance of large pleomorphic is associated with a poor prognosis. The 5-year
cells. overall survival rate of childhood RMS has risen
Although no genetic abnormality prevails, to 62%, and the 5-year relative survival rate is
small subsets of ERMS harbor loss of heterozy- estimated at 63%.
gosity (LOH) at 11p15, as well as FGFR4, P53,
BCOR, ARID1A, and RAS mutations, as shown
in recent large genomic studies. The genetic hall- Tumors of the Temporomandibular
mark of ARMS is either the more common t(2;13) Joints
(q35;q14) translocation or the t(1;13)(q36;q14)
resulting in the PAX3-FOXO1 or PAX7-FOXO1 Tumors of the temporomandibular joint (TMJ) are
fusion, respectively (Owosho et al. 2016). SRMS- rare but comprise a broad spectrum of lesions.
ScRMS share genetic alterations, although these Given the potential for malignancies to mimic
vary depending on the clinical presentation: TMJ pathology or remain asymptomatic, the oral
Fig. 110 Rhabdomyosar-

coma. Monomorphic spin-
dle cells are arranged in
intersecting fascicles,
lacking overt
rhabdomyoblastic differen-
tiation (Hematoxylin and
eosin stain)
medicine clinician should be familiar with osteoma (Fig. 117), and osteoblastoma (Fig. 118)
changes affecting the TMJ. Lesions discussed in (10.9% each). Malignant tumors are mostly sar-
this section constitute a representative sample of comas of various types (synovial sarcoma,
tumors involving the TMJ but are far from com- chondrosarcoma, osteosarcoma) making up
plete. Various conditions affecting the TMJ are 53.8% of malignant disease, followed by meta-
covered in specific chapters such as ▶ “Non- static disease (Fig. 119) (32.7%) (Poveda-Roda
odontogenic Bone Pathology,” ▶ “Arthritic Con- et al. 2013).
ditions Affecting the Temporomandibular Joint,” Tumors of the temporomandibular joint are
and ▶ “Internal Derangements of the Temporo- characteristically found in young adults, and
mandibular Joint.” In this section, we only high- because of the scant specificity of their symptoms,
light the more common tumors and pseudotumors many are initially diagnosed and treated as tem-
affecting the TMJ. poromandibular joint dysfunction or derangement
The most frequent lesions affecting the TMJ (Poveda-Roda et al. 2013). The mean age of pre-
are benign (81.8%); however, the greater sentation is 42 years and 1 month 16 years and
majority of these are pseudotumors (synovial 2 months. Tumors are more common in females.
chondromatosis (Figs. 111 and 112), pigmented The mean time from symptom onset to consulta-
villonodular synovitis (Fig. 113), eosinophilic tion is 30 months and 8 days 41 months and
granuloma, and osteochondroma (Fig. 114)) 9 days, and almost 19.6% of cases are initially
representing 71.6% of lesions and do not repre- diagnosed and treated as TMJ dysfunction. The
sent true benign tumors (Poveda-Roda et al. most frequent clinical manifestations are pain,
2013). The majority of true tumors are indeed swelling, and the limitation of joint movement.
malignant, making up almost two-thirds of cases Both clicks and crepitus are more common among
of true tumors. Of the pseudotumors, the majority the pseudotumors than in true tumors. No signif-
present as synovial chondromatosis (61.8%), icant differences are noted between malignant and
followed by osteochondroma (24%), pigmented benign tumors in terms of joint sounds. Other
villonodular synovitis (4.4%), and eosinophilic more specific alterations such as facial asymmetry
granuloma (4.4%). Of the true benign tumors, or occlusal disorders are less common. Occlusion
chondroblastoma (Fig. 115) represents the largest alterations, one of the signs most suggestive of
single entity (17.2%), followed by osteoid oste- TMJ tumors together with the presence of swell-
oma (Fig. 116) (13.8%) and then chondroma, ing, are reported in 20.5% of patients. The most
common occlusal disorders are ipsilateral poste- common in pseudotumors (61.0%) (Figs. 115,
rior open bite, contralateral cross-bite, and ante- 116, 117, and 118) than among tumors (7.4%).
rior cross-bite (Poveda-Roda et al. 2013). No panoramic radiographic alterations are
Many tumors show no radiological alterations observed in 14.6% of benign tumors and in 7.7%
on routine panoramic imaging (Fig. 113). Radio- of malignant lesions (Poveda-Roda et al. 2013).
lucencies, and especially a poorly defined tumor Treatment usually involves surgery, and
contour, are suggestive of malignancy (Fig. 119). relapse is observed in 10% of the cases – particu-
The most common radiological findings in the larly among malignant tumors. The most frequent
case of benign and malignant lesions are radio- treatment method is total or partial synovectomy,
pacities and radiolucencies, respectively. Radio- which is a commonly used approach for synovial
lucencies are significantly more frequent in chondromatosis which makes up a large propor-
tumors (77.8%) than in pseudotumors (22.0%). tion of cases requiring treatment. Arthroscopic
In contrast, radiopacities are significantly more treatment is used in 7.3% of cases, and
Fig. 111 Synovial chondromatosis with noncalcified (d). White arrows in (b + c) show erosion of the roof of the
bodies in the superior joint space of the right temporoman- glenoid fossa. (Images courtesy of Clinical Associate Pro-
dibular joint. CT sagittal (a), proton density sagittal (b), fat fessor Andy Whyte, Perth Radiological Clinic, Perth WA,
saturation T2 sagittal (c), and coronal proton density MRI Australia)
Fig. 112 Synovial chondromatosis with calcified bodies MRI shows many more bodies than CT for this reason.
in the superior joint space of the left temporomandibular Note remodeled condyle (white arrows in c + d) probably
joint. CT sagittal (a), post-gadolinium T1 fat saturation due to pressure from the distended medial and lateral
sagittal reconstruction (b), CT coronal (c), fat saturation recesses of the upper joint space. (Images courtesy of
T2 coronal (d). Synovial proliferation enhances with gad- Clinical Associate Professor Andy Whyte, Perth Radiolog-
olinium and is hyperintense on T2. The “bodies” are low ical Clinic, Perth WA, Australia)
signal on all sequences whether they are calcified or not.
practically all of these correspond to synovial 11.4 months. Benign lesions respond well to treat-
chondromatosis. The most common surgical pro- ment, with minimal postsurgical complications
cedure in the case of malignant disease is tumor (Poveda-Roda et al. 2013).
resection with margins, followed by simple tumor
resection. Sequelae are noted in 18.2% of cases,
with tumor relapse in 9.1%. The most common Molecular Aspects of Head and Neck
problems are mandibular deviation, limited range Squamous Cell Carcinoma
of movement, facial palsy, crepitus, and pain. The
4-year survival rate in the case of malignant Head and neck squamous cell carcinomas
tumors of TMJ is 72.2%, with a mean survival (HNSCC) arising from the mucosal epithelia of
of 6 years, in comparison with metastatic disease the head and neck region have diverse etiologies
which presents with a mean survival of and are managed differently depending on
Fig. 113 Pigmented villonodular synovitis. Ortho- of the soft tissue that projects into the temporomandibular
pantomogram (a) showing circumscribed lucency overly- joint itself. On MRI (e–g), there is a large multilobulate
ing the right articular eminence (white dotted oval). No mass with dimensions of 36 30 27 mm (e–g) arising
temporomandibular joint arthropathy or other osseous within the markedly distended lateral aspect of the anterior
abnormalities are seen. On CT (b–d) there is an avidly recess of the superior compartment of the right temporo-
enhancing 27 24 27 mm right preauricular mass mandibular joint. The smaller superior lobule represents
lesion which appears to be centered within the posterior the component eroding the articular eminence as seen on
aspect of the masseter muscle (b) and extends ante- the CT. The larger inferolateral lobule indents the post-
rosuperiorly to involve the posterior aspect of both the erosuperior fibers of masseter and the anteromedial aspect
medial and lateral pterygoid muscles (b + c). This compo- of the superficial lobe of the right parotid gland (f + g). On
nent scallops the greater wing of the sphenoid bone (d) and its medial margin, this larger lobule extends to the coronoid
the anterior aspect of the articular eminence of the right notch. The meniscus is normally positioned with an upper
temporomandibular joint. There is only a tiny component compartment effusion and additional small, intra-articular
Fig. 114 Osteochondroma of the right condyle. Axial soft the right condyle (white arrows in b and c). Overlying the
tissue CT reconstruction (a), axial bone window of the bony component, there is a non-ossified cartilage cap (cur-
right condyle (b), and lateral, bone window, sagittal recon- vilinear white dotted line in a). (Images courtesy of Clin-
struction of the right condyle (c). An exostosis of cortical ical Associate Professor Andy Whyte, Perth Radiological
and medullary bone projects anteriorly and laterally from Clinic, Perth WA, Australia)
anatomical site and disease extent. While they composed of distinct diseases at the molecular
may appear to be morphologically similar, molec- level. While much work remains to demonstrate
ular studies have underscored the heterogeneity of how these molecular subtypes affect patient and
HNSCC demonstrating that they are instead treatment outcomes, the development of
Fig. 113 (continued) foci, the largest of which is situated pericapsular edema are consistent with pigmented
in the posterior recess and measures 6 mm in diameter. The villonodular synovitis. (Images courtesy of Clinical Asso-
roof of the glenoid fossa is focally eroded with adjacent ciate Professor Andy Whyte, Dr Gavin Chapeikin, and Dr
synovial proliferation and opacification of overlying mas- Rudolf Boeddinghaus, Perth Radiological Clinic, Perth
toid air cells. The enhancement of the lesion and the WA, Australia)
superior compartment synovitis, capsulitis, and
Fig. 115 Chondroblastoma of the right articular emi- superiorly into the middle cranial fossa with mass effect
nence, glenoid fossa, and middle cranial fossa. Sagittal on the right temporal lobe (TL in b–d). Inferior extension
bone window CT reconstruction (a), sagittal post-contrast of the tumor into the right lateral pterygoid muscle (LP
CT soft tissue reconstruction (b), coronal CT soft tissue in b) and lateral extension into the temporalis (orange
reconstruction (c), and post-gadolinium, fat saturation, arrows in c and d) is also present; the latter is more clearly
coronal T1-weighted MRI (d). There is a large enhancing shown on MRI (d). (Images courtesy of Clinical Associate
mass (black arrows) destroying the articular eminence and Professor Andy Whyte, Perth Radiological Clinic, Perth
glenoid fossa (black dotted oval in a) which extends WA, Australia)
molecular targeted therapies may very well subsites are distinct, much of the literature in
change the way we classify and treat patients HNSCC unfortunately does not distinguish the
with HNSCC. subsites included in studies and typically include
Cancer is a disease that is driven by genetic the major sites within the head and neck region
alterations, and this can occur at multiple levels, such as the oral cavity, oropharynx, hypopharynx,
either at DNA, RNA, or protein. With the advent larynx, and less commonly nasopharynx. There-
of high-throughput technologies, initially micro- fore, this section covers HNSCC in general, but
arrays, array comparative genomic hybridization, data on specific subsites is provided where
and then next-generation sequencing, there cur- possible.
rently exists the capability to catalogue genetic
alterations that occur in cancer cells to unprece-
dented detail. This section discusses recent molec- Genome-Wide Studies
ular findings in HNSCC and where appropriate
how these have impacted on the clinical under- To date, several large-scale genomic studies on
standing of the disease. While etiologies, manage- the characterization of HNSCC have been com-
ment, and outcomes of HNSCC from different pleted (Agrawal et al. 2011; Stransky et al.
Fig. 116 Osteoid osteoma of the left glenoid fossa and tissue edema is present within the nidus of osteoid oste-
articular eminence; presentation with pain and trismus in oma, adjacent sclerotic bone, condyle, joint, and lateral
a young adult patient. Sagittal bone window CT recon- pterygoid muscle (orange dashed outline in c). Following
struction (a), coronal bone window reconstruction (b), fat gadolinium contrast, the nidus and its lucent margin,
saturation T2 sagittal MRI of the left TMJ (c), and post- joint, surrounding soft tissues, and condylar marrow
gadolinium, fat saturation T1 coronal MRI (d). There is a show diffuse enhancement (orange dotted oval in d).
round sclerotic nidus representing an osteoid osteoma Faint enhancement is present in marrow surrounding the
with a lucent margin measuring 10 mm in diameter in nidus in the glenoid fossa with subtle meningeal thicken-
the roof of the glenoid fossa (orange arrows). There is ing in the overlying left middle cranial fossa (white
diffuse sclerosis of the articular eminence, root of the arrows in d). (Images courtesy of Clinical Associate Pro-
zygoma, remainder of the glenoid fossa, and to a lesser fessor Andy Whyte, Perth Radiological Clinic, Perth WA,
extent the condyle (white dotted oval in a, white dotted Australia)
square in b). Extensive, hyperintense marrow and soft
2011). The largest and most comprehensive yet Copy Number Alterations
is the Cancer Genome Atlas (TCGA) study
where 279 head and neck cancer specimens Global genetic alterations can be examined at
were analyzed comprehensively (2015). This different molecular levels; the most fundamental
study included specimens from the oral cavity changes occur at the DNA level. Changes within
(n = 172), oropharynx (n = 33), larynx (n = 72), the DNA have been reported at the chromosomal
and hypopharynx (n = 2), and comprehensive level where advancements in technology have
analyses revealed chromosomal changes, muta- enabled the examination of these alterations
tional profiles, and gene expression signatures in beyond the resolution of classical cytogenetics.
HNSCC. This and previous studies unveiled the Initially analyzed by array comparative
catalogue of genetic alterations in cancer and genomic hybridization (aCGH) and more recently
provide insights into the possible vulnerabilities by single nucleotide polymorphism (SNP) arrays,
within cancer cells that could be targeted for chromosomal aberrations in terms of loss or gain
therapeutic purposes. of focal regions within chromosomes are found to
Fig. 117 Osteoma of the left condylar head and neck. CT condylar head and neck contiguous with the pedicle of
shows a well-defined pedunculated, dense, sclerotic, ovoid the described lesion (b). This lesion had increased in size
lesion with a maximum length of 15 (AP) 17 (transverse) significantly as compared with a CT taken 11 years earlier
9 (height) mm, projecting anteriorly from the junction of (c). (Images courtesy of Clinical Associate Professor Andy
the left condylar head and neck (a). There is diffuse thick- Whyte, Perth Radiological Clinic, Perth WA, Australia)
ening of the anteromedial cortex of the junction of the
be common in HNSCC. This is perhaps not sur- When comparing HPV-positive to

prising as a comprehensive analysis of more than HPV-negative tumors, differences in chromo-
3000 tumors across 12 cancer types showed that somal aberrations are apparent. HPV-positive
HNSCC are broadly categorized as “C” class tumors were characterized by loss of the 11q
tumors, where these tumors are largely driven region (containing the DNA repair gene ATM1),
by chromosomal aberrations (Ciriello et al. TNF receptor-associated factor 3 (TRAF3) impli-
2013). Loss of chromosomal regions of 3p and cated in innate and acquired antiviral responses
8p and gains of 3q, 5p, and 8q are found in the (Oganesyan et al. 2006), and gain of the transcrip-
majority of HNSCC (Agrawal et al. 2011; tion factor E2F1. HPV-positive tumors are also
Stransky et al. 2011; Seiwert et al. 2015), and less likely to have the deletion of the 9p region
these mimic observations in lung squamous cell containing the CDKN2a gene and amplification of
carcinoma (Cancer Genome Atlas Research the 7p region which hosts the EGFR gene. By
2012). The copy number changes within these contrast, HPV-negative tumors are characterized
regions are consistent with changes in the genes by frequent loss of CDKN2a and co-amplification
that reside within these regions such as squa- of 11q13 (CCND1, FADD, and CTTN) and 11q22
mous lineage transcription factors TP63 and (BIRC2 and YAP1) regions. Recurrent focal
SOX2 and the oncogene PIK3CA (3q), the amplifications in receptor tyrosine kinase
c-MYC oncogene (8q), and the fragile histidine (EGFR, ERBB2, and FGFR1) are also more likely
triad gene (FHIT) (3p). to occur in HPV-negative cancers (2015).
Fig. 118 Osteoblastoma of the right glenoid fossa super- condylar marrow edema has resolved; the soft tissue edema
imposed on internal derangement, remodeling, and early posterior to the condyle (white dotted arrows in b) is
arthropathy of the right TMJ in a 17-year-old female. Initial unchanged. The external auditory canal (EAC) is indi-
fat saturation T2 sagittal of the right TMJ demonstrates an cated. Sagittal (c) and coronal (d) CT bone window recon-
attenuated, anteriorly displaced disc (Disc) and marrow structions demonstrate the large, sclerotic nidus (orange
edema in the right condylar head and neck (white dotted arrows), an irregular thin relatively lucent margin, and
oval in a) and retro-condylar soft tissue edema (white marked adjacent sclerosis and thickening of the temporal
dotted arrows). There is a subtle band of edema in the bone. There is joint space narrowing, articular surface
roof of the glenoid fossa (orange dotted arrow in a). Four- flattening, and subarticular sclerosis in the TMJ (white
teen months later, there is now a 16 mm, edematous round arrows in c) due to remodeling and early degenerative
nidus in the expanded posterosuperior aspect of the glenoid arthropathy. (Images courtesy of Clinical Associate Pro-
fossa demarcated by more marked marginal edema (orange fessor Andy Whyte, Perth Radiological Clinic, Perth WA,
arrows in b) on a similar fat saturation T2 sequence. The Australia)
Mutations allowing the cataloguing of mutations that are

associated with diseases including cancer. In
With the advent of Sanger sequencing in 1977 2011, the first literature that comprehensively
(Sanger et al. 1977), mutations at the single described the mutational landscape by whole
base level of DNA could be commonly detected. exome sequencing of HNSCC was published,
At the start of the twenty-first century, and and subsequently other large studies provided fur-
with the advent of next-generation sequencing ther insights into the mutational profiles of
which enables massive parallel sequencing, it is HNSCC (Agrawal et al. 2011; Stransky et al.
now possible to characterize the genome of 2011; India Project Team of the International
many organisms to unprecedented depth, Cancer Genome 2013). These studies reported
Fig. 119 Metastatic renal cell carcinoma. CT coronal (a), and axial (f) images show additional metastases (white
sagittal (b), and axial of the left condyle and ramus (c) dotted arrows) in the clivus and the left articular eminence
demonstrate permeative radiolucency of cortical and med- as well as the lesion seen on CT in the left ramus. (Images
ullary bone of the left ramus with buccal periosteal new courtesy of Clinical Associate Professor Andy Whyte,
bone formation (white arrows and white oval). Combined Perth Radiological Clinic, Perth WA, Australia)
low-dose CT isotope bone scan coronal (d), sagittal (e),
an average of 130 coding mutations per tumor of mutations. Again, distinct differences in the
which is comparable with other smoking-related mutational profiles of HPV-positive and
cancers such as small-cell lung cancer and HPV-negative tumors were obvious. CDKN2A,
lung adenocarcinomas (Lee et al. 2010b; Pleas- TP53, AJUBA, and FAT1 mutations were more
ance et al. 2010). From the largest of the predominantly seen in HPV-negative tumors,
sequencing studies, mutations were found to be and while 86% of HPV-negative tumors had
enriched in 11 significant genes (CDKN2A, FAT1, TP53 mutations, only ~3% of HPV-positive
TP53, CAPS8, AJUBA, PIK3CA, NOTCH1, tumors had these mutations (2015). Gain-of-func-
KMT2D, NSD1, HLA-A, and TGFBR2). The tion mutations in PIK3CA, E542K, E545K, and
majority of these genes regulate and control crit- H1047R/L are predominantly observed in
ical pathways such as the cell cycle (CDKN2A, HPV-positive tumors (2015, Chung et al. 2015;
TP53, AJUBA), squamous differentiation Seiwert et al. 2015). Patients who are
(NOTCH1), or immunosurveillance (KMT2D, HPV-positive and those who are HPV-negative
HLA-A). PIK3CA is the only oncogene that with TP53 wild-type tumors demonstrated favor-
achieved statistical significance in HNSCC; how- able outcomes compared to TP53 mutants and
ever, it is noteworthy that an additional 20% of those with 11q13/CCND1-amplified tumors
tumors have PIK3CA amplified without any sign (2015).
Gene Expression targeted and to improve in efficacy; cetuximab is

now being tested in combination with other targeted
There are four validated gene expression subtypes therapies such as those targeting ERBB2
of HNSCC (Chung et al. 2004; Walter et al. 2013), (NCT02538627). PIK3CA is the most commonly
namely, basal, mesenchymal, atypical, and classi- mutated oncogene in HNSCC, and actionable
cal. More recently these subtypes have been also mutations within PIK3CA afford an opportunity
reported within the TCGA dataset where the larg- to inhibit the PI3K pathway. Indeed, PI3K inhibi-
est subtype was basal (31%), followed by mesen- tors are actively being evaluated either alone or in
chymal (27%), atypical (24%), and classical combination with other agents in HNSCC
(18%). By integrating the genomic features with (NCT02540928, NCT02646748, NCT01602315).
these gene expression subtypes, it is evident that Further, targeting of mTOR, which is a downstream
these subtypes are characterized by distinct fea- target in the PI3K pathway, is also being actively
tures (2015). Mutations in TP53, CDKN2A, 3q pursued (NCT01051791, NCT01009346,
amplification, alteration of oxidative stress NCT01195922).
genes, heavy smoking history, and larynx subsite It is evident that many of the genes that govern
characterize the classical subtype. The basal sub- the cell cycle are altered in HNSCC suggesting
type is represented by activation of EGFR and is that this pathway could be exploited for tumor
associated with NOTCH1 mutations, an intact control. Cyclin-dependent kinase (CDK) inhibi-
oxidative stress signaling, and fewer alterations tors are of much interest especially among
of chromosome 3q. Further, the majority of HNSCC with amplified cyclin D (CCND1) and
tumors with HRAS and CASP8 co-mutations and loss of CDKN2A. Recently, a CDK4/6 inhibitor,
with co-amplification of 11q13/q22 were of this palbociclib, was approved for the treatment of
subtype. The atypical subtype is defined by lack of estrogen receptor (ER)-positive and HER2-
chromosome 7 amplifications and enrichment of negative breast cancers in combination with
HPV-positive tumors with activating mutations in letrozole (Finn et al. 2015). More recently, a
PIK3CA. The mesenchymal subtype has distinct Phase I trial demonstrated that palbociclib admin-
immunological features, where high levels of istered with cetuximab was safe in HNSCC
alterations in innate immunity genes including patients (Michel et al. 2016) making way for a
high expression of natural killer cell marker Phase II trial to evaluate palbociclib in combina-
CD56 and a low frequency of HLA class 1 mutation with cetuximab in recurrent/metastatic
tions are observed, suggesting that this group may HNSCC (NCT02499120). Other drugs targeting
respond particularly well to immunotherapy. the cell cycle including inhibitors of WEE-1, a
kinase that phosphorylates components within
the cell cycle, are also currently being evaluated
Targeting Key Signaling Pathways (NCT02508246, NCT02585973).
Several challenges remain in targeting the
To date, the only approved molecular targeted HNSCC genome. Firstly, biomarkers of response
therapy for head and neck cancers is cetuximab, that could help with the identification of patients
which inhibits EGFR signaling, and the drug is who would likely respond to a particular therapy
indicated for regionally advanced and metastatic are needed. Secondly, it is very likely that single
cancers (Baselga et al. 2005; Vermorken et al. agents may not be able to completely inhibit the
2008). While the molecular subtypes described many perturbed pathways in cancer cells, and
above do not currently dictate therapeutic innovative predictive methods on which drug
regimes, the ability to integrate genomic and combinations would work without causing pro-
gene expression information has given some hibitive toxicity would be important moving for-
insights into the critical pathways that could be ward. Last but not least, novel ways to target
targeted for cancer control. Among these, receptor tumors with loss-of-function mutations and iden-
tyrosine kinases such as EGFR continue to be tification of new targets are necessary to enable
further development of novel ways to treat point is required to illicit a protective immune
HNSCC. Projects such as the Genomics of Drug effect in cancer patients. For example, the
Sensitivity (GDSC) and Cancer Therapeutics presence of CD8+ cytotoxic T cells and high
Response Portal (CTRP) among other emerging immune infiltration has been associated with
studies are enabling the identification of plausible good prognosis in cancer patients, while other
biomarkers of response (Barretina et al. 2012; features including the presence of regulatory T
Garnett et al. 2012; Basu et al. 2013; Seashore- cells (Treg) and other molecules involved in
Ludlow et al. 2015; Rees et al. 2016). Further, immune blockade such as CTLA-4, PD-1, and
techniques such as the gene editing tool CRISPR/ PD-L1 are indicative of immunosuppression and
Cas9 (Koike-Yusa et al. 2014; Shalem et al. 2014; poor prognosis (Teng et al. 2015).
Wang et al. 2014) that can systematically knock A recent bioinformatic analysis of trans-
down genes within the HNSCC genome may criptome data from TCGA revealed the global
reveal genes that are critical for the survival of immune repertoire of HNSCC (Mandal et al.
cancer and hence could be targeted for tumor 2016). This information provides a snapshot of
control. the immune status of HNSCC patients, which
could provide ability to subcategorize HNSCC
into clinically actionable groups with important
Immune Markers and Immunotherapy therapeutic implications, particularly in the appli-
cation of cancer immunotherapy. While this anal-
Molecular characterization of tumors has enabled ysis revealed a wide range in the level of immune
identification of cancers with high mutational bur- infiltrates across HNSCC, overall, HNSCC are
den, i.e., those that have a high number of muta- marked with high levels of immune cell infiltra-
tions within the tumor. Cancers that are associated tion which is also accompanied by a striking
with high mutational burden are typically those observation that these cancers had notable signs
that are associated with external and known car- of immunosuppression marked by high Treg infil-
cinogens such as melanoma which is associated tration and high Treg/CD8+ ratios. Another
with UV exposure and lung cancer which is asso- unique immune feature of HNSCC revealed by
ciated with tobacco use (Lawrence et al. 2013). this study was the presence of natural killer
HNSCC falls within this group of cancers of high (NK) cells within the tumor where among ten
mutational burden, and these cancers have been most common tumor types that were examined,
reported to have a high number of infiltrating HNSCC was the cancer with the highest level of
lymphocytes within the tumor (called tumor- NK cells. With these observations, HNSCC pre-
infiltrating lymphocytes, TIL). This is possibly sents as one of the most exciting and promising
attributed to the increase in mutated proteins that areas of research in immunotherapy and could be
are unique and immunogenic (not been encoun- a tumor type that is highly likely to respond to
tered by the immune system previously) that immunotherapeutic strategies.
could induce the immune system to mount an Comparing among the subsites of HNSCC,
immune response. In fact, HNSCC is among the tumors of the oropharynx have the highest levels
top 10 cancers with the highest level of immune of T cell infiltration and immune activation com-
infiltrates (Senbabaoglu et al. 2015; Mandal et al. pared to the hypopharynx, larynx, and oral cavity;
2016), making this cancer a relevant model to however, in parallel, tumors of the oropharynx
study cancer immunotherapy. also have higher levels of immunoregulatory influ-
The equilibrium between factors that promote ence with higher Treg infiltration and low CD8+/
or suppress anticancer immunity has been Treg ratios. The immune repertoire is also
recently proposed and described as the concept influenced by the gene expression patterns of the
of “cancer-immune set point” (Chen and Mellman tumor. Comparing the immune cell subsets across
2017), and in order to induce a positive immune the four gene expression subgroups of HNSCC
response, induction of an effect that surpasses this (Chung et al. 2004; Walter et al. 2013; Cancer
Genome Atlas 2015), the atypical and mesenchy- influences from the tumor (Zitvogel et al. 2006).
mal subtypes have a higher degree of immune A critical immune checkpoint often found to be
infiltration and T cell activation, compared to the downregulated the patient’s immune response is
basal and classical subtypes. As explained above, programmed cell death 1 (PD-1), an inhibitory
the atypical subtype is highly associated with HPV receptor expressed on many subsets of immune
positivity, while the classical subtype is associated cells including T cells, dendritic cells, natural
with the use of tobacco. Consistently, mutational killer cells, macrophages, and B cells. PD-1 func-
signatures associated with tobacco smoking tion is dependent on the binding of its ligand
(Alexandrov et al. 2013) are also inversely associ- PD-L1 or PD-L2 which are upregulated in many
ated with levels of immune infiltrates. While the solid tumors including HNSCC (Cho et al. 2011;
immunosuppressive mechanism of smoking is not Lyford-Pike et al. 2013; Zandberg and Strome
well defined, a recent study suggests that smoking 2014). Studies have suggested a role for PD-1 in
could have suppressive effects on specific subsets mediating T cell exhaustion in advanced solid
of immune cells including natural killer cancers including the head and neck (Topalian
(NK) cells, CD8+ T cells, and dendritic cells et al. 2012; Lipson et al. 2015). High levels of
(DC) (Stampfli and Anderson 2009). PD-1 on T cells coupled with the presence of
HPV status has a significant influence on the PD-L1 in the tumor could cause a state of anergy
survival of HNSCC patients, and HPV-positive and an impairment in the immune system that
patients experience higher cure rates and better could facilitate tumor growth (Lyford-Pike et al.
overall survival (Ang et al. 2010). While this 2013). Recently, two immune checkpoint inhibi-
could be attributed to the differences in the genetic tors pembrolizumab and nivolumab targeting
background of HPV-positive tumors, it is conceiv- PD-1 were approved for treatment of chemother-
able that the differences in immune infiltration apy refractory HNSCC. Patients treated with
may also mediate part of these survival differ- pembrolizumab showed an overall response rate
ences as suggested in other cancers (Fridman of 18%, and the 6-month progression-free sur-
et al. 2012). Indeed, looking at the TCGA study, vival and overall survival rates were 23% and
patients with high immune infiltration had signif- 59%, respectively (Chow et al. 2016; Ranee
icantly improved survival regardless and indepen- Mehra et al. 2016). On the other hand, nivolumab
dent of HPV status. Interestingly, Treg infiltration demonstrated an overall response rate of 13%
was associated with better prognosis, and higher compared to 5.8% in the standard therapy group,
levels of Treg were associated with superior over- where the overall survival of nivolumab-treated
all survival – however, when examined further patients was 7.5 months compared to 5.1 months
and taking into consideration the trafficking of in the standard therapy group (Ferris et al. 2016).
other immune cells into the tumor, Treg levels These trials have now led to the approval of both
did not remain an independent prognostic factor pembrolizumab and nivolumab for the treatment
underscoring the complexity and the interaction of advanced head and neck cancers, increasing the
between the cells within the immune system and therapeutic options for HNSCC patients with
those that infiltrate into the tumor. NK cells are advanced disease. Several clinical trials combin-
also associated with prognosis. The presence of a ing anti-PD1 with standard and new agents are
subset of activated NK cells (CD56dim) within underway. Further, the use of monoclonal anti-
the tumor is associated with superior survival. bodies targeting the ligand of PD-1 (anti-PD-L1)
There are two basic requirements for the as monotherapy or in combination is also in pro-
immune system to control tumor growth effec- gress (Pai et al. 2016) (NCT02501096,
tively; the immune cells must overcome intersti- NCT02646748, NCT02454179, NCT02586987).
tial pressures in order to infiltrate the tumor and The emerging understanding of the unique
recognize appropriate tumor antigens. In addition, aspects of the immune landscape of HNSCC pro-
to sustain an immune response, the immune sys- vides a strong rationale to use immunotherapy on
tem must be free from immune inhibitory these cancers, and in addition to immune
checkpoint inhibitors that have been recently patients are treated. Clinicians practicing in head
approved, HNSCC could also benefit from and neck oncological teams must stay abreast of
immune agonists which could reactivate the developments in the underlying sciences which
immune system, some of which like vaccines underpin these advancements in diagnosis, strati-
are currently in clinical testing (Yoshitake et al. fication, and management. Primary prevention of
2015). Furthermore, the presence of NK cells HPV-associated tumors through HPV vaccination
within HNSCC affords an opportunity to is an important global challenge and one that
reactivate NK cells by monoclonal antibodies, requires a concerted effort across the globe.
and these strategies are currently in preclinical Finally, evidence-based guidelines for follow-up,
and clinical investigation (NCT02643550). surveillance, and monitoring are urgently required
Therapies such as inhibitors of indoleamine- to better inform our management approaches and
2,3-dioxygenase (IDO) with the potential to tar- to enhance secondary prevention measures in the
get Treg could exhibit activity in HNSCC. These long-term survivor.
work by increasing bioavailable tryptophan
within the tumor microenvironment and decreas-
ing the proliferation and activation of Tregs Cross-References
(Munn 2011). Further, directly targeting mole-
cules that are highly expressed in Tregs such as ▶ Arthritic Conditions Affecting the Temporo-
glucocorticoid-induced tumor necrosis factor- mandibular Joint
related receptor (GITR) or the inducible T cell ▶ Clinical Evaluation of Oral Diseases
co-stimulator (ICOS) have shown promising ▶ Cutaneous Pathology of the Head and Neck
results (Schaer et al. 2013; Mandal and Chan ▶ Diagnostic Imaging Principles and Applica-
2016) but have yet to be used in HNSCC. tions in Head and Neck Pathology
▶ Internal Derangements of the Temporomandib-
ular Joint
Conclusions and Future Directions ▶ Laboratory Medicine and Diagnostic Pathology
▶ Non-Odontogenic Bone Pathology
The head and neck region is a complex part of the ▶ Normal Variation in the Anatomy, Biology, and
human body which necessitates a thorough under- Histology of the Maxillofacial Region
standing of its anatomy and resultant pathologies. ▶ Oral and Maxillofacial Viral Infections
The diversity of lesions, masses, and tumors that ▶ Oral Mucosal Malignancies
arise in this complex structure can be challenging ▶ Pediatric Oral Medicine
to any clinician and underscores the importance of ▶ Salivary Gland Disorders and Diseases
a multidisciplinary team approach in diagnosis, ▶ Soft and Hard Tissue Operative Investigations
management, and surveillance of patients with in the Diagnosis and Treatment of Oral Disease
such lesions. Morbidity and mortality for many ▶ White and Red Lesions of the Oral Mucosa
years have been poor, although in recent time,
mortality and morbidity for HPV-positive oropha-
ryngeal carcinomas have improved significantly, References
as too has our understanding of the molecular
basis of head and neck squamous cell carcinoma. Abergel A, Cavel O, Margalit N, Fliss DM, Gil Z. Com-
parison of quality of life after transnasal endoscopic vs
As HPV-positive tumors of the head and neck
open skull base tumor resection. Arch Otolaryngol
region dominate the attention of practitioners Head Neck Surg. 2012;138(2):142–7.
and researchers alike, an equal amount of effort Abdurehim Y, Hua Z, Yasin Y, Xukurhan A, Imam I, Yuqin
is required to better understand other diseases F. Transoral laser surgery versus radiotherapy: system-
atic review and meta-analysis for treatment options of
with poor outcomes. Targeted immunotherapies,
T1a glottic cancer. Head Neck. 2012;34(1):23–33.
precision medicine approaches, and diagnostic Adegboyega PA, Qiu S. Hemangioma versus vascular
and prognostic biomarkers are shaping the way malformation: presence of nerve bundle is a diagnostic
clue for vascular malformation. Arch Pathol Lab Med. Ali S, Tiwari R, Snow GB, vd Waal I. Incidence of squa-
2005;129(6):772–5. mous cell carcinoma of the head and neck: report of
Adelchi C, Mara P, Melissa L, De Stefano A, Cesare 1,000 cases. J Laryngol Otol. 1986;100(3):315–27.
M. Ectopic thyroid tissue in the head and neck: a case Ambrosch P. The role of laser microsurgery in the treat-
series. BMC Res Notes. 2014;7:790. ment of laryngeal cancer. Curr Opin Otolaryngol Head
Adelstein DJ, Ridge JA, Gillison ML, Chaturvedi AK, Neck Surg. 2007;15(2):82–8.
D’Souza G, Gravitt PE, Westra W, Psyrri A, Kast Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI,
WM, Koutsky LA, Giuliano A, Krosnick S, Trotti A, Nguyen-Tan PF, Westra WH, Chung CH, Jordan RC,
Schuller DE, Forastiere A, Ullmann CD. Head and Lu C, Kim H, Axelrod R, Silverman CC, Redmond KP,
neck squamous cell cancer and the human papilloma- Gillison ML. Human papillomavirus and survival of
virus: summary of a National Cancer Institute State of patients with oropharyngeal cancer. N Engl J Med.
the Science Meeting, November 9–10, 2008, 2010;363(1):24–35.
Washington, D.C. Head Neck. 2009;31(11):1393–422. Anghileri M, Miceli R, Fiore M, Mariani L, Ferrari A,
Adelstein D, Gillison ML, Pfister DG, Spencer S, Mussi C, Lozza L, Collini P, Olmi P, Casali PG,
Adkins D, Brizel DM, Burtness B, Busse PM, Caudell Pilotti S, Gronchi A. Malignant peripheral nerve sheath
JJ, Cmelak AJ, Colevas AD, Eisele DW, Fenton M, tumors: prognostic factors and survival in a series of
Foote RL, Gilbert J, Haddad RI, Hicks WL Jr, Hitch- patients treated at a single institution. Cancer. 2006;
cock YJ, Jimeno A, Leizman D, Lydiatt WM, 107(5):1065–74.
Maghami E, Mell LK, Mittal BB, Pinto HA, Ridge Andersen A, Berge SR, Engeland A, Norseth T. Exposure
JA, Rocco J, Rodriguez CP, Shah JP, Weber RS, to nickel compounds and smoking in relation to inci-
Witek M, Worden F, Yom SS, Zhen W, Burns JL, dence of lung and nasal cancer among nickel refinery
Darlow SD. NCCN guidelines insights: head and workers. Occup Environ Med. 1996;53(10):708–13.
neck cancers, version 2.2017. J Natl Compr Cancer Aoki Y, Tosato G. HIV-1 Tat enhances Kaposi sarcoma-
Netw. 2017;15(6):761–70. associated herpesvirus (KSHV) infectivity. Blood.
Agaram NP, Chen CL, Zhang L, LaQuaglia MP, Wexler L, 2004;104(3):810–4.
Antonescu CR. Recurrent MYOD1 mutations in pedi- Baert AL. Encyclopedia of diagnostic imaging. Berlin:
atric and adult sclerosing and spindle cell rhabdomyo- Springer Verlag; 2008.
sarcomas: evidence for a common pathogenesis. Genes Barnes CM, Christison-Lagay EA, Folkman J. The pla-
Chromosom Cancer. 2014;53(9):779–87. centa theory and the origin of infantile hemangioma.
Agrawal N, Frederick MJ, Pickering CR, Bettegowda C, Lymphat Res Biol. 2007;5(4):245–55.
Chang K, Li RJ, Fakhry C, Xie TX, Zhang J, Wang J, Barretina J, Caponigro G, Stransky N, Venkatesan K,
Zhang N, El-Naggar AK, Jasser SA, Weinstein JN, Margolin AA, Kim S, Wilson CJ, Lehar J, Kryukov
Trevino L, Drummond JA, Muzny DM, Wu Y, Wood GV, Sonkin D, Reddy A, Liu M, Murray L, Berger
LD, Hruban RH, Westra WH, Koch WM, Califano JA, MF, Monahan JE, Morais P, Meltzer J, Korejwa A,
Gibbs RA, Sidransky D, Vogelstein B, Velculescu VE, Jane-Valbuena J, Mapa FA, Thibault J, Bric-Furlong-
Papadopoulos N, Wheeler DA, Kinzler KW, Myers E, Raman P, Shipway A, Engels IH, Cheng J, Yu GK,
JN. Exome sequencing of head and neck squamous Yu J, Aspesi P Jr, de Silva M, Jagtap K, Jones
cell carcinoma reveals inactivating mutations in MD, Wang L, Hatton C, Palescandolo E, Gupta S,
NOTCH1. Science. 2011;333(6046):1154–7. Mahan S, Sougnez C, Onofrio RC, Liefeld T,
Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, MacConaill L, Winckler W, Reich M, Li N,
Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Mesirov JP, Gabriel SB, Getz G, Ardlie K, Chan V,
Borresen-Dale AL, Boyault S, Burkhardt B, Butler AP, Myer VE, Weber BL, Porter J, Warmuth M, Finan P,
Caldas C, Davies HR, Desmedt C, Eils R, Eyfjord JE, Harris JL, Meyerson M, Golub TR, Morrissey MP,
Foekens JA, Greaves M, Hosoda F, Hutter B, Ilicic T, Sellers WR, Schlegel R, Garraway LA. The cancer
Imbeaud S, Imielinski M, Jager N, Jones DT, Jones D, cell line encyclopedia enables predictive modelling of
Knappskog S, Kool M, Lakhani SR, Lopez-Otin C, anticancer drug sensitivity. Nature. 2012;483(7391):
Martin S, Munshi NC, Nakamura H, Northcott PA, 603–7.
Pajic M, Papaemmanuil E, Paradiso A, Pearson JV, Baselga J, Trigo JM, Bourhis J, Tortochaux J, Cortes-
Puente XS, Raine K, Ramakrishna M, Richardson Funes H, Hitt R, Gascon P, Amellal N, Harstrick A,
AL, Richter J, Rosenstiel P, Schlesner M, Schumacher Eckardt A. Phase II multicenter study of the anti-
TN, Span PN, Teague JW, Totoki Y, Tutt AN, Valdes- epidermal growth factor receptor monoclonal anti-
Mas R, van Buuren MM, Van’t Veer L, Vincent- body cetuximab in combination with platinum-based
Salomon A, Waddell N, Yates LR, I. Australian Pan- chemotherapy in patients with platinum-refractory
creatic Cancer Genome, I. B. C. Consortium, I. M.-S. metastatic and/or recurrent squamous cell carcinoma
Consortium, I. PedBrain, Zucman-Rossi J, Futreal PA, of the head and neck. J Clin Oncol. 2005;23(24):
McDermott U, Lichter P, Meyerson M, Grimmond SM, 5568–77.
Siebert R, Campo E, Shibata T, Pfister SM, Campbell Baverstock K, Egloff B, Pinchera A, Ruchti C, Williams D.
PJ, Stratton MR. Signatures of mutational processes in Thyroid cancer after Chernobyl. Nature. 1992;359
human cancer. Nature. 2013;500(7463):415–21. (6390):21–2.
Basu A, Bodycombe NE, Cheah JH, Price EV, Liu K, Califano J, Koch W, Sidransky D, Westra WH. Inverted
Schaefer GI, Ebright RY, Stewart ML, Ito D, Wang S, sinonasal papilloma: a molecular genetic appraisal of
Bracha AL, Liefeld T, Wawer M, Gilbert JC, Wilson AJ, its putative status as a Precursor to squamous cell
Stransky N, Kryukov GV, Dancik V, Barretina J, carcinoma. Am J Pathol. 2000;156(1):333–7.
Garraway LA, Hon CS, Munoz B, Bittker JA, Stockwell Cancer Genome Atlas, N. Comprehensive genomic char-
BR, Khabele D, Stern AM, Clemons PA, Shamji AF, acterization of head and neck squamous cell carcino-
Schreiber SL. An interactive resource to identify cancer mas. Nature. 2015;517(7536):576–82.
genetic and lineage dependencies targeted by small mol- Cancer Genome Atlas Research, N. Comprehensive geno-
ecules. Cell. 2013;154(5):1151–61. mic characterization of squamous cell lung cancers.
Baujat B, Bourhis J, Blanchard P, Overgaard J, Ang KK, Nature. 2012;489(7417):519–25.
Saunders M, Le Maitre A, Bernier J, Horiot JC, Canis M, Ihler F, Martin A, Matthias C, Steiner W. Trans-
Maillard E, Pajak TF, Poulsen MG, Bourredjem A, oral laser microsurgery for T1a glottic cancer: review of
O’Sullivan B, Dobrowsky W, Andrzej H, 404 cases. Head Neck. 2015;37(6):889–95.
Skladowski K, Hay JH, Pinto LH, Fu KK, Fallai C, de Carvalho FK, Pinheiro TN, da Silva RA, de Queiroz
Sylvester R, Pignon JP, M. C. Group. Hyper- AM, da Silva LA, Nelson-Filho P. Lymphangioma of
fractionated or accelerated radiotherapy for head and the lower lip mimicking a mucocele in children. J Dent
neck cancer. Cochrane Database Syst Rev. 2010; (12): Child (Chic). 2015;82(2):116–9.
CD002026. Castellanos JL, Diaz-Guzman L. Lesions of the oral
Becker M. Larynx and hypopharynx. Radiol Clin N Am. mucosa: an epidemiological study of 23785 Mexican
1998;36(5):891–920. vi patients. Oral Surg Oral Med Oral Pathol Oral Radiol
Becker M, Zbaren P, Delavelle J, Kurt AM, Egger C, Endod. 2008;105(1):79–85.
Rufenacht DA, Terrier F. Neoplastic invasion of the Castinetti F, Moley J, Mulligan LM, Waguespack SG.
laryngeal cartilage: reassessment of criteria for diagno- A comprehensive review on MEN 2B. Endocr Relat
sis at CT. Radiology. 1997;203(2):521–32. Cancer. 2018;25(2):T29–T39.
Benson E, Li R, Eisele D, Fakhry C. The clinical impact of Chan JKC, Bray F, McCarron P, Foo W, Lee AWM, Yip T,
HPV tumor status upon head and neck squamous cell Kuo TT, Pilch BZ, Wenig BM, Huang D, Lo KW, Zeng
carcinomas. Oral Oncol. 2014;50(6):565–74. YX, Jia WH. Nasopharyngeal carcinoma. In: Barnes
Bhattacharyya N. Factors affecting survival in maxillary EL, Eveson JW, Reichart P, Sidransky D, editors.
sinus cancer. J Oral Maxillofac Surg. 2003;61 Pathology and genetics of head and neck tumours.
(9):1016–21. Lyon: IARC Press; 2005. p. 85–97.
de Bondt RB, Nelemans PJ, Hofman PA, Casselman JW, Chaturvedi AK, Engels EA, Pfeiffer RM, Hernandez BY,
Kremer B, van Engelshoven JM, Beets-Tan RG. Xiao W, Kim E, Jiang B, Goodman MT, Sibug-Saber-
Detection of lymph node metastases in head and M, Cozen W, Liu L, Lynch CF, Wentzensen N, Jordan
neck cancer: a meta-analysis comparing US, RC, Altekruse S, Anderson WF, Rosenberg PS,
USgFNAC, CT and MR imaging. Eur J Radiol. Gillison ML. Human papillomavirus and rising oropha-
2007;64(2):266–72. ryngeal cancer incidence in the United States. J Clin
Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Oncol. 2011;29(32):4294–301.
Cohen RB, Jones CU, Sur R, Raben D, Jassem J, Chen H. Atlas of genetic diagnosis and counseling.
Ove R, Kies MS, Baselga J, Youssoufian H, New York: Springer Verlag; 2012.
Amellal N, Rowinsky EK, Ang KK. Radiotherapy Chen DS, Mellman I. Elements of cancer immunity and the
plus cetuximab for squamous-cell carcinoma of the cancer-immune set point. Nature. 2017;541
head and neck. N Engl J Med. 2006;354(6):567–78. (7637):321–30.
Bradley PF. A review of the use of the neodymium YAG Chen KH, Chen TD, Chen CW, Lee LY. Iatrogenic
laser in oral and maxillofacial surgery. Br J Oral Kaposi’s sarcoma in nasal cavity: a case report. World
Maxillofac Surg. 1997;35(1):26–35. J Surg Oncol. 2014;12:172.
Bradley PJ. Primary malignant mucosal melanoma of the Chen E, Ricciotti R, Futran N, Oda D. Head and neck
head and neck. Curr Opin Otolaryngol Head Neck rhabdomyosarcoma: clinical and pathologic character-
Surg. 2006;14(2):100–4. ization of seven cases. Head Neck Pathol. 2017;11
Bremer JW, Neel HB 3rd, DeSanto LW, Jones GC. (3):321–326.
Angiofibroma: treatment trends in 150 patients during Cho YA, Yoon HJ, Lee JI, Hong SP, Hong SD. Relation-
40 years. Laryngoscope. 1986;96(12):1321–9. ship between the expressions of PD-L1 and tumor-
Brierley JD, Gospodarowicz MK, Wittekind C, editor. infiltrating lymphocytes in oral squamous cell
TNM Classification of Malignant Tumours, 8th Edi- carcinoma. Oral Oncol. 2011;47(12):1148–53.
tion. Wiley-Blackwell; 2017 Choussy O, Ferron C, Vedrine PO, Toussaint B, Lietin B,
Buckmiller LM, Richter GT, Suen JY. Diagnosis and man- Marandas P, Babin E, De Raucourt D, Reyt E,
agement of hemangiomas and vascular malformations Cosmidis A, Makeiff M, Dehesdin D, G. S. Group.
of the head and neck. Oral Dis. 2010;16(5):405–18. Adenocarcinoma of ethmoid: a GETTEC retrospective
Cabanillas ME, McFadden DG, Durante C. Thyroid can- multicenter study of 418 cases. Laryngoscope.
cer. Lancet. 2016;388(10061):2783–95. 2008;118(3):437–43.
Chow LQ, Haddad R, Gupta S, Mahipal A, Mehra R, chemotherapy plus radiation compared with surgery
Tahara M, Berger R, Eder JP, Burtness B, Lee SH, plus radiation in patients with advanced laryngeal can-
Keam B, Kang H, Muro K, Weiss J, Geva R, Lin CC, cer. N Engl J Med. 1991;324(24):1685–90.
Chung HC, Meister A, Dolled-Filhart M, Pathiraja K, Durante C, Montesano T, Torlontano M, Attard M,
Cheng JD, Seiwert TY. Antitumor activity of Monzani F, Tumino S, Costante G, Meringolo D,
pembrolizumab in biomarker-unselected patients with Bruno R, Trulli F, Massa M, Maniglia A, D’Apollo R,
recurrent and/or metastatic head and neck squamous Giacomelli L, Ronga G, Filetti S, P. T. C. S. Group.
cell carcinoma: results from the phase Ib KEYNOTE- Papillary thyroid cancer: time course of recurrences
012 expansion cohort. J Clin Oncol. 2016;34 during postsurgery surveillance. J Clin Endocrinol
(32):3838–45. Metab. 2013;98(2):636–42.
Chung CH, Parker JS, Karaca G, Wu J, Funkhouser WK, Eeles RA, Fisher C, A’Hern RP, Robinson M, Rhys-Evans
Moore D, Butterfoss D, Xiang D, Zanation A, Yin X, P, Henk JM, Archer D, Harmer CL. Head and neck
Shockley WW, Weissler MC, Dressler LG, Shores CG, sarcomas: prognostic factors and implications for treat-
Yarbrough WG, Perou CM. Molecular classification of ment. Br J Cancer. 1993;68(1):201–7.
head and neck squamous cell carcinomas using patterns Ellis GL, Auclair PL, Gnepp DR. Surgical pathology of the
of gene expression. Cancer Cell. 2004;5(5):489–500. salivary glands. Philadelphia: WB Saunders; 1991.
Chung CH, Guthrie VB, Masica DL, Tokheim C, Kang H, Ettl T, Kleinheinz J, Mehrotra R, Schwarz S, Reichert TE,
Richmon J, Agrawal N, Fakhry C, Quon H, Sub- Driemel O. Infraorbital cutaneous angiosarcoma: a
ramaniam RM, Zuo Z, Seiwert T, Chalmers ZR, diagnostic and therapeutic dilemma. Head Face Med.
Frampton GM, Ali SM, Yelensky R, Stephens PJ, 2008;4:18.
Miller VA, Karchin R, Bishop JA. Genomic alterations Eveson JW, Cawson RA. Tumours of the minor (oropha-
in head and neck squamous cell carcinoma determined ryngeal) salivary glands: a demographic study of
by cancer gene-targeted sequencing. Ann Oncol. 336 cases. J Oral Pathol. 1985;14(6):500–9.
2015;26(6):1216–23. Fakhry C, Zhang Q, Nguyen-Tan PF. Human papillomavi-
Ciriello G, Miller ML, Aksoy BA, Senbabaoglu Y, rus and overall survival after progression of oropharyn-
Schultz N, Sander C. Emerging landscape of oncogenic geal squamous cell carcinoma. J Natl Cancer Inst.
signatures across human cancers. Nat Genet. 2013;45 2008;100(4):261–9.
(10):1127–33. Fanburg-Smith JC, Furlong MA, Childers EL. Oral and
Cohen LM, Schwartz AM, Rockoff SD. Benign salivary gland angiosarcoma: a clinicopathologic study
schwannomas: pathologic basis for CT inhomogenei- of 29 cases. Mod Pathol. 2003;16(3):263–71.
ties. AJR Am J Roentgenol. 1986;147(1):141–3. Favus MJ, Schneider AB, Stachura ME, Arnold JE, Ryo
Colreavy MP, Lacy PD, Hughes J, Bouchier-Hayes D, UY, Pinsky SM, Colman M, Arnold MJ, Frohman LA.
Brennan P, O’Dwyer AJ, Donnelly MJ, Gaffney R, Thyroid cancer occurring as a late consequence of
Maguire A, O’Dwyer TP, Timon CV, Walsh MA. head-and-neck irradiation. Evaluation of 1056 patients.
Head and neck schwannomas – a 10 year review. N Engl J Med. 1976;294(19):1019–25.
J Laryngol Otol. 2000;114(2):119–24. Ferreira JC, Oton-Leite AF, Guidi R, Mendonca
Cove H. Melanosis, melanocytic hyperplasia, and primary EF. Granular cell tumor mimicking a squamous cell
malignant melanoma of the nasal cavity. Cancer. carcinoma of the tongue: a case report. BMC Res
1979;44(4):1424–33. Notes. 2017;10(1):14.
Crippa S, Mazzucchelli L, Cibas ES, Ali SZ. The Bethesda Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas
system for reporting thyroid fine-needle aspiration AD, Licitra L, Harrington K, Kasper S, Vokes EE,
specimens. Am J Clin Pathol. 2010;134(2):343–4. Even C, Worden F, Saba NF, Iglesias Docampo LC,
author reply 345 Haddad R, Rordorf T, Kiyota N, Tahara M, Monga M,
D’Souza G, Kreimer AR, Viscidi R, Pawlita M, Fakhry C, Lynch M, Geese WJ, Kopit J, Shaw JW, Gillison
Koch WM, Westra WH, Gillison ML. Case-control ML. Nivolumab for recurrent squamous-cell carcinoma
study of human papillomavirus and oropharyngeal can- of the head and neck. N Engl J Med. 2016;375
cer. N Engl J Med. 2007;356(19):1944–56. (19):1856–67.
Das Gupta TK, Brasfield RD, Strong EW, Hajdu SI. Fitzpatrick SG, Gordon SC. Benign non-neoplastic lesions
Benign solitary Schwannomas (neurilemomas). Can- of the head and neck. In: Radosevich JA, editor. Head
cer. 1969;24(2):355–66. & neck cancer: current perspectives, advances, and
Dayyani F, Etzel CJ, Liu M, Ho CH, Lippman SM, challenges. Netherlands: Springer; 2013. p. 199–256.
Tsao AS. Meta-analysis of the impact of human papil- Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM,
lomavirus (HPV) on cancer risk and overall survival in Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M,
head and neck squamous cell carcinomas (HNSCC). Shparyk Y, Thummala AR, Voytko NL, Fowst C,
Head Neck Oncol. 2010;2:15. Huang X, Kim ST, Randolph S, Slamon DJ. The
Department of Veterans Affairs Laryngeal Cancer cyclin-dependent kinase 4/6 inhibitor palbociclib in
Study, G, Wolf GT, Fisher SG, Hong WK, Hillman R, combination with letrozole versus letrozole alone as
Spaulding M, Laramore GE, Endicott JW, first-line treatment of oestrogen receptor-positive,
McClatchey K, Henderson WG. Induction HER2-negative, advanced breast cancer (PALOMA-1/
TRIO-18): a randomised phase 2 study. Lancet Oncol. Deng X, Butler A, Choi HG, Chang JW, Baselga J,
2015;16(1):25–35. Stamenkovic I, Engelman JA, Sharma SV, Delattre O,
Fletcher CD. Solitary circumscribed neuroma of the skin Saez-Rodriguez J, Gray NS, Settleman J, Futreal PA,
(so-called palisaded, encapsulated neuroma). A clini- Haber DA, Stratton MR, Ramaswamy S,
copathologic and immunohistochemical study. Am J McDermott U, Benes CH. Systematic identification of
Surg Pathol. 1989;13(7):574–80. genomic markers of drug sensitivity in cancer cells.
Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Nature. 2012;483(7391):570–5.
Morrison W, Glisson B, Trotti A, Ridge JA, Chao C, Gibas Z, Miettinen M. Recurrent parapharyngeal
Peters G, Lee DJ, Leaf A, Ensley J, Cooper rhabdomyoma. Evidence of neoplastic nature of the
J. Concurrent chemotherapy and radiotherapy for tumor from cytogenetic study. Am J Surg Pathol.
organ preservation in advanced laryngeal cancer. N 1992;16(7):721–8.
Engl J Med. 2003;349(22):2091–8. Gildener-Leapman N, Lee J, Ferris RL. Tailored immuno-
Forastiere AA, Zhang Q, Weber RS, Maor MH, therapy for HPV positive head and neck squamous cell
Goepfert H, Pajak TF, Morrison W, Glisson B, cancer. Oral Oncol. 2014;50(9):780–4.
Trotti A, Ridge JA, Thorstad W, Wagner H, Ensley Gnepp DR. Diagnostic surgical pathology of the head and
JF, Cooper JS. Long-term results of RTOG 91-11: a neck. Philadelphia: WB Saunders; 2001.
comparison of three nonsurgical treatment strategies to Golledge J, Fisher C, Rhys-Evans PH. Head and neck
preserve the larynx in patients with locally advanced liposarcoma. Cancer. 1995;76(6):1051–8.
larynx cancer. J Clin Oncol. 2013;31(7):845–52. Gourin CG, Johnson JT. Incidence of unsuspected metas-
Franchi A. Head and neck pathology. M. Volavšek. 2016. tases in lateral cervical cysts. Laryngoscope. 2000;110
https://www.springer.com/gp/book/9783319286174. (10 Pt 1):1637–41.
Fregnani ER, Pires FR, Falzoni R, Lopes MA, Vargas Granata R, Miceli R, Orlandi E, Perrone F, Cortelazzi B,
PA. Lipomas of the oral cavity: clinical findings, histo- Franceschini M, Locati LD, Bossi P, Bergamini C,
logical classification and proliferative activity of Mirabile A, Mariani L, Olmi P, Scaramellini G,
46 cases. Int J Oral Maxillofac Surg. 2003;32 Potepan P, Quattrone P, Ang KK, Licitra L. Tumor
(1):49–53. stage, human papillomavirus and smoking status affect
Fridman WH, Pages F, Sautes-Fridman C, Galon J. The the survival of patients with oropharyngeal cancer: an
immune contexture in human tumours: impact on clin- Italian validation study. Ann Oncol. 2012;23
ical outcome. Nat Rev Cancer. 2012;12(4):298–306. (7):1832–7.
Friedman AB, Munson PD, Richter GT. Vascular anoma- Grau C, Jakobsen MH, Harbo G, Svane-Knudsen V,
lies of head and neck. In: Kountakis SE, editor. Ency- Wedervang K, Larsen SK, Rytter C. Sino-nasal cancer
clopedia of otolaryngology, head and neck surgery. in Denmark 1982–1991 – a nationwide survey. Acta
Berlin: Springer; 2013. p. 2975–88. Oncol. 2001;40(1):19–23.
Gallo RC. The enigmas of Kaposi’s sarcoma. Science. Hamdoon Z, Jerjes W, Al-Delayme R, Hopper C. Solitary
1998;282(5395):1837–9. giant neurofibroma of the neck subjected to photody-
Gallo WJ, Moss M, Shapiro DN, Gaul JV. Neurilemoma: namic therapy: case study. Head Neck Oncol.
review of the literature and report of five cases. J Oral 2012;4:30.
Surg. 1977;35(3):235–6. Hanna EY. Comprehensive management of skull base
Ganly I, Patel SG, Singh B, Kraus DH, Cantu G, Fliss DM, tumors. New York: Informa Healthcare; 2009.
Kowalski LP, Snyderman C, Shah JP. Craniofacial Harnsberger HR, Osborn AG. Diagnostic and surgical
resection for malignant tumors involving the skull imaging anatomy: brain, head & neck, spine. Salt
base in the elderly: an international collaborative Lake City: Amirsys; 2006.
study. Cancer. 2011;117(3):563–71. Harnsberger HR, Wiggins RH, Hudgings PA, Michel MA,
Garden AS, Morrison WH, Wong PF, Tung SS, Rosenthal Swartz J, Davidson CH, Macdonald AJ, Glastonbury
DI, Dong L, Mason B, Perkins GH, Ang KK. Disease- CM, Cure JK, Branstetter B. Diagnostic imaging head
control rates following intensity-modulated radiation and neck. Salt Lake City: Amirsys; 2006.
therapy for small primary oropharyngeal carcinoma. Harrison LB. Head and neck cancer, a multidisciplinary
Int J Radiat Oncol Biol Phys. 2007;67(2):438–44. approach. Philadelphia: Lippincott, Williams & Wil-
Garland SM, Smith JS. Human papillomavirus vaccines: kins; 2014.
current status and future prospects. Drugs. 2010;70 Haugen BR, Alexander EK, Bible KC, Doherty GM,
(9):1079–98. Mandel SJ, Nikiforov YE, Pacini F, Randolph GW,
Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Sawka AM, Schlumberger M, Schuff KG, Sherman
Dastur A, Lau KW, Greninger P, Thompson IR, SI, Sosa JA, Steward DL, Tuttle RM, Wartofsky
Luo X, Soares J, Liu Q, Iorio F, Surdez D, Chen L, L. 2015 American Thyroid Association management
Milano RJ, Bignell GR, Tam AT, Davies H, Stevenson guidelines for adult patients with thyroid nodules and
JA, Barthorpe S, Lutz SR, Kogera F, Lawrence K, differentiated thyroid cancer: the American
McLaren-Douglas A, Mitropoulos X, Mironenko T, Thyroid Association guidelines task force on thyroid
Thi H, Richardson L, Zhou W, Jewitt F, Zhang T, nodules and differentiated thyroid cancer. Thyroid.
O’Brien P, Boisvert JL, Price S, Hur W, Yang W, 2016;26(1):1–133.
Heck JE, Berthiller J, Vaccarella S, Winn DM, Smith EM, surgery. Otolaryngol Head Neck Surg. 2012;146
Shan’gina O, Schwartz SM, Purdue MP, Pilarska A, (1):68–73.
Eluf-Neto J, Menezes A, McClean MD, Matos E, India Project Team of the International Cancer Genome, C.
Koifman S, Kelsey KT, Herrero R, Hayes RB, Mutational landscape of gingivo-buccal oral squamous
Franceschi S, Wunsch-Filho V, Fernandez L, Daudt cell carcinoma reveals new recurrently-mutated genes
AW, Curado MP, Chen C, Castellsague X, Ferro G, and molecular subgroups. Nat Commun. 2013;4:2873.
Brennan P, Boffetta P, Hashibe M. Sexual behaviours ISSVA Classification of Vascular Anomalies ©2018 Inter-
and the risk of head and neck cancers: a pooled analysis national Society for the Study of Vascular Anomalies
in the International Head and Neck Cancer Epidemiol- Available at issva.org/classification Accessed [11 July
ogy (INHANCE) consortium. Int J Epidemiol. 2010;39 2018]
(1):166–81. Itakura E, Yamamoto H, Oda Y, Furue M, Tsuneyoshi M.
Heyer GL, Dowling MM, Licht DJ, Tay SK, Morel K, VEGF-C and VEGFR-3 in a series of lymphangiomas:
Garzon MC, Meyers P. The cerebral vasculopathy of is superficial lymphangioma a true lymphangioma?
PHACES syndrome. Stroke. 2008;39(2):308–16. Virchows Arch. 2009;454(3):317–25.
Higgins KM, Shah MD, Ogaick MJ, Enepekides D. Treat- Jansen EP, Keus RB, Hilgers FJ, Haas RL, Tan IB,
ment of early-stage glottic cancer: meta-analysis com- Bartelink H. Does the combination of radiotherapy
parison of laser excision versus radiotherapy. J and debulking surgery favor survival in paranasal
Otolaryngol Head Neck Surg. 2009;38(6):603–12. sinus carcinoma? Int J Radiat Oncol Biol Phys.
Hirsch B, Moskowitz HS. Benign neoplasia-schwannoma- 2000;48(1):27–35.
neurofibromatosis type 1, Encyclopedia of Otolaryn- Jemal A, Thomas A, Murray T, Thun M. Cancer statistics,
gology, Head and Neck Surgery. Berlin: Springer; 2002. CA Cancer J Clin. 2002;52(1):23–47.
2013. Karligkiotis A, Bignami M, Terranova P, Gallo S,
Hofbauer GF, Boni R, Simmen D, Mihic D, Nestle FO, Meloni F, Padoan G, Lombardi D, Nicolai P,
Burg G, Dummer R. Histological, immunological and Castelnuovo P. Oncocytic Schneiderian papillomas:
molecular features of a nasal mucosa primary mela- clinical behavior and outcomes of the endoscopic endo-
noma associated with nasal melanosis. Melanoma nasal approach in 33 cases. Head Neck. 2014;36
Res. 2002;12(1):77–82. (5):624–30.
Holmstrom M, Lund VJ. Malignant melanomas of the Khan MK, Koyfman SA, Hunter GK, Reddy CA,
nasal cavity after occupational exposure to formalde- Saxton JP. Definitive radiotherapy for early (T1-T2)
hyde. Br J Ind Med. 1991;48(1):9–11. glottic squamous cell carcinoma: a 20 year Cleveland
Hong A, Dobbins T, Lee CS, Jones D, Jackson E, Clark J, Clinic experience. Radiat Oncol. 2012;7:193.
Armstrong B, Harnett G, Milross C, O’Brien C, Rose Klintenberg C, Olofsson J, Hellquist H, Sokjer H.
B. Relationships between epidermal growth factor Adenocarcinoma of the ethmoid sinuses. A review of
receptor expression and human papillomavirus status 28 cases with special reference to wood dust exposure.
as markers of prognosis in oropharyngeal cancer. Eur J Cancer. 1984;54(3):482–8.
Cancer. 2010;46(11):2088–96. Kluwe L, Mautner V, Heinrich B, Dezube R, Jacoby LB,
Horbach SE, Lokhorst MM, Saeed P, de Gouyon Matignon Friedrich RE, MacCollin M. Molecular study of fre-
de Pontouraude CM, Rothova A, van der Horst CM. quency of mosaicism in neurofibromatosis 2 patients
Sclerotherapy for low-flow vascular malformations of with bilateral vestibular schwannomas. J Med Genet.
the head and neck: a systematic review of sclerosing 2003;40(2):109–14.
agents. J Plast Reconstr Aesthet Surg. 2016;69 Kohsaka S, Shukla N, Ameur N, Ito T, Ng CK, Wang L,
(3):295–304. Lim D, Marchetti A, Viale A, Pirun M, Socci ND, Qin
Hourani R, Taslakian B, Shabb NS, Nassar L, Hourani LX, Sciot R, Bridge J, Singer S, Meyers P, Wexler LH,
MH, Moukarbel R, Sabri A, Rizk T. Fibroblastic and Barr FG, Dogan S, Fletcher JA, Reis-Filho JS, Ladanyi
myofibroblastic tumors of the head and neck: compre- M. A recurrent neomorphic mutation in MYOD1
hensive imaging-based review with pathologic correla- defines a clinically aggressive subset of embryonal
tion. Eur J Radiol. 2015;84(2):250–60. rhabdomyosarcoma associated with PI3K-AKT path-
Howard DJ, Lund VJ, Wei WI. Craniofacial resection way mutations. Nat Genet. 2014;46(6):595–600.
for tumors of the nasal cavity and paranasal sinuses: Koike-Yusa H, Li Y, Tan EP, Velasco-Herrera Mdel C,
a 25-year experience. Head Neck. 2006;28 Yusa K. Genome-wide recessive genetic screening in
(10):867–73. mammalian cells with a lentiviral CRISPR-guide RNA
Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, library. Nat Biotechnol. 2014;32(3):267–73.
Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Koujok K, Ruiz RE, Hernandez RJ. Myofibromatosis:
Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA. imaging characteristics. Pediatr Radiol. 2005;35
SEER cancer statistics review, 1975–2013, National (4):374–80.
Cancer Institute. Bethesda: National Cancer Institute; Koutlas IG, Scheithauer BW. Palisaded encapsulated
2016. (“solitary circumscribed”) neuroma of the oral cavity:
Hurtuk AM, Marcinow A, Agrawal A, Old M, Teknos TN, a review of 55 cases. Head Neck Pathol.
Ozer E. Quality-of-life outcomes in transoral robotic 2010;4(1):15–26.
Kraus DH, Dubner S, Harrison LB, Strong EW, Hajdu SI, by multiple mucosal neuroma and its DNA analysis.
Kher U, Begg C, Brennan MF. Prognostic factors for Ann Dermatol. 2010a;22(4):452–5.
recurrence and survival in head and neck soft tissue Lee W, Jiang Z, Liu J, Haverty PM, Guan Y, Stinson J,
sarcomas. Cancer. 1994;74(2):697–702. Yue P, Zhang Y, Pant KP, Bhatt D, Ha C, Johnson S,
La Ferla L, Pinzone MR, Nunnari G, Martellotta F, Kennemer MI, Mohan S, Nazarenko I, Watanabe C,
Lleshi A, Tirelli U, De Paoli P, Berretta M, Cacopardo Sparks AB, Shames DS, Gentleman R, de Sauvage FJ,
B. Kaposi’ s sarcoma in HIV-positive patients: the state Stern H, Pandita A, Ballinger DG, Drmanac R,
of art in the HAART-era. Eur Rev Med Pharmacol Sci. Modrusan Z, Seshagiri S, Zhang Z. The mutation
2013;17(17):2354–65. spectrum revealed by paired genome sequences from
La Vecchia C, Ron E, Franceschi S, Dal Maso L, Mark SD, a lung cancer patient. Nature. 2010b;465(7297):473–7.
Chatenoud L, Braga C, Preston-Martin S, Lee EY, Kim JJ, Seok H, Lee JY. Schwannoma of
McTiernan A, Kolonel L, Mabuchi K, Jin F, the tongue: a case report with review of literature.
Wingren G, Galanti MR, Hallquist A, Lund E, Levi F, Maxillofac Plast Reconstr Surg. 2017;39(1):17.
Linos D, Negri E. A pooled analysis of case-control Lefebvre JL, Chevalier D, Luboinski B, Kirkpatrick A,
studies of thyroid cancer. III. Oral contraceptives, men- Collette L, Sahmoud T. Larynx preservation in
opausal replacement therapy and other female hor- pyriform sinus cancer: preliminary results of a
mones. Cancer Causes Control. 1999;10(2):157–66. European Organization for Research and Treatment
Landis SH, Murray T, Bolden S, Wingo PA. Cancer statis- of Cancer phase III trial. EORTC Head and Neck
tics, 1999. CA Cancer J Clin. 1999;49(1):8–31. 31 Cancer Cooperative Group. J Natl Cancer Inst.
Lassen P, Eriksen JG, Krogdahl A, Therkildsen MH, Ulhøi 1996;88(13):890–9.
BP, Overgaard M, Specht L, Andersen E, Johansen J, Lefebvre JL, Andry G, Chevalier D, Luboinski B,
Andersen LJ, Grau C, Overgaard J; Danish Head and Collette L, Traissac L, de Raucourt D, Langendijk JA,
Neck Cancer Group (DAHANCA). The influence of Head E, Neck Cancer G. Laryngeal preservation with
HPV-associated p16-expression on accelerated frac- induction chemotherapy for hypopharyngeal squamous
tionated radiotherapy in head and neck cancer: evalua- cell carcinoma: 10-year results of EORTC trial 24891.
tion of the randomised DAHANCA 6&7 trial. Ann Oncol. 2012;23(10):2708–14.
Radiother Oncol. 2011;100(1):49–55. Leung SF, Zee B, Ma BB, Hui EP, Mo F, Lai M, Chan KC,
Lawrence MS, Stojanov P, Polak P, Kryukov GV, Chan LY, Kwan WH, Lo YM, Chan AT. Plasma
Cibulskis K, Sivachenko A, Carter SL, Stewart C, Epstein-Barr viral deoxyribonucleic acid quantitation
Mermel CH, Roberts SA, Kiezun A, Hammerman PS, complements tumor-node-metastasis staging prognos-
McKenna A, Drier Y, Zou L, Ramos AH, Pugh TJ, tication in nasopharyngeal carcinoma. J Clin Oncol.
Stransky N, Helman E, Kim J, Sougnez C, 2006;24(34):5414–8.
Ambrogio L, Nickerson E, Shefler E, Cortes ML, Levine PA, Cunningham MJ, Brantley S, Barnes L,
Auclair D, Saksena G, Voet D, Noble M, DiCara D, Schramm VL Jr. Oncocytic Schneiderian papilloma in
Lin P, Lichtenstein L, Heiman DI, Fennell T, a young adult: a rare diagnosis. Otolaryngol Head Neck
Imielinski M, Hernandez B, Hodis E, Baca S, Dulak Surg. 1987;97(1):47–51.
AM, Lohr J, Landau DA, Wu CJ, Melendez-Zajgla J, Lipson EJ, Forde PM, Hammers HJ, Emens LA, Taube JM,
Hidalgo-Miranda A, Koren A, McCarroll SA, Mora J, Topalian SL. Antagonists of PD-1 and PD-L1 in cancer
Lee RS, Crompton B, Onofrio R, Parkin M, treatment. Semin Oncol. 2015;42(4):587–600.
Winckler W, Ardlie K, Gabriel SB, Roberts CW, Biegel Liu HL, Yu SY, Li GK, Wei WI. Extracranial head and neck
JA, Stegmaier K, Bass AJ, Garraway LA, Meyerson M, Schwannomas: a study of the nerve of origin. Eur Arch
Golub TR, Gordenin DA, Sunyaev S, Lander ES, Getz Otorhinolaryngol. 2011;268(9):1343–7.
G. Mutational heterogeneity in cancer and the search Lonneux M, Hamoir M, Reychler H, Maingon P,
for new cancer-associated genes. Nature. 2013;499 Duvillard C, Calais G, Bridji B, Digue L, Toubeau M,
(7457):214–8. Gregoire V. Positron emission tomography with [18F]
Lawson W, Schlecht NF, Brandwein-Gensler M. The role fluorodeoxyglucose improves staging and patient man-
of the human papillomavirus in the pathogenesis of agement in patients with head and neck squamous cell
Schneiderian inverted papillomas: an analytic overview carcinoma: a multicenter prospective study. J Clin
of the evidence. Head Neck Pathol. 2008;2(2):49–59. Oncol. 2010;28(7):1190–5.
Layfield LJ. Fine-needle aspiration in the diagnosis of head Lu B, Kumar A, Castellsague X, Giuliano AR. Efficacy and
and neck lesions: a review and discussion of problems safety of prophylactic vaccines against cervical HPV
in differential diagnosis. Diagn Cytopathol. 2007;35 infection and diseases among women: a systematic
(12):798–805. review & meta-analysis. BMC Infect Dis. 2011;11:13.
Leaute-Labreze C, Dumas de la Roque E, Hubiche T, Lu H, Liu S, Yang W, Zhang C. Unexpected extracardiac
Boralevi F, Thambo JB, Taieb A. Propranolol for multifocal adult rhabdomyomas with 10 lesions of the
severe hemangiomas of infancy. N Engl J Med. head and neck: epidemiology, diagnosis, and therapy. J
2008;358(24):2649–51. Oral Maxillofac Surg. 2017.
Lee MJ, Chung KH, Park JS, Chung H, Jang HC, Kim JW. Luna MA, Pineda-Daboin K. Cysts and unknown primary
Multiple endocrine neoplasia type 2B: early diagnosis and secondary tumours of the neck, and neck
dissection. In: Cardesa A, Slootweg PJ, editors. Pathol- kinase 4/6 inhibitor, in combination with cetuximab in
ogy of the head and neck. Berlin: Springer; 2006. patients with recurrent/metastatic head and neck squa-
p. 262–82. mous cell carcinoma. Oral Oncol. 2016;58:41–8.
Lydiatt WM, Patel SG, O’Sullivan B, Brandwein MS, Mindell RS, Calcaterra TC, Ward PH. Leiomyosarcoma of
Ridge JA, Migliacci JC, Loomis AM, Shah JP. Head the head and neck: a review of the literature and report
and neck cancers-major changes in the American Joint of two cases. Laryngoscope. 1975;85(5):904–10.
Committee on cancer eighth edition cancer staging Montgomery E, Goldblum JR, Fisher C. Leiomyosarcoma
manual. CA Cancer J Clin. 2017;67(2):122–37. of the head and neck: a clinicopathological study. His-
Lyford-Pike S, Peng S, Young GD, Taube JM, Westra WH, topathology. 2002;40(6):518–25.
Akpeng B, Bruno TC, Richmon JD, Wang H, Bishop Moore PS, Chang Y. Detection of herpesvirus-like DNA
JA, Chen L, Drake CG, Topalian SL, Pardoll DM, Pai sequences in Kaposi’s sarcoma in patients with and
SI. Evidence for a role of the PD-1:PD-L1 pathway in those without HIV infection. N Engl J Med. 1995;332
immune resistance of HPV-associated head and neck (18):1181–5.
squamous cell carcinoma. Cancer Res. 2013;73 Morrison PJ, Nevin NC. Multiple endocrine neoplasia type
(6):1733–41. 2B (mucosal neuroma syndrome, Wagenmann-
Maitra A, Baskin LB, Lee EL. Malignancies arising in Froboese syndrome). J Med Genet. 1996;33
oncocytic schneiderian papillomas: a report of 2 cases (9):779–82.
and review of the literature. Arch Pathol Lab Med. Morrison WH, Byers RM, Garden AS, Evans HL, Ang
2001;125(10):1365–7. KK, Peters LJ. Cutaneous angiosarcoma of the head
Mamelle G, Pampurik J, Luboinski B, Lancar R, and neck. A therapeutic dilemma. Cancer. 1995;76
Lusinchi A, Bosq J. Lymph node prognostic factors in (2):319–27.
head and neck squamous cell carcinomas. Am J Surg. Minovi A, Basten O, Hunter B, Draf W, Bockmuhl U.
1994;168(5):494–8. Malignant peripheral nerve sheath tumors of the head
Mancuso AA, Mukherji SK, Schmalfuss I, Mendenhall W, and neck: management of 10 cases and literature
Parsons J, Pameijer F, Hermans R, Kubilis review. Head Neck. 2007;29(5):439–45.
P. Preradiotherapy computed tomography as a predictor Mukherji SK, Bradford CR. Controversies: is there a role
of local control in supraglottic carcinoma. J Clin Oncol. for positron-emission tomographic CT in the initial
1999;17(2):631–7. staging of head and neck squamous cell carcinoma?
Mandal R, Chan TA. Personalized oncology meets immu- AJNR Am J Neuroradiol. 2006;27(2):243–5.
nology: the path toward precision immunotherapy. Munn DH. Indoleamine 2,3-dioxygenase, Tregs and can-
Cancer Discov. 2016;6(7):703–13. cer. Curr Med Chem. 2011;18(15):2240–6.
Mandal R, Senbabaoglu Y, Desrichard A, Havel JJ, Dalin Myers LL, Nussenbaum B, Bradford CR, Teknos TN,
MG, Riaz N, Lee KW, Ganly I, Hakimi AA, Chan TA, Esclamado RM, Wolf GT. Paranasal sinus malignan-
Morris LG. The head and neck cancer immune land- cies: an 18-year single institution experience. Laryngo-
scape and its immunotherapeutic implications. JCI scope. 2002;112(11):1964–9.
Insight. 2016;1(17):e89829. Nabavizadeh SA, Zimmerman RA, Mattei P, Liu GT. Infan-
Mannone F, De Giorgi V, Cattaneo A, Massi D, De tile myofibroma of the carotid space presenting as Horner
Magnis A, Carli P. Dermoscopic features of mucosal syndrome. J Neuroophthalmol. 2017;37(4):459–60.
melanosis. Dermatol Surg. 2004;30(8):1118–23. Nagornaya N, Bhatia RG. Imaging for parapharyngeal
Marks JE, Phillips JL, Menck HR. The National Cancer space tumors, LIPOMA, Encyclopedia of Otolaryngol-
Data Base report on the relationship of race and ogy, Head and Neck Surgery. Berlin: Springer; 2013.
national origin to the histology of nasopharyngeal car- Neel HB 3rd, Whicker JH, Devine KD, Weiland LH.
cinoma. Cancer. 1998;83(3):582–8. Juvenile angiofibroma. Review of 120 cases. Am J
Marocchio LS, Oliveira DT, Pereira MC, Soares CT, Surg. 1973;126(4):547–56.
Fleury RN. Sporadic and multiple neurofibromas in Negri E, Dal Maso L, Ron E, La Vecchia C, Mark SD,
the head and neck region: a retrospective study of Preston-Martin S, McTiernan A, Kolonel L,
33 years. Clin Oral Investig. 2007;11(2):165–9. Yoshimoto Y, Jin F, Wingren G, Rosaria Galanti M,
Marur S, D'Souza G, Westra WH, Forastiere Hardell L, Glattre E, Lund E, Levi F, Linos D, Braga C,
AA. HPV-associated head and neck cancer: a virus- Franceschi S. A pooled analysis of case-control studies
related cancer epidemic. Lancet Oncol. 2010;11 of thyroid cancer. II. Menstrual and reproductive fac-
(8):781–9. tors. Cancer Causes Control. 1999;10(2):143–55.
Meccariello G, Deganello A, Choussy O, Gallo O, Vitali D, Nutting CM, Morden JP, Harrington KJ, Urbano TG,
De Raucourt D, Georgalas C. Endoscopic nasal versus Bhide SA, Clark C, Miles EA, Miah AB, Newbold K,
open approach for the management of sinonasal ade- Tanay M, Adab F, Jefferies SJ, Scrase C, Yap BK,
nocarcinoma: a pooled-analysis of 1826 patients. Head A’Hern RP, Sydenham MA, Emson M, Hall E, P. t.
Neck. 2016;38(Suppl 1):E2267–74. m. group. Parotid-sparing intensity modulated versus
Michel L, Ley J, Wildes TM, Schaffer A, Robinson A, conventional radiotherapy in head and neck cancer
Chun SE, Lee W, Lewis J Jr, Trinkaus K, Adkins D. (PARSPORT): a phase 3 multicentre randomised con-
Phase I trial of palbociclib, a selective cyclin dependent trolled trial. Lancet Oncol. 2011;12(2):127–36.
O’Sullivan B, Huang SH, Siu LL, Waldron J, Zhao H, G. Randomized trial of induction chemotherapy with
Perez-Ordonez B, Weinreb I, Kim J, Ringash J, cisplatin and 5-fluorouracil with or without docetaxel
Bayley A, Dawson LA, Hope A, Cho J, Irish J, for larynx preservation. J Natl Cancer Inst. 2009;101
Gilbert R, Gullane P, Hui A, Liu FF, Chen E, Xu W. (7):498–506.
Deintensification candidate subgroups in human Posner MR, Lorch JH, Goloubeva O, Tan M, Schumaker
papillomavirus-related oropharyngeal cancer LM, Sarlis NJ, Haddad RI, Cullen KJ. Survival and
according to minimal risk of distant metastasis. J Clin human papillomavirus in oropharynx cancer in TAX
Oncol. 2013;31(5):543–50. 324: a subset analysis from an international phase III
Oganesyan G, Saha SK, Guo B, He JQ, Shahangian A, trial. Ann Oncol. 2011;22(5):1071–7.
Zarnegar B, Perry A, Cheng G. Critical role of Poveda-Roda R, Bagan JV, Sanchis JM, Margaix M.
TRAF3 in the Toll-like receptor-dependent and -inde- Pseudotumors and tumors of the temporomandibular
pendent antiviral response. Nature. 2006;439 joint. A review. Med Oral Patol Oral Cir Bucal.
(7073):208–11. 2013;18(3):e392–402.
Oguejiofor KK, Hall JS, Mani N, Douglas C, Slevin NJ, Ranee Mehra TYS, Mahipal A, Weiss J, Berger R, Eder JP,
Homer J, Hall G, West CM. The prognostic signifi- Burtness B, Tahara M, Keam B, Le DT, Muro K,
cance of the biomarker p16 in oropharyngeal squamous Geva R, Chung HC, Lin C-C, Meister A, Hille D,
cell carcinoma. Clin Oncol (R Coll Radiol). 2013;25 Cheng JD, Chow LQM, Haddad RI, Fox Chase Cancer
(11):630–8. Center, Philadelphia, PA; University of Chicago, Chi-
Osguthorpe JD. Sinus neoplasia. Arch Otolaryngol Head cago, IL; H. Lee Moffitt Cancer Center & Research
Neck Surg. 1994;120(1):19–25. Institute, Tampa, FL; Lineberger Comprehensive Can-
Owosho AABCD, Huang SCM, Chen SM, Kashikar SD, cer Center at the University of North Carolina, Chapel
Estilo CLD, Wolden SLM, Wexler LHM, Huryn JMD, Hill, NC; Sheba Medical Center, Tel Hashomer, Israel;
Antonescu CRM. A clinicopathologic study of head Yale Cancer Center, New Haven, CT; National Cancer
and neck rhabdomyosarcomas showing FOXO1 Center Hospital East, Chiba, Japan; Seoul National
fusion-positive alveolar and MYOD1-mutant scleros- University Hospital, Seoul, Korea, The Republic of;
ing are associated with unfavorable outcome. Oral Johns Hopkins University, Baltimore, MD; Aichi Can-
Oncol. 2016;61:89–97. cer Center Hospital, Nagoya, Japan; Sourasky Medical
Pai SI, Zandberg DP, Strome SE. The role of antagonists of Center, Tel Aviv, Israel; Yonsei Cancer Center, Yonsei
the PD-1:PD-L1/PD-L2 axis in head and neck cancer University College of Medicine, Seoul, Korea, The
treatment. Oral Oncol. 2016;61:152–8. Republic of; National Taiwan University Hospital, Tai-
Pleasance ED, Stephens PJ, O’Meara S, McBride DJ, pei, Taiwan; Merck & Co., Inc., Kenilworth, NJ; Seattle
Meynert A, Jones D, Lin ML, Beare D, Lau KW, Cancer Care Alliance, Seattle, WA; Dana-Farber Can-
Greenman C, Varela I, Nik-Zainal S, Davies HR, cer Institute, Boston, MA. Efficacy and safety of
Ordonez GR, Mudie LJ, Latimer C, Edkins S, pembrolizumab in recurrent/metastatic head and neck
Stebbings L, Chen L, Jia M, Leroy C, Marshall J, squamous cell carcinoma (R/M HNSCC): pooled ana-
Menzies A, Butler A, Teague JW, Mangion J, Sun lyses after long-term follow-up in KEYNOTE-012. J
YA, McLaughlin SF, Peckham HE, Tsung EF, Costa Clin Oncol. 2016;34:6012–2.
GL, Lee CC, Minna JD, Gazdar A, Birney E, Rhodes Rasmussen SA, Yang Q, Friedman JM. Mortality in neu-
MD, McKernan KJ, Stratton MR, Futreal PA, Camp- rofibromatosis 1: an analysis using U.S. death certifi-
bell PJ. A small-cell lung cancer genome with complex cates. Am J Hum Genet. 2001;68(5):1110–8.
signatures of tobacco exposure. Nature. 2010;463 Reed RJ, Fine RM, Meltzer HD. Palisaded, encapsulated
(7278):184–90. neuromas of the skin. Arch Dermatol. 1972;106
Pavlov KA, Dubova EA, Shchyogolev AI, Mishnyov (6):865–70.
OD. Expression of growth factors in endotheliocytes Reiners C, Wegscheider K, Schicha H, Theissen P,
in vascular malformations. Bull Exp Biol Med. Vaupel R, Wrbitzky R, Schumm-Draeger PM.
2009;147(3):366–70. Prevalence of thyroid disorders in the working popula-
Pignon JP, le Maitre A, Maillard E, Bourhis J, M.-N. tion of Germany: ultrasonography screening in 96,278
C. Group. Meta-analysis of chemotherapy in head and unselected employees. Thyroid. 2004;14(11):926–32.
neck cancer (MACH-NC): an update on 93 randomised Rees MG, Seashore-Ludlow B, Cheah JH, Adams DJ,
trials and 17,346 patients. Radiother Oncol. 2009;92 Price EV, Gill S, Javaid S, Coletti ME, Jones VL,
(1):4–14. Bodycombe NE, Soule CK, Alexander B, Li A,
Pisharodi LR. False-negative diagnosis in fine-needle aspi- Montgomery P, Kotz JD, Hon CS, Munoz B,
rations of squamous-cell carcinoma of head and neck. Liefeld T, Dancik V, Haber DA, Clish CB, Bittker JA,
Diagn Cytopathol. 1997;17(1):70–3. Palmer M, Wagner BK, Clemons PA, Shamji AF,
Pellitteri PK, Ferlito A, Bradley PJ, Shaha AR, Rinaldo A. Schreiber SL. Correlating chemical sensitivity and
Management of sarcomas of the head and neck in basal gene expression reveals mechanism of action.
adults. Oral Oncol. 2003;39(1):2–12. Nat Chem Biol. 2016;12(2):109–16.
Pointreau Y, Garaud P, Chapet S, Sire C, Tuchais C, Rekhi B, Upadhyay P, Ramteke MP, Dutt A. MYOD1
Tortochaux J, Faivre S, Guerrif S, Alfonsi M, Calais (L122R) mutations are associated with spindle cell
and sclerosing rhabdomyosarcomas with aggressive Weichselbaum RR, Langerman A, Portugal L,

clinical outcomes. Mod Pathol. 2016;29(12):1532–40. Blair E, Stenson K, Lingen MW, Cohen EE, Vokes
Remmelts AJ, Hoebers FJ, Klop WM, Balm AJ, EE, White KP, Hammerman PS. Integrative and com-
Hamming-Vrieze O, van den Brekel MW. Evaluation parative genomic analysis of HPV-positive and
of lasersurgery and radiotherapy as treatment modali- HPV-negative head and neck squamous cell carcino-
ties in early stage laryngeal carcinoma: tumour out- mas. Clin Cancer Res. 2015;21(3):632–41.
come and quality of voice. Eur Arch Senbabaoglu Y, Winer AG, Gejman RS, Liu M, Luna A,
Otorhinolaryngol. 2013;270(7):2079–87. Ostrovnaya I, Weinhold N, Lee W, Kaffenberger SD,
Richards ML. Familial syndromes associated with thyroid Chen YB, Voss MH, Coleman JA, Russo P, Reuter VE,
cancer in the era of personalized medicine. Thyroid. Chan TA, Cheng EH, Scheinberg DA, Li MO, Hsieh JJ,
2010;20(7):707–13. Sander C, Hakimi A. The landscape of T cell infiltration
Rischin D, Young RJ, Fisher R, Fox SB, Le QT, Peters LJ, in human cancer and its association with antigen pre-
Solomon B, Choi J, O’Sullivan B, Kenny LM, senting gene expression. bioRxiv. 2015. https://www.
McArthur GA. Prognostic significance of p16INK4A biorxiv.org/content/early/2015/09/01/025908.
and human papillomavirus in patients with oropharyn- Shalem O, Sanjana NE, Hartenian E, Shi X, Scott DA,
geal cancer treated on TROG 02.02 phase III trial. J Mikkelsen TS, Heckl D, Ebert BL, Root DE, Doench
Clin Oncol. 2010;28(27):4142–8. JG, Zhang F. Genome-scale CRISPR-Cas9 knockout
Robin PE, Powell DJ, Stansbie JM. Carcinoma of the nasal screening in human cells. Science. 2014;343
cavity and paranasal sinuses: incidence and presenta- (6166):84–7.
tion of different histological types. Clin Otolaryngol Steigman SA, Nemes L, Barnewolt CE, Estroff JA,
Allied Sci. 1979;4(6):431–56. Valim C, Jennings RW, Fauza DO. Differential risk
Robinson M, Sloan P, Shaw R. Refining the diagnosis of for neonatal surgical airway intervention in prenatally
oropharyngeal squamous cell carcinoma using human diagnosed neck masses. J Pediatr Surg. 2009;44
papillomavirus testing. Oral Oncol. 2010;46(7):492–6. (1):76–9.
Roush GC. Epidemiology of cancer of the nose and para- Soares AB, Lins LH, Macedo AP, Pereira-Neto JS, Vargas
nasal sinuses: current concepts. Head Neck Surg. PA. Fibrosarcoma originating in the mandible. Med
1979;2(1):3–11. Oral Patol Oral Cir Bucal. 2006;11(3):E243–6.
Rumboldt Z. Imaging the neck in children. Pediatr Society, A. C. Cancer facts & figures, 2015. Atlanta:
Neuroradiol. 2015. https://link.springer.com/ American Cancer Society; 2015.
referenceworkentry/10.1007%2F978-3-662-46258-4_ Spiro RH, Koss LG, Hajdu SI, Strong EW. Tumors of
65-1 minor salivary origin. A clinicopathologic study of
Sakata K, Hareyama M, Tamakawa M, Oouchi A, Sido M, 492 cases. Cancer. 1973;31(1):117–29.
Nagakura H, Akiba H, Koito K, Himi T, Asakura K. Spitz MR. Epidemiology and risk factors for head and neck
Prognostic factors of nasopharynx tumors investigated cancer. Semin Oncol. 1994;21(3):281–8.
by MR imaging and the value of MR imaging in the Stampfli MR, Anderson GP. How cigarette smoke skews
newly published TNM staging. Int J Radiat Oncol Biol immune responses to promote infection, lung disease
Phys. 1999;43(2):273–8. and cancer. Nat Rev Immunol. 2009;9(5):377–84.
Sanger F, Nicklen S, Coulson AR. DNA sequencing with Stransky N, Egloff AM, Tward AD, Kostic AD,
chain-terminating inhibitors. Proc Natl Acad Sci U S A. Cibulskis K, Sivachenko A, Kryukov GV, Lawrence
1977;74(12):5463–7. MS, Sougnez C, McKenna A, Shefler E, Ramos AH,
Schaer DA, Budhu S, Liu C, Bryson C, Malandro N, Stojanov P, Carter SL, Voet D, Cortes ML, Auclair D,
Cohen A, Zhong H, Yang X, Houghton AN, Berger MF, Saksena G, Guiducci C, Onofrio RC,
Merghoub T, Wolchok JD. GITR pathway activation Parkin M, Romkes M, Weissfeld JL, Seethala RR,
abrogates tumor immune suppression through loss of Wang L, Rangel-Escareno C, Fernandez-Lopez JC,
regulatory T cell lineage stability. Cancer Immunol Res. Hidalgo-Miranda A, Melendez-Zajgla J, Winckler W,
2013;1(5):320–31. Ardlie K, Gabriel SB, Meyerson M, Lander ES,
Scudellari M. HPV: sex, cancer and a virus. Nature. Getz G, Golub TR, Garraway LA, Grandis JR. The
2013;503(7476):330–2. mutational landscape of head and neck squamous cell
Seashore-Ludlow B, Rees MG, Cheah JH, Cokol M, Price carcinoma. Science. 2011;333(6046):1157–60.
EV, Coletti ME, Jones V, Bodycombe NE, Soule CK, Szabo G. The number of melanocytes in human epidermis.
Gould J, Alexander B, Li A, Montgomery P, Wawer Br Med J. 1954;1(4869):1016–7.
MJ, Kuru N, Kotz JD, Hon CS, Munoz B, Liefeld T, Szuhai K, de Jong D, Leung WY, Fletcher CD,
Dancik V, Bittker JA, Palmer M, Bradner JE, Shamji Hogendoorn PC. Transactivating mutation of the
AF, Clemons PA, Schreiber SL. Harnessing connectiv- MYOD1 gene is a frequent event in adult spindle
ity in a large-scale small-molecule sensitivity dataset. cell rhabdomyosarcoma. J Pathol. 2014;232(3):
Cancer Discov. 2015;5(11):1210–23. 300–7.
Seiwert TY, Zuo Z, Keck MK, Khattri A, Pedamallu CS, Teng MW, Galon J, Fridman WH, Smyth MJ. From mice to
Stricker T, Brown C, Pugh TJ, Stojanov P, Cho J, humans: developments in cancer immunoediting. J
Lawrence MS, Getz G, Bragelmann J, DeBoer R, Clin Invest. 2015;125(9):3338–46.
Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/ Westra WH, Taube JM, Poeta ML, Begum S,
B7-H1(PD-L1) pathway to activate anti-tumor immu- Sidransky D, Koch WM. Inverse relationship between
nity. Curr Opin Immunol. 2012;24(2):207–12. human papillomavirus-16 infection and disruptive
Trevino-Gonzalez JL, Santos-Lartigue R, Gonzalez- p53 gene mutations in squamous cell carcinoma
Andrade B, Villagomez-Ortiz VJ, Villegas M, of the head and neck. Clin Cancer Res.
Venegas-Garcia EM. Angiosarcoma of the nasal cavity: 2008;14(2):366–9.
a case report. Cases J. 2009;2(1):104. Wingo PA, Ries LA, Rosenberg HM, Miller DS, Edwards
de Trey LA, Schmid S, Huber GF. Multifocal adult BK. Cancer incidence and mortality, 1973–1995: a
rhabdomyoma of the head and neck manifestation in report card for the U.S. Cancer. 1998;82
7 locations and review of the literature. Case Rep (6):1197–207.
Otolaryngol. 2013;2013:758416. WHO Classification of Head and Neck Tumours. WHO
Tucker T, Wolkenstein P, Revuz J, Zeller J, Friedman JM. Classification of Tumours, 4th Edition, Volume 9. Edited
Association between benign and malignant peripheral by El-Naggar AK, Chan JKC, Grandis JR, Takata T,
nerve sheath tumors in NF1. Neurology. Slootweg PJ. IARC Publications. 2017. http://publica
2005;65(2):205–11. tions.iarc.fr/Book-And-Report-Series/Who-Iarc-Classi
van der Wal JE. Granular cell tumor, dental and oral, fication-Of-Tumours/Who-Classification-Of-Head-And-
Encyclopedia of Pathology. Switzerland: Springer Neck-Tumours-2017
International Publishing; 2016. p. 202–4. Wall J, Sylvester K, Albanese C. Lymphatic malformations
van der Waal I. Diseases of the oral mucosa and soft in children. In: Puri P, editor. Pediatric surgery. Ger-
tissues: general aspects, Atlas of Oral Diseases. Berlin: many: Verlag GmbH Springer; 2016.
Springer; 2016. p. 7–66. Walter V, Yin X, Wilkerson MD, Cabanski CR, Zhao N,
Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Du Y, Ang MK, Hayward MC, Salazar AH, Hoadley
Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, KA, Fritchie K, Sailey CJ, Weissler MC,
Cupissol D, Peyrade F, Benasso M, Vynnychenko I, Shockley WW, Zanation AM, Hackman T, Thorne
De Raucourt D, Bokemeyer C, Schueler A, Amellal N, LB, Funkhouser WD, Muldrew KL, Olshan AF,
Hitt R. Platinum-based chemotherapy plus Randell SH, Wright FA, Shores CG, Hayes
cetuximab in head and neck cancer. N Engl J Med. DN. Molecular subtypes in head and neck cancer
2008;359(11):1116–27. exhibit distinct patterns of chromosomal gain and
Vikram B, Mishra UB, Strong EW, Manolatos S. Patterns loss of canonical cancer genes. PLoS One.
of failure in carcinoma of the nasopharynx: I. Failure 2013;8(2):e56823.
at the primary site. Int J Radiat Oncol Biol Phys. Woodruff JM. The pathology and treatment of peripheral
1985;11(8):1455–9. nerve tumors and tumor-like conditions. CA Cancer J
Villa A, Nordio F, Strohmenger L, Abati S. Clin. 1993;43(5):290–308.
Clinical–pathologic agreement for oral lesions in Yoshitake Y, Fukuma D, Yuno A, Hirayama M,
an oral medicine setting. Am J Oral Med. Nakayama H, Tanaka T, Nagata M,
2016;2(1):1–10. Takamune Y, Kawahara K, Nakagawa Y,
Wang T, Wei JJ, Sabatini DM, Lander ES. Genetic screens Yoshida R, Hirosue A, Ogi H, Hiraki A, Jono H,
in human cells using the CRISPR-Cas9 system. Sci- Hamada A, Yoshida K, Nishimura Y, Nakamura Y,
ence. 2014;343(6166):80–4. Shinohara M. Phase II clinical trial of multiple
Ward MJ, Thirdborough SM, Mellows T, Riley C, Harris S, peptide vaccination for advanced head and neck cancer
Suchak K, Webb A, Hampton C, Patel NN, Randall CJ, patients revealed induction of immune responses
Cox HJ, Jogai S, Primrose J, Piper K, Ottensmeier and improved OS. Clin Cancer Res. 2015;21(2):
CH, King EV, Thomas GJ. Tumour-infiltrating 312–21.
lymphocytes predict for outcome in HPV-positive Yu Y, Flint AF, Mulliken JB, Wu JK, Bischoff J.
oropharyngeal cancer. Br J Cancer. 2014; Endothelial progenitor cells in infantile hemangioma.
110(2):489–500. Blood. 2004;103(4):1373–5.
Waldron CA, El-Mofty SK, Gnepp DR. Tumors of the Zak FG, Lawson W. The presence of melanocytes in
intraoral minor salivary glands: a demographic and the nasal cavity. Ann Otol Rhinol Laryngol.
histologic study of 426 cases. Oral Surg Oral Med 1974;83(4):515–9.
Oral Pathol. 1988;66(3):323–33. Zandberg DP, Strome SE. The role of the PD-L1:PD-1
Weber RS, Benjamin RS, Peters LJ, Ro JY, Achon O, pathway in squamous cell carcinoma of the head and
Goepfert H. Soft tissue sarcomas of the head and neck in neck. Oral Oncol. 2014;50(7):627–32.
adolescents and adults. Am J Surg. 1986;152(4):386–92. Zhang L, Wu HW, Yuan W, Zheng JW. Propranolol therapy
Wenig BM. Nasopharyngeal carcinoma. Ann Diagn for infantile hemangioma: our experience. Drug Des
Pathol. 1999;3(6):374–85. Dev Ther. 2017;11:1401–8.
Westra WH. The changing face of head and neck cancer in Zheng JW, Zhou Q, Yang XJ, Wang YA, Fan XD, Zhou
the 21st century: the impact of HPV on the epidemiol- GY, Zhang ZY, Suen JY. Treatment guideline for hem-
ogy and pathology of oral cancer. Head Neck Pathol. angiomas and vascular malformations of the head and
2009;3(1):78–81. neck. Head Neck. 2010;32(8):1088–98.
Zidar N. Branchial cyst in head and neck pathology. In: immunosubversion. Nat Rev Immunol. 2006;6
Volavšek M, editor. Encyclopedia of pathology. Swit- (10):715–27.
zerland: Springer International Publishing; 2016. Ziyeh S, Strecker R, Berlis A, Weber J, Klisch J, Mader
p. 43–6. I. Dynamic 3D MR angiography of intra- and extracra-
Zitvogel L, Tesniere A, Kroemer G. Cancer despite nial vascular malformations at 3T: a technical note.
immunosurveillance: immunoselection and AJNR Am J Neuroradiol. 2005;26(3):630–4.
Cutaneous Pathology of the Head and
Neck
Tami Yap, Johannes S. Kern, Benjamin Wood, and

Laura Scardamaglia
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 764
Skin Cancers and Premalignant Cutaneous Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 765
Actinic Keratosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 765
Actinic Cheilitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 766
Basal Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767
Squamous Cell Carcinoma and Keratoacanthoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 768
Malignant Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 770
Common Benign Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 774
Sebaceous Hyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 774
Milia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 775
Xanthelasma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 775
Telangiectasia/Spider Nevi/Venous Lakes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 776
Cherry Angioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 777
Benign Pigmented Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 778
Nevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 778
Dysplastic Nevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 781
Ephilides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 782
Solar Lentigo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 783
Seborrheic Keratoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 783
T. Yap
Melbourne Dental School, University of Melbourne,
Department of Dermatology, Royal Melbourne Hospital,
e-mail: tspyap@unimelb.edu.au
J. S. Kern · L. Scardamaglia (*)
Department of Dermatology, Royal Melbourne Hospital,
e-mail: Johannes.Kern@mh.org.au;
Laura.Scardamaglia@mh.org.au
B. Wood
QEII Medical Centre, Nedlands, WA, Australia
e-mail: benjamin.wood@health.wa.gov.au

https://doi.org/10.1007/978-3-319-72303-7_24
764 T. Yap et al.
Pigmentation Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 784

Vitiligo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 784
Melasma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 786
Postinflammatory Pigment Alteration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 787
Infectious Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 789
Herpes Simplex Virus 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 789
Varicella Zoster Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 790
Impetigo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 791
Erysipelas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 792
Tinea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 793
Common Dermatological Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 794
Acne . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 794
Rosacea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 795
Perioral Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 797
Seborrheic Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 797
Eczema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 798
Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 799
Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 801
Alopecia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 802
Autoimmune and Immune-Mediated Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 803
Pemphigus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 803
Pemphigoid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805
Bullous Pemphigoid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805
Mucous Membrane Pemphigoid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 806
Linear IgA Bullous Dermatosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 808
Lupus Erythematosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 809
Dermatomyositis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 810
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 811
Abstract Keywords
Cutaneous pathology spans the diverse vari- Cutaneous · Pathology · Head · Neck · Face ·
able landscape of the head and neck, including Squamous cell carcinoma · Basal cell
the periorbital and periocular regions, scalp, carcinoma · Melanoma · Nevus · Skin cancer ·
face, and neck. Ranging from solar ultraviolet Pigmentation · Cheilitis · Dermatitis
radiation exposure-related neoplasms to
chronic inflammatory-mediated conditions,
clinical diagnosis, and management often Introduction
calls for multidisciplinary care. In appreciation
for the expanse of cutaneous conditions that Clinical diagnosis and management of cutaneous
may present in the head and neck, this chapter pathology of the head and neck falls under the
presents a selection of more commonly pre- auspices of multiple specialties, including derma-
senting cutaneous pathology in this area. Con- tology, otolaryngology, oral and maxillofacial sur-
ditions described include skin cancers and gery, plastic surgery, ophthalmology, oral medicine,
premalignant cutaneous conditions, benign and dentistry. In addition, head and neck lesions
tumors, benign pigmented lesions and disor- constitute a significant proportion of those cutane-
ders, infectious conditions, autoimmune disor- ous tumors that require management under multi-
ders, and other common dermatological disciplinary teams, including surgeons, radiation,
conditions. and medical oncologists. Diverse anatomical
Cutaneous Pathology of the Head and Neck 765
regions including the perioral region, periorbital development of a clinical lesion in AK.
region, ears, scalp, face, and neck can be involved Particularly, the specific effect on the p53 tumor
by regionally specific pathological processes and suppressor gene, including its impact on apopto-
can present unique surgical and cosmetic chal- sis, has been demonstrated as causal in animal
lenges when involved by common processes. and humans models (Leffell 2000). Infection
The majority of diseases involving the skin can with Beta human papillomavirus and altered
manifest in the head and neck region. local immunity associated with ultraviolet expo-
sure may also play a role (Weissenborn et al.
2005).
Skin Cancers and Premalignant
Cutaneous Conditions Clinical Features
AKs are typically located in areas that receive
Actinic Keratosis the most sun exposure such as on the scalp, face,
lateral neck, and dorsal forearms and hands.
Epidemiology They present as erythematous and scaly plaques
Actinic keratosis (AK) (solar keratosis) are com- or papules, typically with a “sandpaper” texture
mon benign but dysplastic epidermal lesions. AKs (Fig. 1). Some lesions are pigmented. The
occur most commonly in individuals with pale majority of AKs undergo regression, with more
skin phototypes (Table 1) and are secondary to than 50% not present at the 1-year follow-up,
chronic sun exposure. Reported AK prevalence and 70% not present at the 5-year follow-up
ranges from 11% to 25% in northern hemisphere (Criscione et al. 2009). The risk of malignant
populations. Among Australian adults the range is transformation of a solar keratosis to squamous
from 40% to 60% (Frost et al. 2000). Prevalence cell carcinoma (SCC) within 1 year is likely less
increases with age. than 1/1000. However, 60% of primary SCCs
may arise from a lesion diagnosed clinically as
Etiology a solar keratosis in the previous year (Marks
Exposure to solar ultraviolet radiation is the prin- et al. 1988).
cipal cause of AK. The major risk factors are male An individual with existing AKs is more likely
sex, advanced age, sun-sensitive complexion, to develop additional AKs than an individual with
high lifetime sun exposure, and prolonged immuno AKs (Frost et al. 2000). Further, individuals
nosuppression (Green 2015). with more than 10 AKs have up to a 14% likeli-
hood of developing an SCC within 5 years. Thus,
Pathophysiology they are considered a reliable marker for those
Ultraviolet radiation leads to mutations in multi-
ple genes controlling cell proliferation with the
resulting clonal expansion leading to the
Table 1 Fitzpatrick skin phototype

Skin
Typea Features Burn Tan
I Pale white skin Yes No
II Fair skin Yes Minimal
III Darker white skin Yes Yes
IV Light brown skin No Yes
V Brown skin No Yes
VI Dark brown or black No Yes
skin
a
Adapted from Fitzpatrick 1988 Fig. 1 Actinic keratosis on the forehead
766 T. Yap et al.
people most predisposed to development of an treatments, diclofenac, 5-fluorouracil, imiquimod,

invasive SCC (Salasche 2000). and ingenol mebutate were similarly efficacious,
but varied in their adverse events and cosmetic
Pathologic Features outcomes (Gupta et al. 2012).
AKs are characterized histologically by para-
keratosis, interspersed with tiers of orthokeratotic
keratin overlying the ostia of adnexal structures Actinic Cheilitis
(Fig. 2). There is often budding elongation of the
rete ridges, with cytological atypia of squamous Epidemiology
keratinocytes in the basal layer and lower epider- Actinic cheilitis (solar cheilitis or cheilosis,
mis. The term “bowenoid actinic keratosis” is actinic keratosis of the lip) is most commonly
used for lesions that display full-thickness epider- due to chronic sun exposure and is typically seen
mal dysplasia and is considered synonymous with on the lower lip of adults with fair skin who have
carcinoma in situ. The identification of early inva- significant sun exposure, such as agricultural
sive carcinoma in some examples of actinic kera- workers, and may be as common as 9–40%
tosis is somewhat arbitrary (Ackerman and Mones (Junqueira et al. 2011; de Oliveira Ribeiro et al.
2006), with some authors using terms such as 2014; Wang et al. 2015; Campisi and Margiotta
“proliferative actinic keratosis” to denote lesions 2001; de Souza Lucena et al. 2012).
at this morphological borderline (Goldberg et al.
1994). Etiology
Sun exposure is the most common causal factor. It
Patient Management may be more extensive and aggressive in those
Prevention, with sun avoidance and sun protec- with a genetic photosensitivity disorder such as
tion, is a simple but effective measure. Topical xeroderma pigmentosum, or those with immuno-
treatments include fluorouracil, imiquimod, suppression. Smokers have a greater risk of devel-
keratolytics, ingenol mebutate, diclofenac, and oping carcinoma (Jadotte and Schwartz 2012a).
retinoids, hile physical measures include cryother-
apy, photodynamic therapy, facial peels, and laser Pathophysiology
ablative resurfacing. Rarely, systemic therapy As with actinic keratosis, UV (ultraviolet)
with oral retinoids may be required. A Cochrane radiation-induced DNA damage leads to morpho-
review in 2012 found photodynamic therapy logical changes of keratinocytes. There are also
superior to cryotherapy in efficacy and cosmetic immunological alterations, adhesion molecule
outcome for individual lesions. For field-directed expression, and inhibition of antigen-presenting
cell function that may lead to significantly reduced
immune response (Clydesdale et al. 2001).
Clinical Features
Over 90% of cases involve the lower lip, as this
has the most UV radiation exposure (Fig. 3). The
affected lip is often dry, scaly, fragile, cracked,
with thickened plaques and papules. There may
also be white or yellow areas, with crusting, ero-
sions, or focal ulceration. There may be focal
tenderness.
Pathologic Features
Actinic cheilitis represents actinic keratosis of the
Fig. 2 Actinic keratosis, Hematoxylin and eosin, 100 lip. The degree of cytological atypia is often subtle
Etiology
As with most skin cancers, UV radiation is the
most common trigger. However, immunosuppres-
sion, carcinogens such as arsenic or tar, trauma
such as scars and tattoos, genetic susceptibility
as well as some inherited syndromes such as
Gorlin Syndrome, Bazex-Dupre-Christol syn-
drome, Xeroderma Pigmentosum, Epidermo-
dysplasia Verruciformis, and Rombo syndrome
confer a high risk of developing these tumors
(Fogel et al. 2017).
Fig. 3 Actinic cheilitis of the lower vermilion zone
Pathophysiology
Both genetic susceptibility and UV damage
and the appearances complicated by surface ero- account for genetic changes underpinning BCC.
sion, ulceration, and inflammatory changes. In Embryonic fusion planes on the face are sites with
these circumstances, it can be difficult to deter- a much higher incidence. Abnormalities in the
mine whether true dysplasia is present. sonic hedgehog signaling pathway are considered
to be pathogenic and have particular relevance to
Patient Management the uncommon scenarios of syndromic occur-
As with AK, the key to prevention is UV radiation rence (Gorlin syndrome) and medical manage-
avoidance. Patients should also be counseled to ment of advanced lesions with specific inhibitors
avoid smoking and minimize alcohol intake, as (Silapunt et al. 2016).
these factors increase the risk of progression to
squamous cell carcinoma (Cavalcante et al. 2008). Clinical Features
Topical treatments are similar to those for AK, and The most common clinical presentations of
physical treatments may include surgical exci- BCC include a progressing papule/nodule with
sion, or complete removal of the external lip a characteristic “pearly” surface and telangiectases;
(vermilionectomy) via surgery or laser ablation an ulcerated nodule; an ulcerated or infiltrating
(Shah et al. 2010; Jadotte and Schwartz 2012b). plaque (Fig. 4). Subtle pigmentation is not uncom-
Vermilionectomy allows histopathologic inspec- mon and occasionally lesions can display prominent
tion of the entire vermilion including the possibil- pigmentation (pigmented basal cell carcinoma) that
ity of SCC not seen on biopsy (Menta Simonsen can raise concern for a melanocytic lesion. More
Nico et al. 2007). ominous lesions can present with more extensive
subtle indurated scar like plaques resembling
morphea (“morpheic BCC”) and occasionally pain,
Basal Cell Carcinoma anesthesia, or other neuropathic symptoms may be
present, suggesting neural invasion.
Epidemiology
Basal cell carcinoma (BCC) is the most common Pathologic Features
type of invasive skin cancer, particularly in areas The histogenesis of BCC is disputed, though com-
with fair skinned populations and high UV expo- pelling evidence now indicates predominant follic-
sure. BCC is most often found over the head and ular differentiation. The diverse clinical
neck, as well as on the shoulders and arms. They presentations show correlation with histological
are typically indolent, slow-growing tumors, subtypes, which, while sometimes distinct, are com-
which only very rarely metastasize. The prognosis monly seen admixed in various combinations. Com-
is excellent and the main impact is morbidity, mon to most patterns is a proliferation of “basaloid”
not mortality. epithelial cells, characterized by hyperchromatic
768 T. Yap et al.
Fig. 4 Ulcerated basal cell carcinoma on outer canthus
nuclei, relatively scant cytoplasm with areas of Fig. 5 Basal cell carcinoma, Hematoxylin and eosin
stain, 100
peripheral palisading and clefting separation
between the epithelial cells and the adjacent stroma
(Fig. 5). Extracellular connective tissue mucin is treatment with Hedgehog pathway inhibitors such
frequently present. Small foci of squamoid differen- as vismodegib or sonidegib is usually reserved for
tiation are frequently present and do not warrant advanced forms and patients with Gorlin Syn-
separate designation unless extensive/distinct (vide drome. Treatment is curative in more than 95%
infra). The common growth patterns include nodu- of cases, with a 5-year recurrence rate of approx-
lar, infiltrating, and superficial types. More aggres- imately 5%.
sive subtypes include micronodular and sclerosing/
morpheic. There is some variability in the use of the
term “metatypical,” though as employed by the Squamous Cell Carcinoma
authors this refers to a tumor that shows histological and Keratoacanthoma
features intermediate between BCC and squamous
cell carcinoma. In this approach, the term Epidemiology
“basosquamous” is employed to describe tumors Squamous cell carcinoma (SCC) is the second most
that show distinct components resembling BCC common nonmelanoma skin cancer accounting for
and squamous cell carcinoma. Both of these approximately one-third of cases. It usually arises
patterns appear to be overrepresented among tumors from the squamous cells in the epidermis, and may
with aggressive behavior and among the very rare grow quickly and metastasize if left untreated. It is
reported examples of metastatic BCC (Garcia et al. more common in males, in those with significant
2009). cumulative sun exposure, those with fair skin, and
older age groups. Keratoacanthoma is a related
Patient Management lesion with distinctive clinical behavior, typically
As with other skin cancers, avoidance of sun involving rapid development of a crateriform lesion
exposure is an important part of management. with subsequent involution if untreated.
Treatments vary depending on the site, size,
histological type, and patient factors. Etiology
In the majority, surgery is the treatment of Sixty percent of primary SCCs may arise from a
choice, and techniques involve excision, curettage lesion diagnosed clinically as a solar keratosis
and diathermy, and Mohs surgery. Some cases in the previous year, while 40% may arise from
are adequately treated with topical agents such normal skin (Marks et al. 1988). As with the other
as 5-fluorouracil, imiquimod, and tazarotene. skin cancers, UV radiation and immunosuppres-
Physical treatments include cryotherapy, photo- sion, particularly following organ transplantation,
dynamic therapy, and radiation therapy. Systemic are risk factors for developing SCC. Human
Papillomavirus is associated with some cases and

some genetic disorders (e.g., xeroderma
pigmentosum) confer extreme susceptibility.
Pathophysiology
Multiple genomic mutations lead to development
of SCC, preceded theoretically by a precursor
lesion with genetic instability (AKs). Studies
have demonstrated overexpression of ras, Fyn/
SFKs, c-myc, bcl-2, STTA-3, β-1 integrin, and
MMP and under expression of p53, Srcasm,
Notch, PKC δ, and E-cadherin in the development Fig. 6 Pigmented Bowen’s disease/squamous cell carci-
noma in situ involving cheek/nasolabial fold
of cutaneous SCC (Ratushny et al. 2012). For
example, approximately 58% of cutaneous SCCs
harbor a UVB signature mutation of p53 (Brash
et al. 1991).
Clinical Features
AKs are the most important risk factor identifying
those most predisposed to the development of an
SCC (Salasche 2000). Bowen’s disease/SCC in
situ are slowly growing erythematosquamous
plaques and they can be pigmented (Figs. 6 and 7).
Invasive SCCs often present as a tumor or shallow
ulcer, and may be tender, crusted, indurated, or
keratotic (Fig. 8).
Fig. 7 Bowen’s disease, Hematoxylin and eosin, 100
Pathologic Features
Invasive SCC is characterized by irregular infil-
trating cords and sheets of cytologically atypical
squamous keratinocytes. Squamous differentia-
tion is manifest as keratin production in the form
of squamous pearls, single cell keratinization,
and/or in the formation of intercellular bridges.
The prominence of features of squamous differ-
entiation is used to separate tumors into well,
moderately, and poorly differentiated groups.
Metastasis of SCC of sun-damaged skin is not
common (Smoller 2006). Numerous features have
been associated with a higher risk of metastasis or
poorer prognosis in multiple studies. Most of
these features are intuitively obvious. For the pur-
poses of staging, invasion of underlying structures
defines T3 or T4 disease, with size greater than
2 cm or presence of two or more “high risk fea-
tures” separating T1 and T2 disease. “High-risk
features” are defined as tumor thickness >2 mm; Fig. 8 Poorly differentiated cutaneous squamous cell
Clark level IV or greater; perineural invasion; carcinoma on nose
770 T. Yap et al.
location on the ear or nonhair bearing lip; poorly patients with less favorable outcomes following
differentiated or undifferentiated histology. surgery. Chemotherapy may be required as adju-
The diagnosis of keratoacanthoma has excited vant therapy in high risk cases or metastatic SCC.
considerable discussion and controversy in Topical chemotherapy (5-fluorouracil) may be
the literature (Weedon et al. 2010). Nevertheless, used to treat some cases of SCC in situ, and serial
the histological features of classical examples are cryotherapy may be employed for older patients
sufficiently stereotypical as to allow their imme- with Bowen’s disease in difficult surgical and
diate recognition. The classical keratoacanthoma poor healing sites, such as the lower leg. Systemic
is a cup-shaped endophytic squamoproliferative oral retinoids may be useful in aiming to decrease
lesion, with a central plug of thick keratin, resem- the incidence in patients who have already had
bling in silhouette a cross section of an early numerous SCCs or in those with long-standing
volcano (Fig. 9). The lower border has a immunosuppression such as organ transplant
circumscribed appearance at low power and the patients. Recently studies have shown that oral
lesion is composed of squamous keratinocytes nicotinamide may confer some preventative pro-
with a mild or moderate degree of cytological tection, and as always, prevention of sun exposure
atypia. Central to the diagnosis is the presence of and education is also critical. In general,
a predominant population of cells with volumi- keratoacanthoma should be managed as for SCC.
nous “glassy” eosinophilic cytoplasm. Small col-
lections of neutrophils are often present within the
epithelium and the surrounding inflammatory Malignant Melanoma
infiltrate often contains moderate numbers of
eosinophils. Regressing lesions are characterized Epidemiology
by a cup-shape, with a central keratin plug, a Melanoma is a malignant neoplasm arising from
peripheral rim of attenuated squamous epithelium the malignant transformation of the primary pig-
that lacks the voluminous eosinophilic cytoplasm ment (melanin) producing cell, the melanocyte,
of classical lesions, and an underlying scar. which resides in the skin, in the basal layer of
the epidermis. It accounts for less than 2% of
Patient Management skin cancers, but is responsible for the majority
Surgical excision or Mohs surgery is the mainstay of deaths, particularly in younger people (Torres
of treatment. Curettage and diathermy may be et al. 2017). The incidence of melanoma has been
considered for low risk tumors in low risk sites. steadily increasing worldwide. It is most common
Radiation therapy is used as an adjunct for high in palest skin phototypes, Fitzpatrick skin types
risk lesions or as a definitive treatment in older I-II (Table 1; Parkin et al. 2011).
Etiology
Several factors are important in the pathogenesis
of melanoma. The majority of melanomas that
occur in the head and neck region are of the
type associated with chronic sun damage. Other
types of melanoma, including mucosal mela-
noma, retinal melanoma, melanoma unassociated
with chronic sun damage, and melanoma arising
in pre-existing lesions (e.g., giant congenital
melanocytic nevi) also occur.
Pathophysiology
Solar radiation is implicated in the development of
Fig. 9 Keratoacanthoma, Hematoxylin and eosin stain, 20 many melanomas. Ultraviolet radiation, especially
UVA (320–400 nm) and UVB (290–320 nm wave-

length), appear to be both inducers of malignant
transformation, as well as being potent immunosup-
pressors of the skin, and trigger free radical produc-
tion, induce melanocyte cell division, and damage
melanocyte DNA (Shain and Bastian 2016).
Clinical Features
Melanoma most commonly presents as a new
pigmented lesion on a sun exposed site, or a
changing pigmented lesion. The most important
signs are those of change in size, shape, or color.
The ABCDE rule is used as a screening guide;
A = Asymmetry, where one side is not the same as

the other
B = Border, where the edge is irregular, ragged,
indistinct, or sharply cut off
C = Color, where there are more than two colors, Fig. 10 Lentigo maligna (melanoma in situ) on cheek
and there is differing shades or brown, black, (a) close-up view (note central scar from biopsy), and
white, red, blue or pink. with dermoscopy detail (b)
D = Diameter, where the lesion is greater than
6 mm in size. be seen in more established areas. In many lesions,
E = Evolving, where the lesion is changing in the histological features can vary from area to area,
size, shape or color. with some foci displaying only a very subtle
increase in melanocytes and others showing features
This is a useful tool in the majority of mela- that can resemble solar lentigo or junctional
nomas, but is not helpful in distinguishing melanocytic nevus. In this regard, if partial biopsy
amelanotic, mucosal, or nodular types. Non- samples are taken, it is vital that these are interpreted
healing/ulcerative lesions, nodules, change in sen- in conjunction with the clinical differential diagno-
sation, swelling, oozing or bleeding may be other sis. The diagnosis of “junctional melanocytic
clinical clues (Figs. 10, 11, and 12). nevus” or “dysplastic junctional melanocytic
A careful history is a critical guide in determin- nevus” in severely sun-damaged skin from the
ing whether change has occurred, elucidating head and neck region should not be accepted with-
other risk factors, and a thorough examination to out question and should never be rendered on a
check other nevi, freckling, lymph nodes, and partial biopsy sample.
organomegaly. Some melanomas, particularly on intermittently
sun exposed or sun protected sites in middle aged
Pathologic Features patients, display a more prominently nested and
The majority of lesions on head and neck skin arise Pagetoid in situ component and are referred to as
in the setting of chronic sun-exposure and many superficial spreading melanoma (Fig. 11). It should
have an extended in situ phase, with a slowly be noted that this designation is defined by the
expanding pigmented patch, referred to as lentigo pattern of intraepidermal growth and does not refer
maligna (melanoma in situ). Lentigo maligna is to the depth of the lesion, i.e., a superficial spreading
characterized by growth of atypical melanocytes in melanoma can extend deeply into the dermis or
linear array at the junction, typically in thin epider- subcutis, without altering the nomenclature.
mis, overlying dermis that displays prominent solar The clinical development of plaques or nodules
elastosis (Fig. 13). Formation of junctional nests can within areas of melanoma in situ is an ominous
772 T. Yap et al.
Fig. 12 Nodular malignant melanoma involving hairline
Fig. 13 Lentigo maligna, Hematoxylin and eosin

stain, 200
Fig. 11 Superficial spreading melanoma on forehead

overview (a), close-up view (b), and with dermoscopy (c)
between 1 mm and 4 mm Breslow thickness, in
which it provides prognostic information. The use
of this technique in the head and neck region is
sign, typically heralding the development of inva- somewhat limited by the anatomical complexities
sive melanoma. As elsewhere in the body, inva- of lymph node drainage in this area and false
sive melanoma is characterized by nests, cords, negative sentinel lymph node biopsy is more com-
and sheets of atypical melanocytes within the der- mon in this region (Lee et al. 2016).
mis (Fig. 14). Prognosis is intimately linked to the In some cases, melanoma develops as a rapidly
thickness of the tumor (Breslow thickness), which progressing nodule without clinical evidence of
is measured in millimeters from the top of the a pre-existing in situ component. When such
granular layer to the deepest invasive cell. Addi- lesions show an absent or limited (less than 3 rete
tional prognostic information is provided by ridges beyond the dermal lesion) in situ compo-
assessing for the presence of dermal mitotic activ- nent, they are referred to as nodular melanoma.
ity (particularly in melanomas less than 1 mm While the majority of lesions that appear to repre-
Breslow thickness) and ulceration. Sentinel sent nodular melanoma are established to be pri-
lymph node biopsy may be considered for lesions mary, it is always prudent to review the history and
cases of lentigo maligna, which is frequently

poorly circumscribed, with a periphery which is
difficult to define both clinically and pathologi-
cally. There is some variation in margin recom-
mendations for invasive melanoma, with a
minimum 10 mm clinical margin typically
recommended for invasive tumors. Some suggest
a larger (20 mm) clinical margin for lesions
greater than 2 mm Breslow thickness. In the
head and neck region, these recommendations
must be balanced against cosmetic and functional
considerations, and there is limited evidence that
larger re-excision margins give a better prognosis.
Fig. 14 Invasive melanoma, Hematoxylin and eosin Desmoplastic and/or neurotropic melanomas are
stain, 100
often excised with wider (e.g., 20 mm) margins
and adjuvant radiotherapy may be employed in
examination findings in such lesions to exclude the some cases (Wood 2013).
possibility of a cutaneous metastasis of melanoma. Sentinel lymph node biopsies are used in some
A small number of melanomas present without centers to identify clinically occult nodal involve-
clinical pigmentation (amelanotic melanoma) or ment, which provides prognostic information, and
with a “scar-like” appearance (desmoplastic mela- may be used for entry into trials of adjuvant ther-
noma). The latter can be particularly difficult apy. Primary analysis of a large randomized con-
to diagnose, both clinically and histologically trolled trial found that sentinel node biopsy did not
(Wood 2013). The head and neck region, particu- provide an overall survival benefit, though sub-
larly the scalp, is a relatively frequent site for the group analysis suggested a potential benefit in a
development of unusual melanocytic tumors, small number of patients (Morton et al. 2014;
including “atypical Spitz tumor,” “Spitzoid mela- Madu et al. 2017; Sladden et al. 2015; Faries
noma,” “atypical cellular blue nevus,” and “blue et al. 2015, 2017). Staging PET scan is indicated
nevus-like melanoma” among others. These lesions for patients at high risk of metastatic disease (e.g.,
are disproportionately seen among children and primary melanoma greater than 4 mm Breslow
young adults (Wood 2016). The behavior of these thickness, satellite deposits), and imaging is also
lesions can be difficult to predict with certainty from appropriate for patients with clinically palpable
their histological features, though typically the prog- lymph nodes, organomegaly, possible neurologi-
nosis is better than might be inferred from analogy cal or other organ involvement, and in patients
with conventional melanoma showing equivalent with cutaneous metastases.
Breslow thickness or nodal involvement. Medical treatment of metastatic melanoma is
rapidly evolving, with older and relatively ineffec-
Patient Management tive therapies such as dacarbazine and interferon
The key to management of melanoma is surgical alpha now largely replaced by targeted therapies
excision as early as possible, ideally before inva- (e.g., combination BRAF and MEK inhibitors) or
sive growth has occurred. In general, the aim is to immunomodulatory therapy (e.g., PD1 and CTLA-
establish the diagnosis with an excisional biopsy 4 inhibitors). The optimal timing and combination
with 2 mm clinical margins (where this is feasible of these treatments is the subject of intensive cur-
and cosmetically acceptable); then to re-excise rent investigation and developments in this field are
depending on the histological features found. In ameliorating the heretofore dismal prognosis of
situ melanomas are normally definitively excised advanced melanoma.
with a 5 mm re-excision margin, though some Patient education, avoidance of sun exposure,
data indicate this may be insufficient for some and surveillance for the development of new
774 T. Yap et al.
primary lesions (in addition to surveillance for Clinical Features

recurrence) represent important aspects of long Occurring typically on the forehead, cheeks,
term follow up. Recurrence of melanoma is not and nose, sebaceous hyperplasia may be single
uncommon. Of stage I and II melanoma, patients or multiple and appear as yellowish papules
followed for 36 months after undergoing sentinel (Fig. 15), often with surrounding prominent
lymph node biopsy, 47% experienced recurrence, blood vessels (telangiectases). They are occasion-
compared with 14% sentinel lymph node negative ally also found in the mouth, or on the genitals,
patients (Dalal et al. 2007). Late recurrence rates areolae and chest.
have been reported at were 6.8% and 11.3% at
15 and 20 years, respectively (Faries et al. 2013). Pathologic Features
Based on TNM classification, 5-year survival Sebaceous hyperplasia is characterized by the pres-
rates of localized melanoma range from 97% ence of a discrete lesion composed of increased
patients with T1aN0M0 melanomas to 53% numbers of normal sebaceous glands attached to a
for patients with T4bN0M0 melanomas. Regional follicular canal (Fig. 16). There is frequently slight
metastatic melanoma 5-year survival ranges from acanthosis of the overlying epidermis. This
70% for patients with T1-4N1aM0 melanomas
to 39% for patients with T1-4N3M0 melanomas.
Distant metastatic melanoma 1-year survival
however ranged from 62% for M1a to 33% for
M1c melanomas (Dalal et al. 2007; Faries et al.
2013; Balch et al. 2009).
For discussion on further malignancies of the
head and neck, refer to separate chapters entitled
▶ “Head and Neck Tumors” and ▶ “Oral Mucosal
Malignancies.”
Common Benign Tumors

Fig. 15 Sebaceous hyperplasia on forehead (Image cour-
Sebaceous Hyperplasia tesy of Clinical Associate Professor Kurt Gebauer, Derma-
tology West, Perth WA, Australia)
Epidemiology, Etiology,
and Pathophysiology
Sebaceous hyperplasia, a benign enlargement
of sebaceous glands, is common in individuals
of middle age and over. They are considered a
feature of photoaging although “premature seba-
ceous hyperplasia” can occur in younger people.
They have also been reported in up to 30% of
individuals on cyclosporine. Sebaceous glands
are part of the pilosebaceous unit but occasionally
open directly onto the epithelial skin. On the lips
and buccal mucosae, they are known as Fordyce
spots, the genital mucosa: Montogomery glands,
and the eyelids: Meibomian glands. Androgens
have a significant impact on the growth and activ- Fig. 16 Sebaceous hyperplasia, Hematoxylin and
ity of sebaceous glands. eosin, 20
architecture leads to the formation of a small

domed papule with a central umbilication. When
these architectural features are not demonstrated
(e.g., in small or superficial biopsy samples), care
must be taken not to over interpret the prominent
sebaceous glands normally seen in the central face
as representing sebaceous hyperplasia.
Patient Management
These are benign lesions removed for esthetic
purposes, or because they resemble BCC, for
diagnostic confirmation. A number of surgical
and ablative modalities are used, including fine
wire diathermy and ablative lasers, as well as
topical or systemic retinoids (Simmons et al.
2015; McDonald et al. 2011).
Fig. 17 Milia on forehead presenting as small white pap-

Milia ules (Image courtesy of Clinical Associate Professor Kurt
Gebauer, Dermatology West, Perth WA, Australia)
and Pathophysiology
Patient Management
Milia are keratin filled cysts. They may occur
Most congenital milia will resolve. In adults,
at any time in life. Congenital milia may occur
they may resolve spontaneously, may respond
in up to 50% of infants. Milia are considered to
to topical keratolytics and retinoids, but may
be due to retention of keratin and sebaceous
also be removed by fine wire diathermy, or inci-
material in the pilosebaceous structures or eccrine
sion of the overlying epidermis and expression of
sweat ducts. They may occur with or without
the contents.
superficial trauma.
Clinical Features Xanthelasma

Milia present as 1–2 mm white to yellowish pap-
ules, typically on the face (Figs. 17 and 18). Some Epidemiology, Etiology,
reports include gingival and palatal presentations and Pathophysiology
(Epstein’s pearls and Bohn’s nodules, respec- Xanthelasma are yellowish plaques most com-
tively), although others have attributed these to monly found around the eyelid, especially near
remaining odontogenic epithelium (Cohen 1984). the inner canthus on the upper lid. These are
known as xanthelasma palpebrum. Although not
Pathologic Features particularly common, xanthelasma is the most
Milia are characterized by the formation of common type of xanthoma. Xanthomas develop
small follicular infundibular (epidermoid) through several mechanisms and may be symp-
cysts, lined by stratified squamous epithelium toms of a lipoprotein disorder in up to half
with a granular layer and containing lamellated of presenting individuals (Bergman 1994).
keratin. The histological differential diagnosis Xanthomas are depositions of yellowish choles-
includes steatocystoma, which displays a terol rich material, and frequently occur in
crenellated lining with sebaceous lobules in patients with type II hyperlipidemia and the type
the wall. IV phenotype.
776 T. Yap et al.
Fig. 18 Pseudocysts and solar elastosis of Favre- Fig. 19 Xanthelasma lower eyelid/inner canthus
Racouchot syndrome should be distinguished clinically
from milia (Image courtesy of Clinical Associate Professor
Kurt Gebauer, Dermatology West, Perth WA, Australia)
Telangiectasia/Spider Nevi/Venous
Lakes
Clinical Features Epidemiology, Etiology,

Xanthelasma may present as a well or and Pathophysiology
ill-defined macule, papule, patch, or plaque. Telangiectasia, spider nevi/angiomas, and venous
They are characteristically yellow to orange lakes are not vascular proliferations, but dilations
in hue (Fig. 19). They are often symmetrical of preexisting vessels (Requena and Sangueza
and more often over the upper lids than lower 1997). Telangiectasia, persistent dilated capil-
eyelids. They often slowly progress and coa- laries in the superficial dermis are common benign
lesce with time, and usually do not self- cutaneous findings in the head and neck, com-
resolve. Patients usually present with concern monly seen in middle-aged to older patients.
regarding appearance as they are typically Spider nevi or spider angiomas may be more
asymptomatic. common in younger people and additionally in
pregnant individuals in the second to fifth month
Pathologic Features of pregnancy (Elling and Powell 1997). Venous
Xanthelasma show aggregates of foamy (lipid- lakes commonly occur on the lips in older
laden) macrophages in the dermis, often with a individuals.
perivascular distribution. There is sometimes a
sparse lymphocytic infiltrate. Clinical Features
Telangiectasia can appear as fine red to purple
Patient Management lines and typically blanch with pressure
Investigation for hyperlipidemia is warranted (diascopy) (Fig. 20). They are most often associ-
(Segal et al. 1986). Those with a younger onset ated with rosacea and may be a variant of this
or strong family history of hyperlipidemia are disorder.
more likely to have an underlying lipid disorder. Spider nevi present as a central papule that
They can be a predictor or risk for myocardial represents the central arteriole, with a radiating
infarction, ischemic heart disease, severe ath- pattern of visible capillaries, thus the name “spi-
erosclerosis, and death in the general popula- der” nevus. They commonly present on the face,
tion. Treatment methods include surgical particularly around the eye (Fig. 21).
excision, blepharoplasty, cryotherapy, electro- Venous lakes typically appear as blue papules
cauterization, chemical cauterization (e.g., tri- or nodules, but they may also occur intraorally.
chloroacetic acid), and laser ablation (Gungor They typically blanch with compression but may
et al. 2014). also be thrombosed (Fig. 22).
Fig. 22 Thrombosed varix on lower lip

Fig. 20 Telangiectasia on face (Image courtesy of Clinical
Associate Professor Kurt Gebauer, Dermatology West, through the dermis, with superficial thin walled
Perth WA, Australia) channels radiating from the superficial portion.
Venous lakes are characterized by a solitary
ectatic thin walled vascular space, often filled with
blood or fibrin thrombus, within the upper dermis.
Avariety of other benign vascular lesions, includ-
ing malformations and benign neoplasms are seen
on the head and neck skin. These include lobular
capillary hemangioma (pyogenic granuloma), arte-
riovenous hemangioma, epithelioid hemangioma
(angiolymphoid hyperplasia with eosinophilia),
and lymphatic lesions such as lymphangioma
circumscriptum (superficial lymphangioma). A
facial vascular malformation, capillary malforma-
tion/port wine stain may be an isolated finding, or
may be seen as part of Sturge-Weber Syndrome.
Patient Management
Dilated capillaries do not need to be removed unless
the diagnosis is unclear or due to esthetic reasons.
Recurrence is an issue. They are usually best
removed with vascular laser therapy, but cryother-
Fig. 21 Spider nevi on nose (Image courtesy of Clinical
Associate Professor Kurt Gebauer, Dermatology West, apy or electrosurgery may also be utilized.
Pathologic Features Cherry Angioma

Telangiectasia represents the dilatation of venules
within the superficial dermis. They are only occa- Epidemiology, Etiology,
sionally biopsied (e.g., due to concern for BCC). and Pathophysiology
Facial telangiectasias are seen in hereditary hem- Cherry angiomas or Campbell de Morgan spots
orrhagic telangiectasia (Osler-Rendu-Weber dis- represent the most common vascular skin tumors
ease) and ataxia-telangiectasia (Mortimer and and are due to a benign proliferation of small
Burnand 2008). vessels in the upper dermis. They typically appear
Spider nevi are also common but rarely biopsied at 40–50 years of age and tend to increase in
lesions. These lesions are characterized by a “feed- number and size with time. They are more com-
ing” ascending arteriole ascending vertically mon on the trunk than on the head and neck.
778 T. Yap et al.
Clinical Features common acquired nevi carry the V600E BRAF

Cherry angiomas appear as dome-shaped papules mutation, which appears to be tumorigenic.
less than 5 mm in diameter (Fig. 23). They may Other mutations (e.g., NRAS mutations) are more
appear darkly pigmented and may occasionally common in larger congenital nevi and a range of
mimic melanoma. Dermatoscopic presence of mutually exclusive tumorigenic genetic abnor-
red-purple or blue-black lagoons is characteristic, malities (e.g., tyrosine kinase fusions, G-protein
and will identify that they are truly vascular, with mutations) are recognized in specific types of nevi
no melanin pigment at all. such as Spitz nevi and blue nevi (Shain and
Bastian 2016; Wiesner et al. 2014). Common
Pathologic Features acquired nevi usually present in early childhood
Histologically cherry angiomas show a papular or and continue to evolve in the first three decades,
slightly polypoid proliferation of dilated vascular and then slowly involute in older age. The peak
channels within the superficial dermis. incidence of acquired nevi is in the fourth to
fifth decade of life. There is a very low prevalence
Patient Management in the elderly as they tend to disappear in
They may be treated for esthetic reasons with advanced years.
the same modalities as other vascular prolifera-
tions above. Clinical Features
Nevi can be found anywhere on the body. They
are classified by their appearance in the skin and
Benign Pigmented Lesions their histological subtype as either junctional
(Fig. 24), compound (Fig. 25), or intradermal. In
Nevi lighter skin types, they are often over the torso and
particularly where there has been sun exposure. In
Epidemiology, Etiology, darker skin types, they are more commonly found
and Pathophysiology in acral areas. They are typically brown, ranging
As many as 22% of a fair-skinned population have from pale or even red in those with lighter skin
100 nevi or more, and only 18% fewer than type, to dark brown, and are usually uniform in
25 (Augustsson et al. 1991). The majority of shape. They may have hair, but this has no impact
Fig. 23 Cherry angioma

(hemangioma) (a), and with
dermoscopy (b)
on determining benignity versus malignancy.

They are typically evenly colored and less than
10 mm in diameter. On the face, there are often
intradermal nevi, which may have minimal pig-
mentation and mainly be flesh colored raised pap-
ules (Fig. 26), often with increased numbers of
hairs. Some individuals will have amelanotic
nevi, deep nevi which appear blue (Fig. 27), or
red or pink nevi. The term “dysplastic nevus” is
variably applied to lesions that display clinical
and/or histological irregularities.
Pathologic Features
Melanocytic nevi are benign proliferations of
melanocytes, the pigment producing cell in the
skin. Lesions may be (Augustsson et al. 1991)
intraepidermal (junctional melanocytic nevi),
have both an intraepidermal and intradermal com-
ponent (compound melanocytic nevi), or be
entirely intradermal. With age, the junctional
component tends to diminish such that purely
junctional nevi are uncommon in older adult
patients. Pigmentation varies, with most lesions
becoming less pigmented with age. Congenital
Fig. 24 Junctional nevus (a), and with dermoscopy (b) melanocytic nevi are recognized at birth or shortly
after. These lesions can range in size, from
Fig. 25 Compound nevus (a), dermoscopy (b)

780 T. Yap et al.
Fig. 26 Intradermal nevus
Fig. 28 Intradermal nevus, Hematoxylin and eosin

stain, 20
Fig. 29 Compound melanocytic nevus, Hematoxylin and

eosin stain, 200
display a papillated architecture with papillary der-

mal expansion and are designated Unna’s nevus.
Fig. 27 Blue nevus (a), dermoscopy (b) Common acquired melanocytic nevi tend to be
small, circumscribed and symmetrical. If there is
an intraepidermal component it is present as nests
clinically unapparent to giant lesions that cover an at the dermo-epidermal junction (Fig. 29). The
entire body segment. The risk of developing mel- constituent cells are cytologically bland and tend
anoma in such lesions is proportional to the size of to show “maturation” with descent into the der-
the lesion, being considerable in large and giant mis, becoming smaller with more compact chro-
lesions. Many acquired melanocytic nevi of the matin. Somewhat counterintuitively, dispersal of
face are intradermal, with a domed surface and single cells between dermal collagen fibers (rather
deep reticular dermal extension, a pattern referred than compact growth) at the deep aspect of the
to as Meischer’s nevus (Fig. 28). Other lesions, lesion is a reassuring finding. Mitotic figures are
seen more frequently on the posterior scalp, absent or rare.
Blue nevi are a specific subset of Dysplastic Nevi

melanocytic nevi, characterized by the pres-
ence of melanocytes within the dermis having Epidemiology
dendritic processes, often highlighted by Dysplastic nevi are thought to occur in a signifi-
intracytoplasmic melanin pigment. There is cant proportion of the population. In Australia and
typically a background of thickened collagen New Zealand, the prevalence is reported as
fibers and scattered melanophages (Fig. 30). 5–10%, with those with the lightest skin photo
The distinctive “blue” pigmentation seen clin- types, typically those of Northern European
ically is due to scattering of light by the Tyn- of Celtic racial backgrounds, with light hair,
dall effect. eyes, and freckles, having the highest number.
They are rare in Asian, Black, or Middle Eastern
Patient Management populations. They tend to develop in the earlier
Melanocytic nevi are benign and if they are not decades of life, but may appear at any age, and
changing, or becoming clinically suspicious, no may change or involute throughout adulthood.
treatment is required. Change in the nevus, partic-
ularly rapid change, in size, shape, or color is the Etiology
key factor on history taking. Dermatoscopy or These are clinically and histologically irregular
serial mapping photography are useful tools for melanocytic nevi. These acquired melanocytic
clinical examination by an experienced clinician. lesions are more common in lighter skin photo
Large congenital melanocytic nevi need regular types, and are found more often in those with
monitoring, especially in childhood as there is a significant sun exposure and sunburn histories,
significant risk of malignant transformation as well as in some families (dysplastic nevus
(Wood 2016). Patient education about self-exam- syndrome). Genetic factors, skin photo type, and
ination is the mainstay of skin surveillance, as UV exposure are the key etiological features.
well as strict sun protection. Ideally children
should be protected from the sun to remove the Pathophysiology
major etiological factor triggering nevi and Germline mutations in three genes, CDK2NA,
increasing the risk of malignancy. If treatment CDK4, and CMM1 have been linked to a subset
is required for esthetic reasons or for a chang- of familial and inherited melanomas and dyspla-
ing nevus, excisional surgical removal is the pre- stic nevi. Ultraviolet light is thought to both
ferred method. initiate and promote the development and trans-
formation of dysplastic nevi and melanoma.
Clinical Features
Dysplastic nevi tend to be irregular in either
size, shape, or color, but are not as irregular as
the typical findings in melanoma. The terms atyp-
ical nevus and dysplastic nevus are used inter-
changeably; however correctly, atypical nevus is
a clinical descriptor, and dysplastic nevus the his-
tological term. There is an increased risk of devel-
oping melanoma both in the dysplastic nevus and
elsewhere in the body, especially if there are six or
more on an individual.
Typically, they are larger than benign
melanocytic nevi, may have irregular borders,
may have “target” or “fried egg” appearance of
Fig. 30 Blue nevus, Hematoxylin and eosin stain, 100 their pigment, or may have raised components of
782 T. Yap et al.
the center or the edge (Fig. 31). Often, serial generally be by complete excision. Lesions con-
observation with clinical and/or photographic sidered to be “severely dysplastic” histologically
monitoring is implemented to ensure there is no should always be excised with clear margins
rapid change to suggest malignant transformation. (including re-excision if margins are involved).
If there is only one dysplastic nevus, or a regular A more nuanced approach to re-excision may be
nevus has changed to look dysplastic, often the tenable for lesions with “mild dysplasia.”
clinical management involves removing it to
ensure there is no malignant transformation.
Ephilides
Pathologic Features
Dysplastic nevi are characterized by varying Epidemiology, Etiology,
degrees of architectural “atypia” including the pres- and Pathophysiology
ence of a junctional component extending beyond Commonly known as freckles, ephilides are par-
the intradermal component, bridging growth join- ticularly common in those from racial back-
ing adjacent rete ridges and lamellar fibroplasia of grounds with pale skin living in areas with
the papillary dermis. In addition, some degree of significant UV exposure. They often present in
cytological atypia is seen, though assessment of childhood.
this is extremely subjective in practice. In general, UV exposure is the key factor. They may be
dysplastic nevi are not common on the head and particularly prevalent in some tumor syndromes
neck region and are seldom seen on sun-damaged such as xeroderma pigmentosum. UV exposure
facial skin. In the latter location, melanoma with triggers the melanocyte to produce melanin that
dysplastic nevus-like features is a serious consid- is released to protect the skin from harmful rays.
eration. However, a number of atypical features In darker skin types, a tan will occur, but in those
that show some overlap with the changes described with more phaeomelanin than eumelanin, a
in dysplastic nevi are a feature of nevi on the auricle freckle ensues. Those that experience significant
and scalp (particularly in adolescent patients) (Saad sunburn, especially blistering ones, will often
et al. 2005; Fabrizi et al. 2007). have long-term freckling in the sunburnt
area that do not fade with time and are a marker
Patient Management of significant sun exposure.
Management of dysplastic nevi is similar to
benign nevi except that these tend to be reviewed Clinical Features
more often, and require prompt action if there is Ephilides are small macules typically arising in
any suggestion of malignancy. Biopsy should sun exposed areas including the face (Fig. 32).
They are most common in fair skinned individ-
uals, especially redheads with familial clustering
a feature. They can increase in summer and fade
in winter.
Pathologic Features
An ephelis is characterized by an increase in basal
keratinocyte pigmentation, without evidence of a
melanocytic or keratinocytic proliferation.
Patient Management
These are benign lesions, and the key factor is to
ensure that there isn’t a malignant lesion within
the field of ephilides, as typically they are an
Fig. 31 Dysplastic nevus outer canthus indicator of significant sun exposure beyond that
Fig. 33 Solar lentigines can look clinically indistinguish-

able from lentigo maligna and should be carefully investi-
gated (Image courtesy of Clinical Associate Professor Kurt
Fig. 32 Ephilides (freckles) (Image courtesy of Clinical Gebauer, Dermatology West, Perth WA, Australia)
Associate Professor Kurt Gebauer, Dermatology West,
occur (Fig. 33). They may also enlarge and darken
which the skin phototype can handle without over time or alternatively, fade. They may look
some mild damage. For esthetic purposes similar to lentigo simplex, ephilides, junctional
bleaching cream, peels, topical retinoids, and pig- nevi, pigmented actinic keratosis, and reticulated
ment lasers may be useful. The simplest measure seborrheic keratoses.
is to ensure that strict sun protection is employed
to prevent further freckling. Pathologic Features
Solar lentigines are characterized by budding
elongation of the rete ridges with an increase in
Solar Lentigo basal keratinocyte pigmentation. The architectural
features are not well developed in some lesions
Epidemiology, Etiology, from the face. In other lesions, the architecture
and Pathophysiology overlaps with reticular seborrheic keratosis.
Solar lentigines are associated with skin photo- There is also not infrequently morphological over-
types that are more prone to sunburn. It is lap and/or merging with areas of (pigmented)
suggested that up to 90% of individuals over actinic keratosis.
60 years of age with such skin types have solar
lentigines, and the prevalence increases with age. Patient Management
Solar lentigines are likely to occur in a susceptible Reduction of sun exposure is fundamental to pre-
individual who has had accumulated UVR expo- vention of further solar lentigines. They may not
sure or intermittent high-intensity exposure. Their require therapy once present but topical retinoids
presence is considered a risk factor for the devel- and peels, cryotherapy, lasers, or intense pulsed
opment of melanoma, SCC, and BCC. light (IPL) may present options. Typically, hydro-
quinone has no effect.
Clinical Features
Solar lentigines occur in sun-exposed areas, par-
ticularly at sites of greatest cumulative exposure, Seborrheic Keratoses
including the face. They may also occur due to
therapeutic UV exposure, although this is not well Epidemiology
supported in the literature. They appear as demar- Seborrheic keratoses are very common cutaneous
cated pigmented macules, frequently multiple, are tumors. Prevalence increases from 12% of 12–25-
typically light brown, though black variants may year-olds to up to 100% of those aged more than
784 T. Yap et al.
50 years (Yeatman et al. 1997). More than one-third variety of architectural patterns. There is typically
of patients present with more than 15 seborrheic abundant delicate orthokeratotic hyperkeratosis
keratoses lesions (Jackson et al. 2015), and up to on the surface. The most common patterns include
40% will have lesions localized to the face (Kyriakis acanthotic epidermal expansion with pseudo-horn
et al. 2012). Seborrheic keratosis is the most com- cysts, a papillated architecture and a reticular
mon benign epidermal tumor of skin, typically aris- architecture (Fig. 35). The keratinocytes fre-
ing in middle-age, although they may present quently contain prominent melanin pigmentation,
earlier. They occur in all racial types, but may though genuine proliferation of scattered dendritic
have differing appearances in size or shape or color. melanocytes within the lesion is an uncommon
finding (melanoacanthoma). Some lesions show
Etiology a prominent inflammatory reaction that can be
Seborrheic keratoses remain idiopathic, although associated with surface parakeratosis and reactive
factors including sun exposure, genetics, and infec- atypia of the keratinocytes. In such lesions, sepa-
tion are likely to play a role. The majority represents ration from genuine dysplasia (bowenoid transfor-
monoclonal neoplasms (Nakamura et al. 2001). The mation) can be problematic.
role of HPV has been considered due to clinical
similarities with warts, though it is doubtful that the Patient Management
presence of HPV is a causative factor, and in fact Removal may be required due to clinical
there are no viral features in seborrheic keratoses, suspicion (Squillace et al. 2016). Otherwise,
nor are they contagious (Li et al. 2004). these lesions may be removed if they are symp-
tomatic or for esthetic reasons. Modalities include
Pathophysiology surgical excision, cryotherapy, laser ablation,
Seborrheic keratoses are thought to result as a electrocautery, curettage, dermabrasion, and topi-
clonal expansion of a mutated epidermal cal therapies (e.g., fluorouracil, keratolytics, and
keratinocyte. They have a higher proliferative retinoids). Complications include recurrence,
rate than normal keratinocytes, and apoptosis scarring, and alteration in pigmentation.
is suppressed compared with healthy skin.
Clinical Features Pigmentation Disorders

Seborrheic keratoses may occur in isolation or
number in the hundreds. They appear on any Vitiligo
nonmucosal surface and may be distributed
along skin folds. Clinical appearance, in particular Epidemiology
color, may be variable but they usually begin as Vitiligo is the most common disorder of pigmen-
flat, well demarcated tan to brown patches. Over tation with a frequency of 0.1–2.0% (Alkhateeb
time they may become papular and verrucous with et al. 2003). Half of all patients develop the dis-
pseudo horn cysts (Fig. 34). Development of ease before age 20 years (Alikhan et al. 2011), and
malignancy in these lesions, including melanoma, it is uncommonly seen in old age. Approximately
SCC, and BCC, has been reported and so clinical one-third of patients have a familial history of
dermatological expertise, including dermoscopy, either vitiligo or other autoimmune disease.
is required for the assessment of these lesions.
Closely related lesions include dermatosis Etiology
papulosa nigra, stucco keratosis, inverted follicu- The etiology of vitiligo remains unclear although
lar keratosis, and flat seborrheic keratosis. various hypotheses have been suggested.
It is an acquired depigmentary disorder; how-
Pathologic Features ever, family clustering of vitiligo suggests a
Seborrheic keratosis is a benign proliferation of genetic basis for the disease. It is further likely
uniform cuboidal keratinocytes that can show a that generalized vitiligo shares common genetic
Fig. 34 Large flat

seborrheic keratosis on
cheek (a), and popular
seborrheic keratosis (b).
Seborrheic keratosis on
forehead (c), and
dermoscopy seborrheic
keratosis on forehead with
typical horn cysts (d)
etiologic links with some autoimmune disorders in innate immune response and T-cell–mediated
(Alkhateeb et al. 2003). More than 50 genes have melanocyte destruction (Rashighi and Harris 2017).
been evaluated for links in vitiligo, however, few
present clear associations. The most commonly Clinical Features
associated autoimmune disorder is thyroid disease Generalized vitiligo, involving the face and
associations (Iannella et al. 2016). acral regions, is the most common clinical presen-
tation (Fig. 36). Spontaneous repigmentation may
Pathophysiology occur in a few people (10–20%), mainly in chil-
Pathogenesis of vitiligo involves multifactorial dren, but this tends to be only partial. Cutaneous
interaction of intrinsic defects, which reduce the and/or mucous membranes may be involved.
capacity to manage cellular stress, the exposure The lesions are classically depigmented and well
to particular environment factors, and defects demarcated, may range in size from millimeters
786 T. Yap et al.
Fig. 36 Vitiligo
UVB light being preferred, and a form of laser

Fig. 35 Acanthotic seborrheic keratosis, Hematoxylin with the same wavelength can provide more
and eosin stain, 40
targeted foci for sensitive localized areas. Surgical
methods have shown promise in stable or segmen-
to centimeters, and may have various levels tal vitiligo plaques, where grafts are taken from
of pigmentation included normal pigmentation, pigmented donor skin and reconstituted into the
hypopigmentation, and depigmentation within vitiligo patches. In some cases, where there is a
the one area. strong family history of autoimmune disease, it is
helpful to screen patients for underlying thyroid or
Pathologic Features other autoimmune involvement. Vitamin D and
Vitiligo is characterized in its early stages by a nicotinamide (Vitamin B3) are occasionally
subtle lichenoid interface inflammatory reaction. supplemented but the role of these has not ade-
As the lesions develop there is loss of melanocytes quately been proven to date.
in the basal layer and an absence of melanin
pigmentation. These features are often best
revealed by staining with SOX10 and Masson Melasma
Fontana respectively.
Epidemiology
Patient Management Reported prevalence of melasma ranges from
This is an unpredictable and at times frustrating 8.8% among Latino females in Texas to 40% in
condition to treat, as not all patients respond well Southeast Asia (Werlinger et al. 2007; Sheth and
to any form of treatment. The closer to the periph- Pandya 2011). Melasma is much more common in
eries, the “lip-tip” type of vitiligo affecting the women, being affected in 90% of cases. It is very
hands, feet, and around the mouth, is often the rare before puberty and commonly occurs in
most recalcitrant to treatment. Patients should be women during their reproductive years.
counselled and advised about this and expectations
for complete repigmentation should be conserva- Etiology
tive at best. Camouflage make-ups can be very The major factor in the development of melasma
effective for cosmesis. The simplest form of active is a genetic predisposition, with up to half of all
treatment is to use topical steroids and calcineurin patients having a positive family history. The
inhibitors in areas where steroids are best avoided, other main factor is sunlight. Two other contrib-
such as the face and in sensitive flexures. Pulse uting factors to the onset of melasma are hormonal
steroids may also be useful in those with acutely ones, particularly pregnancy, and the oral contra-
active vitiligo, and some modalities include week- ceptive pill. Thyroid disease is also often associ-
end only use of oral dexamethasone pulsing. Pho- ated in patients with melasma compared to control
totherapy may also be useful, with narrowband (Ortonne et al. 2009).
Pathophysiology brown, but dermal melasma may also be evident

Melasma is an acquired hypermelanosis, but the and will thus be more blue or black. It is unclear
pathophysiology is uncertain. There seems to be a why only certain parts of the face are involved
direct relationship with estrogen, with females (Passeron 2013).
being more commonly affected, and pregnancy
(melasma is known as chloasma in this specific Pathologic Features
scenario) a common trigger, with up to one half of Melasma is characterized pathologically by
all cases presenting initially during pregnancy increased pigmentation of the basal layer and
(Ortonne et al. 2009). Estrogen receptor expres- often by small numbers of melanophages in the
sion appears to be upregulated in melasma superficial dermis. Distinction of the former find-
lesions, and other factors implicated in the patho- ing from variation in constitutional skin pigmen-
genesis are photosensitizing medications. The tation can be difficult in the absence of an
most important factor in the pathophysiology of appropriate clinical history or photograph.
melasma is sunlight, and overexpression of c-kit
(the tyrosine kinase receptor) and certain stem cell Patient Management
factors have been identified in melasma lesions, Prevention relies on broad spectrum sunscreen
and these aim in increasing pigmentation via and sun avoidance. First-line therapy usually
melanogenesis (Demirkan et al. 2017; Kang consists of topical compounds that affect the
et al. 2006). pigment production pathway and camouflage
(Sheth and Pandya 2011). The most common
Clinical Features topical treatment for melasma is hydroquinone
Melasma is an irregular brown or grayish-brown although other lightening agents used include
facial hypermelanosis with those of Fitzpatrick retinoic acid and azelaic acid, sometimes com-
skin phototypes III and IV the most commonly bined with corticosteroids. Laser, IPL and chem-
affected, although any skin type may develop ical therapies are also utilized but also carry a
this (Fig. 37). Melasma is typically seen over significant risk of worsening the disease. Novel
the cheeks, forehead, and upper lip in trials include kojic acid, isopropylcatechol,
sun-exposed areas of the face of susceptible N-acetyl-4-cysteaminylphenol, and flavonoid
women. It may also occur over the nose, chin, extracts (Gupta et al. 2006). Most recently
and jawline. It is often more obvious in summer low-dose oral tranexamic acid has been found
months, following more prolonged sun expo- to be successful for some patients. Regardless
sure. It is macular in nature, and usually tan to of response, melasma often recurs, requiring
retreatment, and without strict sun exposure pre-
vention, most treatments will fail.
Postinflammatory Pigment Alteration
Epidemiology
Postinflammatory pigment alteration (PIPA)
develops after an inflammatory process of the
skin such as acne, folliculitis, eczema, or frictional
irritation and thus epidemiologically follows the
distribution of these conditions in darker skin
individuals. Postinflammatory hyperpigmentation
Fig. 37 Melasma appearing as irregular brown pigmenta-
has been reported at rates of four fold in darker
tion on the face (Image courtesy of Clinical Associate
Professor Kurt Gebauer, Dermatology West, Perth WA, skinned individuals when compared to lighter
Australia) skinned individuals (Chang 2012).
788 T. Yap et al.
Etiology hypopigmentation. They both often spontane-

Etiology of postinflammatory pigment alteration ously resolve, although timing and complete res-
is wide ranging and includes infections, allergic olution is variable. PIPA distributes according to
reactions after insect bites or a contact dermatitis, the initial inflammatory process. Epidermal
papulosquamous diseases (e.g., eczema, psoria- hypermelanosis will appear tan, brown, or dark
sis, lichen planus), medication-induced, or fric- brown and may take months to years to resolve
tional, thermal or chemical injury. Very common without treatment. When the hyperpigmentation
causes include acne vulgaris, atopic dermatitis, is within the dermis, the appearance will be blue-
and impetigo, with at least half of darker-skinned gray that may even be permanent without
individuals experiencing acne-induced posttreatment.
inflammatory hyperpigmentation (Taylor et al.
2002). Pathologic Features
PIPA is characterized by the accumulation
Pathophysiology of macrophages containing melanin pigment
PIPA is the overproduction of melanin or an (melanophages) in the upper dermis. In some
irregular pigment dispersion following inflamma- cases, features of an underlying inflammatory
tion. It may be confined to the epidermis or process (e.g., cutaneous lupus erythematosus,
involve the dermis. Increase in melanocytic activ- regression of a solar lentigo/benign lichenoid ker-
ity is likely stimulated by prostanoids, cytokines, atosis) are apparent, while in other cases a specific
chemokines, and other inflammatory mediators as etiology cannot be determined histologically at
well as reactive oxygen species resulting from the this stage. The uncommon finding of expansile
inflammatory process. nodules of melanophages (tumoral melanosis) is
always an ominous finding, usually associated
Clinical Features with regression of a melanoma (Grohs and
PIPA can be an increase or loss of pigmen- Mesbah Ardakani 2017).
tation following inflammation (Fig. 38). Post-
inflammatory hyperpigmentation is seen much Patient Management
more frequently than postinflammatory Prevention includes the use of sunscreen, treatment
of the underlying dermatosis, and avoiding irritating
topical agents. Observation and time are usually the
only treatment required, as PIPA often resolves
spontaneously, although it may take many months
and occasionally years. First-line therapy typically
consists of topical agents such as tyrosinase inhib-
itors (e.g., hydroquinone), azelaic acid, kojic acid,
arbutin, and certain licorice extracts. Other agents
include retinoids, mequinol, ascorbic acid, niacin-
amide, and N-acetyl glucosamine (Gupta et al.
2006; Taylor et al. 2009; Amer and Metwalli
2000; Hakozaki et al. 2002; Boissy et al. 2005).
Pigmentation refractory to topical therapy may
require procedural options, such as chemical peel-
ing and laser therapy. All treatments carry the risk of
worsening postinflammatory alteration, particularly
in more pigmented skin phototypes.
For discussion of intraoral pigmented lesions,
Fig. 38 Post inflammatory hyperpigmentation associated refer to the chapter on ▶ “Pigmented Lesions of
with acne vulgaris (arrow) the Oral Mucosa.”
Infectious Diseases skin adjacent to the nostril. There may be a pro-

dromal prickling sensation preceding vesicle for-
Herpes Simplex Virus 1 mation (McCullough and Savage 2005). The
lesions of secondary infection are usually red
Epidemiology macules that rapidly become vesicular (Fig. 39),
Over 90% of people are seropositive for HSV-1 by being highly infective at this stage, later forming
the fourth decade of life (Corey and Spear 1986). pustular scabs and ulcers. Healing occurs within
It has been suggested that reactivation (herpes 1–10 days of the onset of initial symptoms
labialis) only arises in 25–40% of HSV-1-seropos- (Arduino and Porter 2008). Herpes simplex virus
itive individuals (Shulman 2004; Stock et al. reactivations are recognized as the most common
2001). The frequency can be as high as fortnightly associated triggering infection in erythema multi-
to monthly (Spruance et al. 1977). At least 70% of forme (EM) (Schofield et al. 1993; Celentano
the population shed HSV-1 asymptomatically at et al. 2015). Typically, the onset of EM lesions
least once a month with a rate of daily detection of begins 10–14 days after the clinical manifestation
33.3% of individuals when using PCR (Miller and of an HSV infection (Al-Johani et al. 2007).
Danaher 2008). HSV-1 shedding in the oral cavity
occurs independently of the presentation of herpes Pathologic Features
labialis (da Silva et al. 2005). The viral cytopathic effect of HSV is seen in
keratinocytes, which show smudging of nuclear
Etiology chromatin with a distinct “ground glass” intra-
The human Herpes Simplex Virus-1 is a ubiqui- nuclear inclusion and peripheral chromatin mar-
tous double stranded DNA virus with oral epithe- gination. There is frequently multinucleation,
lial tropism. It can be spread by contact with with molding of the nuclei. Areas of ulceration
herpetic lesions or oral secretions can produce and a mixed inflammatory infiltrate are present in
infection with HSV-1. established lesions. Some cases show a necrotiz-
ing folliculitis.
Pathophysiology
Following primary infection, HSV-1 lives in a latent Patient Management
state in trigeminal ganglion neurons and can Individuals with occasional episodes may elect
reactivate. The “ganglion theory” suggests that no treatment or may utilize topical therapies,
when an appropriate trigger occurs (such as illness, predominantly based on acyclovir. Simple
sunlight, trauma, emotional stress), the virus hygiene measures to avoid spread are useful in
reactivates, replicates in the ganglion, and travels minimizing contagiousness particularly to inti-
along the axon to the skin or mucosal site where it is mate contacts and family members. Oral antiviral
directly cytopathic to the epithelial cells resulting in
vesicles and ulcers (Woo and Challacombe 2007).
Clinical Features
The incubation period of primary infection ranges
from 1 to 26 days. Primary gingivostomatitis
arises acutely in childhood with the appearance
of characteristic often coalescing oral mucosal
vesicular lesions on an erythematous base. This
is often accompanied by fever and malaise with
lesions persisting up to a week.
Herpes simplex reactivation lesions, also
known as herpes labialis, most commonly occur Fig. 39 Herpes simplex reactivation with vesicles upper
at the mucocutaneous junction of the lip or on the left vermilion zone
790 T. Yap et al.
therapy with acyclovir, famcyclovir, or Clinical Features

valacyclovir, particularly initiated during the Herpes zoster in the trigeminal region is not
prodromal stage, or within the first 3 days of uncommon, with the ophthalmic division (V1)
onset, decreases the infectivity of affected chil- involved in 10–25% of all HZ cases (Ragozzino
dren, and shortens the duration and severity of et al. 1982) (Fig. 40). A prodromal onset of sen-
symptoms (Gilbert 2007). There is also evidence sation of burning, throbbing, stabbing, or itching
that prophylactic oral acyclovir may reduce the (features of allodynia, dysesthesia, and hyper-
frequency and severity of recurrent attacks with algesia) occur in approximately 75% of patients.
relevance to immunocompromised patients This may occur days or even weeks before the
(Arduino and Porter 2006). characteristic rash accompanied by headache,
lymphadenopathy, and malaise. Onset of the rash
may begin with patchy erythema in the distribu-
Varicella Zoster Virus tion of the dermatome of involved skin, followed
by a predominantly vesicular eruption that erodes
Epidemiology and crusts. Acute HZ pain occurs in almost all
Herpes Zoster or the reactivation of Varicella Zos- patients aged above 50 years with 60–70% having
ter virus (VZV) has an incidence rate between persistent pain after 1 month (Werner et al. 2017).
3 and 5/1000 person-years in North America,
Europe, and Asia-Pacific with a lifetime risk of Pathologic Features
25–30% (Kawai et al. 2014). Risk of incidence The histopathological features of VZV infection
increases with age, with over 65% of cases occur- are similar to those of HSV.
ring above 50 years.
Patient Management
Etiology Antiviral treatment administered within 72 h of
Varicella zoster virus is a ubiquitous, highly symptoms, including intravenous or oral acyclovir,
neuro-, and T-cell tropic alpha herpes virus. Pri- valacyclovir, or famcyclovir, reduce the severity
mary infection presents as varicella or commonly and duration of acute HZ symptoms and rash.
known “chickenpox.” The virus is not cleared, but Early management is supported to prevent compli-
VZV remains dormant in sensory dorsal root cations including sight threatening keratitis (Neoh
ganglia with the potential for reactivation in one et al. 1994). Acute retinal necrosis (ARN) as com-
or more sensory neurons leading to herpes zoster plication of HZ ophthalmicus is an ophthalmic
(HZ) or “shingles.” Risk factors for reactivation emergency. There is currently a lack of evidence
include physiological or emotional stress, that antiviral treatment impacts the development
re-exposure to the virus, and immunosuppression
due to disease or therapy.
Pathophysiology
Latent VZV is predominantly located in human
ganglionic neurons. Virus gene transcription dur-
ing latency is regulated and restricted (Kennedy
and Cohrs 2010). Viral reactivation in the dorsal
root ganglion and its spread through the affected
nerve result in severe ganglionitis and neuritis
with local hemorrhagic necrosis. There is also
accompanying sympathetic stimulation and
nearby vasoconstriction. There is resultant neuro-
nal loss with subsequent afferent fiber fibrosis,
particularly type C nociceptors (Fields et al. Fig. 40 Herpes zoster/shingles involving first division of
1998). the trigeminal nerve
and persistence of postherpetic neuralgia (Chen Pathophysiology

et al. 2014), which significantly impacts quality The pathophysiology typically commences with
of life, although many anecdotally report that it disruption of either the skin barrier via injury or
may help (Serpell et al. 2014). Corticosteroids underlying inflammation such as eczema, other
given acutely during zoster infection are ineffective cutaneous infections with fungi viruses or other
in preventing postherpetic neuralgia (Chen et al. bacteria, or underlying immunosuppression. If
2010). Prompt analgesic management, including normal healthy skin is exposed and colonized
topical and systemic therapies, of acute HZ pain due to close contact with others with impetigo,
is recommended with the additional inclusion of any minor breakdown in the skin barrier, includ-
neuromodulators such as amitriptyline, gabapentin, ing insect bites, allows infection to occur.
or pregabalin if the baseline severity is moderate to
severe, or risk factors for postherpetic neuralgia are Clinical Features
present (Werner et al. 2017). Impetigo typically manifests on the face and
Attenuated virus vaccination has been extremities (Fig. 41). Papular lesions become
available since 2006 and was found to be effective vesicular, then pustular before crusting. A golden
in preventing herpes zoster disease with protec- oozing crust is evident early, with redness around
tion lasting 3 years (Gagliardi et al. 2016) More the base and under the crust. After several days,
recently, an HZ subunit (HZ/su) vaccine has been this dries to become an adherent scab. It is more
developed and studies are ongoing regarding its commonly nonbullous, but the bullous form,
impact on preventing HZ (Bharucha et al. 2017). more common in the younger child, may be diffi-
cult to distinguish clinically from Herpes virus
infection. It only seldom progresses to systemic
Impetigo infection, although poststreptococcal glomerulo-
nephritis is a potentially rare complication of
Epidemiology impetigo due to group A beta-hemolytic strepto-
Impetigo is a contagious superficial bacterial infec- cocci. The typical patient is otherwise well. Typ-
tion most frequently observed in children aged ically, these lesions are nonscarring unless
from 2 to 5, and in fact is the commonest bacterial complicated with abscess or ecthyma.
infection found in children. It is commonly known
as “school sores.” It is very contagious, comes on Pathologic Features
acutely, and involves the superficial epidermis. It is Impetigo is characterized by surface inflammatory
especially common in hot, tropical climates. scale crust or a subcorneal pustule, including neu-
trophils admixed with serum and parakeratotic
Etiology debris. There are admixed gram positive coccoid
The principal pathogen in 80% of cases is Staph- bacteria. In some cases, there is acantholytic
ylococcus aureus, and Streptococcus pyogenes is
the pathogen found in 10% cases, with both
organisms found in the other 10%. Nonbullous
impetigo is caused by both infections, but
bullous impetigo is caused almost exclusively by
S. aureus and is a toxin-mediated process, via
exfoliative toxins, or exotoxins. One of the target
proteins for these exotoxins is desmoglein 1,
which explains why the lesions are bullous. Bul-
lous impetigo is more commonly seen in infants
and neonates, and 90% of cases occur in those
Fig. 41 Impetigo in young child with orofacial Crohn’s
under the age of 2 years. Unfortunately, increasing
disease (Image courtesy of Dr Antonio Celentano,
cases of methicillin resistant S. aureus are being Melbourne Dental School, University of Melbourne,
found more recently. Carlton VIC, Australia)
792 T. Yap et al.
vesicle formation within the upper epidermis (bul- extremity. An increasing incidence has been noted
lous impetigo). There is usually only a sparse in the last several decades. It is thought to affect
perivascular inflammatory infiltrate within the the lower legs more often due to an aging popu-
upper dermis. In contrast to primary impetigo, lation with risk factors such as underlying periph-
which is seldom biopsied, similar changes (sec- eral edema and lymphedema. It affects persons
ondary impetiginization) are commonly seen of all races and both males and females alike.
associated with a wide range of other lesions, Combined with all cellulitis, the incidence is
including dermatoses (e.g., eczema) and neoplas- approximately 200 per 100,000 person-years and
tic lesions (e.g., actinic keratosis). significantly increased with age (McNamara et al.
2007). The infection rapidly spreads to involve
Patient Management cutaneous lymphatics, and red streaks may be
Even without treatment, impetigo usually resolves seen in the skin, with draining lymphadenopathy.
within 2–3 weeks, with spontaneous resolution Streptococci are the primary cause; most facial
occurring in 15–50%. Swabbing the lesion for infections are due to Group A streptococci inocu-
microscopy and culture is useful particularly if it is lation following injury to the skin. The source is
bullous or there are other cutaneous infections usually the patient’s own nasopharynx, and up to a
underlying the impetigo. It may help to distinguish third of cases have a preceding sore throat.
from herpes infection. Treatment does however
induce a more rapid response and clinical resolution, Clinical Features
decreases the infectivity, and aids in preventing Erysipelas is a superficial form of cellulitis affect-
potentially serious sequelae, such as ecthyma and ing the upper dermis and superficial lymphatics
scarring, cellulitis, lymphangitis, and suppurative that presents with erythema, warmth, and swelling
lymphadenitis, as well as widespread Staph-scalded of the affected area of skin (Fig. 42).
skin syndrome from bullous impetigo. Treatment of It is an extremely tender, well-demarcated
impetigo with systemic antibiotics does not seem to cutaneous infection and presents acutely with
prevent the rare but serious development of acute warmth, bright erythema, induration, and swell-
poststreptococcal glomerulonephritis. Gentle ing. The condition’s well-defined nature is a clue
cleansing and removal of the crusts with anti- to diagnosis. When erysipelas involves the face, it
bacterial soaps or saline soaks, and frequent wet may have butterfly like distribution over the
dressings are useful. Good hygiene is important to cheeks and nose. Systemic features such as fevers
decrease spread to close contacts. Patients should be and chills may accompany the rash.
educated to refrain from touching the lesions, to
apply topical antibiotics to small lesions, and chil- Pathologic Features
dren need to be kept away from school and daycare Erysipelas typically shows prominent super-
until 24 h after appropriate antimicrobial therapy has ficial dermal edema and a dermal neutrophilic
been commenced. Appropriate antibiotics, such as inflammatory infiltrate. The latter finding should
dicloxacillin or cephalexin, should cover both always prompt a thorough investigation for an
S. aureus and S. pyogenes. Widespread involvement infectious etiology (including staining of tissue
may require hospital admission for dressing, fluid sections, microbiological examination and cul-
balance, and intravenous antibiotics. ture) before diagnosis of a primary neutrophilic
dermatosis (e.g., Sweet’s syndrome) is made.
Erysipelas Patient Management

The prognosis is good, however it is important
Epidemiology, Etiology, that correct antibiotic treatment is initiated
and Pathophysiology promptly to prevent serious complications and
The most frequent site involved in erysipelas is a rapid progression. Simple measures such as ele-
lower extremity, followed by the face or an upper vation, ice, compression, and wound care are
Fig. 43 Tinea faciei (Image courtesy of Clinical Associate

Professor Kurt Gebauer, Dermatology West, Perth WA,
Australia)
men, the infection is usually in the beard area

and then known as tinea barbae.
Tinea faciei accounts for 3–4% of cases of tinea
corporis (Lin et al. 2004). It occurs worldwide and
is more common in warm, humid climates. It is
commonly misdiagnosed as an inflammatory or
photosensitive inflammatory dermatosis. Derma-
Fig. 42 Cutaneous submandibular cellulitis masquerad- tophytes of all types, anthropophilic, geophilic,
ing as an odontogenic infection in an infant. (Image cour- and zoophilic, may be involved, but most com-
tesy of Dr Omar Breik, Royal Melbourne Hospital,
Parkville VIC, Australia) monly, particularly in children, zoophilic species
from playing with pets is noted on history.
useful. Most cases are successfully treated with Clinical Features

oral antibiotics, with a mortality of less than 1%. Tinea faciei may have diagnostic clues like other
Penicillin is the antibiotic of first choice. Up to forms of cutaneous tinea, with an annular scaly outer
third of cases recur due to an underlying pre- edged patch with a clearing center (Fig. 43). It is
disposing factor such as lymphedema. Complica- often aggravated by sunlight, and may be secondar-
tions are uncommon, but the most typical are ily infected with S. aureus. In some it is very itchy,
abscesses, gangrene, and thrombophlebitis. Rare but in others it may insidiously became more wide-
but serious complications include sepsis, endocar- spread and have a very slow onset before presenta-
ditis, toxic shock syndrome, and acute glomeru- tion. Often it is treated incorrectly with topical
lonephritis. Erysipelas may be fatal in the very steroids after being misdiagnosed as a dermatitis. It
young, elderly, or immunocompromised. is worthwhile checking other sites commonly
infected such as the toe web spaces, the toenails,
and the folds, especially the groin, and the scalp.
Tinea
Pathologic Features
Epidemiology, Etiology, Most cases of dermatophyte infection show surface
and Pathophysiology scale with neutrophils and a spongiotic inflamma-
Tinea faciei is a relatively uncommon superficial tory reaction pattern. Fungi are classically seen
dermatophyte infection limited to the nonhair “sandwiched” between layers of orthokeratotic and
bearing skin of the face. It is usually seen in parakeratotic keratin. The organisms are frequently
pediatric patients, but may affect any age. In subtle on hematoxylin and eosin staining and liberal
794 T. Yap et al.
use of PAS stain is mandatory in excluding derma- may trigger some forms of acne, particularly oral
tophyte infection. Follicular involvement is associ- or anabolic steroids, iodides, some antipsychotic
ated with a suppurative infundibular folliculitis, mediations such as lithium, some antiepileptics,
frequently with evidence of rupture and inflamma- cyclosporine, and certain hormones. Endocrine
tory changes in the intervening dermis. Fungi can be disorders such as congenital adrenal hyperplasia,
demonstrated on the surface of the hair shafts polycystic ovarian syndrome, and excess andro-
(ectothrix) or within the shafts (endothrix). Exclu- gens, even pregnancy and certain oral or
sion of a fungal folliculitis is particularly important implanted contraceptive agents play a role. Other
when considering the differential diagnosis of a factors include occupational triggers, such as
neutrophil mediated scarring alopecia. moist and humid environments, topical chemicals
and occlusion with hair styling products and cos-
Patient Management metics, or fabrics or physical occlusion with hats,
The key is to make the diagnosis, and a simple headgear, or masks (Simpson and Cunliffe 2008).
skin scraping and microscopy and culture will
confirm this. Treatment is simple, utilizing topical Pathophysiology
antifungals in small areas of involvement, and oral Various factors are implicated in the pathogenesis
antifungals such as terbinafine, itraconazole, or of acne. The key to acne is the pilosebacous unit,
griseofulvin being required in more severe cases. with closed or open comedones (“blackheads” and
Further discussion on infectious diseases can “whiteheads”’) being the first sign and a clue to
be found in chapters on ▶ “Oral and Maxillofacial diagnosis. The four main pathogenic pathways
Viral Infections,” ▶ “Non-odontogenic Bacterial are: (1) Excess sebum production; (2) Follicular
Infections” and ▶ “Oral and Maxillofacial Fungal plugging; (3) Propionibacterium acnes coloniza-
Infections.” tion; and (4) Release of inflammation into the
skin. Excess sebum is particularly influenced
by circulating androgens, which is why acne
Common Dermatological Conditions usually heralds puberty. Stress, diet, and sleep,
which influence other hormones such as growth
Acne hormone, insulin-like growth hormone, and
corticotrophin-releasing hormones also impact
Epidemiology sebum production. Keratinocytes proliferate and
Acne is a common chronic inflammatory disorder fill the comedone, causing plugging and comedo-
of the skin involving the pilosebacous unit. nes. P. acnes is commonly found in acne lesions,
Estimates of the prevalence of acne vulgaris in but its true implication in pathogenesis is uncer-
adolescents range from 35% to over 90%. It typi- tain. It may be that those with a hypersensitivity
cally involves the face, but often the chest and back response to these anerobic bacteria are more likely
are also affected. It seems to affect some races more to develop inflammatory acne. Lastly, inflamma-
than others, but across all races tends to be seen tory responses are key to causing inflamed acne
typically in puberty, where in adolescence males beyond open and closed comedones, and may be
are more commonly affected. In adulthood, more the initiating step for hyperkeratinization.
females develop acne than males. It is occasionally
seen in neonates and infants also. Clinical Features
Acne vulgaris is characterized by comedones, open
Etiology (blackhead), or closed (whitehead), papules, pus-
Genetics is a key factor in the etiology of acne, tules, and nodules. Depending on the extent and
with many sufferers having a positive family his- depth of inflammation, as well as whether there are
tory. Diet and lifestyle factors are also implicated deep nodules, and large pustules, determines the
in the etiology, with some evidence showing ben- severity as well as the sequelae of scarring
efit of a low glycemic index diet. Medications (Fig. 44). Most clinicians stage it according to
Patient Management
The aim is to educate about avoiding triggers,
remove or treat underlying etiological factors,
avoid physical trauma and picking, and target spe-
cific treatment to the pathogenic factors present in
the individual patient. Grading and staging of acne,
and determining the presence of scars and nodules
is also crucial. Topical treatments include retinoids,
which are comedolytic, anti-inflammatory, and
aid in decreasing superficial small scars. Anti-
keratolytic agents include salicylic, lactic, and
glycolic acids, and these aid in decreasing follicular
plugging. Benzoyl peroxide and topical antibiotics
are useful in decreasing both P. acnes as well as
inflammation. Systemic agents are useful in mod-
erate and severe acne, and include oral antibiotics,
the tetracycline group such as doxycycline and
minomycin. Other antibiotics occasionally used
include erythromycin, trimethoprim alone, or in
Fig. 44 Acne vulgaris combination with sulfamethoxazole. Hormonal
treatments are often useful in some cases of acne
severity, with mild acne being mainly characterized in women, such as antiandrogen-containing oral
by comedones and only few papulopustules, mod- contraceptives, spironolactone, and cyproterone
erate acne having more inflammation and papules acetate. For the more severe cases, and particularly
and pustules, and severe acne having nodules as when scarring is evident, oral isotretinoin, an oral
well as scars. Severe forms of acne include acne retinoid, is highly effective treatment. This is a
conglobata, with abscesses and nodules and scars teratogen, thus great care must be employed when
but no systemic symptoms, and acne fulminans, prescribing this medication, and in many countries
which is severe acne with systemic symptoms and only authorized clinicians with a retinoid warrant,
signs including pain and fever as well as deep and usually restricted to dermatologists, can use this.
inflamed nodules, cysts and abscesses. The psy- Physical measures are also useful, with the extrac-
chological impact of patients with acne must not tion of comedones either manually or with fine
be underestimated, and a key feature choosing wire diathermy, superficial face peels, and certain
appropriate management is to minimize and pre- types of lasers are potentially useful. Intralesional
vent scarring. steroids are helpful to decrease inflammation in
large inflammatory nodules. Psychological support
Pathologic Features is often required particularly in those with signifi-
The basic lesion of acne is the comedone – a hair cant scarring. Ideally patients with acne should be
follicle occluded by impacted keratin. Closed seen and treated early to prevent any long-term
comedones (whiteheads) show a narrow opening scarring sequelae.
to the surface, while open comedones (black-
heads) have a patulous orifice. There is inflamma-
tion, in many cases with rupture of the follicular Rosacea
structure. If the inflammatory reaction is suffi-
ciently severe, a clinically visible scar may be Epidemiology, Etiology,
left after resolution. In severe cases cysts, nodules and Pathophysiology
and sinus tracts may develop. Complications such Rosacea is a common condition. It mostly
as hypertrophic or keloidal scarring may develop. affects fair-skinned individuals; peak incidence
796 T. Yap et al.
and severity occur around 40–50 years of age.

Rosacea’s multifactorial pathophysiology includes
vascular hyperreactivity and foods (e.g., hot or
spicy foods, alcohol), heat, UV light, and medica-
tions that induce facial vasodilation may acceler-
ate its development. Patients with rosacea may
also have hyperirritable skin. Recently, Demodex
folliculorum colonization has been thought to
have a significant role in the inflammatory papules
and pustules of rosacea: and treatment specifically
targeting this parasite has been utilized.
Clinical Features
Rosacea primarily affects the central face. Fea-
tures include transient and non-transient ery-
thema, papules and pustules and telangiectasia
(Fig. 45). Secondary features include burning or
stinging symptoms, plaques, dry appearance,
facial edema, ocular manifestations, and seba-
ceous overgrowth. Granulomatous rosacea is
diagnosed histologically. Severe cases of rosacea
can lead to the development of rhinophyma. Ocu- Fig. 45 Rosacea (Image courtesy of Clinical Associate
Professor Kurt Gebauer, Dermatology West, Perth WA,
lar involvement of rosacea can also occur (includ- Australia)
ing conjunctival hyperemia, anterior blepharitis,
and keratitis). Periocular and perioral dermatitis –
presenting as recurrent small papules and pustules
– can frequently be found in patients with vascular
rosacea (Fig. 46).
Pathologic Features
The histological findings in rosacea reflect the clin-
ical type. Erythematous telangiectatic rosacea is
seldom biopsied and is characterized by dilated ves-
sels in the superficial dermis, sometimes with
a striking “staghorn” arborizing pattern. There
is typically a mild perivascular inflammatory
Fig. 46 Erythematous, papular and pustular rosacea of
infiltrate that includes lymphocytes and plasma the face
cells. Papulopustular lesions show a perifollicular
inflammatory infiltrate. Formation of perifollicular
granulomas is seen in granulomatous rosacea. moisturizing, good sun protection, and avoidance
Rhinophyma is characterized by follicular dilatation of irritants. Triggers of flushing and factors aggra-
with keratin plugging and prominent sebaceous vating the disease should be avoided (including
glands, though these changes can show significant UV light, heat, alcohol, hot or spicy foods). Ery-
overlap with alterations associated with aging. thema and telangiectasia can be treated with
pulsed dye or KTP lasers, intense pulsed light
Patient Management devices, and pharmacologically with brimonidine
Treatment of rosacea is symptomatic and includes gel. Inflammatory lesions (papules and pustules)
general measures such as gentle cleansing, are treated topically with metronidazole, azelaic
acid, ivermectin, or sulfacetamide-sulfur. More features of eczema and rosacea reflecting clinical
severe cases of rosacea warrant systemic therapy presentation.
with oral tetracycline (doxycycline, minocycline,
or tetracycline). Severe or treatment resistant Patient Management
cases can sometimes be successfully treated with Management of perioral dermatitis can be most
low-dose oral isotretinoin. challenging. Avoidance of triggering factors is
essential, including strict avoidance of topical cor-
ticosteroids. This condition often resolves but
Perioral Dermatitis recurs. Frequently this leads to an initial flare up
before the condition slowly improves. Any topical
Epidemiology, Etiology, agent applied can also aggravate the condition.
and Pathophysiology Topical pimecrolimus and tacrolimus are most fre-
Perioral dermatitis is a common inflammatory quently used as an anti-inflammatory agent. Short
facial skin disorder that predominantly affects courses of oral tetracycline treatment (doxycycline,
women. The etiology of perioral dermatitis is minocycline, tetracycline) are often helpful (Oppel
unknown, but use of topical corticosteroids often et al. 2007; Lipozencic and Ljubojevic 2011).
precedes skin lesions. Patients commonly also
have a predisposition to develop rosacea and
triggers can be similar. Others may have a history Seborrheic Dermatitis
of atopic dermatitis. Use of heavy make-up fre-
quently aggravates the condition. In chronic Epidemiology, Etiology,
cases, contact allergies can also play a role and Pathophysiology
(Berth-Jones 2008). Seborrheic dermatitis (SD) is a common inflamma-
tion of the skin including the face and scalp. SD
Clinical Features trimodal peak incidence correspond to (1) the first
A typical perioral dermatitis presentation involves three months of life, (2) during puberty, and
the eruption of papules and pustules (Fig. 47) that (3) between 40 and 60 years of age. In infancy,
may recur over weeks to months, erythema is incidence can be up to 42%, affecting 1–3% of
present, occasionally with fine scales (Lipozencic the general adult population. There is a mild
and Hadzavdic 2014). male predominance. SD is more prevalent in
immuno-compromised patients suggesting that
Pathologic Features immunological defects may play a role in SD. It is
Biopsies of perioral dermatitis are not also associated with neurological disorders and psy-
frequently performed. Histology generally shows chiatric diseases (Borda and Wikramanayake 2015).
Fig. 47 Perioral dermatitis (a) and seborrheic dermatitis (b). (Images courtesy of Clinical Associate Professor Kurt
Gebauer, Dermatology West, Perth WA, Australia)
798 T. Yap et al.
The etiology of SD remains unknown. It Eczema

has been postulated that SD is caused by
Malassezia yeasts, based upon positive pres- Epidemiology, Etiology,
ence in affected skin and the therapeutic and Pathophysiology
response to antifungal agents in most sufferers. Eczema (atopic dermatitis) is one of the most
Malassezia are commensal skin organisms that frequent skin conditions. Prevalence ranges from
are lipid-dependent and proliferate in sebum. It 5–20%, it seems to be more prevalent in devel-
is thought that the host inflammatory response oped countries. Generally, disease onset is in
to the yeast and its metabolites result in, or childhood, although an adult onset form seems
contribute to SD. Others contrast that the yeast to be more prevalent than previously thought. A
are incidental to a primary inflammatory der- large percentage of patients suffer from chronic
matosis. It is sometimes found to be part of a ongoing disease or episodes of flare-ups.
psoriasis spectrum, and in these patients called The etiology of eczema is not fully under-
“sebo-psoriasis.” stood. Genetic and environmental factors play a
role (frequent showers, use of soap, inadequate
Clinical Features moisturizing, dry air, skin superinfection, stress/
SD often presents as well-defined erythematous anxiety). Eczema patients frequently suffer
plaques with greasy-looking, yellowish scales. from other atopic conditions such as asthma or
Typical regions involved are those with a con- hay fever. Skin barrier defects, including
centration of sebaceous glands, such as the filaggrin gene mutations, have been identified
face and scalp, but also the upper chest. Dis- as a key-contributing factor in eczema patho-
tribution is generally symmetrical. SD appears genesis. Other major pathogenic factors include
of change seasonally, presenting more fre- altered skin microbiome, altered innate, and
quently during winter, and improving usually Th2-skewed adaptive immune response. The
during summer. Stress can play an exacerbat- exact relevance of individual factors and
ing role in SD. whether they are causative or bystander effects
is still a matter of ongoing research and debate
Pathologic Features (Friedmann and Holden 2008).
SD is characterized by a spongiotic inflammatory
reaction, with variation in the relative prominence Clinical Features
of spongiosis and epidermal hyperplasia Eczema is characterized by pruritic, nonsharply
depending upon the age of the lesion. Para- demarcated erythematous scaly plaques (Fig. 48).
keratotic scale surrounding follicular ostia is a Affected body areas usually show excoriation.
typical feature leading to the pathological consid- Eczema more frequently affects the flexor sur-
eration of seborrheic dermatitis, but definitive faces but can be present on every body region.
pathological diagnosis is not possible without Acute disease often shows serous exudation and
clinical correlation. crusting. Bacterial super infection is not uncom-
mon. Lichenification develops in chronically
Patient Management affected areas. In general, the skin of eczema
A recent systematic review of topical therapies patients is often very dry (asteatosis). Vesicles
for facial SD found that ciclopirox olamine, keto- may occur particularly over glabrous areas,
conazole, lithium (gluconate and succinate), and where it is known as “pomphylox dermatitis.”
tacrolimus were the most consistently effective
across high-quality clinical trials. Additionally, Pathologic Features
promiseb, desonide, mometasone furoate, and The histological features of eczema are character-
pimecrolimus were found to be effective alterna- ized by a spongiotic reaction pattern, though
tive topical treatments (Gupta and Versteeg lesions in the head and neck region are seldom
2017). biopsied. Spongiotic dermatitis shows a spectrum
but especially soaps and reducing the amount of

washing. Rehydration of the skin can be
achieved with bland emollients, containing as
little as possible irritants and potential contact
allergens (e.g., aqueous cream, petroleum jelly).
Avoidance of known clinically relevant type
1 allergens and contact allergens can be useful
in individual patients. Clinicians should bear in
mind though that many eczema patients test
positive (prick testing or specific IgE serum test-
ing) for multiple, clinically irrelevant type 1 sen-
sitizations. Superinfection is treated with
antiseptic washes, bleach baths, or systemic
antibiotics. Antihistamines can be useful to
treat itch. Topical anti-inflammatory therapies
consist of topical corticosteroids, the potency
and formulation depending on the body area
and presentation of disease, e.g., medium potent
and shorter term in the face, creams for acute
Fig. 48 Eczema/atopic dermatitis on the face exudative flare-ups, and ointments for chronic
lesions. Tacrolimus and pimecrolimus can be
from acute lesions with prominent intercellular used longer-term, especially in sensitive areas
edema of the epidermis but minimal architectural such as the face. Cases of acute eczema occa-
change, through to more chronic lesions in which sionally require short-term oral corticosteroid
spongiosis can be subtle and the appearances are treatment. In cases of severe eczema, wet dress-
dominated by surface parakeratosis and epidermal ings and soak and smear therapy can be useful.
acanthosis with vertical streaking of papillary der- UV therapy (PUVA, UVA/B, narrowband UVB,
mal collagen, representing the addition of features UVA1) can be beneficial for some eczema
of lichen simplex chronicus. Emigration of lym- patients. Most severely affected patients require
phocytes to the epidermis (exocytosis) and a longer-term systemic immunosuppressive ther-
superficial perivascular lymphocytic infiltrate apy, e.g., with mycophenolate mofetil, azathio-
with a variable admixture of eosinophils is typical. prine, methotrexate, or cyclosporine. The
The presence of aggregates of Langerhan’s cells anti-interleukin 4 antibody, dupilumab, is the
within the epidermis is common and may be a clue first biologic to have gained FDA approval for
to the presence of allergic contact dermatitis (Rosa the treatment of severe eczema. The JAK inhib-
et al. 2016). In general, however, the various itor, tofacitinib, has shown promising results in
causes of a spongiotic reaction are not definitively clinical trials, and the anti-interleukin 31 recep-
separable on histopathological examination, tor A antibody, nemolizumab, seems to be prom-
except for fungal infection (dermatophytosis), ising in the treatment of eczema-related itch.
which should be sought with PAS stain on all
cases showing this pattern.
Contact Dermatitis
Patient Management
As with other forms of dermatitis, general mea- Epidemiology, Etiology,
sures are paramount, and sufferers require and Pathophysiology
education to avoid heat, soap, and dryness. Contact dermatitis (irritant/allergic dermatitis) is
Re-establishment of the skin barrier is achieved any dermatitis arising from direct exposure of the
through the avoidance of use of any detergents, skin to a substance.
800 T. Yap et al.
The clear majority of contact dermatitis Hands are most frequently involved, but contact
cases is irritant. Although anyone can develop dermatitis on the face is frequent, with lips and
irritant contact dermatitis, lighter skin individuals eyelids being commonly affected.
and those with susceptible skin (e.g., atopic der-
matitis) are more prone. Contact dermatitis is Pathologic Features
extremely common, especially irritant contact Allergic contact dermatitis is characterized by
dermatitis in work contexts where wet work and a spongiotic reaction pattern, with separation
hand washing occur frequently (hair dressers, of keratinocytes by edema and variable lympho-
manufacturing industry, health workers). cyte exocytosis. Spongiotic vesiculation and
Irritant contact dermatitis results from direct the formation of “flask-shaped” Langerhans cell
exposure to substances that cause irritation to aggregates may occur. There is a superficial peri-
skin, typically caused by common, repeated expo- vascular inflammatory infiltrate that frequently
sures (e.g., soap, rubbing alcohol). Normal epi- includes a component of eosinophils in addition
dermal barrier is disrupted by a physical, to lymphocytes. As in other forms of spongiotic
mechanical, or chemical irritant and inflammation dermatitis, chronicity is characterized by the
develops secondarily. superimposition of secondary changes including
Allergic contact dermatitis occurs when con- epidermal hyperplasia. Some cases of irritant con-
tact with a particular allergen elicits a delayed tact dermatitis show similar histological features
hypersensitivity (type IV) reaction. Allergic con- to allergic contact dermatitis. In cases with more
tact hypersensitivity reactions involve antigen potent irritants or heavy exposure, damage to the
presenting by epidermal Langerhans cells to upper portions of the epidermis lying on a spec-
naive T-lymphocytes in regional lymph nodes trum to full-thickness epidermal necrosis can
and the subsequent release of a population of be seen.
sensitized T-lymphocytes into the circulation.
This sensitization process requires around Patient Management
10–14 days. Upon re-exposure, the antigen is Avoidance of irritants and contact allergens is
presented to sensitized lymphocytes which release paramount in treating contact dermatitis, but can
cytokines that lead to the clinical picture of often be practically challenging. Where contact
inflammation. The resulting dermatitis occurs allergies are suspected patients should be patch
within 12–48 h. tested. Re-establishment of the skin barrier is
achieved through the avoidance of use of any
Clinical Features detergents, but especially soaps and reducing
Typical physical findings include papular ery- the amount of washing. Rehydration of the
thematous plaques, scaling, and loss of skin integ- skin can be achieved with bland emollients,
rity including fissures in the distribution of containing as little as possible irritants and
exposure with poorly defined margins (Fig. 49). potential contact allergens (e.g., aqueous
cream, petroleum jelly). Anti-inflammatory
therapy consists of topical corticosteroids, the
potency of which depends on the body area,
e.g., on the face, only medium potency and
short duration. In severe cases, wet dressings
and soak and smear therapy can be useful.
Tacrolimus and pimecrolimus can be used lon-
ger term, especially in sensitive areas such as
the face. Cases of acute contact dermatitis, espe-
cially in the face, occasionally require short-
Fig. 49 Periorbital allergic contact dermatitis term oral corticosteroid treatment.
Psoriasis
and Pathophysiology
Psoriasis is a common disease in adults, preva-
lence ranges widely from about 1–8%. It is less
common in hotter climates. Age of disease-onset
peaks in the thirties and fifties to sixties (Parisi
et al. 2013).
There is a strong polygenetic predisposition
for the development of psoriasis. It is linked to
certain MHC and HLA classes. Other risk factors
include smoking, obesity, and alcohol. Psoriasis
flares can be triggered by multiple drugs (most
commonly beta blockers, lithium, and antimalar-
ial drugs) and infections (commonly streptococ-
cal, occasionally HIV).
Psoriasis is characterized by hyperproliferation
and abnormal differentiation of keratinocytes. It is
a complex immune mediated disease with neutro-
phils, T-lymphocytes, and dendritic cells playing Fig. 50 Hairline (a), and postauricular (b) psoriasis
a role. The advent of new biologic therapies has
led to evidence of TNF-alpha, interleukins 12, 17, Pathologic Features
and 23 playing an important role in psoriasis Psoriasis shows varying histology with clinical
pathophysiology. pattern and duration of the lesions. The character-
istic plaques of psoriasis show parakeratosis with
Clinical Features admixed neutrophils but a little or no serum.
Psoriasis is a multiorgan disorder (mainly skin There is loss of the granular layer and regular
and joints). On the skin, it is characterized by (psoriasiform) acanthosis with thin suprapapillary
sharply demarcated erythematous raised plaques plates, resembling the teeth of a comb. Slight
with silver scaling. Predilection sites, in the head spongiosis is not rare. There is tortuosity of cap-
and neck region, are the ear canal, pre- and post- illary vessels in the papillary dermis, with capil-
auricular, the hairline and scalp (Figs. 50 and 51). laries “kissing” the undersurface of the epidermis.
The “seborrheic” sites of between the eyebrows There is usually a mild superficial perivascular
and around the nose are also commonly inflammatory infiltrate. An absence of eosinophils
involved, as in seborrheic dermatitis. Oral psori- is an important feature in the distinction from a
asis is comparatively rare and there is debate lichenified spongiotic dermatitis. Unfortunately,
about the true extent and nature of oral involve- such classical plaques are seldom biopsied. Early
ment. Geographic tongue, benign migratory lesions and guttate psoriasis typically lack
glossitis, and fissured tongue are considered by psoriasiform epidermal hyperplasia (Ragaz and
some authors to fall within the psoriasis spec- Ackerman 1979).
trum. If psoriasis is suspected clinically, a full-
body examination with specific attention to pre- Patient Management
dilection sites such as the extensor sites of the General lifestyle measures are often helpful in
extremities, palms and soles, the intertriginous decreasing psoriasis activity, including optimizing
areas, and the nails can be most helpful in making diet and weight, smoking cessation, and avoidance
the diagnosis. of alcohol. There remains a link with psoriasis and
802 T. Yap et al.
Fig. 51 Atypical psoriasis involving the scalp (Image Fig. 52 Scarring alopecia in a patient with discoid
courtesy of Clinical Associate Professor Kurt Gebauer, lupus erythematosus (Image courtesy of Clinical Associate
Dermatology West, Perth WA, Australia) Professor Kurt Gebauer, Dermatology West, Perth WA,
Australia)
metabolic syndrome and cardiovascular risk fac-
tors. Topical therapy consists of salicylic acid and scarring and nonscarring forms. Scarring alope-
tar-based formulations for hyperkeratosis/scaling, cias include lupus erythematosus, lichen
potent to ultrapotent corticosteroids (e.g., planopilaris, frontal fibrosing alopecia, folliculitis
betamethasone diproprionate and clobetasol pro- decalvans, and dissecting cellulitis (Fig. 52). Non-
prionate), the vitamin D derivative calcipotriol, scarring alopecias include androgenetic alopecia,
and short contact therapy with dithranol/cignolin telogen effluvium, alopecia areata, syphilitic alo-
(Menter et al. 2009; Svendsen et al. 2017). Photo- pecia, trichotillomania, and traction alopecia
therapy can be very helpful in the treatment of (Fig. 53).
psoriasis (Menter et al. 2010). Moderate to severe
disease often requires systemic therapy. Tradition- Clinical Features
ally used agents are immunomodulatory or immu- In scarring alopecia, inflammation is usually prom-
nosuppressive, such as fumaric acid, acitretin, inent and leads to destruction of hair follicles. In
methotrexate, and cyclosporine (Kelly et al. lichen planopillaris, inflammation is centered on
2015). Modern biologic therapies are very efficient hair follicles; discoid lupus is characterized by
and safe but expensive. They comprise TNF-alpha inflammatory plaques, folliculitis decalvans, and
antagonists (infliximab, etanercept, adalimumab), dissecting cellulitis by some degree of pustule
interleukin 12/23 antagonists (ustekinumab), inter- formation. In the end-stage of all these subtypes
leukin 23 antagonists (guselkumab), and interleu- scarring only remains. In nonscarring alopecia,
kin 17 antagonists (brodalumab, ixekizumab, inflammation is usually less prominent. Hair loss
secukinumab) (Norris et al. 2017; Brimhall et al. can be sharply demarcated and annular (alopecia
2008; Rodgers et al. 2011). areata) or more diffuse (androgenetic alopecia and
telogen effluvium). In general, the degree of
inflammation, pattern of alopecia, other body
Alopecia areas affected, screening for infectious causes
(tinea capitis and syphilitic alopecia) and medical
Epidemiology, Etiology, history are essential for making the diagnosis. His-
and Pathophysiology topathology can be very helpful.
The full spectrum, pathophysiology, diagnosis,
and treatment of alopecia is complex and beyond Pathologic Features
the scope of this text. Alopecia is common. It can Biopsies are typically examined in both horizontal
be a sign of systemic disease or localized to the and vertical sections and laboratory handling
scalp. Commonly alopecia is grouped into of these specimens should be overseen by a
The mainstay of androgenetic alopecia treatment

are hormonal treatments and minoxidil (Mella
et al. 2010; Olsen et al. 2002). It is important to
remember that scarring is usually irreversible
(Harries and Paus 2010).
Autoimmune and Immune-Mediated

Conditions
Pemphigus
Fig. 53 Non-scarring alopecia areata (Image courtesy of
Clinical Associate Professor Kurt Gebauer, Dermatology Pemphigus (from the Greek pemphix meaning
West, Perth WA, Australia) bubble or blister) is a chronic, autoimmune, blis-
tering disease involving the Malpighian layer
subspecialist dermatopathologist. In broad terms, (stratum basale and stratum spinosum together)
lesions can be (imperfectly) grouped into scarring of skin and mucous membranes (Baroni et al.
and non-scarring forms. Scarring alopecia is char- 2007). Pemphigus subtypes may affect oral muco-
acterized by destruction of the follicular unit sae but also the skin and the mucosae of the nose,
arrangement on horizontal sections, loss of seba- conjunctivae, genitals, esophagus, pharynx and
ceous glands, formation of higher-order com- larynx (Black et al. 2005). Subtypes can be
pound follicles and scarring fibrosis. The causes divided into those in which blisters occur deep
of cicatricial alopecia can be grouped into within the epidermis, just above the basal-cell
neutrophil mediated forms (e.g., folliculitis layer, such as pemphigus vulgaris (PV), and
decalvans, dissecting cellulitis) and lymphocyte those affecting the most superficial layer, just
mediated forms (e.g., lichen planopilaris, frontal below the stratum corneum that includes pemphi-
fibrosing alopecia). Non-scarring causes of alope- gus foliaceus (Bystryn and Rudolph 2005). Other
cia include conditions such as alopecia areata subtypes include pemphigus erythematosus, para-
and telogen effluvium. Common androgenetic neoplastic pemphigus (PNP), and IgA pemphigus
alopecia (male or female pattern alopecia) does (IAP) (Celentano and Cirillo 2016).
not fit easily into this classification; it is com-
monly considered a non-scarring alopecia, though Epidemiology, Etiology,
with chronicity there is irreversible follicular loss and Pathophysiology
(Olsen et al. 2003). In the evaluation of any Although pemphigus occurs worldwide, the fre-
patient with alopecia it is important to consider quency is influenced by geographic location and
reversible causes (e.g., tinea capitis) and patho- ethnicity. Incidence rates between 0.1 and 0.5 per
logical processes in which alopecia is frequently 100,000 people per year (Ahmed et al. 1980;
one manifestation of a more complex disease Becker and Gaspari 1993) have been reported
(e.g., syphilitic alopecia, alopecia in lupus most frequently. Individuals of Southeast
erythematosus) (Templeton et al. 1996). European, Middle Eastern, Indian, and Ashkenazi
Jewish ancestry have the highest risk of devel-
Patient Management oping pemphigus (Kneisel and Hertl 2011;
Management depends on the underlying condi- Otten et al. 2014). PV is more common than pem-
tion. If there is underlying inflammation, topical, phigus foliaceus in most populations (Murrell et al.
intralesional or systemic corticosteroids or immu- 2008). Pemphigus usually occurs in adults, with an
nosuppressants are used (Kang et al. 2008). Neu- average age of onset of 40–60 years for PV and
trophil mediated forms often require long-term nonendemic pemphigus foliaceus. The sex ratio
antibiotic treatment (Whiting and Olsen 2008). for PV and pemphigus foliaceus has been reported
804 T. Yap et al.
more commonly in females as 1.7: 1 in a USA of reactants at the dermo-epidermal junction in

study of 249 patients (Brenner and Wohl 2007). pemphigus erythematosus.
Genetic predisposition likely has an essential PV is characterized by suprabasilar
role. Triggering exogenous factors may include acantholytic vesiculation. The basal keratinocytes
drugs, physical agents, viruses, hormones, food, remain attached at the base of the vesicle,
and emotional stress (Baroni et al. 2007). giving rise to a pattern classically described
The basic abnormality in all forms of pemphi- as a “tombstone” appearance. When present,
gus is the separation of keratinocytes from one prominent extension of the acantholytic process
another, a process known as acantholysis (Mihai into hair follicle epithelium is a useful
and Sitaru 2007). Dissolution of the intercellular diagnostic clue in the separation from other
substance is followed by separation of desmo- acantholytic dermatoses. As expected, there is
somes. An enlarging cleft within the epidermis intercellular deposition of immunoreactants by
becomes a bulla (Bystryn and Rudolph 2005). direct immunofluorescence.
Oral epithelium is closely similar to skin how- The histological features of pemphigus
ever, desmosomal components differ. Cadherin- vegetans are dominated by prominent acanthosis,
type adhesion molecules Dsg1 and Dsg3 are both which can assume a pseudoepitheliomatous char-
expressed in skin, however in oral epithelium the acter. There is a mixed inflammatory infiltrate that
130 kD molecule Dsg3 is preferentially expressed includes a prominent eosinophilic component.
(Shirakata et al. 1998). Acantholysis is identifiable, but often quite subtle
in these lesions.
Clinical Features IAP shows histological and clinical
PV usually begins with painful, persistent heterogeneity as a reflection of its variable
intraoral ulceration. The blisters are fragile, burst- immunopathogenesis. In general, two forms are
ing quickly, and are rarely seen. This disease will recognized, one resembling subcorneal pustular
progress within weeks to months onto the skin dermatosis (Sneddon-Wilkinson syndrome) and
(Mignogna et al. 2010; Scully et al. 1999). Typical one characterized by an intraepidermal neutro-
sites, of first cutaneous involvement, are the scalp, philic pattern (Baum et al. 2014).
face, and upper torso. Skin lesions usually begin The histology of PNP is usually dominated by
as small flaccid blisters that rupture, leaving a lichenoid interface inflammatory pattern.
sharply outlined, superficial erosions with a rim Acantholysis may be seen, but is not an invariable
of loose epidermis. Involvement of other mucosal finding and when present is frequently subtle.
sites may also occur (Fig. 54) (Bystryn and
Rudolph 2005). Oral involvement is rare in pem- Patient Management
phigus foliaceus. Lesions typically appear as mul- Early treatment may prevent extension or progres-
tiple, pruritic, crusted patches covering erosions sion of disease in PV. If treated early, most oral
on the face, scalp, and upper torso. and pharyngeal involved pemphigus vulgaris
patients have a good clinical response and a dis-
Pathologic Features ease, and drug-free clinical remission is possible
Pemphigus foliaceus and pemphigus erythe- (Mignogna et al. 2010). The proportion of patients
matosus are characterized histologically by in which continued remission may be achieved
acantholytic splitting of the upper epidermis, lead- increases steadily with time, and therapy can be
ing to the formation of flaccid subcorneal vesicles discontinued in approximately 75% of patients
and erosions. In many cases, the fragile roof of the after 10 years (Herbst and Bystryn 2000).
blister is denuded, which can render clinical and Systemic corticosteroids are used as the first-
histological recognition of the vesiculobullous line treatment until control is reached and then
character of the process difficult. Direct immuno- tapered to a lower maintenance dose (<15 mg).
fluorescence shows deposition of reactants in an There is debate of the most ideal level to “start,”
intercellular pattern, with the additional presence most experts describe in the 0.5–1.5 mg/kg range.
Fig. 54 Pemphigus
vulgaris involving scalp
(a), pemphigus vulgaris
on the face (b)
Steroid-sparing agents are employed to reduce Before the introduction of corticosteroids in the
the cumulative exposure and side effects associ- 1950s, PV was almost invariably fatal (Bystryn
ated with long-term steroid use. Such agents 1984) mainly from dehydration or secondary sys-
include azathioprine, mycophenolate mofetil temic infections (Bystryn 1984; Bystryn and
(MMF), intravenous immunoglobulin (IVIg) Steinman 1996). The disease is still associated
(Mimouni et al. 2003), rituximab (Arin et al. with a mortality rate of approximately 6% (Bystryn
2005; Ahmed et al. 2006; Joly et al. 2007), cyclo- 1984; Bystryn and Steinman 1996), despite the
phosphamide, methotrexate, and cyclosporine development of various newer therapies.
(Daniel and Murrell 2014).
Because of the similarities in efficacy and side
effect profiles, clinicians often use azathioprine or Pemphigoid
MMF as the first-line therapy. No study has been
able to prove one to be more effective than the Pemphigoid, exemplified by bullous pemphigoid
other (Mimouni et al. 2003; Daniel and Murrell (BP) and mucous membrane pemphigoid (MMP),
2014; Chams-Davatchi et al. 2007; Beissert et al. are subepithelial blistering conditions that are
2006, 2010). Topical steroids are useful to associated with immunoglobulin and complement
actively manage involved erosions in the mouth deposition within the basement membrane zone
and on the skin, and are often required even once (Baum et al. 2014).
systemic treatments have been ceased. Avoiding
triggers, and simplifying the diet to avoid alliums
and aggravating foods are also useful measures. Bullous Pemphigoid
Oral lesions of pemphigus heal much more
slowly than skin lesions and are often recalcitrant BP is considered the most common immune blis-
to treatment (Kalra et al. 2005). The delay of healing tering disease. It does not occur commonly in the
of oral lesions may have contribution from mastica- head and neck, however mucosal disease is pre-
tory trauma or opportunistic candida or herpetic sent in 10–30% of patients; most commonly the
contribution (Kalra et al. 2005; Mahajan et al. oral cavity, but the ocular, nasopharyngeal, esoph-
2005). Treatment should not be decreased until ageal, and anogenital regions may be affected
healing of most lesions (Qasmi et al. 2009). (Loo and Burrows 2004).
806 T. Yap et al.
Epidemiology, Etiology, eosinophils at the dermoepidermal junction provide

and Pathophysiology a diagnostic clue. The deposition of reactants at the
BP is still rare at incidence rates of 6 (range 4–22) dermoepidermal junction can be demonstrated in
cases per million individuals per year. Childhood most cases by direct immunofluorescence. Staining
BP occurs below the age of 18 (Fig. 55), and for C4d on fixed tissue may also be of value.
the mean age of adult onset BP is over 70 years
with equal sex incidence (Marazza et al. 2009; Patient Management
Schmidt et al. 2011). The goal of treatment in BP is to arrest disease
The target antigens are components of the progression, reduce itch, and rapidly stimulate
hemidesmosome in cutaneous basal cells. Most healing of blisters. Some investigators have
BP patients have bound and circulating IgG anti- suggested that the disease usually resolves after
bodies against either the extracellular non- 5 years, but prospective studies addressing the
collagenous (NC16) domain of type 17 collagen, long-term course of BP are lacking. There is an
or transmembrane protein BP180 (previously increased mortality rate of BP patients compared
BPAG2) (Parker and MacKelfresh 2011). to the general population (Gual et al. 2014).
Very potent topical steroids are effective and
Clinical Features safe treatments for BP, but are of more limited use
There may be a prodromal phase of pruritis and in extensive disease (Kirtschig et al. 2010). Sys-
urticarial patches, plaques and erythema before temic corticosteroids are effective in managing
the bullous phase. The bullous phase usually BP. High-quality trials supporting adjuvant ther-
sees 1–3 cm bullae as well as erosions and crusts apy in BP (plasma exchange, azathioprine or
at sites of ruptured bullae, typically on the trunk mycophenolate mofetil, combination treatment
and extremities. Lesions of BP usually heal with- with tetracycline and nicotinamide) are unfortu-
out scarring. nately lacking (Daniel et al. 2011).
Pathologic Features
BP is characterized by formation of a subepidermal Mucous Membrane Pemphigoid
vesicle (Fig. 56), which usually contains an inflam-
matory cell population including readily identified The international consensus in 2002 defines mucous
eosinophils. There is a superficial perivascular membrane pemphigoid as an immunobullous
inflammatory infiltrate, again including eosino-
phils. Prebullous lesions are characterized by an
“urticaria-like” appearance, with a perivascular
and interstitial infiltrate with prominent eosinophils.
In some prebullous lesions, short linear arrays of
Fig. 56 Bullous pemphigoid, Hematoxylin and eosin

Fig. 55 Childhood bullous pemphigoid stain, 100
disease with autoantibodies against components

of the dermal-epidermal junction and predomi-
nant mucosal involvement (Chan et al. 2002).
Previously, the name cicatricial pemphigoid
was used interchangeably with MMP; however,
this term is now reserved for the rare clinical
variant in that mucous membranes are not pre-
dominantly affected and cutaneous lesions heal
with scarring (Chan et al. 2002; Schmidt and
Zillikens 2013).
Fig. 57 Mucous membrane pemphigoid demonstrating
and Pathophysiology scarring
MMP is rare, the estimated incidence rate in the
general population is two cases per million inhab-
itants per year (Bertram et al. 2009). Patients are with minimal clinical significance. “High-risk”
usually aged from 60 to 80 years. Women are patients are those who have disease occurring in
affected more often than men with a female-to- any of the following sites: ocular, nasopharyngeal,
male ratio of nearly 2:1 (Xu et al. 2013). esophageal, laryngeal, and genital mucosa (Chan
The major basement membrane zone proteins et al. 2002; Xu et al. 2013).
targeted in MMP include BP180, BP230, Laminin
332 (aka laminin 5 or epiligrin), α6β4 integrin, Pathologic Features
and type VII collagen (Rashid et al. 2006; MMP is a subepidermal vesicular process with a
Lazarova et al. 2001). variable inflammatory reaction. In many cases, the
underlying superficial dermis displays scarring,
Clinical Features reflecting recurrence at sites of prior involvement.
Approximately a quarter of patients have cutaneous Direct immunofluorescence, performed on peri-
disease, but mucosal disease predominates in most lesional tissue, can demonstrate linear deposition
cases of true MMP (Parker and MacKelfresh 2011). of reactants at the junction. It is important to be
The sites of most frequent mucosal involvement are aware that the sensitivity of DIF testing is rela-
the oral mucosa (85%), ocular conjunctiva (65%), tively low in this context (in the order of 70%),
nasal mucosa (20–40%), skin (25–30%), anogenital and that repeat biopsies and/or testing for circu-
area and/or pharynx (20%), larynx (5–15%), and lating antibodies against basement membrane
esophagus (5%–15%). Lesions occurring at any components may be required to confirm the diag-
site may heal with scarring (Fig. 57) (Chan et al. nosis (Shimanovich et al. 2017).
2002; Schmidt and Zillikens 2013; Xu et al. 2013;
Thorne et al. 2004; Chan 2001). Patient Management
In the mouth, both fixed (attached gingiva, hard Large randomized controlled clinical trials in MMP
palate) and mobile (buccal mucosa) epithelium are not available (Kirtschig et al. 2003). Treatment
may be affected. A common presentation is that should be individualized depending on the severity
of a painful, erosive gingivitis; intact blisters are of disease, age, general health, medical history, and
often not apparent (Parker and MacKelfresh 2011). any contraindications to the use of systemic medi-
There is a great variability in the presentation cations. Topical corticosteroids may be used as
and severity among patients with both localized monotherapy for patients with mild oral disease or
and extensive involvement. Localized disease can as an adjunct to systemic treatment in patients with
progress to extensive disease. “Low-risk” patients more extensive disease. Initial therapy from 0.25 to
are those where only the oral mucosa and/or the 0.5 mg/kg of prednisolone has been suggested for
skin is involved, there is less tendency of scarring mild–moderate presentations not responding to
808 T. Yap et al.
topical therapy. For patients with severe, refractory against the 97 kDa collagen XVII (BPAG2,
oral MMP, a dose of 1 mg/kg per day of prednisone BP180) ectodomain (also referred to as
in addition to immunosuppressive agents has been LABD97). LABD can be drug induced, most
suggested (Kourosh and Yancey 2011). commonly by vancomycin. There are reports
Dapsone in doses of 50–200 mg per day may be about association of LABD cases with gluten-
used for oral MMP that cannot be adequately man- sensitive enteropathy (Egan et al. 2001) and
aged with local therapy (Gurcan and Ahmed 2009). inflammatory bowel disease (Shipman et al.
Immunosuppressants, such as azathioprine, 2012; Onoe et al. 2017; Yamada et al. 2013).
mycophenolate mofetil, and cyclophosphamide,
are used in combination with systemic glucocorti- Clinical Features
coids for patients with severe, refractory oral MMP Individual lesions can present as herpetiform or
(Kourosh and Yancey 2011). Intravenous immuno- annular vesicles and tense blisters. It may have a
globulin (IVIg) is an often well-tolerated therapy particular “string of pearls” appearance (Fig. 58),
that may be beneficial in this group of patients but otherwise may be very similar clinically to
although the response to treatment is variable pemphigus and pemphigoid variants. The face is
(Ahmed and Colon 2001; Sami et al. 2004; commonly affected and may be perioral and peri-
Ahmed and Dahl 2003; Segura et al. 2007). ocular including the eyelids (Venning 2011).
Rituximab (a monoclonal antibody directed against
the CD20 antigen on the surface of B-lymphocytes) Pathologic Features
has also been used successfully for the treatment of Linear IgA bullous dermatosis is a subepidermal
severe, refractory MMP, in combination with sys- vesicular dermatosis with a neutrophilic inflam-
temic steroids and other immunosuppressants matory infiltrate. There is significant histological
(Le Roux-Villet et al. 2011; Foster et al. 2010). overlap with dermatitis herpetiformis, from which
Patients with ocular involvement have a risk it is best distinguished by clinical features and the
of irreversible conjunctival fibrosis and should pattern of IgA deposition at the dermoepidermal
be referred to ophthalmology with priority. Multi- junction on direct immunofluorescence study.
disciplinary care may include oral medicine
specialists, dermatologists, ophthalmologists,
ENTs, and gastroenterologists. After clinical remis-
sion is attained, treatment is slowly tapered. The
pace of tapering should be slow (e.g., over several
months) to minimize the risk for disease flares. If
discontinuation of all therapy is not possible due to
relapses, patients are maintained on the lowest effec-
tive topical or systemic maintenance regimen.
Linear IgA Bullous Dermatosis
Linear IgA bullous dermatosis (LABD), also

known as Linear IgA disease, is an IgA autoanti-
body-mediated, subepidermal, blistering disease.
and Pathophysiology
LABD in adults is very rare. It is more frequently
Fig. 58 Linear IgA disease (Image courtesy of Clinical
seen in children, but the true incidence is Associate Professor Kurt Gebauer, Dermatology West,
unknown. LABD is caused by IgA autoantibodies Perth WA, Australia)
Patient Management Subacute cutaneous lupus erythematosus

Commonly LABD responds very well to treat- (SCLE) typically presents in sun-exposed areas
ment with dapsone. Sometimes systemic cortico- with annular plaques that can cause hypo-
steroids, steroid sparing immunosuppressants or pigmentation but usually heal without scarring.
antibiotics (erythromycin, tetracyclines), espe- The main and most common type of chronic
cially in children, are used (Powell et al. 2001). cutaneous lupus erythematosus (CLE) is discoid
lupus erythematosus (DLE) (Gronhagen et al.
2011). Discoid plaques are most common on the
Lupus Erythematosus face, scalp, and ears but can be widespread
(Fig. 59). Lesions can be photo distributed; they
Epidemiology, Etiology, tend to heal with hypopigmentation and often scar-
and Pathophysiology ring (Fig. 60). Rare subtypes of CLE include lupus
Cutaneous lupus erythematosus (CLE) occurs in tumidus, lupus panniculitis, chilblain lupus, and bul-
around 80% of systemic lupus erythematosus lous lupus. Often patients with SLE also present
(SLE) patients (Kole and Ghosh 2009). The with unspecific skin lesions (livedo, palmar ery-
majority of CLE is independent of SLE, although thema, vasculitis, ulcerations, Raynaud’s phenome-
the development of SLE may rise to over 35% non, telangiectasia).
(Gronhagen et al. 2011). The annual incidence of
CLE is similar to SLE at around 4 per 100,000 Pathologic Features
peaking at 60–69 years (Jarukitsopa et al. 2015). CLE shows a range of histological features that
The female to male ratio is 10:1 for SLE and 3:1 reflect the different patterns of clinical disease.
for CLE (Watanabe and Tsuchida 1995). Overlap between patterns is common.
Lupus erythematosus is an autoimmune
connective tissue disease. The pathophysiology
is complex and only partially understood. Under-
lying genetic factors include B- and T-cell
function, innate immunity, immune complex
clearance, apoptosis, cellular adhesion, and
others. External contributing or triggering factors
are UV-radiation, drugs, viruses, and hormonal
factors. As a response, a complex interplay
of chemokines and cytokines by keratinocytes
and endothelial cells leads to a lichenoid inflam-
matory reaction and tissue damage (Goodfield Fig. 59 Discoid lupus of the face presenting as a typical
malar butterfly rash
et al. 2010).
Clinical Features
SLE can affect virtually any organ. Bones and
joints, skin, hematologic system, lung, kidneys,
and central nervous system are the most com-
monly involved organs. Skin features of lupus
are divided into three major groups (which may
exist in parallel):
Acute cutaneous lupus erythematosus
(ACLE), is the skin presentation of SLE charac-
terized by malar erythema (butterfly rash). Occa-
sionally lesions are more widespread. Oral ulcers Fig. 60 Chronic discoid lupus erythematosus of the face
are common. and neck
810 T. Yap et al.
Prototypical lesions of DLE show a complex of et al. 2010) with a peak incidence between 40 and
findings including hyperkeratosis with para- 50 years and a 2:1 female to male predominance
keratosis, variable epidermal acanthosis and (Tymms and Webb 1985).
focal atrophy, follicular plugging, and thickening Dermatomyositis is an autoimmune condition,
of the epidermal basement membrane. There is which can be triggered by malignancies, drugs, or
typically a superficial and deep perivascular and infections. Patients may have a genetic predispo-
periadnexal inflammatory infiltrate associated sition. Antinuclear antibodies and complement
with an increase in connective tissue mucin in activation are often present. Inflammation leads
the lower portions of the dermis. The hypertrophic to destruction of small vessels and microinfarction
variant of DLE shows prominent acanthosis. in muscle and skin. Specific autoantibodies found
Tumid lupus is dominated by an increase in con- in dermatomyositis, useful for diagnosis and prog-
nective tissue mucin and typically a dense super- nosis are anti-Jo1, -SRP, -Mi-2, -p155, -p140, and
ficial and deep perivascular lymphocytic infiltrate. -CADM-140.
Lupus profundus shows a lymphocytic lobular
panniculitis. The histopathology of lesions of sub- Clinical Features
acute cutaneous lupus erythematosus shows over- Important cutaneous features are poikiloderma
lap with DLE, though generally there is less (hypo- and hyperpigmentation, telangiectasia,
hyperkeratosis, and atrophy is a more prominent atrophy) and photo-distributed violaceous ery-
feature. The CSLE can show significant overlap thema (Fig. 61). Periorbital (heliotrope) erythema
with DLE. In other cases, a dermal neutrophilic and varying degrees of edema, cuticular dystro-
infiltrate can be seen. phy, nail-fold telangiectasia, and lichenoid
plaques on the knuckles (Gottron’s papules) are
Patient Management
It is most important to eliminate triggering
factors such as drugs, UV-exposure, and
smoking (Winkelmann et al. 2013). Therapy con-
sists of topical and intralesional corticosteroids
and topical calcineurin inhibitors. Systemic
therapy usually includes the immunomodulator
hydroxychloroquine and potentially steroid-sparing
immunosuppressants such as mycophenolate, meth-
otrexate, rituximab, and belimumab (Chang and
Werth 2011; Presto et al. 2016). Multisystem organ
involvement, especially renal disease, needs to be
regularly screened for, and multidisciplinary care is
often utilised. Joint care may occur between oral
medicine, rheumatologists, dermatologists, nephrol-
ogists, respiratory, and cardiology physicians. Vita-
min D levels should be monitored and potentially
vitamin D supplemented (Yap et al. 2015).
Dermatomyositis
and Pathophysiology
The annual incidence of dermatomyositis of all Fig. 61 Dermatomyositis on face, noting heliotrope
types is approximately 1 per 100,000 (Bendewald erythema
characteristic. Patients can suffer from skin dis- Cross-References

ease alone, but frequently suffer from systemic
symptoms such as malaise, fatigue, and myopa- ▶ Clinical Immunology in Diagnoses of Maxillo-
thy, especially of the proximal muscles of the facial Disease
extremities. Features can overlap with other con- ▶ Head and Neck Tumors
nective tissue disorders (Callen 2010; Callen and ▶ Non-odontogenic Bacterial Infections
Wortmann 2006). ▶ Oral and Maxillofacial Fungal Infections
▶ Oral and Maxillofacial Viral Infections
Pathologic Features ▶ Oral Mucosal Malignancies
Skin biopsy in dermatomyositis typically shows a ▶ Oral Vesicular and Bullous Lesions
relatively subtle pauci-inflammatory vacuolar ▶ Pediatric Oral Medicine
interface dermatitis. In more florid cases, there is ▶ Pigmented Lesions of the Oral Mucosa
significant morphological overlap with lesions
seen in cutaneous lupus erythematosus.
Acknowledgements The authors acknowledge the clini-
cal photography team at the Royal Melbourne Hospital.
Patient Management
Identification of potential triggers, especially
drugs or malignancy, is of utmost importance.
Initial treatment consists of systemic oral or References
IV corticosteroids (Drake et al. 1996). For long-
term treatment, immunomodulators such as Ackerman AB, Mones JM. Solar (actinic) keratosis
is squamous cell carcinoma. Br J Dermatol.
hydroxychloroquine and steroid-sparing immu-
2006;155(1):9–22.
nosuppressants such as azathioprine, cyclospor- Ahmed AR, Colon JE. Comparison between intravenous
ine, mycophenolate, IVIg, or rituximab are used immunoglobulin and conventional immunosuppressive
(Callen 2010; Joffe et al. 1993; Marie et al. 2010; therapy regimens in patients with severe oral
pemphigoid: effects on disease progression in patients
Oddis et al. 2013).
nonresponsive to dapsone therapy. Arch Dermatol.
For further discussion on mucosal predomi- 2001;137(9):1181–9.
nant immunobullous disorders, refer to the chap- Ahmed et al. Pemphigus: current concepts. Ann Intern
ter on ▶ “Oral Vesicular and Bullous Lesions.” Med. 1980;92(3):396–405.
Ahmed AR, Dahl MV. Consensus statement on the use of
intravenous immunoglobulin therapy in the treatment
of autoimmune mucocutaneous blistering diseases.
Conclusions and Future Directions Arch Dermatol. 2003;139(8):1051–9.
Ahmed AR, et al. Treatment of pemphigus vulgaris
with rituximab and intravenous immune globulin.
There is heterogeneity in cutaneous pathology
N Engl J Med. 2006;355(17):1772–9.
that can present in the head and neck region. Alikhan A, et al. Vitiligo: a comprehensive overview
From infectious to immune mediated to part I. Introduction, epidemiology, quality of life, diag-
UV-exposure driven and beyond, there is nosis, differential diagnosis, associations, histopathol-
ogy, etiology, and work-up. J Am Acad Dermatol.
no restriction to age groups or ethnicity. Presenta-
2011;65(3):473–91.
tions often represent disease that involves Al-Johani KA, Fedele S, Porter SR. Erythema
other cutaneous regions of the body. Correct multiforme and related disorders. Oral Surg Oral
diagnosis and management demands clinical Med Oral Pathol Oral Radiol Endod. 2007;103(5):
642–54.
acuity and often the meeting of multiple clinical
Alkhateeb A, et al. Epidemiology of vitiligo and associated
disciplines beginning with dermatology and der- autoimmune diseases in Caucasian probands and their
matopathology. Clinical advances in immunolog- families. Pigment Cell Res. 2003;16(3):208–14.
ical understanding and therapeutic fronts continue Amer M, Metwalli M. Topical liquiritin improves
melasma. Int J Dermatol. 2000;39(4):299–301.
to expand the treatment of this diverse group
Arduino PG, Porter SR. Oral and perioral herpes simplex
of conditions that is cutaneous head and neck virus type 1 (HSV-1) infection: review of its manage-
pathology. ment. Oral Dis. 2006;12(3):254–70.
812 T. Yap et al.
Arduino PG, Porter SR. Herpes simplex virus type 1 infec- Brimhall AK, et al. Safety and efficacy of alefacept,
tion: overview on relevant clinico-pathological fea- efalizumab, etanercept and infliximab in treating
tures. J Oral Pathol Med. 2008;37(2):107–21. moderate to severe plaque psoriasis: a meta-analysis
Arin MJ, et al. Anti-CD20 monoclonal antibody of randomized controlled trials. Br J Dermatol.
(rituximab) in the treatment of pemphigus. 2008;159(2):274–85.
Br J Dermatol. 2005;153(3):620–5. Bystryn JC. Adjuvant therapy of pemphigus. Arch
Augustsson A, et al. Prevalence of common and dysplastic Dermatol. 1984;120(7):941–51.
naevi in a Swedish population. Br J Dermatol. Bystryn JC, Rudolph JL. Pemphigus. Lancet.
1991;124(2):152–6. 2005;366(9479):61–73.
Balch CM, et al. Final version of 2009 AJCC Bystryn JC, Steinman NM. The adjuvant therapy of pemphi-
melanoma staging and classification. J Clin Oncol. gus. An update. Arch Dermatol. 1996;132(2):203–12.
2009;27(36):6199–206. Callen JP. Cutaneous manifestations of dermatomyositis
Baroni A, et al. Vesicular and bullous disorders: pemphi- and their management. Curr Rheumatol Rep.
gus. Dermatol Clin. 2007;25(4):597–603, ix. 2010;12(3):192–7.
Baum S, et al. Diagnosis and classification of Callen JP, Wortmann RL. Dermatomyositis. Clin
autoimmune blistering diseases. Autoimmun Rev. Dermatol. 2006;24(5):363–73.
2014;13(4–5):482–9. Campisi G, Margiotta V. Oral mucosal lesions and
Becker BA, Gaspari AA. Pemphigus vulgaris and risk habits among men in an Italian study population.
vegetans. Dermatol Clin. 1993;11(3):429–52. J Oral Pathol Med. 2001;30(1):22–8.
Beissert S, et al. A comparison of oral methylprednisolone Cavalcante AS, Anbinder AL, Carvalho YR. Actinic
plus azathioprine or mycophenolate mofetil for cheilitis: clinical and histological features. J Oral
the treatment of pemphigus. Arch Dermatol. Maxillofac Surg. 2008;66(3):498–503.
2006;142(11):1447–54. Celentano A, Cirillo N. Desmosomes in disease: a guide
Beissert S, et al. Treating pemphigus vulgaris with for clinicians. Oral Dis. 2017;23:157–67.
prednisone and mycophenolate mofetil: a multicenter, Celentano A, et al. Oral erythema multiforme: trends and
randomized, placebo-controlled trial. J Invest clinical findings of a large retrospective European case
Dermatol. 2010;130(8):2041–8. series. Oral Surg Oral Med Oral Pathol Oral Radiol.
Bendewald MJ, et al. Incidence of dermatomyositis and 2015;120:707.
clinically amyopathic dermatomyositis: a population- Chams-Davatchi C, et al. Randomized controlled
based study in Olmsted County, Minnesota. Arch open-label trial of four treatment regimens for pem-
Dermatol. 2010;146(1):26–30. phigus vulgaris. J Am Acad Dermatol. 2007;57(4):
Bergman R. The pathogenesis and clinical significance of 622–8.
xanthelasma palpebrarum. J Am Acad Dermatol. Chan LS. Mucous membrane pemphigoid. Clin Dermatol.
1994;30(2 Pt 1):236–42. 2001;19(6):703–11.
Berth-Jones J. Rosacea, perioral dermatitis and similar der- Chan LS, et al. The first international consensus on mucous
matoses, flushing and flushing syndromes. In: Rook’s membrane pemphigoid: definition, diagnostic criteria,
textbook of dermatology: Blackwell Publishing, Inc; pathogenic factors, medical treatment, and prognostic
Hoboken, New Jersey, USA; 2008. p. 2197–216. indicators. Arch Dermatol. 2002;138(3):370–9.
Bertram F, et al. Prospective analysis of the incidence of Chang MW. Disorders of hyperpigmentation. In:
autoimmune bullous disorders in Lower Franconia, Jorizzo JL, Bolognia JL, Schaffer JV, editors. Derma-
Germany. J Dtsch Dermatol Ges. 2009;7(5):434–40. tology, vol. 1. 3rd ed. Philadelphia: Elsevier Saunders;
Bharucha T, Ming D, Breuer J. A critical appraisal of 2012. p. 1049.
‘Shingrix’, a novel herpes zoster subunit (HZ/Su Chang AY, Werth VP. Treatment of cutaneous lupus.
or GSK1437173A) vaccine for varicella zoster virus. Curr Rheumatol Rep. 2011;13(4):300–7.
Hum Vaccin Immunother. 2017;14:1–9. Chen N, et al. Corticosteroids for preventing postherpetic
Black M, Mignogna MD, Scully C. Number II. Pemphigus neuralgia. Cochrane Database Syst Rev. 2010;12:
vulgaris. Oral Dis. 2005;11(3):119–30. Cd005582.
Boissy RE, Visscher M, DeLong MA. DeoxyArbutin: Chen N, et al. Antiviral treatment for preventing post-
a novel reversible tyrosinase inhibitor with effective herpetic neuralgia. Cochrane Database Syst Rev.
in vivo skin lightening potency. Exp Dermatol. 2014;2:Cd006866.
2005;14(8):601–8. Clydesdale GJ, Dandie GW, Muller HK. Ultraviolet light
Borda LJ, Wikramanayake TC. Seborrheic dermatitis induced injury: immunological and inflammatory
and dandruff: a comprehensive review. J Clin Invest effects. Immunol Cell Biol. 2001;79(6):547–68.
Dermatol. 2015;3(2):10. Cohen RL. Clinical perspectives on premature tooth erup-
Brash DE, et al. A role for sunlight in skin cancer: tion and cyst formation in neonates. Pediatr Dermatol.
UV-induced p53 mutations in squamous cell carci- 1984;1(4):301–6.
noma. Proc Natl Acad Sci USA. 1991;88(22):10124–8. Corey L, Spear PG. Infections with herpes simplex
Brenner S, Wohl Y. A survey of sex differences in 249 pem- viruses (1). N Engl J Med. 1986;314(11):686–91.
phigus patients and possible explanations. Skinmed. Criscione VD, et al. Actinic keratoses: natural history and
2007;6(4):163–5. risk of malignant transformation in the veterans affairs
topical Tretinoin chemoprevention trial. Cancer. Friedmann PS, Holden CA. Atopic dermatitis. In: Rook’s
2009;115(11):2523–30. textbook of dermatology: Blackwell Publishing, Inc;
da Silva LM, et al. Herpes simplex virus type 1 shedding in Hoboken, New Jersey, USA; 2008. p. 755–86.
the oral cavity of seropositive patients. Oral Dis. Frost C, Williams G, Green A. High incidence and regres-
2005;11(1):13–6. sion rates of solar keratoses in a queensland commu-
Dalal KM, et al. Patterns of first-recurrence and post- nity. J Invest Dermatol. 2000;115(2):273–7.
recurrence survival in patients with primary cutaneous Gagliardi AM, et al. Vaccines for preventing herpes zoster
melanoma after sentinel lymph node biopsy. Ann Surg in older adults. Cochrane Database Syst Rev. 2016;3:
Oncol. 2007;14(6):1934–42. Cd008858.
Daniel BS, Murrell DF. Management of pemphigus. Garcia C, Poletti E, Crowson AN. Basosquamous carci-
F1000Prime Rep. 2014;6:32. noma. J Am Acad Dermatol. 2009;60(1):137–43.
Daniel BS, et al. Evidence-based management of bullous Gilbert SC. Management and prevention of recurrent her-
pemphigoid. Dermatol Clin. 2011;29(4):613–20. pes labialis in immunocompetent patients. Herpes.
de Oliveira Ribeiro A, da Silva LC, Martins-Filho 2007;14(3):56–61.
PR. Prevalence of and risk factors for actinic cheilitis Goldberg LH, Joseph AK, Tschen JA. Proliferative actinic
in Brazilian fishermen and women. Int J Dermatol. keratosis. Int J Dermatol. 1994;33(5):341–5.
2014;53(11):1370–6. Goodfield MJD, Jones SK, Veale DJ. The ‘connective
de Souza Lucena EE, et al. Prevalence and factors associ- tissue diseases’. In: Rook’s textbook of dermatology.
ated to actinic cheilitis in beach workers. Oral Dis. Chichester: Wiley-Blackwell; 2010. p. 1–138.
2012;18(6):575–9. Green AC. Epidemiology of actinic keratoses. Curr Probl
Demirkan S, Gündüz Ö, Sayan CD. Retrospective Dermatol. 2015;46:1–7.
analysis of endemic Melasma patients. Derm Rep. Grohs RL, Mesbah Ardakani N. Melanoma manifesting as
2017;9(1):7027. Tumoral melanosis; Now you see it, now you don’t.
Drake LA, et al. Guidelines of care for dermatomyositis. Am J Dermatopathol. 2017;
American Academy of Dermatology. J Am Acad Gronhagen CM, et al. Cutaneous lupus erythematosus and
Dermatol. 1996;34(5 Pt 1):824–9. the association with systemic lupus erythematosus:
Egan CA, et al. Linear IgA bullous dermatosis a population-based cohort of 1088 patients in Sweden.
responsive to a gluten-free diet. Am J Gastroenterol. Br J Dermatol. 2011;164(6):1335–41.
2001;96(6):1927–9. Gual A, et al. Mortality of bullous pemphigoid in the first
Elling SV, Powell FC. Physiological changes in the skin year after diagnosis: a retrospective study in a Spanish
during pregnancy. Clin Dermatol. 1997;15(1):35–43. medical centre. J Eur Acad Dermatol Venereol.
Fabrizi G, et al. Atypical nevi of the scalp in adolescents. 2014;28(4):500–6.
J Cutan Pathol. 2007;34(5):365–9. Gungor S, Canat D, Gokdemir G. Erbium: YAG laser
Faries MB, et al. Late recurrence in melanoma: clinical ablation versus 70% trichloroacetic acid application
implications of lost dormancy. J Am Coll Surg. in the treatment of xanthelasma palpebrarum.
2013;217(1):27–34; discussion 34–6. J Dermatolog Treat. 2014;25(4):290–3.
Faries MB, et al. Multicenter selective lymphadenectomy Gupta AK, Versteeg SG. Topical treatment of facial sebor-
trial-I confirms the central role of sentinel node rheic dermatitis: a systematic review. Am J Clin
biopsy in contemporary melanoma management: Dermatol. 2017;18(2):193–213.
response to ‘No survival benefit for patients with Gupta AK, et al. The treatment of melasma: a review of
melanoma undergoing sentinel lymph node biopsy: clinical trials. J Am Acad Dermatol. 2006;55(6):
critical appraisal of the multicenter selective 1048–65.
lymphadenectomy trial-I final report’. Br J Dermatol. Gupta AK, et al. Interventions for actinic keratoses.
2015;172(3):571–3. Cochrane Database Syst Rev. 2012;12:Cd004415.
Faries MB, et al. Completion dissection or observation for Gurcan HM, Ahmed AR. Efficacy of dapsone in the
sentinel-node metastasis in melanoma. N Engl J Med. treatment of pemphigus and pemphigoid: analysis
2017;376(23):2211–22. of current data. Am J Clin Dermatol. 2009;10(6):
Fields HL, Rowbotham M, Baron R. Postherpetic 383–96.
neuralgia: irritable nociceptors and deafferentation. Hakozaki T, et al. The effect of niacinamide on reducing
Neurobiol Dis. 1998;5(4):209–27. cutaneous pigmentation and suppression of melano-
Fitzpatrick TB. The validity and practicality of some transfer. Br J Dermatol. 2002;147(1):20–31.
sun-reactive skin types I through VI. Arch Dermatol. Harries MJ, Paus R. The pathogenesis of primary cicatri-
1988;124(6):869–71. cial alopecias. Am J Pathol. 2010;177(5):2152–62.
Fogel AL, Sarin KY, Teng JMC. Genetic diseases associ- Herbst A, Bystryn JC. Patterns of remission in pemphigus
ated with an increased risk of skin cancer development vulgaris. J Am Acad Dermatol. 2000;42(3):422–7.
in childhood. Curr Opin Pediatr. 2017;29(4):426–33. Iannella G, et al. Vitiligo: pathogenesis, clinical
Foster CS, Chang PY, Ahmed AR. Combination of variants and treatment approaches. Autoimmun Rev.
rituximab and intravenous immunoglobulin for recalci- 2016;15(4):335–43.
trant ocular cicatricial pemphigoid: a preliminary Jackson JM, et al. Current understanding of seborrheic
report. Ophthalmology. 2010;117(5):861–9. keratosis: prevalence, etiology, clinical presentation,
814 T. Yap et al.
diagnosis, and management. J Drugs Dermatol. G domain of the laminin 5 alpha-subunit. Clin
2015;14(10):1119–25. Immunol. 2001;101(1):100–5.
Jadotte YT, Schwartz RA. Solar cheilosis: an ominous Le Roux-Villet C, et al. Rituximab for patients with refrac-
precursor: part I. Diagnostic insights. J Am Acad tory mucous membrane pemphigoid. Arch Dermatol.
Dermatol. 2012a;66(2):173–84. quiz 185–6. 2011;147(7):843–9.
Jadotte YT, Schwartz RA. Solar cheilosis: an ominous Lee DY, et al. Predictors and survival impact of false-
precursor part II. Therapeutic perspectives. J Am negative sentinel nodes in melanoma. Ann Surg
Acad Dermatol. 2012b;66(2):187–98; quiz 199–200. Oncol. 2016;23(3):1012–8.
Jarukitsopa S, et al. Epidemiology of systemic lupus Leffell DJ. The scientific basis of skin cancer. J Am Acad
erythematosus and cutaneous lupus erythematosus Dermatol. 2000;42(1 Pt 2):18–22.
in a predominantly white population in the United Li YH, et al. Detection of epidermodysplasia
States. Arthritis Care Res (Hoboken). 2015;67(6): verruciformis-associated human papillomavirus DNA
817–28. in nongenital seborrhoeic keratosis. Br J Dermatol.
Joffe MM, et al. Drug therapy of the idiopathic inflamma- 2004;151(5):1060–5.
tory myopathies: predictors of response to prednisone, Lin RL, Szepietowski JC, Schwartz RA. Tinea faciei,
azathioprine, and methotrexate and a comparison of an often deceptive facial eruption. Int J Dermatol.
their efficacy. Am J Med. 1993;94(4):379–87. 2004;43(6):437–40.
Joly P, et al. A single cycle of rituximab for the Lipozencic J, Hadzavdic SL. Perioral dermatitis. Clin
treatment of severe pemphigus. N Engl J Med. Dermatol. 2014;32(1):125–30.
2007;357(6):545–52. Lipozencic J, Ljubojevic S. Perioral dermatitis. Clin
Junqueira JL, et al. Actinic cheilitis among agricultural Dermatol. 2011;29(2):157–61.
workers in Campinas, Brazil. Community Dent Health. Loo WJ, Burrows NP. Management of autoimmune
2011;28(1):60–3. skin disorders in the elderly. Drugs Aging.
Kalra A, et al. Role of herpes simplex and cytomegalo 2004;21(12):767–77.
viruses in recalcitrant oral lesions of pemphigus Madu MF, Wouters MW, van Akkooi AC. Sentinel node
vulgaris. Int J Dermatol. 2005;44(3):259–60. biopsy in melanoma: current controversies addressed.
Kang HY, et al. The dermal stem cell factor and c-kit Eur J Surg Oncol. 2017;43(3):517–33.
are overexpressed in melasma. Br J Dermatol. Mahajan VK, et al. Twelve-year clinico-therapeutic expe-
2006;154(6):1094–9. rience in pemphigus: a retrospective study of 54 cases.
Kang H, et al. Lichen planopilaris. Dermatol Ther. Int J Dermatol. 2005;44(10):821–7.
2008;21(4):249–56. Marazza G, et al. Incidence of bullous pemphigoid and
Kawai K, Gebremeskel BG, Acosta CJ. Systematic review pemphigus in Switzerland: a 2-year prospective study.
of incidence and complications of herpes zoster: Br J Dermatol. 2009;161(4):861–8.
towards a global perspective. BMJ Open. 2014;4(6): Marie I, et al. Intravenous immunoglobulins for steroid-
e004833. refractory esophageal involvement related to polymyo-
Kelly JB 3rd, Foley P, Strober BE. Current and future oral sitis and dermatomyositis: a series of 73 patients.
systemic therapies for psoriasis. Dermatol Clin. Arthritis Care Res (Hoboken). 2010;62(12):1748–55.
2015;33(1):91–109. Marks R, Rennie G, Selwood TS. Malignant transforma-
Kennedy PG, Cohrs RJ. Varicella-zoster virus human gan- tion of solar keratoses to squamous cell carcinoma.
glionic latency: a current summary. J Neurovirol. Lancet. 1988;1(8589):795–7.
2010;16(6):411–8. McCullough MJ, Savage NW. Oral viral infections and the
Kirtschig G, et al. Interventions for mucous membrane therapeutic use of antiviral agents in dentistry. Aust
pemphigoid and epidermolysis bullosa acquisita. Dent J. 2005;50(4 Suppl 2):S31–5.
Cochrane Database Syst Rev. 2003;1:Cd004056. McDonald SK, Goh MS, Chong AH. Successful treatment
Kirtschig G, et al. Interventions for bullous pemphigoid. of cyclosporine-induced sebaceous hyperplasia with
Cochrane Database Syst Rev. 2010;10:Cd002292. oral isotretinoin in two renal transplant recipients.
Kneisel A, Hertl M. Autoimmune bullous skin diseases. Australas J Dermatol. 2011;52(3):227–30.
Part 1: clinical manifestations. J Dtsch Dermatol Ges. McNamara DR, et al. Incidence of lower-extremity
2011;9(10):844–56; quiz 857. cellulitis: a population-based study in Olmsted county,
Kole AK, Ghosh A. Cutaneous manifestations of systemic Minnesota. Mayo Clin Proc. 2007;82(7):817–21.
lupus erythematosus in a tertiary referral center. Indian Mella JM, et al. Efficacy and safety of finasteride therapy
J Dermatol. 2009;54(2):132–6. for androgenetic alopecia: a systematic review. Arch
Kourosh AS, Yancey KB. Therapeutic approaches to Dermatol. 2010;146(10):1141–50.
patients with mucous membrane pemphigoid. Menta Simonsen Nico M, Rivitti EA, Lourenco SV.
Dermatol Clin. 2011;29(4):637–41. Actinic cheilitis: histologic study of the entire vermil-
Kyriakis KP, et al. Epidemiologic aspects of seborrheic ion and comparison with previous biopsy. J Cutan
keratoses. Int J Dermatol. 2012;51(2):233–4. Pathol. 2007;34(4):309–14.
Lazarova Z, et al. IgG autoantibodies in patients with Menter A, et al. Guidelines of care for the management
anti-epiligrin cicatricial pemphigoid recognize the of psoriasis and psoriatic arthritis. Section 3.
Guidelines of care for the management and treatment of vehicle-controlled study in 40 patients. J Eur Acad
psoriasis with topical therapies. J Am Acad Dermatol. Dermatol Venereol. 2007;21(9):1175–80.
2009;60(4):643–59. Ortonne JP, et al. A global survey of the role of ultraviolet
Menter A, et al. Guidelines of care for the management radiation and hormonal influences in the development
of psoriasis and psoriatic arthritis: section 5. Guidelines of melasma. J Eur Acad Dermatol Venereol.
of care for the treatment of psoriasis with phototherapy 2009;23(11):1254–62.
and photochemotherapy. J Am Acad Dermatol. Otten JV, et al. Molecular diagnosis in autoimmune skin
2010;62(1):114–35. blistering conditions. Curr Mol Med. 2014;14(1):
Mignogna MD, et al. Oropharyngeal pemphigus vulgaris 69–95.
and clinical remission: a long-term, longitudinal study. Parisi R, et al. Global epidemiology of psoriasis: a system-
Am J Clin Dermatol. 2010;11(2):137–45. atic review of incidence and prevalence. J Invest
Mihai S, Sitaru C. Immunopathology and molecular diag- Dermatol. 2013;133(2):377–85.
nosis of autoimmune bullous diseases. J Cell Mol Med. Parker SR, MacKelfresh J. Autoimmune blistering dis-
2007;11(3):462–81. eases in the elderly. Clin Dermatol. 2011;29(1):69–79.
Miller CS, Danaher RJ. Asymptomatic shedding of Parkin DM, Mesher D, Sasieni P. 13. Cancers attributable
herpes simplex virus (HSV) in the oral cavity. Oral to solar (ultraviolet) radiation exposure in the UK in
Surg Oral Med Oral Pathol Oral Radiol Endod. 2010. Br J Cancer. 2011;105(S2):S66–9.
2008;105(1):43–50. Passeron T. Melasma pathogenesis and influencing factors
Mimouni D, et al. Treatment of pemphigus vulgaris and – an overview of the latest research. J Eur Acad
pemphigus foliaceus with mycophenolate mofetil. Dermatol Venereol. 2013;27(Suppl 1):5–6.
Arch Dermatol. 2003;139(6):739–42. Powell J, et al. Mixed immunobullous disease of child-
Mortimer PS, Burnand KG. Diseases of the veins and hood: a good response to antimicrobials. Br J Dermatol.
arteries: leg ulcers. In: Rook’s textbook of dermatol- 2001;144(4):769–74.
ogy: Blackwell Publishing, Inc; Hoboken, New Jersey, Presto JK, Hejazi EZ, Werth VP. Biological therapies in
USA; 2008. p. 2441–94. the treatment of cutaneous lupus erythematosus.
Morton DL, et al. Final trial report of sentinel-node biopsy Lupus. 2016. https://doi.org/10.1177/09612033166
versus nodal observation in melanoma. N Engl J Med. 70731.
2014;370(7):599–609. Qasmi S, et al. Impact of oral lesions on diagnosis, treat-
Murrell DF, et al. Consensus statement on definitions of ment and prognosis of pemphigus. J Eur Acad
disease, end points, and therapeutic response for pem- Dermatol Venereol. 2009;23(4):469–70.
phigus. J Am Acad Dermatol. 2008;58(6):1043–6. Ragaz A, Ackerman AB. Evolution, maturation, and
Nakamura H, et al. Clonal nature of seborrheic keratosis regression of lesions of psoriasis. New observations
demonstrated by using the polymorphism of the human and correlation of clinical and histologic findings.
androgen receptor locus as a marker. J Invest Dermatol. Am J Dermatopathol. 1979;1(3):199–214.
2001;116(4):506–10. Ragozzino MW, et al. Population-based study of
Neoh C, et al. Comparison of topical and oral acyclovir herpes zoster and its sequelae. Medicine (Baltimore).
in early herpes zoster ophthalmicus. Eye (Lond). 1982;61(5):310–6.
1994;8(Pt 6):688–91. Rashid KA, Gurcan HM, Ahmed AR. Antigen specificity
Norris D, et al. Biologics and dermatology life quality in subsets of mucous membrane pemphigoid. J Invest
index (DLQI) in the Australasian psoriasis population. Dermatol. 2006;126(12):2631–6.
J Dermatolog Treat. 2017:1–6. Rashighi M, Harris JE. Vitiligo pathogenesis and emerging
Oddis CV, et al. Rituximab in the treatment of refractory treatments. Dermatol Clin. 2017;35(2):257–65.
adult and juvenile dermatomyositis and adult polymyo- Ratushny V, et al. From keratinocyte to cancer: the patho-
sitis: a randomized, placebo-phase trial. Arthritis genesis and modeling of cutaneous squamous cell car-
Rheum. 2013;65(2):314–24. cinoma. J Clin Invest. 2012;122(2):464–72.
Olsen EA, et al. A randomized clinical trial of 5% topical Requena L, Sangueza OP. Cutaneous vascular anomalies.
minoxidil versus 2% topical minoxidil and placebo in Part I. Hamartomas, malformations, and dilation
the treatment of androgenetic alopecia in men. J Am of preexisting vessels. J Am Acad Dermatol.
Acad Dermatol. 2002;47(3):377–85. 1997;37(4):523–49; quiz 549–52.
Olsen EA, et al. Summary of North American Hair Rodgers M, et al. Etanercept, infliximab and adalimumab
Research Society (NAHRS)-sponsored Workshop on for the treatment of psoriatic arthritis: a systematic
Cicatricial Alopecia, Duke University Medical Center, review and economic evaluation. Health Technol
February 10 and 11, 2001. J Am Acad Dermatol. Assess. 2011;15(10):i–xxi, 1–329.
2003;48(1):103–10. Rosa G, et al. Langerhans cell collections, but not eosino-
Onoe A, et al. Linear immunoglobulin A/G bullous der- phils, are clues to a diagnosis of allergic contact der-
matosis associated with ulcerative colitis. J Dermatol. matitis in appropriate skin biopsies. J Cutan Pathol.
2017;44:1295. 2016;43(6):498–504.
Oppel T, et al. Pimecrolimus cream (1%) efficacy in peri- Saad AG, Patel S, Mutasim DF. Melanocytic nevi of
oral dermatitis – results of a randomized, double-blind, the auricular region: histologic characteristics and
816 T. Yap et al.
diagnostic difficulties. Am J Dermatopathol. evidence and clinical usefulness. Ther Adv Med
2005;27(2):111–5. Oncol. 2016;8(5):375–82.
Salasche SJ. Epidemiology of actinic keratoses and Simmons BJ, Griffith RD, Falto-Aizpurua LA. Light and
squamous cell carcinoma. J Am Acad Dermatol. laser therapies for the treatment of sebaceous gland
2000;42(1 Pt 2):4–7. hyperplasia a review of the literature. J Eur Acad
Sami N, et al. Intravenous immunoglobulin therapy in Dermatol Venereol. 2015;29(11):2080–7.
patients with ocular-cicatricial pemphigoid: a long- Simpson NB, Cunliffe WJ. Disorders of the sebaceous
term follow-up. Ophthalmology. 2004;111(7):1380–2. glands. In: Rook’s textbook of dermatology: Blackwell
Schmidt E, Zillikens D. Pemphigoid diseases. Lancet. Publishing, Inc; 2008. p. 2121–96.
2013;381(9863):320–32. Sladden M, et al. No survival benefit for patients with
Schmidt E, della Torre R, Borradori L. Clinical features melanoma undergoing sentinel lymph node biopsy:
and practical diagnosis of bullous pemphigoid. critical appraisal of the multicenter selective
Dermatol Clin. 2011;29(3):427–38, viii–ix. lymphadenectomy trial-I final report. Br J Dermatol.
Schofield JK, Tatnall FM, Leigh IM. Recurrent erythema 2015;172(3):566–71.
multiforme: clinical features and treatment in a large Smoller BR. Squamous cell carcinoma: from
series of patients. Br J Dermatol. 1993;128(5):542–5. precursor lesions to high-risk variants. Mod Pathol.
Scully C, et al. Pemphigus vulgaris: the manifestations and 2006;19(S2):S88–92.
long-term management of 55 patients with oral lesions. Spruance SL, et al. The natural history of recurrent herpes
Br J Dermatol. 1999;140(1):84–9. simplex labialis: implications for antiviral therapy.
Segal P, et al. The association of dyslipoproteinemia N Engl J Med. 1977;297(2):69–75.
with corneal arcus and xanthelasma. The Lipid Squillace L, et al. Unusual Dermoscopic patterns of sebor-
Research Clinics Program Prevalence Study. Circula- rheic keratosis. Dermatology. 2016;232(2):198–202.
tion. 1986;73(1 Pt 2):I108–18. Stock C, et al. Risk factors of herpes simplex type
Segura S, et al. High-dose intravenous immunoglobulins 1 (HSV-1) infection and lifestyle factors associated
for the treatment of autoimmune mucocutaneous blis- with HSV-1 manifestations. Eur J Epidemiol.
tering diseases: evaluation of its use in 19 cases. J Am 2001;17(9):885–90.
Acad Dermatol. 2007;56(6):960–7. Svendsen MT, et al. Worldwide utilization of topical rem-
Serpell M, et al. Burden of post-herpetic neuralgia in a edies in treatment of psoriasis: a systematic review.
sample of UK residents aged 50 years or older: findings J Dermatolog Treat. 2017;28(5):374–83.
from the Zoster Quality of Life (ZQOL) study. Health Taylor SC, et al. Acne vulgaris in skin of color. J Am
Qual Life Outcomes. 2014;12:92. Acad Dermatol. 2002;46(2 Suppl Understanding):
Shah AY, Doherty SD, Rosen T. Actinic cheilitis: a treat- S98–106.
ment review. Int J Dermatol. 2010;49(11):1225–34. Taylor S, et al. Postinflammatory hyperpigmentation.
Shain AH, Bastian BC. From melanocytes to melanomas. J Cutan Med Surg. 2009;13(4):183–91.
Nat Rev Cancer. 2016;16(6):345–58. Templeton SF, Santa Cruz DJ, Solomon AR. Alopecia:
Sheth VM, Pandya AG. Melasma: a comprehensive histologic diagnosis by transverse sections. Semin
update: part II. J Am Acad Dermatol. 2011;65(4): Diagn Pathol. 1996;13(1):2–18.
699–714; quiz 715. Thorne JE, Anhalt GJ, Jabs DA. Mucous membrane
Shimanovich I, Nitz JM, Zillikens D. Multiple pemphigoid and pseudopemphigoid. Ophthalmology.
and repeated sampling increases the sensitivity of 2004;111(1):45–52.
direct immunofluorescence testing for the diagnosis Torres SM, Hughes CR, Berwick M. Melanoma and skin
of mucous membrane pemphigoid. J Am Acad aging. In: Farage MA, Miller KW, Maibach HI, editors.
Dermatol. 2017;77(4):700–705.e3. Textbook of aging skin. Berlin/Heidelberg: Springer;
Shipman AR, Reddy H, Wojnarowska F. Association 2017. p. 903–12.
between the subepidermal autoimmune blistering dis- Tymms KE, Webb J. Dermatopolymyositis and other
eases linear IgA disease and the pemphigoid group connective tissue diseases: a review of 105 cases.
and inflammatory bowel disease: two case reports and J Rheumatol. 1985;12(6):1140–8.
literature review. Clin Exp Dermatol. 2012;37(5): Venning VA. Linear IgA disease: clinical presentation,
461–8. diagnosis, and pathogenesis. Dermatol Clin.
Shirakata Y, et al. Lack of mucosal involvement in pem- 2011;29(3):453–8, ix.
phigus foliaceus may be due to low expression of Wang Z, et al. Identification of saliva using MicroRNA
desmoglein 1. J Invest Dermatol. 1998;110(1):76–8. biomarkers for forensic purpose. J Forensic Sci.
Shulman JD. Recurrent herpes labialis in US children and 2015;60(3):702–6.
youth. Community Dent Oral Epidemiol. 2004;32(6): Watanabe T, Tsuchida T. Classification of lupus
402–9. erythematosus based upon cutaneous manifestations.
Silapunt S, Chen L, Migden MR. Hedgehog pathway Dermatological, systemic and laboratory findings in
inhibition in advanced basal cell carcinoma: latest 191 patients. Dermatology. 1995;190(4):277–83.
Weedon DD, et al. Squamous cell carcinoma arising in Evidence-Based Medicine Criteria. J Clin Aesthetic
keratoacanthoma: a neglected phenomenon in the Derm. 2013;6(1):27–38.
elderly. Am J Dermatopathol. 2010;32(5):423–6. Woo SB, Challacombe SJ. Management of recurrent
Weissenborn SJ, et al. Human papillomavirus-DNA loads oral herpes simplex infections. Oral Surg Oral
in actinic keratoses exceed those in non-melanoma skin Med Oral Pathol Oral Radiol Endod. 2007;103(Suppl):
cancers. J Invest Dermatol. 2005;125(1):93–7. S12.e1–18.
Werlinger KD, et al. Prevalence of self-diagnosed melasma Wood BA. Desmoplastic melanoma: recent advances
among premenopausal Latino women in Dallas and fort and persisting challenges. Pathology. 2013;45(5):
worth, Tex [2]. Arch Dermatol. 2007;143(3):424–5. 453–63.
Werner RN, et al. European consensus-based (S2k) guide- Wood BA. Paediatric melanoma. Pathology. 2016;48(2):
line on the management of Herpes Zoster – guided by 155–65.
the European Dermatology Forum (EDF) in coopera- Xu HH, et al. Mucous membrane pemphigoid. Dent Clin
tion with the European Academy of Dermatology and N Am. 2013;57(4):611–30.
Venereology (EADV), part 2: treatment. J Eur Acad Yamada S, et al. Association of linear IgA bullous disease
Dermatol Venereol. 2017;31(1):20–9. with ulcerative colitis: a case of successful treatment
Whiting DA, Olsen EA. Central centrifugal cicatricial alo- with infliximab. Dermatology. 2013;227(4):295–8.
pecia. Dermatol Ther. 2008;21(4):268–78. Yap KS, et al. Association of low vitamin D with high disease
Wiesner T, et al. Kinase fusions are frequent in Spitz activity in an Australian systemic lupus erythematosus
tumours and spitzoid melanomas. Nat Commun. cohort. Lupus Sci Med. 2015;2(1):e000064.
2014;5:3116. Yeatman JM, Kilkenny M, Marks R. The prevalence of
Winkelmann RR, Kim GK, Del Rosso JQ. Treatment of seborrhoeic keratoses in an Australian population: does
cutaneous lupus erythematosus: review and assessment exposure to sunlight play a part in their frequency?
of treatment benefits based on Oxford Centre for Br J Dermatol. 1997;137(3):411–4.
Odontogenic Bacterial Infections
Stuart G. Dashper, Alf Nastri, and Paul V. Abbott
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 820
Oral Microbiome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 821
Summary of the Recent Advances in Characterization of the Human Oral
Microbiome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 821
Culture Independent Analyses and the Discovery of New Species Associated with
Health and Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 822
Overview of the Diversity of the Human Oral Microbiome . . . . . . . . . . . . . . . . . . . . . . . . . . . . 822
Oral Bacterial Ecology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 823
Genetic Diversity and Physiological Flexibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 823
Growth as Polymicrobial Biofilm Communities and Interactions Between Species . . . 823
Escape from the Oral Cavity and Life on the Inside . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 824
Common Bacterial Associated Diseases of the Oral Cavity . . . . . . . . . . . . . . . . . . . . . . . . 825
Polymicrobial Nature of Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 825
Periodontal Diseases: Gingivitis and Chronic Periodontitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 825
Dental Caries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 828
Significant Bacterial Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 831
The Dental Pulp . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 833
S. G. Dashper (*)
Melbourne Dental School, Oral Health Cooperative
Research Centre, The University of Melbourne,
Melbourne, Australia
e-mail: stuartgd@unimelb.edu.au
A. Nastri
Department of Maxillofacial Surgery, Royal Melbourne
Hospital, The University of Melbourne, Melbourne,
Australia
e-mail: anastri@me.com
P. V. Abbott
Australia, The University of Western Australia, Perth,
Australia
e-mail: paul.v.abbott@uwa.edu.au

https://doi.org/10.1007/978-3-319-72303-7_45
820 S. G. Dashper et al.
Pulp, Root Canal, and Periapical Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 838

Management of Pulp, Root Canal, and Periapical Conditions . . . . . . . . . . . . . . . . . . . . . 842
Assessment/Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 842
Managing Pulpitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 845
Managing Infected Root Canal Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847
Periapical Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 851
Antibiotics: When and When Not to Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 853
Treatment and Prevention of Odontogenic Maxillofacial Infections . . . . . . . . . . . . . . 854
Principles of Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 854
Medical Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 855
Antibiotic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 856
Surgery and Drainage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 856
Airway Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 857
Prevention of Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 858
Osteomyelitis, Osteoradionecrosis (ORN), and Antiresorptive Agent-Induced
Osteonecrosis of the Jaws (ARONJ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 858
Osteomyelitis of the Jaws . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 858
Osteoradionecrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 862
Antiresorptive Agent-Induced Osteonecrosis of the Jaws (ARONJ) . . . . . . . . . . . . . . . . . . . 863
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 867
Abstract simple dental restorations, periodontal treatment

The oral cavity is home to over 700 species of (scaling, root planing), root canal treatment to
bacteria, known as the human oral microbiome. extraction of the tooth. Various medical and
The oral cavity is an ideal environment for bac- surgical procedures plus the use of antimicrobial
terial colonization and growth. Although the drug therapy are required in cases with severe
majority of these bacteria are beneficial to infections and/or systemic signs of the infection.
human health and do not cause disease, under Other conditions such as osteonecrosis of the
particular circumstances, bacterial infections can jaws must be differentiated from oral infections
occur. The most common bacterial diseases that but they may have secondary bacterial
occur in the oral cavity are in the form of dental involvement.
caries, periodontal diseases, and pulp, root canal,
and periapical diseases. These diseases are over- Keywords
whelmingly due to bacteria that are part of the Oral microbiome · Dental caries · Periodontal
normal oral microbiota, and not exogenous path- diseases · Gingivitis · Pulpitis · Apical
ogens. Pulp and root canal diseases can lead to periodontitis · Apical abscesses · Facial
periradicular conditions such as apical periodon- cellulitis · Oesteomyelitis · Osteonecrosis
titis, apical abscesses, facial cellulitis (with pos-
sible airway involvement), and osteomyelitis.
Management of these diseases is based initially Introduction
on obtaining a complete history and performing
a thorough clinical and radiographic examina- Bacterial infections are common causes of human
tion in order to develop an accurate diagnosis. disease. The oral cavity is home to over 700 species
Various treatment procedures can be provided, of bacteria, known as the human oral microbiome.
depending on the diagnosis – these range from The oral cavity is an ideal environment for bacterial
Odontogenic Bacterial Infections 821
colonization and growth, and the dental hard and Nearly 80% of people exhibit clinical signs of
soft tissues are commonly exposed to the effects of periodontal disease and between 20% and 40%
such bacterial infections. Dental caries is one of the have periodontitis, with those aged over 65 years
most prevalent dental diseases in the world, the more likely to demonstrate moderate to severe
prevalence and severity of which varies around forms of the disease.
the world. Despite improvements in the last Bacterial odontogenic infections and diseases
20–30 years, there is considerable evidence of can be treated by a variety of medical or surgical
poor oral health. Bacterial infections affecting den- means that are common place in dental practice.
tal hard tissues, the pulp, and the periodontal tissues The oral medicine specialist must be aware of
are commonplace in various population and socio- complications of these conditions and be prepared
economic groups. Recent trends suggest changes in to distinguish their sequalae from other more sin-
diet and behavior, such as increased consumption of ister pathologies affecting the teeth, periodontal
bottled water, sports drinks, and soft drinks, may tissues, and bone.
be having negative impacts on oral health.
Low-income households have a much higher prev-
alence of toothache, periodontal disease, tooth Oral Microbiome
decay, and missing teeth. Over half of the popula-
tion over the age of 65 years have gum disease or Summary of the Recent Advances
periodontitis, and almost 20% of those over the age in Characterization of the Human Oral
of 65 years have complete tooth loss as a conse- Microbiome
quence of dental caries and periodontal disease.
Indigenous populations are over 150% more likely Some observers see the human body as a mobile
to be hospitalized for potentially preventable dental ecosystem, with bacterial cells outnumbering
conditions compared to nonindigenous populations. human cells by somewhere between 1.3:1 and
Additionally, more than half of children aged 6 have 10:1, and this is before fungi, viruses, archaea, and
experienced decay in their primary teeth, and almost other microorganisms that share our body space are
half of children aged 12 have experienced decay in taken into account (Sender et al. 2016). Indeed, live
their permanent teeth. bacteria constitute between 1 and 2 kg of the human
Pulp disease is a direct result of the presence of body mass, and considering that the genes
bacteria in the tooth, and typically this is a direct contained in the microbiome exceed the human
consequence of progression of caries through genome by one to two orders of magnitude, this
enamel and dentin into the pulp, although makes humans more microbial than human. Bacte-
bacteria can also find their way through fractures ria are not just passengers in, and on, the human
or accessory canals. Once the root canal system body but play a major role in bodily functions,
becomes infected, the periapical tissues respond including immunity, digestion, and nutrition. Leder-
initially with inflammation and this can then pro- berg and McCray (2001) first used the term micro-
gress to other conditions such as extraradicular biome at the start of this century “to signify the
infections, apical abscesses, facial cellulitis, and ecological community of commensal, symbiotic,
osteomyelitis. and pathogenic microorganisms that literally share
Periodontal diseases range from the relatively our body space and have been all but ignored as
mild form, gingivitis, to the more aggressive determinants of health and disease.” Colonization
forms, including aggressive and chronic peri- of the human body by microorganisms occurs at the
odontitis, which are characterized by the destruc- beginning of life, and it is becoming increasingly
tion of the tooth’s supporting structures. Chronic obvious that unless correct colonization and bacte-
periodontitis is by far the most prevalent bacterial rial community development occurs, a range of
associated inflammatory disease of the supporting chronic diseases and syndromes will ensue.
tissues of the tooth resulting in irreversible alveo- The human oral cavity contains a significant
lar bone loss and, if left untreated, tooth loss. number of distinct hard and soft tissues, including
the teeth, tongue, buccal mucosa, hard and soft bacterial species to be identified. The recent appli-
palates, gingival mucosa, and tonsils. These cation of DNA-based culture independent meth-
diverse parts of the oral cavity of humans are odologies coupled with advanced computational
inhabited by a diverse range of microbial species, techniques (bioinformatics) has shown that
including bacteria, viruses, fungi, archaea, and the oral microbiome is much more species rich
protozoans, that collectively are known as the and diverse than was thought at the turn of
human oral microbiome. Largely in this chapter the century. The oral microbiome has now been
the term microbiome will be used to describe the extensively characterized by cultivation- and
bacterial diversity of the human oral cavity. The culture-independent molecular methods such as
oral cavity offers many opportunities for bacterial 16S rRNA gene sequencing. This gene encodes
growth, and on the whole, it is a warm, moist ribosomal RNA that is essential for all bacterial
environment that provides surfaces for attachment life. The gene contains some sections that are
and growth, and a constant supply of nutrients in highly conserved and other highly variable
the form of saliva. In addition, regular dietary regions that enable the classification of bacteria
intake provides times of excess nutrient supply. to a species level. Unfortunately, the majority of
As a consequence, the oral cavity has a unique, newly discovered unnamed oral taxa have only
varied, and large microbiome, second only to the been assigned identifying numbers and lack taxo-
lower gastrointestinal tract in humans. nomic names (Dewhirst et al. 2010). It is now
Oral bacteria were the first single celled organ- estimated that there are more than 700 different
isms to be examined when, in the latter half of the types of bacteria that can be isolated from the
seventeenth century, Anton van Leeuwenhoek mouth but that more than 50% of these cannot
developed a novel way of producing high magnifi- currently be grown in pure culture in the labora-
cation glass lenses and turned them to examine tory (Marsh 2010).
small instead of distant objects. Described as the In parallel with its use for the discovery of new
father of microbiology, he famously wrote “There uncultivated bacterial species, DNA sequence anal-
are more animals living in the scum on the teeth in a ysis has also revolutionized bacterial taxonomy and
man’s mouth than there are men in the whole king- phylogeny. In the long term, this will enable a
dom.” Oral bacteria were also tied to disease early clearer picture of bacterial infections to be deter-
when Miller in the 1880s described dental caries as a mined and will greatly help the development of
chemoparasitic process (Miller 1890). Interestingly, efficacious treatments and preventive regimes. In
Miller believed that all bacteria in the oral cavity had the short term, it does create confusion regarding
equal cariogenic potential. The bacteria that will be the names of bacterial species and reading of the
discussed in this chapter are largely part of the scientific and clinical literature. Keeping abreast of
normal oral microbiome and not exogenous patho- taxonomic revisions is a major undertaking. How-
gens. Bacteria involved in frank infections of the ever, these changes are important to both clinicians
oral cavity and systemic diseases that affect the oral and clinical microbiologists, since taxonomic place-
cavity are dealt with in the chapter on ▶ “Non- ment is a useful tool that can be an indicator of
odontogenic Bacterial Infections.” virulence potential or antimicrobial resistance.
Culture Independent Analyses Overview of the Diversity of the Human

and the Discovery of New Species Oral Microbiome
Associated with Health and Disease
The human oral microbiome is comprised of well
Until relatively recently bacteria were character- over 600 prevalent species of bacteria (Dewhirst
ized solely using isolation, laboratory culture, et al. 2010). Due to the distinct bacterial habitats
and biochemical techniques. Current estimates within the oral cavity, distinct subsets of species
indicate that this only enabled a third of all oral form ecological communities or consortia at
different sites. A curated phylogeny-based data- eukaryotic cell of 50–100 μm in diameter. As

base, the Human Oral Microbiome Database such, bacteria have a fairly narrow range of hab-
(www.homd.org), provides comprehensive infor- itats that they can effectively exploit on their own
mation on the more than 700 prokaryote species due to their limited ability to encode complex
that are present in the human oral cavity. Currently, metabolic pathways. However, when coexisting
13 phyla of bacteria are known from the human with a range of other species they can potentially
oral cavity with a divergent evolution including collaborate and use their distinctive genomes for
Firmicutes, Bacteroidetes, Spirochaetes, and Syn- symbiosis, allowing them a greater degree of
ergistes. The oral cavity has one of the highest physiological flexibility. This, for example, may
diversities of bacterial species of any region of the enable them to cooperatively breakdown host pro-
human body. Although over 700 species of bacteria teins by providing a complete catabolic pathway
have been identified as components of the human lacking in the individual species. In addition, the
oral microbiome, many are quite rare and by most localization of a large number of species and
estimates 400–450 species account for around 95% strains of bacteria in a polymicrobial biofilm can
of the bacterial cells in an individual’s oral cavity. greatly enhance genetic exchange between spe-
Commensalism is too mild a term to describe cies, enabling them to rapidly acquire new char-
the relationship between many oral bacteria acteristics such as antibiotic resistance or the
and their human host. A commensal relationship ability to catabolize new energy sources. There-
implies that one partner benefits from the relation- fore, polymicrobial communities can rapidly
ship while the other is unaffected, and it was long respond to changing environmental conditions.
believed that while they did us little harm, oral
bacteria also did us little good. However, recent
evidence indicates that mutualism is a more apt Growth as Polymicrobial Biofilm
description, since both the bacteria and the human Communities and Interactions Between
experience increased fitness as a result of the rela- Species
tionship (Backhed et al. 2005). This has been ele-
gantly demonstrated recently with regard to Dental plaque consists of a complex microbial com-
beneficial nitrite production by oral bacterial spe- munity found on the tooth surface, embedded in a
cies resulting in a decrease in systemic blood pres- matrix of polymers of bacterial and salivary origin
sure (Kapil et al. 2013). Oral bacteria can also be (Fig. 1). Biofilms are defined as matrix-enclosed
seen as an arm of the innate immune response in bacterial populations adherent to each other and/or
that they exclude potentially pathogenic exogenous to surfaces or interfaces (Costerton et al. 1995).
bacteria from colonizing the oral cavity. Polymicrobial biofilms are complex, dynamic
microbial communities formed by two or more bac-
terial species that are important for the persistence
Oral Bacterial Ecology and proliferation of participating microbes in the
environment. Interspecies adherence, which often
Genetic Diversity and Physiological involves bacterial surface-associated molecules,
Flexibility and communications are essential in the spatial and
temporal development of a polymicrobial biofilm,
Bacterial cells singly are small in size and which in turn is necessary for the overall fitness of a
their genome is correspondingly diminutive. well-organized multispecies biofilm community.
Most spherical (coccoid) bacterial cells range in The vast majority of bacteria in the oral cavity
size from 0.4 to 2.0 μm, while elongate species exist as components of polymicrobial biofilms.
can reach 15 μm in length. Most genomes for Supragingival and subgingival plaques are poly-
bacteria that are associated with humans are in microbial biofilms (Fig. 2) accreted to the non-
the range of 500–4,000 genes. This is in contrast shedding surfaces of the tooth. The nonshedding
to the human genome of over 30,000 genes and a nature of teeth is unique in the human body and
to have bacterial DNA or viable oral bacteria

dispersed throughout their bodies in atheroscle-
rotic plaques and the placenta, for example. The
tissue disruptive effects of periodontal diseases in
the periodontal pocket that is home to a large
number of bacterial cells and species lead to tran-
sient bacteremia events. Many oral bacteria have
been shown to be able to colonize and survive, if
not thrive, once in the vascular system. Oral
viridans streptococci, for example, can colonize
damaged heart valves and are the most common
Fig. 1 Dental plaque smear Gram stain (Image courtesy of cause of subacute bacterial endocarditis.
Professor Camile Farah, UWA Dental School, University A number of oral bacterial species have been
of Western Australia, Perth WA, Australia)
shown to be internalized by oral epithelial cells
and some can reproduce within these host cells, as
well as move between these cells and reemerge
under favorable environmental conditions. This
capacity may also predispose them to similarly
invade and persist within endothelial and other
host cell types once inside the body. Other species,
in particular the oral spirochaetes that are some of
the only motile bacteria in the mouth, can pene-
trate oral epithelial layers in vitro, thereby raising
the possibility that under particular conditions
they are tissue invasive, which could lead to
their colonization of the vascular system.
One of the best studied examples of an oral
Fig. 2 Supragingival plaque accumulating on teeth, par-
ticularly around the gingival margins (Image courtesy of bacterium that can enter the host and cause a
Associate Professor Robert Anthonappa, UWA Dental range of infections is Fusobacterium nucleatum.
School, University of Western Australia, Perth WA, This bacterium is a common component of both
Australia) supra- and subgingival dental plaque. It is an inva-
sive, adherent, and pro-inflammatory anaerobic
they allow the buildup of considerable bacterial Gram-negative bacterium. It has been associated
biofilms that act as reservoirs of potentially infec- with cerebral abscesses and pericarditis and impli-
tious agents. The high numbers of bacterial cells in cated in acute appendicitis. More recently,
these biofilms can provide large inocula for infec- F. nucleatum has been shown to be involved in the
tion under the right (or wrong) circumstances. The promotion of colorectal cancer (Castellarin et al.
ability to form tenacious biofilms is a predisposing 2012). Recently, F. nucleatum has been shown to
factor for oral bacteria to become established in target the placenta and has been implicated in
other parts of the body should the opportunity arise. adverse pregnancy outcomes that are sometimes
associated with maternal periodontal disease status
(Stockham et al. 2015). F. nucleatum, like many
Escape from the Oral Cavity and Life other oral bacteria, can invade endothelial and epi-
on the Inside thelial cells and is preadapted to grow at 37 C and
to evade the host immune response. These preadap-
There is increasing evidence that the oral cavity is tations make the transition from the oral cavity to
relatively porous to oral bacteria. Chronic peri- inside host tissues relatively easy for some oral
odontitis sufferers in particular have been shown bacteria.
Common Bacterial Associated Diseases tooth’s supporting structures that can lead to tooth
of the Oral Cavity loss (Armitage 1999). A more detailed description
of periodontal disease classification can be found
Polymicrobial Nature of Diseases in the chapter on ▶ “Odontogenic Pathology,” but
is also outlined in Table 1. Gingival lesions are
The major oral bacterial diseases of dental caries detailed in a separate chapter on ▶ “Gingival
and periodontitis arise not from an extrinsic infec- Pathology.” This chapter will focus on the micro-
tion but from an imbalance, or dysbiosis, in the biological basis of odontogenic diseases.
bacterial species composition of the complex Chronic periodontitis is by far the most preva-
polymicrobial biofilms attached to the tooth sur- lent of the destructive forms of the disease.
face. A change in environmental conditions leads Chronic periodontitis is a bacterial associated
to changes in the relative abundances of bacterial inflammatory disease of the supporting tissues of
species in the biofilm enabling a subset of more the tooth. It results in irreversible alveolar bone
pathogenic species to become dominant. In the loss and, if left untreated, can result in tooth loss.
case of dental caries, this is believed to be due to It is often preceded by gingivitis which is a non-
increased frequency of sugar intake. Periodontitis specific inflammatory response to a buildup of
and dental caries account for ~90% of all tooth bacteria in dental plaque at the gingival margins
loss in developed countries, indicating that (Figs. 3 and 4). An oral health survey of
chronic periodontitis is a major public health Australians found that in the 30–34 age group
problem. more than 80% of people exhibited clinical
In the case of chronic periodontitis, the poly- signs of periodontal disease and over 20% had
microbial nature of disease was first made clear periodontitis (Armfield et al. 2000). Eke et al.
by Socransky and coworkers who demonstrated (2012) determined in 2010/2011 that over 47%
the consistent association of groups of particular of American adults, or 64.7 million people, had
species with the severity of periodontal disease. periodontitis that was distributed as 8.7% mild,
In particular, they defined a climax community 30.0% moderate, and 8.5% severe. More than
of three bacterial species, Porphyromonas 64% of Americans aged 65 years and older had
gingivalis, Treponema denticola, and Tannerella either moderate or severe periodontitis.
forsythia, which they referred to as the Red Com- In conjunction with the direct symptoms of
plex that was associated with clinical indicators disease, chronic inflammatory molecules also cir-
of advanced chronic periodontitis (Socransky culate throughout the body, and chronic inflam-
et al. 1998). Since their pioneering research, the mation is considered to be one of the major causes
advent of new DNA-based technologies for of early death (Ritchie et al. 2015). Clinical indi-
the identification and enumeration of bacteria cators of periodontal disease, such as tooth loss
has resulted in many other species being associ- and bleeding gums, are associated with a greater
ated with disease initiation and/or progression, risk of certain cancers as well as systemic diseases
including Filobacter alocis (Hajishengallis and and disorders such as cardiovascular disease, pre-
Lamont 2012). term and underweight birth. Periodontitis has
recently been associated with an increased risk
of squamous cell carcinoma of the head, neck,
Periodontal Diseases: Gingivitis and esophagus, cancer of the tongue, pancreatic
and Chronic Periodontitis cancer, and systemic inflammation in solid-organ
transplant recipients. There are also correlations
Periodontal diseases are classified into a number between periodontal disease severity and diabetes
of discrete forms ranging from the relatively mild and rheumatoid arthritis (Meyer et al. 2008).
form, gingivitis, to the more aggressive forms, The bacterial etiology of chronic periodontitis
including aggressive and chronic periodontitis, is still somewhat controversial but is widely
which are characterized by the destruction of the acknowledged to be polymicrobial in nature.
Table 1 Classification of bacterially induced peri- not dealt with in this Table. Readers are directed to
odontal diseases, adapted from Armitage (1999). Some the 2017 new classification scheme for periodontal and
rarer forms of periodontal disease relate to a dysfunctional peri-implant diseases and conditions for more detail
host immune response to systemic diseases or conditions (Caton et al. 2018).
and have little involvement of oral bacteria, and these are
Classification Subclassification Notes
Gingivitis Nonspecific inflammation related to plaque accumulation at the
gingival margin that does not lead to host tissue destruction.
Treatable by plaque removal. Likely to result from proliferation
of Gram-negative bacteria as plaque thickens
Chronic periodontitis A. Localized The commonest form of periodontitis initiated by specific
B. Generalized bacteria in subgingival plaque that induce a destructive
inflammatory response. Usually slowly progressing disease
can be refractory to treatment. Treatment is largely plaque
removal by scaling and root planing, sometimes with minor
surgery to improve access followed by antibiotic therapy.
Replaced the confusing and ambiguous term “Adult
Periodontitis”
Aggressive periodontitis A. Localized Has a different bacterial aetiology to chronic periodontitis and
B. Generalized is more likely to involve Actinobacillus
actinomycetemcomitans. Can be rapidly progressing and result
in rapid tooth loss if untreated. Replaced the confusing and
ambiguous term “Early Onset Periodontitis”
Necrotizing periodontal A. Necrotizing The bacterial etiology of these conditions remains in dispute as
diseases ulcerative gingivitis does the influence of underlying systemic conditions.
(NUG) Characterized by necrotic lesions. NUP, unlike NUG, results in
B. Necrotizing bony tissue destruction
ulcerative periodontitis
(NUP)
Abscesses of the A. Gingival abscess Abscesses present diagnostic and treatment challenges and are
periodontium B. Periodontal abscess classified apart from other periodontal diseases
C. Pericoronal abscess
Periodontitis associated Combined periodontic- Has pulpal involvement. The lesion can either be the result of
with endodontic lesions endodontic lesions an endodontic infection or the consequence of periodontally
associated bacteria gaining entry to the pulp chamber
especially Porphyromonas gingivalis, Treponema

denticola, and Tannerella forsythia, play a crucial
role in both initiation and progression of disease
(Darveau 2010; Hajishengallis and Lamont
2012). A recent study of the bacterial composition
of subgingival plaque in individuals with chronic
periodontitis showed that P. gingivalis and
T. denticola and T. forsythia were routinely
Fig. 3 Marginal gingivitis with blunting of the interdental found together in subgingival plaque (Byrne
papilla, gingival inflammation with erythematous change
et al. 2009). P. gingivalis has recently been pro-
and plaque formation around the gingival margins (Image
courtesy of Dr Marie Anne Matias, Western Periodontics, posed to be a “keystone pathogen” that manipu-
Perth WA, Australia) lates the host response to allow proliferation of the
plaque bacterial biofilm community which then
While the concepts of the roles of particular oral results in dysbiosis and disease (Hajishengallis
bacterial species in disease have changed over the et al. 2011). Interactions between key oral bacte-
past two decades, there is consensus that anaero- rial species are essential for the progression of
bic, proteolytic, amino acid fermenting species, chronic periodontitis. The unifying features of
Fig. 5 Chronic periodontal disease in a older male with

calculus formation on the lower incisors and associated
bone loss, with erythematous gingiva (Image courtesy of
Dr Marie Anne Matias, Western Periodontics, Perth WA,
Australia)
periodontal pocket biofilms often reveals spiro-

chaetes swimming on the surface of the adjacent
biofilm that has a sessile population of the same
morphotypes (Ellen and Galimanas 2005; Zijnge
Fig. 4 Gingivitis demonstrating generalised inflammation
et al. 2010). In vitro, P. gingivalis and T. denticola
in the underlying connective tissues () (Image courtesy of
Professor Camile Farah, UWA Dental School, University display a symbiotic relationship in nutrient utili-
of Western Australia, Perth WA, Australia) zation and growth promotion (Tan et al. 2014).
P. gingivalis and T. denticola microcolonies co-
localized in the surface layers of subgingival
these three bacteria are their extracellular proteo- plaque adjacent to the periodontal pocket epithe-
lytic activity, their complex anaerobic fermenta- lium help explain why emergence of relatively
tions of amino acids, production of toxic low proportions of these opportunistic pathogens
metabolites, and outer membrane (or sheath) ves- can be associated with disease (Zijnge et al. 2010).
icles. Of the three species, only the treponeme is When co-inoculated in animal models of peri-
motile and able to respond chemotactically to odontitis, P. gingivalis and T. denticola exhibit a
environmental stimuli. synergistic virulence (Orth et al. 2011). Together
In vivo, P. gingivalis and T. denticola are fre- these data suggest there is an intimate relation-
quently found to coexist in deep periodontal ship between these two species that has evolved
pockets, and they increase in numbers at similar to enhance their survival and virulence (Ng
times, suggesting possible interbacterial interac- et al. 2016).
tions that contribute towards disease. In a longi- Current diagnosis of chronic periodontitis
tudinal human study, the imminent progression of is based on clinical (Fig. 5) and radiographic
chronic periodontitis could be predicted by (Figs. 6, 7 and 8) detection of tissue damage
increases in the relative proportions of (Fig. 9). Treatment relies on the nonspecific
P. gingivalis and T. denticola in subgingival removal of the pathogenic subgingival biofilm
plaque (Byrne et al. 2009). The motility and che- by scaling and root planing and antibiotic therapy
motactic ability of T. denticola, although not con- when indicated. There are currently no specific
sidered as classic virulence factors, are likely to be treatments available, and prevention of disease
important in the synergistic biofilm formation progression relies on an increased attention to
with P. gingivalis (Dashper et al. 2011). Direct oral hygiene by the sufferer and regular mainte-
microscopy of freshly prepared samples of nance visits to a clinician.
Fig. 6 Orthopantomograph demonstrating horizontal fragments, excluding other radiographic features

bone loss in a patient with chronic periodontitis. Note not described (Image courtesy of Dr Marie Anne Matias,
minimal calculus deposits, some caries, and retained root Qscan Radiology Clinics, Brisbane QLD, Australia)
Fig. 7 Orthopantomograph demonstrating severe hori- the floor of the right maxillary sinus. Note some caries
zontal and vertical bone loss and abundant calculus and displaced teeth, excluding other radiographic features
deposits in a patient with advanced aggressive periodontal not described (Image courtesy of Dr Marie Anne Matias,
disease. There is chronic apical periodontitis involving the Qscan Radiology Clinics, Brisbane QLD, Australia)
maxillary right molars and reactive mucosal thickening at
Dental Caries caries this is produced by the fermentation of

sugars by oral bacteria as elegantly demonstrated
Dental caries is a dynamic process that occurs in in 1867 by Emil Magitot. Streptococcus mutans is
the polymicrobial biofilms accreted to the surfaces often named as the major (or only) etiological
of the tooth. The net result is a disturbance to the agent of this disease although there has been con-
equilibrium between tooth substance and the sur- siderable debate over the last 120 years regarding
rounding fluid that results in mineral loss from the how specific the etiology of the disease really
tooth surface (Figs. 10 and 11). Acidic pH is the is and the polymicrobial nature of disease is now
main culprit in the dissolution of enamel, and in widely accepted. Currently, the consensus is
Fig. 8 Orthopantomograph demonstrating severe bone features not described (Image courtesy of Dr Marie Anne
loss particularly in quadrant 1, on a background of gener- Matias, Qscan Radiology Clinics, Brisbane QLD,
alized horizontal bone loss in a 31-year-old male. There is Australia)
minimal calculus present, excluding other radiographic
Fig. 9 Periodontal bone

destruction and loss of
attachment seen in chronic
periodontal disease.
a: periodontal soft tissues,
b: alveolar bone, d: dentin,
e: enamel space (Image
WA, Australia)
that there is a subgroup of oral bacteria in supra- hidden surfaces results in an increase in the abun-
gingival plaque that is acidogenic as well as dance of these cariogenic species in plaque. This
aciduric and, as such, is able to produce sufficient increase leads to caries initiation. This is referred
organic acids as the end products of sugar fermen- to as the ecological plaque hypothesis (Marsh
tation to lower the plaque pH below that is neces- 2010) and with the advent of DNA sequencing
sary for enamel (hydroxyapatite) dissolution and technologies, the major species involved in this
maintain it at a substantially acidic pH for shift are now being identified.
extended periods of time. These species are also S. mutans remains a model cariogenic bacte-
found at healthy sites but in numbers too low to rium due to its long and uncontested associa-
have a pathological impact. A change in environ- tion with human dental caries. Recent genome
mental conditions such as an increase in the fre- sequencing of S. mutans strains from around the
quency of sugar consumption, decreased salivary world has shown that the S. mutans population
flow rate or function or exposure of previously started expanding exponentially around
10,000 years ago, which coincides with the onset sucrose. The bacterium adapted to the availability
of human agriculture (Cornejo et al. 2013). This of free sugars by genetically acquiring better
shows how a formerly commensal species can transport systems for free sugars, faster enzymes
rapidly adapt to environmental pressure, in this to catabolize the sugars, and more efficient ways
case the provision of free sugars – in particular of dealing with the consequences of rapid sugar
fermentation – that is, low pH. Undoubtedly, other
bacterial species in the oral cavity will have sim-
ilarly modified their genomes through natural
selection and evolved to make use of the relatively
abundant free sugar in an agricultural-based diet
as opposed to hunter-gatherer style diets. It has
been shown that by extracting bacterial DNA
from the calculus of ancient skeletons that the
transition from hunter-gatherer to farming shifted
the oral microbial community composition
towards a disease-associated consortium (Adler
et al. 2013). During the Industrial Revolution,
the cariogenic bacteria became dominant, leaving
the modern oral microbiota significantly less
diverse, which may contribute to chronic oral
disease.
Caries is usually associated with the more shel-
tered sites on the tooth with low salivary flow
including interproximal sites and fissures on the
occlusal surfaces. These sites enable the establish-
ment of dense, cariogenic species-containing
polymicrobial biofilms. A low salivary flow rate
Fig. 10 Caries in primary dentition affecting maxillary
and mandibular teeth (Image courtesy of Associate Profes-
allows the buildup of organic acids and the main-
sor Robert Anthonappa, UWA Dental School, University tenance of low pH for extended periods. This
of Western Australia, Perth WA, Australia) results in a subsurface demineralization of the
Fig. 11 Orthopantomograph of a patient in the mixed teeth, excluding other radiographic features not described
dentition demonstrating large carious lesions involving (Image courtesy of Dr Marie Anne Matias, Qscan Radiol-
the lower first permanent molars affecting the pulpal cham- ogy Clinics, Brisbane QLD, Australia)
bers. Some caries is also evident on several of the primary
Fig. 12 Dentin caries ()

with associated reversible
pulpitis. d: dentin, p: pulp
(Image courtesy of
UWA Dental School,
Australia)
enamel commonly known as a white spot lesion. Significant Bacterial Species

At this stage, the enamel surface remains intact
and the lesion can be remineralized under the right A detailed description of all the bacterial species
conditions. These include the removal of the car- causing infections of the oral cavity is well
iogenic bacteria, provision of supersaturated cal- beyond the scope of this chapter. So here we
cium and phosphate, and limitation of free shall only deal with some of the more significant
sugars. Once the surface of the enamel cavitates, species. Acute oral infections usually have a poly-
the tissue damage becomes irreversible and microbial etiology and often result in abscess
restorative measures are needed. In addition, formation. The source of infection is mainly
cavitation enables bacteria to penetrate the odontogenic and may be triggered by inoculation
enamel surface into the lesion providing a highly of bacteria during dental extraction or root canal
sheltered environment. This favors the prolifera- therapy. The use of non-culture-dependent tech-
tion of even more acidogenic and aciduric niques, namely DNA sequencing technologies
bacterial species such as Lactobacillus casei and computational biology, has greatly improved
(Fejerskov and Kidd 2003). This can result in a our understanding of the bacterial diversity of the
rapid expansion of the carious lesion towards the microbiota associated with acute apical abscesses
dentin, eventually resulting in pulp involvement (dentoalveolar infections). Abscesses from which
(Fig. 12). The large variety of bacterial species six or more bacterial species are isolated tend to be
and high numbers of bacterial cells in the larger and more painful than those that have fewer
advancing lesion provides an inoculum for infec- species present, which may be due to synergistic
tion of the pulp. pathogenicity (Marsh and Martin 1999). The
Caries is controlled at a human population diversity and variety of species and consortia
level mainly through the use of fluoride to associated with disease emphasizes the roles
strengthen the enamel. With early diagnosis of symbioses and other interactions among
prior to cavitation, remineralizing agents and species in the development of acute infections.
varnishes can be utilized following a minimal These DNA-sequencing technologies have also
intervention approach. This can be coupled implicated a range of previously unidentified spe-
with dietary advice to reduce the frequency and cies such as treponemes and anaerobic Gram-
amount of free sugar intake. Due to the complex positive rods including Bulleidia extructa,
aetiology of caries, antibacterial therapies are Cryptobacterium curtum, and Mogibacterium
restricted mainly to physical removal of supra- timidum in disease (Robertson and Smith 2009).
gingival plaque and the application of broad The combination of culture and molecular
spectrum antibacterial agents such as chlorhexi- studies has conclusively demonstrated that the
dine when required. apical abscess microbiota is polymicrobial and
dominated by anaerobic bacteria. The Firmicutes with periapical abscesses (Facklam 2002). The
phylum (Streptococcus, Dialister, Filifactor, and S. anginosus group (comprising Streptococcus
Pseudoramibacter) and the Bacteroidetes phylum milleri or Streptococcus anginosus) is also
(Prevotella, Porphyromonas, and Tannerella) reported to be involved.
contribute to more than 70% of the species found Enterococcus faecalis, a close relative of the
in abscesses. However, species from another oral streptococci, is the bacterium most often
five bacterial phyla can routinely be detected associated with endodontic infections. However,
from apical abscesses, comprising Fusobacteria, the role of E. faecalis as an endodontic pathogen is
Actinobacteria, Spirochaetes, Synergistetes, and still disputed (Spangberg 2006). Its association
Proteobacteria (Siqueira and Rocas 2013). with disease is in part due to its abilities to form
Our understanding of the taxonomy of oral biofilms inside dentinal tubules, to tolerate the
bacteria is evolving rapidly, and many species alkaline pH used as a medicament for root canal
are grouped together for convenience into “spe- therapy and to remain in a persister (vegetative)
cies groups” that emphasize their high degree of state for extended time periods. Peptostreptococci
similarity, our inability to separate them, and/or are frequently isolated from apical abscesses,
the very fluid nature of the species concept as it being detected in nearly 80% of cases. The
applies to bacteria. The pigmented Prevotella genus Peptostreptococcus has recently been
intermedia group (comprising Prevotella divided into Parvimonas and Anaerococcus and
intermedia, Prevotella nigrescens, and Prevotella the asaccharolytic, anaerobic, small coccus
pallens), Porphyromonas endodontalis, and Parvimonas micra (formerly Peptostreptococcus
P. gingivalis are anaerobic Gram-negative bacilli micros) is one of the most commonly identified
often associated with periapical abscesses (Jacinto species. It has been shown to be pathogenic in
et al. 2006). Until relatively recently, these species animal studies, especially in polymicrobial infec-
were grouped together as “black-pigmented tions (Siqueira and Rocas 2013).
Bacteroides” and they share many common fea- Treponemes play a role in the etiology of a
tures including extracellular proteolytic activity number of human chronic diseases including
that enables them to break down host tissues syphilis and yaws (Treponema pallidum), peri-
and thwart host responses, the ability to acquire odontal diseases including chronic periodontitis
and store iron usually in the form of heme and acute necrotizing ulcerative gingivitis (Trep-
from host molecules such as hemoglobin, and onema denticola, Treponema lecithinolyticum,
the production of outer membrane vesicles Treponema pectinovorum, Treponema socranskii,
that extend their sphere of influence (Gui et al. and others), endodontic infections and some acute
2016). F. nucleatum is frequently recovered from dental abscesses. Treponemes are members of the
the acute dental abscess, as are closely related Spirochaetes phylum, a clade that is distinct from
species such as Fusobacterium periodonticum. both Gram-positive and Gram-negative bacteria,
A variety of oral streptococci are reported from as such they have evolved unusual and unique
acute infections, which is unsurprising given their virulence characteristics (Dashper et al. 2011).
abundance in supragingival plaque and the roles Treponemes are all strictly anaerobic, motile, heli-
they play in the caries process. Most oral strepto- cally shaped bacteria. They are extremely difficult
cocci anaerobically ferment simple sugars and to culture, and their small slender morphology
sugar alcohols to organic acids, are tenacious bio- often makes them difficult to detect; however,
film formers, adhere to a wide variety of host their characteristic corkscrew shape is diagnostic.
molecules, can invade epithelial cells, and have Treponemes have a high prevalence within acute
been shown to interact synergistically with a dental abscesses, which may be due in part to their
range of other oral bacterial species. In particular, motile and chemotactic natures coupled with their
the α-hemolytic “viridans streptococci group” that biofilm forming ability (Dashper et al. 2011).
is made up of the S. mitis, S. oralis, S. salivarius, Using molecular based techniques, T. denticola
S. sanguinis, and S. mutans groups is associated has been detected in up to 79% of dental abscesses
(Siqueira and Rocas 2004), while other trepo- bacterial plaque is protected to some extent from
nemes including T. socranskii, T. pectinovorum, cleaning and the cavity becomes deeper. Once the
T. amylovorum, and T. medium are found at cavity reaches dentine, which consists of tens of
lower but significant prevalence (Robertson and thousands of dentinal tubules per square millime-
Smith 2009). ter (Garberoglio and Brannstrom 1976), there are
direct pathways for the bacteria and their
by-products to reach the dental pulp via these
tubules (Fig. 14). Hence, pulp irritation occurs
The Dental Pulp once the caries reaches the dentin. This irritation
initially leads to the formation of reactionary den-
The dental pulp is a soft tissue consisting mainly tine (also known as reparative or tertiary dentine)
of connective tissue with many cells (such as as the pulp attempts to wall itself off from
fibroblasts, odontoblasts, undifferentiated mesen- the irritant bacteria and/or their by-products
chymal cells) and a rich network of blood vessels (Fig. 15). However, if the caries is left untreated,
and nerves. It is surrounded by the hard dental the pulp will eventually become inflamed
tissues (dentin, enamel, and cementum) (Yu and (pulpitis) and then it will necrose as the bacteria
Abbott 2007). Hence, it is protected from external and the caries spread closer to the pulp chamber
influences as long as the hard tissues remain (Siquiera 2011).
intact. The most important protective tissue for Chemicals applied to the tooth enamel can also
the pulp is the enamel, since this tissue is exposed lead to demineralization. Acids may be produced
to the oral cavity and, more importantly, to the by bacteria (as above for caries) or they may be
bacteria contained within the oral cavity. Once the present in foods and drinks consumed by the
structural integrity of the enamel is interrupted, patient. Loss of enamel may occur through direct
potential pathways can exist for oral bacteria to dissolution or by softening the enamel which is
invade the tooth (Fig. 13) which, in turn, can lead then easily abraded by the normal actions of
to pulp disease (Yu and Abbott 2007; Siquiera chewing, grinding, clenching, brushing, etc.
2011). The typical ways in which the integrity of Once the dentine is exposed via this process,
the enamel is destroyed are through the action of bacteria can invade the tubules and subsequently
bacteria, the effects of chemicals (such as acids), affect the pulp in the same manner as outlined
and mechanical events (such as cracks and frac- above for caries (Yu and Abbott 2007).
tures) (Siquiera 2011). If a restoration is present, Cracks in teeth are defects through which bac-
then the interface between the restoration and teria can enter the tooth (Abbott 2004b; Abbott
the tooth structure is also critical as any and Leow 2009; Ricucci et al. 2015). If the crack
opening or space between them is an area through is confined to enamel, then there is usually no
which bacteria may enter the tooth and this can consequence as far as the pulp is concerned but
lead to pulp disease (Abbott 2004a; Kwang and the crack may lead to a fracture which can expose
Abbott 2012). the dentin tubules. Alternately, the crack
Dental caries is one of the most common may “grow” and extend into the dentin, thus pro-
diseases that occurs in humans. It is essential viding a direct pathway for bacteria to enter the
to understand that caries is a bacterial process tooth and cause pulp disease (Ricucci et al. 2015).
which results in loss of the mineralized sub- As mentioned above, a gap between the tooth
stance of teeth. Dental caries can have serious and a restoration provides a pathway for potential
consequences if not treated as the bacteria will bacterial invasion. Likewise, breakdown of a res-
progress through the tooth to involve the pulp toration leads to the development of a similar
and eventually the periapical tissues (Yu and gap where bacteria may invade (Abbott 2004a;
Abbott 2007). Kwang and Abbott 2012). They may be cario-
Once a cavity develops in a tooth, the carious genic bacteria and cause caries (and subsequent
lesion tends to develop more readily as the pulp disease), or they may be other bacteria that
Fig. 13 Schematic diagram showing the common pathways of entry of bacteria into teeth to cause an infected root canal
system and the resultant periapical response
Fig. 14 Caries ()

extending into the dentinal
tubules. (Image courtesy of
UWA Dental School,
Australia)
Fig. 15 Reactionary
dentin () and associated
pulpal inflammation.
d: dentin, p: pulp (Image
WA, Australia)
Fig. 16 Pulp hyperemia

(). d: dentin, p: pulp
(Image courtesy of
UWA Dental School,
Australia)
do not cause caries but they lead to pulp disease (and especially the bacteria causing the caries),
via the dentinal tubules. the irritant is removed and the pulp can recover
The dental pulp will undergo inflammatory provided an adequate dental restoration can be
changes long before the bacteria actually reach placed in the tooth (Fig. 17). Reversible pulpitis
the pulp itself as a result of the dentin tubule can be an acute or chronic condition, depending
pathways. The pulp will progress through various on the severity of symptoms and how long they
stages of inflammation, known as pulpitis, with a have been present (Abbott and Yu 2007; Abbott
consequent range of different symptoms and signs and Leow 2009; Abbott 2016).
(Abbott and Yu 2007; Ricucci et al. 2014; Abbott If a tooth with reversible pulpitis is not
2016). In the early stages of the disease process, treated, then the pulpitis will progress to become
the inflammation will be mild and therefore the irreversible pulpitis (Fig. 18). The symptoms
symptoms are also relatively mild (Fig. 16). The associated with this condition are generally
pain associated with this condition is usually stim- quite severe and the tooth is usually reactive to
ulated by extreme temperature changes – that is, mild temperature changes – such as tap water, or
very hot or very cold foods/drinks – and the pain is warm food/drink. Often the patient will have
usually only momentary or disappears once the spontaneous pain and the pain may wake them
stimulus has been removed from the tooth. This up at night. The pain usually lingers for a long
first stage of pulpitis is called reversible pulpitis as period after the stimulus has been removed from
it is believed by clinicians that the inflammation the tooth. When these severe symptoms are pre-
can resolve once the cause of the problem has sent, the condition will be acute irreversible
been removed – that is, by removing the caries pulpitis (Figs. 19 and 20), but some patients
Fig. 17 Reversible pulpitis

with caries () at the upper
left aspect of the image.
d: dentin, p: pulp (Image
WA, Australia)
Clinically Normal Pulp
Chronic Reversible Pulpitis Acute Reversible Pulpitis
Chronic Irreversible Pulpitis Acute Irreversible Pulpitis
+ TRAUMA
(e.g. Luxation, Necrobiosis
avulsion, etc.)
Pulp Necrosis Necrotic and Infected Pulp
Pulpless and Infected

Root Canal System
Fig. 18 The progression of pulp disease through different displacement injury or via the “coronal pathway” as a
stages. There are two main pathways of progression – result of invasion of microorganisms through caries,
either via the “trauma pathway” as a result of the pulp’s cracks, restoration margins, or fractures of the coronal
blood supply being severed at the apex during a part of the tooth (Adapted from (Abbott and Yu 2007))
have less severe symptoms that persist for many As the inflammation spreads throughout the
months and hence they will have chronic irre- pulp in teeth with untreated irreversible pulpitis,
versible pulpitis (Fig. 21) (Abbott and Yu 2007; the bacteria will also continue to progress through
Ricucci et al. 2014; Abbott 2016). the carious defect, crack, or marginal gap and will
Fig. 19 Caries ()

extending into the pulp
showing signs of
irreversible pulpitis. d:
dentin, p: pulp (Image
WA, Australia)
Fig. 20 Irreversible
pulpitis. d: dentin, p: pulp
(Image courtesy of
UWA Dental School,
Australia)
soon invade the pulp space itself. The pulp then present and the progression of the disease process
typically begins to necrose with the necrosis com- will be faster. This is typical of a tooth that has a
mencing in the region of the pulp adjacent to the crack, a restoration breaking down, or a carious
caries, crack, or gap – that is, the pulp at the base lesion without a frank pulp exposure. Teeth with
of the involved dentine tubules. The necrosis will large carious lesions that have pulp exposure tend
then spread throughout the entire pulp space (i.e., to have a more aerobic environment, at least in the
into the radicular pulp and root canal system) as coronal part of the root canal, and hence the dis-
the bacteria have no hindrances to their progres- ease progresses at a slower rate. However, over
sion since the pulp can no longer provide the usual time, all untreated teeth will have a pulpless,
defense mechanisms as it necroses. infected root canal system that leads to periapical
Necrotic pulps are fairly rapidly digested by diseases (Jansson et al. 1993).
the bacteria so the tooth becomes pulpless and Infections of the root canal system may also
infected within 1–2 months, depending on the develop as a result of trauma to the tooth. In
availability of oxygen and the type of bacteria particular, if the apical blood supply has been
that have invaded the root canal system (Jansson severed and the pulp does not revascularize, then
et al. 1993). When the environment is more anaer- the pulp effectively becomes instantly necrotic. If
obic, there will be more pathogenic bacteria bacteria have contaminated the damaged tooth or
if they are able to penetrate into the tooth subse- Pulp, Root Canal, and Periapical
quently, then the tooth will become pulpless and Infections
infected (Fig. 22), thus causing periapical inflam-
mation, as outlined below. The classic studies of Kakehashi and coworkers
(1965, 1969) clearly demonstrated that pulp dis-
ease is a direct result of the presence of bacteria in
the tooth. In those studies, the pulps of teeth in
germ-free rats and normal rats (rats with normal
oral microbiota) were exposed when cavities were
cut in the teeth. The cavities were left unrestored
so the pulps were open to the oral environment
until the animals were killed for histological eval-
uation. In the germ-free animals, the pulps recov-
ered whereas the pulps in the normal rats
degenerated, necrosed, and became infected.
Hence, it was clearly demonstrated that bacteria
cause pulp disease.
Further classic studies by Möller (1966),
Korzen et al. (1974), Sundqvist (1976), Fabricius
et al. (1982a, b), and Möller et al. (1981) subse-
quently demonstrated that periapical disease is
also a direct result of the presence of bacteria in
the tooth – that is, once the root canal system
becomes infected, the periapical tissues respond
Fig. 21 Chronic irreversible pulpitis. d: dentin, p: pulp initially with inflammation and this can then pro-
(Image courtesy of Professor Camile Farah, UWA Dental gress to other conditions such as extraradicular
School, University of Western Australia, Perth WA, infections, apical abscesses, facial cellulitis, or
Australia) cysts (Nair et al. 1996; Nair 1997; Abbott 2002,
Fig. 22 The interaction Infected Root Canal System

between the different
periapical conditions that
are a result of an infected
1° Acute Apical Periodons
root canal system. This
illustrates the dynamic
nature of these periapical
conditions (Adapted from
(Abbott 2004a))
· Intensificaon of Inflammaon +
1° Acute Apical Abscess
symptoms
· Facial Cellulis
· Periapical Cyst (pocket/true), OR
· Chronic Apical Abscess (i.e. draining sinus)
Chronic Apical Periodons
2° Acute Apical Abscess
2° Acute Apical Periodons

2004a, b, 2016; Siquiera 2011). The above studies continual replenishment with new bacteria from
also showed that the presence of necrotic pulp the oral cavity (Sundqvist 1976).
tissue does not in itself induce a periapical Once there are bacteria present within the root
response as long as there are no bacteria present. canal system, the periapical tissues become
A converse way of viewing this is that once a inflamed, as outlined above. This is a response to
periapical radiolucency is evident radiographi- the bacteria and subsequent infection that develops.
cally, the root canal should be considered to be The inflammatory response will usually be an acute
pulpless and infected. response initially (known as primary acute apical
Infection of the root canal system is a poly- periodontitis) (Nair 1997) but generally becomes
microbial infection (Sundqvist 1990) that exists as chronic fairly rapidly (i.e., chronic apical periodon-
a complex biofilm (Siquiera 2011). There is no titis) (Figs. 23, 24 and 25). As it becomes chronic,
single species that typically dominates these clastic cells (osteoclasts, cementoclasts, and
infections. An important aspect of root canal dentinoclasts) are activated and remove bone and
infections is the coexistence of various species tooth structure to create space for the inflammatory
whereby most species provide essential nutrients response in the periapical region. Many patients do
for other species to survive. Hence, the bacteria not experience any symptoms, or perhaps only mild
exist as a “community” in what is essentially an symptoms for a short period of time, when peri-
anaerobic environment (Siquiera 2011; Siquiera apical inflammation commences (Abbott 2016).
and Rôças 2011). As the pulp becomes necrotic This inflammation is the body’s defense system’s
and then the root canal becomes pulpless (Jansson attempt at fighting the infection, but all it is able to
et al. 1993), there is no blood supply to the root do is contain the infection – usually only succeeding
canal system once it is infected. Hence the body in stopping the bacteria from exiting the root canal
has no mechanism by which to fight or resist the and causing a local or a systemic infection (Nair
infection that develops. This results in a “stand- et al. 1996). The body’s ability to continue to pre-
off” between the bacteria and the host with a vent the bacteria from spreading is limited by local
“battle zone” at the apical foramen or at other conditions, the type and virulence of the bacteria,
accessory foramina, if present in the tooth and the overall general health of the patient (i.e., the
(Fig. 13). effectiveness of the immune system). At times,
Infections within the root canal system persist patients experience symptoms associated with the
as long as no treatment is provided to the tooth to infected tooth – these symptoms could be due to
remove or destroy the bacteria. As time pro- secondary acute apical periodontitis, a secondary
gresses, bacterial numbers increase since the path- acute apical abscess, or facial cellulitis (Nair et al.
way(s) for bacterial penetration into the tooth are 1996; Abbott 2004b, 2016). Other conditions can
still present (Fig. 13). These pathways not only also develop but without symptoms or with only
allow new bacteria to continue to enter the tooth, occasional symptoms – such as a chronic apical
but they also allow nutrients from the oral cavity abscess (Fig. 26), chronic periapical granuloma
to enter the tooth to help the bacteria survive. (Figs. 27 and 28), an extraradicular infection, a
Typically, such nutrients come from foods and periapical pocket cyst (Fig. 29), or a periapical true
drinks consumed by the patient. In addition, cyst (Figs. 30, 31 and 32) as specifically described
inflammatory exudate from the inflamed peri- by Nair (Nair 1997; Abbott 2004b, 2016). While the
radicular tissues may enter the root canal system latter two conditions are not defined as infections, it
through the apical or lateral foramina and this is important to understand that they are sequelae to
fluid may also provide some nutrients. Hence, an infected root canal system and they can become
bacteria that are present in an established infection infected at times (Nair 1997).
within a pulpless root canal system have an ideal While the pulp progresses through several
environment in which to survive and flourish – stages of increasing severity of inflammation to
one that is rich in nutrients, low in oxygen, inac- then become necrotic and infected (and then the
cessible to the host defense system, and allows root canal system becomes pulpless) (Fig. 18),
Fig. 23 Orthopantomograph demonstrating radiographic mucosal changes. Other radiographic features not
evidence of chronic apical periodontitis associated with the described (Image courtesy of Dr Marie Anne Matias,
upper left first and second molar teeth. There is elevation of Qscan Radiology Clinics, Brisbane QLD, Australia)
the floor of the left maxillary sinus and associated reactive
Fig. 24 CT demonstrating features of chronic apical peri- the pulpless, infected upper left first molar (26) (Images
odontitis. There is reactive mucosal thickening in the infe- courtesy of Clinical Associate Professor Andy Whyte,
rior aspect of the left maxillary sinus related to subtle Perth Radiological Clinic, Perth WA, Australia)
inflammatory (arrows) radiolucency around the apices of
Fig. 25 Chronic apical

periodontitis with root to
the left of the image (Images
courtesy Professor Camile
Farah, UWA Dental School,
Australia)
Fig. 26 Periapical abscess. Slightly irregular radiolu- perforates the buccal cortex (white dashed arrow in b + c)
cency (white dashed oval in a and b) is associated with resulting in a buccal abscess (white arrows in c + d)
the distal apex of the lower right first molar (46) with (Images courtesy of Clinical Associate Professor Andy
widening of the periodontal ligament space around the Whyte, Perth Radiological Clinic, Perth WA, Australia)
mesial root and adjacent sclerosing osteitis. The abscess
the periapical tissues can alternate between the become chronic apical periodontitis as the body’s
various conditions in a dynamic manner (Fig. 22) immune system responds to the situation. Epi-
(Nair 1997; Abbott 2002, 2004a). As an exam- sodes of secondary acute apical periodontitis
ple, the most typical sequence for a tooth with an may develop when conditions suit, and some
infected root canal system is to initially develop bacteria exit through the apical foramen to
primary acute apical periodontitis which can then reach the periapical tissues. When the body’s
Fig. 27 Chronic periapical granuloma. A cropped ortho- with adjacent sclerosing osteitis of medullary bone. All
pantomograph (a) shows a well-defined 7 mm periapical lesions were asymptomatic and likely to represent peri-
inflammatory radiolucency associated with the apices of apical granulomas (Images courtesy of Clinical Associate
47 (white arrows). Image (b) is an oblique sagittal CT scan Professor Andy Whyte, Perth Radiological Clinic, Perth
reconstruction showing small, well-defined radiolucencies WA, Australia)
associated with 37 and the mesial root of 36 (black arrows)
Fig. 28 Periapical
granuloma with tooth root
to the left of the image
demonstrating external
apical inflammatory root
resorption (Image courtesy
of Professor Camile Farah,
UWA Dental School,
Australia)
immune system regains control, the tissues pocket cysts, periapical true cysts, and facial
return to having chronic apical periodontitis. cellulitis can all occur at this dynamic interface
This may occur several times and the patient that exists in the periapical region (Fig. 22).
may ignore it if the symptoms are not too severe
or do not last for long. However, at some stage
the symptoms of secondary acute apical peri-
odontitis may be more severe or a secondary Management of Pulp, Root Canal,
acute apical abscess may develop with localized and Periapical Conditions
swelling, and this may stimulate the patient to
seek treatment. Alternatively, a draining sinus Assessment/Diagnosis
may develop leading to a chronic apical abscess.
This could persist for some time before the The first and most important stage in managing
patient seeks treatment or until a secondary pulp, root canal, and periapical conditions is to
acute apical abscess forms and causes significant formulate an accurate diagnosis since the treatment
discomfort. Other conditions such as periapical provided will vary for each condition (Abbott
Fig. 29 Periapical pocket

cyst with tooth root to the
left of the image (Image
WA, Australia)
Fig. 30 Orthopantomograph showing well-circumscribed also presents with chronic periodontal bone loss. Other
periapical radiolucency associated with the endodontically radiographic features not described (Image courtesy of Dr
treated upper right lateral incisor and canine teeth consis- Marie Anne Matias, Qscan Radiology Clinics, Brisbane
tent with a radicular cyst (periapical true cyst). The patient QLD, Australia)
2016). The important aspects of diagnosis are to and electric tests), percussion, palpation, mobility,
understand the conditions that may be present and periodontal probing, transillumination (Fig. 33),
to know the pathogenesis of the conditions. Each and biting tests. All teeth with suspected pulp,
condition will have some typical symptoms and/or root canal, and periapical conditions must have at
clinical and radiographic signs, so the clinician least one periapical radiograph but sometimes fur-
must be familiar with these (Table 2). In most ther images may be required – such as a tube shift
cases, specific – but simple – clinical tests can be periapical radiograph, a bitewing radiograph, or a
performed to provide the necessary information to CT scan. The typical clinical examination findings
make the diagnosis (Abbott 2016). The tests that and responses to tests for the most common pulp
should always be performed when assessing these and root canal conditions are summarized in
conditions are pulp sensibility tests (especially cold Table 3.
Fig. 31 Apical radicular cyst (periapical true cyst). In the being obscured by superimposition of the “ghost opacity”
right mandibular body, associated with a carious lower of the palate and air above the tongue. A 24 mm cyst
right first premolar (44) root remnant, there is an 18 mm extends from the apex of upper left second premolar
apical radicular cyst (white arrows in a + b) that extends (25) to the apices of the upper left third molar (28) (white
distally to the apex of the carious and pulpless lower right dashed arrows). The lesion is more clearly shown on a
second premolar (45) and mesially to the apex of the lower coronal CT reconstruction (d); it elevates the sinus floor,
right canine (43). There is a further periapical inflamma- typical of a lesion of odontogenic origin and protrudes into
tory radiolucency associated with the pulpless, infected the inferior half of the left maxillary sinus (white dashed
lower right lateral incisors (42) (white dotted arrows) likely arrows). There is an additional small retention cyst (RC) in
to represent a granuloma. The patient was asymptomatic. the zygomatic recess of the left maxillary sinus (Images
Apical radicular cysts, even when large, can be difficult to courtesy of Clinical Associate Professor Andy Whyte,
see on panoramic radiographs in the posterior maxilla (c) Perth Radiological Clinic, Perth WA, Australia)
When a patient presents with pain suggesting a If the patient reports pain with temperature
pulp, root canal, or periapical condition, the first changes (i.e., cold, hot foods/drinks), then some
step is to take a very detailed history since this will form of pulpitis should be suspected (Abbott and
enable the clinician to formulate a provisional Yu 2007; Abbott 2016). Further questions regard-
diagnosis before examining the patient. Having ing specific stimuli for the pain (e.g., very cold
such a provisional diagnosis will enable the clini- water from the fridge or tap water), the nature of
cian to target the specific region with pain and to the pain, its severity, and how long it lasts will
perform the appropriate tests. The clinician should enable the clinician to distinguish between revers-
seek information from the patient through appro- ible and irreversible pulpitis as well as whether the
priate questions to determine whether the pain is condition is acute or chronic.
related to some form of pulpitis or some form of If the patient complains of a dull ache or pain
apical periodontitis (Abbott 2016). on biting/chewing without thermal symptoms,
Fig. 32 Periapical true cyst

(radicular cyst)
demonstrating simple
epithelial lining () and
cholesterol crystals (c) in
cystic lumen. (Image
WA, Australia)
then some form of apical periodontitis should be Managing Pulpitis

suspected along with an infected root canal
system. Further questions, clinical tests, and Reversible pulpitis should be managed conserva-
radiographs will enable the clinician to be more tively by removing the cause of the problem (e.g.,
specific with the diagnosis – for example, lack caries, cracks, restoration), placing a sedative lin-
of responses to pulp sensibility tests in conjunc- ing and a temporary restoration. The tooth should
tion with a periapical radiolucency will indicate then be monitored for 3–4 months to determine
a pulpless, infected root canal system with whether the pulp recovers and returns to a clini-
secondary acute apical periodontitis (if no swell- cally normal state. This can be determined via a
ing or pus present) or a secondary acute clinical examination including pulp sensibility
apical abscess (if there is swelling and pus) testing to assess whether the pulp responds nor-
(Abbott 2004a, 2016). mally. If the symptoms continue after the initial
An essential part of the diagnostic process is to management, then this likely indicates that the
also determine the cause of the problem. This is pulpitis was irreversible or has progressed to an
essential as removal of the cause should be the irreversible state and therefore root canal treat-
first stage of treatment for any condition in order ment will be necessary. However, if the symptoms
to avoid continuation or recurrence of the disease resolve and the tooth responds normally to pulp
process (Abbott and Yu 2007). Pulp, root canal, sensibility testing after 3–4 months, then the
and periapical conditions are generally caused by pulpitis has resolved and the tooth can be restored
bacteria, as discussed above – however, the in a more definitive manner. Alternatively, if
important issue is to determine how the bacteria the symptoms resolve and the tooth does not
entered the tooth. Typically, the pathway of entry respond to pulp sensibility tests after 3–4 months,
will be via caries, cracks in the tooth structure or then the pulp has likely necrosed in which case,
between the restoration and the tooth structure as a root canal treatment will be necessary (Abbott and
result of marginal breakdown of the restoration Leow 2009).
(Kwang and Abbott 2012). Other potential path- Teeth presenting with irreversible pulpitis will
ways are via a fracture of the tooth or the restora- require either extraction or root canal treatment
tion if dentin is exposed, or via a periodontal (Fig. 35), with the latter being the preferred man-
pocket if it reaches a lateral canal foramen or the agement as it retains the tooth. However, the
apical foramen (Fig. 34). prognosis and the feasibility of undertaking this
Table 2 Typical symptoms reported by patients that are associated with the most common pulp and root canal
conditions. Adapted from Abbott (2016)a
Acute Acute Pulpless and Root-filled and
Symptoms/ reversible irreversible Necrotic and infected root canal infected root canal
signs pulpitis pulpitis infected pulp system system
Stimuli that Thermal Thermal Usually Nil – but Usually Nil – but Usually Nil – but
cause pain changes changes may be pain on may be pain on may be pain on
chewing or biting if chewing or biting if chewing or biting if
acute apical acute apical acute apical
periodontitis or periodontitis or periodontitis or
abscess present abscess present abscess present
Thermal Extreme Mild heat or No No No
sensitivity heat or cold cold
Nature of Short, Short, sharp Dull ache Dull ache Dull ache
pain sharp pain which
becomes a
dull ache
Duration of Very brief Lingers Short – usually only Short – usually only Short – usually only
pain (a few (>5–10 min) while biting or while biting or while biting or
seconds up chewing chewing chewing
to 1–2 min)
Spontaneous No May be No No No
pain present
Pain worse No May be No No No
with lying present
down
Pain wakes No May be No No No
patient at present
night
Pain on May be May be No – unless acute No – unless acute No – unless acute
biting and/or present present apical periodontitis apical periodontitis apical periodontitis
chewing or abscess present or abscess present or abscess present
a
Chronic reversible pulpitis will have similar symptoms and signs but they will be less severe and will have been present for
longer periods of time than acute reversible pulpitis. Likewise, chronic irreversible pulpitis will have similar symptoms and
signs but they will be less severe and will have been present for longer periods of time than acute irreversible pulpitis
treatment will be dependent on the tooth having processes (such as filling and enlarging the root
sufficient coronal tooth structure to enable it to canal) and the chemical processes such as irriga-
be restored adequately and with a restoration tion with sodium hypochlorite (NaOCl). This
that will prevent bacteria re-entering the tooth solution is a powerful antibacterial agent as well
for many years. Hence, an integral part of the as an excellent solvent of organic tissue, even at
root canal treatment is to remove all existing res- relatively low concentrations such as 1%. Hence,
torations, caries, and cracks prior to commencing in irreversible pulpitis cases, its major function is
root canal treatment in order to investigate the to dissolve the inflamed pulp. Other irrigants are
suitability of the tooth for further restoration also recommended (such as 17% ethylenediamine
(Abbott 2004a). tetra-acetic acid with cetrimide – EDTAC) to
The main aims of root canal treatment when remove inorganic matter from the canals as well
treating irreversible pulpitis are to remove the as the smear layer that forms during root canal
cause of the disease (as above) and to remove instrumentation (Baumgartner and Mader 1987).
the inflamed pulp tissue. The latter is achieved Anti-inflammatory and antibacterial intracanal
through a combination of the mechanical medicaments are usually recommended to help
will prevent bacteria re-entering the tooth for

many years, then root canal treatment is the pre-
ferred option. The main aims of root canal treat-
ment for infected teeth are to remove the bacteria
and all debris from the root canals and to destroy
any bacteria that remain within the rest of the root
canal system. This treatment should also remove all
sources of nutrition for the bacteria. Once the canal
has been disinfected, the apical periodontitis or
apical abscess should resolve (Figs. 36 and 37).
If the tooth has an infected root canal system
then irrigation with sodium hypochlorite has two
functions – one is to dissolve any organic tissue
and the other is to disinfect the root canal system
(Baumgartner and Mader 1987). EDTAC should
also be used as it has some antibacterial action in
Fig. 33 Transillumination of a molar tooth reveals a crack addition to its ability to prevent and remove the
(red arrow) on the distal surface. Another likely crack inorganic smear layer that forms during treatment
(green arrow) is also visible. Note that the tooth structure
on the buccal side of the crack is illuminated by the strong
(Baumgartner and Mader 1987).
light source, while the lingual side is not illuminated Intracanal medicaments play an important, and
because the light rays have been deflected by the crack essential, role in treating infected root canal sys-
tems as they are able to diffuse through the dentin
resolve the periapical inflammation that will also be tubules and reach bacteria that are not accessible to
present and to help ensure there are no bacteria in the mechanical instrumentation or the irrigating solu-
root canal system, respectively (Abbott 1990). Once tions. Medicaments are typically in the form of a
all symptoms have resolved and initial healing is corticosteroid/antibiotic paste or calcium hydrox-
evident, the root canal filling can be completed and ide. The corticosteroid/antibiotic pastes are indi-
the coronal part of the tooth can be restored. cated for severe pain of an inflammatory nature
Systemic antibiotics are not indicated and they (Abbott 1990). Calcium hydroxide is the most
are not necessary for irreversible pulpitis since it is effective, predictable, and commonly used exam-
an inflammatory condition. While it is caused by ple of an antibacterial medicament. It largely works
the presence of bacteria in the tooth, this should as a result of its high pH of 12.2. It is used in a paste
not be considered as an “infection.” Any adjunc- form which should be left in the root canal for at
tive systemic medication following treatment least 3–4 weeks to allow time for the hydroxyl ions
should only be nonsteroidal anti-inflammatory to diffuse through the dentin and the entire root
drugs (NSAID) or analgesics to control inflamma- canal system and to reach its maximum pH level of
tion and pain, if present (Hargreaves and Abbott about 8.5–9.5 in the outer dentin (i.e., adjacent to
2005; Therapeutic Guidelines 2012a). the cementum) (Nerwich et al. 1993).
Once the root canal system has been ade-
quately disinfected and initial signs of healing
Managing Infected Root Canal Systems are evident, the root canal filling can be placed
along with a definitive coronal restoration. The
When a tooth has an infected root canal system that tooth should then be reviewed clinically and
is causing any of the periapical conditions outlined radiographically on a regular basis to ensure that
above, the treatment options are either root canal the periapical healing continues. Complete
treatment or extraction. If there is sufficient tooth healing can take varying time periods ranging
structure remaining to enable the tooth to be from a few months up to 5 years (Bystrom et al.
restored adequately and with a restoration that 1987). Healing is quite predictable following root
848
Table 3 Typical clinical examination findings and responses to tests for the most common pulp and root canal conditions. Refer to Abbott (2016) for further detailsa
Clinical findings/ Clinically Acute reversible Acute irreversible Necrotic and infected Pulpless and infected Root-filled and infected
responses to tests normal pulp pulpitis pulpitis pulp root canal system root canal system
Cold pulp Responds Painful response – Very painful No response No response No response
sensibility test without pain similar to response – similar
presenting to presenting
complaint complaint
Electric pulp Responds Responds without Responds without No response No response No response
sensibility test without pain pain pain – may respond
to lower level of
current
Hot pulp No response May be a painful May be a very No response No response No response
sensibility test response – similar painful response –
to presenting similar to
complaint presenting
complaint
Swelling No No No If a primary acute apical If a primary or secondary If a primary or secondary
abscess is present acute apical abscess is acute apical abscess is
present present
Percussion No No (unless a crack No (unless a crack Tooth may feel “different” Tooth may feel “different” Tooth may feel “different”
undermining a undermining a if chronic apical if chronic apical if chronic apical
cusp) cusp) periodontitis or may be periodontitis or may be periodontitis or may be
tender if acute apical tender if acute apical tender if acute apical
periodontitis or abscess periodontitis or abscess periodontitis or abscess
present present present
Palpation No No No Not if chronic apical Not if chronic apical Not if chronic apical
periodontitis but may be periodontitis but may be periodontitis but may be
tender if acute apical tender if acute apical tender if acute apical
periodontitis or abscess periodontitis or abscess periodontitis or abscess
present present present
S. G. Dashper et al.
Draining sinus No No No No Only if chronic apical Only if chronic apical
present abscess abscess
Mobility Normal Normal (unless Normal (unless Normal (unless Normal (unless Normal (unless
(unless concurrent concurrent concurrent periodontal concurrent periodontal concurrent periodontal
concurrent periodontal disease) periodontal disease) disease) disease) disease)
periodontal
disease)
Periodontal Normal Normal (unless Normal (unless Normal (unless Normal (unless Normal (unless
probing (unless concurrent concurrent concurrent periodontal concurrent periodontal concurrent periodontal
concurrent periodontal disease) periodontal disease) disease) disease) disease)
periodontal
Odontogenic Bacterial Infections
disease)
Transillumination May reveal May reveal cracks if May reveal cracks if May reveal cracks if May reveal cracks if May reveal cracks if
cracks if present present present present present
present
Radiographic Normal Normal, or may be Normal, or may be Normal, or may be Radiolucency present Radiolucency present
findings periapical slightly widened slightly widened slightly widened PDL
tissues PDL space, or PDL space, or space
condensing osteitis condensing osteitis
Caries, crack, or No Yes Yes Yes Yes Yes
restoration
breakdown
present
a
Chronic reversible pulpitis will have similar findings to those of acute reversible pulpitis. Likewise, chronic irreversible pulpitis will have similar findings to those of acute
irreversible pulpitis. In cases with infected root canals, the periapical findings will depend on whether the tooth has acute or chronic apical periodontitis, an acute or chronic abscess,
or any of the other periapical conditions mentioned in the text
849
Fig. 34 Endodontic-periodontic lesion. Heavily restored instrumentation and dressing with calcium hydroxide
lower left first molar (tooth 36) showing location of 5 mm showing healing of apical and periradicular radiolucencies
periodontal pocket (a). Radiograph showing separate distal (c). Radiograph at 12 month recall after root canal filling
apical radiolucency and mesial periradicular radiolucency and core placement with continued periradicular health
in the location of the periodontal pocket (b). The tooth had (Images courtesy of Dr Oliver Pope, Endodontists on Col-
a pulpless, infected root canal system and secondary acute lins, Melbourne VIC, Australia)
apical periodontitis. Radiograph at 6 month review after
Fig. 35 The mandibular first molar tooth (tooth 46) had treatment was done which relieved the symptoms. (a)
acute irreversible pulpitis and primary acute apical peri- Preoperative periapical radiograph. (b) Postoperative
odontitis following placement of a crown. This problem radiograph after placing the root canal filling. (c)
most likely developed as a result of irritation from the Eighteen-year review showing a stable tooth and normal
operative procedure of the crown preparation. Root canal periapical tissues
Fig. 36 The maxillary right central incisor (tooth 11) had medicaments to arrest the resorptive process, to encourage
an uncomplicated crown fracture which was restored with apexification of the open apical foramen, and to encourage
composite resin 5 years prior to the patient presenting with periapical repair. (a) Preoperative periapical radiograph.
a pulpless, infected root canal system and a secondary (b) “Working length” determination radiograph. (c) Post-
acute apical periodontitis with external apical inflamma- operative radiograph showing apical closure with a hard
tory resorption after the restoration had broken down. The tissue barrier and periapical bone repair
tooth had root canal treatment using a series of intracanal
Fig. 37 The mandibular left first molar (tooth 36) had a was provided and the periapical tissues healed unevent-
pulpless, infected root canal system with secondary acute fully. (a) Preoperative periapical radiograph. (b) Postoper-
apical periodontitis as a result of breakdown of an old ative radiograph showing periapical bone repair,
restoration and the presence of a crack under the distal reestablishment of a normal periodontal ligament space
aspect of the restoration. Routine root canal treatment and lamina dura
canal treatment (Figs. 36 and 37) unless there is an uncommon with modern endodontic procedures
extraradicular infection, a foreign body reaction, and materials. The cases that will require peri-
or a periapical true cyst (Nair 1997). apical surgery are those with:
Periapical Surgery • A persistent intracanal infection that has not

responded to root canal treatment
Some teeth with infected root canal systems may • An extraradicular infection
require periapical surgery to remove the diseased • A foreign body reaction
tissue from the periapical region. However, this is • A periapical true radicular cyst
The differential diagnosis of these conditions is Radiolucencies that appear (or reappear) many
difficult, and it is usually not possible to distin- years after root canal treatment has been com-
guish between them based on clinical and radio- pleted may be an indication of a new disease
graphic (including CT scans) findings (Bornstein process within the tooth – that is, the restoration
et al. 2015). These conditions are not common and has broken down (or there is a crack or caries) and
likely constitute only less than 1% of all cases of the root canal system has become infected again.
periapical radiolucencies, although there are no This will particularly be the case if the periapical
data available to determine this. Biopsy studies tissues had radiographic evidence of healing fol-
that have been reported in the past merely provide lowing the initial root canal treatment.
information about the relative frequency of each A persistent periapical radiolucency may or
condition within the biopsy cohort, and they do may not be associated with symptoms or clinical
not indicate how often these problems occur signs other than the radiolucency. Hence, it is
among all periapical radiolucencies (Franklin essential that all teeth be followed up and moni-
and Jones 2006; Jones and Franklin 2006; Ha tored by the clinician until there is radiographic
et al. 2014; Kelloway et al. 2014). It is impossible evidence of healing. If the patient has symptoms
to estimate this because the vast majority of radio- or there are clinical signs such as a draining sinus,
lucencies heal with routine root canal treatment. then further investigation is warranted. If the root
Hence, these conditions are usually only consid- canal treatment has been adequately performed
ered when a periapical radiolucency persists and there have been no lost or fractured restora-
within the first 4–5 years following root canal tions, then the clinician might assume that
treatment (Abbott 2011) or symptoms do not the ongoing problem is a “periapical problem”
resolve during the root canal treatment (Fig. 38). (Abbott 2011). However, it must be noted that
Fig. 38 The maxillary right central incisor (tooth 11) had a conjunction with a periapical curettage to remove the
pulpless, infected root canal system with pulp canal calcifi- affected tissue. Histological examination of the biopsied
cation and secondary acute apical periodontitis following a tissue was suggestive of a radicular cyst. The adjacent lateral
lateral luxation injury 15 years prior to presentation. The incisor (tooth 12) responded normally to pulp sensibility
tooth had several infractions within the crown. The patient testing with cold and electric tests before, during, and after
also reported having occasional episodes of secondary acute treatment of the central incisor. (a) Preoperative periapical
apical abscesses. Root canal treatment was instigated but the radiograph. (b) Postoperative radiograph following root
abscesses continued to occur every few months and the large canal filling and periapical surgery. (c) Two-year review
periapical radiolucency showed no signs of reduction in radiograph shows periapical bone repair, reestablishment
size. Hence, the root canal filling was completed in of a normal periodontal ligament space and lamina dura
most cases of persistent radiolucency have been systems – such as when the bacteria have spread
reported to be due to an intracanal infection, and from the root canal system to the adjacent jaw
therefore root canal retreatment is usually the and beyond (Therapeutic Guidelines 2012a).
treatment of choice initially (Abbott 2011). However, in most cases of an infected root
Then, if the radiolucency still persists, one can canal system, systemic antibiotics should only
assume it is truly a “periapical problem” such as be used when the patient has definite signs of
an extraradicular infection, a foreign body reac- systemic infection – that is, malaise, fever,
tion, or a periapical true cyst. These conditions increased body temperature, or lymph node
will require periapical surgery to remove the involvement. Systemic antibiotics may also be
affected tissue from the periapical region – usually considered when the patient is immunocompro-
only a periapical curettage (Fig. 38) is required but mised. In any patient where systemic antibiotics
in some teeth, retrograde root canal cleaning and are indicated, it is also essential to provide the
filling may be performed (Abbott 2011). appropriate dental treatment (commence root
canal treatment or extract the tooth) as such
interceptive treatment is the most predictable
Antibiotics: When and When Not means of reducing the number of bacteria pre-
to Use sent, thus leading to far more rapid resolution of
symptoms. Removing as many bacteria as possi-
Systemic antibiotics are not required when the ble via dental treatment also reduces the number
patient has inflammatory conditions such as of bacteria that could develop resistance, thus
reversible or irreversible pulpitis. In fact, systemic reducing the chances of potential complications
antibiotics are contraindicated in these cases as (Therapeutic Guidelines 2012a).
there are potential disadvantages of bacterial If the patient has developed severe swelling
resistance and patient sensitization. and/or a spreading infection as a result of
Systemic antibiotics are not often required an infected root canal system, then prompt and
when treating an infected root canal system, and thorough treatment is required. These cases typi-
they are contraindicated unless the patient is cally require aggressive therapy in the form of
showing systemic signs of an infection. Most extraction or root canal treatment in conjunction
teeth that develop symptoms associated with an with systemic antibiotics given intramuscularly or
infected root canal system will have secondary intravenously in a hospital setting, particularly if
acute apical periodontitis (i.e., an inflammatory the airway has become involved. Further discus-
reaction in the periapical region) or a secondary sion of such conditions is presented later in this
acute apical abscess (i.e., a localized infection in chapter.
the periapical conditions) (Nair 1997; Abbott If a patient does require antibiotics, then the
2004b, 2016). These conditions should be man- antibiotics should only be considered as an
aged with root canal treatment or extraction. They adjunct to the treatment provided to the tooth.
do not require systemic antibiotics, and adminis- The antibiotics should only be required for a
tration of such agents should be avoided in order short term – typically 4–5 days in most cases – if
to reduce the potential problems of bacterial resis- adequate dental treatment has been provided. The
tance and patient sensitization to antibiotics. Sys- antibiotic chosen should be one with a narrow, but
temic antibiotics will not help to resolve the appropriate, spectrum of activity. Its dose needs to
disease since the antibiotic will not be distributed be high enough to be effective since higher doses
to the site of infection as there is no blood supply are more likely to rapidly kill or inhibit bacteria
to the root canal once the pulp has necrosed, and before they can develop resistance and survive
especially once the tooth has become pulpless, or (Therapeutic Guidelines 2012a). The principles
if it has had previous root canal treatment. of “selective pressure” apply whereby the stronger
Systemic antibiotics are occasionally needed (i.e., more resistant) species survive while the
for some patients with infected root canal weaker (i.e., less resistant) species die. If the
Table 4 Recommended antibiotics for a localized odontogenic infection where the patient displays systemic symptoms
and/or signs. Adapted from (Therapeutic Guidelines 2012b)
If there is NO history of allergy/hypersensitivity to penicillin
Recommended antibiotic Adult dose regimen Child dose regimen
First Phenoxymethyl 500 mg to be taken orally every 6 h on an 12.5 mg/kg up to 500 mg, to be
choice penicillin (also empty stomach (i.e., 1 h before meals) for taken orally every 6 h on an empty
known as penicillin 5 days (an initial loading dose of 1000 mg stomach (i.e., 1 h before meals) for
V) can be considered) 5 days
Second Amoxicillin 500 mg to be taken orally every 8 h for 12.5 mg/kg up to 500 mg, to be
choice 5 days (an initial loading dose of 1000 mg taken orally every 8 h for 5 days
can be considered)
If there IS a history of allergy/hypersensitivity to penicillin
Recommended antibiotic Adult dose regimen Child dose regimen
Clindamycin 300 mg to be taken orally every 8 h for 7.5 mg/kg up to 300 mg, to be taken
5 days (an initial loading dose of 600 mg can orally every 8 h for 5 days
be considered)
stronger species survive, then resistance becomes

more common, the antibiotic is less effective and
the infection continues.
When patients display systemic symptoms but
there is no sign of a spreading infection – that is, a
localized abscess – then oral administration of anti-
biotics is indicated. The typical bacteria associated
with infected root canal systems and that have been
isolated from periapical abscesses are quite suscep-
tible to phenoxymethyl penicillin (commonly
known as penicillin V). They are also susceptible
to amoxicillin, but this is a broader spectrum drug
that is commonly used for many infections in
humans (Baumgartner and Xia 2003; Skucaite
et al. 2010). Hence, phenoxymethyl penicillin is
considered to be the best “first choice” drug to use
as long as the patient is not hypersensitive to pen-
icillin. If the patient is hypersensitive to penicillin,
then clindamycin is recommended. See Table 4 for
recommended dosing regimens.
Fig. 39 Buccal and submandibular space involvement
and abscess progression
Treatment and Prevention

of Odontogenic Maxillofacial first-line medical and surgical management epi-
Infections sodes underlie many preventable and serious
maxillofacial infections.
Several causes exist in the development of maxil-
lofacial fascial space infections; however,
odontogenic issues, mostly untreated periapical Principles of Management
infection and pericoronitis, account for the
great majority of clinical presentations (Figs. 39 The key to effective management of fascial space
and 40). Socioeconomic factors and inappropriate infections is to recognize the severity of the infection
Table 5 Multifactorial influence on the patient condition

in determining the severity of infection and decision mak-
ing by practitioners
Infection/
pathology Practitioner
Patient/host factors factors factors
Age Source of Level of
Immune compromise infection experience
Poly pharmacy Neck space Confidence in
Previous/preceding involvement diagnosing and
infection Airway managing
Lifestyle factors compromise infection
including smoking Rate of Ability to manage
tobacco, alcohol progression complications
consumption, and Airway skills
other drug use Access to hospital
facilities and
diagnostic
imaging
unwell or in systemic inflammatory response syn-

drome (SIRS), it may be treated with a conservative
Fig. 40 Buccal space collection with extension into sub-
approach, on an out-patient basis, with regular
cutaneous tissues 12 weeks post lower right third molar follow-up and definitive management. This might
surgery following repeated courses of antibiotics include a localized infection resulting from a
recently restored or endodontically treated tooth. In
and the potential for patient decompensation. In such a situation, it may be appropriate to refer the
doing so, the patient’s treatment should be tailored patient for a single dose of intravenous antibiotics
to ensure that medical and surgical treatment is for loading before commencing oral antibiotics. In
adequate, and that it is located and timed appropri- more serious infections, or in cases where there is no
ately. Attempts have been made to quantify severity improvement despite attempts to manage conserva-
(Flynn 2000) in order to assist in treatment planning, tively, intravenous access should be obtained to
but this is not practical, as the patient’s condition is facilitate fluid resuscitation and intravenous antibi-
changeable and influenced by multiple factors. The otic therapy. Empirical antibiotics should be used
factors influencing severity are summarized in initially, and then they can be tailored according to
Table 5. In terms of the infection itself, the rate of the results of microbiological testing.
progression, location, and state of the airway are the It is essential to recognize reduced patient
most important factors. Patient-specific factors reserve in even seemingly minimally complicated
including age and medical-comorbidities are taken infections because of the risk of rapid progression
into consideration because of the importance of the and host compromise. It is the balance between
host response in the presence of potentially life- microbial virulence and host immunity that deter-
threatening infection. If in doubt, the decision mines the extent of spread and ultimately the risk of
regarding management should be made by an oral morbidity and death. The host response to severe
and maxillofacial surgeon. infection can cause physiologic disruption to the
patient, increasing insensible fluid losses, and calo-
ric requirements. Blood sugar levels must be mon-
Medical Management itored and controlled, and all patients with diabetes
should be managed collaboratively with an endo-
In some situations, where infection is localized in crinologist. Not only do these patients have
the buccal or canine space and the patient is not increased susceptibility to odontogenic infections,
depending on the requirements of the patient.

Input by allied health care professionals such as
dieticians and speech pathologists is also an essen-
tial part of management. Nutrition should be opti-
mized to ensure wound healing and to avoid
excessive catabolism. Speech pathologists may be
particularly helpful in the management of a trache-
ostomy or oropharyngeal dysfunction.
Antibiotic Therapy
Neck space infections are usually polymicrobial in

nature, and the bacteria are part of the normal oral
microbiota. When local and systemic host defenses
are overcome, these commensals become patho-
logic. Local host defenses include anatomical
boundaries, and these may be breached as a result
of inflammation or injury, causing direct bacterial
Fig. 41 Ludwig’s angina. Overlying cellulitis marked to contamination of tissues, hematogenous or lym-
monitor clinical progression phatic spread.
Empirical therapy is commenced ideally after
pus, blood, or tissue samples are obtained
for microscopy, culture, and sensitivity testing.
These cover the β-hemolytic streptococcus and
associated anaerobic bacteria such as Peptostrep-
tococcus, pigmented Bacteroides, Prevotella, and
Porphyromonas, all of which have been described
as causative agents in odontogenic infections.
Other isolates include viridans streptococci
and S. milleri (part of the S. anginosus group)
S. aureus, and S. epidermis, and Actinomyces
species. A penicillin derivative in addition to met-
ronidazole is usually recommended. Penicillins
combined with a beta-lactamase inhibitor such as
clavulanic acid are an alternative to dual therapy
and have been shown to be effective against
anaerobic infection. In cases of penicillin allergy,
clindamycin is the drug of choice. In severe infec-
Fig. 42 Ludwig’s angina. Bilateral involvement of sub-
lingual and submandibular spaces (arrows) tions gentamycin may be recommended in addi-
tion to tazocin (pipercillin/tazobactam) and
vancomycin (Har-El et al. 1994).
requiring prolonged hospital admission, but they
have reduced resistance to the more severe
sequelae such as necrotizing fasciitis and Ludwig’s Surgery and Drainage
angina (Figs. 41 and 42). Other medical team
members may include the general and infectious While cellulitis alone may be treated with anti-
disease physicians, and intensive care doctors, biotic therapy, surgical treatment by way of
incision and drainage has the advantage of able to irrigate the neck with dependent flow
decompressing neck spaces for airway protec- from the oral cavity out of the neck incision.
tion in addition to facilitating removal of pus. Common drains include Penrose, which is sim-
The presence of pus is often underestimated on ilar to the cut finger of a glove and the corru-
clinical and radiological assessment, so the gated or Yeates drains. They assist in drainage
threshold for intervention should be low, partic- of pus by capillary action. Drains have the dis-
ularly in infections that fail to respond to advantages of being a portal of infection in to
medical management. Surgery also allows a the wound, and they are uncomfortable and
thorough examination under anesthesia, for the contribute to scarring.
source of infection to be removed (usually by Some patients may require multiple drainage
tooth extraction) and for tissue samples of any and wash-out operations, particularly if they fail
associated pathology to be taken. The principles to respond to treatment or re-collect pus in the
of surgical drainage have been well documented same or other previously uninvolved neck
by other authors. In particular, the incision spaces. These patients usually have identifiable
should be placed in healthy skin and mucosa host factors causing reduced immunity or a par-
when possible, in a natural skin fold and in a ticularly virulent organism or both. Thus, in the
dependent position (Fig. 43); dissection should postoperative phase, regular clinical and bio-
be blunt; and drains should be placed initially chemical assessment is necessary, and further
and removed when the discharge is minimal radiological assessment may also assist in the
(Topazian et al. 2002). Incisions may be intra- decision to return to theater. Other causes of
or extraoral depending on these principles and treatment failure include incorrect diagnosis or
the severity of infection and location, but the inadequate primary surgical intervention or med-
process of making such decisions is beyond the ical management.
scope of this chapter. In general, an extraoral
approach is preferred for moderate-to-severe
infections, with placement of extraoral drains, Airway Considerations
because of the dependence of drainage (Bottin
et al. 2003). A combined intra- and extraoral Unrecognized impending airway loss due to pro-
approach is not uncommon in multilevel deep gression of infection/swelling and patient fatigue
neck space involvement. Through-and-through causes asphyxiation and death (Fig. 44). Close
drainage has the advantage of two portals of pus
drainage, but it is not realistic to expect to be
Fig. 44 Axial CT (level of mid ramus) showing abscess

Fig. 43 Access to left pterygoid space via submandibular formation within left parapharyngeal space (arrows) and
approach for dependent drainage shift of the airway to contralateral side
liaison with anesthetic staff should facilitate safe Osteomyelitis, Osteoradionecrosis

and timely general anesthetic for patients with (ORN), and Antiresorptive Agent-
an emergent airway or if access to the airway Induced Osteonecrosis of the Jaws
has been significantly impeded by trismus or swell- (ARONJ)
ing. Safe options for such patients include awake
fiber-optic intubation and urgent elective tracheos- Osteomyelitis, osteoradionecrosis (ORN), and
tomy under local anesthetic. Tracheostomy allows anti-resorptive-induced osteonecrosis of the jaws
the upper airway obstruction to be bypassed to (ARONJ) are potentially devastating chronic
facilitate intraoperative patient ventilation and res- pathologic conditions of the jaws. Accurate diag-
olution of the obstruction in the postoperative nosis and differentiation between them is essen-
phase. It has been suggested that elective tracheos- tial, and in particular, underlying bony pathology
tomy should be the airway of choice in Ludwig’s or malignancy needs to be ruled out. While oste-
angina (Parhiscar and Har-El 2001) in order to omyelitis may occur in isolation, patients with
avoid failed intubation and facilitate patient ORN and ARONJ may develop osteomyelitis
weaning. It is, however, rarely performed in devel- secondarily. Combined surgical and medical man-
oped countries, due to advanced anesthetic tech- agement is often required, and they are difficult to
niques and equipment. It may be appropriate to treat.
keep some patients sedated and ventilated postop-
eratively to allow resolution of swelling prior to
extubation. Osteomyelitis of the Jaws
Prevention of Infection Osteomyelitis is inflammatory destruction of the

bone marrow. The condition is summarized in
Prevention of oral disease, most notably caries, Table 6. The etiology of osteomyelitis of the jaws
periodontitis, and pericoronitis, is a complex is usually, but not always, microbial. Convention-
and multifaceted. A significant proportion of ally, secondary osteomyelitis is identified as a
patients usually seek treatment from their gen- microbe-induced progressive inflammation of the
eral dental or medical practitioner before pre- bone marrow of the jaws that may or may not result
senting to hospital (Bridgeman et al. 1995), in suppuration (pus formation). The source of
and so it falls on these practitioners to make infection is usually odontogenic and may be trig-
potentially life-saving decisions. From a sur- gered by inoculation of bacteria during dental
geon’s perspective, the key elements of pre- extraction or root canal therapy. Infection, inflam-
venting life-threatening neck space infections mation, and pus spreads via haversian and
are to: Volkmann’s canals through the marrow and then
to the cortices and periosteum towards oral mucosa
or skin. When advanced, the skin may rarely be
1. Recognize and diagnose early. involved, resulting in oro-cutaneous fistulation.
2. Treat localized infection the first time it occurs Staphylococcus aureus, Staphylococcus epi-
and not allow it to progress to a chronic dermis, and Pseudomonas aeruginosa are some-
(or acute-on-chronic) problem. times reported from chronic abscesses and
3. Remove the source of infection, which osteomyelitis, especially in immunocompromised
may require extraction of one or multiple teeth. subjects. These exogenous opportunistic patho-
4. Drain pus on presentation. gens can cause infection during operative proce-
5. Refer the patient early and do not hesitate to dures or by gaining access through sinuses
speak directly with the admitting team to (Marsh and Martin 1999). A more recent micro-
obtain advice and/or keep them abreast biomic study of chronic osteomyelitis of the jaws
of recent events. Good communication can demonstrated the highly polymicrobial nature of
potentially be life-saving. this disease, with an average of 80 bacterial
Table 6 Summary of key features of osteomyelitis

Definition Inflammation of bone marrow
Etiology Usually infectious-bacterial
Pathogenesis Contiguous spread from odontogenic
infection or trauma
Hematogenous spread
Lymphatic spread
Natural history Progressive in nature with potential for
extension in to the temporomandibular
joints (septic arthritis), periosteum
(peri-osteitis), or collection of pus
(abscess)
Risk factors – Reduced vascularity of tissues
local Mobile fracture
Underlying bony pathology – benign
or malignant
Risk factors – Immune compromise
systemic Steroid therapy
Antiresorptive agents Fig. 45 Plain film radiographic bony changes in
Smokers osteomyelitis
Symptoms Asymptomatic
Pain
Swelling etiology of disease (Goda et al. 2014). Osteomy-
Reduced mouth opening
elitis can be extremely difficult to eradicate with-
Numb lip and chin (Vincent’s sign)
Systemic symptoms of infection out extensive and often repetitive surgical
Clinical signs Trismus debridement (see above). The major virulence
Erythema and cellulitis factors or characteristics of bacteria associated
Fever and malaise with osteomyelitis include biofilm formation that
Lymphadenopathy
limits the efficacy of antibiotics and the innate
Key Blood tests: FBE, CRP, ESR, renal and
investigations liver function tests
host defense, invasion of and replication within
OPG host cells including osteoblasts and genomic
CT diversity and horizontal gene transfer that enables
MRI the emergence of phenotypic variants including
Nuclear medicine techniques
Microscopy, culture, and sensitivities
persistent cells that have limited antibiotic suscep-
Histopathology tibility (Loughran et al. 2016).
Tetracycline and Woods (UV) lamp to The radiological characterization of osteomy-
detect necrotic bone elitis is varied and assists in the diagnosis.
Treatment Surgical – Removal of source of Plain radiographic appearances include bone
infection, debridement, sequestrectomy,
saucerization, decortication, drainage of resorption and osteolysis, osteosclerosis, mixed
pus, resection, fracture immobilization, radiolucency/radio-opacity with a moth-eaten
reconstruction, and dental rehabilitation appearance, onion-peeling, periosteitis, seques-
Medical – Infectious disease team input tration, and cortical discontinuity indicative of
with long-term antibiotic coverage
Adjunctive – Hyperbaric oxygen pathological fracture. Some examples of these
therapy easily recognizable abnormalities are given in
Fig. 45. Useful summaries of the options for
diagnostic imaging have been published
(Underhill et al. 2003; Pineda et al. 2009), and
species detected in each sample. F. nucleatum, a more detailed description outlined in the chap-
P. gingivalis, and T. denticola were among the ter on ▶ “Diagnostic Imaging Principles and
core microbiome associated with disease although Applications in Head and Neck Pathology” in
further work is needed to elucidate the bacterial this textbook.
Table 7 Classification of osteomyelitis

Diffuse Localized
Acute Acute diffuse suppurative Acute localized suppurative
Chronic > 1 month Chronic diffuse suppurative Chronic localized suppurative
Chronic diffuse sclerosing with proliferative periositis Chronic focal sclerosing
(Garré’s osteomyelitis) (Bevin et al. 2008) (condensing osteitis) (MacDonald-
Chronic diffuse sclerosing (Montonen and Lindqvist Jankowski 1999)
2003)
May be part of SAPHO syndrome (synovitis, acne,
pustulosis, hyperostosis, osteitis) (Suei et al. 1996;
Eyrich et al. 1999)
Juvenile chronic mandibular osteomyelitis (Heggie
et al. 2003)
Fig. 46 Osteomyelitis of the left mandibular body. There around two of the screws in the buccal fixation plate
has been previous open reduction and internal fixation of (dotted white arrows in b and c) with irregular cortical
right parasymphyseal and left mandibular fractures. The lysis (b). A gallium isotope scan with low-dose CT
right parasymphyseal fracture has healed (a) and there is coregistration shows intense uptake in the left mandibular
extensive periosteal new bone formation on the buccal and body consistent with osteomyelitis (black arrows in d)
to a lesser extent lingual cortices on the left mandibular (Images courtesy of Clinical Associate Professor Andy
body (white arrows) in a and b. Radiolucency is present Whyte, Perth Radiological Clinic, Perth WA, Australia)
Table 8 Summary of key features of osteoradionecrosis Table 8 (continued)

Definition Radiation-induced devitalization and Key Blood tests: FBE, CRP, ESR, renal
necrosis of bone investigations and liver function tests
Irradiated bone is exposed without Dental panoramic tomography
healing for >3 months in absence of Computerized tomography (CT)
antiresorptive medication or Magnetic resonance imaging (MRI)
malignancy (Schwartz and Kagan Nuclear medicine techniques
2002) Histopathology
Etiology Ionizing radiation of the jaws, usually Microscopy, culture, and sensitivities
60Gy. The greater the absorbed Prevention Dental prophylaxis and treatment as
radiation dose, the greater the risk required, particularly to manage
(Morrish et al. 1981) radiation-induced xerostomia and
Pathogenesis Multiple theories have been proposed high caries risk
but still not fully understood Extraction of teeth with dubious
Incidence 2.6–15% of people exposed to prognosis 2–3 weeks prior to
ionizing radiation (O’Dell and Sinha commencement of radiotherapy
2011) Oral hygiene
Avoidance of tobacco, alcohol,
Natural ORN is a late complication of
ill-fitting dentures
history radiation exposure
Intensity-modulated radiation
May remain stable for years or
therapy (IMRT)
progress to severe disease requiring
surgical intervention
Necrotic bone may become
secondarily infected Table 9 Treatment of osteoradionecrosis by stage
Risk factors – High mineral content of bone, in (Schwartz and Kagan 2002)
local particular posterior mandible
Higher radiation dose, higher the risk Stage Clinical features Treatment
Previous surgery to treat malignancy I Exposure of bone Antibiotic
Bulky tumors (T3/T4 stage) Superficial with therapy if
Usually triggered by local trauma – minimal infection present
e.g., dental extraction or implant or ulceration Topical
dental infection – but may be Asymptomatic antiseptic, e.g.,
spontaneous chlorhexidine
Risk factors – Immunocompromised II Localized Consideration of
systemic Concurrent chemotherapy with A – Minimal mandibular conservative
radiotherapy soft tissue involvement; debridement,
Steroid therapy involvement cortical and sequestectomy,
Smokers B– medullary saucerization
Poor nutritional status Extensive necrosis; possible
Symptoms Asymptomatic soft tissue oro-cutaneous
Dysgeusia involvement fistula
Halitosis III Diffuse Surgery with
Pain
A – Minimal mandibular possible resection
Dysesthesia involvement to and vascularized
soft tissue
Local and systemic symptoms of lower border reconstruction
involvement
infection including swelling, trismus, Pathological
dysphagia B–
Extensive fracture
Clinical signs Bone exposure Oro-cutaneous
soft tissue
Jaw mobility
involvement fistula
Sequestration of bone
Fistulation
Local and systemic symptoms of
infection including erythema, For completeness, it should be noted that there
cellulitis, lymphadenopathy, fever, are other forms of marrow inflammation that do
and malaise not present or progress in this conventional man-
(continued) ner and that may not be associated with a
(detectable) bacterial pathogen. These conditions (2002), and Hudson (1993). However clinically,
are labeled as primary osteomyelitis by some it is useful to consider whether the disease is focal
authors (Bevin et al. 2008) and they occur in or diffuse, acute (up to 4 weeks) or chronic
specific situations and may be age dependent. (>1 month), and suppurative versus non-
They are included in the classification of osteo- suppurative (Suei et al. 2005).
myelitis in Table 7, with references listed for Osteomyelitis is more common in the mandi-
additional reading, but further discussion is ble due to poorer blood supply and denser corti-
beyond the scope of this chapter. There are multi- ces, as compared to the maxilla (Fig. 46). Factors
ple classifications for osteomyelitis, as suggested that affect vascularity also include increasing
by Lew and Waldovgel (1997), Topazian et al. age, smoking, and other pathology that adversely
affects local blood supply such as radiotherapy,
osteopetrosis, Paget’s disease of bone, and fibro-
osseous diseases. Blood supply is further reduced
by increased medullary pressure, pus formation,
and periosteal stripping, exacerbating the patho-
logical process. The aim of surgical treatment (see
Table 5) is to reduce bacterial load, increase vas-
cularity of the site, and enable primary closure at
the affected site.
Osteoradionecrosis
Osteoradionecrosis (ORN) is progressive devital-

Fig. 47 Panoramic tomograph of stage III osteoradio-
necrosis (ORN) with full-thickness moth-eaten appearance ization over time of bone that has been exposed to
and pathological fracture ionizing radiation, usually following the primary
Fig. 48 Osteoradionecrosis (ORN) of the left mandibular posterior maxillary alveolus (white dashed oval in a) with
body. Eighteen months post radiotherapy for an oropha- extensive distal caries in 27 and mucosal thickening in the
ryngeal carcinoma, an oblique sagittal CT reconstruction left maxillary sinus. Following a left hemi-
shows extensive irregular radiolucency and sclerosis mandibulectomy, reconstruction with a fibula flap and
within alveolar and basal bone in the molar region of the extraction of the left posterior maxillary teeth (b), ORN
left mandibular body with involvement of the IAC. There has progressed in the left maxilla (white dotted oval in b)
is a nonhealed 38 socket, destruction of the crown of and also the left ramus. (Images courtesy of Clinical Asso-
37 and distal caries in 36 (dotted black oval in a). There ciate Professor Andy Whyte, Perth Radiological Clinic,
is similar but less marked changes of ORN in the left Perth WA, Australia)
Fig. 49 Radiographic evidence of bisphosphonate-related radiographic features not described (Image courtesy of Dr
osteonecrosis of the jaw involving the posterior left man- Marie Anne Matias, Qscan Radiology Clinics, Brisbane
dible, angle and extending into the ramus. Other QLD, Australia)
or adjunctive treatment of head and neck cancer. tocopherol, and clodronate, a controversial new
The condition is summarized in Table 8. Clinical regimen suggested by some authors for the pre-
staging represents the spectrum of severity, from a vention and/or treatment of ORN by preventing
small stable intraoral area(s) of bone exposure free radical damage and fibrosis (Lyons and
(stage I) to progressive pain, chronic infection, Ghazali 2008; Delanian et al. 2011).
pathological fracture, and oro-cutaneous fistula Diagnosis of ORN relies on ensuring that there
(stages II and III) (Schwartz and Kagan 2002). is no underlying primary or recurrent malignancy.
Table 9 delineates the treatment options according For this, radiography and biopsy are essential
to stage of disease. There are multiple staging (Figs. 47 and 48).
systems, including Marx’s initial system that Surgery is indicated for the treatment of ORN
was based on response to hyperbaric oxygen ther- in stage III disease and in failed conservative
apy (HBO) (Marx 1983). Schwartz and Kagan management (Alam et al. 2009). Resection,
(2002) have suggested a more contemporary stag- extended back to bleeding, seemingly healthy
ing based on clinical features that can be used to bone, and vascularized reconstruction may be
guide treatment. the only viable treatment option. An osseo-
The pathophysiology of ORN is not fully cutaneous free flap such as the fibula has been
understood but has been well covered by shown to be reliable and successful in the recon-
other authors (Lyons and Ghazali 2008; O’Dell struction of resultant segmental mandibular
and Sinha 2011). There are multiple theories defects (Chaine et al. 2009).
attempting to explain ORN but the main ones
include radiation, trauma, and infection resulting
in radiation osteomyelitis (Meyer 1970); hypo- Antiresorptive Agent-Induced
vascularity, hypocellularity, and hypoxia, with Osteonecrosis of the Jaws (ARONJ)
aberrant wound healing due to reduced oxygen
supply to the tissues (Marx 1983); and This condition, a form of osteonecrosis of the
fibroatrophy due to deregulation of fibroblastic jaws (ONJ), was first recognized in patients
activity in the jaws (Delanian and Lefaix 2004). being treated with long-term bisphosphonate
Adjunctive therapies available reflect these theo- therapy (Ruggiero et al. 2014). More
ries, and include HBO to increase tissue oxygen recently, it has been recognized as a rare
tension (Marx et al. 1985) or pentoxifylline, complication of antiresorptive therapy, of
Table 10 Summary of key features of antiresorptive agent-induced osteonecrosis of the jaws (ARONJ)
Definition Antiresorptive agent-induced osteonecrosis of the jaws
People exposed to systemic antiresorptive therapy in absence of radiation therapy or malignancy
resulting in nonhealing lesions lasting greater than 8 weeks (Ruggiero et al. 2014)
Etiology Bisphosphonates – intravenous or oral
RANK ligand inhibitors – e.g., denosumab
Antiangiogenic medication – e.g., VEGF inhibitors, tyrosine kinase inhibitors
Pathogenesis Multiple theories have been proposed but still not fully understood
Incidence 0.7–7% in patients being treated for malignancy (3% best estimate after tooth extraction)
0–0.2% in patients being treated for osteoporosis (0.5% best estimate after tooth extraction)
10% patients on antiresorptive therapy for renal cell carcinoma
Natural history May remain stable for years or progress to severe disease requiring surgical intervention
Necrotic bone may become secondarily infected
Risk factors – Operative treatment – dentoalveolar surgery
local Oral disease
Traumatic dentures
Mandible (vs. maxilla)
Risk factors – Increased risk in:
systemic Dose – higher dose and intravenous administration
Cumulative dose – longer duration of therapy
Drug type
Indication – therapeutic indications, particularly malignancy (bony metastases and multiple
myeloma)
Immune-deficiency, particularly simultaneous administration of steroids and diabetes
Comorbidities including anemia
Smokers
Potential genetic susceptibility
Symptoms Asymptomatic
Dysgeusia
Halitosis
Pain
Dysesthesia
Local and systemic symptoms of infection including swelling, trismus, dysphagia
Clinical signs Bone exposure
Jaw mobility
Sequestration of bone
Fistulation
Local and systemic symptoms of infection including erythema, cellulitis, lymphadenopathy,
fever, and malaise
Key investigations Blood tests: FBE, CRP, ESR, renal and liver function tests; CTX (C-telepeptide) as a measure of
bone turnover
Dental panoramic tomography
Computerized tomography (CT)
Magnetic resonance imaging (MRI)
Nuclear medicine techniques
Histopathology
Microscopy, culture, and sensitivities
Prevention Dental screening, prophylaxis, and treatment of patients about to commence antiresorptive
therapy
Extraction of teeth with dubious prognosis and healing prior to commencement of drug therapy
Oral hygiene
Avoidance of tobacco, alcohol, ill-fitting dentures, or other risk factors
Drug holiday (if indicated) (Ruggiero et al. 2014)
Fig. 50 Medication-induced osteonecrosis of the jaw adjacent alveolar bone. Periodontitis is present around the
right mandible. Current treatment with antiresorptive anterior mandibular teeth. Defects in the buccal and lingual
agents with exposed bone in the lower right second cortices (white arrows in b) suggest incipient sequestrum
molar region (tooth 47) for over 8 weeks. Sagittal (a) and formation (Images courtesy Clinical Associate Professor
axial (b) reconstructions from a CT scan demonstrate a Andy Whyte, Perth Radiological Clinic, Perth WA,
nonhealed 47 socket, ill-defined lysis, and sclerosis in Australia)
The pathophysiology if ARONJ is still not

understood. There are multiple theories described,
and it is likely that the disease aetiology is multi-
factorial. Osteoclastic bone resorption and
remodeling is inhibited by multiple agents includ-
ing some bisphosphonates and denosumab,
resulting in interferences in the natural (rapid)
bony turnover in the jaws. It is suggested that
this reduction in remodeling results in reduced
capacity to heal and ultimately bone necrosis
(Baron et al. 2011). A second theory is that
the inhibition of angiogenesis may result in inter-
ruption of vascular supply to bone, causing
osteonecrosis (Allen and Burr 2009). Zoledronic
Fig. 51 Medication induced osteonecrosis of the jaw.
Cone Beam CT shows focal areas of necrosis involving acid is a bisphosphonate with antiangiogenic
the lingual tori on the right side (arrows). This patient properties (Wood et al. 2002). Other hypotheses,
presented with pain in the anterior right mandible was on or more likely contributing factors, include
Actonel (risedronate) but also had a history of breast cancer
the presence of inflammation, infection or com-
(Image courtesy of Dr Marie Anne Matias, Perth Radiolog-
ical Clinic, Perth WA, Australia) plex polymicrobial biofilms in the oral cavity
that make the jaws specifically susceptible
to osteonecrosis (Sedghizadeh et al. 2008),
which bisphosphonates are one group of agents potential soft tissue toxicity of bisphosphonates
(Fig. 49). Table 10 summarizes the key features (Landesberg et al. 2008), the presence of innate or
of this condition. acquired immune dysfunction (Sonis et al. 2009),
Table 11 Treatment of established antiresorptive agent-induced osteonecrosis of the jaws (ARONJ) by stage, modified
from the AAOMS position paper 2014 (Ruggiero et al. 2014)
Stage Clinical features Treatment
At None Prevention measures
risk
0 Nonspecific symptoms and Analgesia and antibiotics as required
radiological changes
I Exposure of bone Antiseptic rinses
Intraoral fistulation Review of antiresorptive therapy
No evidence of infection Regular follow-up
II Stage I but with infection +/ Stage I with addition of antibiotic therapy
pus Conservative debridement to relieve soft tissue irritation and
sequestrectomy as required with primary closure if possible
III Stage II but with one or more Stage II but with more extensive surgical debridement or resection and
of: microvascular reconstruction
Involvement of basal bone Palliation for patients with poor prognosis
Pathological fracture
Oro-cutaneous fistula
Oro-nasal communication
border
Pathological fracture
Oro-cutaneous fistula
and microtrauma of tissues due to oral function when compared to the remaining skeleton,
(Figs. 50 and 51). because of its high bone turnover and ingress of
Treatment of ARONJ is dependent on the bacteria through minor breakdown portals in the
stage of disease and the oncological status of the oral mucosa or the dentition. Radiotherapy and
patient. The decision to treat a patient with or at bisphosphonate medication have been discussed
risk of ARONJ should be made in full consulta- as important contributors.
tion with the patient’s physician or oncologist and Advances in imaging, and the ability to
an oral and maxillofacial surgeon. A position replace and reconstruct diseased hard and soft
paper of the American Association of Oral and tissues, have been numerous in the last two
Maxillofacial Surgeons (AAOMS; (Ruggiero decades. Microvascular and tissue transfer
et al. 2014)) outlines the complexities in decision techniques combined with dental implantology
making and the risk of developing ARONJ are currently the mainstay for rehabilitation.
according to type and duration of therapy. Tissue engineering, the use of biological scaf-
Table 11 is a summary of treatment according to folds, and the emerging success of targeted
the stage of the disease. The aim of treatment is to stem cell use combined with these technolo-
eliminate pain, control infection, and minimize gies may have a place in maxillary and man-
progression of necrosis. Unproven adjunctive dibular reconstruction. It remains to be seen
therapies include HBO, platelet rich plasma, whether these can be used during the active
bone morphogenic protein, and parathyroid phases of infection or varying forms of
hormone. osteonecrosis, to curb or inhibit the progress
of these pathologies.
At present mandibular osteonecrosis is a
Conclusions and Future Directions relatively uncommon condition, but its relevance
lies in the fact that no cure is forthcoming.
The jaw bones have a predisposition to develop- Those who are at risk require a lifetime of
ing varying forms of infection and osteonecrosis. extreme prophylactic dental care. There are
The mandible is more predisposed to necrosis, clear consequences and relevance of this
topic to the dental and medical professions. Abbott PV, Yu C. A clinical classification of the status of
Several new cancer drugs are reported to the pulp and the root canal system. Aust Dent
J. 2007;52(1 Suppl):S17–31.
induce osteonecrosis. As oncological outcomes Adler CJ, Dobney K, Weyrich LS, Kaidonis J, Walker AW,
improve, the number of patients presenting with Haak W, Bradshaw CJA, Townsend G, Soltysiak A,
ARONJ will increase. Alt KW, Parkhill J, Cooper A. Sequencing ancient cal-
cified dental plaque shows changes in oral microbiota
with dietary shifts of the Neolithic and Industrial revo-
lutions. Nat Genet. 2013;45(4):450–5.
Cross-References Alam DS, Nuara M, Christian J. Analysis of outcomes
of vascularized flap reconstruction in patients with
▶ Classification of Orofacial Pain advanced mandibular osteoradionecrosis. Otolaryngol
▶ Clinical Evaluation of Oral Diseases Head Neck Surg. 2009;141(2):196–201.
Allen MR, Burr DB. The pathogenesis of bisphosphonate-
▶ Diagnostic Imaging Principles and Applica- related osteonecrosis of the jaw: so many hypotheses,
tions in Head and Neck Pathology so few data. J Oral Maxillofac Surg. 2009;
▶ Gingival Pathology 67(5 Suppl):61–70.
▶ Laboratory Medicine and Diagnostic Pathology Armfield J, Roberts-Thomson K, Spencer A. Australia’s
health 2000: the seventh biennial health report of the
▶ Non-odontogenic Bacterial Infections Australian Institute of Health & Welfare, Canberra;
▶ Non-odontogenic Bone Pathology 2000.
▶ Odontogenic Pathology Armitage GC. Development of a classification system for
▶ Orofacial Pain in Patients with Cancer and periodontal diseases and conditions. Ann Periodontol.
1999;4(1):1–6.
Mucosal Diseases Backhed F, Ley RE, Sonnenburg JL, Peterson DA,
▶ Orofacial Pain in the Medically Complex Gordon JI. Host-bacterial mutualism in the human
Patient intestine. Science. 2005;307(5717):1915–20.
▶ Pharmacotherapeutic Approaches in Oral Baron R, Ferrari S, Russell RG. Denosumab and
bisphosphonates: different mechanisms of action and
Medicine effects. Bone. 2011;48(4):677–92.
▶ Soft and Hard Tissue Operative Investigations Baumgartner JC, Mader CL. A scanning electron micro-
in the Diagnosis and Treatment of Oral Disease scopic evaluation of four root canal irrigation regimens.
J Endod. 1987;13(4):147–57.
Baumgartner JC, Xia T. Antibiotic susceptibility of bacte-
ria associated with endodontic abscesses. J Endod.
References 2003;29(1):44–7.
Bevin CR, Inwards CY, Keller EE. Surgical management
Abbott PV. Medicaments: aids to success in endodontics. of primary chronic osteomyelitis: a long-term
Part 2. Clinical recommendations. Aust Dent J. retrospective analysis. J Oral Maxillofac Surg.
1990;35(6):491–6. 2008;66(10):2073–85.
Abbott PV. The periapical space – a dynamic interface. Bornstein MM, Bingisser AC, Reichart PA, Sendi P,
Aust Endod J. 2002;28(3):96–107. Bosshardt DD, von Arx T. Comparison between radio-
Abbott PV. Assessing restored teeth with pulp and peri- graphic (2-dimensional and 3-dimensional) and histo-
apical diseases for the presence of cracks, caries and logic findings of periapical lesions treated with apical
marginal breakdown. Aust Dent J. 2004a;49(1):33–9; surgery. J Endod. 2015;41(6):804–11.
quiz 45. Bottin R, Marioni G, Rinaldi R, Boninsegna M,
Abbott PV. Classification, diagnosis and clinical manifes- Salvadori L, Staffieri A. Deep neck infection: a
tations of apical periodontitis. Endod Top. present-day complication. A retrospective review of
2004b;8:36–54. 83 cases (1998–2001). Eur Arch Otorhinolaryngol.
Abbott PV. Diagnosis and management planning for root- 2003;260(10):576–9.
filled teeth with persisting or new apical pathosis. Bridgeman A, Wiesenfeld D, Hellyar A, Sheldon W. Major
Endod Top. 2011;19:1–21. maxillofacial infections. An evaluation of 107 cases.
Abbott PV. Examination and diagnosis of pulp, root canal, Aust Dent J. 1995;40(5):281–8.
and periapical/periradicular conditions. In: Rotstein II, Byrne SJ, Dashper SG, Darby IB, Adams GG,
Raleigh JI, editors. Ingle’s endodontics. Shelton: Hoffmann B, Reynolds EC. Progression of chronic
PMPH-USA Ltd; 2016. p. 215–66. periodontitis can be predicted by the levels of
Abbott P, Leow N. Predictable management of Porphyromonas gingivalis and Treponema denticola
cracked teeth with reversible pulpitis. Aust Dent J. in subgingival plaque. Oral Microbiol Immunol.
2009;54(4):306–15. 2009;24(6):469–77.
Bystrom A, Happonen RP, Sjogren U, Sundqvist G. osteitis (SAPHO syndrome). J Oral Pathol Med.
Healing of periapical lesions of pulpless teeth after 1999;28(10):456–64.
endodontic treatment with controlled asepsis. Endod Fabricius L, Dahlen G, Holm SE, Moller AJ. Influence of
Dent Traumatol. 1987;3(2):58–63. combinations of oral bacteria on periapical tissues of
Castellarin M, Warren RL, Freeman JD, Dreolini L, monkeys. Scand J Dent Res. 1982a;90(3):200–6.
Krzywinski M, Strauss J, Barnes R, Watson P, Allen- Fabricius L, Dahlen G, Ohman AE, Moller AJ. Predomi-
Vercoe E, Moore RA, Holt RA. Fusobacterium nant indigenous oral bacteria isolated from infected
nucleatum infection is prevalent in human colorectal root canals after varied times of closure. Scand J Dent
carcinoma. Genome Res. 2012;22(2):299–306. Res. 1982b;90(2):134–44.
Caton JG, Armitage G, Berglundh T, Chapple ILC, Jepsen Facklam R. What happened to the streptococci: overview
S, Kornman KS, Mealey BL, Papapanou PN, Sanz M, of taxonomic and nomenclature changes. Clin
Tonetti MS. A new classification scheme for periodon- Microbiol Rev. 2002;15(4):613–30.
tal and peri-implant diseases and conditions - Introduc- Fejerskov O, Kidd EAM. Dental caries: the disease and its
tion and key changes from the 1999 classification. J clinical management. Oxford: Blackwell Munksgaard;
Periodontol. 2018;89(1 Suppl):S1-S8. https://doi.org/ 2003.
10.1002/JPER.18-0157. Flynn TR. Surgical management of orofacial infections.
Chaine A, Pitak-Arnnop P, Hivelin M, Dhanuthai K, Atlas Oral Maxillofac Surg Clin North Am.
Bertrand JC, Bertolus C. Postoperative complica- 2000;8(1):77–100.
tions of fibular free flaps in mandibular reconstruc- Franklin C, Jones A. A survey of oral and maxillofacial
tion: an analysis of 25 consecutive cases. Oral Surg pathology specimens submitted by general dental
Oral Med Oral Pathol Oral Radiol Endod. 2009;108 practitioners over a 30-year period. Br Dent J.
(4):488–95. 2006;200:447–50.
Cornejo OE, Lefebure T, Bitar PD, Lang P, Richards VP, Garberoglio R, Brannstrom M. Scanning electron micro-
Eilertson K, Do T, Beighton D, Zeng L, Ahn SJ, scopic investigation of human dentinal tubules. Arch
Burne RA, Siepel A, Bustamante CD, Stanhope MJ. Oral Biol. 1976;21(6):355–62.
Evolutionary and population genomics of the cavity Goda A, Maruyama F, Michi Y, Nakagawa I, Harada K.
causing bacteria Streptococcus mutans. Mol Biol Analysis of the factors affecting the formation of
Evol. 2013;30(4):881–93. the microbiome associated with chronic osteomyelitis
Costerton JW, Lewandowski Z, Caldwell DE, Korber DR, of the jaw. Clin Microbiol Infect. 2014;20(5):O309–17.
Lappin-Scott HM. Microbial biofilms. Annu Rev Gui MJ, Dashper SG, Slakeski N, Chen YY, Reynolds EC.
Microbiol. 1995;49:711–45. Spheres of influence: Porphyromonas gingivalis outer
Darveau RP. Periodontitis: a polymicrobial disruption of host membrane vesicles. Mol Oral Microbiol. 2016;
homeostasis. Nat Rev Microbiol. 2010;8(7):481–90. 31(5):365–78.
Dashper SG, Seers CA, Tan KH, Reynolds EC. Virulence Ha WN, Kelloway E, Dost F, Farah CS. A retrospective
factors of the oral spirochete Treponema denticola. analysis of oral and maxillofacial pathology in an
J Dent Res. 2011;90(6):691–703. Australian paediatric population. Aust Dent J. 2014;
Delanian S, Lefaix JL. The radiation-induced fibroatrophic 59(2):221–5.
process: therapeutic perspective via the antioxidant Hajishengallis G, Lamont RJ. Beyond the red complex and
pathway. Radiother Oncol. 2004;73(2):119–31. into more complexity: the polymicrobial synergy and
Delanian S, Chatel C, Porcher R, Depondt J, Lefaix JL. dysbiosis (PSD) model of periodontal disease etiology.
Complete restoration of refractory mandibular Mol Oral Microbiol. 2012;27(6):409–19.
osteoradionecrosis by prolonged treatment with a Hajishengallis G, Liang S, Payne MA, Hashim A,
pentoxifylline-tocopherol-clodronate combination Jotwani R, Eskan MA, McIntosh ML, Alsam A,
(PENTOCLO): a phase II trial. Int J Radiat Oncol Kirkwood KL, Lambris JD, Darveau RP, Curtis MA.
Biol Phys. 2011;80(3):832–9. Low-abundance biofilm species orchestrates inflamma-
Dewhirst FE, Chen T, Izard J, Paster BJ, Tanner AC, tory periodontal disease through the commensal micro-
Yu WH, Lakshmanan A, Wade WG. The human oral biota and complement. Cell Host Microbe.
microbiome. J Bacteriol. 2010;192(19):5002–17. 2011;10(5):497–506.
Eke PI, Dye BA, Wei L, Thornton-Evans GO, Genco RJ, Har-El G, Aroesty JH, Shaha A, Lucente FE. Changing
Douglass G, Page R, CDC Periodontal Disease trends in deep neck abscess. A retrospective study of
Surveillance Workgroup: James Beck. Prevalence of 110 patients. Oral Surg Oral Med Oral Pathol.
periodontitis in adults in the United States: 2009 and 1994;77(5):446–50.
2010. J Dent Res. 2012;91(10):914–20. Hargreaves K, Abbott PV. Drugs for pain management in
Ellen RP, Galimanas VB. Spirochetes at the forefront dentistry. Aust Dent J. 2005;50(4 Suppl 2):S14–22.
of periodontal infections. Periodontol 2000. Heggie AA, Shand JM, Aldred MJ, Talacko AA. Juvenile
2005;38:13–32. mandibular chronic osteomyelitis: a distinct clinical
Eyrich GK, Harder C, Sailer HF, Langenegger T, Bruder E, entity. Int J Oral Maxillofac Surg. 2003;32(5):459–68.
Michel BA. Primary chronic osteomyelitis associated Hudson JW. Osteomyelitis of the jaws: a 50-year perspec-
with synovitis, acne, pustulosis, hyperostosis and tive. J Oral Maxillofac Surg. 1993;51(12):1294–301.
Jacinto RC, Gomes BP, Shah HN, Ferraz CC, Zaia AA, Marsh PD, Martin MV. Oral microbiology. Oxford: Wright
Souza-Filho FJ. Incidence and antimicrobial suscepti- Publishers; 1999.
bility of Porphyromonas gingivalis isolated from Marx RE. Osteoradionecrosis: a new concept of its patho-
mixed endodontic infections. Int Endod J. 2006; physiology. J Oral Maxillofac Surg. 1983;41(5):283–8.
39(1):62–70. Marx RE, Johnson RP, Kline SN. Prevention of osteoradio-
Jansson L, Ehnevid H, Lindskog S, Blomlof L. Develop- necrosis: a randomized prospective clinical trial of
ment of periapical lesions. Swed Dent J. 1993; hyperbaric oxygen versus penicillin. J Am Dent
17(3):85–93. Assoc. 1985;111(1):49–54.
Jones A, Franklin C. An analysis of oral and maxillofacial Meyer I. Infectious diseases of the jaws. J Oral Surg.
pathology found in children over a 30-year period. Int J 1970;28(1):17–26.
Paediatr Dent. 2006;16:19–30. Meyer MS, Joshipura K, Giovannucci E, Michaud DS. A
Kakehashi S, Stanley HR, Fitzgerald RJ. The effects of review of the relationship between tooth loss, periodon-
surgical exposures of dental pulps in germ-free and tal disease, and cancer. Cancer Causes Control.
conventional laboratory rats. Oral Surg Oral Med Oral 2008;19(9):895–907.
Pathol. 1965;20:340–9. Miller W. The microorganisms of the human mouth. Phil-
Kakehashi S, Stanley HR, Fitzgerald R. The exposed adelphia: SS White Manufacturing Company; 1890.
germ-free pulp: effects of topical corticosteroid medi- Moller AJ. Microbiological examination of root canals and
cation and restoration. Oral Surg Oral Med Oral Pathol. periapical tissues of human teeth. Methodological stud-
1969;27(1):60–7. ies. Odontol Tidskr. 1966;74(5): Suppl:1–380.
Kapil V, Haydar SM, Pearl V, Lundberg JO, Weitzberg E, Moller AJ, Fabricius L, Dahlen G, Ohman AE, Heyden G.
Ahluwalia A. Physiological role for nitrate-reducing Influence on periapical tissues of indigenous oral bac-
oral bacteria in blood pressure control. Free Radic teria and necrotic pulp tissue in monkeys. Scand J Dent
Biol Med. 2013;55:93–100. Res. 1981;89(6):475–84.
Kelloway E, Ha W, Dost F, Farah CS. A retrospective Montonen M, Lindqvist C. Diagnosis and treatment
analysis of oral and maxillofacial pathology in an of diffuse sclerosing osteomyelitis of the jaws.
Australian adult population. Aust Dent J. 2014; Oral Maxillofac Surg Clin North Am. 2003;15(1):
59(2):215–20. 69–78.
Korzen BH, Krakow AA, Green DB. Pulpal and periapical Morrish RB Jr, Chan E, Silverman S Jr, Meyer J, Fu KK,
tissue responses in conventional and monoinfected Greenspan D. Osteonecrosis in patients irradiated
gnotobiotic rats. Oral Surg Oral Med Oral Pathol. for head and neck carcinoma. Cancer. 1981;47
1974;37(5):783–802. (8):1980–3.
Kwang S, Abbott PV. Bacterial contamination of the fitting Nair PN. Apical periodontitis: a dynamic encounter
surfaces of restorations in teeth with pulp and periapical between root canal infection and host response.
disease: a scanning electron microscopy study. Aust Periodontol 2000. 1997;13:121–48.
Dent J. 2012;57(4):421–8. Nair PNR, Pajarola G, Schroeder H. Types and incidence
Landesberg R, Cozin M, Cremers S, Woo V, Kousteni S, of human periapical lesions obtained with extracted
Sinha S, Garrett-Sinha L, Raghavan S. Inhibition of oral teeth. Oral Surg Oral Med Oral Pathol Oral Radiol
mucosal cell wound healing by bisphosphonates. J Oral Endod. 1996;81:93–102.
Maxillofac Surg. 2008;66(5):839–47. Nerwich A, Figdor D, Messer HH. pH changes in root
Lederberg J, McCray A. ‘Ome sweet ‘omics – a genealog- dentin over a 4-week period following root canal dress-
ical treasury of words. Scientist. 2001;15:8–10. ing with calcium hydroxide. J Endod. 1993;
Lew DP, Waldvogel FA. Osteomyelitis. N Engl J Med. 19(6):302–6.
1997;336(14):999–1007. Ng HM, Kin LX, Dashper SG, Slakeski N, Butler CA,
Loughran AJ, Gaddy D, Beenken KE, Meeker DG, Reynolds EC. Bacterial interactions in pathogenic sub-
Morello R, Zhao H, Byrum SD, Tackett AJ, gingival plaque. Microb Pathog. 2016;94:60–9.
Cassat JE, Smeltzer MS. Impact of sarA and phenol- O’Dell K, Sinha U. Osteoradionecrosis. Oral Maxillofac
soluble modulins on the pathogenesis of osteomyelitis Surg Clin North Am. 2011;23(3):455–64.
in diverse clinical isolates of Staphylococcus aureus. Orth RK, O’Brien-Simpson NM, Dashper SG,
Infect Immun. 2016;84(9):2586–94. Reynolds EC. Synergistic virulence of Porphyromonas
Lyons A, Ghazali N. Osteoradionecrosis of the jaws: current gingivalis and Treponema denticola in a murine
understanding of its pathophysiology and treatment. Br J periodontitis model. Mol Oral Microbiol. 2011;
Oral Maxillofac Surg. 2008;46(8):653–60. 26(4):229–40.
MacDonald-Jankowski DS. Idiopathic osteosclerosis in Parhiscar A, Har-El G. Deep neck abscess: a retrospective
the jaws of Britons and of the Hong Kong Chinese: review of 210 cases. Ann Otol Rhinol Laryngol.
radiology and systematic review. Dentomaxillofac 2001;110(11):1051–4.
Radiol. 1999;28(6):357–63. Pineda C, Espinosa R, Pena A. Radiographic imaging in
Marsh PD. Microbiology of dental plaque biofilms and osteomyelitis: the role of plain radiography, computed
their role in oral health and caries. Dent Clin North tomography, ultrasonography, magnetic resonance imag-
Am. 2010;54(3):441–54. ing, and scintigraphy. Semin Plast Surg. 2009;23(2):80–9.
Ricucci D, Loghin S, Siqueira JF Jr. Correlation between Sonis ST, Watkins BA, Lyng GD, Lerman MA,
clinical and histologic pulp diagnoses. J Endod. Anderson KC. Bony changes in the jaws of rats treated
2014;40(12):1932–9. with zoledronic acid and dexamethasone before
Ricucci D, Siqueira JF Jr, Loghin S, Berman LH. The dental extractions mimic bisphosphonate-related
cracked tooth: histopathologic and histobacteriologic osteonecrosis in cancer patients. Oral Oncol. 2009;45
aspects. J Endod. 2015;41(3):343–52. (2):164–72.
Ritchie SC, Wurtz P, Nath AP, Abraham G, Havulinna AS, Spangberg LS. Infatuated by Enterococci. Oral Surg
Fearnley LG, Sarin AP, Kangas AJ, Soininen P, Oral Med Oral Pathol Oral Radiol Endod.
Aalto K, Seppala I, Raitoharju E, Salmi M, 2006;102(5):577–8.
Maksimow M, Mannisto S, Kahonen M, Juonala M, Stockham S, Stamford JE, Roberts CT, Fitzsimmons TR,
Ripatti S, Lehtimaki T, Jalkanen S, Perola M, Marchant C, Bartold PM, Zilm PS. Abnormal preg-
Raitakari O, Salomaa V, Ala-Korpela M, Kettunen J, nancy outcomes in mice using an induced periodontitis
Inouye M. The biomarker GlycA is associated with model and the haematogenous migration of
chronic inflammation and predicts long-term risk of Fusobacterium nucleatum sub-species to the murine
severe infection. Cell Syst. 2015;1(4):293–301. placenta. PLoS One. 2015;10(3):e0120050.
Robertson D, Smith AJ. The microbiology of the Suei Y, Taguchi A, Tanimoto K. Diffuse sclerosing osteo-
acute dental abscess. J Med Microbiol. 2009; myelitis of the mandible: its characteristics and possible
58(Pt 2):155–62. relationship to synovitis, acne, pustulosis, hyperostosis,
Ruggiero SL, Dodson TB, Fantasia J, Goodday R, osteitis (SAPHO) syndrome. J Oral Maxillofac Surg.
Aghaloo T, Mehrotra B, O’Ryan F, American Associ- 1996;54(10):1194–9; discussion 1199–200.
ation of Oral and Maxillofacial Surgeons. American Suei Y, Taguchi A, Tanimoto K. Diagnosis and classifica-
Association of Oral and Maxillofacial Surgeons position of mandibular osteomyelitis. Oral Surg Oral Med
tion paper on medication-related osteonecrosis of Oral Pathol Oral Radiol Endod. 2005;100(2):207–14.
the jaw – 2014 update. J Oral Maxillofac Surg. Sundqvist G. Bacteriologic studies of necrotic dental
2014;72(10):1938–56. pulps. PhD, University of Umea; 1976.
Schwartz HC, Kagan AR. Osteoradionecrosis of the man- Sundqvist G. Endodontic microbiology. In:
dible: scientific basis for clinical staging. Am J Clin Spångberg LSW, editor. Experimental endodontics.
Oncol. 2002;25(2):168–71. Boca Raton: CRC Press Inc; 1990. p. 131–53.
Sedghizadeh PP, Kumar SK, Gorur A, Schaudinn C, Tan KH, Seers CA, Dashper SG, Mitchell HL, Pyke JS,
Shuler CF, Costerton JW. Identification of microbial Meuric V, Slakeski N, Cleal SM, Chambers JL,
biofilms in osteonecrosis of the jaws secondary to McConville MJ, Reynolds EC. Porphyromonas
bisphosphonate therapy. J Oral Maxillofac Surg. gingivalis and Treponema denticola exhibit metabolic
2008;66(4):767–75. symbioses. PLoS Pathog. 2014;10(3):e1003955.
Sender R, Fuchs S, Milo R. Are we really vastly Therapeutic Guidelines. Post-treatment pain management.
outnumbered? Revisiting the ratio of bacterial to host Therapeutic Guidelines Oral and Dental Version.
cells in humans. Cell. 2016;164(3):337–40. 2012a;2:127–36.
Siqueira JF Jr, Rocas IN. Treponema species associated Therapeutic Guidelines. Acute odontogenic and salivary
with abscesses of endodontic origin. Oral Microbiol gland infections. Therapeutic Guidelines Oral and
Immunol. 2004;19(5):336–9. Dental Version. 2012b;2:61–70.
Siqueira JF Jr, Rocas IN. Microbiology and treatment Topazian RG, Goldberg MH, Hupp JR. Oral and
of acute apical abscesses. Clin Microbiol Rev. maxillofacial infections. Philadelphia: W.B. Saunders;
2013;26(2):255–73. 2002.
Siquiera JF. Endodontic infections and the etiology of Underhill TE, Laine FJ, George J. Diagnostic imaging of
apical periodontitis – an overview. In: Siquiera JF, maxillofacial infections. Oral Maxillofac Surg Clin
editor. Treatment of endodontic infections. Berlin: North Am. 2003;15(1):39–49.
Quintessence Publishing; 2011. p. 7–16. Wood J, Bonjean K, Ruetz S, Bellahcene A, Devy L,
Siquiera JF, Rôças IN. The invaders: bacterial biofilm Foidart JM, Castronovo V, Green JR. Novel anti-
communities and pathogenicity. In: Siquiera JF, editor. angiogenic effects of the bisphosphonate
Treatment of endodontic infections. Berlin: Quintes- compound zoledronic acid. J Pharmacol Exp Ther.
sence Publishing; 2011; p. 17–39. 2002;302(3):1055–61.
Skucaite N, Peciuliene V, Vitkauskiene A, Yu C, Abbott PV. An overview of the dental pulp: its
Machiulskiene V. Susceptibility of endodontic patho- functions and responses to injury. Aust Dent J.
gens to antibiotics in patients with symptomatic apical 2007;52(1 Suppl):S4–16.
periodontitis. J Endod. 2010;36(10):1611–6. Zijnge V, van Leeuwen MB, Degener JE, Abbas F,
Socransky SS, Haffajee AD, Cugini MA, Smith C, Thurnheer T, Gmur R, Harmsen HJ. Oral biofilm
Kent RL Jr. Microbial complexes in subgingival architecture on natural teeth. PLoS One. 2010;5(2):
plaque. J Clin Periodontol. 1998;25(2):134–44. e9321.
Non-odontogenic Bacterial Infections
Agnieszka M. Frydrych and Camile S. Farah
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 873
Impetigo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 873
Etiology and Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 873
Clinical-Pathologic Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 874
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 875
Patient Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 875
Erysipelas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 876
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 877
Cat-Scratch Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 877
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 878
Leprosy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 879
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 884
A. M. Frydrych (*)
e-mail: agnieszka.frydrych@uwa.edu.au
C. S. Farah

https://doi.org/10.1007/978-3-319-72303-7_46
872 A. M. Frydrych and C. S. Farah
Syphilis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 886
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 891
Gonorrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 893
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 895
Actinomycosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 895
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 898
Nocardiosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 900
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 902
Necrotizing Fasciitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 903
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 904
Noma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 905
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 907
Diphtheria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 907
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 909
Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 910
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 913
Bacterial Sialadenitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 915
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 917
Bacterial Rhinosinusitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 919
Acute Rhinosinusitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 920
Chronic Rhinosinusitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 922
Maxillary Sinusitis of Odontogenic Origin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 923
Group A Streptococcal Pharyngotonsillitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 925
Non-odontogenic Bacterial Infections 873
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 927
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 928
Abstract widespread in the developed world. Depending

Non-odontogenic bacterial infections are not on which part of the world clinicians practice in,
commonly seen in contemporary oral medicine the conditions explored in this chapter will have
practice, but there is a worldwide resurgence of more poignant significance. Given that many con-
these conditions, and they have become more ditions are highly contagious, and often spread
important in differential diagnosis and can pose through sexual contact, they still constitute a for-
a significant health problem for both patients and midable foe in modern-day practice of oral medi-
clinicians. Given the widespread etiology and cine. Conditions covered in this chapter include
pathophysiology of such bacterial infections, it bacterial infections of the skin and mucous mem-
is prudent that the oral medicine specialist is well branes, sexually transmitted diseases, and bacterial
aware and familiar with these diseases and their infections of the salivary glands and paranasal
treatment regimens. This chapter explores sexu- sinuses. Although treatment often comprises anti-
ally transmitted conditions such as syphilis and bacterial and antibiotic regimens, correct diagnosis
gonorrhea, and cutaneous infections such as lep- through laboratory and imaging modalities is often
rosy, impetigo, erysipelas, and cat-scratch dis- required for efficient and effective treatment. Sev-
ease, in addition to granulomatous and eral conditions such as syphilis can mimic sinister
suppurative conditions such as tuberculosis, mucosal pathology, so recalling the presence and
nocardiosis, and actinomycosis. Bacterial reemergence of such conditions is of paramount
sialadenitis, rhinosinusitis, and pharyngoton- importance to a comprehensive approach to con-
sillitis are also explored in significant depth. temporary oral medicine practice.
Keywords
Bacterial infections · Non-odontogenic Impetigo
infections · Syphilis · Impetigo · Leprosy ·
Diphtheria · Actinomycosis · Gonorrhea · Etiology and Pathophysiology
Tuberculosis · Sialadenitis · Sinusitis
Impetigo represents a highly contagious bacterial
infection of the superficial layers of the epidermis,
Introduction commonly encountered in tropical climates or dur-
ing the summer and early autumn in temperate
Although odontogenic bacterial infections are by areas (Brown et al. 2003; Hirschmann 2002;
far more common than non-odontogenic bacterial Bangert et al. 2012). Staphylococcus aureus and
infections in the oral cavity, the latter can pose Streptococcus pyogenes, either in combination or
serious health concerns for patients and significant individually, are the responsible infective agents
diagnostic challenges for clinicians. With ever- (Kolokotronis et al. 2005). While these organisms
increasing globalization, rare and somewhat forgot- do not normally infect intact skin, portals of entry
ten non-odontogenic bacterial conditions are may be created by minor trauma such as that asso-
emerging as serious threats to human health. ciated with insect bites, lacerations, scratches, and
Some conditions are still more prevalent in devel- abrasions (Brown et al. 2003; Hirschmann 2002).
oping countries, but these are becoming Modes of spread include close contact with the
infected individual and fomites (Bangert et al. most frequently affected sites due to colonization of
2012). Epidemics in child day care centers and the perioral skin and nares by S. aureus and
schools may occur (Faergemann and Dahlen S. pyogenes (Bangert et al. 2012; Kolokotronis
2009). Worldwide, impetigo is considered the et al. 2005). Extremities and various other sites
most common infection in children, usually affect- may also be affected (Bangert et al. 2012).
ing those aged 2–5 years, although the infection can Non-bullous impetigo is the most common type,
present across the broader age spectrum, including accounting for about 70% of all cases (Bangert et al.
adults (Bangert et al. 2012). Globally, it is estimated 2012). The infection typically begins as a small
that at any one time more than 162 million children (2–4 mm) erythematous macule or papule, which
are afflicted with the disease, with the poor com- quickly becomes vesicular or pustular (Brown et al.
munities of high-income countries bearing a very 2003; Hirschmann 2002). The resultant delicate
high disease burden (Romani et al. 2015; Bowen vesicles/pustules easily rupture. A “honey-colored”
et al. 2015). In the current era of ever-growing yellow, dark brown, or reddish black crust forms as
concerns surrounding antimicrobial resistance, the the released contents dry on the skin (Hirschmann
high prevalence of impetigo and associated antibi- 2002; Bangert et al. 2012; Kolokotronis et al.
otic use render this infection a significant public 2005). Purulent material may be found beneath
health concern (Bowen et al. 2015). (Hirschmann 2002). Satellite lesions in adjacent
areas are not uncommon, due to the highly conta-
gious nature of the disease (Bangert et al. 2012).
Clinical-Pathologic Features The lesions expand and coalesce but generally
remain less than 2 cm in diameter (Hirschmann
Impetigo is classified as bullous or non-bullous and 2002). Lesional pruritus or pain can be a feature
on occasion may complicate an underlying cutane- and mild associated regional lymphadenopathy
ous disease such as eczema (secondary impetigo) may be encountered (Brown et al. 2003;
(Hirschmann 2002; Koning et al. 2012). Multiple Hirschmann 2002; Bangert et al. 2012; Koning
types of impetigo may coexist in the same individ- et al. 2012). Acute post-streptococcal glomerulone-
ual (Brown et al. 2003). The face, and in particular phritis may complicate non-bullous impetigo in up
the perioral region (Fig. 1), constitutes one of the to 5% of affected individuals (Brown et al. 2003;
Kolokotronis et al. 2005). Other complications may
include guttate psoriasis and scarlet fever (Koning
et al. 2012). Fever, anorexia, malaise, lymphangitis,
cellulitis, and septicemia can occur but are unusual
(Hirschmann 2002; Koning et al. 2012). Leukocy-
tosis occurs in about 50% of affected individuals
(Hirschmann 2002). Lesions heal without scarring,
although areas of depigmentation may remain
(Hirschmann 2002). Differential diagnosis of
non-bullous impetigo includes herpes simplex, var-
icella, atopic and contact dermatitis, discoid lupus
erythematosus, eczema, dermatophytosis, candidi-
asis, and scabies (Brown et al. 2003; Kolokotronis
et al. 2005; Koning et al. 2012). Spontaneous reso-
lution of the infection may occur within 2–3 weeks,
but more rapid healing occurs with adequate treat-
ment (Koning et al. 2012).
Fig. 1 Impetigo on the face with characteristic weeping,
oozing, and yellow-green crusting (Image courtesy of
Bullous impetigo is characterized by the pres-
Associate Professor Ajay Parihar, Government College of ence of vesicles or bullae and is almost always
Dentistry, Madhya Pradesh, India) caused by S. aureus which produces exfoliative
toxins specific for desmoglein 1 (Brown et al. neutrophils and lymphocytes is also found in the
2003; Bangert et al. 2012; Koning et al. 2012). underlying connective tissue (Brown et al. 2003;
Resultant blisters initially contain a clear and yel- Hirschmann 2002). Serologic testing for skin infec-
low fluid that later becomes darker and cloudy tions with S. pyogenes (anti-DNase B or anti-hyal-
(Hirschmann 2002). As the blisters rupture and uronidase antibodies) may be indicated when acute
the released contents dry a thin yellow/brown post-streptococcal glomerulonephritis is suspected
crust results, which upon removal reveals an ery- (Hirschmann 2002).
thematous, moist base that oozes serum
(Hirschmann 2002; Kolokotronis et al. 2005).
Newborns and infants are most frequently affected, Patient Management
although the infection may also be seen in older
children and adults (Brown et al. 2003; While limited information is available regarding
Hirschmann 2002; Kolokotronis et al. 2005). the natural history of impetigo, it has been
Lymph node enlargement and cellulitis may occur observed that spontaneous resolution occurs in
but are unusual (Hirschmann 2002). Weakness, 13–52% of cases; thus, in uncomplicated infec-
fever, and diarrhea constitute the most common tions, observation may be an option (Bangert et al.
systemic symptoms of bullous impetigo (Brown 2012). Treatment of impetigo (bullous and
et al. 2003). Meningitis and pneumonia are rare non-bullous) entails the use of oral or topical anti-
and represent the most severe potential complica- microbial agents, although oral agents are
tions of the infection (Brown et al. 2003). Differ- recommended when numerous lesions are present
ential diagnosis includes burns, pemphigus or in epidemic situations to decrease the risk of
vulgaris, bullous pemphigoid, Stevens-Johnson disease transmission (Bangert et al. 2012; Stevens
syndrome, bullous erythema multiforme, necrotiz- et al. 2014). Topical treatment involves the use of
ing fasciitis, and epidermolysis (Brown et al. 2003; mupirocin or retapamulin twice daily for 5 days
Kolokotronis et al. 2005; Koning et al. 2012). and appears as effective as oral treatment (Koning
et al. 2012; Stevens et al. 2014). Resistance rates
to mupirocin however are increasing and have
Diagnosis been reported to range from 5% to 50% (Bangert
et al. 2012). Oral treatment comprises a 7-day
Gram stain and culture of the pus or exudates from course with an agent active against S. aureus
skin lesions are advised to identify the offending (such as dicloxacillin or cephalexin) unless cul-
organism(s) (Stevens et al. 2014). Gram stains reveal tures yield streptococci alone (Stevens et al.
neutrophils and (depending on whether streptococci, 2014). In the latter case, oral penicillin is the
staphylococci, or both are present) gram-positive recommended agent (Stevens et al. 2014). In
cocci in chains and/or clusters (Hirschmann 2002). the case of MRSA infections, doxycycline,
Histopathology of non-bullous impetigo lesions is clindamycin, or sulfamethoxazole-trimethoprim
characterized by spongiosis and intraepithelial vesi- is recommended (Stevens et al. 2014). Absence
cles and pustules containing neutrophils and gram- of clinical response to treatment within 7 days of
positive cocci and a mixed inflammatory infiltrate its initiation generally signals either lack of patient
composed of neutrophils and lymphocytes in the compliance or antimicrobial resistance, and in
upper dermis (Hirschmann 2002). In the case of such instances, a second sample of exudate should
bullous impetigo lesions, the histopathology reveals be obtained for culture and sensitivity testing
spongiosis, clefting, and acantholysis either within (Kolokotronis et al. 2005). Whether treatment of
or below the granular cell layer (Hirschmann 2002). impetigo reduces the incidence of glomerulone-
Typically, gram-positive cocci and no or few neu- phritis is unclear (Bangert et al. 2012). There is
trophils are noted within the blisters, although the currently a lack of evidence to support the use of
fluid may at times be purulent (Hirschmann 2002). disinfection measures to manage impetigo
Mixed inflammatory cell infiltrate composed of (Hirschmann 2002; Koning et al. 2012).
Erysipelas 2010). Serious complications may nonetheless

occur in the form of abscess, necrotizing fasciitis,
Etiology and Pathophysiology septicemia, meningitis, and endocarditis
(Faergemann and Dahlen 2009; Hannula-Jouppi
Erysipelas is a superficial skin infection charac- et al. 2013; O’Connor and Paauw 2010). The
terized clinically by a sharply demarcated inflam- affected individual’s immune status, factors local-
matory reaction (Kilburn et al. 2010; Blackberg izing the infection, and the pathogens involved
et al. 2015; Ochs and Dolwick 1991). In European will ultimately govern the clinical presentation,
countries, the estimated incidence is 19–24 per course, and the potential complications of erysip-
10,000 inhabitants (Inghammar et al. 2014). The elas (Torok 2005). Rapid progression and life-
exact etiology of erysipelas continues to be threatening complications of the infection are
debated, although it is generally agreed that beta- more typical in the elderly (Torok 2005). Erysip-
hemolytic streptococci (usually group A or group elas among infants and young children is also
G) are the main causative agents (Kilburn et al. concerning due to its potential for rapid progres-
2010; Blackberg et al. 2015). Whether erysipelas sion and spread (Torok 2005). Recurrences are a
can also be caused by Staphylococcus aureus or common complication of erysipelas, occurring in
gram-negative bacteria is yet to be established about 9–29% of the cases, and are largely attrib-
(Inghammar et al. 2014). Breaks in the skin sec- uted to the persistence of local factors that remain
ondary to trauma or another skin disease create a untreated (Inghammar et al. 2014; Krasagakis
portal for bacterial entry (Faergemann and Dahlen et al. 2010; Bonnetblanc and Bedane 2003).
2009). While pediatric cases do occur, it is the
older adults who are most commonly affected as a
result of predisposing co-morbidities such as Clinical-Pathologic Features
venous insufficiency, impaired lymphatic drain-
age, immunosuppression, diabetes, obesity, corti- Clinically, erysipelas is characterized by a rapidly
costeroid therapy, chemotherapy, and substance expanding, well-demarcated, erythematous, glossy
abuse (Faergemann and Dahlen 2009; Ochs and plaque, associated with warmth, pain, swelling,
Dolwick 1991; Krasagakis et al. 2010; Hannula- and perifollicular edema (peau d’orange) (Fig. 2)
Jouppi et al. 2013). Male predilection has been (Hannula-Jouppi et al. 2013; O’Connor and Paauw
reported (Blackberg et al. 2015). 2010; Giunta 1987). Various clinical forms of ery-
Historically, facial involvement was consid- sipelas have been described including vesiculous,
ered to be the most common (Faergemann and bullous, pustulous, hemorrhagic, absceding, and
Dahlen 2009). More recent literature however,
identifies the lower limbs as the predominantly
affected site with facial involvement accounting
for only about 6–19%, of all cases (Faergemann
and Dahlen 2009; Inghammar et al. 2014;
Krasagakis et al. 2010; Bonnetblanc and Bedane
2003). Greater emphasis on facial appearance,
improved hygiene, and predisposition of the
lower extremities to local risk factors such as
trauma and venous insufficiency have been the
explanations put forward to account for this shift
(Ochs and Dolwick 1991; Krasagakis et al. 2010).
Erysipelas is in general considered to represent
Fig. 2 Erysipelas appearing as a well-demarcated ery-
a mild disease when managed appropriately, and
thematous plaque (Image courtesy of Clinical Associate
with early diagnosis and treatment, the prognosis Professor Kurt Gebauer, Dermatology West, Perth WA,
is good (Inghammar et al. 2014; Krasagakis et al. Australia)
phlegmonous forms (Torok 2005). Fever, chills, 2003). Neutrophils are present in the venule walls
malaise, regional lymphadenopathy, and and thrombosis may occur (Bonnetblanc and
lymphangitis may be present (Krasagakis et al. Bedane 2003).
2010; Bonnetblanc and Bedane 2003). Laboratory Microbiological studies indicate that strepto-
studies usually reveal leukocytosis and elevated cocci are responsible for most cases of erysipelas
C-reactive protein or erythrocyte sedimentation and streptococcal toxins are believed to account
rate (Ochs and Dolwick 1991; Krasagakis et al. for the clinical inflammation (Stevens et al. 2014;
2010; Hannula-Jouppi et al. 2013). Malar or “but- Blackberg et al. 2015; Bonnetblanc and Bedane
terfly” pattern may be a feature of facial erysipelas 2003). Group A streptococci are most commonly
(O’Connor and Paauw 2010). Mucosal cases of implicated, but group B, C, G, or F streptococci
erysipelas are very rare but have been described, and other organisms may also be involved (Ste-
primarily affecting the pharynx and the larynx vens et al. 2014). The source of these pathogens is
(Torok 2005). Differential diagnosis includes con- often unclear (Stevens et al. 2014).
tact dermatitis, angioedema, lupus, odontogenic
cellulitis, and other bacterial, viral, and fungal
skin infections (Bonnetblanc and Bedane 2003; Patient Management
Giunta 1987).
At present the evidence governing the
recommended treatment protocols of erysipelas is
Diagnosis limited (Kilburn et al. 2010). Nonetheless, the cur-
rently recommended antibiotic choices for typical
The diagnosis of erysipelas is usually clinical, and cases include penicillin, amoxicillin, amoxicillin-
cultures of blood or cutaneous aspirates, biopsies, clavulanate, dicloxacillin, cephalexin, or
or swabs are not routinely advised (Stevens et al. clindamycin, and the recommended duration of
2014; Ochs and Dolwick 1991). Such investiga- treatment in most cases is 5 days (Stevens et al.
tions should however be considered in the context 2014). With appropriate treatment, a rapid and
of immersion injuries and animal bites or in indi- favorable response is expected with resolution of
viduals with significant comorbidities such as fever and pain occurring within 72 h (Bonnetblanc
those with malignancy on chemotherapy and neu- and Bedane 2003). While most patients are treated
tropenia or with severe cell-mediated immunode- on an outpatient basis, hospitalization should be
ficiency (Stevens et al. 2014). Unfortunately, considered if there is uncertainty about the possi-
isolation of bacteria from erysipelas lesions bility of a deeper or a necrotizing infection, if
remains difficult and is the reason why the patho- treatment compliance is likely to be poor, in non-
genesis of this disease is not yet fully understood responsive cases, or when the infection is present in
(Krasagakis et al. 2010). Culture yields of punch an immunocompromised individual (Stevens et al.
biopsy specimens or needle aspirations of the 2014). Any predisposing conditions should also be
inflamed skin are low and are reported in the ranges managed appropriately to decrease the risk of dis-
from 20% to 30% and 5% to 40% of the cases, ease recurrence (Bonnetblanc and Bedane 2003).
respectively (Stevens et al. 2014). Blood cultures
are positive in 5% of cases (Stevens et al. 2014).
Histopathology reveals a dense neutrophilic infil- Cat-Scratch Disease
trate and fibrin-rich edema within the dermis, with
a less intense neutrophilic infiltrate within the Etiology and Pathophysiology
hypodermis (Bonnetblanc and Bedane 2003). Pus-
tules, abscesses, focal necrosis, or subepidermal Cat-scratch disease (CSD) is a zoonotic disease
bullae may be noted (Bonnetblanc and Bedane caused by Bartonella henselae – a small, fastidi-
2003). Dilated lymphatics are filled with neutro- ous, hemotropic, gram-negative bacillus (Chiu
phils and macrophages (Bonnetblanc and Bedane et al. 2001; Nelson et al. 2016). Cats, and in
particular kittens, constitute the principal mammal Eisenbeis 2004). The surrounding area is typically
reservoir of the bacterium, which can be transmit- tender, warm, erythematous, and indurated
ted to humans via scratches and bites (Nelson (Munson et al. 2008). In about 10% of cases, the
et al. 2016). Fleas are believed responsible for nodes suppurate (Stevens et al. 2014). Constitu-
cat-to-cat transmission (Dean and Eisenbeis tional symptoms and laboratory abnormalities are
2004). While most cases of CSD are associated usually lacking (Barr and Qiu 2005; Munson et al.
with a cat bite or a scratch, flea bites and exposure 2008). Fever is reported in about one third of the
to dogs have also been linked to the condition patients (Munson et al. 2008).
(Lindeboom 2015). The disease is reported world- Atypical manifestations of CSD (with or with-
wide, affecting people of all ethnic groups, with a out lymphadenopathy) predominantly occur in
slight male predilection (Ray et al. 1999). While immunocompromised patients, although may
CSD may occur at any age, the mean age of also occasionally occur in immunocompetent
presentation is 33 years (Lindeboom 2015; Ridder individuals (Nelson et al. 2016; Ridder et al.
et al. 2002). In the United States, the estimated 2005). Atypical forms of CSD include Parinaud
annual incidence of the disease is 4.7 per 100,000 oculoglandular syndrome, swelling of the parotid
persons under the age of 65 years, and in children gland, erythema nodosum, erythema marginatum,
and adolescents, CSD represents one of the most bacillary angiomatosis, peliosis hepatis, bacter-
common causes of a benign neck mass (Nelson emia, osteomyelitis, pulmonary disease, splenic
et al. 2016; Barr and Qiu 2005). The infection is involvement, endocarditis, aseptic meningitis,
considered mostly preventable, and interventions encephalopathy, and transient dysfunction of cra-
such as flea control in cats or the simple washing nial and/or peripheral nerves (Chiu et al. 2001;
of hands after contact with cats represent useful Nelson et al. 2016; Ray et al. 1999; Barr and Qiu
preventive measures (Nelson et al. 2016). 2005; Carithers 1985; Ridder et al. 2005; dos
Santos et al. 2007).
Diagnosis
The clinical presentation of CSD is governed by
the immune status of the affected individual Diagnosis of CSD is based on the fulfillment of
(Ridder et al. 2002). Classically, in an immuno- three of the four diagnostic criteria: (1) history of
competent host, CSD presents as a benign, self- cat or flea contact with or without an inoculation
limiting illness (Lindeboom 2015; Ray et al. lesion, (2) purified protein derivative or serological
1999). The disease begins as a red-brown papule testing negative for other infectious causes of
or a pustule at the site of inoculation which lymphadenopathy and PCR assay positive for
develops 3–30 days following a scratch or a bite Bartonella DNA, (3) enzyme-linked immunosor-
(Stevens et al. 2014; Chiu et al. 2001; Munson bent assay positive for B. henselae or indirect
et al. 2008). This is followed 2–3 weeks later by immunofluorescence assay (IFA) serological test
the development of regional lymphadenopathy result of greater than 1:64 for B. henselae (IFA is
(Stevens et al. 2014; Chiu et al. 2001; Carithers the most reliable serological test with a sensitivity
1985). Head and neck lymphadenopathy accounts of 88% and a specificity of 97% for IgG and IgM
for one of the most common disease presenta- antibodies), and (4) tissue biopsy showing granu-
tions, with the submandibular and preauricular lomatous inflammation compatible with CSD or a
lymph nodes being the most frequently affected Warthin-Starry silver stain positive for CSD
(Chiu et al. 2001; Lindeboom 2015; Ridder et al. (Munson et al. 2008). While culture of
2002; Carithers 1985; Ridder et al. 2005). The B. henselae is possible, it is difficult to achieve
lymphadenopathy generally resolves in 1–6 due to the extremely fastidious nature of these
months, although in some cases it may persist organisms (Dean and Eisenbeis 2004; dos Santos
for longer (Stevens et al. 2014; Dean and et al. 2007).
Histologically, the classic CSD lymphadenitis is Leprosy

characterized by lymphoid hyperplasia in the early
stages, eventually progressing to reticular or stellate Etiology and Pathophysiology
necrotizing granulomatous lesions with multi-
nucleated giant cells (Barr and Qiu 2005; Munson Leprosy (Hansen’s disease) is a chronic, slowly
et al. 2008). In the final stages, numerous stellate progressive, nonfatal, infectious disease caused
micro-abscesses form and may suppurate to form by acid-fast bacillus Mycobacterium leprae – an
larger abscesses (Munson et al. 2008). Both granu- intracytoplasmic parasite with an affinity for
loma and abscesses may be found in the same spec- keratinocytes, macrophages, histiocytes, and
imen (Chiu et al. 2001). Bartonella may be Schwann cells (White and Franco-Paredes 2015;
identified using Warthin-Starry silver stain as gram- Taheri et al. 2012; Dave and Bedi 2013). While
negative, argyrophilic, non-acid-fast, pleomorphic the disease affects humans, it can also be found or
bacilli within macrophages and necrotic foci and reproduced in armadillos, monkeys, and mice,
along proliferating blood vessels (Chiu et al. 2001; and armadillo-to-man disease transmission has
Barr and Qiu 2005). Differential diagnosis includes been reported (Bratschi et al. 2015; Ramos-e-
lymphogranuloma venereum, tularemia, mycobac- Silva and Rebello 2001). The organism is highly
terium tuberculosis, brucellosis, fungal infection, infective, but has low pathogenicity and low vir-
Kikuchi necrotizing lymphadenitis, Kawasaki dis- ulence with a long incubation period ranging from
ease, and malignancy (Barr and Qiu 2005). 2 to 20 years (White and Franco-Paredes 2015;
Ramos-e-Silva and Rebello 2001). The mycobac-
terium causes chronic granulomatous inflamma-
Patient Management tion affecting mainly the skin (Fig. 3) and
peripheral nerves, although internal organs and
In most cases, CSD is a benign, self-limiting dis- oral mucosa may also be affected (Taheri et al.
ease and treatment with antibiotics is not neces-
sarily required (Lindeboom 2015). Antimicrobial
therapy may however be considered in individuals
with painful or suppurating lymph nodes or in
those who are systemically ill (Chiu et al. 2001;
Lindeboom 2015). Azithromycin is the
recommended antibiotic at a dose of 10 mg/kg
(up to 500 mg) on day 1, followed by 5 mg/kg
(up to 250 mg) for four additional days (Stevens
et al. 2014). Erythromycin (500 mg four times
daily) or doxycycline (100 mg twice daily) for
2 weeks to 2 months is recommended for the
treatment of bacillary angiomatosis (Stevens
et al. 2014). Prolonged therapy may be necessary
in individuals experiencing relapses, and
HIV-infected patients may require lifelong treat-
ment (Stevens et al. 2014). Surgery in the form of
drainage or needle aspiration is not typically
recommended, although it may be helpful in
selected cases such as in individuals presenting
with a painful lymph node abscess (Lindeboom
2015). Whether such intervention significantly
Fig. 3 Granulomatous lesions of leprosy on the face
influences the natural disease progression, has (Image courtesy of Associate Professor Ajay Parihar, Gov-
not been established (Lindeboom 2015). ernment College of Dentistry, Madhya Pradesh, India)
2012; Dave and Bedi 2013; de Abreu et al. 2007; globally was 8.9%, indicating continued transmis-
Motta et al. 2008). Nerve damage leads to muscle sion of the infection in the community (World
weakness and anesthesia, a combination often Health Organization 2015).
culminating in limb misuse and injury, elevating Infection with M. leprae depends on the infec-
leprosy to the leading infectious cause of disabil- tivity of contagious cases and on the level of cell-
ity (Dave and Bedi 2013). mediated immune response expressed by that indi-
Leprosy is associated with poverty, and living in vidual toward the organism (Dave and Bedi 2013;
close contact with an infected individual is a sig- Ramos-e-Silva and Rebello 2001). The level of
nificant risk factor for disease transmission, cell-mediated immune response thus governs the
although the exact transmission pathways of clinical presentation and dictates disease classifica-
M. leprae have not been elucidated (White and tion (Ridley–Jopling classification) into tubercu-
Franco-Paredes 2015; Bratschi et al. 2015). Skin- loid (TT), borderline tuberculoid (BT), borderline
to-skin contact, aerosols/droplets, and shedding of (BB), borderline lepromatous (BL), and leproma-
bacteria into the environment and subsequent tous leprosy (LL) (Dave and Bedi 2013). At one
infection through dust or small wounds all remain end of the spectrum, the tuberculoid form is asso-
plausible (Bratschi et al. 2015). In the environment, ciated with high levels of cell-mediated immunity,
the bacilli may remain viable for up to 9 days or few lesions, and undetectable mycobacteria, while
even longer (Costa et al. 2003). The nose, oral at the other, lepromatous leprosy is associated with
cavity, and skin have been tentatively identified as absent cell-mediated immunity, multiple lesions,
entry and exit points of the organism (Taheri et al. and detectable mycobacteria (Dave and Bedi
2012; Bratschi et al. 2015). While “curable,” the 2013). The borderline leprosy types lie in between.
disease remains a significant global public health To simplify multidrug therapy, particularly in areas
concern due to its permanently mutilating nature in where access to laboratory facilities is limited, the
the absence of early detection and treatment WHO classifies leprosy into (1) paucibacillary lep-
(Bratschi et al. 2015). The resultant deformities rosy (PB) characterized by the presence of one to
may drastically compromise cosmesis, leading to five skin lesions with definite sensory loss or any
major psychological and social problems (Martins one nerve trunk affected by leprosy and (2) multi-
et al. 2007; Pereira et al. 2013). bacillary leprosy (MB) characterized by the pres-
Since the introduction of multidrug therapy ence of six or more skin lesions with definite
based leprosy programs in the mid-1980s, a con- sensory loss, or two or more nerve trunks affected
siderable reduction in the prevalence of the disease by leprosy, or the presence of five skin patches and
has been observed (World Health Organization one nerve trunk (Dave and Bedi 2013).
2015). Despite this achievement however, the
WHO still identifies 22 counties as having a high
leprosy burden, including Angola, Bangladesh, Clinical-Pathologic Features
Brazil, Comoros, Côte d’Ivoire, Democratic
Republic of the Congo, Egypt, Ethiopia, Federated The main clinical features of leprosy are skin
States of Micronesia, India, Indonesia, Kiribati, lesions with loss of sensitivity, peripheral nerve
Madagascar, Mozambique, Myanmar, Nepal, involvement (sensory and motor), and muscle
Nigeria, Philippines, South Sudan, Sri Lanka, weakness (Ramos-e-Silva and Rebello 2001;
Sudan, and United Republic of Tanzania (World Pereira et al. 2013). Skin lesions are usually bilat-
Health Organization 2015). Of those, India and eral and symmetric, and may present as erythem-
Brazil are most severely impacted. In 2015, India atous (Fig. 4) or hypopigmented macules,
reported 127,326 new leprosy cases, while Brazil papules, and nodules (Fig. 5) (Ramos-e-Silva
reported 26,395 new cases, accounting for 60% and Rebello 2001). Reduced sensation is a feature
and 13% of the global new leprosy cases, respec- (Mustafa 2015). Depending on disease severity,
tively (World Health Organization 2015). In that the papules and plaques may or may not be well
same year, the proportion of new cases in children defined (Ramos-e-Silva and Rebello 2001). The
Fig. 4 Skin lesion of leprosy appearing as an erythema-

tous patch (Image courtesy of Associate Professor Ajay
Parihar, Government College of Dentistry, Madhya
Pradesh, India)
Fig. 6 Erythematous patch above the eye (Image courtesy
of Associate Professor Ajay Parihar, Government College
of Dentistry, Madhya Pradesh, India)
Fig. 5 Leprosy on skin appearing as a hypopigmented

lesion (Image courtesy of Dr Tim Hodgson, Oral Medicine
Unit, Eastman Dental Institute, UCL, London, UK)
most commonly affected sites are the face (Fig. 6),

legs, and buttocks although other cutaneous areas
are also involved (Figs. 7 and 8) (Ramos-e-Silva Fig. 7 Raised erythematous nodule of leprosy on arm
and Rebello 2001). Skin lesions may at times be (Image courtesy of Associate Professor Ajay Parihar, Gov-
mistaken for allergic reactions (Fig. 6), midline ernment College of Dentistry, Madhya Pradesh, India)
granuloma, fungal infections, vitiligo, other
mycobacterial infections, mucocutaneous leish- inflammatory reactions (Pereira et al. 2013;
maniasis, syphilis, or diabetes (White and Scollard and Skinsnes 1999). Involvement of the
Franco-Paredes 2015). The eyes may be affected nasal mucosa may lead to complaints of a stuffy
either due to the presence of M. leprae in the eye nose, epistaxis, and hyposmia, while destruction of
itself or by the involvement of the associated the maxillary alveolar process leads to the loosen-
cranial nerves (Taheri et al. 2012; Ramos-e-Silva ing or loss of the incisors (Dave and Bedi 2013;
and Rebello 2001). Scollard and Skinsnes 1999; Marta et al. 2014).
Destructive lesions of the facial bones are char- The pathogenesis of the anterior maxillary lesions
acteristic of leprosy and constitute the so-called remains unclear and may be multifactorial
facies leprosa – a triad of anterior nasal spine (Scollard and Skinsnes 1999). Neurotrophic alter-
atrophy, atrophy and recession of the alveolar pro- ations, reactive bone changes, and chronic inflam-
cess of the anterior maxilla, and endonasal mation in the adjacent soft tissue may be
Fig. 9 Palatal nodules produced by leprosy (Image cour-

tesy of Professor Mariana Villarroel Dorrego, Caracas,
Venezuela)
Fig. 8 Lepromatous lesions involving the soles of feet

(Image courtesy of Associate Professor Ajay Parihar, Gov-
ernment College of Dentistry, Madhya Pradesh, India)
contributory (Scollard and Skinsnes 1999). The

possible role of reduced temperature in the region
and preference of M. leprae for cooler sites is often
quoted (Dave and Bedi 2013; Motta et al. 2008;
Costa et al. 2003; Scollard and Skinsnes 1999).
Given that the growth of M. leprae can also be Fig. 10 Leprosy involving lower lip (Image courtesy of
observed at sites of core body temperature such as Dr Tim Hodgson, Oral Medicine Unit, Eastman Dental
in the liver, the pathogenesis of the anterior maxil- Institute, UCL, London, UK)
lary lesions remains uncertain (Scollard and
Skinsnes 1999). gingiva, the soft and hard palate (Fig. 9), the
Oral involvement has been reported in up to uvula, and the tonsils/glossopharyngeal arches,
60% of leprosy cases, predominantly in the lepro- although other sites such as the lips (Figs. 10 and
matous type, and is directly proportional to the 11), tongue, and the buccal mucosa may also be
duration of the disease (Taheri et al. 2012; Costa involved (Costa et al. 2003; Mustafa 2015;
et al. 2003; Mustafa 2015). It may be the result of Scollard and Skinsnes 1999; Reichart et al. 1976).
hematogenous or lymphatic dissemination or direct The lesions may bleed easily and be hyper- or
extension of the nasal lesions (Motta et al. 2008; hyposensitive (Reichart et al. 1976). High oral
Mustafa 2015). Intraoral manifestations are char- carriage of C. albicans, C. krusei, and C. glabrata
acterized as nodular, soft, or hard, mostly sessile has been reported in these individuals (Reichart
lesions (Costa et al. 2003; Reichart et al. 1976). The et al. 2007). Poor generalized dental status is also
nodules tend to ulcerate leading to necrosis and not uncommon (Pereira et al. 2013; Reichart et al.
fibrosis in the later stages (Costa et al. 2003; 1976; Souza et al. 2009). This may in part be
Reichart et al. 1976). Commonly affected sites are related to poor oral hygiene secondary to physical
the incisive papilla and the anterior maxillary disability, depression, and general lack of interest
in oneself (Reichart et al. 1976). The oral manifes-

tations of leprosy are considered to be nonspecific,
and differential diagnosis may include systemic
lupus erythematosus, sarcoidosis, cutaneous leish-
maniasis, syphilis, systemic mycosis, traumatic
lesions, and malignancy (Martins et al. 2007;
Mustafa 2015; Marta et al. 2014).
Cranial nerve involvement, especially of the
trigeminal and facial nerves, may have dental
implications (Dave and Bedi 2013). Involvement
of the trigeminal nerve may lead to anesthesia of the
orofacial tissues, and patients may, for example, be
Fig. 11 Asymptomatic nodular cutaneous and labial unable to give an accurate account of their symp-
lesions of lepromatous leprosy (Image courtesy of Profes- toms such as pain (Fig. 12) (Scollard and Skinsnes
sor Mariana Villarroel Dorrego, Caracas, Venezuela) 1999). Facial nerve palsies may have implications
Fig. 12 Leprosy. Axial T1-weighted (a) and post- foramen rotundum (arrow in c) and marked thickening and
gadolinium T1-fat saturated MR images in a 51-year-old increased enhancement of the trigeminal ganglion (arrow
woman presenting with pain and dysesthesia in the distri- in d) within Meckel’s cave. The imaging appearances are
bution of the maxillary division of the right trigeminal nonspecific and were thought most likely due to perineural
nerve (V2). Subtle thickening (arrow in a) and increased spread of malignancy (although there was no history of
enhancement (arrow in b) of the infraorbital nerve imme- mucosal or cutaneous malignancy). Biopsy of the
diately below the infraorbital foramen. Coronal post- infraorbital nerve revealed leprosy (Images courtesy of
gadolinium T1 fat saturated MR images (c) and (d) show Dr Rudolf Boeddinghaus, Perth Radiological Clinic,
thickening and enhancement of the main trunk of V2 in Perth WA, Australia)
for mastication, speech, and cosmesis, potentially

leading to profound social sequelae (Dave and Bedi
2013; Scollard and Skinsnes 1999).
On occasion, leprosy may be complicated by
two types of reactions: type 1 (reversal reaction)
and type 2 (erythema nodosum leprosum)
(White and Franco-Paredes 2015; Ramos-e-Silva
and Rebello 2001). While these reactions are usu-
ally seen in patients undergoing treatment, they may
also be observed in untreated individuals (Ramos-e-
Silva and Rebello 2001). Type 1 reactions occur
mainly in borderline leprosy and represent exces-
sive activation of the cell-mediated immune
response to M. leprae. The reaction is characterized
by inflammation and pain in pre-existing skin
lesions (which may ulcerate) and increased neuritis
manifesting as tenderness and nerve injury (White
and Franco-Paredes 2015). Type 2 reactions occur
in borderline and tuberculoid leprosy and are char-
acterized by inflammatory infiltrates of neutrophils
accompanied by vasculitis and/or panniculitis.
Affected individuals may develop new painful sub-
cutaneous nodules, which may be accompanied by
constitutional symptoms such as fever and malaise
as well as inflammation of nerves, lymph nodes,
eyes, and extremities (White and Franco-Paredes Fig. 13 Lepromatous leprosy stained with haematoxylin
and eosin (100 magnification) (Image courtesy of Pro-
2015). Oral mucosa may also be affected by these
fessor Mariana Villarroel Dorrego, Caracas, Venezuela)
reactions (Costa et al. 2003; Reichart et al. 1976;
Souza et al. 2009).
Biopsy specimens of leprosy reveal different
histopathologic patterns, depending on disease
Diagnosis severity. In the lepromatous pattern, well-formed
granulomas are not seen, instead an infiltrate is
Bacilloscopy, histopathology, and the lepromin noted containing macrophages with many bacilli
test (intradermal reaction that is usually negative and lipid drops in their cytoplasm (Fig. 13)
in lepromatous leprosy and positive in the tuber- (Ramos-e-Silva and Rebello 2001). Cutaneous
culoid type) are the diagnostic tests usually nerves show lamination of the perineurium
employed in the diagnosis of leprosy (Ramos-e- (Ramos-e-Silva and Rebello 2001). In contrast,
Silva and Rebello 2001; Mustafa 2015). Fluores- in the tuberculoid pattern, well-formed granulo-
cent leprosy antibody in which the antigen is mas are evident composed of epithelioid cells,
M. leprae, immunohistochemical markers for lymphocytes, and Langhans giant cells (Ramos-
the detection of the bacillus, DNA amplification e-Silva and Rebello 2001; Scollard and Skinsnes
methodologies, and phenolic glycolipid-I (PGL-I) 1999). Cutaneous nerves are edematous (Ramos-
marker of M. leprae represent some of the e-Silva and Rebello 2001). The borderline pattern
more modern diagnostic approaches, although exhibits features of both the lepromatous and
currently these tests are not routinely utilized in tuberculoid patterns to varying degrees (Ramos-
the diagnosis of leprosy (Ramos-e-Silva and e-Silva and Rebello 2001). M. leprae can be dem-
Rebello 2001). onstrated by the use of Ziehl-Neelsen or Fite-
Fig. 14 Histopathological staining of Mycobacterium leprae (arrows) with Ziehl Neelsen (a) and Fite-Faraco (b) stains
(40 magnification) (Images courtesy of Professor Mariana Villarroel Dorrego, Caracas, Venezuela)
Faraco stains (Fig. 14), and the presence of globi recommended regimen is a single dose of rifampi-
(globoid masses containing bacilli) is diagnostic cin 600 mg, ofloxacin 400 mg, and minocycline
(Ramos-e-Silva and Rebello 2001). Globi are 100 mg (World Health Organization 2017a).
found in 100% and 75% of patients with leproma- While drug resistance is known to occur in leprosy,
tous and borderline-type lesions, respectively, but fortunately to date, only a low level of ofloxacin
are rare in patients with tuberculoid lesions resistance has been found, and rifampicin resistance
(Ramos-e-Silva and Rebello 2001). is considered rare (Saunderson 2016). Corticoste-
roids are the primary recommended treatment for
leprosy reactions (White and Franco-Paredes 2015).
Patient Management Research into a vaccine for the prevention of
leprosy is ongoing (Kar and Gupta 2015).
Early detection and appropriate treatment of leprosy Following elimination of the infection, preven-
is important in the prevention of permanent disabil- tion of further tissue injury (due to permanent
ity and deformity. The WHO-recommended multi- nerve damage) and treatment of any resultant
drug therapy forms the mainstay of current deformities and disabilities should be paramount
treatment (World Health Organization 2017a). The to facilitate the physical and psychological reha-
standard adult regimen for MB leprosy is rifampicin bilitation and promote the social reintegration of
600 mg once a month, dapsone 100 mg daily, the affected individual (Kar and Gupta 2015).
clofazimine 300 mg once a month, and 50 mg Appropriate adaption of oral hygiene procedures
daily for 12 months (World Health Organization should be employed according to the individual’s
2017a). The regimen for PB leprosy is rifampicin level of disability. Routine dental care can proceed
600 mg once a month and dapsone 100 mg daily for as per normal using standard infection control as
6 months (World Health Organization 2017a). In the disease has low rates of infectivity (Dave and
the case of single skin lesion PB leprosy, the Bedi 2013).
Syphilis syphilis occur in men who have sex with men

and are strongly associated with HIV infection
Etiology and Pathophysiology (Leuci et al. 2013; Ficarra and Carlos 2009). As
is the case with other STIs, syphilis in children
Syphilis is a systemic, sexually transmitted infec- after the neonatal period raises strong suspicion of
tious disease caused by Treponema pallidum with sexual abuse (Vinals-Iglesias and Chimenos-
estimated global prevalence of 0.5% in both men Kustner 2009; Rogstad et al. 2016).
and women in the 15–49-year age group (Newman
et al. 2015). Treponema pallidum is an anaerobic
filamentous spirochete capable of invading any Clinical-Pathologic Features
organ of the human body, its only known vector
(Kelner et al. 2014; Leuci et al. 2013). Its limited Acquired Syphilis
metabolic capabilities preclude its survival outside Acquired syphilis is classified into four disease
of the human body, and, as is the case with other stages (primary, secondary, latent, and tertiary)
virulent treponemes, it cannot be cultured in vitro based on the level of disease activity and infectiv-
(Ficarra and Carlos 2009). The infection is spread ity. It is often referred to as “the great imitator”
by sexual (acquired syphilis) or vertical (congenital owing to its frequently nonspecific presentation
syphilis) transmission and less frequently through and remarkable ability to mimic other diseases
indirect routes, such as blood transfusions (Kelner (Compilato et al. 2009). Patients may therefore
et al. 2014). The primary mode of transmission seek help across the entire spectrum of healthcare
however is sexual contact with about 50% likeli- providers.
hood of developing syphilis after exposure to an
infected individual (Ficarra and Carlos 2009). In Primary Syphilis
contrast to other sexually transmitted infections The primary stage of the infection is characterized
(STIs), T. pallidum is also easily transmissible by by a chancre. This highly infectious lesion occurs
kissing and other close contact with an infectious at the site of inoculation, following an incubation
lesion (Ficarra and Carlos 2009). The organism’s period of about 3–90 days, depending on the size
innate ability to evade the immune system enables of the inoculum (Ficarra and Carlos 2009). It
its survival in the human host for decades (Ficarra typically presents as a large, painless ulcer with
and Carlos 2009). an indurated margin (Kelner et al. 2014; Ficarra
While historically syphilis was considered a and Carlos 2009). In about 80% of cases, painless
common disease for centuries, the introduction regional lymphadenopathy develops about 7–10
of penicillin in the 1940s and preventive cam- days after the appearance of the chancre (Leuci
paigns lead to its significant decline, for decades, et al. 2013). Given that transmission of
affording it a rare disease status (Ficarra and Car- T. pallidum occurs mostly through sexual inter-
los 2009). A dramatic resurgence however has course, the sites of inoculations are usually geni-
recently been observed worldwide due to the tal, although in about 10–20% of cases the
growing sex industry, sexual promiscuity, primary lesion is intrarectal, perianal, or oral
decreasing use of barrier protection, and errone- (Ficarra and Carlos 2009; Czerninski et al.
ous beliefs surrounding STIs (Leuci et al. 2013). 2011). Oral chancres (Figs. 15 and 16) are
This resurgence is a major global public health observed in about 4–12% of patients, with the
concern, given the significant morbidity of syph- commonly affected sites being the tongue, gin-
ilis and its ability to facilitate the acquisition and giva, palate, and lips (upper in men and lower in
transmission of HIV (Leuci et al. 2013; Stamm women) (Kelner et al. 2014; Ficarra and Carlos
2015; Compilato et al. 2009). HIV infection can in 2009). Chancres on the hands of healthcare
turn influence the clinical features and treatment workers have also been described (Ficarra and
outcomes of syphilis (Leuci et al. 2013). In the Carlos 2009). Even in the absence of treatment,
present day, more than half of new cases of chancres heal within 8 weeks without scarring
(30–40%) of patients being diagnosed in the pri-

mary stage of the disease (Kelner et al. 2014).
Secondary Syphilis
Secondary syphilis occurs about 2–12 weeks after
the first contact with T. pallidum and is the result of
the hematogenous dissemination and the organism
(Leuci et al. 2013; Ficarra and Carlos 2009). This
stage of the disease is characterized by a variety of
signs and symptoms, such as localized/generalized
skin rash (Fig. 17), alopecia, malaise, sore throat,
headache, weight loss, low-grade fever, generalized
lymphadenopathy, and muscle aches (Stamm 2015;
Little 2005). Renal, ophthalmologic, hepatic, bone
and joint diseases as well as CNS involvement can
also be seen owing to the hematogenous dissemi-
nation of the organism (Ficarra and Carlos 2009).
CNS involvement can manifest as meningitis or
Fig. 15 Primary syphilitic ulcer on the commissure cranial nerve involvement. Deafness and optic neu-
(Image courtesy of Dr Tim Hodgson, Oral Medicine Unit, ritis may develop as sequelae (Ficarra and Carlos
Eastman Dental Institute, UCL, London, UK) 2009). Not all patients will have a history of a
preceding chancre, as it is not uncommon for the
chancres to go unnoticed (Kelner et al. 2014).
Maculopapular lesions on the palms and soles
are the most common presenting sign and occur in
about 60–80% of patients with secondary syphilis
(Fig. 18) (Little 2005). The rash does not gener-
ally cause pruritus (Ficarra and Carlos 2009).
Although the maculopapular rash is the most
pathognomonic sign of secondary syphilis,
eczema, psoriasis, drug eruption, pityriasis, and
lichen planus can be mimicked by syphilis
(Fig. 19) (Ficarra and Carlos 2009). Oral mucosal
lesions are present in at least 30% of individuals
with secondary syphilis and may be painful
(Kelner et al. 2014; Compilato et al. 2009). The
most common oral manifestation are the so-called
mucous patches (Figs. 20 and 21), although
Fig. 16 Syphilitic ulcer on lower lip (Image courtesy of
macroglossia, painful fissuring, and papular
Professor Mariana Villarroel Dorrego, Caracas, Venezuela)
lesions of the anterior two-thirds of the dorsum
of the tongue and lesions resembling oral hairy
(Kelner et al. 2014; Ficarra and Carlos 2009). In leukoplakia, erythema multiforme, oral lichen
untreated individuals, systemic dissemination of planus, and pemphigus vulgaris have also been
T. pallidum occurs during the primary stage of reported (Little 2005; de Paulo et al. 2015; Barrett
infection (Little 2005). Unfortunately, due to et al. 2004). Mucous patches are highly infectious
their self-limiting nature, the lesions of primary and can present as slightly elevated plaques which
syphilis often go unnoticed or become may be ulcerated or as multiple lesions that may
non-concerning, accounting for the low rate coalesce to give rise to serpiginous lesions,
Fig. 17 Secondary syphilis skin rash involving the torso Parihar, Government College of Dentistry, Madhya
(a), the palms (b), and the soles of the feet (c) in the same Pradesh, India)
patient (Image courtesy of Associate Professor Ajay
described as snail track ulcers (Fig. 22) (Little not exhibit any signs of the primary or secondary
2005; de Paulo et al. 2015). The lips, tongue, disease, which during this phase, can only be
buccal, and labial mucosa may be affected (Little detected by serologic testing (Leuci et al. 2013).
2005). Often nonspecific pharyngitis, tonsillitis, Latent syphilis acquired within the preceding year
and laryngitis are associated (Ficarra and Carlos is referred to as early latent syphilis; all other cases
2009). Condyloma lata are mainly found in the of latent syphilis are referred to as late latent
genital or anal area in 5–22% of patients; less syphilis or syphilis of unknown duration
frequently, they may develop in other sites such (Workowski et al. 2015). During this time, sexual
as the axilla, inframammary folds, face, oral com- transmission is unlikely; however, the individual
missures, and toe webs (Ficarra and Carlos 2009). may develop tertiary syphilis, with neurological,
Secondary syphilis lasts for weeks or months with cardiovascular, and other life-threatening compli-
relapses occurring in about one-quarter of cations (Leuci et al. 2013).
untreated patients (Stamm 2015).
Tertiary Syphilis
Latent Syphilis This is the final stage of the disease, which
After the secondary stage, the syphilis, if develops in one third of untreated patients and
untreated, becomes latent. The individual does can manifest as early as 1 year after the initial
Fig. 18 Maculopapular rash on the palm of the hand in a patient with secondary syphilis (a) and presentation on the
middle digit (b) (Images courtesy of Professor Mariana Villarroel Dorrego, Caracas, Venezuela)
Fig. 20 Mucous patch on lower lip in a patient with

secondary syphilis (Image courtesy of Professor Mariana
Fig. 19 Localized skin eruptions with rash involving the
Villarroel Dorrego, Caracas, Venezuela)
scalp in a patient with secondary syphilis (Image courtesy
of Professor Mariana Villarroel Dorrego, Caracas,
Venezuela)
Fig. 21 Syphilis mucous patch at corner of mouth (Image

courtesy of Associate Professor Ajay Parihar, Government
College of Dentistry, Madhya Pradesh, India)
Fig. 23 Dehisced gumma with syphilitic leukoplakia and

glossitis (Image courtesy of Dr Tim Hodgson, Oral Medi-
cine Unit, Eastman Dental Institute, UCL, London, UK)
2005). CNS manifestations are tabes dorsalis, gen-

eral paralysis, or insanity (Little 2005). Iritis and
choroidoretinitis may also be found (Little 2005).
In the oral cavity, the gummas may affect the
palate, tongue, tonsils, or lips (Fig. 23) (Ficarra
and Carlos 2009; Vinals-Iglesias and Chimenos-
Kustner 2009). Bone involvement can lead to
significant destruction manifesting as palatal per-
foration, oronasal fistula formation, and extensive
Fig. 22 Syphilitic mucous patch on lower lip (Image osteonecrosis characterized by pain, swelling,
courtesy of Dr Tim Hodgson, Oral Medicine Unit, Eastman suppuration, and sequestration (Fig. 24) (Leuci
Dental Institute, UCL, London, UK)
et al. 2013). Atrophic glossitis, syphilitic leuko-
plakia (Fig. 23), and parotid gland involvement
infection or decades later (Ficarra and Carlos 2009; have also been described (Vinals-Iglesias and
Little 2005). Transmission of the infection at this Chimenos-Kustner 2009; Czerninski et al. 2011).
stage is unlikely, probably due to the low numbers Although associations between tertiary syphilis
of T. pallidum (Stamm 2015). The classic lesion and oral squamous cell carcinoma have been pro-
defining this stage is a nodular, ulcerative lesion posed, the risk of malignancy is probably better
referred to as the gumma, which can involve the explained by the carcinogenic agents, such as
skin, mucous membranes, CNS, liver, spleen, arsenicals, formerly used to treat syphilis, or by
bones, and other organs (Ficarra and Carlos the exposure to the well-recognized causative fac-
2009). Cardiovascular complications include tors such as tobacco and alcohol use (Compilato
aortitis, aneurysm, and aortic regurgitation (Little et al. 2009).
Fig. 24 Syphilis in advanced stage periodontal disease in Warthin Starry stain demonstrating Treponema pallidum
an HIV-positive patient. Periapical radiograph (a), hema- organisms (c) (Images courtesy of Professor Tiago Novaes
toxylin and eosin stain of periodontal tissues (b), and Pinheiro, Amazonas State University, Brazil)
Congenital Syphilis lymphadenopathy, maculopapular rash, hepatosple-

Syphilis can be transmitted in utero or during deliv- nomegaly and glomerulonephritis, and, in the later
ery if the newborn comes in contact with a conta- stages, gummas, bone alterations - which include
gious genital lesion (Ficarra and Carlos 2009). among others saddle nose, high arched palate and
Miscarriage may occur in 25–50% of women frontal bossing of the skull; interstitial keratitis,
acutely infected with syphilis during pregnancy, hydrocephalus, mental retardation, and neurosyp-
and up to 70% of women with active syphilis will hilis. (Ficarra and Carlos 2009; Little 2005). Oral
give birth to a syphilis-infected infant (Little 2005). manifestations of congenital syphilis are character-
The risk of vertical transmission ranges from 70 to ized by dental abnormalities in the form of
100% for primary syphilis to 40% for early latent peg-shaped permanent central incisors with
disease to 10% for late latent disease (Ficarra and notching of the incisal edge (Hutchinson’s inci-
Carlos 2009). Infected infants may have symptoms sors), defective molars with multiple supernumer-
at birth, and most will show symptoms within ary cusps (Mulberry molars), atrophic glossitis, and
2 weeks to 3 months following birth (Little 2005). perioral rhagades (skin fissures) (Little 2005).
The majority of untreated children who survive the
first 6–12 months of life will progress to latent and Diagnosis
tertiary syphilis (Little 2005).
The clinical manifestations of neonatal syphilis Diagnosis of syphilis generally relies on clinical and
are once again variable and include generalized serological findings, without the need for a biopsy
(Ficarra and Carlos 2009). A biopsy of oral mucosal

lesions may however be undertaken if a diagnosis of
syphilis is not suspected or to rule out other pathosis.
The key microscopic findings of syphilitic oral
lesions are plasma cell infiltration and proliferative
endarteritis – at least in primary and secondary
disease (Ficarra and Carlos 2009). Plasma cell,
along with lymphocytes and macrophages can be
found in a perivascular distribution or as a band-like
infiltrate in the lamina propria (Fig. 25) (Ficarra and
Carlos 2009). Plasma cell infiltration however in
oral mucosal lesions is common and is not consid-
ered diagnostic for syphilis (Czerninski et al. 2011;
Barrett et al. 2004). Oral tertiary syphilis character-
istically shows the absence of the epithelial lamina
with peripheral pseudoepitheliomatous hyperplasia.
The lamina propria contains foci of granulomatous
inflammation with large central zone of acellular Fig. 25 Hematoxylin and eosin stain demonstrating Trep-
necrosis and well-circumscribed collections of his- onema pallidum organisms (Image courtesy of Professor
tiocytes and multinucleated giant cells (Ficarra and Mariana Villarroel Dorrego, Caracas, Venezuela)
Carlos 2009). T. pallidum may be demonstrated in
some lesions by the use of a silver stain (Fig. 26) or
immunohistochemistry, although the results should
be interpreted with caution, in view of the other
species of spirochetes which inhabit the oral cavity
that may also be labeled (Kelner et al. 2014; Barrett
et al. 2004).
Serological tests are central in the diagnosis
and follow-up of syphilis and consist of two
types, namely, nontreponemal tests, which are
used for screening, and treponemal tests,
which are used for diagnostic confirmation as
they differentiate true-positive from false-positive
results obtained with the standard nontreponemal
antibody tests (Ficarra and Carlos 2009; Little
2005). The nontreponemal tests become positive
1–4 weeks after the appearance of the primary Fig. 26 Warthin Starry (silver) stain demonstrating Trep-
lesion and 6 weeks after exposure (Leuci et al. onema pallidum organisms (arrow) (Image courtesy of
2013). The most commonly used is the Venereal
Disease Research Laboratory (VDRL) test and
its simplified version, the rapid plasma reagin cases of latent and tertiary syphilis (Little
(RPR) test (Little 2005). The tests are quantitative 2005). The most common qualitative treponemal
and are the method of choice for follow-up tests are based on fluorescent treponemal
testing during and after treatment (Leuci et al. antibody absorption (FTA-ABS) and agglutina-
2013). These tests detect IgM and IgG antibodies tion (TP-PA) (Leuci et al. 2013). Once a
to lipoidal material released from damaged patient tests positive to any one of these tests,
host cells and to lipoidal-like antigens of they remain positive for life, even after treatment
T. pallidum and may become negative in some (Little 2005).
Patient Management Appropriate management of sex partners is equally

important, and relevant guidelines have been
Since its introduction, penicillin remains the published (Workowski et al. 2015). Unless oral
cornerstone of treatment and control of syphilis lesions are present, necessary dental care may be
(Workowski et al. 2015). Unlike most other bac- provided and normal treatment can recommence
teria, T. pallidum has remained highly sensitive once oral lesions have been successfully treated
to penicillin due to its lack of horizontal gene (Little 2005). It is important to bear in mind how-
transfer mechanisms (Little 2005). High-level ever that in about 10% of affected individuals, the
macrolide resistance however has emerged presence of syphilis is accompanied by additional
(Stamm 2015). The Centers for Disease Control STIs, which may or may not have been diagnosed
and Prevention-recommended treatment regimen (Little 2005).
for primary, secondary and early latent syphilis As is the case with all STIs, disease prevention
involves the administration of benzathine peni- is centered around education, reduction of the
cillin G 2.4 million units IM in a single dose or in number of sexual partners, and consistent use of
the case of infants and children 50,000 units/kg appropriate barrier protection, particularly in gen-
IM, up to the adult dose of 2.4 million units in a ital and oral sex with men (Little 2005).
single dose (Workowski et al. 2015). Clinical and
serologic evaluation should be performed at
6 and 12 months after treatment (Workowski Gonorrhea
et al. 2015). The recommendation for late latent
syphilis or latent syphilis of unknown duration is Etiology and Pathophysiology
the administration of benzathine penicillin G 7.2
million units total, as three doses of 2.4 million Gonorrhea is a sexually transmitted infection
units IM each at 1-week intervals or in the case of (STI) caused by the obligate pathogen Neisseria
infants and children 50,000 units/kg IM, up to the gonorrhoeae. It constitutes one of the most com-
adult dose of 2.4 million units, as three doses at mon STIs with estimated global prevalence of
1-week intervals (total 150,000 units/kg up to the 0.6% and 0.8% in men and women, respectively
adult total dose of 7.2 million units) (Workowski (15–49-year age group) (Newman et al. 2015). In
et al. 2015). Quantitative nontreponemal serologic 2015 in the United States alone, a total of 395,216
tests should be repeated at 6, 12, and 24 months cases of gonorrhea were reported (Centers for
(Workowski et al. 2015). In the case of tertiary Disease Control and Prevention 2015). The global
syphilis with normal CSF examination, the nature of this infection and the organism’s remark-
recommended regimen involves the administration able ability to develop and retain antimicrobial
of benzathine penicillin G 7.2 million units total, as resistance render gonorrhea a significant public
three doses of 2.4 million units IM each at 1-week health concern (Unemo and Shafer 2014).
intervals (Workowski et al. 2015). Neurosyphilis The oral mucosa and skin are generally resis-
requires the administration of crystalline penicillin tant to gonococcal infection as the organism can-
G 18–24 million units per day, as 3–4 million units not invade intact squamous epithelium, although
IVevery 4 h or continuous infusion, for 10–14 days infection can occur when the integrity of this
(Workowski et al. 2015). barrier is compromised (Giunta and Fiumara
Data to support the use of second-line drugs for 1986). Neisseria gonorrhoeae does however
syphilis treatment are limited, although individuals invade transitional and pseudostratified epithelia
with early syphilis who are allergic to penicillin of the urinary and respiratory tracts (Siegel 1996).
may be treated with doxycycline, tetracycline, or The gonococcus is transmitted primarily by sex-
ceftriaxone (Leuci et al. 2013; Ficarra and Carlos ual activity and needs a moist environment to
2009; Stamm 2015). All individuals who have remain viable (Giunta and Fiumara 1986). During
primary and secondary syphilis should also be vaginal intercourse, the highest risk of transmis-
tested for HIV infection (Workowski et al. 2015). sion occurs from an infected male to female
partner with an approximate transmission rate of ulceration, may result from autoinoculation in
50–70% per sexual contact (Little 2006). Infected adults (Little 2006). Newborns of women with
women transmit the infection less efficiently at an gonorrhea are at risk of ophthalmia neonatorum,
approximate rate of 20% (Little 2006). While the which can lead to blindness (Unemo and Shafer
infection can occur at any age, the peak incidence 2014). In about 0.5–1% of affected individuals,
occurs in the 15–30-year age group, particularly disseminated gonococcal infection may occur
in singles and individuals of lower socioeconomic (Unemo and Shafer 2014; Siegel 1996), particu-
status (Giunta and Fiumara 1986; Little 2006). larly in those men and women who lack the mem-
Gonorrhea in preadolescent children of more brane attack complex complement proteins (Little
than 1 year of age is almost always an indicator 2006). Gonococcemia may result in febrile ill-
of sexual abuse (Little 2006). ness, endocarditis, pericarditis, meningitis, migra-
tory polyarthritis, cutaneous rash, and ulceration
of the soft palate and oropharynx (Siegel 1996).
Clinical-Pathologic Features Two major syndromes, the dermatitis-tenosynovi-
tis syndrome and septic arthritis syndrome, have
Neisseria gonorrhoeae causes urethritis in men and been associated with disseminated disease (Siegel
cervicitis in women (Unemo and Shafer 2014). The 1996). The temporomandibular joint may be
majority of men (>90%) present with mildly symp- involved in gonococcal arthritis (Siegel 1996).
tomatic urogenital infections and may report dys- Anal sex may result in proctitis, which may be
uria and a clear to mucopurulent discharge (Fig. 27) painful with purulent discharge and bleeding may
(Unemo and Shafer 2014; Little 2006). In contrast, occur (Giunta and Fiumara 1986; Little 2006).
up to 80% of women remain asymptomatic, About 20–25% of individuals with gonorrhea
although pain when urinating, purulent vaginal will have oral or oropharyngeal involvement,
discharge, and vaginal bleeding may be present resulting from orogenital contact with an infected
(Little 2006). Asymptomatic infections are prob- sexual partner (Siegel 1996; Williams 2002). Pha-
lematic as they hinder disease control (Giunta and ryngeal gonorrhea is usually associated with con-
Fiumara 1986). Infections in children are also often comitant urethritis, cervicitis, or proctitis (Giunta
asymptomatic (Little 2006). and Fiumara 1986). It typically presents as a
Severe reproductive complications resulting in sore throat with diffuse oropharyngeal erythema
infertility can occur in both men and women with (Fig. 28) (Giunta and Fiumara 1986; Siegel 1996;
gonorrhea (Unemo and Shafer 2014). Acute puru- Little 2006). Small pustules may be noted
lent conjunctivitis, which can lead to corneal (Siegel 1996; Little 2006). Submandibular or
Fig. 27 Gonorrhea of the penis demonstrating yellow

discharge (Image courtesy of Associate Professor Ajay Fig. 28 Gonorrhea involving the soft palate and orophar-
Parihar, Government College of Dentistry, Madhya ynx (Image courtesy of Dr Tim Hodgson, Oral Medicine
Pradesh, India) Unit, Eastman Dental Institute, UCL, London, UK)
cervical lymphadenopathy may or may not be resistance to most antimicrobials used in treatment
present (Siegel 1996). Gonococcal tonsillitis is (Unemo and Shafer 2014). Recommendations for
reported less frequently than pharyngitis the use of dual antimicrobial therapy are founded in
(Balmelli and Gunthard 2003). Tonsils appear the concern that the infection may become
enlarged and exhibit some degree of inflammation untreatable using antimicrobial monotherapy
(Balmelli and Gunthard 2003). Fever is infrequent (Unemo and Shafer 2014). To this effect, the Cen-
(Balmelli and Gunthard 2003). ters for Disease Control and Prevention 2015 Sex-
Oral gonorrhea is uncommon and may or may ually Transmitted Diseases Treatment Guidelines
not be symptomatic (Giunta and Fiumara 1986; recommend the combined use of ceftriaxone
Little 2006; Bruce and Rogers 3rd 2004). It is 250 mg intramuscularly and azithromycin 1 g
nonspecific in presentation, ranging from slight orally, both in a single dose, for uncomplicated
erythema to severe ulceration with a white pseudo- gonococcal infections of the cervix, urethra, rec-
membrane (Fig. 28) (Giunta and Fiumara 1986; tum, and pharynx (Workowski et al. 2015). All
Little 2006). Lesions resembling acute necrotizing infected individuals should be counseled about
ulcerative gingivitis/periodontitis, aphthous sto- the importance of referring anyone with whom
matitis, oral lichen planus, erythema multiforme, they have had sexual contact in the preceding
and primary herpetic gingivostomatitis have been 60 days for screening (Little 2006). It is also impor-
described (Siegel 1996; Williams 2002). Signs of tant to remember that individuals diagnosed with
oral involvement generally appear within 1 week gonorrhea will often have more than one STI and
of contact with an infected individual, and should therefore be appropriately investigated. For
submandibular lymphadenopathy is frequently example, a coinfected with Chlamydia trachomatis
noted (Siegel 1996; Little 2006). Oral burning, is present in about 50% of cases (Little 2006).
xerostomia, hypersalivation, dysgeusia, and hali- Individuals with gonorrhea pose little threat of
tosis may be reported (Siegel 1996). In severe disease transmission in the dental setting, although
cases, affected individuals may be febrile (Siegel the high risk of additional STIs mandates caution
1996). Secondary infection of the parotid glands is (Little 2006). All clinicians should be aware of
rare but has been encountered in patients with oral their local legislative STI reporting requirements.
or oropharyngeal gonorrhea (Siegel 1996).
Actinomycosis
Diagnosis
Etiology and Pathophysiology
Diagnosis of gonorrhea is based on the detection
of N. gonorrhoeae or its genetic material in genital Actinomycosis is a rare, chronic, suppurative,
or extragenital specimens by microscopy, culture, granulomatous infection caused by non-spore-
or nucleic acid amplification tests (Unemo and forming, anaerobic, or microaerophilic bacterial
Shafer 2014). It is recommended that antimicro- species of the genus Actinomyces (Moghimi et al.
bial sensitivity testing be a part of the diagnostic 2013; Hansen et al. 2007). Consequently, the term
process as antimicrobial resistance remains an actinomycosis is a misnomer and stems from the
important consideration in the treatment of this historical misclassification of Actinomyces species
infection (Unemo and Shafer 2014; Little 2006). as fungi (Hansen et al. 2007). Actinomyces are
gram-positive pigment-producing bacilli that form
branching filaments and are considered normal
Patient Management human commensals found mainly in the orophar-
ynx, the gastrointestinal, and the female genital
Alarms have recently been raised that Neisseria tracts (Moghimi et al. 2013; Bonnefond et al.
gonorrhoeae is evolving into a “superbug” as 2016). Actinomycosis is therefore often classified
there is now a high prevalence of strains with anatomically, with cervicofacial actinomycosis
continued growth of the Actinomyces (Valour

et al. 2014; Haggerty and Tender 2012).
Data regarding the incidence of actinomycosis
is largely lacking and the infection is believed to be
generally under-reported, owing to its frequent
misdiagnosis (Bonnefond et al. 2016). In the
1960s, the incidence of actinomycosis in the Neth-
erlands and Germany was reported to be
1:100,000, while in the 1970s in Cleveland, USA,
it was reported as 1:300,000 (Bonnefond et al.
2016; Jin et al. 2000). In England between 2002
and 2003, 71 cases were noted, accounting for
0.0006% of hospital consultations (Bonnefond
et al. 2016).
The relative rarity of the infection is explained
by the low virulence and invasion potential of
Actinomyces (Lo Muzio et al. 2014). Although
the role of immunosuppression is not entirely
clear, actinomycosis is not generally considered
an opportunistic infection (Bonnefond et al. 2016;
Fig. 29 Cervicofacial actinomycosis (Image courtesy of
Miller and Haddad 1998). It is also not a commu-
nicable disease (Miller and Haddad 1998). As
long as the organisms stay on the mucosal surface,
being the most common (Fig. 29), accounting for they are nonpathogenic (Kaplan et al. 2009). The
over half of reported cases (Moghimi et al. 2013; infection usually develops after trauma which
Crossman and Herold 2009; Curi et al. 2000; Val- compromises the integrity of the oral mucosa,
our et al. 2014). While more than 30 species of allowing the organisms to invade the tissues
Actinomyces have been described, A. israelii and where they can incite a destructive chronic inflam-
A. gerencseriae are responsible for about 70% of matory reaction (Lo Muzio et al. 2014; Kaplan
cervicofacial infections (Valour et al. 2014). Other et al. 2009). Fractures, surgery, tooth extraction,
species which may also be involved include endodontic treatment, sinusitis, periodontal dis-
A. meyeri, A. odontolyticus, A. naeslundii, ease, periapical infection, or more trivial events
A. georgiae, A. pyogenes, or A. viscosus (Valour such as tooth eruption, administration of a local
et al. 2014; Miller and Haddad 1998). Actinomy- anesthetic, or dental pulp exposure may all pre-
cotic infections are almost always polymicrobial in cipitate actinomycosis (Crossman and Herold
nature, and the Actinomyces are often isolated with 2009; Lo Muzio et al. 2014).
other normal commensals, such as Aggregatibacter
actinomycetemcomitans, Eikenella corrodens,
Capnocytophaga, Fusobacteria, Bacteroides, Clinical-Pathologic Features
Staphylococci, Streptococci, or Enterobac-
teriaceae, depending on the site of infection The so-called lumpy jaw, which is associated with
(Moghimi et al. 2013; Hansen et al. 2007; Valour odontogenic infection, is the most common clini-
et al. 2014; Haggerty and Tender 2012). It has cal manifestation of cervicofacial actinomycosis
therefore been hypothesized that these other organ- (Fig. 30), accounting for about 60% of all reported
isms may contribute to the initiation and develop- cases (Valour et al. 2014). The mandible is
ment of infection by inhibiting host defenses or by involved more commonly than the maxilla at a
reducing the oxygen tension in infected tissue, thus ratio of 4:1 (Miller and Haddad 1998). Recently,
creating favorable conditions to support the Actinomyces species have also been linked to
bisphosphonate-related osteonecrosis of jaw- pathogenesis of these conditions is yet to be elu-

bones, osteoradionecrosis, and osteomyelitis cidated (Hansen et al. 2007; Curi et al. 2000;
(Fig. 31), although their exact role (if any) in the Valour et al. 2014; Kaplan et al. 2009). Aside
from jaw involvement, cervicofacial actinomyco-
sis has also been described involving numerous
other sites including the larynx, hypopharynx,
lacrimal and salivary glands, oral mucosa,
sinuses, middle ear, thyroid gland, and the scalp
(Valour et al. 2014; Kaplan et al. 2009). The
infection is usually seen in young healthy adults,
being more common in men than women with no
racial predilection (Curi et al. 2000; Miller and
Haddad 1998). Pediatric cases have been reported
(Robinson et al. 2005).
Cervicofacial actinomycosis (Fig. 29) typically
presents as a hard swelling in the mandible and/or
Fig. 30 Actinomycosis presenting as “lumpy jaw” (Image
the neck with an associated abscess in the adjoin-
courtesy of Professor Mariana Villarroel Dorrego, Caracas,
Venezuela) ing soft tissues, pain, and a mild fever (Lo Muzio
Fig. 31 A case of chronic sclerosing osteomyelitis asso- (GMS) demonstrating Actinomyces species (d) (Images
ciated with a root remnant. Clinical presentation (a), gross courtesy of Professor Tiago Novaes Pinheiro, Amazonas
specimen (b), haematoxylin and eosin stain of sample (c), State University, Brazil)
and with Grocott-Gomori’s methenamine silver stain
et al. 2014). The infection may be acute, of rapid 2016; Smith et al. 2011). Actinomyces are also
onset with multiple sinus tracts draining pus very difficult to culture due to the anaerobic nature
containing sulfur granules; chronic, slowly proof the organism and the prolonged incubation
gressing with little suppuration; or present clini- period of up to 14 days, with the success rates of
cally with features that fall anywhere along this cultural procedures being reported to be only
disease continuum (Miller and Haddad 1998; Lo about 10 to 20% (Moghimi et al. 2013; Valour
Muzio et al. 2014). The most common presenta- et al. 2014; Lo Muzio et al. 2014). Thus, while a
tion however is of a chronic soft tissue swelling definite diagnosis of actinomycosis requires iden-
(Moghimi et al. 2013; Miller and Haddad 1998). tification of the involved bacteria as Actinomyces
Disease progression eventually leads to the devel- species, this is not always achieved (Crossman
opment of a hard, board-like lesion that has a and Herold 2009; Ricucci and Siqueira Jr 2008).
lumpy appearance, hence the term “lumpy jaw” The recent emergence of molecular techniques
disease (Miller and Haddad 1998). The infection such as 16S rRNA sequencing and polymerase
spreads through the tissues ignoring fascial plane chain reaction has improved organism identifica-
and, rarely, may lead to CNS involvements (Miller tion (Valour et al. 2014; Lo Muzio et al. 2014;
and Haddad 1998). Lymphatic and hematogenous Smith et al. 2011).
spread is rare, although dissemination to distant Gram staining of pus and histopathology
organs including the brain, lungs, and digestive (Figs. 32 and 33) are often relied upon in
tract can occur (Valour et al. 2014; Haggerty and
Tender 2012; Smith et al. 2011). The overlying
skin can be dark red to purple and associated with
nonhealing sinus tracts (Miller and Haddad 1998).
Regional lymphadenopathy is rare (Valour et al.
2014). Bone involvement is observed in approxi-
mately 10% of cases (Valour et al. 2014). Paresthe-
sia of the inferior alveolar nerve has been described
(Miller and Haddad 1998). Pain is usually minimal,
and trismus secondary to masticatory muscle
involvement is not a common occurrence but may
occur (Valour et al. 2014; Miller and Haddad
1998). The most common systemic manifestations
are low-grade fever, chills, lethargy, and some
weight loss, although individuals are not usually Fig. 32 Actinomycosis (Hematoxylin and eosin stain)
febrile and often do not feel ill (Miller and Haddad
1998). Differential diagnosis includes other bacte-
rial infections, tuberculosis, nocardiosis, cyst, and
malignancy (Moghimi et al. 2013; Valour et al.
2014; Miller and Haddad 1998).
Diagnosis
Diagnosis of cervicofacial actinomycosis can be

very difficult as the infection commonly mimics
other pathosis (Moghimi et al. 2013). Adding to
the problem is Actinomycetes’ high sensitivity to
many common antimicrobials, the empiric use of Fig. 33 Actinomycosis in cyst (Hematoxylin and eosin
which leads to negative cultures (Bonnefond et al. stain)
Fig. 34 Actinomycotic granuloma in submandibular lymph node at low magnification (a) and at higher magnification
(b) (Hematoxylin and eosin stain)
the diagnosis of actinomycosis (Curi et al. 2000; protection against the host’s immune system
Valour et al. 2014). Lesions of actinomycosis (Haggerty and Tender 2012; Ricucci and Siqueira
may exhibit granulomatous inflammation (lympho- Jr 2008). While the sulfur granules are easy to
cytes, plasma cells, epithelioid cells, histiocytes, identify histologically, they can be lost during tis-
and occasional giant cells) with central suppurative sue handling and processing (Lo Muzio et al.
necrosis (Miller and Haddad 1998; Lo Muzio et al. 2014).
2014). The outermost periphery of the lesion can be Various imaging modalities may be used in the
fibrotic and relatively avascular, permitting the evaluation of the disease process including com-
spread of the organisms, inhibiting the penetration puted tomography, magnetic resonance imaging,
of antibiotics (hence the need for surgical excision sialography, radionuclide imaging, and ultraso-
of the lesion and long-term antibiotic use), and nography (Miller and Haddad 1998). While none
keeping the lesion anaerobic (Fig. 34) (Miller and of the techniques can be used in the identification
Haddad 1998; Haggerty and Tender 2012). The of the actinomycotic infection per se, imaging
so-called sulfur granules (there is no evidence that may be useful in identifying bone involvement
the granules contain sulfur) are considered charac- and determining disease extent, evaluating treat-
teristic of Actinomyces infection; however, they are ment effectiveness, and differentiating between
not pathognomonic as they may also be produced inflammation and neoplasia and in patient
by other groups of bacteria, such as Staphylococ- follow-up (Miller and Haddad 1998).
cus, Actinobacillus lignieresii, Sporotrichum, and
Phialophora (Miller and Haddad 1998; Haggerty
and Tender 2012; Ricucci and Siqueira Jr 2008). Patient Management
The granules are round to oval, hard, gritty, and
whitish gray, yellow, brownish green, or green in Surgical removal of the infected tissue and appro-
color; are found only in vivo; and represent colo- priate antibiotic therapy form the cornerstone of
nies of bacteria (Miller and Haddad 1998). Masses treatment (Crossman and Herold 2009). At pre-
of filaments extend in a radiating, spoke-like fash- sent, no evidence-based guidelines exist to pre-
ion, all mineralized and cemented by host calcium cisely guide the antibiotic selection or the
phosphate (Miller and Haddad 1998). At the end of treatment duration (Moghimi et al. 2013; Valour
the filaments are club-shaped extensions or rosettes et al. 2014). The current treatment recommenda-
formed by the adherence of neutrophils (Miller and tions are simply based on small case series and
Haddad 1998). The granules offer bacteria in vivo studies (Bonnefond et al. 2016).
Fortunately, antimicrobial resistance is not con-

sidered a problem in the treatment of actinomyco-
sis (Valour et al. 2014). Given that Actinomyces
species are very susceptible to beta-lactams, pen-
icillin G or amoxicillin are considered the drugs of
choice (Moghimi et al. 2013; Bonnefond et al.
2016; Valour et al. 2014; Haggerty and Tender
2012). Initial treatment with intravenous amoxi-
cillin (up to 200 mg/kg/day) or penicillin G (up to
24 MIU/day) is preferred in the more severe cases
as the penetration of beta-lactams in bone is low
(Moghimi et al. 2013; Valour et al. 2014). This is Fig. 35 Draining of soft tissue abscess of actinomycosis
then followed by oral treatment (Haggerty and (Image courtesy of Professor Mariana Villarroel Dorrego,
Tender 2012). As Actinomyces do not produce Caracas, Venezuela)
beta-lactamases, there is no need to combine
amoxicillin with beta-lactam inhibitors such as good, mortality rates up to 28% have been
clavulanic acid, unless co-pathogens such as reported, depending on site of infection and diag-
Enterobacteriaceae are also involved in the dis- nostic delays (Bonnefond et al. 2016).
ease (Valour et al. 2014). Third-generation ceph-
alosporins are less frequently used, and some
species are resistant to ceftriaxone (Valour et al. Nocardiosis
2014). Broad-spectrum antibiotics such as
piperacillin-tazobactam, imipenem, and Etiology and Pathophysiology
meropenem are effective but not recommended
in view of the possible emergence of resistant Nocardiosis is a suppurative bacterial infection
flora (Valour et al. 2014). Macrolides (such as caused by Nocardiae and is associated with
erythromycin, clarithromycin, or azithromycin) acute and granulomatous inflammation that may
and clindamycin may be used (Valour et al. affect the lungs, the skin, and the central nervous
2014). A number of conventionally used antibi- system with the potential to disseminate via the
otics are ineffective against Actinomyces species hematogenous route to various distant sites
including oxacillin, cloxacillin, cephalexin, met- (Welsh et al. 2013; Corazza et al. 2002). In some
ronidazole, and aminoglycosides (Valour et al. instances the infection may also be subclinical and
2014; Lo Muzio et al. 2014). Ciprofloxacin and resolve spontaneously (Welsh et al. 2013).
moxifloxacin are also generally considered to be Nocardiae are aerobic actinomycetes, partially
inactive (Valour et al. 2014). Doxycycline is con- acid-fast, slow-growing, beaded, branching gram-
sidered to have poor activity (Valour et al. 2014). positive rods (Schlaberg et al. 2008). These sap-
The use of traditionally prolonged course of up to rophytic organisms are ubiquitous in the environ-
6–12 months of treatment in all cases of actino- ment and are found in soil, decomposing
mycosis is questionable (Bonnefond et al. 2016; vegetation and other organic matter, dust, air, as
Valour et al. 2014). As the infection can recur after well as fresh and salt water (Welsh et al. 2013;
a period of quiescence, long-term follow-up is Schlaberg et al. 2008; Kumar et al. 2005).
recommended (Crossman and Herold 2009). Nocardia asteroides may be found as part of the
Surgical management involves drainage of normal oral cavity and upper respiratory tract flora
abscesses (Fig. 35), removal of necrotic bone, (Corazza et al. 2002). Over 50 different species of
dental extraction(s) and/or marsupialization of Nocardia are known, with many being linked to
chronic sinus tracts (Moghimi et al. 2013; Valour human disease (Schlaberg et al. 2008). Of partic-
et al. 2014). While the prognosis of early-treated ular importance in human infections is the
patients with actinomycosis is generally very N. asteroides complex comprising a group of
related bacteria with different patterns of antimi- (Welsh et al. 2013; Wilson 2012; Uhde et al.
crobial susceptibility (Welsh et al. 2013; Wilson 2010). Nocardiosis is therefore generally consid-
2012). Based on this susceptibility, the complex is ered an opportunistic infection (Wilson 2012).
further subdivided into: Nocardia abscessus, While in the late 1970s it was estimated that
Nocardia brevicatena-paucivorans complex, about 500–1000 nocardiosis cases occurred annu-
Nocardia nova complex (Nocardia nova, ally in the United States, more recently, it has been
Nocardia veterana, Nocardia africana, and proposed that this number has likely risen in line
Nocardia kruczakiae), Nocardia transvalensis with advances in oncology, rheumatology, and
complex (Nocardia transvalensis sensu stricto, transplant medicine (Schlaberg et al. 2008; Uhde
Nocardia wallacei, and Nocardia blacklockiae), et al. 2010).
Nocardia farcinica, and Nocardia asteroides
(Welsh et al. 2013). Nocardia cyriacigeorgica
has also recently emerged as a clinically relevant Clinical-Pathologic Features
pathogen (Schlaberg et al. 2008). Nocardia
brasiliensis is responsible for about 80% of pri- Pulmonary nocardiosis is the most common initial
mary cutaneous nocardiosis, including those of presentation of the infection, which follows inha-
the face and the neck (Outhred et al. 2011). lation of the offending organism (Fig. 36) (Wilson
Nocardiosis is usually, although not exclu- 2012; Outhred et al. 2011). Of those infections,
sively, seen in the debilitated and immunocom- about half will spread via the hematogenous route
promised individuals such as those with to distant sites such as the central nervous system,
autoimmune disease, malignancy, diabetes, or skin, and various other organs (Welsh et al. 2013;
AIDS, in solid organ or hematopoietic stem cell Kumar et al. 2005; Wilson 2012; Outhred et al.
transplant recipients, and in individuals receiving 2011). Nosocomial transmission of the infection
chemo- or immunosuppressive therapy (Fig. 36) has also been reported (Schlaberg et al. 2008).
Fig. 36 Pulmonary nocardiosis in a patient receiving che- marked and confluent in the inferior aspect of the left upper
motherapy for metastatic disease. Posterior-anterior CXR lobe. In addition, there is cavitation (black dotted arrows)
(a) and axial pulmonary window CT (b) at the level of the which is seen in 30% of cases, with a fluid level seen on the
aorto-pulmonary window (white dotted line). Multiple erect CXR and also on the supine CT scan. There is a small
small nodules represent pulmonary metastases (red left pleural effusion (black arrows) (Images courtesy of Dr
arrows). Bilateral parenchymal opacification representing Stephen Melsom, Perth Radiological Clinic and Fiona
infective consolidation is present in both lungs and is more Stanley Hospital, Perth WA, Australia)
Pulmonary nocardiosis is characterized by pro- N. brasiliensis to cause cervicofacial infections

ductive or a nonproductive cough with or without has not been elucidated (Outhred et al. 2011). In
hemoptysis with fever, dyspnea, chest pain, chills, the head and neck region, sites other than the skin
diaphoresis, malaise, fatigue, and weight loss may also be affected by Nocardia infections
(Welsh et al. 2013). Chest radiographs may portray including the eyes, the major salivary glands,
focal or multifocal disease with nodular and/or and the thyroid gland (Welsh et al. 2013; Outhred
consolidation infiltrate and cavitary lesions (Wil- et al. 2011; Chawla et al. 2010).
son 2012). Pleural effusions may or may not be
present (Wilson 2012). Central nervous system is
Diagnosis
the most frequent site of infection spread (Wilson
2012). Affected individuals may have one or more
Diagnosis of nocardiosis is based on histopathol-
brain abscesses and present with headache, confu-
ogy and culture (Welsh et al. 2013). Histopathol-
sion, altered consciousness, nausea, vomiting, and
ogy of lesional tissue reveals abscesses with
seizures (Welsh et al. 2013; Outhred et al. 2011).
neutrophils in the center and lymphocytes, histio-
Disseminated pulmonary diseases are the
cytes, giant cells, and foam cells in the periphery
most common cause of cutaneous infections
(Welsh et al. 2013). Sulfur granules may be pre-
(Corazza et al. 2002; Schlaberg et al. 2008;
sent (Welsh et al. 2013). Gram stain of abscess
Chawla et al. 2010). Primary cutaneous
material reveals the presence of gram-positive
nocardiosis (which usually affects immunocom-
branching, beaded, filamentous organisms
petent hosts) can also occur, accounting for about
(Outhred et al. 2011). Imaging modalities such
5% of all cases, and may present as a mycetoma,
as ultrasound, CT, or MRI may be useful in defin-
a lymphocutaneous infection, superficial celluli-
ing disease extent (Outhred et al. 2011). Antimi-
tis, or as a localized abscess (Welsh et al. 2013;
crobial sensitivity testing is considered important
Chawla et al. 2010). Cutaneous nocardiosis pre-
to guide the most appropriate antibiotic selection
dominantly affects the extremities, but any site
(Outhred et al. 2011). Molecular methods are
may be affected, including the head and neck
increasingly used for accurate species identifica-
(Outhred et al. 2011). The lymphocutaneous var-
tion, of which 16S rRNA gene sequence analysis
iant may present either in the sporotrichoid or,
is considered the “gold standard” (Outhred et al.
the less frequently encountered, cervicofacial
2011). Depending on the site of involvement,
form, which is most commonly seen in children
differential diagnosis includes actinomycosis,
(Corazza et al. 2002). Cervicofacial nocardiosis
tuberculosis, Staphylococcus aureus or Strepto-
is considered rare and most likely occurs as a
cocci soft tissue infections, sporotrichosis, coccid-
result of tissue trauma and subsequent contami-
ioidomycosis, atypical mycobacteriosis, and
nation of the wound with the organism from an
neoplasias (Welsh et al. 2013; Wilson 2012).
environmental source (Kumar et al. 2005;
Outhred et al. 2011). In children, cervicofacial
nocardiosis manifests initially as an erythema- Patient Management
tous pustule, usually in the nasolabial region
eventually progressing to involve the draining Treatment recommendations of Nocardia infec-
lymph nodes (Outhred et al. 2011). Fever may tions are limited by the lack of prospective con-
be present (Outhred et al. 2011). Adults may trolled trials (Wilson 2012). In adults, the current
present with pustules, ulcers, or suppurating treatment of choice is trimethoprim-sulfamethox-
abscesses surrounded by cellulitis, with associ- azole (TMP-SMX) in two to four divided doses of
ated regional lymphadenopathy (Outhred et al. 5–10 mg/kg per day of the trimethoprim compo-
2011). Mycetomas of the face have been reported nent (or 25–50 mg/kg per day of sulfamethoxa-
(Outhred et al. 2011). With extension of the zole) (Wilson 2012; Outhred et al. 2011). Data
infection, underlying bone may become involved concerning optimal daily dosage in children is
(Outhred et al. 2011). The predilection of generally lacking (Outhred et al. 2011). While
TMP-SMX is active against most Nocardia spe- relapses can occur (Outhred et al. 2011). While
cies, sulfonamide-resistant Nocardia infections the mortality rates associated with Nocardia
are a well-recognized problem, and ultimately infections may be as high as 50%, infections
treatment decisions should be based on appropri- localized to the face and neck, which are recog-
ate antimicrobial susceptibility testing (Stevens nized early and treated appropriately, are gener-
et al. 2014; Welsh et al. 2013; Wilson 2012; ally considered curable (Schlaberg et al. 2008;
Uhde et al. 2010). Alternative antimicrobial Kumar et al. 2005; Outhred et al. 2011).
agents with activity against Nocardia include
amikacin, imipenem, meropenem, ceftriaxone,
cefotaxime, minocycline, moxifloxacin, Necrotizing Fasciitis
levofloxacin, linezolid, tigecycline, and
amoxicillin-clavulanic acid (Wilson 2012). For Etiology and Pathophysiology
most forms of nocardiosis, initial combination
drug therapy (imipenem and cefotaxime, Necrotizing fasciitis (NF) is a rapidly progressive,
amikacin and TMP-SMX, imipenem and life-threatening infection, characterized by necrosis
TMP-SMX, amikacin and cefotaxime, or of the subcutaneous fat and fascia, although the
amikacin and imipenem) is recommended process may involve any adjacent tissue, including
(Welsh et al. 2013; Wilson 2012). The addition muscle (Yadav et al. 2012; Wolf et al. 2010;
of a third agent may be necessary in individuals McMahon et al. 2003). For this reason some advo-
with severe nocardiosis (Wilson 2012; Outhred cate the use of the more clinically appropriate term
et al. 2011). Combination therapy should continue necrotizing soft tissue infections (McMahon et al.
until clinical improvement is observed, and anti- 2003). The disease is considered rare with reported
microbial susceptibility testing results are known incidence rates ranging from 0.4 to 1 cases per
(Wilson 2012). Single-drug therapy may be ade- 100,000 inhabitants, depending on the population
quate thereafter (Wilson 2012). The new potent studied (Paz Maya et al. 2014). Necrotizing fasci-
antimicrobials such as oxazolidinones and itis can be seen across the entire age spectrum,
benzothiazinones constitute a therapeutic reserve exhibits no definitive gender nor racial predilec-
in cases of drug resistance (Welsh et al. 2013). tions, and can affect individuals with or without
Clinical improvement is generally expected any comorbidities (Yadav et al. 2012). The extrem-
within 3–10 days of starting the appropriate anti- ities, trunk, and perineum are the most commonly
microbial treatment (Outhred et al. 2011). affected sites, with the head and neck region
Although the optimal length of antimicrobial ther- accounting for about 3–10% of all cases (Yadav
apy is not known, long-term treatment is consid- et al. 2012; Christensen et al. 2015). The lower
ered important, in view of the possibility of incidence in the head and neck can be explained
disease recurrence (Corazza et al. 2002; Outhred by the higher vascularity of that region (Yadav et al.
et al. 2011). In the case of cutaneous nocardiosis, 2012). Cervicofacial NF is usually caused by an
it is recommended that treatment be continued for odontogenic infection, although infections second-
1–3 months while in the case of pulmonary or ary to trauma, acute tonsillitis, peritonsillar abscess,
disseminated disease for 6–12 months (Welsh osteoradionecrosis, or salivary gland infections
et al. 2013; Wilson 2012). Treatment duration of may also be responsible (Yadav et al. 2012; Wolf
at least 12 months is recommended for infection et al. 2010; Suarez et al. 2014). Depending on how
of the CNS or in immunocompromised individ- promptly the diagnosis is made and appropriate
uals (Welsh et al. 2013; Wilson 2012). When treatment started, the mortality rates can range
necrotic nodules or subcutaneous abscesses are from 7 to 80% (Yadav et al. 2012; Christensen
present, surgical debridement is also et al. 2015; Suarez et al. 2014). Females, individ-
recommended (Stevens et al. 2014; Outhred uals older than 60 years, and those with renal
et al. 2011). Follow-up of at least 6–12 months impairment tend to exhibit a worse prognosis
posttreatment completion is advised as late (McMahon et al. 2003).
Two main types of NF are recognized. Type I reason why in many cases the disease is diagnosed
(70–80% of cases) is the result of a mixed infection in the later stages, accounting for the high mortality
of anaerobes plus facultative species, such as Strep- rates (Yadav et al. 2012). Clinical judgment is the
tococci or Enterobacteriaceae, while type II most important diagnostic element (Stevens et al.
(20–30% of cases) represents a group A strepto- 2014). Magnetic resonance imaging is the
coccal infection (Yadav et al. 2012; Paz Maya et al. recommended imaging modality due to its superior
2014). The pathogenesis of NF is not completely soft tissue defining properties (Paz Maya et al.
understood. Dominance of viable Streptococci over 2014). Computed tomography however may be
the level of specific antibodies has been proposed, more readily available and may show edema
as has the possibility of an aberrant antigen- extending along the fascial planes, blurring of the
antibody reaction (Wolf et al. 2010). Large amounts fat layers, and the presence of gas in the soft tissues
of bacterial enzymes such as collagenase and hyal- (Stevens et al. 2014; Wolf et al. 2010; Christensen
uronidase and toxins enable the spread of the organ- et al. 2015). Exploratory surgery reveals swollen
isms along the superficial and deep fascial planes, fascia with a dull gray appearance and areas of
causing vascular occlusion, ischemia, and necrosis necrosis. Pus is not present (Stevens et al. 2014).
(Yadav et al. 2012; Christensen et al. 2015). Tissue planes separate easily (Stevens et al. 2014;
Christensen et al. 2015). A definitive microbiologi-
cal diagnosis is established by culture and Gram
Clinical-Pathologic Features stain of deep tissue samples or by positive blood
cultures (Stevens et al. 2014). Histologically, the
In the early stages, the skin of the affected site is presence of dense polymorphonuclear infiltrates
warm, tense, and tender with absence of clear within the dermal layers is characteristic of NF
demarcation from the normal skin (Yadav et al. (Christensen et al. 2015).
2012). Pain may be severe and disproportional to
the clinical findings, likely the result of neural
involvement (Stevens et al. 2014; Wolf et al. Patient Management
2010). With time, the skin becomes dusky and
small blisters appear, eventually leading to gan- Suspicion of NF warrants prompt admission to
grene (Yadav et al. 2012). Crepitus may be a the hospital for comprehensive assessment, anti-
feature indicating the presence of gas in the tissues biotic therapy, and supportive care. Surgical
and implies an anaerobic tissue environment intervention forms the mainstay of treatment
(McMahon et al. 2003). Damage of the superficial including aggressive surgical debridement with
nerves leads to localized sensory loss tissue removal until normal bleeding tissue is
(Christensen et al. 2015). Septicemia eventually encountered (Stevens et al. 2014; Christensen
results with systemic toxicity, with the majority of et al. 2015). Since necrotizing soft tissue infec-
patients developing sepsis within 48 h of symp- tions can result in the discharge of copious
tom onset (Wolf et al. 2010). The individual amounts of tissue fluid and a pronounced hemo-
appears clearly unwell with fever, chills, tachy- dynamic response, appropriate fluid replacement
cardia, malaise, and altered levels of conscious- is important (Stevens et al. 2014). Antibiotic
ness (Yadav et al. 2012). In the head and neck therapy is guided by wound and blood cultures
region, the spreading infection may compromise (McMahon et al. 2003; Christensen et al. 2015).
the airway (Yadav et al. 2012). Empiric antibiotic treatment should be broad
spectrum (e.g., vancomycin or linezolid plus
piperacillin-tazobactam or a carbapenem or plus
Diagnosis ceftriaxone and metronidazole), as the etiology
can be polymicrobial or monomicrobial (group A
Diagnosis of NF is mainly based on the clinical streptococci, community-acquired MRSA) (Ste-
presentation, which may be nonspecific, and is the vens et al. 2014). Penicillin plus clindamycin is
recommended for treatment of group A strepto- The exact cause of noma remains elusive
coccal NF (Stevens et al. 2014). Once the although tissue necrosis is believed to be primar-
specific microbial etiology has been deter- ily the result of a poly-bacterial infection occur-
mined through culture, antibiotic treatment can ring in an immunocompromised individual
be appropriately modified (Stevens et al. 2014). (Whiteson et al. 2014). Recent studies using
Adjunctive therapies in the form of hyperbaric genomic approaches indicate the presence of an
oxygen therapy and intravenous immuno- imbalance in the normal oral flora with a reduc-
globulin G have also been suggested (Stevens tion of bacterial diversity that may promote the
et al. 2014; Yadav et al. 2012; Wolf et al. overgrowth of opportunistic pathogens (Srour
2010; McMahon et al. 2003; Christensen et al. et al. 2017; Baratti-Mayer et al. 2013). Acute
2015). noma seems to be associated with a reduced
proportion of Fusobacterium, Capnocytophaga,
Neisseria, and Spirochaeta and an increased
Noma proportion of Prevotella in the oral cavity
(Baratti-Mayer et al. 2013). The anaerobic bac-
Etiology and Pathophysiology teria can release proteolytic enzymes that
degrade the extracellular matrix, produce toxic
Noma (cancrum oris) is an uncommon, necrotiz- metabolites, and release mediators that have the
ing, highly destructive disease which affects the capacity to compromise the host’s local immune
orofacial tissues (Feller et al. 2014). While noma competence and, in a susceptible individual,
is often described as a “gangrenous” disease, it lead to tissue destruction characteristic of noma
does not strictly fit this definition, as the necrotic (Feller et al. 2014). The role of bacteria in the
process does not follow the affected tissue’s pathogenesis of noma is evident from the fetid
blood supply, nor is it considered primarily an odor that characterizes the disease and its
ischemic condition (Feller et al. 2014; Srour et al. response to antibiotic treatment (Srour et al.
2017; Masipa et al. 2013). The disease is pre- 2017; Masipa et al. 2013).
dominantly seen in 2–7-year-old children of sub- Reported risk factors include poverty, severe
Saharan Africa and is generally viewed as a malnutrition (which may lead to immune
disease of extreme poverty and a humanitarian deficiency), a high number of previous pregnan-
concern (Srour et al. 2017; Whiteson et al. 2014). cies in the mother, low birthweight, absence
The United Nations Human Rights Council has of exclusive breastfeeding, young age, viral
labeled noma as “the most brutal face of poverty infections (e.g., measles, HIV, herpes viruses),
and malnutrition in children” representing “some parasitic infections (e.g., malaria), persistent
of the worst violations of the rights of the child” diarrhea/dehydration, poor sanitation, unsafe
(United Nations 2012). While noma is extremely drinking water, poor oral hygiene, limited access
rare in high-income countries, it may be seen in to appropriate healthcare facilities, delay in
patients with severe immunosuppression seeking treatment, lack of parental education,
(Baratti-Mayer et al. 2013). The exact global and proximity of livestock (Feller et al. 2014;
incidence of noma is unknown, although esti- Srour et al. 2017; Baratti-Mayer et al. 2013;
mates range from 30,000 to 140,000 (Feller Ashok et al. 2015; Enwonwu et al. 2006).
et al. 2014; Srour et al. 2017). The disease is While malnutrition appears to be the most impor-
associated with a mortality rate of 90%, which tant risk factor, the importance of other
can be reduced to 8–10% with appropriate treat- co-factors (not necessarily understood) is
ment (Ashok et al. 2015). Survivors however are underscored by the fact that most malnourished
generally left with significant facial disfigure- individuals do not develop the disease (Feller
ment and functional impairment (Ashok et al. et al. 2014; Masipa et al. 2013). Cases of noma
2015). Noma is not considered contagious nor have also been reported in individuals with
recurrent (Masipa et al. 2013). cyclic neutropenia, leukemia, Down’s syndrome,
Burkett’s disease, and herpetic stomatitis (Ashok

et al. 2015).
Most cases of noma are believed to originate in the

oral cavity, although reports of cases exist where
the disease did not appear to be preceded by
intraoral necrotizing lesions, presumably originat-
ing in the skin of the cheeks or the lips (Feller et al.
2014; Masipa et al. 2013).
Acute necrotizing ulcerative gingivitis Fig. 37 Acute necrotizing ulcerative gingivitis (Image
(Fig. 37), characterized by gingival pain, ulcera- courtesy of Associate Professor Alessandro Quaranta,
tion of the interdental papillae, and bleeding, is UWA Dental School, University of Western Australia,
believed to precede noma (Feller et al. 2014;
Srour et al. 2017; Whiteson et al. 2014). While
easily treated with appropriate oral hygiene reg-
imens and antibiotics, without treatment, the dis-
ease may progress to necrotizing periodontitis,
eventually spreading beyond the mucogingival
junction to affect the alveolar, buccal, labial,
lingual, and the palatal mucosa, when it is
referred to as necrotizing stomatitis (Feller et al.
2014; Srour et al. 2017). This progression may
take as little as 48 h (Feller et al. 2014). When the
necrotizing stomatitis progresses to involve full
thickness of the buccal/labial muscle layer and
Fig. 38 Necrotizing stomatitis (noma) (Image courtesy of
perforates the skin, it is referred to as noma
Dr Tim Hodgson, Oral Medicine Unit, Eastman Dental
(Fig. 38) (Feller et al. 2014). Remarkably, the Institute, UCL, London, UK. Used with permission from
infection overcomes structural barriers such as Buchanan et al. 2006)
muscle and bone (Whiteson et al. 2014;
Enwonwu et al. 2006). Halitosis, facial edema,
and a bluish discoloration of the skin precede the matter of days from secondary infection, septi-
perforation (Srour et al. 2017; Whiteson et al. cemia, severe malnutrition, dehydration, or hem-
2014). An unusual feature of the necrosis is its orrhage (Feller et al. 2014; Masipa et al. 2013;
apparent self-limiting character ending in a well- Ashok et al. 2015). If the individual survives and
demarcated defect (Srour et al. 2017). Once following elimination of the necrotic tissue,
demarcated, the blackened necrotic tissue starts granulation tissue forms, wound contracts, and
to slough and bone sequesters (Srour et al. 2017; epithelium starts to grow from the margins of the
Enwonwu et al. 2006). The mandible, maxilla, wound over the granulation tissue (Srour et al.
nose, and infraorbital tissue may be involved 2017). Depending on the defect, the healing
(Ashok et al. 2015; Enwonwu et al. 2006). Sys- process may take many months (Srour et al.
temic manifestations of noma include fever, 2017). Sadly, noma only serves to further debil-
tachycardia, lymphadenopathy, high respiratory itate the nutritional status of the already malnour-
rate, anorexia, general edema, ascites, and hema- ished child (Srour et al. 2017). Severe facial
tological abnormalities (Ashok et al. 2015; deformity, trismus, and oral incontinence result
Enwonwu et al. 2006). Death may occur in a in compromised cosmesis, feeding and speech
difficulties, social isolation, and psychological Prevention of noma is multifaceted and reliant
sequelae (Srour et al. 2017; Ashok et al. 2015; on elimination of malnutrition, provision of
Enwonwu et al. 2006). immunization programs against endemic diseases
such as measles, prevention and treatment of asso-
ciated diseases such as HIV and malaria,
Diagnosis instilment of proper oral hygiene practices, and
education and provision of access to appropriate
Diagnosis of noma is generally based on history medical care (Srour et al. 2017; Ashok et al.
and clinical examination. History of a recent ill- 2015). All in all, the prevention of noma is ulti-
ness combined with facial swelling and a foul- mately dependent on the elimination of human
smelling discharge from the oral cavity of a mal- indifference, conflict, and extreme poverty.
nourished child is strongly suggestive (Srour et al.
2017). The development of facial necrosis a few
days later solidifies the diagnosis (Srour et al. Diphtheria
2017). While the clinical presentation is charac-
teristic, differential diagnosis includes leprosy, Etiology and Pathophysiology
leishmaniasis, tuberculosis, squamous cell carci-
noma, clostridial or streptococcal gangrene, lethal Diphtheria is an acute, life-threatening, commu-
midline granuloma, cleft lip, yaws, and trauma nicable disease caused by exotoxin-producing
(Ashok et al. 2015). Corynebacterium (Hadfield et al. 2000). The
main causative agent is C. diphtheriae, a non-
motile, non-encapsulated gram-positive rod
Patient Management (Zakikhany and Efstratiou 2012). Four biotypes
of C. diphtheriae have been identified including
Treatment of noma involves the use of antibiotics gravis, mitis, intermedius, and belfanti, all of
(amoxicillin and metronidazole), correction of which are capable of producing the lethal diph-
dehydration and electrolyte imbalances, nutri- theria exotoxin, which inhibits protein synthesis
tional support, and treatment of associated dis- in mammalian cells (Zakikhany and Efstratiou
eases such as malaria and measles (Srour et al. 2012; Moore et al. 2015). The organism is trans-
2017; Ashok et al. 2015). The choice of antibi- mitted by direct contact, sneezing, or coughing, and
otics is empirical, and little is known about the while humans have traditionally been considered to
presence of multidrug-resistant microorganisms represent the only reservoir for infection and trans-
in the affected communities (Srour et al. 2017). mission, more recently C. pseudotuberculosis and
Appropriate wound care is important. Once the C. ulcerans have been described as emerging zoo-
patient is stable, the facial lesion should be irri- notic pathogens also capable of producing the
gated regularly and any slough, bony sequestra or lethal exotoxin and the disease (Zakikhany and
mobile teeth removed (Feller et al. 2014; Efstratiou 2012; Moore et al. 2015; Wagner et al.
Enwonwu et al. 2006). Daily chlorhexidine 2010). In the absence of treatment, diphtheria can
digluconate (0.12–0.20%) rinses are be fatal in up to 50% of those affected, and, even
recommended (Ashok et al. 2015; Enwonwu with treatment, the overall case fatality rate may be
et al. 2006). Once the disease has been controlled, as high as 10% (Centers for Disease Control and
and following a period of stability of 6–18 Prevention 2016a). Clinically, diphtheria is gener-
months, surgical and functional rehabilitation ally classified into respiratory and cutaneous,
can commence, although definitive surgical depending on the site of the disease. Classically
reconstruction may be delayed in children until (and most severely), diphtheria presents as a dis-
maturity (Feller et al. 2014; Ashok et al. 2015). ease of the respiratory tract, characterized by a
Screening for HIV infection is advised (Ashok swollen “bull neck” and a strongly adherent
et al. 2015). pseudomembrane obstructing the airway (Wagner
et al. 2010). The infection however may also predilection (Zakikhany and Efstratiou 2012;
involve other mucous membranes and may Wagner et al. 2010; Santos et al. 2015). While
undergo a number of serious complications infection with C. ulcerans was traditionally asso-
(Zakikhany and Efstratiou 2012; Santos et al. ciated with the consumption of raw milk or dairy
2015). Although the diphtheria exotoxin does not products or with close contact with cattle, more
have a specific target organ, the myocardium and recently, domestic cats and dogs have been pro-
peripheral nerves are predominantly affected (Had- posed as potential vectors (Wagner et al. 2010;
field et al. 2000). Farfour et al. 2013). Although at present there is
Despite diphtheria once representing the leading no direct evidence of person to person transmis-
cause of childhood death in the industrialized sion for C. ulcerans, this possibility has not been
nations, the introduction and implementation of ruled out (Moore et al. 2015; Wagner et al. 2010).
vaccination programs dramatically reduced the The efficacy of the diphtheria vaccine against
global disease burden, with 4530 cases reported C. ulcerans strains also remains unknown
in 2015 (Zakikhany and Efstratiou 2012; Wagner (Zakikhany and Efstratiou 2012).
et al. 2010; Farfour et al. 2013; World Health
Organization 2017b). To date, the diphtheria toxoid
vaccine represents one of the oldest and safest Clinical-Pathologic Features
vaccines available (Zakikhany and Efstratiou
2012; Santos et al. 2015). Nonetheless, diphtheria Clinically, diphtheria develops following an incu-
continues to pose a serious threat, given the right bation period of 2–4 days, with the affected indi-
conditions, as was illustrated by the Russian epi- vidual exhibiting malaise and low-grade fever
demic of the 1990s where, in the period of (Zakikhany and Efstratiou 2012). Mucosa of the
1990–1997, more than 115,000 cases of diphtheria upper respiratory tract represents a common site of
were reported and 3,000 individuals succumbed to infection, although other mucosal sites of involve-
the disease (Markina et al. 2000). Diphtheria con- ment have also been described such as the buccal
tinues to be reported worldwide (Zakikhany and mucosa, the upper and lower lips, the hard and soft
Efstratiou 2012). palate, and the tongue (Hadfield et al. 2000). Nasal
It is well recognized that the epidemiology of involvement presents with a serosanguinous or
diphtheria is changing (Zakikhany and Efstratiou seropurulent nasal discharge (Hadfield et al.
2012; Moore et al. 2015; Santos et al. 2015; 2000). Most pathognomonic presentation of the
Galazka 2000). While historically the disease pre- infection however involves a sore throat and
dominantly affected children, in the recent development of a pseudomembrane (composed
decades, significant shifts in the age distribution of necrotic epithelial cells, fibrin, neutrophils,
have been observed toward the adult cohort and numerous colonies of C. diphtheriae) on one
(Galazka 2000). This shift is not entirely under- or both tonsils which may extend to the tonsillar
stood but may in part be explained by the impact pillars, uvula, soft palate, oropharynx, and the
of mass immunization and the general improve- nasopharynx (Hadfield et al. 2000; Moore et al.
ments in living standards (Galazka 2000). Child- 2015). The pseudomembrane may range in color
hood immunization confers high-level immunity from white to gray to green or black, depending on
in children; however, this level declines in late the disease stage (Kakisi et al. 2010). Aspiration
childhood and adolescence (Zakikhany and of the membrane may lead to suffocation and
Efstratiou 2012; Galazka 2000). Thus, in the death (Zakikhany and Efstratiou 2012). Involve-
absence of booster vaccination or repeated expo- ment of the larynx, trachea, and bronchi can com-
sures to the microorganism, adults again become promise the airway. Associated neck swelling
susceptible to the disease (Galazka 2000). In the gives rise to the so-called “bull neck” appearance
industrialized countries, a change has also been (Moore et al. 2015). Infectious foci may occur in
observed in the most common toxigenic isolate the esophagus and the stomach (Hadfield et al.
from C. diphtheriae to C. ulcerans, with a female 2000; Zakikhany and Efstratiou 2012). Regional
lymph nodes may be enlarged and may appear epithelial necrosis and a fibrinosuppurative exu-
blackish red and be hemorrhagic (Hadfield et al. date, the coagulation of which produces the
2000; Santos et al. 2015). pseudomembrane (Hadfield et al. 2000). Neutro-
Cutaneous disease is characterized initially by philic infiltrate is found in the underlying connec-
the development of vesicles or pustules filled with tive tissues (Hadfield et al. 2000).
straw-colored fluid, which eventually break down
to produce chronic, single, or multiple nonhealing
ulcers with elevated margins (Hadfield et al. 2000; Patient Management
Wagner et al. 2010). A gray pseudomembrane
may also occasionally be evident (Moore et al. Provided that diagnosis is made in a timely fash-
2015). Concurrent infection with Staphylococcus ion, the most effective treatment for diphtheria is
aureus or group A streptococci is common the early intramuscular or intravenous administra-
(Zakikhany and Efstratiou 2012). The lesions are tion of 10,000–60,000 units of diphtheria anti-
usually found on the legs, feet, and hands and are toxin and appropriate antibiotic (Zakikhany and
painful in the early stages (Hadfield et al. 2000). Efstratiou 2012). Given however that the antitoxin
Rarely, infections of the ear, eyes, and the female only neutralizes non-tissue-bound toxin, its
genital region have been reported, as have inva- administration must be early (within two days of
sive infections resulting in complications such as symptom onset) to be effective and is therefore
endocarditis and septicemia, which carry a high usually administered on the basis of clinical sus-
mortality rate (Zakikhany and Efstratiou 2012). picion rather than a laboratory-proven diagnosis
While generally the growth of the organism (Moore et al. 2015; Wagner et al. 2010). The
remains localized, the exotoxin enters the blood- antitoxin is a preparation of immunoglobulins
stream, potentially culminating in severe systemic produced through immunization of horses, and,
effects such as neuropathy (including cranial nerve being an animal blood product, its administration
neuropathies) myocarditis, and cardiac failure may produce severe side effects in the form of
(Hadfield et al. 2000; Moore et al. 2015). Systemic acute and delayed hypersensitivity (Zakikhany
side effects may be seen with both respiratory and and Efstratiou 2012; Wagner et al. 2010). The
cutaneous diphtheria (Moore et al. 2015). recent discovery of human monoclonal antibody
that binds the diphtheria toxin receptor binding
domain shows promise in combating this problem
Diagnosis (Moore et al. 2015; Sevigny et al. 2013).
Antibiotic use does not influence established
Diagnosis of diphtheria is based on lesions, but controls the bacterial burden and toxin
identification of C. diphtheriae, C. ulcerans, or production (Zakikhany and Efstratiou 2012). The
C. pseudotuberculosis from clinical samples disease usually becomes noncontagious 48 h after
and the determination of its toxigenic potential initiation of antibiotics use (Centers for Disease
by the Elek immunoprecipitation test and PCR Control and Prevention 2016a). Erythromycin,
(Zakikhany and Efstratiou 2012). In confirmed azithromycin, clarithromycin, and selected
cases, electrocardiography, echocardiography, b-lactam (penicillin) antibiotics have been shown
and nerve conduction studies should also be under- to be effective against C. diphtheriae and may
taken in view of the potential systemic complica- also be administered to exposed contacts
tions of toxigenic diphtheria (Moore et al. 2015). (Zakikhany and Efstratiou 2012). The Centers
Other bacterial, mycobacterial, and fungal for Disease Control and Prevention (CDC) rec-
infections are included in the differential diagno- ommends administration of erythromycin orally
sis, and a biopsy may be necessary to establish a or by injection (40 mg/kg/day, maximum, 2 gm/
diagnosis (Moore et al. 2015). Histologically, day) for 14 days or procaine penicillin G daily,
early lesions are characterized by tissue edema intramuscularly (300,000 units every 12 h for
and hyperemia, followed by the development of those weighing 10 kg or less and 600,000 units
every 12 h for those weighing more than 10 kg) contributing to the pathogenesis of this disease
for 14 days, with oral penicillin V 250 mg four (Samaranayake 2002; Yepes et al. 2004). Infre-
times daily administered to those who can swal- quently, Mycobacterium bovis and Mycobacterium
low (Centers for Disease Control and Prevention africanum may also be responsible for producing
2016a). Elimination of the organism should be TB (Samaranayake 2002; Yepes et al. 2004;
documented by two consecutive negative cultures Sandhu 2011). Mycobacterium tuberculosis is
after therapy is completed (Centers for Disease transmitted mainly through respiratory droplets
Control and Prevention 2016a). While antimicro- produced by coughing, sneezing, or talking, while
bial resistance is generally considered rare, it has infection with M. bovis may be acquired through
been reported, including multidrug resistance and the ingestion of unpasteurized infected cow milk
antimicrobial susceptibility testing on all diphthe- (Yepes et al. 2004; Singhaniya et al. 2011; Cruz-
ria toxin-producing Corynebacterium species has Knight and Blake-Gumbs 2013). Transmission of
been recommended (Zakikhany and Efstratiou M. tuberculosis by ingestion or skin inoculation
2012; Moore et al. 2015; Farfour et al. 2013; has only rarely been reported (Samaranayake
Mina et al. 2011; FitzGerald et al. 2015). 2002). While TB most commonly affects the pul-
Given that diphtheria infection does not always monary system, it is by no means limited to that site
confer protective immunity, administration of and has the potential to affect any organ system of
diphtheria vaccine is recommended upon recov- the body (Wang et al. 2009a; Cruz-Knight and
ery (Zakikhany and Efstratiou 2012; Wagner et al. Blake-Gumbs 2013). The mortality rate of TB
2010). In the case of respiratory diphtheria, air- exceeds 50% if untreated (Sandhu 2011).
way management may become necessary, while in Although TB can affect individuals of all ages, it
cutaneous diphtheria, surgical debridement may is the immunocompromised who are at greatest risk
be indicated (Moore et al. 2015). (Sandhu 2011). In contrast to immunocompetent
Inherent to all cases of respiratory and cutane- individuals, who are usually able to wall off the
ous diphtheria is the need for contact tracing to mycobacteria and present with an asymptomatic
identify individuals at risk, and in the case of infection, HIV-positive individuals are 20–40 times
C. ulcerans diphtheria, identification of animal more likely to develop active disease, which consti-
contacts is important (Moore et al. 2015). Preven- tutes the leading cause of death in this patient group
tive measures for close contacts have been (Sandhu 2011). Not only is TB the most common
published by the CDC (Centers for Disease Con- HIV-associated opportunistic disease, it also accel-
trol and Prevention 2016a). Diphtheria remains a erates the progression of HIVand adversely impacts
notifiable disease (Centers for Disease Control the efficacy of HIV treatment (Sandhu 2011;
and Prevention 2016a). Hodgson and Rachanis 2002). Poverty and social
disadvantage are also closely interlinked with TB
(Kolokotronis et al. 1996).
Tuberculosis Despite the availability of a live attenuated
vaccine, worldwide TB constitutes one of the
Etiology and Pathophysiology most common killing diseases of infectious ori-
gin, surpassed only by HIV/AIDS, with India,
Tuberculosis (TB) is a communicable disease Indonesia, China, Nigeria, Pakistan, and
caused by Mycobacterium tuberculosis, an aerobic, South Africa bearing the highest disease burden
acid-fast, non-motile, non-encapsulated and non- (Sandhu 2011; Smith 2003; World Health Orga-
spore-forming bacillus (Wang et al. 2009a; nization 2016). While globally the incidence of
Samaranayake 2002). Humans are its only known TB and the number of related deaths continues to
reservoir (Yepes et al. 2004). The unique lipid wall fall, in 2015 alone, there were an estimated 10.4
of the organism offers it relative resistance to many million new cases worldwide, of which 56% were
disinfectants as well as host defense mechanisms among men, 34% among women, and 10%
and accounts for many of the immune responses among children (World Health Organization
2016). Eleven percent of all the new TB cases (1.2 successfully control the infection at all sites,
million) were among people living with HIV with the aid of T cells and macrophages by
(World Health Organization 2016). In that same forming granulomas which prevent the growth
year, there were an estimated 1.4 million and spread of mycobacterium (Samaranayake
TB-related deaths and an additional 0.4 million 2002; Cruz-Knight and Blake-Gumbs 2013).
deaths resulting from TB among people living This is the basis of a latent TB infection, and
with HIV (World Health Organization 2016). such individuals are noninfectious (Cruz-Knight
Over time, control of TB has proven difficult and Blake-Gumbs 2013). With time, small lesions
owing to M. tuberculosis tissue persistence and may resolve completely, whereas larger lesions
antimicrobial resistance, the first reports of which become walled off by a fibrous capsule usually
were documented soon after the introduction of harboring viable mycobacteria with a potential for
antibiotic treatment for TB (Tovaru et al. 2008; future disease reactivation (Singhaniya et al.
Zignol et al. 2016). To this day, this antimicrobial 2011; Cruz-Knight and Blake-Gumbs 2013).
resistance continues to pose a major threat to Some such lesions may calcify or ossify (Cruz-
global health and security (Zignol et al. 2016). Knight and Blake-Gumbs 2013). About 5–10% of
the infected individuals will develop clinical dis-
ease at some stage in their lifetime (Samaranayake
Clinical-Pathologic Features 2002). Less than one percent of those affected,
usually children and the immunocompromised,
Following inhalation, M. tuberculosis bacilli are will develop progressive primary disease, marked
ingested by alveolar macrophages where they by rapid progression from initial infection to clin-
continue to multiply by manipulating the normal ical illness (Samaranayake 2002). Reactivation of
phagosomal maturation cycle (Samaranayake dormant disease may occur decades after initial
2002; Cruz-Knight and Blake-Gumbs 2013; infection and is characterized by a vigorous
Smith 2003). As little as only one to five organ- immune response. Immunosuppression due to
isms can produce an infection (Yepes et al. 2004). disease (especially HIV infection) or medication
Mild local reaction ensures with further recruit- use represents the main risk factor (Samaranayake
ment of macrophages and lymphocytes 2002; Kolokotronis et al. 2006). Development of
(Samaranayake 2002). Within 2–4 weeks, the active disease in individuals with latent infection
infected macrophages carry the organism to poses a continual threat of disease transmission
regional lymph nodes where the organisms con- and hinders disease control (Yepes et al. 2004).
tinue to multiply in the presence of a minimal The most common site of reactivation disease is
inflammatory response (Samaranayake 2002). the lung, although the disease may occur at any
Four to six weeks after inhalation of the organism, site where the organisms were implanted during
the bacilli become disseminated by the hematog- the initial bacillemia (Samaranayake 2002).
enous route from the regional nodes, favoring Pulmonary TB accounts for 85% of all clinical
certain sites, namely, the posterior apical seg- presentations of the disease (Fig. 39)
ments of the lung, bones, kidneys, peripheral (Samaranayake 2002; Cruz-Knight and Blake-
lymph nodes, meninges, brain parenchyma, and Gumbs 2013). In about 15–25% of affected indi-
the choroid layer of the retina (Samaranayake viduals, active infection manifests at an extra-
2002). In an immunocompetent host, the initial pulmonary site (Fig. 40), with the most common
infection and subsequent bacillemia are fre- sites of involvement being the lymph nodes, pleura,
quently asymptomatic or accompanied by a mild bones, meninges, and the genitourinary tract
self-limiting systemic illness (Samaranayake (Samaranayake 2002; Kakisi et al. 2010). Extra-
2002). After 2–8 weeks, cell-mediated immunity pulmonary disease may or may not be accompanied
and hypersensitivity develops, marked by a posi- by pulmonary disease (Samaranayake 2002).
tive tuberculin skin test (Samaranayake 2002). Oral manifestations of TB are uncommon,
About 90–95% of the exposed individuals will with only 0.1–5.0% of the total TB cases
Fig. 39 Pulmonary tuberculosis. Axial CT through the so-called “tree-in-bud” appearance (black dotted ovals);
upper lobes (a) and a coronal reconstruction (b). There is both features are typical findings of TB (Images courtesy
cavitating dense consolidation in the left upper lobe (black of Dr Stephen Melsom, Perth Radiological Clinic and
arrows) with multiple small, “soft” nodules giving the Fiona Stanley Hospital, Perth WA, Australia)
saliva comprise an effective barrier to the pene-

tration of the bacilli (Singhaniya et al. 2011;
Kolokotronis et al. 1996). Mucosal injury such
as that produced through chronic irritation or
inflammation may create portals for organism
entry, and in some cases, the bacilli may reach
the oral mucosa through hematogenous or lym-
phatic spread (Singhaniya et al. 2011;
Kolokotronis et al. 1996). Oral lesions tend to
be more common in men than women and may be
primary, whereby the oral cavity represents the
initial site of infection or (more often) may pre-
sent secondary to systemic disease (Kakisi et al.
2010; Miziara 2005). Primary oral TB is gener-
ally reported to be more common in younger
individuals (Samaranayake 2002; Tovaru et al.
2008). Oral lesions most commonly present on
the tongue, although any oral site can be affected
including the hard and soft palate, uvula, buccal
mucosa, lips, gingivae, maxilla, and mandible
(Samaranayake 2002; Kolokotronis et al. 1996;
Fig. 40 Tuberculosis cutis orifacialis (Image courtesy of Kakisi et al. 2010). Oral mucosal involvement
Associate Professor Ajay Parihar, Government College of tends to be nonspecific, and when the index of
Dentistry, Madhya Pradesh, India)
suspicion is low, this may lead to a delay in
diagnosis (Tovaru et al. 2008). While oral muco-
presenting with oral lesions (Singhaniya et al. sal ulceration represents the most common oral
2011; Tovaru et al. 2008). It has been proposed presentation of the infection, oral manifestations
that intact oral mucosa together with the mechan- of TB are diverse ranging from patches, papillo-
ical cleansing and antimicrobial properties of matous lesions, to indurated soft tissue lesions
(Singhaniya et al. 2011; Tovaru et al. 2008; inflammatory disease and may lead to sterility
Kakisi et al. 2010; Miziara 2005). Ulcers usually (Cruz-Knight and Blake-Gumbs 2013). Difficulty
present with indurated, ill-defined margins and a swallowing, abdominal pain, malabsorption, diar-
hard necrotic base or covered with grayish or rhea, hematochezia, and nonhealing anal ulcers
yellow slough (Kakisi et al. 2010). Oral lesions are also characteristic of gastrointestinal TB
may be single or multiple and may present with (Cruz-Knight and Blake-Gumbs 2013).
or without symptoms such as pain or bleeding
(Samaranayake 2002; Miziara 2005). Tubercu-
lous osteomyelitis may involve the maxilla or Diagnosis
mandible and present as a slow rarefying osteitis
resulting in sequestration of bone and accompa- Standard methods for identifying individuals
nied by pain, particularly in the later stages infected with M. tuberculosis are the tuberculin
(Samaranayake 2002). Rare tubercular involve- skin test and interferon-γ release assay (Cruz-
ment of the parotid gland has been reported, Knight and Blake-Gumbs 2013). Individuals
presenting as a localized mass (mimicking neo- with positive screens and suspicious for active
plasia), as a periauricular sinus, or as an abscess disease should have a chest radiograph, three spu-
(Tovaru et al. 2008; Sethi et al. 2006; Holmes tum samples for acid-fast bacilli, and a nucleic
et al. 2000). Associated facial palsy has also been acid amplification test (Cruz-Knight and Blake-
described (Samaranayake 2002). Gumbs 2013). Culture may also be used in the
Extrapulmonary TB in the neck presents as diagnosis of TB; however, it may take 4–8 weeks
cervical lymphadenitis, which may be unilateral to obtain results (Yepes et al. 2004; Cruz-Knight
or bilateral with single or multiple involved nodes and Blake-Gumbs 2013). Antimicrobial suscepti-
(Wang et al. 2009a; Samaranayake 2002). The bility testing is important in view of the high
bacilli may reach this site through hematogenous prevalence of multidrug-resistant TB with the
or lymphatic spread (Samaranayake 2002). WHO recommending the use of line probe assays
The affected individual may present with a neck for the detection of resistance to isoniazid, rifam-
swelling, which may or may not be painful, pin, and second-line anti-TB drugs (World Health
firm but mobile, later becoming fixed, with the Organization 2011, 2016).
formation of a cold abscess and sinuses Fine-needle aspiration cytology, histopathol-
(Samaranayake 2002). ogy, and imaging such as ultrasound, MRI, or
Symptoms of TB are generally mild and non- contrast-enhanced CT may additionally be used
specific and include night sweats, fever, weight in the diagnosis of TB of the major salivary
loss, anorexia, and weakness and, in the case of glands (Tovaru et al. 2008; Miziara 2005; Sethi
pulmonary involvement, may also include cough, et al. 2006). Histopathological examination of
pleuritic pain, and hemoptysis (Yepes et al. 2004). oral lesions may aid diagnosis; however, it can-
Other signs and symptoms are governed by the not be solely relied upon as similar histopatho-
specific site of involvement. Tuberculous menin- logic picture may also be seen in conditions
gitis follows CNS involvement (Cruz-Knight and other than tuberculosis (Kolokotronis et al.
Blake-Gumbs 2013). Pain, joint stiffness, and 1996). Histopathology is characterized by the
lower extremity paralysis may be associated with presence of a central area of caseous necrosis,
skeletal tuberculosis and tuberculous arthritis epithelioid macrophages, Langerhans giant
(Cruz-Knight and Blake-Gumbs 2013). Genito- cells, and lymphocytes with and an outer zone
urinary TB is characterized by pain, dysuria, and of lymphocytes, plasma cells, and immature
frequent urination (Cruz-Knight and Blake- macrophages and peripheral fibrosis (Fig. 41)
Gumbs 2013). Men may experience prostatitis, (Cruz-Knight and Blake-Gumbs 2013). Special
orchitis, and epididymitis or present with a painful stains such as Ziehl-Neelsen stain are positive
scrotal mass (Cruz-Knight and Blake-Gumbs for the bacilli in some but not all cases
2013). In women, the disease may mimic pelvic (Samaranayake 2002).
Fig. 41 Tuberculosis of the lung at low power (a) and higher power (b) demonstrating multinucleated Langerhans giant cells
Due to the varied presentation of oral mucosal not known to be drug resistant involves a
TB, differential diagnosis includes fungal and 2-month-long course of the combination of isoni-
other bacterial infections, traumatic and aphthous azid, rifampin (rifampicin), pyrazinamide, and
ulcers, Wegener’s granulomatosis, sarcoidosis, ethambutol (intensive phase), followed by a fur-
Crohn’s disease, Melkersson-Rosenthal syn- ther 4-month-long course of treatment with the
drome, and neoplastic disease such as Hodgkin’s combination of isoniazid and rifampin (continua-
disease, Kaposi sarcoma, and squamous cell car- tion phase) (Nahid et al. 2016). If, however, treat-
cinoma (Kakisi et al. 2010; Miziara 2005). Inter- ment is being initiated after antimicrobial
estingly, reports exist of TB in the head and neck susceptibility test results are known and the indi-
region coexisting with cancer, namely, adenoid vidual’s isolate is susceptible to both isoniazid and
cystic carcinoma, mucoepidermoid carcinoma, rifampin, ethambutol is not necessary, and the
and oral squamous cell carcinoma (Wang et al. intensive phase of treatment may be reduced to
2009a; Kakisi et al. 2010). Therefore any lesion the use of three agents only: isoniazid, rifampin,
which does not respond to antimicrobial therapy and pyrazinamide (Nahid et al. 2016). During the
as expected should be further investigated. course of treatment, a sputum specimen for acid-
fast bacilli and culture is obtained at monthly
intervals, until two consecutive specimens are
Patient Management negative on culture, and the length of the contin-
uation phase is ultimately governed by these
Treatment of TB is based on the use of appropriate results (Nahid et al. 2016). Detailed treatment
antimicrobial agents with the aim of curing the protocols for individuals with HIV infection,
affected individual and minimizing any further extrapulmonary tuberculosis, culture-negative
transmission of the infection. Antimicrobial resis- pulmonary tuberculosis, tuberculosis during preg-
tance poses a major challenge to the successful nancy and breastfeeding, renal disease, and
treatment of TB and develops from the inadequate hepatic disease, in individuals of advanced age,
treatment of active pulmonary TB (Johnston et al. and in children have recently been co-jointly
2009). Soon after the introduction of antibiotic use published by the American Thoracic Society, the
in the treatment of TB, it became apparent that Centers for Disease Control and Prevention, and
combination therapy was required to combat the the Infectious Diseases Society of America
emergence of drug resistance (Zignol et al. 2016). (Nahid et al. 2016).
The currently recommended treatment regimen Multidrug resistance (defined as resistance to
for adults with TB caused by organisms that are at least rifampin and isoniazid) and extensive drug
resistance (defined as multidrug-resistant tubercu- Tuberculosis is well recognized as an occupa-

losis plus resistance to a fluoroquinolone and at tional risk for healthcare workers, including those
least one second-line injectable agent: amikacin, in the dental setting, although the true risk of
kanamycin, or capreomycin) is a significant transmission of M. tuberculosis in the dental set-
global problem and a barrier to achieving success- ting remains unknown (Samaranayake 2002;
ful control of TB (Zignol et al. 2016; Johnston Kolokotronis et al. 1996). Infection control guide-
et al. 2009). Although the true magnitude of drug- lines have been published by the CDC to mini-
resistant TB in the world is in fact unknown, in mize the risk of transmission and are centered
2015 alone, there were an estimated 580 000 new around vaccination, the rigid and routine imple-
cases of multidrug-resistant TB, with India, mentation of universal infection control policies,
China, and the Russian Federation accounting and the use of appropriate ventilation, filtration,
for 45% of these cases (World Health Organiza- control of aerosols and the use of good quality
tion 2016; Zuur et al. 2016). There are currently facemasks (Samaranayake 2002; Yepes et al.
four groups of second-line antituberculosis 2004; Jensen et al. 2005; Centers for Disease
agents used in the treatment of TB with resistant Control and Prevention 2016b). Given the sub-
isolates (World Health Organization 2011). stantial impact of TB on public health, the infec-
These include second-line parenteral agent (kana- tion remains a notifiable disease (Cruz-Knight and
mycin, amikacin, capreomycin), fluoroquinolones Blake-Gumbs 2013).
(levofloxacin, moxifloxacin, gatifloxacin,
ofloxacin), oral bacteriostatic second-line anti-
tuberculosis drugs (ethionamide, prothionamide, Bacterial Sialadenitis
cycloserine, terizidone, p-aminosalicylic acid),
and group 5 drugs (clofazimine, linezolid, amox- Etiology and Pathophysiology
icillin/clavulanate, thioacetazone, clarithromycin,
imipenem) (World Health Organization 2011). Bacterial sialadenitis represents a relatively infre-
Treatment guidelines of multidrug-resistant tuber- quent infection, most commonly associated with
culosis have been published by the WHO with the sialoliths (Cascarini and McGurk 2009). A British
combination therapy regimen including at least study of hospital admissions during the period of
pyrazinamide, a fluoroquinolone, a parenteral 1991–1995 found that the annual incidence of
agent, ethionamide (or prothionamide), and either symptomatic sialadenitis and sialolithiasis was
cycloserine or p-aminosalicylic acid if cycloserine 27.5 and 31.5 per million population, respectively
cannot be used (World Health Organization (Escudier and McGurk 1999). While bacterial
2011). Toxicity and treatment costs pose signifi- sialadenitis may affect any of the major or minor
cant challenges to the use of second-line anti-TB salivary glands, the submandibular and parotid
drugs (World Health Organization 2016; Zuur glands are the most commonly affected (Carlson
et al. 2016). 2009). Advanced age, salivary gland hypo-
There are currently nine drugs in advanced function due to medication use, radiation therapy,
phases of clinical trials for the treatment of systemic disease or dehydration, and the presence
drug-susceptible, drug-resistant, or latent TB of ductal obstruction constitute important risk fac-
infection. These are bedaquiline, delamanid, tors (Ship 2002). Bacterial sialadenitis may pre-
linezolid, PBTZ169, pretomanid, Q203, sent as an acute or as a chronic infection.
rifampin (high dose), rifapentine, and sutezolid
(World Health Organization 2016). There
are also a number of vaccine candidates in clin- Clinical-Pathologic Features
ical trials for the prevention of TB infection as
well as disease prevention in individuals with Acute bacterial sialadenitis may manifest as a
latent TB infection (World Health Organization single event or as recurrent episodes and may
2016). affect any salivary gland, although the parotid
Fig. 42 Bacterial sialadenitis. Swelling and suppuration of the left parotid duct opening (a) associated with an intraductal
sialolith (Hematoxylin and eosin stain) (b)
glands are the most commonly affected (Fig. 42) Constitutional symptoms such as fever and chills
and involvement of the minor salivary glands is may also be noted (Carlson 2009).
rare (Cascarini and McGurk 2009; Brook 2009). Staphylococcus aureus and anaerobic bacteria
Persons of all ages may be affected, with the (Prevotella spp., Porphyromonas spp.,
newborns and the elderly accounting for the Fusobacterium spp., and Peptostreptococcus spp.)
highest proportion of cases (Brook 2009). Male are the most common pathogens associated with
predilection has been noted (Cascarini and acute bacterial sialadenitis (Brook 2009). In
McGurk 2009). The infection is usually the result hospital-acquired infections, methicillin resistance
of bacteria from the oral cavity ascending a sal- should be investigated in the Staphylococcus
ivary gland duct, enabled by some impairment of aureus isolates (Carlson 2009). Other organisms
the saliva’s natural flushing ability (Cascarini which may also be involved include S. pyogenes
and McGurk 2009). In an immunocompromised and less commonly S. pneumoniae, E. coli,
individual, however, bacteremia may also repre- H. influenzae, K. pneumoniae, Salmonella spp.,
sent the precipitating event (Cascarini and P. aeruginosa, T. pallidum, B. henselae, and
McGurk 2009). It has been proposed that the E. corrodens (Brook 2009). On rare occasions,
higher mucoid content of the submandibular parotitis may be attributed to mycobacterium tuber-
and sublingual gland saliva, with its antimicro- culosis and atypical mycobacteria (Brook 2009).
bial properties, offers these glands greater pro- Persistence of infection beyond 1 month sig-
tection against bacterial infections (Cascarini nifies chronicity (Hodgson and Rachanis 2002).
and McGurk 2009). Obstruction, usually by a Chronic bacterial sialadenitis may be seen in
sialolith, is the most common cause, and its pres- adults as well as children. Chronic recurrent juve-
ence or absence should always be ascertained in nile sialadenitis, which affects the parotid glands,
the affected individual (Figs. 43 and 44) may arise secondary to a congenital salivary gland
(Cascarini and McGurk 2009). Immunosuppres- duct abnormality or trauma (Cascarini and
sion and salivary gland hypofunction, particu- McGurk 2009). Chronic bacterial parotitis is ten
larly in an immunocompromised individual, times more common in children than adults, and
may also be a factor (Cascarini and McGurk about 30% of the affected children will continue
2009). Clinically, the infection presents as a to suffer with this affliction into their adulthood
painful swelling of the affected salivary gland, (Cascarini and McGurk 2009). In many adults,
which may be exacerbated by eating (Carlson however, the precipitating event in chronic bacte-
2009). Pus may be present in the glandular duct rial sialadenitis is not always clear, but is believed
and expressed by palpation (Carlson 2009). to be multifactorial eventually culminating in
Fig. 43 CT image of bacterial sialadenitis. Within the left sialadenitis. Within the right parotid gland (b), there is a
parotid gland (a), there is a small (2.5 mm) ovoid calculus slightly larger calculus (3.0 mm) lying in the main duct
within the anterior parenchyma of the superficial lobe, anteriorly, lateral to the anterior third of the right masseter
lying in the line of the main parotid duct, immediately muscle. There is very mild wall thickening of the main duct
superficial to the posterior margin of the masseter muscle. immediately adjacent to the calculus consistent with mild
There is subtle heterogeneous increased enhancement sialodochitis but no intraglandular duct dilatation is shown
within the left parotid gland consistent with chronic and there is no evidence of parotitis
salivary gland damage and stasis, therefore facil- described in the context of the submandibular
itating the development of reoccurring and persis- gland (chronic sclerosing submandibular
tent infections (Cascarini and McGurk 2009; sialadenitis), other major salivary glands may
Carlson 2009). In some cases, acute bacterial also be affected (Fig. 46) (Cascarini and McGurk
sialadenitis may progress to chronic when treat- 2009). Staphylococcus aureus and Streptococcus
ment of the acute infection is delayed or when the viridans are the most commonly isolated patho-
treatment is inadequate by, for example, failing to genic organisms in adult and juvenile chronic
address the initial cause of the problem such as a bacterial sialadenitis, respectively (Carlson 2009).
sialolith (Carlson 2009).
Chronic bacterial sialadenitis is characterized
by swellings of the affected gland, which may be Diagnosis
relapsing and remitting, or by persisting symp-
toms (Fig. 45) (Cascarini and McGurk 2009; As is the case with any bacterial infection, identifi-
Carlson 2009). The swellings may last for days, cation of the causative organisms is important and
weeks, or months, and there may be varying guides antimicrobial therapy (Brook 2009). Needle
degrees of discomfort and a low-grade fever aspiration of the purulent gland is the preferred
(Carlson 2009). Generally, pus is not observed method for identification of the causative organisms
and its persistent presence should raise suspicion to minimize contamination (Brook 2009). The aspi-
of an acute infection (Carlson 2009). Long- rates should be cultured and stained for aerobic and
standing disease may produce a tumor-like mass anaerobic bacteria, fungi, and mycobacteria (Brook
referred to as a Kuttner tumor, with the affected 2009). In some cases, surgical exploration and
gland being painful and swollen (Cascarini and drainage or biopsy may be necessary to establish a
McGurk 2009). While this presentation is diagnosis, and drainage may be therapeutic (Brook
Fig. 44 Right submandibular sialadenitis. Postcontrast sublingual space of the right side of the floor of the
multidetector CT with multiplanar soft tissue (a, c, and d) mouth. The right submandibular gland is slightly swollen
and bone-window sagittal (b) reconstructions. A 4 mm and hypervascular when compared to the left (SMG).
long calculus (white arrows in a and b) is situated in the There is edema and small reactive nodes in the right sub-
distal aspect of the right submandibular duct, just proximal mandibular space surrounding the gland (white oval in d)
to the meatus. Fusiform dilatation of the right submandib- (Images courtesy of Clinical Associate Professor Andy
ular duct (black dotted arrows) is seen in the swollen Whyte, Perth Radiological Clinic, Perth WA, Australia)
2009). Polymerase chain reaction may be employed (Zenk et al. 2009). Sialography however is
in the diagnosis of the more unusual causative contraindicated in acute bacterial sialadenitis (Zenk
agents such as mycobacterium and B. henselae et al. 2009). Non-enhanced CT is the most sensitive
(Brook 2009). Ultrasound, MRI, or CT imaging imaging technique for the detection of salivary
may also be utilized in the diagnostic process gland calculi (Zenk et al. 2009). Diagnostic tests
(Figs. 43 and 44) (Zenk et al. 2009). Major salivary have an important role to play not only in defining
glands are amenable to ultrasound imaging, and this the disease but also in confirming diagnosis. Differ-
imaging modality may be safely and reliably used in ential diagnosis to consider includes nonspecific
children and in adults (Zenk et al. 2009). MRI or inflammatory conditions, chronic granulomatous
MR sialography is the next preferred imaging disease, and neoplasia (Cascarini and McGurk
modality for evaluating salivary gland lesions 2009).
Fig. 45 Soft tissue abscess and chronic sialadenitis in left sent through the connective tissue. Lobules of minor sali-
buccal space (a). Histopathology (b) shows sections of vary gland tissue with some loss of acinar architecture are
mature fibrous connective tissue and an intense mixed present. Lobules contain a diffuse chronic inflammatory
acute and chronic inflammatory cell infiltrate. Pus is pre- cell infiltrate
cephalosporins, as first-line therapy in the conserva-

tive treatment of sialadenitis (Troeltzsch et al. 2014).
Fluoroquinolones and macrolides also appeared to
exhibit favorable pharmacokinetics in salivary gland
tissues (Troeltzsch et al. 2014). When a glandular
abscess is identified or suspected (based on clinical
deterioration, increasing glandular pain and swell-
ing, and increased volume of pus), hospital admis-
sion becomes necessary for the consideration of
incision and drainage and intravenous antibiotic
administration (Carlson 2009). In those cases of
Fig. 46 Kuttner tumour as a result of long-standing chronic bacterial sialadenitis, where conservative
inflammatory disease associated with chronic bacterial treatment approaches have failed, removal of the
sialadenitis affected gland may become necessary (Carlson
2009; Wang et al. 2009b).
Patient Management
Treatment of bacterial sialadenitis is centered Bacterial Rhinosinusitis

around elimination of the causative or predisposing
factors (if that is possible, e.g., removal of a Etiology and Pathophysiology
sialolith), the use of systemic antibiotics (amoxicil-
lin with clavulanate, clindamycin, or cephalexin), Rhinosinusitis is one of the most common afflic-
hydration, and salivary stimulation (Carlson 2009; tions managed by primary care physicians
Ship 2002). Antibiotics may be administered orally (DeCastro et al. 2014). Although the term “sinus-
for 10 days or intravenously, depending on disease itis” is still widely used with reference to the same,
severity (Ship 2002; Troeltzsch et al. 2014). While it given that rhinitis and sinusitis usually coexist,
is recommended that the choice of antibiotic be “rhinosinusitis” more accurately describes the dis-
ultimately based on results of microbial sensitivity ease and is in fact the correct term (Fokkens et al.
tests, a recent systematic review aiming to identify 2012). Use of the term “sinusitis” should only be
most appropriate antibiotics for the treatment of restricted to situations where a specific reference
bacterial sialadenitis supported the use of β-lactam is made to inflammation of a particular sinus
antibiotics and in particular the later-generation cavity (Lemiengre et al. 2012).
The paranasal sinuses represent several bilat- nasal drip) with/without facial pain/pressure and
eral bony cavities, namely, maxillary, frontal, with/without a reduction or loss of smell (or, in the
sphenoid, and ethmoid, lined by pseudostratified case of children, a cough), and (2) either
ciliated columnar epithelium (covered by a layer (a) endoscopic signs of nasal polyps and/or
of mucus), that drain into the nose through several mucopurulent discharge primarily from middle
ostia (DeCastro et al. 2014). The frontal, maxil- meatus and/or edema/mucosal obstruction pri-
lary, and anterior ethmoid sinus ostia all share a marily in middle meatus or (b) mucosal CT
common connection with the nose, through the changes within the ostiomeatal complex and/or
ostiomeatal complex, lying in the medial nasal sinuses (Figure 47) (Fokkens et al. 2012).
meatus, lateral to the middle turbinate (DeCastro Rhinosinusitis in adults and in children is consid-
et al. 2014). Most cases of bacterial rhinosinusitis ered acute when present for less than 12 weeks,
are the result of some obstruction of the opening with complete symptom resolution, and chronic
of the ostiomeatal complex, impairing the natural when present for more than 12 weeks (Fokkens
drainage of the protective mucous layer (DeCastro et al. 2012).
et al. 2014). Infection (usually viral), trauma, ana-
tomical variations, allergy, and pregnancy repre-
sent some of the many possible causes of Acute Rhinosinusitis
obstruction (DeCastro et al. 2014; Forer 1999).
Following obstruction, negative pressure Clinical-Pathologic Features
develops in the sinus relative to the nasal cavity, In adults, acute rhinosinusitis is most commonly
fluid accumulates with the sinus, and bacteria associated with involvement of the maxillary and
migrate from the nasal cavity in a retrograde fash- anterior ethmoid sinuses, while in children the
ion into the sinus and cause secondary bacterial posterior ethmoidal and sphenoid sinuses are
infection (DeCastro et al. 2014). more commonly affected (DeCastro et al. 2014).
In adults, rhinosinusitis is defined as (1) inflam- Reported prevalence rates for acute disease vary
mation of the nose and the paranasal sinuses char- from 6 to 12%, depending on the population stud-
acterized by two or more symptoms, one of which ied, with viral infections, usually due to rhino-,
should be either nasal blockage/obstruction/con- influenza, adeno-, or parainfluenza viruses,
gestion or nasal discharge (anterior/posterior representing the most common cause (Fokkens
Fig. 47 Coronal reconstructions from multidetector CT shown in (b). Both respond to nasal steroids; eosinophilia
scans in two patients with chronic rhinosinusitis (CRS). In predominates in CRS with polyps and surgery is more
(a), there is maxillary and ethmoid sinusitis as well as commonly indicated (Images courtesy of Clinical Associ-
extensive nasal polyps: CRS with polyps. This has a dif- ate Professor Andy Whyte, Perth Radiological Clinic,
ferent immune mechanism to CRS without polyps which is Perth WA, Australia)
et al. 2012; Brook 2005; Chow et al. 2012). Other 2. severe local pain with unilateral predomi-
causes include dental infections, sinus surgery, nance, 3. fever (>38 C), 4. elevated ESR/CRP,
nasogastric tubes, nasal packing, mechanical ven- and 5. “double sickening” representing a phe-
tilation, immunodeficiency, impaired ciliary nomenon of clinical deterioration after an initial
motility, mechanical obstruction secondary to improvement (Fokkens et al. 2012). Other signs and
anatomical variations, foreign bodies, or other symptoms include headache, sensation of facial
pathosis (Aring and Chan 2016). It is estimated pressure, nasal obstruction, hyponasal speech,
that an average adult will experience 2–5 bouts of hyposmia, maxillary toothache, otalgia, and malaise
acute rhinosinusitis in any given year (van den (DeCastro et al. 2014; Feldt et al. 2013). Numerous
Broek et al. 2014). Only 0.5–2.0% of all acute microorganisms have been implicated in acute bac-
cases are attributed to bacterial rhinosinusitis, usu- terial rhinosinusitis, the most common of which are
ally secondary to a viral infection (Fokkens et al. S. pneumoniae, H. influenza, M. catarrhalis, and
2012). Allergy and smoking have been identified S. aureus (Fokkens et al. 2012; Aring and Chan
as important predisposing factors (Fokkens et al. 2016; Feldt et al. 2013).
2012). Despite the fact that over 90% of all cases Computed tomography, the “gold standard” of
of acute rhinosinusitis are attributed to viral infec- sinus imaging, is not generally recommended in the
tions, antibiotics are still frequently, and in many evaluation of acute uncomplicated rhinosinusitis as,
cases inappropriately, prescribed, stemming in part while it can rule out the presence of fluid, it cannot
from the difficulty in differentiating bacterial from distinguish viral from bacterial rhinosinusitis (Aring
viral infections (Lemiengre et al. 2012; Chow et al. and Chan 2016; Feldt et al. 2013). When severe
2012; Aring and Chan 2016). This practice is pain or headache, periorbital edema, visual changes,
concerning as it contributes to the increasing bac- or altered mental status are present suggesting com-
terial resistance and in some cases may place the plicated acute bacterial rhinosinusitis, a CT scan is
individual at risk of significant harm, due to the indicated (DeCastro et al. 2014). Magnetic reso-
drugs’ adverse effects (Lemiengre et al. 2012). nance imaging may be used in conjunction with
CT to assess orbital or intracranial complications
Diagnosis (DeCastro et al. 2014; Forer 1999).
Although a culture obtained from either a sinus
puncture or an antral aspirate obtained by a nasal Patient Management
endoscopy provides a means of distinguishing In most cases, acute bacterial rhinosinusitis resolves
between bacterial and viral rhinosinusitis, and without the use of antibiotics, and symptomatic
constitutes the gold standard for the diagnosis treatment with reassurance and monitoring is all
of acute bacterial rhinosinusitis, it is an invasive that is required (Fokkens et al. 2012). Symptomatic
and often impractical test to undertake in treatment involves the use of analgesics such as
daily practice (Chow et al. 2012; van den paracetamol or nonsteroidal anti-inflammatory
Broek et al. 2014). In light of this, current clinical drugs, intranasal corticosteroids, and intranasal
practice guidelines attempt to make the distinc- saline irrigation (Chow et al. 2012; Aring and
tion on clinical grounds with acute post-viral Chan 2016; Feldt et al. 2013). Evidence supporting
rhinosinusitis being defined as “an increase of the use of antimicrobial agents in the management
symptoms after 5 days or persistent symptoms of acute rhinosinusitis is very limited, and their use
after 10 days with less than 12 weeks duration” must always be weighed against the risk of antimi-
(Fokkens et al. 2012). After 10 days, the proba- crobial resistance and the very low risk of serious
bility of a bacterial rhinosinusitis rises to 60% disease complications (Lemiengre et al. 2012).
(van den Broek et al. 2014). The presence of at Potential complications of acute bacterial
least three of the following five signs/symptoms rhinosinusitis include orbital cellulitis, subperiosteal
is suggestive of acute bacterial rhinosinusitis: abscess, intra-orbital abscess, altered mental status,
1. discolored discharge (with unilateral predom- meningitis, cavernous sinus thrombosis, intracranial
inance) and purulent secretion in the nasal cavity, abscess, and osteomyelitis (Aring and Chan 2016).
The reported annual incidence rates of complica- Chronic Rhinosinusitis

tions such as orbital, intracranial, and soft tissue
involvement are 2.5–4.3 per million patients Clinical-Pathologic Features
(Kaper et al. 2013). Antibiotic use should therefore Intense inflammation of the nasal and sinus mucosa
only be reserved for individuals presenting with characterizes chronic rhinosinusitis (Russell and
high fever or severe, unilateral facial pain or in Bekeny 2014). Data from Europe and the United
whom the condition persists beyond 10 days States indicate prevalence rates to range from 5 to
(Fokkens et al. 2012; Aring and Chan 2016). 15% of the general population (Fokkens et al.
When a decision is made to prescribe antibiotics 2012; Sarber et al. 2013). Although historically
for adults with acute rhinosinusitis, most guidelines considered to represent a response to a bacterial
recommend the use of amoxicillin, with or without infection, the precise role of bacteria in the patho-
clavulanate, for 5–10 days, as the first-line of treat- genesis of chronic rhinosinusitis remains unknown,
ment (Forer 1999; Chow et al. 2012; Aring and as the exact mechanisms underpinning disease
Chan 2016). Amoxicillin with clavulanate should pathogenesis have not been fully elucidated. A
be used in individuals with other comorbidities, role for bacterial infection or colonization is none-
those presenting with moderate to severe disease, theless established. Tissue from individuals with
those who are at high risk of bacterial resistance, chronic rhinosinusitis has been shown to be asso-
and in children, due to the higher prevalence of ciated with an increased bacterial burden (particu-
β-lactamase-producing H. influenzae than in adults larly S. aureus), and bacterial biofilms with other
(Forer 1999; Chow et al. 2012; Aring and Chan organisms, including P. aeruginosa, are not only
2016). Antimicrobial therapy in children should be often present but the presence of bacterial biofilms,
continued for 10–14 days (Chow et al. 2012). In in particular containing S. aureus, appear to be
adults, doxycycline may be used as an alternative to associated with more severe disease (Fokkens
amoxicillin-clavulanate for initial empiric antimi- et al. 2012; Ramakrishnan et al. 2016; Hamilos
crobial therapy (Chow et al. 2012). Although 2014; Mahdavinia et al. 2016).
methicillin-resistant S. aureus is a potential patho- Chronic rhinosinusitis may present with or
gen in acute bacterial rhinosinusitis, its routine without nasal polyps, and while the symptom
coverage during initial empiric therapy is not profile may be identical in both cases, evidence
recommended (Chow et al. 2012). Failure to exists that immunologically these two pheno-
improve by 5–7 days, or worsening symptoms, types differ. Although traditionally, chronic
signal treatment failure and an antibiotic with a rhinosinusitis without nasal polyps was associ-
broader antimicrobial spectrum such as high-dose ated with a TH1 immune response and chronic
amoxicillin-clavulanate (2 g orally twice daily), a rhinosinusitis with nasal polyps with a TH2
respiratory fluoroquinolone (levofloxacin or response, recent studies indicate that this pattern
moxifloxacin), or the combination of clindamycin does not apply worldwide (Fokkens et al. 2012;
plus a third-generation oral cephalosporin is Sarber et al. 2013). According to the latest
required (Forer 1999; Chow et al. 2012; Aring hypothesis, fibrosis, high levels of TGF-β, and
and Chan 2016). In the case of treatment failure, it increased regulatory T cell activity characterize
is important to obtain cultures by direct sinus aspi- chronic rhinosinusitis without nasal polyps,
ration or endoscopically guided cultures of the while edema, low TGF-β levels, and low regula-
middle meatus to ascertain the presence of a persis- tory T cell activity are typical of chronic
tent bacterial infection and guide antibiotic selec- rhinosinusitis with nasal polyps (Fokkens et al.
tion (Chow et al. 2012). Surgery is rarely indicated 2012). While this hypothesis remains to be vali-
in the management of acute bacterial rhinosinusitis dated, chronic rhinosinusitis appears to be the
but may be necessary in the case of recurrent infec- product of dysfunctional host-environment inter-
tions or in the setting of certain complications such actions involving various exogenous agents and
as subperiosteal abscess, orbital abscess, or intra- changes in the nasal and sinus mucosa (Fokkens
cranial extension (Feldt et al. 2013). et al. 2012).
Diagnosis limited evidence supports the use oral corticoste-

Clinically, chronic rhinosinusitis with or without roids in individuals without nasal polyps
nasal polyps is characterized by the presence of (Schwartz et al. 2016). Antimicrobial therapy in
two or more symptoms, one of which should be chronic rhinosinusitis is predominantly based on
either nasal blockage/obstruction/congestion or the short-term (less than 3–4 weeks) use of oral
nasal discharge (anterior/posterior nasal drip) non-macrolide antibiotics, with the strongest evi-
and the others may include facial pain/pressure dence supporting the use of doxycycline in indi-
and/or reduction or loss of smell (or, in the case viduals with nasal polyps (Schwartz et al. 2016;
of children, cough), lasting for more than Soler et al. 2013). Long-term (more than 3–4
12 weeks (Fokkens et al. 2012). Direct visualiza- weeks) low-dose macrolide therapy has been
tion with the aid of nasopharyngeal endoscopy is recommended as an alternative approach; how-
important in identifying inflammation, edema, ever, unequivocal evidence of a definite benefit
purulent discharge, polyps, and factors pre- is currently lacking (Schwartz et al. 2016). Intra-
disposing to chronic rhinosinusitis such as septal nasal saline irrigation has been shown to be of
deviation or a pneumatized middle turbinate significant benefit to individuals with all types of
(Sarber et al. 2013). Computed tomography (with- chronic rhinosinusitis (Sarber et al. 2013;
out contrast media) is the imaging modality of Schwartz et al. 2016; Huang and Govindaraj
choice for individuals with chronic rhinosinusitis 2013; Adappa et al. 2012). Surgical intervention
(Fig. 47) (Aring and Chan 2016). may be necessary if signs (including on the CT)
and symptoms of chronic rhinosinusitis continue
Patient Management despite appropriate medical treatment (Sarber
While antibiotics are often prescribed in the man- et al. 2013). The intention of endoscopic sinus
agement of chronic rhinosinusitis, high quality surgery is to open and widen the natural drainage
evidence supporting antimicrobial therapy is pathways, remove nasal polyps, and obtain cul-
lacking (Russell and Bekeny 2014; Head et al. tures to guide antimicrobial selection (Forer 1999;
2016; Adelson and Adappa 2013; Schwartz et al. Sarber et al. 2013). In children, rhinosinusitis may
2016). Positive response to macrolides and corti- occur secondarily to adenoid hypertrophy, neces-
costeroids seems to suggest that controlling sitating adenoidectomy (Forer 1999).
mucosal inflammation is particularly important Complications of chronic rhinosinusitis are not
in the management of this disease (Russell and as well documented as in acute rhinosinusitis but
Bekeny 2014). are also considered to be rare and include forma-
Medical management of chronic rhinosinusitis tion of mucoceles, osteitis, bone erosion and
is recommended prior to any surgical intervention expansion, metaplastic bone formation, visual
(Schwartz et al. 2016). The most common regi- impairment, and intracranial infection (Kaper
mens include the use of topical intranasal cortico- et al. 2013; Head et al. 2016).
steroids (such as budesonide, dexamethasone,
betamethasone, triamcinolone, beclomethasone,
and ciclesonide) and oral antibiotics, with or with- Maxillary Sinusitis of Odontogenic
out the administration of systemic corticosteroids Origin
(Schwartz et al. 2016). Individuals with chronic
rhinosinusitis, with and without nasal polyps, Clinical-Pathologic Features
have been shown to benefit from the use of topical Maxillary sinusitis of odontogenic origin deserves a
corticosteroids (Sarber et al. 2013; Huang and special mention as it is of particular interest to the
Govindaraj 2013). Individuals with chronic oral healthcare providers and differs in its patho-
rhinosinusitis with nasal polyps also benefit from genesis and management from sinusitis of other
the use of oral corticosteroids, with strong evi- causes (Brook 2006). The infection may be acute
dence supporting their use in this patient group or chronic, with chronic maxillary sinusitis of
(Schwartz et al. 2016). In contrast, only very odontogenic origin accounting for about 10–12%
of all cases of maxillary sinusitis (Costa et al. 2007). tissue examination in addition to comprehensive
It occurs when the integrity of the sinus membrane medical and dental history taking and medical
is compromised by an odontogenic infection, other assessment. Although rarely seen, the presence
odontogenic pathosis or iatrogenically through sur- of swelling and erythema in the maxillary buccal
gery or displacement of foreign bodies such as sulcus may be indicative of maxillary sinusitis
dental restorative materials or tooth fragments (Brook 2006). Careful clinical and radio-
(even whole teeth) into the sinus (Costa et al. graphical dental examination will identify an
2007). Not surprisingly therefore the microbiology infected tooth or teeth. Nasal and sinus endos-
of maxillary sinusitis of odontogenic origin differs copy, aspiration of sinus contents for cytological
from that of other causes. In both acute and chronic and microbiological assessments, aids diagnosis
infections, anaerobic organisms have been shown (Brook 2006). As with other forms of sinusitis,
to dominate, with anaerobic gram-negative bacilli, CT is the imaging modality of choice (Figs. 48
Peptostreptococcus spp., and Fusobacterium spp. and 49), which will also aid in the identification
being the most common (Brook 2006). Alpha- of odontogenic pathosis and/or the presence of
hemolytic streptococci, microaerophilic strepto- foreign bodies (Brook 2006).
cocci, and Staphylococcus aureus represent the
dominant aerobic organisms (Brook 2006). Patient Management
Clinically, maxillary sinusitis of odontogenic Treatment of maxillary sinusitis of odontogenic
origin may be associated with minimal symptoms origin must focus not only on the management of
as it differs from that of other causes by the absence the sinus infection but also on the elimination of
of osteomeatal obstruction, allowing the sinus to its odontogenic cause (Brook 2006; Costa et al.
drain normally (Brook 2006). Headache, tooth- 2007). Appropriate dental treatment and surgical
ache, anterior maxillary tenderness, nasal conges- intervention (which may involve drainage,
tion, and discharge may occur (Brook 2006). removal of foreign bodies, closure of an oroantral
fistula, and removal of infected unsalvageable
Diagnosis teeth and/or odontogenic cysts) is of primary
Diagnosis of sinus disease of odontogenic origin importance (Costa et al. 2007). Antimicrobial
involves a comprehensive intraoral soft and hard therapy is also essential, and ideally antibiotic
Fig. 48 Maxillary sinusitis of odontogenic origin. Sag- chronic periapical inflammatory lucency (black arrows)
ittal (a) and coronal (b) reconstructions from a multi- associated with the root-filled 16 which protrudes into the
detector CT scan. Extensive mucosal thickening diseased sinus. Vertical impaction of the unerupted 18 is
subtotally opacifies the right maxillary sinus with occlu- also present (Images courtesy of Clinical Associate Pro-
sion of the sinus ostium and infundibulum of the right fessor Andy Whyte, Perth Radiological Clinic, Perth WA,
ostiomeatal unit (black dotted arrow). There is a 10 mm Australia)
Fig. 49 Acute left maxillary sinusitis without an pneumatised (“bubbly”) secretions (white open arrows).
odontogenic aetiology. Coronal (a) and sagittal (b) recon- These findings strongly suggest acute sinusitis. There is no
structions from a multidetector CT scan of the paranasal periapical pathology or significant periodontitis as a cause for
sinuses. The left sinus ostium and ostiomeatal unit (white maxillary sinusitis (b). 28 is vertically impacted and
arrows) are occluded by mucosal thickening and the sinus is unerupted (Images courtesy of Clinical Associate Professor
extensively opacifed by the same process as well as fluid and Andy Whyte, Perth Radiological Clinic, Perth WA, Australia)
selection should be based on the results of culture et al. 2015). More than 230 emm-sequence
sensitivity tests. types have been identified (Good et al. 2015).
The M proteins are capable of interfering with
various host immune responses by interacting
Group A Streptococcal with plasma proteins such as immuno-
Pharyngotonsillitis globulin G, fibrinogen, and the C4-binding pro-
tein (Stjernquist-Desatnik and Orrling 2009).
Etiology and Pathophysiology Other virulence factors include the hyaluronic
capsule, erythrogenic toxins, cysteine proteases,
Acute pharyngotonsillitis is one of the most streptolysins S and O, and streptokinase
common illnesses prompting individuals to (Stjernquist-Desatnik and Orrling 2009). The
seek medical attention (Altamimi et al. 2012; highest incidence of GAS pharyngotonsillitis
Stjernquist-Desatnik and Orrling 2009). While is seen during the winter and the early spring
the disease is more commonly the result of a with half of all cases occurring in children
viral rather than a bacterial infection, group A between the ages of 5–15 years (Altamimi
streptococci are responsible for 15–30% of all et al. 2012; Stjernquist-Desatnik and Orrling
cases (Stjernquist-Desatnik and Orrling 2009; 2009). Asymptomatic pharyngeal carriage also
Shulman et al. 2010; Gerber et al. 2009). The peaks in this age group (Shulman et al. 2010).
group A streptococcus (GAS) (or Streptococcus Person to person transmission, which occurs
pyogenes) is a gram-positive, beta-hemolytic, primarily by inhalation of contaminated drop-
human-specific member of the pyogenic strep- lets or by direct contact with saliva or respira-
tococcus family (Good et al. 2015). Its surface- tory secretions, is facilitated in crowded
associated M protein, encoded by the emm environments such as classrooms, households,
gene, represents the organism’s major virulence and barracks (Shulman et al. 2010). Globally,
factor, and variations in the emm gene are used GAS infections are often indicative of social
to identify the different strains of GAS (Good disadvantage (May et al. 2016).
Clinical-Pathologic Features rash (scarlatina), composed of fine papules that

give the skin the so-called sandpaper feel (Shulman
Although GAS pharyngotonsillitis is generally a et al. 2010; Jaggi and Shulman 2006; Feeney et al.
self-limiting illness, usually lasting 3–5 days even 2005). The rash usually begins on the chest and
in the absence of treatment (following a short abdomen and travels distally, sparing the soles and
incubation period of 2–5 days), its potential com- hands (Paul and Heaton 2014; Feeney et al. 2005).
plications are highly significant, and their preven- Intraorally, a white tongue coating may initially be
tion is the main reason for advocating treatment noted, followed by enlargement of the lingual
(Jaggi and Shulman 2006). These include acute papillae (“strawberry tongue”) (Jaggi and Shulman
rheumatic fever and subsequent rheumatic heart 2006; Paul and Heaton 2014). The cheeks may be
disease, post-streptococcal glomerulonephritis, flushed and circumoral pallor may be noted (Jaggi
post-streptococcal reactive arthritis, Sydenham’s and Shulman 2006). Other signs and symptoms
chorea, and possibly others such as the pediatric include cervical lymphadenopathy and Pastia’s
autoimmune neuropsychiatric disorders associ- lines (accentuation of erythema in flexor skin
ated with streptococci (PANDAS) (Shulman creases of the neck, axillae, groin, elbow, and
et al. 2010; Gerber et al. 2009; May et al. 2016; knees), which may appear petechial or slightly
Jackson et al. 2011; Paul and Heaton 2014; hemorrhagic, headache, fatigue, nausea and
Carapetis et al. 2016). Other potential complica- vomiting, myalgias, and malaise (Shulman et al.
tions include otitis media, acute rhinosinusitis 2010; Paul and Heaton 2014). Rarely complica-
and mastoiditis, peritonsillar abscess, retrop- tions such as mastoiditis, rhinosinusitis, peri-
haryngeal abscess, cervical lymphadenitis, tonsillar abscesses, acute rheumatic fever, or acute
pneumonia, meningitis and brain abscess, endo- renal failure secondary to glomerulonephritis may
carditis, osteomyelitis, and liver abscess (Jack- occur (Feeney et al. 2005).
son et al. 2011; Paul and Heaton 2014; Shulman The classic symptoms of acute GAS
et al. 2012). On a global scale, GAS represents an pharyngotonsillitis include a sudden onset of
important cause of morbidity and mortality, and fever and a sore throat (Shulman et al. 2010;
it is estimated that more than half a million deaths Gerber et al. 2009). Dysphagia, headache, mal-
each year can be attributed to severe GAS dis- aise, abdominal pain, nausea, and vomiting may
eases such as acute rheumatic fever, rheumatic also be present (Stjernquist-Desatnik and Orrling
heart disease, post-streptococcal glomerulone- 2009; Shulman et al. 2010). Examination may
phritis, and invasive infections (Carapetis et al. reveal pharyngeal erythema, uvulitis, enlarged
2005). Rheumatic heart disease represents the tonsils and exudate, palatal petechiae, enlarged
greatest disease burden and is estimated to and tender anterior cervical nodes, and in some
account for 275,000 deaths each year with the cases a scarlet fever rash (Shulman et al. 2010;
highest mortality rates reported in the indigenous Gerber et al. 2009; Jaggi and Shulman 2006).
populations of Australia (Jackson et al. 2011; Early in the course of the disease, the tongue
Carapetis et al. 2016). may have a white coating and later the tongue
On rare occasions, scarlet fever may accom- papillae may be swollen and red (“strawberry
pany GAS pharyngotonsillitis (Jaggi and tongue”) (Shulman et al. 2010). The presence of
Shulman 2006). It represents a syndrome char- cough, rhinitis, stridor, hoarseness, conjunctivi-
acterized by a sore throat, fever, and a rash and tis, and diarrhea usually signal another (i.e.,
is caused by an infection with erythrogenic viral) cause (Shulman et al. 2010; Jaggi and
toxin-producing strains of group A β-hemolytic Shulman 2006). Very young children (under
streptococci (Paul and Heaton 2014; Lamden 3 years of age) may present with low-grade
2011). The illness usually affects children fever, rhinitis, copious purulent coryza with
between the ages of 2 and 8 years and is generally crusting below the nares, diffuse cervical lymph-
mild and self-limiting and characterized by adenopathy, otitis media, and pharyngitis
a distinctive, diffuse, erythematous, blanching (Shulman et al. 2010).
Diagnosis inhibit beta-hemolytic group A streptococci; an

increase in beta-lactamase-producing bacteria
Accurate diagnosis of GAS pharyngotonsillitis inactivating the drug; penicillin-tolerant strepto-
cannot be based on clinical presentation alone as cocci; low antibiotic concentration at the site of
a great deal of overlap exists between the signs infection; and intracellular beta-hemolytic group
and symptoms of GAS and viral infections A streptococci surviving therapy (Stjernquist-
(Stjernquist-Desatnik and Orrling 2009; Shulman Desatnik and Orrling 2009). Although efforts are
et al. 2010; Shulman et al. 2012). Throat swab and underway to develop a vaccine against group A
testing by rapid antigen detection test (RADT) streptococcus to diminish the global disease bur-
and/or culture should therefore be performed den, the need to cover multiple strains and a
(Shulman et al. 2010; Shulman et al. 2012). In standardized immunoassay for efficacy and
children and adolescents only, negative RADT immunogenicity monitoring are currently hinder-
tests should be followed up with a throat culture ing this process (May et al. 2016).
(Shulman et al. 2012).

Patient Management
With the rise of globalization, increased travel,
Although GAS pharyngotonsillitis is a self- and an upsurge in migration, we are experiencing
limiting illness, treatment is recommended for an exponential expansion of communicable bac-
several reasons (Stjernquist-Desatnik and Orrling terial infections. Antibiotic resistance and limited
2009; Jaggi and Shulman 2006). These include development of new antimicrobial, antibacterial,
prevention of the many possible complications, of and antibiotic agents by major pharmaceutical
which acute rheumatic fever is the most impor- companies are hindering our fight against these
tant; symptomatic improvement; and the reduc- infections. Bacterial non-odontogenic infections
tion of contagiousness and disease transmission are increasingly seen in oral medicine practice,
(Stjernquist-Desatnik and Orrling 2009; Shulman adding to the multitude of diseases to be managed,
et al. 2010; Jaggi and Shulman 2006; Shulman but also posing serious challenges in terms of
et al. 2012). The treatment of choice includes a treatment regimes, bacterial resistance, diagnostic
10-day course of penicillin or amoxicillin or, in workflow, and public health messages. With the
penicillin-allergic individuals, a first-generation rise of oral sexual practices, many conditions such
cephalosporin, clindamycin or clarithromycin, or as syphilis and gonorrhea are becoming more
azithromycin for 5 days (Shulman et al. 2012). widespread and their oral manifestations more
Affected individuals cease being contagious 24 h commonly encountered. The contemporary oral
after initiation of treatment (Jaggi and Shulman medicine clinician is expected to keep abreast of
2006). Adjunctive therapy with nonsteroidal anti- changing trends in disease prevalence, to contrib-
inflammatory drugs may also be useful in the ute to wider public health messages, and to pro-
symptomatic management of the illness (Shulman mote antimicrobial stewardship.
et al. 2012).
Despite decades of penicillin use, no
penicillin-resistant beta-hemolytic group A strep- Cross-References
tococcal strains have been encountered, although
treatment failures do occur with failure rates of ▶ Clinical Evaluation of Oral Diseases
5–40% reported (Stjernquist-Desatnik and ▶ Cutaneous Pathology of the Head and Neck
Orrling 2009; Pichichero and Casey 2007). ▶ Diagnostic Imaging Principles and Applica-
Possible reasons include lack of treatment com- tions in Head and Neck Pathology
pliance, re-infection; antibiotic-mediated eradica- ▶ Gingival Pathology
tion of alpha-hemolytic streptococci, which ▶ Interface Between Oral and Systemic Disease
▶ Laboratory Medicine and Diagnostic Pathology Bonnetblanc JM, Bedane C. Erysipelas: recognition and
▶ Odontogenic Bacterial Infections management. Am J Clin Dermatol. 2003;4(3):157–63.
Bowen AC, Mahe A, Hay RJ, Andrews RM, Steer AC,
▶ Oral and Maxillofacial Fungal Infections Tong SY, et al. The global epidemiology of impetigo: a
▶ Oral and Maxillofacial Viral Infections systematic review of the population prevalence of impe-
▶ Oral Manifestations of Systemic Diseases and tigo and pyoderma. PLoS One. 2015;10(8):e0136789.
Their Treatments Bratschi MW, Steinmann P, Wickenden A,
Gillis TP. Current knowledge on Mycobacterium leprae
▶ Oral Ulcerative Lesions transmission: a systematic literature review. Lepr Rev.
▶ Salivary Gland Disorders and Diseases 2015;86(2):142–55.
Brook I. Microbiology and antimicrobial management of
sinusitis. J Laryngol Otol. 2005;119(4):251–8.
Brook I. Sinusitis of odontogenic origin. Otolaryngol Head
References Neck Surg. 2006;135(3):349–55.
Brook I. The bacteriology of salivary gland infections.
Adappa ND, Wei CC, Palmer JN. Nasal irrigation with or Oral Maxillofac Surg Clin North Am. 2009;21
without drugs: the evidence. Curr Opin Otolaryngol (3):269–74.
Head Neck Surg. 2012;20(1):53–7. Brown J, Shriner DL, Schwartz RA, Janniger CK. Impetigo:
Adelson RT, Adappa ND. What is the proper role of oral an update. Int J Dermatol. 2003;42(4):251–5.
antibiotics in the treatment of patients with chronic Bruce AJ, Rogers RS 3rd. Oral manifestations of
sinusitis? Curr Opin Otolaryngol Head Neck Surg. sexually transmitted diseases. Clin Dermatol.
2013;21(1):61–8. 2004;22(6):520–7.
Altamimi S, Khalil A, Khalaiwi KA, Milner RA, Buchanan JAG, Cedro M, Mirdin A, Joseph T, Porter SR,
Pusic MV, Al Othman MA. Short-term late-generation Hodgson TA. Clinical concise report: Necrotising sto-
antibiotics versus longer term penicillin for acute strep- matitis in the developed world. Clinical and Experi-
tococcal pharyngitis in children. Cochrane Database mental Dermatology 2006;31:372–374
Syst Rev. 2012;8:CD004872. Carapetis JR, Steer AC, Mulholland EK, Weber M. The
Aring AM, Chan MM. Current concepts in adult acute global burden of group A streptococcal diseases.
rhinosinusitis. Am Fam Physician. 2016;94(2):97–105. Lancet Infect Dis. 2005;5(11):685–94.
Ashok N, Tarakji B, Darwish S, Rodrigues JC, Altamimi Carapetis JR, Beaton A, Cunningham MW, Guilherme L,
MA. A review on noma: a recent update. Glob J Health Karthikeyan G, Mayosi BM, et al. Acute rheumatic
Sci. 2015;8(4):53–9. fever and rheumatic heart disease. Nat Rev Dis Primers.
Balmelli C, Gunthard HF. Gonococcal tonsillar infection – 2016;2:15084.
a case report and literature review. Infection. 2003;31 Carithers HA. Cat-scratch disease. An overview based on a
(5):362–5. study of 1,200 patients. Am J Dis Child.
Bangert S, Levy M, Hebert AA. Bacterial resistance and 1985;139(11):1124–33.
impetigo treatment trends: a review. Pediatr Dermatol. Carlson ER. Diagnosis and management of salivary gland
2012;29(3):243–8. infections. Oral Maxillofac Surg Clin North
Baratti-Mayer D, Gayet-Ageron A, Hugonnet S, Am. 2009;21(3):293–312.
Francois P, Pittet-Cuenod B, Huyghe A, et al. Risk Cascarini L, McGurk M. Epidemiology of salivary gland
factors for noma disease: a 6-year, prospective, infections. Oral Maxillofac Surg Clin North
matched case-control study in Niger. Lancet Glob Am. 2009;21(3):353–7.
Health. 2013;1(2):e87–96. Centers for Disease Control and Prevention. Gonorrhea.
Barr YR, Qiu S. A 16-year-old adolescent boy with unilat- https://www.cdc.gov/std/Gonorrhea/ (2015).
eral cervical lymphadenopathy suspicious for malig- Centers for Disease Control and Prevention. Diphtheria.
nancy. Arch Pathol Lab Med. 2005;129(8):1065–6. https://www.cdc.gov/diphtheria/index.html (2016a).
Barrett AW, Villarroel Dorrego M, Hodgson TA, Centers for Disease Control and Prevention. Summary of
Porter SR, Hopper C, Argiriadou AS, et al. The histo- infection prevention practices in dental settings: basic
pathology of syphilis of the oral mucosa. J Oral Pathol expectations for safe care. Atlanta: Centers for Disease
Med. 2004;33(5):286–91. Control and Prevention, US Dept of Health and Human
Blackberg A, Trell K, Rasmussen M. Erysipelas, a large Services; 2016b.
retrospective study of aetiology and clinical presenta- Chawla K, Mukhopadhayay C, Shetty PV. First report of
tion. BMC Infect Dis. 2015;15:402. submandibular and parotid abscess due to Nocardia
Bonnefond S, Catroux M, Melenotte C, Karkowski L, asteroides. Braz J Infect Dis. 2010;14(5):544–5.
Rolland L, Trouillier S, et al. Clinical features of acti- Chiu AG, Hecht DA, Prendiville SA, Mesick C, Mikula S,
nomycosis: a retrospective, multicenter study of Deeb ZE. Atypical presentations of cat scratch disease
28 cases of miscellaneous presentations. Medicine in the head and neck. Otolaryngol Head Neck Surg.
(Baltimore). 2016;95(24):e3923. 2001;125(4):414–6.
Chow AW, Benninger MS, Brook I, Brozek JL, the cost of hospital treatment. Br Dent
Goldstein EJ, Hicks LA, et al. IDSA clinical practice J. 1999;186(9):463–6.
guideline for acute bacterial rhinosinusitis in children Faergemann J, Dahlen G. Facial skin infections.
and adults. Clin Infect Dis. 2012;54(8):e72–e112. Periodontol. 2009;49:194–209.
Christensen L, Evans H, Cundick D, McShane M, Farfour E, Badell E, Dinu S, Guillot S,
Penna K, Sadoff R. Necrotizing fasciltis case presenta- Guiso N. Microbiological changes and diversity in
tion and literature review. N Y State Dent J. 2015;81 autochthonous non-toxigenic Corynebacterium
(4):24–8. diphtheriae isolated in France. Clin Microbiol Infect.
Compilato D, Amato S, Campisi G. Resurgence of syphi- 2013;19(10):980–7.
lis: a diagnosis based on unusual oral mucosa lesions. Feeney KT, Dowse GK, Keil AD, Mackaay C,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. McLellan D. Epidemiological features and control of
2009;108(3):e45–9. an outbreak of scarlet fever in a Perth primary school.
Corazza M, Ligrone L, Libanore M, Virgili A. Primary Commun Dis Intell Q Rep. 2005;29(4):386–90.
cervicofacial nocardiosis due to nocardia asteroides in Feldt B, Dion GR, Weitzel EK, McMains KC. Acute sinus-
an adult immunocompetent patient. Acta Derm itis. South Med J. 2013;106(10):577–81.
Venereol. 2002;82(5):391–2. Feller L, Altini M, Chandran R, Khammissa RA,
Costa A, Nery J, Oliveira M, Cuzzi T, Silva M. Oral lesions Masipa JN, Mohamed A, et al. Noma (cancrum oris)
in leprosy. Indian J Dermatol Venereol Leprol. in the South African context. J Oral Pathol Med.
2003;69(6):381–5. 2014;43(1):1–6.
Costa F, Emanuelli E, Robiony M, Zerman N, Polini F, Ficarra G, Carlos R. Syphilis: the renaissance of an old
Politi M. Endoscopic surgical treatment of chronic disease with oral implications. Head Neck Pathol.
maxillary sinusitis of dental origin. J Oral Maxillofac 2009;3(3):195–206.
Surg. 2007;65(2):223–8. FitzGerald RP, Rosser AJ, Perera DN. Non-toxigenic pen-
Crossman T, Herold J. Actinomycosis of the maxilla – a icillin-resistant cutaneous C. diphtheriae infection: a
case report of a rare oral infection presenting in general case report and review of the literature. J Infect Public
dental practice. Br Dent J. 2009;206(4):201–2. Health. 2015;8(1):98–100.
Cruz-Knight W, Blake-Gumbs L. Tuberculosis: an over- Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I,
view. Prim Care. 2013;40(3):743–56. Baroody F, et al. European position paper on
Curi MM, Dib LL, Kowalski LP, Landman G, rhinosinusitis and nasal polyps 2012. Rhinol Suppl.
Mangini C. Opportunistic actinomycosis in osteoradio- 2012(23):3 p preceding table of contents, pp. 1–298.
necrosis of the jaws in patients affected by head and Forer M. Clinical update – the teeth and the maxillary
neck cancer: incidence and clinical significance. Oral sinus: the mutual impact of clinical procedures, disease
Oncol. 2000;36(3):294–9. conditions and their treatment implications. Part
Czerninski R, Pikovski A, Meir K, Casap N, Moses AE, 5. Medical and surgical management of sinusitis. Aust
Maly A. Oral syphilis lesions – a diagnostic approach Endod J. 1999;25(1):40–1.
and histologic characteristics of secondary stage. Galazka A. The changing epidemiology of diphtheria in
Quintessence Int. 2011;42(10):883–9. the vaccine era. J Infect Dis. 2000;181(Suppl 1):S2–9.
Dave B, Bedi R. Leprosy and its dental management Gerber MA, Baltimore RS, Eaton CB, Gewitz M, Rowley
guidelines. Int Dent J. 2013;63(2):65–71. AH, Shulman ST, et al. Prevention of rheumatic fever
de Abreu MA, Alchorne MM, Michalany NS, Weckx LL, and diagnosis and treatment of acute Streptococcal
Pimentel DR, Hirata CH. The oral mucosa in pharyngitis: a scientific statement from the American
paucibacillary leprosy: a clinical and histopathological Heart Association Rheumatic Fever, Endocarditis, and
study. Oral Surg Oral Med Oral Pathol Oral Radiol Kawasaki Disease Committee of the Council on Car-
Endod. 2007;103(5):e48–52. diovascular Disease in the Young, the Interdisciplinary
de Paulo LF, Servato JP, Oliveira MT, Durighetto AF Jr, Council on Functional Genomics and Translational
Zanetta-Barbosa D. Oral manifestations of secondary Biology, and the Interdisciplinary Council on Quality
syphilis. Int J Infect Dis. 2015;35:40–2. of Care and Outcomes Research: endorsed by the
Dean RL, Eisenbeis JF. Neck abscess secondary to cat-scratch American Academy of Pediatrics. Circulation.
disease. Ear Nose Throat J. 2004;83(11):781–3. 2009;119(11):1541–51.
DeCastro A, Mims L, Hueston WJ. Rhinosinusitis. Prim Giunta JL. Comparison of erysipelas and odontogenic cel-
Care. 2014;41(1):47–61. lulitis. J Endod. 1987;13(6):291–4.
dos Santos RP, Cartell A, Goldani LZ. An HIV-positive Giunta JL, Fiumara NJ. Facts about gonorrhea and dentistry.
patient with cervical lymphadenopathy and skin Oral Surg Oral Med Oral Pathol. 1986;62(5):529–31.
lesions. Clin Infect Dis. 2007;44(6):849. 84-5 Good MF, Pandey M, Batzloff MR, Tyrrell GJ. Strategic
Enwonwu CO, Falkler WA Jr, Phillips RS. Noma (cancrum development of the conserved region of the M protein
oris). Lancet. 2006;368(9530):147–56. and other candidates as vaccines to prevent infection
Escudier MP, McGurk M. Symptomatic sialoadenitis and with group A streptococci. Expert Rev Vaccines.
sialolithiasis in the English population, an estimate of 2015;14(11):1459–70.
Hadfield TL, McEvoy P, Polotsky Y, Tzinserling VA, Kaper NM, Breukel L, Venekamp RP, Grolman W, van der
Yakovlev AA. The pathology of diphtheria. J Infect Heijden GJ. Absence of evidence for enhanced benefit of
Dis. 2000;181(Suppl 1):S116–20. antibiotic therapy on recurrent acute rhinosinusitis epi-
Haggerty CJ, Tender GC. Actinomycotic brain abscess and sodes: a systematic review of the evidence base.
subdural empyema of odontogenic origin: case report Otolaryngol Head Neck Surg. 2013;149(5):664–7.
and review of the literature. J Oral Maxillofac Surg. Kaplan I, Anavi K, Anavi Y, Calderon S, Schwartz-
2012;70(3):e210–3. Arad D, Teicher S, et al. The clinical spectrum of
Hamilos DL. Host-microbial interactions in patients with Actinomyces-associated lesions of the oral mucosa
chronic rhinosinusitis. J Allergy Clin Immunol. and jawbones: correlations with histomorphometric
2014;133(3):640–53. e4 analysis. Oral Surg Oral Med Oral Pathol Oral Radiol
Hannula-Jouppi K, Massinen S, Siljander T, Makela S, Endod. 2009;108(5):738–46.
Kivinen K, Leinonen R, et al. Genetic susceptibility Kar HK, Gupta R. Treatment of leprosy. Clin Dermatol.
to non-necrotizing erysipelas/cellulitis. PLoS One. 2015;33(1):55–65.
2013;8(2):e56225. Kelner N, Rabelo GD, da Cruz Perez DE, Assuncao JN Jr,
Hansen T, Kunkel M, Springer E, Walter C, Weber A, Witzel AL, Migliari DA, et al. Analysis of nonspecific
Siegel E, et al. Actinomycosis of the jaws – histopath- oral mucosal and dermal lesions suggestive of syphilis:
ological study of 45 patients shows significant involve- a report of 6 cases. Oral Surg Oral Med Oral Pathol Oral
ment in bisphosphonate-associated osteonecrosis and Radiol. 2014;117(1):1–7.
infected osteoradionecrosis. Virchows Arch. Kilburn SA, Featherstone P, Higgins B,
2007;451(6):1009–17. Brindle R. Interventions for cellulitis and erysipelas.
Head K, Chong LY, Piromchai P, Hopkins C, Philpott C, Cochrane Database Syst Rev. 2010;6:CD004299.
Schilder AG, et al. Systemic and topical antibiotics for Kolokotronis A, Antoniadis D, Trigonidis G, Papanagiotou.
chronic rhinosinusitis. Cochrane Database Syst Rev. Oral tuberculosis. Oral Dis. 1996;2(3):242–3.
2016;4:CD011994. Kolokotronis A, Doumas S, Lambroudi M, Lysitsa S,
Hirschmann JV. Impetigo: etiology and therapy. Curr Clin Epivatianos A, Antoniades D. Facial and perioral pri-
Top Infect Dis. 2002;22:42–51. mary impetigo: a clinical study. J Clin Pediatr Dent.
Hodgson TA, Rachanis CC. Oral fungal and bacterial 2005;29(4):341–5.
infections in HIV-infected individuals: an overview in Kolokotronis A, Avramidou E, Zaraboukas T,
Africa. Oral Dis. 2002;8(Suppl 2):80–7. Mandraveli K, Alexiou S, Antoniades D. Oral tubercu-
Holmes S, Gleeson MJ, Cawson RA. Mycobacterial dis- losis associated with a treatment with anti-rheumatic
ease of the parotid gland. Oral Surg Oral Med Oral drugs. J Oral Pathol Med. 2006;35(2):123–5.
Pathol Oral Radiol Endod. 2000;90(3):292–8. Koning S, van der Sande R, Verhagen AP, van Suijlekom-
Huang A, Govindaraj S. Topical therapy in the manage- Smit LW, Morris AD, Butler CC, et al. Interventions for
ment of chronic rhinosinusitis. Curr Opin Otolaryngol impetigo. Cochrane Database Syst Rev. 2012;1:
Head Neck Surg. 2013;21(1):31–8. CD003261.
Inghammar M, Rasmussen M, Linder A. Recurrent erysip- Krasagakis K, Valachis A, Maniatakis P, Kruger-
elas – risk factors and clinical presentation. BMC Infect Krasagakis S, Samonis G, Tosca AD. Analysis of epi-
Dis. 2014;14:270. demiology, clinical features and management of ery-
Jackson SJ, Steer AC, Campbell H. Systematic review: sipelas. Int J Dermatol. 2010;49(9):1012–7.
estimation of global burden of non-suppurative Kumar TS, Scott JX, Viswanathan S, Agarwal I, Raj PM,
sequelae of upper respiratory tract infection: rheumatic Lalitha MK. Cervicofacial nocardiosis in an immuno-
fever and post-streptococcal glomerulonephritis. competent child. Acta Paediatr. 2005;94(9):1342–3.
Tropical Med Int Health. 2011;16(1):2–11. Lamden KH. An outbreak of scarlet fever in a primary
Jaggi P, Shulman ST. Group A streptococcal infections. school. Arch Dis Child. 2011;96(4):394–7.
Pediatr Rev. 2006;27(3):99–105. Lemiengre MB, van Driel ML, Merenstein D, Young J, De
Jensen PA, Lambert LA, Iademarco MF, Ridzon R, CDC. Sutter AI. Antibiotics for clinically diagnosed acute
Guidelines for preventing the transmission of Myco- rhinosinusitis in adults. Cochrane Database Syst Rev.
bacterium tuberculosis in health-care settings, 2005. 2012;10:CD006089.
MMWR Recomm Rep. 2005;54(RR-17):1–141. Leuci S, Martina S, Adamo D, Ruoppo E, Santarelli A,
Jin SL, Lee HP, Kim JI, Chin JY, Choi SJ, Joo M, et al. A Sorrentino R, et al. Oral syphilis: a retrospective anal-
case of endobronchial actinomycosis. Korean J Intern ysis of 12 cases and a review of the literature. Oral Dis.
Med. 2000;15(3):240–4. 2013;19(8):738–46.
Johnston JC, Shahidi NC, Sadatsafavi M, Lindeboom JA. Pediatric cervicofacial lymphadenitis
Fitzgerald JM. Treatment outcomes of multidrug- caused by Bartonella henselae. Oral Surg Oral Med
resistant tuberculosis: a systematic review and meta- Oral Pathol Oral Radiol. 2015;120(4):469–73.
analysis. PLoS One. 2009;4(9):e6914. Little JW. Syphilis: an update. Oral Surg Oral Med Oral
Kakisi OK, Kechagia AS, Kakisis IK, Rafailidis PI, Pathol Oral Radiol Endod. 2005;100(1):3–9.
Falagas ME. Tuberculosis of the oral cavity: a system- Little JW. Gonorrhea: update. Oral Surg Oral Med Oral
atic review. Eur J Oral Sci. 2010;118(2):103–9. Pathol Oral Radiol Endod. 2006;101(2):137–43.
Lo Muzio L, Favia G, Lacaita M, De Lillo A, Scully C, Mustafa AHK. Orofacial manifestations of leprosy: a
Napoli A, et al. The contribution of histopathological review. IOSR J Dent Med Sci. 2015;14(6):77–9.
examination to the diagnosis of cervico-facial actino- Nahid P, Dorman SE, Alipanah N, Barry PM, Brozek JL,
mycosis: a retrospective analysis of 68 cases. Eur J Clin Cattamanchi A, et al. Official American Thoracic Soci-
Microbiol Infect Dis. 2014;33(11):1915–8. ety/Centers for Disease Control and Prevention/Infec-
Mahdavinia M, Keshavarzian A, Tobin MC, Landay AL, tious Diseases Society of America Clinical Practice
Schleimer RPA. comprehensive review of the nasal Guidelines: Treatment of drug-susceptible tuberculo-
microbiome in chronic rhinosinusitis (CRS). Clin Exp sis. Clin Infect Dis. 2016;63(7):e147–95.
Allergy. 2016;46(1):21–41. Nelson CA, Saha S, Mead PS. Cat-scratch disease in the
Markina SS, Maksimova NM, Vitek CR, Bogatyreva EY, United States, 2005–2013. Emerg Infect Dis.
Monisov AA. Diphtheria in the Russian Federation in 2016;22(10):1741–6.
the 1990s. J Infect Dis. 2000;181(Suppl 1):S27–34. Newman L, Rowley J, Vander Hoorn S, Wijesooriya NS,
Marta SN, Sgavioli C, Saraiva PP, Carvalho RS, Unemo M, Low N, et al. Global estimates of the
Nogueira MG, Monti FC, et al. Evaluation of light- prevalence and incidence of four curable sexually
touch sensation in the buccal mucosa of leprosy transmitted infections in 2012 based on systematic
patients. Clin Oral Investig. 2014;18(8):1913–7. review and global reporting. PLoS One. 2015;10
Martins MD, Russo MP, Lemos JB, Fernandes KP, (12):e0143304.
Bussadori SK, Correa CT, et al. Orofacial lesions in O’Connor K, Paauw D. Erysipelas: rare but important
treated southeast Brazilian leprosy patients: a cross- cause of malar rash. Am J Med. 2010;123(5):414–6.
sectional study. Oral Dis. 2007;13(3):270–3. Ochs MW, Dolwick MF. Facial erysipelas: report of a case
Masipa JN, Baloyi AM, Khammissa RA, Altini M, and review of the literature. J Oral Maxillofac Surg.
Lemmer J, Feller L. Noma (cancrum oris): a report 1991;49(10):1116–20.
of a case in a young AIDS patient with a review Outhred AC, Watts MR, Chen SC, Sorrell TC. Nocardia
of the pathogenesis. Head Neck Pathol. 2013;7 infections of the face and neck. Curr Infect Dis Rep.
(2):188–92. 2011;13(2):132–40.
May PJ, Bowen AC, Carapetis JR. The inequitable burden Paul SP, Heaton PA. At a glance: scarlet fever in children.
of group A streptococcal diseases in Indigenous J Fam Health Care. 2014;24(3):25–7.
Australians. Med J Aust. 2016;205(5):201–3. Paz Maya S, Dualde Beltran D, Lemercier P, Leiva-
McMahon J, Lowe T, Koppel DA. Necrotizing soft tissue Salinas C. Necrotizing fasciitis: an urgent diagnosis.
infections of the head and neck: case reports and liter- Skelet Radiol. 2014;43(5):577–89.
ature review. Oral Surg Oral Med Oral Pathol Oral Pereira RMS, Silva TSO, Silva LS, Santos TC,
Radiol Endod. 2003;95(1):30–7. Falcao CAM, Pinto LSS. Orofacial and dental condi-
Miller M, Haddad AJ. Cervicofacial actinomycosis. Oral tion in leprosy. Braz J Oral Sci. 2013;12(4):330–4.
Surg Oral Med Oral Pathol Oral Radiol Endod. 1998;85 Pichichero ME, Casey JR. Systematic review of factors
(5):496–508. contributing to penicillin treatment failure in Strepto-
Mina NV, Burdz T, Wiebe D, Rai JS, Rahim T, Shing F, coccus pyogenes pharyngitis. Otolaryngol Head Neck
et al. Canada’s first case of a multidrug-resistant Cory- Surg. 2007;137(6):851–7.
nebacterium diphtheriae strain, isolated from a skin Ramakrishnan VR, Hauser LJ, Frank DN. The sinonasal
abscess. J Clin Microbiol. 2011;49(11):4003–5. bacterial microbiome in health and disease. Curr Opin
Miziara ID. Tuberculosis affecting the oral cavity in Otolaryngol Head Neck Surg. 2016;24(1):20–5.
Brazilian HIV-infected patients. Oral Surg Oral Med Ramos-e-Silva M, Rebello PF. Leprosy. Recognition and
Oral Pathol Oral Radiol Endod. 2005;100(2):179–82. treatment. Am J Clin Dermatol. 2001;2(4):203–11.
Moghimi M, Salentijn E, Debets-Ossenkop Y, Ray M, Marwaha RK, Trehan A, Banerjee AK. Palatal
Karagozoglu KH, Forouzanfar T. Treatment of nerve palsy and cervical adenopathy in a probable
cervicofacial actinomycosis: a report of 19 cases and case with cat scratch disease. Indian Pediatr.
review of literature. Med Oral Patol Oral Cir Bucal. 1999;36(11):1154–7.
2013;18(4):e627–32. Reichart P, Ananatasan T, Reznik G. Gingiva and peri-
Moore LS, Leslie A, Meltzer M, Sandison A, Efstratiou A, odontium in lepromatous leprosy. A clinical, radiolog-
Sriskandan S. Corynebacterium ulcerans cutaneous ical, and microscopical study. J Periodontol.
diphtheria. Lancet Infect Dis. 2015;15(9):1100–7. 1976;47(8):455–60.
Motta AC, Komesu MC, Silva CH, Arruda D, Simao JC, Reichart PA, Samaranayake LP, Bendick C, Schmidt-
Zenha EM, et al. Leprosy-specific oral lesions: a report Westhausen AM, Jayatilake JA. Prevalence of oral
of three cases. Med Oral Patol Oral Cir Bucal. Candida species in leprosy patients from
2008;13(8):E479–82. Cambodia and Thailand. J Oral Pathol Med.
Munson PD, Boyce TG, Salomao DR, 2007;36(6):342–6.
Orvidas LJ. Cat-scratch disease of the head and Ricucci D, Siqueira JF Jr. Apical actinomycosis as a con-
neck in a pediatric population: surgical indications tinuum of intraradicular and extraradicular infection:
and outcomes. Otolaryngol Head Neck Surg. case report and critical review on its involvement with
2008;139(3):358–63. treatment failure. J Endod. 2008;34(9):1124–9.
Ridder GJ, Boedeker CC, Technau-Ihling K, Grunow R, to management. Expert Rev Anti-Infect Ther.
Sander A. Role of cat-scratch disease in lymphadenop- 2010;8(2):137–50.
athy in the head and neck. Clin Infect Dis. Shulman ST, Bisno AL, Clegg HW, Gerber MA,
2002;35(6):643–9. Kaplan EL, Lee G, et al. Clinical practice guideline
Ridder GJ, Boedeker CC, Technau-Ihling K, for the diagnosis and management of group A strepto-
Sander A. Cat-scratch disease: Otolaryngologic mani- coccal pharyngitis: 2012 update by the Infectious Dis-
festations and management. Otolaryngol Head Neck eases Society of America. Clin Infect Dis. 2012;55(10):
Surg. 2005;132(3):353–8. e86–102.
Robinson JL, Vaudry WL, Dobrovolsky W. Actinomycosis Siegel MA. Syphilis and gonorrhea. Dent Clin N
presenting as osteomyelitis in the pediatric population. Am. 1996;40(2):369–83.
Pediatr Infect Dis J. 2005;24(4):365–9. Singhaniya SB, Barpande SR, Bhavthankar JD. Oral tuber-
Rogstad KE, Wilkinson D, Robinson A. Sexually transmit- culosis in an asymptomatic pulmonary tuberculosis.
ted infections in children as a marker of child sexual Oral Surg Oral Med Oral Pathol Oral Radiol Endod.
abuse and direction of future research. Curr Opin Infect 2011;111(3):e8–10.
Dis. 2016;29(1):41–4. Smith I. Mycobacterium tuberculosis pathogenesis and
Romani L, Steer AC, Whitfeld MJ, Kaldor JM. Prevalence molecular determinants of virulence. Clin Microbiol
of scabies and impetigo worldwide: a systematic Rev. 2003;16(3):463–96.
review. Lancet Infect Dis. 2015;15(8):960–7. Smith MH, Harms PW, Newton DW, Lebar B, Edwards SP,
Russell PT, Bekeny JR. Oral antibiotics and the manage- Aronoff DM. Mandibular Actinomyces osteomyelitis
ment of chronic sinusitis: what do we know? Curr Opin complicating florid cemento-osseous dysplasia: case
Otolaryngol Head Neck Surg. 2014;22(1):22–6. report. BMC Oral Health. 2011;11:21.
Samaranayake P. Re-emergence of tuberculosis and its Soler ZM, Oyer SL, Kern RC, Senior BA, Kountakis SE,
variants: implications for dentistry. Int Dent Marple BF, et al. Antimicrobials and chronic
J. 2002;52(5):330–6. rhinosinusitis with or without polyposis in adults: an
Sandhu GK. Tuberculosis: current situation, challenges evidenced-based review with recommendations. Int
and overview of its control programs in India. J Glob Forum Allergy Rhinol. 2013;3(1):31–47.
Infect Dis. 2011;3(2):143–50. Souza VA, Emmerich A, Coutinho EM, Freitas MG, Silva
Santos LS, Sant’anna LO, Ramos JN, Ladeira EM, EH, Mercon FG, et al. Dental and oral condition in
Stavracakis-Peixoto R, Borges LL, et al. Diphtheria leprosy patients from Serra, Brazil. Lepr Rev. 2009;80
outbreak in Maranhao, Brazil: microbiological, clinical (2):156–63.
and epidemiological aspects. Epidemiol Infect. Srour ML, Marck K, Baratti-Mayer D. Noma: overview of
2015;143(4):791–8. a neglected disease and human rights violation. Am J
Sarber KM, Dion GR, Weitzel EK, McMains KC. Trop Med Hyg. 2017;96(2):268–74.
Approaching chronic sinusitis. South Med Stamm LV. Syphilis: antibiotic treatment and resistance.
J. 2013;106(11):642–8. Epidemiol Infect. 2015;143(8):1567–74.
Saunderson PR. Drug-resistant M leprae. Clin Dermatol. Stevens DL, Bisno AL, Chambers HF, Dellinger EP,
2016;34(1):79–81. Goldstein EJ, Gorbach SL, et al. Practice guidelines for
Schlaberg R, Huard RC, Della-Latta P. Nocardia the diagnosis and management of skin and soft tissue
cyriacigeorgica, an emerging pathogen in the United infections: 2014 update by the Infectious Diseases Soci-
States. J Clin Microbiol. 2008;46(1):265–73. ety of America. Clin Infect Dis. 2014;59(2):e10–52.
Schwartz JS, Tajudeen BA, Cohen NA. Medical manage- Stjernquist-Desatnik A, Orrling A. Pharyngotonsillitis.
ment of chronic rhinosinusitis – an update. Expert Rev Periodontol. 2009;49:140–50.
Clin Pharmacol. 2016;9(5):695–704. Suarez A, Vicente M, Tomas JA, Floria LM, Delhom J,
Scollard DM, Skinsnes OK. Oropharyngeal leprosy in art, Baquero MC. Cervical necrotizing fasciitis of non-
history, and medicine. Oral Surg Oral Med Oral Pathol odontogenic origin: case report and review of literature.
Oral Radiol Endod. 1999;87(4):463–70. Am J Emerg Med. 2014;32(11):1441. e5–6.
Sethi A, Sareen D, Sabherwal A, Malhotra V. Primary Taheri JB, Mortazavi H, Moshfeghi M, Bakhshi M,
parotid tuberculosis: varied clinical presentations. Bakhtiari S, Azari-Marhabi S, et al. Oro-facial mani-
Oral Dis. 2006;12(2):213–5. festations of 100 leprosy patients. Med Oral Patol Oral
Sevigny LM, Booth BJ, Rowley KJ, Leav BA, Cir Bucal. 2012;17(5):e728–32.
Cheslock PS, Garrity KA, et al. Identification of a Torok L. Uncommon manifestations of erysipelas. Clin
human monoclonal antibody to replace equine diphthe- Dermatol. 2005;23(5):515–8.
ria antitoxin for treatment of diphtheria intoxication. Tovaru S, Costache M, Sardella A. Primary oral tubercu-
Infect Immun. 2013;81(11):3992–4000. losis: a case series from Bucharest, Romania. Oral Surg
Ship JA. Diagnosing, managing, and preventing salivary Oral Med Oral Pathol Oral Radiol Endod. 2008;105(5):
gland disorders. Oral Dis. 2002;8(2):77–89. e41–5.
Shulman ST, Tanz RR, Group A. streptococcal pharyngitis Troeltzsch M, Pache C, Probst FA, Troeltzsch M,
and immune-mediated complications: from diagnosis Ehrenfeld M, Otto S. Antibiotic concentrations in
saliva: a systematic review of the literature, with clin- high-throughput sequencing of 16S rRNA gene frag-
ical implications for the treatment of sialadenitis. J Oral ments. PLoS Negl Trop Dis. 2014;8(12):e3240.
Maxillofac Surg. 2014;72(1):67–75. Williams LN. The risks of oral-genital contact: a case
Uhde KB, Pathak S, McCullum I Jr, Jannat-Khah DP, report. Gen Dent. 2002;50(3):282–4.
Shadomy SV, Dykewicz CA, et al. Antimicrobial- Wilson JW. Nocardiosis: updates and clinical overview.
resistant nocardia isolates, United States, 1995–2004. Mayo Clin Proc. 2012;87(4):403–7.
Clin Infect Dis. 2010;51(12):1445–8. Wolf H, Rusan M, Lambertsen K, Ovesen T. Necrotizing
Unemo M, Shafer WM. Antimicrobial resistance in fasciitis of the head and neck. Head Neck.
Neisseria gonorrheae in the 21st century: past, evolution, 2010;32(12):1592–6.
and future. Clin Microbiol Rev. 2014;27(3):587–613. Workowski KA, Bolan GA, Centers for Disease Control
United Nations, General Assembly, Study of the Human and Prevention. Sexually transmitted diseases treat-
Rights Council Advisory Committee on severe mal- ment guidelines, 2015. MMWR Recomm Rep.
nutrition and childhood diseases with children 2015;64(RR-03):1–137.
affected by noma as an example, General, A/HRC/ World Health Organization. Guidelines for the program-
19/73 (24 Feb 2012). https://documents-dds-ny.un. matic management of drug-resistant tuberculosis:
org/doc/UNDOC/GEN/G12/107/96/PDF/G1210796. 2011 update. http://apps.who.int/iris/bitstream/10665/
pdf?OpenElement. 2012. 44597/1/9789241501583_eng.pdf (2011).
Valour F, Senechal A, Dupieux C, Karsenty J, Lustig S, World Health Organization. Global leprosy update, 2015:
Breton P, et al. Actinomycosis: etiology, clinical fea- time for action, accountability and inclusion. Wkly
tures, diagnosis, treatment, and management. Infect Epidemiol Rec. 2015;91(35):405–20.
Drug Resist. 2014;7:183–97. World Health Organization. Global tuberculosis report
van den Broek M, Gudden C, Kluijfhout W, Stam-Slob M, 2016. http://www.searo.who.int/tb/documents/global-
Aarts M, Kaper N, et al. No evidence for distinguishing tuberculosis-report-2016/en/ (2016).
bacterial from viral acute rhinosinusitis using symptom World Health Organization. Leprosy elimination – WHO
duration and purulent rhinorrhea: a systematic review recommended MDT regimens. http://www.who.int/lep/
of the evidence base. Otolaryngol Head Neck Surg. mdt/regimens/en/ (2017a).
2014;150(4):533–7. World Health Organization. Immunization, vaccines and
Vinals-Iglesias H, Chimenos-Kustner E. The reappearance biologicals. Diphtheria. http://www.who.int/immuniza
of a forgotten disease in the oral cavity: syphilis. Med tion/diseases/diphtheria/en/ (2017b).
Oral Patol Oral Cir Bucal. 2009;14(9):e416–20. Yadav S, Verma A, Sachdeva A. Facial necrotizing fasciitis
Wagner KS, White JM, Crowcroft NS, De Martin S, from an odontogenic infection. Oral Surg Oral Med
Mann G, Efstratiou A. Diphtheria in the United Oral Pathol Oral Radiol. 2012;113(2):e1–4.
Kingdom, 1986–2008: the increasing role of Coryne- Yepes JF, Sullivan J, Pinto A. Tuberculosis: medical man-
bacterium ulcerans. Epidemiol Infect. 2010;138(11): agement update. Oral Surg Oral Med Oral Pathol Oral
1519–30. Radiol Endod. 2004;98(3):267–73.
Wang WC, Chen JY, Chen YK, Lin LM. Tuberculosis of Zakikhany K, Efstratiou A. Diphtheria in Europe: current
the head and neck: a review of 20 cases. Oral Surg problems and new challenges. Future Microbiol.
Oral Med Oral Pathol Oral Radiol Endod. 2009a; 2012;7(5):595–607.
107(3):381–6. Zenk J, Iro H, Klintworth N, Lell M. Diagnostic imaging in
Wang S, Marchal F, Zou Z, Zhou J, Qi S. Classification and sialadenitis. Oral Maxillofac Surg Clin North
management of chronic sialadenitis of the parotid Am. 2009;21(3):275–92.
gland. J Oral Rehabil. 2009b;36(1):2–8. Zignol M, Dean AS, Falzon D, van Gemert W, Wright A,
Welsh O, Vera-Cabrera L, Salinas-Carmona MC. Current van Deun A, et al. Twenty years of global surveillance
treatment for nocardia infections. Expert Opin of antituberculosis-drug resistance. N Engl J Med.
Pharmacother. 2013;14(17):2387–98. 2016;375(11):1081–9.
White C, Franco-Paredes C. Leprosy in the 21st century. Zuur MA, Bolhuis MS, Anthony R, den Hertog A, van der
Clin Microbiol Rev. 2015;28(1):80–94. Laan T, Wilffert B, et al. Current status and opportuni-
Whiteson KL, Lazarevic V, Tangomo-Bento M, Girard M, ties for therapeutic drug monitoring in the treatment of
Maughan H, Pittet D, et al. Noma affected children from tuberculosis. Expert Opin Drug Metab Toxicol.
Niger have distinct oral microbial communities based on 2016;12(5):509–21.
Oral and Maxillofacial Fungal Infections
Maddalena Manfredi, Luciano Polonelli, Laura Giovati,

Ali Alnuaimi, and Michael J. McCullough
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936
Carriage of Candida and Non-Candida Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 937
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 939
Virulence Factors of Candida and Non-Candida spp. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 939
Predisposing Factors to Oral and Maxillofacial Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 945
Pathophysiology and Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 948
Candidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 948
Aspergillosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 955
Mucormycosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 955
Histoplasmosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 956
Cryptococcosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 958
Blastomycosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 960
Paracoccidioidomycosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 960
Patient Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 961
Laboratory Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 962
Specific Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 967
M. Manfredi
Dipartimento di Medicina e Chirurgia, Centro
Universitario di Odontoiatria, University of Parma,
Parma, Italy
e-mail: maddalena.manfredi@unipr.it
L. Polonelli · L. Giovati
Dipartimento di Medicina e Chirurgia, University of
Parma, Parma, Italy
e-mail: luciano.polonelli@unipr.it; laura.giovati@unipr.it
A. Alnuaimi · M. J. McCullough (*)
Oral Anatomy, Medicine, and Surgery Section, Melbourne,
Dental School, Faculty of Medicine, Dentistry and Health,
Sciences, The University of Melbourne,
e-mail: ali.alnuaimi@unimelb.edu.au;
m.mccullough@unimelb.edu.au

https://doi.org/10.1007/978-3-319-72303-7_1
936 M. Manfredi et al.
Association Between Candida and Oral Squamous Cell Carcinoma . . . . . . . . . . . . . . 968

Theory of Oral Carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 969
Clinical Observations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 969
Experimental Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 971
Possible Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 972
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 973
Abstract Introduction
Human fungal infections caused by opportu-
nistic fungi generally do not cause lesions The majority of human fungal infections are deter-
in healthy individuals but rather in patients mined by opportunistic fungi that generally do not
who are immunocompromised in some cause lesions in healthy individuals but may cause
manner. In the oral and maxillofacial region, superficial and deep life-threatening infections in
these can be principally attributed to oral immunocompromised patients. The incidence of
candidosis as well as other potentially superficial as well as invasive opportunistic fun-
life-threatening opportunistic fungal infec- gal infections has increased in the past two
tions, such as aspergillosis, mucormycosis, decades. This increase may be attributed to sev-
blastomycosis, and histoplasmosis. eral factors, such as to the growing number of
Although they are considered as systemic immunocompromised patients; to the usage of
mycoses, in the orofacial area, they broad-spectrum antibiotics, cytotoxics, and corti-
may also be involved with intraoral costeroids; and to common endocrine disorders
manifestations. Microscopic examination such as diabetes mellitus and severe nutritional
of cultures from biopsies or swabs is deficiencies (Vidya et al. 2016). Furthermore,
essential to diagnose and differentiate in recent years, diagnostic markers have taken
between these pathologies. This chapter a considerable significance allowing an early
outlines the carriage of Candida species, diagnosis of invasive fungal infections, especially
the etiology of diseases caused by in immunocompromised hosts (Williams and
Candida, as well as the clinical presentation Lewis 2011).
of diseases caused by fungi in the oral The range of human infections caused by
and maxillofacial area. Factors important Candida spp. is considerable. They vary from
in the management of patients with local and superficial conditions, such as oral and
these diseases, including diagnostic tech- genital candidosis, to invasive disseminated dis-
niques and specific antifungal treatment, eases in patients who are seriously ill by other
are presented. Finally, the role of Candida underlying pathologies, such as oncological or
in the development of oral squamous cell transplant patients (Rautemaa and Ramage
carcinoma is discussed. 2011). Oral candidosis is the most common myco-
sis of the mouth either in healthy or immunodefi-
Keywords cient patients. Several local and systemic host
Fungal infections · Oral candidosis · Candida · predisposing factors may facilitate the transition
Candidal virulence · Aspergillosis · to harmless commensal of the oral cavity to path-
Mucormycosis · Blastomycosis · ogen, causing the establishment of the disease. In
Histoplasmosis · Cryptococcosis · addition, different candidal virulence factors also
Blastomycosis · Paracoccidioidomycosis · contribute to the development of the infection.
Patient management · Oral carcinogenesis Ultimately the disease is a result of an imbalance
Oral and Maxillofacial Fungal Infections 937
between fungal virulence factors and host Oral candidosis is mainly caused by intraoral
defenses (Samaranayake et al. 2009). The clinical commensal yeasts. Candida is the yeast genus that
features of the disease may vary from acute to is found in the majority of healthy individuals
chronic often asymptomatic lesions, but some- (Farah et al. 2000). It is kept under control by
times oral candidal infections can cause pain and means of specific and non-specific host defense
discomfort, limiting nutrition in elderly or hospi- mechanisms and by the competition of other
talized patients (Samaranayake et al. 2009). microorganisms in the oral flora. All oral candidal
In addition to oral candidosis, there are a infections are opportunistic in nature, and the
number of other potentially life-threatening epithet “disease of the diseased” has been applied
opportunistic fungal infections, such as aspergil- to these infections. The yeast C. albicans is the
losis, mucormycosis, blastomycosis, and histo- primary etiological agent of oral candidosis that
plasmosis. These diseases generally arise among has been isolated in over 80% of lesions
individuals with relevant risk factors such as (McCullough et al. 1999b; Reichart et al. 2000).
poorly controlled diabetes mellitus, prolonged However, other Candida species that cause
neutropenia, long-term use of corticosteroids, the disease less commonly are C. tropicalis,
or immunocompromised status (Manfredi et al. C. glabrata, C. parapsilosis, C. stellatoidea,
2006; Samaranayake et al. 2009). Among these, C. krusei, C. kefyr, and C. dubliniensis
aspergillosis is the second most prevalent oppor- (McCullough et al. 1996; Al-Karaawi et al. 2002).
tunistic mycotic infection after candidosis. It is Oral yeast carriage is not indicative of disease.
also one of the most rapidly progressing and In many individuals, Candida represents only a
lethal forms of fungal infection, with high mor- minority of their oral flora, and they have no
tality rates in the pediatric population (about associated clinical symptoms. It is difficult to
85%). Along with aspergillosis, mucormycosis give a precise oral carriage rate for Candida, as
is another common invasive fungal infection this depends on the age and the health of the
affecting immunosuppressed subjects. Despite population studied (Cannon and Chaffin 1999).
aggressive surgical and systemic antifungal ther- A review of data from a number of previous
apy, the mortality of mucormycoses remains reports showed that the mean carriage rates of
high, with ranges varying from 20% to 50%. C. albicans for healthy and hospitalized individ-
These infections are considered as systemic uals were 17.7 and 40.6%, respectively (Odds
mycoses, but the orofacial area may also be 1988). It has been reported that prevalence of C.
involved with intraoral manifestations, usually albicans in clinically healthy mouths ranges from
necrotic ulcers, both as primary lesions and as 3% to 48% (Arendorf and Walker 1980) with
secondary manifestations of systemic higher prevalence figures found in healthy
diseases. Microscopic examination of cultures children and young adults (Odds 1994a; Qi et al.
from biopsies or swabs is essential to diagnose 2005). A higher carriage rate of Candida has
and differentiate between these pathologies also been noticed in hospitalized patients (Odds
(Dojcinovic and Richter 2008). 1994a; Qi et al. 2005). These data indicate that
the ill health of an individual is a predisposing
factor for Candida colonization. More recently,
Carriage of Candida and Non-Candida oral carriage has been analyzed in a group of
Species patients clinically diagnosed with various oral
mucosal diseases and orofacial pain conditions
Candida can cause a broad range of infections, including oral dysesthesia (Farah et al. 2018).
ranging from non-life-threatening mucocutaneous Statistical analysis of the frequency of Candida
infections such as oral and vaginal candidosis to carriage among the subgroups showed no
serious invasive infections such as candidemia or significant differences with exception of the
disseminated candidosis. subgroups of patients diagnosed with xerostomia,
Candida-associated denture-induced stomatitis, mouths of individuals colonized with the yeast

and oral candidosis/angular cheilitis. The oral (Arendorf and Walker 1980), allowing transfer
load of Candida species was significantly higher during kissing and saliva-saliva direct contact.
in these three groups relative to patients with oral There are at least seven Candida species
dysesthesia (Farah et al. 2018). of major medical importance, the most impor-
It is believed that high Candida counts do not tant and the most frequently isolated being
necessarily result in clinical signs and symptoms C. albicans. The other pathogenic Candida spe-
of oral candidosis. Previous research has shown cies are C. dubliniensis, C. tropicalis, C. glabrata,
that it is not possible to equate specific numbers of C. parapsilosis, C. stellatoidea, C. krusei, and
Candida with health and disease (Arendorf and C. kefyr (McCullough et al. 1996). The relatively
Walker 1980). Previously, higher prevalence and high DNA homology between C. albicans and
density of C. albicans have been reported in eden- C. stellatoidea led to reclassification of the latter
tulous patients who wear dentures and have ery- organism based on the ability of sucrose assimi-
thematous candidosis than in healthy patients. lation as a sucrose-negative variant of C. albicans
However, a study found that although higher (Meyer et al. 1984). Also, species such as
occurrence of C. albicans has been recorded in C. guilliermondii, C. lusitaniae, C. inconspicua,
these patients, no differences were found in C. norvegensis, and C. rugosa have been isolated
concentration of Candida when present in both from human infections (Odds 1988; Cannon
groups (Borromeo et al. 1992). Colonization of and Chaffin 1999).
the oral cavity by Candida has been defined as the It has been reported that C. albicans is the
acquisition and maintenance of a stable popula- most common Candida species isolated from
tion of Candida cells that does not give rise to a the oral cavity of healthy and diseased subjects
clinical disease (Cannon and Chaffin 1999). (McCullough and Savage 2005; Rautemaa et al.
Based on the above definition, a model of interre- 2006). C. albicans is a polymorphic, diploid
lated factors involved in colonization of the oral fungus that exists as an obligate associate of
cavity by Candida has been proposed (Cannon warm-blooded animals including humans and is
and Chaffin 1999). If the rate of removal of Can- believed to be the most virulent Candida spp. in
dida, by swallowing or oral hygiene, is greater humans (McCullough and Savage 2005). This
than the acquisition/entry of yeast into the oral yeast is typically present intraorally in a non-
cavity and growth, clearance of the yeast will pathogenic state in about 50% of individuals
take place. If the rate of removal is the same as and possibly in greater percentage (over 90%) if
that of acquisition and growth, this will result in sensitive enough tests were developed (Borromeo
colonization. Tissue damage and candidosis will et al. 1992). A characteristic feature of C. albicans
occur if rate of removal is lower. The clinical is its ability to form true hyphae as detected by the
outcome of candidosis will depend on the tissue germ tube test, although this ability is also seen in
colonized, the virulence factors expressed by C. dubliniensis to a lesser degree (Stokes et al.
Candida cells, and the host response (Cannon 2007). Many studies have investigated the patho-
and Chaffin 1999). genic attributes of C. albicans, and the most inves-
Numerous studies have been conducted to tigated virulence factors are those in relation to
determine how patients acquire infections in cell wall, adhesion and extracellular proteolytic
many clinical settings. The most common means enzyme production (McCullough et al. 1996).
of Candida transfer is via contact with hands C. albicans is usually more sensitive to conven-
of health workers (nosocomial transmission) tional antifungal agents than C. glabrata, but
(Strausbaugh et al. 1994). Candida can also be resistance to azole therapy has been reported
cultured from inanimate objects and food given in severely immunodepressed patients (Yoon
to patients (Vazquez et al. 1993; Pfaller 1996). et al. 1999; Rex et al. 2000).
Furthermore, Candida can be found at concentra- It is generally agreed that most humans are
tions of 300–500 cells per mL of saliva in the colonized by a single Candida strain at different
body sites that they retain for a long period It was thought that C. glabrata could cause
of time. However, a small proportion and parti- oral infections only when detected with
cularly immunocompromised and hospitalized C. albicans. However, there have been several
patients may harbor more than one Candida strain reports on increased C. glabrata infections in
or species at the same time (Odds 1994b). Earlier, immunocompromised and hospitalized patients
it was considered that C. albicans is the only (Hoegl et al. 1998; Redding et al. 2002), and it is
causative agent of candidal infections and other currently considered as an important pathogen in
Candida species were considered only as infre- both mucosal and bloodstream infections (Li et al.
quent pathogens (Moran et al. 2002). 2007). The major clinical concern associated with
The emergence of human immunodeficiency infections caused by C. glabrata is the ability of
virus (HIV) infections and acquired immunodefi- this species to develop rapid resistance to flucon-
ciency syndrome (AIDS), the development of azole and newer azoles creating difficulties in
new medical therapies for the treatment of cancer treatment and high mortality rates in systemic
patients, and the increased and prolonged use of infections (Redding 2001; Nucci and Marr 2005).
broad-spectrum antimicrobial agents lead to C. krusei has been isolated from infections in
higher recovery rates of many other non-albicans critically ill patients such as neutropenic patients
Candida (NAC) species from human infections. and has been found to be inherently resistant to
Although all Candida species cause the same fluconazole (Tumbarello et al. 1996; Cartledge
kind of mucositis, there are differences in their et al. 1999). It can replace C. albicans in the oral
invasiveness and fungal susceptibilities. It is cavities of HIV-infected patients after azole ther-
thought that candidosis caused by NAC species apy (Coleman et al. 1997; Ruhnke et al. 2000).
is less virulent in comparison to that caused by Other pathogenic Candida species including
C. albicans. This has been attributed to the fact C. parapsilosis and C. tropicalis are rarely iso-
that NAC species lack some of the virulence fac- lated from the oral cavity and generally recovered
tors of virulent C. albicans species such as hyphae from skin and blood cultures. C. tropicalis is the
formation and phenotypic switching. In addition, most virulent among NAC species (De Bernardis
they have lower adherence capability to the et al. 1999; Moran et al. 2002). C. lusitaniae
buccal epithelial and vascular endothelial cells has been isolated from immunocompromised
and lower production of proteolytic enzymes patients, and it is a rare pathogen and less virulent
(Moran et al. 2002). than C. parapsilosis and C. tropicalis (Viudes
Candida dubliniensis is the species along et al. 2002).
with C. albicans associated with oral lesions
in immunocompromised patients. It was first
isolated in 1995 from the oral cavities of Etiology
HIV-infected individuals, and since this time,
the species has been extensively detected Virulence Factors of Candida and Non-
from a variety of sources including oral Candida spp.
cavities of diabetes mellitus patients (Willis
et al. 1999; Manfredi et al. 2002). In comparison Several virulence factors have been characterized
to C. albicans, C. dubliniensis is not a common in the different species of Candida, to define the
constituent of the oral microflora (Pinjon et al. degree of strain pathogenicity. The pathogenic
2005) and less virulent due to its lower activity of members of the genus Candida is
capability to form hyphae (Stokes et al. 2007). more supported by invasiveness rather than by
C. dubliniensis is phenotypically and genotypi- toxigenicity. The prejudicial phase for candidal
cally closely related to C. albicans, and it is the pathogenicity is represented by adhesion, which
only Candida species in addition to C. albicans is a necessary but insufficient condition for
and C. tropicalis that has the ability to form invasiveness, as it could only imply surface colo-
hyphae (Sullivan et al. 1995). nization of the epithelial cells of the mucous
membranes by commensal blastoconidia. The host organism, while some of C. lusitaniae

major specific adhesins in C. albicans have been appear to be less sensitive to the action of conven-
characterized as the proteins of the agglutinin-like tional antifungal drugs such as amphotericin B
sequence (ALS) family (ALS1–7 and ALS9) (Spampinato and Leonardi 2013).
(Fukayama and Calderone 1991). In connection
with predisposing conditions, C. albicans can Cell Surface Hydrophobicity
infect the host causing mycoses varying from The surface hydrophobic/hydrophilic properties
superficial to deep-seated. Germ tubes can be in C. albicans and non-C. albicans spp. (NAC)
produced by yeast cells, and the incipient hyphae play a significant role in the pathogenicity of the
penetrate actively or are internalized by endocy- genus. The specific virulence factor is mediated
tosis resulting in tissue damage according to by the CSH1 protein, mainly characterized in
various virulence factors such as switching, C. albicans, the expression of which depends on
cell surface hydrophobicity, enzyme production, the strain and temperature (Cannon et al. 1995).
dimorphism, biofilm formation, quorum sensing, The hydrophobic phenotype, in particular, is asso-
toxin production, and environmental fitness that ciated with the early stages of the processes of
basically may damage the epithelial barrier or adhesion (colonization) and biofilm formation.
interfere with the host immune response, enabling The characteristics of cell surface hydrophobicity,
the fungus to enter the bloodstream and dissemi- moreover, are important in the dispersion of yeast
nate in the body (Wachtler et al. 2011). cells from the mature biofilm, a prejudicial condi-
tion for the formation of new biofilms. Using
Phenotype Switching biochemical approaches, Candida cell wall has
The reversible morphological changes of the yeast been mainly investigated in C. albicans. The
cells (rounded-elongated) and of the phase of the cell wall of C. albicans is primarily composed
colonies (white-opaque) in C. albicans strains, of carbohydrates, glucan, mannan, and chitin.
particularly in relation to modifications of envi- Glucan is the main constituent and represents
ronmental conditions (pH, temperature, etc.), about 40–60% of the cell wall’s dry weight, man-
have been called phenotypic switching and asso- nan 23%, chitin 0.6–9%, protein 6–25%, and lipid
ciated with the virulence potential of the fungus about 1–7%. It is generally accepted that mannan
(Calderone and Fonzi 2001). is distributed throughout the cell wall, while glu-
The high frequency of morphological changes can is the main component of the inner cell wall
of the colonies results in a modification of the cell (Calderone and Braun 1991).
surface antigens (Selmecki et al. 2010). The phe- Experimental studies have shown a higher
notypic switching, in addition, with regard to pathogenicity of C. albicans strains characterized
diversity in the composition of the cell wall in by an increased hydrophobicity that can contrib-
the different phases, influences the adhesion and ute to the process of adhesion to epithelial cells of
biofilm formation as well as the production of the mucous membranes in an indirect way,
enzymes (aspartyl proteases SAP2 in white cells although this is realized primarily by means of
and SAP1 and SAP3 in opaque cells) and the specific receptors for adhesins of the yeast in a
resistance to antifungal agents, to phagocytosis, direct way. The reasons why strains of C. albicans
and to oxidants by yeasts (Selmecki et al. 2010). characterized by a higher surface hydrophobicity
Overall, the white phase has been found more are more virulent have not been precisely defined
efficient to survive in parasitized organisms, yet, even though the most hydrophobic yeast
while the opaque phase more prone to mating cells, showing to adhere more tightly to biotic
with other cells (Gee et al. 2002). and abiotic substrates, are more resistant to
Although less studied, the phenomenon of phe- phagocytosis and germinate more efficiently
notypic switching was found in other species of (Hazen 1989).
the genus Candida. Different forms of C. glabrata Candida albicans varies in conne-
may prevail in some anatomical areas of the ction with acid-labile, phosphodiester-linked
β-1,2-oligomannoside components of the N-linked (Williams and Lewis 2011). SAPs 4–6 have
glycans of cell wall mannoprotein thus justifying been found to promote hyphal growth and
the different state of surface hydrophobicity of the facilitate systemic infections, whereas the
two major serotypes (A and B) (Netea et al. 2006). expression of SAPs 1–3 appears to be important
Although genetically similar, C. dubliniensis in phenotypic switching and pathogenesis of
shows different characteristics of hydrophobicity C. albicans in superficial candidosis (Schaller
from C. albicans, in relation to surface glycopro- et al. 2001; Chen et al. 2002). In terms of
teins (Sullivan and Coleman 1998). virulence, C. albicans proteinases are carboxyl
proteinases capable of degrading host immuno-
Enzyme Production globulins such as IgA and other defense proteins.
The production of enzymes is one of the major Further, some of these enzymes have
mechanisms of pathogenicity of C. albicans and keratinolytic activity facilitating initial penetra-
NAC species reported to be critical to invasive- tion of the keratinized cells and providing a rich
ness. These enzymes of hydrolytic nature, such as source of nitrogen during colonization, and some
secreted aspartic proteinases (SAPs), a family of play a role in candidal adhesion to host tissue
ten members (Sap1–10), which can be either surfaces by exposure of receptor sites (Hattori
released or retained bound to the cell surface; et al. 1984; Douglas 1988; Odds 1994; Gropp
phospholipases (PL), a family of four classes et al. 2009).
(A, B, C, and D); and lipase (LIP), a family of The relevance of SAPs in the pathogenic arma-
ten members (LiP 1–10), of which only the mentarium of C. albicans, in particular, has been
secreted LIP1–5 are particularly implicated in documented through the use of SAP-disrupted
the damage of the host cell membranes, are phys- mutants, demonstrating the correlation between
iologically designed for digestion of external mac- in vitro production and in vivo virulence, the
romolecules for metabolic purposes (Hube and possible association with other virulence factors,
Naglik 2002; Naglik et al. 2004). and the modulation of virulence by means of
SAPs, in particular, are able during infection SAP inhibitors (anti-SAP monoclonal antibodies)
to destroy the host cell membranes by degrading (Naglik et al. 2004).
their surface molecules, thus favoring the adhe- A number of phospholipases have been identi-
sion process, as well as to interact with the cells fied in C. albicans and have been classified based
of the immune system by reducing their anti- on their mode of action into phospholipases A,
fungal potential. These enzymes are believed B, C, and D. This group of hydrolytic enzymes
to be produced by only the most pathogenic acts by breaking the ester linkage of the phospho-
Candida species (C. albicans, C. tropicalis, lipids, degrading the membranes of the host cells,
and C. parapsilosis) (Cannon et al. 1995). and facilitating candidal invasion (Hube and
C. albicans possesses at least ten members of Naglik 2002; Tsang et al. 2007). Interestingly,
the SAP gene family designated as SAPs 1–10. these enzymes have also been shown to be pro-
All Candida SAPs are inhibited by the agent duced (although at small quantities) also by NAC
pepstatin A, and they belong to the same class species (Ghannoum 2000).
of proteinases as the HIV aspartyl proteinases, The role of lipases produced by Candida spe-
human pepsin, and rennin. SAP enzymes work cies in virulence is less well-understood (Schaller
more efficiently in acidic pH (pH 2–7 range et al. 2005). They have the ability to hydrolyze the
activity), although differences in pH optima ester bond of triglyceride compounds (Hube and
have been found between the different SAPs Naglik 2002). To date, a family of 10 lipases
(Williams and Lewis 2011). This heterogenicity designated as LIP1–10 has been identified in
in optimal pH in SAP activities is thought to be C. albicans (Hube et al. 2000; Stehr et al. 2004).
beneficial for Candida in its survival under dif- Furthermore, sequence-related genes were also
ferent environmental conditions. The most detected in C. tropicalis, C. parapsilosis, and
widely studied Candida SAPs are SAPs 1–6 C. krusei (Fu et al. 1997). C. albicans lipases
have been demonstrated to have a cytotoxic effect the capacity in yeast filamentation, and in the
on host cells (Paraje et al. 2009), and an increased synthesis of protein kinase (MAPK) (Selmecki
gene expression of LIP has been detected in oral et al. 2010).
candidosis (Stehr et al. 2004). Blastoconidia and filamentous forms are
differently involved in the pathogenicity of
Dimorphism C. albicans during the various stages of infection:
Candida albicans has to be considered, possibly the former for dissemination and the latter for
together with C. dubliniensis, a dimorphic or, adhesion through specific proteins such as the
rather, a polymorphic fungus, being able to agglutinin-like sequence protein (Als3) and the
assume, in vitro and in vivo, different morphol- hyphal wall protein (HWp1), invasiveness, pro-
ogies (yeastlike or with production of hyphae, duction of proteolytic enzymes and immunomod-
pseudohyphae, and/or chlamydoconidia) accor- ulatory antigens, and the formation of biofilms
ding to predisposing environmental factors (Jacobsen et al. 2012).
(Brand 2012). The reversion of phase from The processes of hyphal differentiation and
blastoconidia to hyphae is favored by various production of biofilm are mediated by common
environmental factors, such as the rise of the genes (SUV3, NUP85, MDs3, and KEM1)
temperature (37 C), the concentration of CO2 (Blankenship and Mitchell 2006).
(5%), the increase of pH (>7), the presence of Hyphae, moreover, are the only forms of
serum, the occurrence of N-acetylglucosamines C. albicans able to seize, from the epithelial
(GlcNAc), the activation of heat-shock protein cells of the oral mucosa during the infection of
HSP90, and a lack of metabolic sources of the host, the ferritin (an essential iron source for
carbon and nitrogen. The reversion of hyphae to the fungus), through the receptor represented
blastoconidia, by contrast, is favored by lower by Als3 (Liu and Filler 2011). When produced
temperatures (24 C), lowering of pH (<7), and inside phagocytic cells, moreover, hyphae can
higher concentration of glucose (Shapiro and permit escaping by expressing mechanical forces
Cowen 2010). (Romani 2004). The various forms of C. albicans
The filamentation of a yeast cell, favored by the lead to different interactions with the immune
lack of metabolites and contact sensing often system. While neutrophils and dendritic cells are
resulting in thigmotropism, is regarded as an able to eliminate both cells in the yeast form and in
in vivo pathogenicity factor and is mediated by filamentation, albeit to varying degrees being the
the protein kinase pathway (MAPK, cAMP-PKA) resistance to phagocytosis in the hyphal form
and regulated by a number of genes (EFG1, Cph1, increased by overexpression of the SOD5 gene
Eed1, RAS1, Rim101, Ssn6, Tec1, Ume6, Gat2, that codes for a superoxide dismutase, macro-
CaMYO5, SMI1, SSK1, SKN7, SRR1, CaLAG1, phages phagocyte in particular the blastoconidia
ECE1, HWP1, CaLAC1) variously implicated in that are, however, able to survive within them,
biofilm formation; maintenance of cell polarity; to germinate and leak through the membrane
formation of hyphae; synthesis of myosin I, (Romani 2004).
sphingolipids, glucosylceramides, and glucan The different cell wall composition of the var-
cell wall; response to oxidative and osmotic ious forms of C. albicans, which present specific
stresses; virulence associated with the production superficial pathogen-associated molecular pat-
of hyphae; and resistance to antifungal drugs terns (PAMP), is reflected in the different stimu-
(azoles) (Shapiro and Cowen 2010). lation and consequent production of cytokines by
The factors that determine the conversion of dendritic cells and Th1 lymphocytes, in relation to
hyphal forms to blastoconidia (RBP 1, NRG1, the presence of specific pathogen recognition
Tup1, Sko1, HSL1, Hog1) relate to the regulation receptors (PRR) (Biswas et al. 2007). Quorum
of the expression of the gene PGA13 implicated in sensing molecules secreted by fungal cells
the synthesis of the GPI-anchored protein, local- (farnesol, inversely acting tyrosol, dodecanol)
ized in the cell wall, in the repression of are of significant importance in the reversion
of blastoconidia to the hyphal form, while cause of persistence of these organisms on inert
tyrosol secreted by blastoconidia stimulates the surfaces of indwelling devices such as catheters,
filamentation process (Gow et al. 2012). joint replacements, dentures, and prosthetic heart
The criterion of pathogenicity based on valves as well as natural host surfaces (Tunnet
the ability of filamentation is important but not et al. 1996; Donlan 2001).
absolute, as C. tropicalis, producing only pseudo- The development of a fungal biofilm, by
hyphae, is Iess pathogenic than C. albicans and C. albicans in particular, is a multistep process
C. famata and C. lusitaniae, producing only that is realized in the course of a few days con-
blastoconidia, are less important human patho- trolled by different transcription factors (Bcr1,
gens. C. glabrata, however, which exclusively Tec1, Efg1, Ndt80, Rob1, and Brg1). Starting
occurs in the form of yeast cells, is able to from an early phase, characterized by the adhe-
invade the tissues of the host. Significantly, strains sion/colonization of fungal cells to the supporting
belonging to this species are characterized, surface, it follows an intermediate phase, in
in vitro on suitable growth media, by the core- which hyphae are formed and the extracellular
switching phenomenon, that is, to switch from a matrix is produced, mainly constituted by proteins
white form to a light brown, to a dark brown, the and polysaccharides, to evolve to a maturation
most virulent phenotype, and ultimately to a very phase, resulting into an imbricate structure of
dark brown being able to turn into a wrinkled blastoconidia, pseudohyphae, hyphae, and extra-
phenotype (Negri et al. 2010). cellular matrix that may include, in vivo, cells of
the host such as macrophages, neutrophils, plate-
Biofilm Formation lets, etc. and, then, to the leakage of yeast cells
Biofilms are communities of microorganisms, from the surface of the mature biofilm, a phenom-
consisting of one or more species, embedded in enon regulated by the major heat-shock protein
their own extracellular matrix generally on a (Hsp) 90 (LaFleur et al. 2006).
natural (e.g., epithelial cells of the mucous mem- If the structure of the fungal biofilm is
branes of the mouth, vagina, etc.) or artificial observed in vitro, it can be distinguished as a
surface (e.g., central venous catheters, artificial thin basal portion, adhering to the surface and
valves, contact lens, etc.) (Donlan and Costerton essentially consisting of blastoconidia, and an
2002). Biofilms are not to be considered, from upper, thicker portion, essentially consisting of
the phenotypical point of view, as the sum of the hyphae, in the case of C. albicans, or mainly
phenotypes of the constituting microbial species, by a thin layer of blastoconidia only, in the case
but rather in relation to synergistic and antago- of other species of the genus, such as C. krusei,
nistic interactions, as a new resulting phenotype, C. glabrata, and C. parapsilosis, significantly
characterized by important properties, such as considered as less pathogenic species (Negri
increased resistance to antibiotics, drying, etc. et al. 2010). The features of roughness and hydro-
(Williams et al. 2011). They are formed in phobicity of the adhering surface perform a pri-
response to a variety of environmental and phys- mary role in the formation of fungal biofilms of all
ical cues such as high cellular density, nutrient Candida spp., and significantly, materials like
deprivation, and physical stresses (O’Toole et al. polyacrylate, silicone, elastomer, etc. used in the
2000). Their self-contained and protected envi- production of dentures, catheters, prostheses, and
ronment allows biofilms to act as a nidus of other medical devices are particularly permissive
organism dissemination and, thus, an ongoing (Kojic and Darouiche 2004). Of importance, the
source of infection (Chandra et al. 2008). In biofilm cells are phenotypically distinct from their
nature, biofilms represent the most prevalent free living or planktonic counterparts and exhibit
type of microbial life and are deemed as crucial elevated resistance to host defenses and antifungal
to the development of clinical infections (Davey agents (Baillie and Douglas 2000; Samaranayake
and O’Toole 2000). They can be formed by path- et al. 2002). In one study, it was estimated that
ogenic bacteria and fungi and thought to be the 65% of all hospital infections originate from these
microbial aggregates (Mah and O’Toole 2001). within a biofilm community (LaFleur et al.
Further, a positive association exists between 2006). However, other studies have demonstrated
Candida biofilm forming ability and both Can- that biofilm resistance mechanisms are not
dida virulence and mortality rate of patients with completely dependent on changes in cell growth
candidemia (Rajendran et al. 2010). Due to their rate (Baillie and Douglas 1998) and could be the
clinical significance, researchers are now recog- result of upregulation of certain resistance genes
nizing the value of investigating the biofilm induced by contact with a surface. Genes coding
communities rather than planktonic forms when for ATP-binding cassette (ABC) transporter pro-
characterizing the pathogenic potential of micro- teins that are associated with azole drug resistance
organisms (Silva et al. 2010). by efflux pump mechanisms in C. albicans have
In addition to the physical characteristics of the been found to be upregulated during biofilm for-
substrate, for the formation of the fungal biofilm, mation (Mateus et al. 2004). In relation to the
other conditions are important, such as the occur- glucans released in the extracellular matrix, bio-
rence of other microorganisms, (e.g., bacteria), film constituted by C. albicans shows resistance
that can either promote (e.g., Streptococcus to the activity of neutrophils and does not
gordonii) or delay (Porphyromonas gingivalis) prime reactive oxygen species (ROS) (Mateus
its maturation, the host immune defenses, and et al. 2004).
the modulation of fungal genes (CDR1, CDR2,
MDR) that may entail an increase of resistance to Quorum Sensing
antifungal drugs of the constituting fungi (quorum Morphogenic switching in C. albicans (variation
sensing) (Kojic and Darouiche 2004). from the yeast to the hyphal form) is mediated by
It is now well recognized that the biofilm life- transcriptional modulators and changes in cell
style of Candida is intimately involved in a broad density with regulatory mechanisms similar to
range of clinical problems. In the oral cavity, those characterized in bacteria and defined as
biofilms are not only protected from the normal “quorum sensing” (QS). Various cross-strain
mechanical flushing action of saliva and gingival reactive extracellular QS molecules (e.g.,
crevicular fluid, but the biofilm itself is a defen- farnesol, a sesquiterpene alcohol; tyrosol, an
sive barrier against host immune factors and anti- alcohol related to tyrosine; and dodecanol, a
fungal agents. The exact mechanism of Candida fatty alcohol), abundantly produced during fun-
biofilm resistance to antifungals is not fully under- gal growth between a wide range of temperature
stood and thought to be multifactorial. The extra- (23–43 C) and independent from the chemical
cellular polysaccharide of the biofilm could limit composition of the culture medium, have been
or exclude the diffusion of antifungal agents or identified capable of preventing the morphologi-
ionically bind the drug as it diffuses through the cal variation from yeast to hypha in different
biofilm reducing its bioavailability (Al-Fattani C. albicans isolates, without inhibiting cellular
and Douglas 2004). The limited nutrient access growth, and to modulate, consequently, their vir-
to the basal cell layer is a feature of multilayered ulence as well as biofilm formation (Blankenship
biofilm, which may result in reduced growth rate and Mitchell 2006). In C. albicans, QS molecules
and activity. This slow growth rate is often accom- can mediate communication with other fungal
panied by changes in cell surface composition that and bacterial species, resulting in the farnesol-
could affect the microorganisms’ susceptibility to dependent growth inhibition of Aspergillus
antimicrobial agents or inhibit biochemical nidulans and virulence factors in Staphylococcus
pathways associated with actively growing cells. aureus, Streptococcus mutans, and Pseudomonas
Growth rate could, therefore, be an important aeruginosa, a condition that could be of rele-
determinant of drug activity in biofilm (Donlan vance for the homeostasis of the human micro-
and Costerton 2002). The slowly growing cells in biome (ten Cate et al. 2009). In C. albicans, the
biofilm could represent the “persister cells” that inhibition of the yeast/hyphae transition by
have been suggested as the resistant phenotype farnesol has been related to the occurrence of a
receptor histidine kinase homolog (Chk1). A sig- alternative metabolites in the variable environ-
naling pathway, comprising the small GTPase ments encountered during infection (ten Cate
Ras, adenylate cyclase as its downstream effector, et al. 2009).
and Nrg1, a DNA-binding repressor, however, is Environmental stress responses such as (i) heat
requested for farnesol reception, while much less shock, mediated by HSPs, including small heat-
is known for the tyrosol mechanism of reception shock proteins (sHSPs), acting as chaperones in
(ten Cate et al. 2009). the prevention of aggregation and unfolding of
proteins; (ii) osmotic, attaining intracellular accu-
Toxins mulation of glycerol to face dehydration; (iii)
In C. albicans, a cytolytic peptidic exotoxin oxidative, production of superoxide dismutases,
(Candidalysin) was characterized as able to dam- Sod1 and Sod5 and Catalase Cta1, in order
age the membranes of epithelial cells through to detoxify reactive oxygen species (ROS); and
increased permeabilization and to stimulate a sig- (iv) nitrosative, production of flavohemoglobin-
naling pathway response. Significantly, the strains related protein Yhb1 for the detoxification of
unable to secrete Candidalysin fail to harm the reactive nitrogen species (RNS) produced by neu-
epithelial cells of mucous membranes resulting trophils, are important responses enabling the sur-
in avirulent experimental infections of animal vival of C. albicans by adaptation to the variable
models (Gow et al. 2012). conditions of the host (ten Cate et al. 2009).
Fitness to Environment
Other than on conventional virulence factors, in Predisposing Factors to Oral
the course of infection, C. albicans may rely on a and Maxillofacial Infections
series of fitness attributes to succeed as a patho-
gen. Sensing and regulation to adapt to changes in A wide range of local and systemic host factors
environmental pH, dependent on the host niche, has been implicated in the pathogenesis of oral
are mediated by the two cell wall proteins and maxillofacial fungal infections. These factors
α-glycosidases Phr1 and Phr2 through the that predispose to oral candidal infection were
Rim101 signal transduction pathway assessed by initially classified as natural factors, dietary fac-
receptors Dfg16 and Rim21.78 on the plasma tors, mechanical factors, and iatrogenic factors
membrane (ten Cate et al. 2009). Metabolic adap- (Odds 1988). These factors have been reviewed
tation (through glycolysis, gluconeogenesis, and in the past (Oksala 1990; Scully et al. 1994) and
activation of the glycosylate cycle) allows updated and have been categorized into local and
the fungus to gain an effective assimilation of systemic factors (Farah et al. 2010) (Table 1).
Table 1 Predisposing factors to oral candidosis

Local predisposing factors Systemic predisposing factors
Prostheses (changes in environmental conditions, trauma, denture Physiological (e.g., elderly, pregnancy, infancy)
usage, oral hygiene)
Endogenous epithelial changes (atrophy, hyperplasia, dysplasia) Endocrine disorders (e.g., diabetes mellitus)
Qualitative (pH, glucose concentrations) and quantitative Nutritional deficiency (e.g., iron, folate, vitamin
(xerostomia, Sjogren’s syndrome, radiotherapy, drug-therapy) B12)
salivary changes
Commensal flora Malignancies (e.g., leukemia, agranulocytosis,
others)
High-carbohydrate diet Primary immunodeficiency (e.g., DiGeorge’s
syndrome)
Smoking (?) Secondary immunodeficiency (e.g., HIV
disease, corticosteroids, anticancer therapy)
Systemic Predisposing Factors cell adhesion. This may result in unhampered

Different systemic conditions have been evalu- candidal overgrowth (Soysa et al. 2008; Farah
ated as predisposing to oral fungal infections and et al. 2010). Due to their anti-inflammatory and
oral candidosis in particular. Oral candidosis is a immunosuppressive properties, topical and sys-
common fungal infection in patients with immu- temic corticosteroids and other immunomodula-
nological disorders such as HIV infections and tory drugs used in many clinical settings can also
other secondary immunodeficiencies (Farah et al. be followed by oral yeast infection as an adverse
2000). Systemic diseases characterized by quali- effect (Samaranayake 1990). Other drugs that
tative and quantitative immunodeficiency (cell- have been implicated in predisposition to oral
mediated and/or humoral immunity) have been candidosis are those with xerogenic side effects
investigated and proven to be involved in the such as antidepressants, antipsychotics, anticho-
pathogenesis of systemic and mucosal candidosis. linergics, antihypertensives, and antiadrenergics.
It has been reported that up to 90% of A decrease in salivary flow may result in the
HIV-infected patients develop oropharyngeal reduction of salivary antimicrobial functions.
candidosis at some time during the progression Diabetes mellitus (DM) is one of the syste-
of their disease (Samaranayake 1992; Vazquez mic diseases most frequently implicated with
2010). Indeed, oropharyngeal candidosis can be enhanced carriage of oral Candida spp. and a
used as a predictor for the progress of HIV infec- higher risk of developing oral candidosis (Ueta
tions in affected individuals (Samaranayake et al. et al. 1993; Guggenheimer et al. 2000). A number
2009). This is exemplified by the finding that of factors have been associated with increased oral
about 50% of HIV patients who present with carriage of yeast in DM patients, such as the type
oral candidosis develop acquired immuno- and duration of disease and the degree of glycemic
deficiency syndrome (AIDS) within 3 years control (Scully et al. 1994). High salivary glucose
(Samaranayake 1992). The progressive depletion levels in patients affected by DM favor yeast
in CD4+ T lymphocytes has been thought to be the growth, and the hyperglycemia of poorly con-
main reason for the increased susceptibility to trolled DM may influence the pathogenic coloni-
opportunistic infections in these patients (Farah zation of Candida. The reduced capacity for
et al. 2000). Chronic mucocutaneous candidosis killing Candida by neutrophils in presence of
can also be a feature of primary immune defects high glucose concentrations may also account
such as severe combined immunodeficiency syn- for any increased colonization by Candida.
drome as a result of depressed phagocytic immu- However, oral candidosis may not be significantly
nity or cell-mediated immunity (Porter and Scully higher in controlled diabetic patients, and proba-
1990). Other immunodeficiencies that increase bly oral local factors, such as denture wearing,
susceptibilities to oral fungal infections include have been postulated to contribute more to yeast
solid organ (e.g., lymphoma) and hematological colonization in DM patients than the pathology
malignancies (e.g., leukemia). Immunosuppression itself (Manfredi et al. 2002, 2006). Uncontrolled
(neutropenia) arising from the tumor itself or DM, especially complicated by diabetic keto-
its cytotoxic chemotherapy and radiotherapy is acidosis, is also considered a major predisposing
a major contributor to the development of oppor- factor in infections caused by Zygomycetes and
tunistic infections including oral candidosis Aspergillus. It is reported that approximately
(Glasmacher et al. 2006; Clarkson et al. 2007). 50–70% of patients with rhinocerebral mucor-
Administration of several classes of pharmaco- mycoses are affected by DM (Dojcinovic and
logic agents predisposes to oral candidosis. Post- Richter 2008).
antibiotic Candida infections have been previ- Systemic and/or superficial candidal infec-
ously recognized (Midtvedt 1990). Patients on tions can arise with both solid (e.g., lymphoma)
broad-spectrum antibiotics may be predisposed and nonsolid (e.g., leukemia) malignancies.
to alterations in the oral flora, minimizing the These candidal infections occur as a result
competition for dietary substrates and epithelial of tumor-related immunosuppression (e.g.,
neutropenia) as well as therapy that ablates the maxillary dentures, can lead to a continuous mac-
bone marrow (e.g., cytotoxic drug regimens). eration of the oral fitting mucosa, resulting in
Bone marrow transplant recipients are particu- microscopic breaches of the epithelium
larly susceptible to aspergillosis, with a reported (Samaranayake 1990). In addition, the ability of
incidence ranging from 5% to 14% (Denning and Candida spp. to adhere to the acrylic resins of
Chakrabarti 2017). dentures, in combination with reduced salivary
Due to their efficacious anti-inflammatory and flow under the prostheses and/or poor hygiene,
immunosuppressive properties, corticosteroids, creates a potential reservoir of yeasts, in contrast
used systemically or topically, may also result in to a prosthesis-free oral cavity (Radford et al.
a lower resistance to fungal infections. Inhaled 1998). Epithelial changes to the oral mucosa,
steroids in particular appear to play a primary such as atrophy, hyperplasia, and dysplasia, may
role in increasing the risk of oral and oropharyn- compromise the structure of the mucosal barrier
geal candidosis. Other immunosuppressive regi- and facilitate candidal invasion (Sitheeque and
mens (e.g., post-allograft receipt) may also Samaranayake 2003). The breakdown of skin
predispose to fungal infections. Broad-spectrum and/or soft tissue injuries, caused by local trauma
antibiotic therapy is one of the most common or burns, is also a risk factor for mucormycosis.
iatrogenic factors that is implicated in the devel- These soft tissue infections have been linked to
opment of oral candidosis, altering the local oral the use of contaminated bandages, needles, or
microflora and creating a suitable environment for wooden tongue depressors in the clinical setting
the proliferation of Candida spp., even in an oth- (Sitheeque and Samaranayake 2003).
erwise immunocompetent host. It is important to Adequate salivary flow is essential in pre-
emphasize that local mucosal immunity and nor- venting oral colonization and invasion of Candida
mal microflora are restored once these therapies spp. because it removes unattached or poorly
are suspended (Denning and Chakrabarti 2017). adherent Candida spp. from the mucosa and
Different studies show that several nutritional inhibits candidal adhesion to host surfaces by the
deficiencies are also implicated in the patho- inhibitory action of salivary IgA (Samaranayake
genesis of oral candidosis (Samaranayake 1990; 1990). Furthermore, saliva itself has a candida-
Sherman et al. 2002). Of these, iron deficiency can cidal activity because it contains several antifun-
cause a series of alterations that may increase the gal proteins. In particular, it has been reported that
susceptibility of oral mucosa to yeasts. Iron defi- one of these proteins, histatin 5, possesses the
ciency results in depression of cell-mediated most potent antifungal action (Eyerich et al.
immunity both in vitro and in vivo and may deter- 2008). It has also been shown that other proteins,
mine defects in phagocytosis and inadequate anti- such as LL-37 and defensins, that are produced by
body production. Other nutritional deficiencies, neutrophils or mucosal tissues are able to kill
such as those involving zinc, magnesium, sele- C. albicans by disrupting the cell membrane or
nium, folic acid, and vitamins A, B6, and B12, by increasing its permeability (Eyerich et al.
are also involved in the causation of oral 2008). Furthermore, the presence of lysozyme, a
candidosis often in combination with other low molecular weight protein present in high con-
systemic and local cofactors (Sitheeque and centration of saliva and gingival crevicular fluids,
Samaranayake 2003). increases Candida permeability and stimulates
phagocytosis in combination with IgA. Therefore,
Local Predisposing Factors a reduced salivary flow resulting from pathologi-
The integrity of the oral mucosa is essential in cal conditions, such as Sjogren’s syndrome or
preventing the adhesion and penetration of Can- head and neck radiation therapy, may determine
dida spp. into deeper tissues. Although various an increase in oral candidal carriage and predis-
factors could lead to a breach of oral tissue, trauma position to oral candidosis (Williams et al. 2011).
caused by natural and artificial teeth is relatively Furthermore, qualitative changes of saliva, such
common. Dental prostheses, particularly as high glucose concentration and low pH ranges
(pH <5), may also enhance oral candidal carriage, (premature newborns and catheterized patients),
thus promoting subsequent oral infections. and C. dubliniensis (HIV-infected patients and
There is still controversy regarding the rela- patients with DM), are often recovered in
tionship between tobacco smoking and develop- human infections, usually in combination with
ment of oral candidosis. Some studies (Bastiaan C. albicans (Muadcheingka and Tantivitayakul
and Reade 1982) have suggested that smoking 2015; Patil et al. 2015). Recently, epidemiological
habits do not affect oral candidal carriage or pre- data reveals a shift from C. albicans to NAC as a
disposition to oral candidosis. However, other result of several different factors, such as the
authors have reported that smoking may lead to increased use of immunosuppressive therapies
localized epithelial alterations, such as keratiniza- and the widespread use of broad-spectrum antibi-
tion, reduction in salivary IgA, and possible otics. In addition, the inherent ability of some
depression of polymorphonuclear leukocyte func- NAC to be resistant to traditional antifungal
tion, favoring oral candidal colonization. In addi- agents may also contribute to their presence in
tion, it has been hypothesized that cigarette mixed-species oral infections.
smoking provides nutrition for Candida spp., The transition of Candida spp. from harmless
which are able to enzymically convert some poly- commensals to pathogenic microorganisms is
cyclic aromatic hydrocarbons to produce carcino- most often related to a weakening of the host
gens (Krogh et al. 1987a). immune defenses. Infections caused by Candida
spp. are most frequently localized and superficial,
but in severely immunocompromised patients,
Pathophysiology and Clinical candidosis can be systemic (invasive candidosis)
Presentation and associated with a high mortality rate
(50–60%) (Romani et al. 2002; Williams and
Candidosis Lewis 2011). Diagnosis of oral candidosis is gen-
erally based on clinical signs and symptoms in
Candida spp. are the most common fungal path- conjunction with a through medical history
ogens isolated from the oral cavity (Scully et al. (Farah et al. 2010). Different classifications for
1994). The genus Candida is a collection of some oral candidosis have been proposed over the
150 asporogenous yeast species ubiquitously dis- years. The currently accepted classification of
tributed in soil and aquatic environments (Odds oral Candida infections is based on two catego-
1988; Calderone 2002; Williams and Lewis 2011; ries: primary and secondary OC (Table 2).
Manfredi et al. 2013). It is well established that
only a small amount are human pathogens; about Primary
65% of Candida spp. are unable to grow at 37 C In primary OC, the oral candidal infection is con-
(Schauer and Hanschke 1999). The presence of fined to the oral and perioral tissues. OC is not a
Candida itself is not indicative of disease. Can- single infection, and three primary oral manifes-
dida spp. are ubiquitous organisms, and most of tations (acute and chronic pseudomembranous,
them are commensal or transient commensal in erythematous, and chronic hyperplastic – once
the gastrointestinal tract (Samaranayake 1990). named candidal leukoplakia) are recognized
C. albicans, the most common human commensal together with some Candida-associated lesions
of the genus Candida, is generally regarded as (denture-associated erythematous stomatitis
the most virulent of the Candida spp., being (DAES), angular cheilitis, median rhomboid glos-
recovered from the oral cavity of healthy sub- sitis (MRG), and linear gingival erythema)
jects (40–60%) or from patients affected by dif- (Williams and Lewis 2011; Manfredi et al. 2013).
ferent diseases (70–85%). Other NAC, such as
C. glabrata (frequently isolated in elderly Pseudomembranous Candidosis
patients), C. tropicalis (hematological malignan- Pseudomembranous candidosis (PC) (also known
cies), C. krusei, C. kefyr, C. parapsilosis as oral thrush) usually presents as acute, although,
Table 2 Classification of oral candidosis

Primary oral Clinical features Site involved
candidosis (Group I)
Pseudomembranous Semi-adherent, whitish, soft and creamy, drop- Acute form: palate, dorsum of the tongue,
candidosis (acute like, or confluent patches. They can be buccal mucosa
and chronic) removed leading to a red and slightly bleeding Chronic form: palate, oral pharynx, dorsum
surface. The lesions may recur in patients of the tongue
using corticosteroids topically or by aerosol, in
HIV-infected patients or in
immunocompromised patients
Erythematous Small or large erythematous areas following Dorsum of the tongue, opposing palate
candidosis (acute topical or systemic corticosteroid use, broad- surface, rarely buccal mucosa
and chronic) spectrum antibiotic therapy, or HIV disease
Chronic hyperplastic Small or large erythematous areas following Commissures of the mouth, less commonly
candidosis topical or systemic corticosteroid use, broad- on the buccal mucosa, palate, tongue
spectrum antibiotic therapy, or HIV disease
Candida-associated Clinical features Site involved
lesions
Angular cheilitis Edema, soreness, burning, and fissuring with a Angles of the mouth
tendency to local bleeding. Candida spp. and
Staphylococcus aureus involved
Median rhomboid Area of papillary atrophy (occasionally Midline of the tongue, centrally, anterior to
glossitis hyperplastic, exophytic) elliptical or rhomboid the circumvallate papillae
in shape
Denture-associated Chronic erythema and edema of the oral Palatal mucosa, the mucosa below the
erythematous mucosa in contact with a denture mandibular denture is rarely affected
stomatitis
Linear gingival Non-plaque-induced linear erythematous Localized or diffuse marginal gingivae and
erythema gingival band of 2–3 mm. First described in attached gingiva
HIV-infected patients
Secondary oral Clinical features Site involved
candidosis
Chronic Persistent or recurrent candidal infections of Infections of the oral cavity (90%), possibly
mucocutaneous the oral cavity and other sites of the body. the larynx and pharynx. Cutaneous and
candidosis Associated with several immunodeficiency vulvovaginal involvement is frequent
disorders
especially in immunocompromised patients, The plaques can be removed from the

it can become chronic, with a characteristic mucosa with a gauze or tongue blade and, once
spread to the oropharyngeal mucosa (Fig. 1). removed, reveals erythematous and sometimes
The chronic form is typical in individuals who a slightly bleeding surface (Reichart et al.
are immunosuppressed or in patients using corti- 2000; Samaranayake et al. 2009; Farah et al.
costeroids topically or by aerosol. PC may also 2010). Usually, the adjacent oral mucosa is
affect newborn babies (5–10%) (Samaranayake normal in appearance. The possibility to remove
et al. 2009; Williams and Lewis 2011), elderly these plaques is considered as a diagnostic feature
people, and patients affected by uncontrolled that differentiates this form from other white
DM or by malignancies. oral diseases, such as oral lichen planus, prolifera-
Clinically this form is characterized by the tive verrucous leukoplakia, white sponge nevus, or
presence of semi-adherent soft, whitish-yellow morsicatio buccarum. The pseudomembranes con-
creamy plaques, resembling milk or cottage sist of desquamated epithelial cells, tangled aggre-
cheese, usually spread to mucosal surfaces of gates of fungal hyphae, fibrin, and necrotic material
the cheeks, lips, tongue, and soft palate. (Samaranayake et al. 2009; Lalla et al. 2013).
Fig. 1 Pseudomembranous candidosis presenting on the soft palate (a) and tongue (b) in same patient
Fig. 2 (a) Histopathology of pseudomembranous Hematoxylin and eosin, 200. (b) Periodic Acid-Schiff
candidosis showing intraepithelial edema and micro- stained smear from a patient with pseudomembranous
abscesses, acanthosis and inflammatory infiltrate. candidosis. Periodic Acid-Schiff 200
Histologically, hyphae penetrate the epithelium 4–5 times per day for 4 weeks) will accelerate the
up to the spinous cell layer. The presence of resolution of the disease.
edema and microabscesses, containing polymor-
phonuclear leukocytes, is typical within the outer Erythematous Candidosis
layers of epithelium. The deeper parts of the epi- Similar to PC, erythematous candidosis
thelium show acanthosis and an inflammatory (EC) may present as an acute or chronic form.
infiltrate (Fig. 2). It is often associated with the use of corticoste-
Lesions are usually asymptomatic, although roids or broad-spectrum antibiotics (often called
sometimes patients may complain of burning antibiotic sore mouth). Clinically the lesions are
and dysphagia, especially in the oropharyngeal characterized by erythematous areas that may
forms. PC may resolve spontaneously without affect any part of the oral cavity, although the
treatment, but topical antifungal therapy (e.g., dorsum of the tongue is the most common loca-
amphotericin B lozenge 10 mg 4 per day for tion (Fig. 3). The lesions on the tongue present
2–3 weeks or nystatin/amphotericin B suspension as depapillated areas, and usually the palate is
Fig. 3 Erythematous candidosis of the dorsum of the Fig. 4 Erythematous candidosis of the palate occurring
tongue simultaneously with tongue lesions (kissing lesions)
simultaneously involved (kissing lesions) are tobacco smokers. Less frequently the lesions
(Fig. 4). The histopathology of EC is similar to may be present on the lateral border of the tongue
that of PC, with hyphae and pseudohyphae pen- and palate. In contrast to the pseudomembranous
etrating and extending the superficial layers of variants, the hyperplastic candidosis lesions are
the epithelium and an inflammatory reaction non-scrapable (Sitheeque and Samaranayake
both in the epithelium and connective tissue. 2003). This form may require biopsy, because it
This form of oral candidosis is painful, and has been associated with varying grades of dys-
antifungal therapy is required for resolution plasia, particularly the nonhomogeneous type.
together with correction of underlying pre- The risk of cancer development will depend
disposing factors (e.g., amphotericin B lozenge on whether the lesion is speckled or homoge-
10 mg 4 per day for 2–3 weeks or nystatin/ nous, the presence and degree of epithelial
amphotericin B suspension 4 times per day for dysplastic changes, and the management adopted
3–4 weeks). (Field et al. 1989). The histopathology of hyperplas-
tic candidosis includes parakeratotic and hyperplas-
Chronic Hyperplastic Candidosis tic epithelium accompanied by an inflammatory
Hyperplastic candidosis (once incorrectly infiltrate and Candida hyphae invasion to the
termed candidal leukoplakia) is a chronic form upper layers of the epithelium (Samaranayake
of oral candidosis characterized by adherent et al. 2009; Williams and Lewis 2011).
white lesions ranging from small translucent to
large opaque plaques (Fig. 5). It may present as Candida-Associated Lesions
one of two variants: homogeneous or nodular/ In addition to the three typical variants of oral
speckled type. The lesions usually arise bilater- candidosis, there are other oral lesions associated
ally on the retro-commissural region of the buc- with the presence of Candida spp. where yeasts
cal mucosa, typically in middle-aged men who are not the unique etiological agents.
Fig. 5 Chronic hyperplastic candidosis in the postmodiolus area of the right (a) and left (b) buccal mucosa (same patient)
with reduced vertical occlusal dimension by old

age or ill-fitting dentures) are often correlated
with initiation and persistence of these lesions.
Sometimes angular cheilitis may be observed in
young children, due to the habit of lip licking,
thumb-sucking, or biting of the corners of the
mouth (Appleton 2000; Sharon and Fazel 2010).
Median Rhomboid Glossitis

Median rhomboid glossitis (MRG) is a charac-
teristic lesion of the dorsum of the tongue, char-
Fig. 6 Angular cheilitis acterized by an erythematous atrophic area, more
or less rhomboidal in shape, located in the
Angular Cheilitis mid-posterior part of the dorsum of the tongue
Angular cheilitis (angular stomatitis or perlèche) slightly anterior to the circumvallate papillae
is a chronic inflammatory lesion of the labial (Fig. 7). In general, it is an asymptomatic, sym-
commissures that can be affected unilaterally or metric, and flat/smooth lesion, although in some
bilaterally. Clinically it appears as erythematous, cases, it may be lobulated or mammillary. A
fissured lesions at the angles of the mouth (Fig. 6). predilection for middle-aged men consuming
It is usually symptomatic and both the skin and tobacco has been reported, with an incidence
oral mucosa may be affected. The commissures that varies from 0.2% to 3% (Arendorf and
appear wrinkled and the fissures, with time, may Walker 1984; Williams and Lewis 2011;
develop a tendency to bleed. Candida spp. and Manfredi et al. 2013). The etiology of the lesion
bacteria (mainly Staphylococcus aureus) are is controversial, and different hypotheses have
implicated in the etiology of the lesions. However, been reported, ranging from a developmental
there are several predisposing factors that have a abnormality of the tongue to an inflammatory,
role in the development of this condition. Anemia infectious, or degenerative process of the tongue
or vitamin B12 deficiency, impaired immunity, in adults. Candida spp. are frequently isolated
and saliva maceration of tissues (due to facial from the lesion, and it is possible to find a kissing
skinfolds along labial commissures in patients lesion on the palate, in affected patients.
Lesions have been classified into three sub-

types depending on their extension: (I) localized
inflammation or pinpoint hyperemia, (II) more
diffuse erythema involving part of, or the entire,
denture-covered mucosa, and (III) granular or
papillary type (inflammatory papillary hyperpla-
sia) involving the central part of the hard palate
and alveolar ridges (McCullough and Savage
2005). Histologic examination of tissues affected
by this condition reveals non-specific inflam-
matory changes, without the characteristic
intraepithelial invasion by candidal hyphae usu-
ally present in other forms of OC.
Usually the lesions are asymptomatic and may
be discovered during routine dental examination.
There has been considerable research on the role
of Candida in the etiopathogenesis of denture-
Fig. 7 Median rhomboid glossitis associated erythematous stomatitis, and a recent
extensive systematic review suggested that
However, there is no good evidence that MRG conclusive evidence of a direct etiopathogenic
lesions completely resolve after topical antifun- relationship between denture-associated erythem-
gal therapy (Manfredi et al. 2013). atous stomatitis and candidal infection has not
MRG biopsies show epithelium with loss of been found; and there is only limited evidence
papillae and a variable degree of hyperplasia, even for any treatment, thus making it impossible to
pseudoepitheliomatous, with elongated rete pegs, make strong therapeutic recommendations with
variable hyperparakeratosis, and a submucosal management directed to the treatment of the bio-
lymphocytic infiltrate. Fungal hyphae can usually film present on the denture surface with good
be found in parakeratin and/or invading the spi- denture hygiene (Manfredi et al. 2013).
nous layers, although this often requires multiple
sections before this can be demonstrated. A find- Linear Gingival Erythema
ing of intraepithelial polymorphonuclear cells Linear gingival erythema is defined as a non-
often leads to a suspicion of the presence of yeasts plaque-induced localized or generalized gingivitis
in these lesions. presenting as a distinct erythematous band of
2–3 mm along the margin of gingivae (Fig. 9). It
Denture-Associated Erythematous may be associated with discomfort and occasional
Stomatitis bleeding. This condition was firstly described in
Denture-associated erythematous stomatitis is char- HIV-infected patients, with a prevalence ranging
acterized by a chronic erythema affecting almost from 2% to 38%, but it may also be present in
exclusively the palate mucosa and alveolar ridges non-HIV subjects. Diagnosis of the condition
that are in contact with the fitting surface of a should be reserved to lesions that remain resistant
denture (Fig. 8). Apart from an overgrowth of com- to plaque removal after multiple treatments.
mensal Candida spp., other causal factors associated Linear gingival erythema is probably caused by
with this condition are poor oral and dental hygiene, a combined infection of mixed bacterial and
nocturnal denture wearing, and ill-fitting dentures. Candida spp. (C. albicans and C. dubliniensis in
Candida-associated erythematous candidosis is the particular) on a background of generalized immu-
most frequent form of oral candidosis affecting up to nodeficiency (Samaranayake et al. 2009).
50–75% of denture wearers (Farah et al. 2000; It is one of the oral manifestations of
Williams and Lewis 2011). HIV infections and is thought to be a type
Fig. 8 Denture-associated erythematous stomatitis in a Farah, Queensland Oral Medicine & Pathology, Brisbane
completely edentulous patient (a), and a partially edentu- QLD, Australia)
lous patient (b). (Image (a) courtesy of Professor Camile
differentiate these lesions from other gingival

pathologies such as conventional gingivitis, it
has been recently emphasized that a diagnosis of
linear gingival erythema should be assigned to
lesions that remain resistant to multiple plaque
removal visits (Umadevi et al. 2006).
Treatment of the condition consists of profes-
sional periodontal scaling and debridement, dili-
gent plaque control at home, and mouth rising
with chlorhexidine gluconate, but antifungals are
not always needed.
Fig. 9 Linear gingival erythema showing clearly demar-
cated erythematous free gingival margin Secondary Oral Candidal Lesions
Oral lesions that are a manifestation of general-
of HIV-associated periodontal lesion, together ized systemic or mucocutaneous candidal infec-
with necrotizing ulcerative gingivitis, necrotizing tions are classified as secondary oral candidosis. A
ulcerative periodontitis, and necrotizing stomatitis few patients may experience chronic candidosis
(Coogan et al. 2005; Reznik 2005; Umadevi et al. from an early age (endocrinopathic patients),
2006). Indeed, some authors consider the lesion as sometimes with a definable immune defect. In
a harbinger of more severe necrotizing periodon- contrast to the primary oral candidosis lesions
titis commonly seen with very low CD4 counts. It that are limited to the oral cavity, the lesions in
is likely that mixed fungal and bacterial opportu- this category affect the oral mucosa, tongue, skin,
nistic infections are responsible for this gingival and other body parts.
condition (Samaranayake et al. 2009). A debate Chronic mucocutaneous candidosis (CMC) syn-
existed about whether linear gingival erythema dromes are classical examples of these lesions and
is specific to HIV infection and what appropriate include several subtypes: autosomal recessive,
guidelines may be used for the diagnosis of autoimmune polyendocrinopathy-candidiasis-ecto-
this condition. There is consensus, however, dermal dystrophy (APECED), autosomal dominant
that although linear gingival erythema may CMC with or without thyroid disease, and autoso-
occur in HIV-free subjects, its prevalence is mal recessive, isolated CMC (Farah et al. 2000; Liu
markedly higher in HIV-infected individuals. To and Hua 2007). They are a group of heterogeneous
rare illnesses characterized by persistent or recur- individual that occasionally has acute exacerbations
rent candidal infection of the skin, nail, and mucosa (Denning and Chakrabarti 2017). The most com-
with more than 90% presenting with oral mon is the noninvasive Aspergillus mycetoma, or
candidosis (Farah et al. 2000; Liu and Hua 2007). fungus ball (Falworth and Herold 1996), which is a
In general, the more severe the lesion, the greater noninvasive or extra-mucosal mycotic infection
the probability that the patient will exhibit immu- (Fig. 12). These sinus infections can remain asymp-
nological problems, especially in cell-mediated tomatic for many years but, however, can cause
immunity (Scully 1988). Defects in production of disseminated disease or invasion in the immuno-
cytokines like interleukin-2 and gamma interferon compromised host (Cho et al. 2010; Ganesh et al.
in response to candidal and bacterial antigens, with 2015). Treatment of choice is for the surgical
the reduced serum level of IgG2 and IgG4, have removal of these fungal masses. Drainage is critical,
been suggested as a major cause of the infection and it has been recommended that endoscopic sinus
(Lilic et al. 1996). Recently, a study on the etiology surgery is preferred over a traditional Caldwell-Luc
of autosomal dominant CMC has suggested that surgical approach as this latter approach can have
mutations in the coiled-coil (CC) domain of signal long-term detrimental consequences for sinus phys-
transducer and activator of transcription 1 (STAT1) iology (Costa et al. 2007).
underlie autosomal dominant CMC and lead to Invasive fungal rhinosinusitis (fulminant fungal
defective Th1 and Th17 responses, which may sinusitis) can be very difficult to detect, with
explain the increased susceptibility to fungal infec- patients presenting with antibiotic-resistant fever,
tion (van de Veerdonk et al. 2011). and often general symptoms such as nasal dis-
charge and stuffiness (Denning and Chakrabarti
2017). More extensive disease results in nasal
Aspergillosis ulceration, epistaxis, visual impairment, facial
pain and/or maxillary tenderness, periorbital swell-
Aspergillus is a species of fungus that is diverse and ing, black necrotic lesions or perforation of the hard
aerobic and commonly grows as molds on the palate, and even facial paralysis. The infection is
surface of carbon-rich substances. Aspergillosis difficult to diagnose early but should be suspected
commonly affects only immunocompromised indi- when a neutropenic patient or uncontrolled diabetic
viduals and can cause subacute to chronic infec- develops persistent fever without a known source,
tions with sinus tracts, fistula, or abscess formation symptoms of rhinitis or sinusitis, cutaneous find-
due to invasion of surrounding tissue (Vinay et al. ings over the nose or sinuses, symptoms and signs
2017). Intraoral infections caused by aspergillus of orbital or cavernous sinus disease, or an ulcerat-
would appear to be only very rare instances of ing lesion of the hard palate or gingivae. Manage-
osteomyelitis (Urs et al. 2016), post-endodontic ment consists of surgical debridement, preferably
treatment (Urs et al. 2015), or infections following endoscopically, and antifungal therapy (Denning
surgical treatment (Sohn et al. 2009; Patil and and Chakrabarti 2017; Goh et al. 2017).
Bhadani 2011; Ganesh et al. 2015).
Aspergillosis of the paranasal sinuses, although
also very rare, occurs more frequently (Burnham Mucormycosis
and Bridle 2009; Gavito-Higuera et al. 2016;
Scolozzi et al. 2016) (Fig. 10). Fungal rhinosinusitis Mucormycosis, or zygomycosis, is an uncommon
can be classified into four broad clinical presenta- and aggressive fungal infection that usually affects
tions: (a) an acute invasive disease in immunocom- patients with alteration of their immunological sys-
promised patients; (b) a mild chronic invasive or tem with high mortality. These saprophytic fungi
granulomatous disease with no discernible impair- exist widely in nature, and their spores may be
ment of immunity; (c) a chronic course colonization found in soil, air, spoilt food, and other decaying
of nasal passage and sinus, such as a fungal ball; and organic materials. Patients with immunosuppres-
(d) chronic allergic fungal rhinosinusitis in an atopic sion such as diabetes, ketoacidosis, severe burns,
Fig. 10 Acute invasive

fungal rhinosinusitis. A 58-
year-old man known to
have acute myeloid
leukemia (AML) presented
with a 5 day history of
febrile neutropenia, nasal
congestion and facial pain.
MRI scan performed the
following day demonstrated
lack of enhancement of the
mucosa of the right middle
turbinate, the superior half
of the right nasal cavity, and
the adjacent nasal septum
on the post contrast fat
saturated sequence (a + c)
signifying devitalized
mucosa “the black turbinate
sign.” The involved mucosa
demonstrated mild T2
hypointensity on T2
sequence (b) and
isointensity on T1 sequence
(d). Histopathology of the
surgical debridement
specimens confirmed angio-
invasive aspergillosis with
infarction of the right nasal
mucosa and mucosal
necrosis. (Images courtesy
of Dr Ziyad Khaleel, Perth
Radiological Clinic, Perth
WA, Australia)
and solid organ transplant can result in germination poor, and the mortality rates vary depending
of the fungus within the paranasal sinuses with on its form and severity, with variation in mor-
spread to the palate, orbit, and brain and ultimately tality rates reported between 30% and 70%
possible intracranial extension and death (Fig. 11) (Singh et al. 2012). Oral involvement most
(Singh et al. 2012). Even with a prompt diagnosis, frequently presents as necrotic and well
treating underlying diseases and aggressive delimited with well-defined palatal ulcers.
medical and surgical management, management is Although very rare, mandibular involvement
often not effective, leading to an extension of the can occur, but has only been reported in patients
infection and death (Gonzalez Ballester et al. otherwise immunocompromised, and has a
2012). Even apparently trivial skin lacerations good prognosis with successful treatment by
have been reported to be the instigating factor simple surgical debridement and concurrent
in apparently immunocompetent patients (Klatt antifungal treatment (Aras et al. 2012).
et al. 2011; Gonzalez Ballester et al. 2012; Metzen
et al. 2012).
The hallmark of mucormycosis infection Histoplasmosis
is the invasion of arteries, thrombosis, and
subsequent necrosis (Srivastava et al. 2015). In Endemic in many areas across the world, such
most cases, the prognosis of mucormycosis is as parts of the USA, Latin America, India, the
Fig. 11 Sinonasal mucormycosis. A 65-year-old man lesion was T1 hypointese (a + d), T2 mildly hyperintense
known to have type I diabetes mellitus presented with a 3 (c), heterogeneously enhancing with areas of lack of
day history of diabetic ketoacidosis (DKA) and facial enhancement (b + e). Despite aggressive surgical debride-
swelling. The MRI scan demonstrated heterogeneously ment and intravenous antifungal treatment the patient died
enhancing mass-like soft tissue thickening in the left max- a few days later from rhinocerebral mucormycosis.
illary sinus destroying the sinus walls and the left maxillary (Images courtesy of Dr Ziyad Khaleel, Perth Radiological
alveolus. There is extra-sinus extension in the left buccal Clinic, Perth WA, Australia)
space and the anterior aspect of left masseter muscle. The
Far East, and Australia, the dimorphic fungus of the oral mucosa (Fig. 13) (Singh et al. 2014;
Histoplasma capsulatum is found especially in Folk and Nelson 2017). These are granular masses
bird and bat feces (Samaranayake et al. 2009). and ulceration with a nodular, indurated texture
Lung infection can occur when the organism is and cause tissue destruction with bone erosion
inhaled. However, the immunocompromised host (Fig. 13). Oral histoplasmosis has been reported
and particularly patients with advanced HIV in immunocompetent patients, and this has caused
infection with impairment of cellular immunity significant diagnostic dilemma and inappropriate
are particularly at risk. treatment as it can clinically appear as oral squa-
Oral lesions of histoplasmosis are generally mous cell carcinoma (Iqbal et al. 2014).
associated with the disseminated form of histo- The diagnosis of oral histoplasmosis is
plasmosis in immunocompromised patients and usually made with histopathological assessment
may present as a fungating or ulcerative lesion of biopsy tissue (Figs. 14 and 15) and can be
Fig. 12 (a, b) CT of Aspergillus mycetoma, or fungus ball, mycetoma showing the edge of a colony of Aspergillus
in the right superior lobe of the lung (a), and pathological forming a fungal ball. The fungal hyphae exhibit dichoto-
gross specimen of an Aspergillus mycetoma, surgically mous 45 angle branching and septae typical of Aspergil-
removed from same patient. (Images courtesy of Professor lus. Hematoxylin and eosin, 400. (Used with permission
David Denning, University Hospital of South Manchester, of Yale Rosen - http://www.flickr.com/photos/pulmonary_
Manchester, UK). (c) Histopathology of an Aspergillus pathology/5390379559)
confirmed with culture and serology. Patient’s Cryptococcosis

prognosis and treatment are directly related to
the severity of any underlying immunosuppres- The fungus Cryptococcus is found in bird roosting
sion and overall health of the patient. Although it sites, particularly pigeons, and only one species
has been reported that in some patients, histo- Cryptococcus neoformans causes human infec-
plasmosis will resolve without intervention tions with a primary site of C. neoformans infec-
(Folk and Nelson 2017), generally patients will tion in the lung (Iatta et al. 2009). It occurs
require comprehensive treatment with an through aspiration of airborne spores that lodge
antimycotic. in the lungs producing pulmonary cryptococcosis
Fig. 13 Clinical appearance of histoplasmosis in an granular, indurated masses on the buccal mucosa (c).
HIV-infected patient showing widespread ulceration of (Images courtesy of Professor Mariana Villarroel Dorrego,
the external corner of the mouth (a and b) and nodular, Caracas, Venezuela)
Fig. 14 Photomicrograph showing macrophages and Fig. 15 Grocott-Gomori methenamine silver stain clearly
potential, but difficult to discern intracellular histoplasmo- demonstrating histoplasmosis. Grocott, 400. (Image
sis. Hematoxylin and eosin, 200. (Image courtesy courtesy of Professor Mariana Villarroel Dorrego, Caracas,
of Professor Mariana Villarroel Dorrego, Caracas, Venezuela)
Venezuela)
although its incidence has greatly decreased due

and by hematogenous dissemination of crypto- to treatment with highly active antiretroviral ther-
coccosis to the CNS. Cryptococcosis remains apy in developing countries, although cryptococ-
one of the most common life-threatening systemic cosis in HIV patients is still exceedingly high in
fungal infections in HIV-infected patients, developing countries (Iatta et al. 2009).
Cutaneous, mucocutaneous, osseous, and vis- blastomycosis in the differential diagnosis of oral/
ceral forms of the disease may occur through palatal soft tissue masses (Thomas et al. 2014).
dissemination from the primary pulmonary
focus. Oral and skin lesions are not uncommon
in the disseminated form of the disease, but rarely Paracoccidioidomycosis
represent the site of primary infection. Oral
lesions have been described on the gingiva, the Paracoccidioides brasiliensis, a dimorphic fun-
hard and soft palates, the pharynx, the gus, can infect via inhalation of spores present in
oral mucosa, the tonsillar pillar, and a tooth socket damp soil rich in organic matter in temperatures
after extraction (Dodson et al. 1989; Tzerbos et al. that are characteristic of subtropical climates
1992; Mehrabi et al. 2005; Delgado and Romero resulting in paracoccidioidomycosis (Barbosa de
de Leon 2008). The lesions have been variously Paulo et al. 2014; Denning and Chakrabarti 2017).
described as violaceous nodules of granulation It occurs mainly in Central and South America
tissue, swellings, or ulcers. Diagnosis must be with about 3,500 new cases occurring in Brazil
confirmed by microscopy and subsequent culture each year usually in the south and southeast
confirmation. regions. There are two forms of the disease rec-
ognized: an acute form that tends to affect young
patients and has a rapid onset and a more chronic
Blastomycosis form that has a gradual onset and tends to affect
males engaged in rural activities (Abreu e Silva
Blastomyces dermatitidis is a thermally et al. 2013; Denning and Chakrabarti 2017).
dimorphic fungus that produces mycelia and Initial infection is in the lungs and then may
forms aleurioconidia at 25 C, while at 37 C, spread to other organs, including the oral cavity
it takes the form of a broad-based budding yeast. (Abreu e Silva et al. 2013; Denning and
It is isolated from soil with a geographic distribu- Chakrabarti 2017).
tion that overlaps with that of Histoplasma The oral lesions, known as moriform stomati-
capsulatum. Human disease is acquired by tis, can occur simultaneously in a number of ana-
inhaling conidia, which causes local pulmonary tomical sites and present as ulcerated, red, and
infection, often accompanied by extrapul- granulomatous lesions that tend to bleed on the
monary dissemination. It has been shown that lips, gingiva, buccal mucosa, palate, tongue, and
B. dermatitidis is not transmissible from person floor of the mouth (Figs. 16 and 17) (Godoy and
to person (McCullough et al. 2000). Reichart 2003; Brazao-Silva et al. 2011; Barbosa
Oral infections caused by B. dermatitidis are de Paulo et al. 2014; Pedreira Rdo et al. 2014).
exceedingly rare. A very early report from 1977 There may be periodontal involvement leading to
in South Africa related a tongue ulcer in a 63-year- tooth mobility (Figs. 16 and 17). These lesions
old man that was shown histologically and by can often be difficult to diagnose with similarities
culture to be due to B. dermatitidis as well as to oral squamous cell carcinoma (Sargenti Neto
the observation of pulmonary B. dermatitidis at et al. 2012).
autopsy (Simon et al. 1977). More recently there In some instances, the oral lesions may be
has been a single reported case of an infection of the first and main clinical manifestation of the
the hard palate caused by B. dermatitidis (Thomas disease, and dentists play a significant role in
et al. 2014). Radiographic soft tissue mass in the the diagnosis and subsequent timely treatment
paranasal sinus and cultivation of B. dermatitidis (Azenha et al. 2012). Diagnosis is usually made
from the biopsy material of a diabetic patient pre- with biopsy and hematoxylin, and eosin-stained
senting with headache and malaise showed dissem- sections reveal ulceration with a fibrous leuko-
inated disease without acute respiratory distress cytic surface, a lymphoplasmacytic infiltrate, and
(Thomas et al. 2014). Clinicians practicing in multinuclear giant cells containing round bodies
areas of B. dermatitidis endemicity should include with a double membrane (Fig. 18) (Barbosa de
Fig. 16 Intraoral paracoccidioidomycosis presenting in courtesy of Professor Mariana Villarroel Dorrego, Caracas,
the anterior mandible (a), and as demonstrated on an Venezuela)
orthopantomogram in the same patient (b). (Images
Fig. 17 Intraoral paracoccidioidomycosis presenting in courtesy of Professor Mariana Villarroel Dorrego, Caracas,
the left posterior mandible (a) and as demonstrated on a Venezuela)
periapical radiograph in the same patient (b). (Images
Paulo et al. 2014; do Prado Gomes Pedreira et al.

2016). Gomori-Grocott staining reveals budding
and blastoconidia suggestive of mycoses (Fig. 19)
that can also be demonstrated with periodic acid-
Schiff (PAS) staining (Fig. 20) (Barbosa de Paulo
et al. 2014).
Patient Management
Proper management of oral candidal infection is

based on differentiation of candidal lesions from
other similar clinical presentations. White plaques
on inflamed mucosa and erosive erythroplakic and
Fig. 18 Histopathology of intraoral paracoccidioido-
leukoplakic lesions on oral mucosa may be caused
mycosis showing characteristic giant cells. Hematoxylin
and eosin, 200. (Image courtesy of Professor Mariana by factors other than oral candidosis (Scully et al.
Villarroel Dorrego, Caracas, Venezuela) 2004). Generally, diagnosis of oral candidosis is
Fig. 19 Grocott-Gomori methenamine silver stain clearly Fig. 20 Periodic Acid-Schiff stain of biopsy specimen
demonstrating paracoccidioidomycosis. Grocott Silver, showing paracoccidioidomycosis. Periodic Acid-Schiff,
400. (Image courtesy of Professor Mariana Villarroel 400. (Image courtesy of Professor Mariana Villarroel
Dorrego, Caracas, Venezuela) Dorrego, Caracas, Venezuela)
valuable support for the specific identification

based on clinical signs and symptoms conjugated of the etiological agent involved. Significant
with a careful medical history. Provisional diag- progress has been achieved in the laboratory diag-
noses should be confirmed by additional labora- nosis of fungal infections, such as the characteri-
tory tests after failure of initial therapy or if zation of new pathogenic species, the molecular
the patient possesses risk factors of systemic fun- identification and typing of responsible strains,
gal infections (McCullough and Savage 2005; the detection of antigens in clinical materials,
Rautemaa and Ramage 2011). Identification sys- and the definition of effective markers of infec-
tems for yeasts may vary from simple tests used in tion. Despite the advance of the state of the art,
the speciation of Candida to a large set of tests that early diagnosis of fungal infections is still consid-
enables differentiation of all medically important ered the result of the synthesis of clinical and
yeasts. Such systems include a smear, a swab, an laboratory investigations, carried out jointly and
imprint culture, salivary culture technique, oral in synergy (Williams and Lewis 2011). From an
rinse technique, and histopathology. In cytologi- epidemiological point of view, the last decades
cal smears and histopathological sections, the have been characterized by a significant increase
presence of candidal hyphae is usually confirmed in fungal diseases. The phenomenon is attribut-
by PAS staining as hyphae stain poorly by hema- able not only to the pandemic of the acquired
toxylin and eosin (Scully et al. 1994). In case of immunodeficiency syndrome (AIDS) but also to
refractory candidal infections and in the presence the increased use of immunosuppressive drugs,
of risk factors for systemic candidosis, diagnosis particularly in cases of bone marrow and organ
should be based on culture-verified infection, transplants and cancer, and to the insertion of
species-level identification, and antifungal sus- prosthetic implants and catheters for therapeutic
ceptibility testing (Rautemaa and Ramage 2011). purposes. Paradoxically, the same progress in
medical research, which led to a significant
improvement in prognosis of the underlying
Laboratory Diagnosis pathology, represents a risk factor for the onset
of invasive fungal infections (Calderone 2002).
Fungal infections are characterized by a wide Most human fungal infections are caused by
spectrum of pathological manifestations that Candida spp. and Aspergillus spp., although other
often make early clinical diagnosis problematic, emerging pathogens are more and more fre-
and the medical mycology laboratory can provide quently found, including species belonging, in
particular, to the genera Acremonium, Fusarium, The laboratory methods for the diagnosis of
Geotrichum, Scedosporium, Trichosporon, fungal infections are fundamentally based on
Mucor, and Rhizopus. The diagnosis of fungal direct (detection of the etiological agent or its
infection is particularly problematic for the envi- components in the clinical specimen) and indirect
ronmental diffusion of the causative agents, the (detection of a specific antibody titer in the serum)
physiological fungal colonization of the human methods (Denning and Chakrabarti 2017).
upper airways (Aspergillus spp.) and mucous Fundamental conditions for the effective diag-
membranes (Candida albicans), the possibility nosis of fungal infections are the appropriate
of obtaining suitable clinical samples, the relative procedures for collection and transport of the clin-
lack of effective markers, and the difficulty of ical specimens to the medical mycology labora-
differential clinical diagnosis (Pfaller 1996). tory because of the possible simultaneous
Yeasts are among the most frequent causative occurrence of bacteria more rapidly growing
agents of fungal infections in humans and can be than opportunistic fungal pathogens (Ellepola
isolated from the clinical materials of any anatom- and Morrison 2005).
ical area. The majority of yeast infections are Depending on the depth of the infection in the
caused by endogenous species (intestinal, skin, various anatomical sites and the consequential
and mucous membrane colonization) belonging entity of the host’s immune response, fungal
to the genus Candida. The isolation of a yeast is diseases are conventionally classified as superfi-
diagnostic for a mycosis only if performed by cial, mucocutaneous, subcutaneous, and deep
physiologically sterile materials (such as blood, (that may develop into systemic or disseminated).
urine, or cerebrospinal fluid). With the possible Any clinical material, therefore, can be subjected
exception of Cryptococcus neoformans, the isola- to microscopic, cultural, serological, and/or mole-
tion of the same yeast obtained from clinical cular investigations (Ellepola and Morrison 2005).
material of possibly colonized anatomical sites
may result in the need for additional diagnostic Collection and Transport of Clinical
tests. The presence of filamentous fungi in soil Specimens
or decaying organic materials is constant and For the clinical materials to be subjected to myco-
may cause the environmental spread of conidia logical investigations (blood, cerebrospinal fluid,
and/or spores that can be inhaled and cause urine, bone marrow, biopsy material, sputum, pus,
opportunistic infections of the respiratory system aspirated drainage, vaginal and cervical secre-
in immunocompromised hosts (Denning and tions, scales and skin appendages, catheters, pros-
Chakrabarti 2017). theses, surgical materials, etc.), it is essential to
The cultural isolation of filamentous fungi observe some basic rules concerning the modali-
from clinical materials may be attributable to ties of the specimen sampling, the sterility of the
environmental contamination. As a diagnostic containers, and the use of suitable transport media
support, factors related to the underlying disease when needed. Moreover, the clinical specimen
that involve a risk of invasive fungal infection, must be accompanied by a specific request of the
the clinical anamnesis, and the endemicity of laboratory test to be performed, the indication of
the geographic area of residence of the patient the suspected diagnosis, the information about the
can be of value. Aside from HIV-infected patient, the department of recovery, the type
individuals, the highest risk of invasive fungal of specimen, the date and time of its collection,
infection by filamentous fungi concerns and possibly the undertaken antibiotic treatments
patients suffering from hematological malignan- (Rautemaa and Ramage 2011).
cies or undergoing bone marrow or solid organ
transplant. For infectious zygomycetes, there are Microscopic Examination of Clinical
also additional risk factors not necessarily Specimens
related to the state of the host’s immune system The direct microscopic examination is character-
(Denning and Chakrabarti 2017). ized by rapidity, simplicity, and cheapness in its
performance. The observation of fungal structures and therefore, this antibiotic should not be used
directly in the pathological material may enable a exclusively in mycological media
generic diagnosis of fungal infection, usable by (Neppelenbroek et al. 2013).
the mycologist to inoculate the clinical material in After treatment and inoculation of the clinical
the most suitable media to facilitate the isolation specimen in the appropriate media, the cultural
of the pathogen (Peman et al. 2011). While test implies the incubation at different tempera-
privileging the cultural test, because more tures (37 and 25 C, to differentiate the growth of
specific, all clinical materials in sufficient quanti- thermal dimorphic fungi), for periods of time that
ties can be microscopically observed in fresh vary in relation to the inoculated pathological
or stained slides, saline, lactophenol cotton material and the clinical suspicion of fungal infec-
blue, potassium hydroxide, Indian ink, fluores- tion (Neppelenbroek et al. 2013).
cence, Gram, Gomori, Gridley, PAS, etc. (Peman
et al. 2011). Isolation and Identification of Fungal
Cultures
Treatment and Culture of Clinical The daily observation of the cultures allows note
Specimens of any fungal growth that can be in the form of
Many clinical materials sent to the laboratory with whitish colonies with creamy appearance (yeasts)
a request of cultural examination for fungi do not or with different shades of color with cotton
need to be treated and can be directly inoculated appearance (molds). The macroscopic character-
into the appropriate media. Others may need to be istics of the fungal colony as color and type of
concentrated by centrifugation (urine, cerebrospi- surface (smooth, dusty, cottony, granular, or wrin-
nal fluid), homogenized (sputum), pulverized in a kled) may provide useful information for identifi-
mortar (bones), or cut with sterile scalpel (bioptic cation purposes. Yeasts are not a distinct
material) or scissors (nails, hair). The media used taxonomic group, but they represent a form of
for the isolation and cultivation of fungi are dif- growth shared by a wide variety of fungi (Ellepola
ferent, either in the solid state (plates, slant tubes) and Morrison 2005).
or in the liquid state (broth), and, in most cases, The first investigation to be carried out is based
commercially available (Sabouraud dextrose, on a fresh slide to observe microscopically the
bromocresol green agar, CHROMagar, brain- structure of the fungal colony. The observation
heart infusion, Converse medium, potato-dextrose of single-celled structures that reproduce by bud-
agar, Czapek-Dox agar). The Sabouraud dextrose ding is indicative of yeastlike fungi whose identi-
agar, originally formulated for the cultivation of fication is based primarily on the assessment of
dermatophytes, is generally recognized as the uni- their biochemical properties and, second, of
versal medium for fungi, but cannot allow, by morphological characteristics. The observation
itself, the growth of all the fungal agents, and of tubular structures (hyphae), with or without
therefore, various substrates (blood, brain-heart septa, is indicative of filamentous fungi, whose
infusion, etc.) should be added in relation to identification is based essentially on the observa-
the clinical sample to be investigated and tion of the modalities of asexual reproduction
the suspected fungal agent to be cultivated (production of conidia or sporangiospores). Any
(Neppelenbroek et al. 2013). fungus isolated in culture and morphologically
The growth media may also be added with associated with the direct microscopic examina-
antibiotics (gentamicin, chloramphenicol), for tion must be identified at the species level (Scully
inhibiting bacteria that may be present, and/or et al. 1994).
with cycloheximide, an antifungal which
inhibits most of the environmental saprophytic Identification of Yeasts
fungi. It is important to consider, however, that The generic and specific identification of yeasts is
some relevant pathogenic fungi (e.g., pursued through the study of their biochemical
C. neoformans) are sensitive to cycloheximide, characteristics (assimilation and fermentation of
carbohydrates, urease production, utilization of safety cabinet. The cultural identification of

nitrates, etc.) and morphological features (forma- dimorphic fungi, in particular, can be obtained
tion of germ tube, presence or absence of pseudo- through the conversion of the form in vitro
hyphae, chlamydoconidia, arthroconidia, etc.) and/or by using the exoantigen test or molecular
(Ellepola and Morrison 2005). approaches (Alnuaimi et al. 2014).
The identification at the species level is impor-
tant not only for a correct etiological diagnosis but Exoantigen Test
also because it allows acquisition of more epide- The methodology of exoantigens consists to
miological knowledge and useful information for test, in a double immunodiffusion procedure,
the choice of the therapeutic treatment to be a concentrated acellular antigen (exoantigen),
adopted. The microscopic observation of the mor- obtained from the mycelial culture of interest,
phological characteristics of the yeast is required comparatively to a specific serological system
to determine its relationship with a genus that for each dimorphic fungus, consisting of a refer-
allows, together with the biochemical properties, ence antigen and a reference antiserum. The result
to achieve the identification at the species level is considered positive when, between the exo-
(Ellepola and Morrison 2005). antigen and the reference antiserum, precipitin
Both types of investigations are to be bands homologous to those evidenced in the reac-
conducted independently since the only bio- tion of the control system are formed. The method
chemical profile may be insufficient when shared is very simple and can be performed with com-
by species belonging to different genera. The mercially available reference reagents (Taschdjian
most important methods for the study of the et al. 1973).
morphological characteristics of yeasts are the
germ tube assay and its observation in the Molecular Investigations
Dalmau plate. For the determination of the bio- The laboratory diagnosis of invasive fungal infec-
chemical characteristics of yeasts, commercially tions is particularly complex, and the traditional
available miniaturized, manual, partially, or approach, performed by direct microscopic exam-
totally automated systems are usable, based on ination and culture, can take a long time, hardly
the assimilation of carbohydrates (Ellepola and compatible with the clinical needs and not being
Morrison 2005). very sensitive and/or specific. The technology
of molecular amplification of fungal nucleic
Identification of Molds acids may constitute a valid alternative although,
The filamentous fungi are identified at the species despite the considerable effort of the studies car-
level essentially based on their macroscopic and ried out, it has not yet achieved a sufficiently
microscopic features of the colony. Additional reliable and shared amplification system to be
diagnostic criteria may be the tolerance to certain applied to the diagnosis of fungal infection
critical temperatures for growth, the ability to directly from the clinical sample. The main prob-
manifest the thermal dimorphism phenomenon lem is related to the high sensitivity of molecular
in vitro, the evidence of nutritional requirements methods such as PCR, nested PCR, NASBA,
(growth factors), and the production of enzymes DNA analysis of restriction fragment polymor-
(Ellepola and Samaranayake 2000). phism (RFLP) by conventional electrophoresis
Because the microscopic morphology of fila- or pulsed-field gel electrophoresis, DNA finger-
mentous fungi is particularly important for cor- printing with arbitrarily primed repeated probes
rect identification, a slide culture, a specific (AP-PCR), electrophoretic analysis of karyotype,
methodology useful to improve the observation, or others, which, in clinical mycology, may not
has been developed. It should be stressed that, to allow the fine distinction in the host between the
ensure the operator’s safety, all the operations states of colonization and infection. The use of
involving the handling of filamentous fungi methods such as real-time PCR, which allows
must be carried out in a double laminar flow quantification of the target nucleic acid occurring
in the clinical sample, can only partially overcome methodology used (double immunodiffusion,
this limitation (Stevens et al. 1990). passive agglutination, complement fixation,
Another not negligible critical factor is consti- immunoenzymatic, etc.), useful information
tuted by the methods adopted for the extraction of (number of precipitation bands, antigenic and/or
fungal nucleic acid, from the possibility of con- antibody titer in serial samples, etc.) of prognostic
tamination of the pathological material during value, although they can be affected by low
the extraction procedure and by the presence of specificity and/or sensitivity and by the lack of
potential inhibiting substances to the reaction of commercial availability of some reagents (Fenn
amplification. Finally, but not last in importance, et al. 1994).
the choice of the target sequence to be amplified
(usually consisting of three nuclear rRNA genes, Diagnostic Markers
26S or 28S, 18S, and 5,8S separated by the ITS In recent years, diagnostic markers have taken
regions or genes for β-tubulin or actin) is to be considerable significance as potentially allowing
considered, in order to obtain reliable results not early diagnosis of invasive fungal infections,
only in the presence of a fungus (universal primer) especially in immunocompromised hosts.
but also for its identification (species-specific Among these, particularly consolidated are the
primer) (McCullough et al. 1999a, b). detection of galactomannan (GM) (disseminated
Several recent assays have been developed for aspergillosis) and (1!3) β-D-glucan
the accurate, rapid, and economical identification (BG) (systemic candidosis). GM is a poly-
of isolated yeasts. One is using high-resolution saccharidic component of the cell wall of Asper-
melting curve analysis of internal transcribed gillus spp. (closely related to Penicillium spp.)
regions ITS1 and ITS2 in ribosomal DNA that is released into the bloodstream during fungal
(rDNA) for a rapid, simple, and inexpensive dif- growth in the tissues (exoantigen). The presence
ferentiation of eight clinically relevant Candida of GM is not constant in the course of infection, so
species as well as classifying C. albicans strains the test should be performed on serial samples.
into four previously described genotypes (A, B, C, The assay is significantly specific for the diagno-
and D) with results obtainable in 4 h and without sis of invasive aspergillosis at an early stage
the need for any post-amplification handling (sometimes earlier than the onset of symptoms).
(Alnuaimi et al. 2014). Such simplified and The application of immunoenzymatic assay (EIA)
speedy techniques potentially allow for future has greatly improved the sensitivity of the GM
genotypic analysis of hundreds of clinical strains test. However, the possibility of false-positive or
in large epidemiological settings. false-negative results remains. The diagnostic
reliability of the test is closely related to the
Serological Assays positivity of serial clinical specimens (serum,
The certainty of the laboratory diagnosis of an bronchoalveolar lavage, cerebrospinal fluid,
invasive fungal infection is usually acquired etc.), taken at least twice a week, and to the adop-
through the comprehensive assessment of the tion of a suitable breakpoint for the interpretation
results obtained with microscopic investigations, of results (Taff et al. 2011).
cultivation, and serological assays. For unavoid- The research of glucuronoxylomannan (GXM),
able reasons, it is sometimes difficult to jointly the main component of the polysaccharidic capsule
prosecute all these diagnostic approaches. In this of C. neoformans, has a significant diagnostic rel-
case, the serological approach could, by itself, evance whatever methodology, such as latex agglu-
offer a valuable diagnostic contribution both for tination (LA) or EIA, is used for its detection.
the qualitative and quantitative determination of Several reliable commercial products are available
antigens (direct diagnosis) and antibodies (indi- for the determination of GXM in all recognized
rect diagnosis) occurring in the patient serum and serotypes (A, B, C, D, and AD) or species
in other biological fluids. The serological investi- (C. neoformans, C. gattii) subject to possible
gations may also offer, in relation to the false-negative results (infection in the early stage,
causative strains with poor production of the cap- agents are the polyenes (nystatin and
sular antigen, prozone effects) or false-positive amphotericin B), the azoles (miconazole, clotri-
results (cases of disseminated trichosporonosis). mazole, ketoconazole, itraconazole, fluconazole),
The search for mannans, for the diagnosis of inva- and less frequently 5-fluorocytocine. The newer
sive candidosis by EIA, has a good specificity but antifungal agents include the echinocandins
requires a high sampling rate for the remarkable (caspofungin, micafungin, and anidulafungin)
speed with which those antigens are eliminated and the latest azoles, posaconazole and ravuco-
from the blood. Recent studies have shown a nazole, which are in development for clinical use
good diagnostic efficacy when the assay is (Spampinato and Leonardi 2013). Furthermore,
performed at the same time looking for antimannan mouth rinses containing chlorhexidine have
antibodies in critically ill, but not immunocompro- also been proposed as an adjunctive, or some-
mised, patients. Commercial systems are currently times as an alternative, to conventional anti-
available for the detection of specific antigens for fungal treatment of oral candidosis, particularly
H. capsulatum, particularly in the blood and urine denture-associated stomatitis (Budtz-Jorgensen
of patients with disseminated histoplasmosis, while 1990; Samaranayake et al. 2009). The fungal
for pulmonary forms, the assay has a lower diag- ergosterol biosynthesis is specific to fungi and
nostic value (Denning and Chakrabarti 2017). required for correct cell membrane function. As
a result, this feature has been used as the main
MALDI-TOF target of antifungal therapy. Most antifungals act
Recently, mass spectrometry (MS) has found, by either direct or indirect interference in ergos-
based on matrix-assisted laser desorption ioni- terol biosynthetic pathway, resulting in altered
zation-time-of-flight (MALDI-TOF) technol- cell wall permeability, loss of vital cytoplasmic
ogy, important applications also for the components, and cell death (Sanglard and Bille
identification of fungal species in medical 2002). Owing to the emergence of azole-resistant
mycology. The MALDI-TOF technology can Candida strains such as C. glabrata and C. krusei,
provide two different approaches for specific it is generally recommended to use the polyenes as
identification: comparison of spectra with data- first line of treatment and the azoles as a second line
bases containing reference profiles or of defense. In addition, for the same reason, it is
“matching” of biomarkers with proteomic data- recommended that uncomplicated superficial oral
bases (Dhiman et al. 2011). candidosis in generally healthy patients should be
treated topically and oral candidosis lesions in
immunocompromised patients should be treated
Specific Treatment systemically as well as topically (Samaranayake
et al. 2009; Rautemaa and Ramage 2011).
Antifungal Treatment Antifungal agents commonly used in the treat-
Candidosis characteristically develops in the pres- ment of oral candidosis, as well as their dosage
ence of compromising factors. Therefore, identi- and duration of therapy, are outlined in Table 3.
fication and correction, if possible, of the Not all of these medications may be available in
underlying predisposing factors is a therapeutic all countries.
cornerstone in the treatment of these infections
(Farah et al. 2000). Pharmacological treatment Non-antifungal Treatment of Denture-
should be started if the correction of the above Associated Erythematous Stomatitis
factors is not possible or indicated (Farah et al. As outlined above, there is no clear link of Can-
2010). Drug choice is dictated by the immunolog- dida in the causation of denture-associated ery-
ical status of the patient, the surface area of thematous stomatitis. Thus, management should
erosive lesions, and the chronicity of the pre- be directed to the treatment of the biofilm present
disposing factors (Rautemaa and Ramage 2011). on the denture surface with good denture hygiene
Currently, the most frequently used antifungal (Manfredi et al. 2013).
Table 3 Antifungal agents commonly used in the treatment of oral candidosis

Antifungal
agent Form Dosage
Amphotericin Lozenge, 10 mg Slowly dissolved in the mouth 3–4 times a day after meals for 2 weeks
B Oral suspension, Placed in the mouth after meal and retained near lesions 4 times daily for
100 mg/ml 2 weeks
Nystatin Pastille, 100,000 units Dissolve 1 pastille slowly after meals 4 times daily, usually for 7 days
Oral suspension, Apply after meals 4–5 times daily, usually for 15 days, and continue use
100,000 units for several days after post-clinical healing
Clotrimazole Cream Apply to affected area 2–3 times daily for 3–4 weeks
Solution 5 ml 3–4 times daily for at least 2 weeks
Miconazole Oral gel Apply to affected area 3–4 times daily for 3–4 weeks
Cream Apply twice per day and continue for 10–14 days after post-clinical
healing
Muco-adhesive buccal Apply on the upper gum once a day for 7–14 days
tables, 50 mg
Ketoconazole Tablets 200–400 mg tablets taken once or twice daily with food for 2 weeks
Fluconazole Capsules 50–200 mg capsules once daily for 2–3 weeks
Oral suspension 200 mg once on the first day, then 100 mg for at least 2 weeks
Itraconazole Capsules 100 mg capsule once daily taken after meals for 2 weeks
Regular nocturnal denture use should be long-term use of chlorhexidine solution may
avoided, and traditionally, it has been recom- cause discoloration of the denture. Use of an anti-
mended that dentures are kept in a liquid over- fungal gel such as miconazole applied directly to
night. However, it has been shown that allowing the tissue-bearing surface of the denture during
the denture to dry out at night is much more daytime use can also expedite resolution of
effective in reducing yeast colonization and denture-associated erythematous stomatitis. This
plaque re-accumulation compared with either should be applied 4 times daily for up to 4 weeks
denture cleansers or water. Dimensional changes for complete resolution.
in the denture can occur during repeated cycles
of hydration and dehydration; however, these
changes are very small and are not clinically Association Between Candida and Oral
significant. Therefore, clinicians should advise Squamous Cell Carcinoma
patients to take their dentures out at night, clean
them, and place them in a dry environment During the last four decades, there has been
(Manfredi et al. 2013). increasing clinical and experimental evidence to
Mechanical cleaning with a soft toothbrush suggest a putative role for Candida in the multi-
and soap on a regular (at least twice daily) basis step process of oral mucosal carcinogenesis. Can-
is the most effective way of removing the biofilm dida yeasts can cause a spectrum of oral mucosal
from the denture material. It is not only lesions including chronic hyperplastic candidosis,
recommended for preventing disease but also as also known as candidal leukoplakia. It has been
first-line treatment of denture-associated erythem- postulated that this variant of oral candidosis
atous candidosis (can take 1 month before carries a significant risk of malignant transforma-
improvement is seen). To aid in mechanical tion (Samaranayake and Yaacob 1990; Bartie
cleaning, twice weekly soaking for 15–30 min in et al. 2004). Although this evidence could be
white vinegar (diluted 1:20), 0.1% hypochlorite circumstantial, reflecting an association rather
solution (diluted Milton’s solution), or chlorhexi- than a true causality, a considerable number
dine solution should be encouraged; however, of clinical and experimental investigations
demonstrated that bacteria and yeasts can promote promotion, such as the effect of chronic inflam-
carcinogenesis either directly or indirectly and mation on carcinogenesis, has been hypothesized.
that some C. albicans biotypes may contribute The hypothesis states that initiated cells accumu-
more to carcinogenesis than others. The following late during life and that promoters act to (i) cause
sections detail the results of investigations about these cells to accumulate more mutations (possi-
this putative carcinogenic role and the possible bly by preventing apoptosis of carcinogen-
mechanisms by which yeasts may promote oral damaged cells and through reactive oxygen spe-
cancer. cies formation), (ii) drive these mutant cells to
proliferate, and (iii) give preneoplastic and neo-
plastic cells a growth advantage through “Darwin-
Theory of Oral Carcinogenesis ian selection” (Klein and Klein 1985; Philip et al.
2004). The initiators are usually DNA-reactive
Carcinogenesis is considered as a multistep substances (carcinogenic mutagens), while pro-
process with subsequent stages of initiation, promoters are usually non-DNA reactive. A single
motion, and progression. Initiation is an irrevers- exposure to mutagens may be sufficient to cause
ible, nonlethal genetic change that may be cancer, while promoters must act over time for
hereditary or acquired by an insult from environ- tumors to develop, eventually progressing to can-
mental agents, such as chemical carcinogen or cer (Philip et al. 2004).
oncogenic microbes such as human papilloma
virus (HPV) (La Vecchia et al. 1997; Smith et al.
1998). These genetic alterations occur mainly in Clinical Observations
regulatory genes such as proto-oncogenes, tumor
suppressor genes (TSG), and genes involved A role for candidal infection in the development
in apoptosis and DNA repair (Weinberg 1996). of oral squamous cell carcinoma was suggested by
Proto-oncogenes are cellular genes involved Cawson and Lehner who investigated 12 individ-
in normal cell growth and differentiation (Field uals with chronic hyperplastic candidosis whose
et al. 1989). They encode growth factors, growth lesions are postulated to be associated with
factor receptors, and proteins involved in signal malignant change (Cawson and Lehner 1968).
transduction and transcription, as wells as cyclin Interestingly, individuals demonstrated high anti-
and cyclin-dependent kinase. Mutations in these Candida antibody titers; histological changes
genes may result in the transition of proto- consistent with candidal infection and lesions
oncogene to an oncogene, whose expression showed responsiveness to antifungal treatment,
and/or product is not influenced by regulatory suggesting C. albicans had an etiological role
elements (Weinberg 1996). In contrast, TSG rather than a secondary infection of an existing
encode components that suppress cell prolifera- lesion. A year later, a report presented biopsies
tion. Inhibition of both alleles of a TSG can lead to from two individuals with chronic hyperplastic
aberrant cell growth, a key event in carcinogenesis candidosis, which demonstrated hyphal infiltra-
(Weinberg 1996). Further, genetic alterations in tion with one showing epithelial changes consis-
genes encoding components involved in apopto- tent with squamous cell carcinoma (Williamson
sis or DNA repair ultimately facilitate persistence 1969). A further study investigating three patients
and replication of mutated cells. with chronic oral candidosis reported that two had
This initiation (mutation) is followed by a pro- associated malignant change (Eyre and Nally
motion step, which is the accumulation of the 1971). These authors postulated that malignant
genetic changes that can stimulate transformation transformation may occur after prolonged
of normal cells into neoplastic cells. These cells local candidal infection (Eyre and Nally 1971).
may then form malignant tumors that are charac- Interestingly, similar rates of malignant transfor-
terized by excessive cell growth, invasiveness, mation do not occur clinically in other chronic
and metastasis (Ruoslahti 1996). The role of mucosal candidal lesions, such as erythematous
candidosis, angular cheilitis, and chronic muco- An investigation used the method of strain dif-
cutaneous candidosis. ferentiation (Odds and Abbott 1980) to compare
Nonhomogeneous leukoplakias have higher C. albicans isolated from healthy and
malignant transformation potential than the pathological mucosa (Rindum et al. 1994). Three
homogeneous types (Pindborg 1980; Axéll et al. different phenotypically defined sub-species types
1984). Previous studies reported that the majority of C. albicans were isolated from leukoplakic
of nonhomogeneous leukoplakias are invaded by lesions exhibiting epithelial dysplasia, while none
yeast, particularly C. albicans (Renstrup 1970; of these types were isolated from healthy individ-
Bánóczy and Sugár 1972; Cawson and Binnie uals. The results of this study suggested that par-
1977). It has been suggested that the presence of ticular subgroups of C. albicans had a predilection
Candida in association with dysplastic or malig- to oral lesions with dysplasia (Rindum et al. 1994).
nant lesions may represent a secondary infection Other investigators screened yeast isolates,
with a pre-existing altered epithelium, but the including C. albicans, from oral leukoplakias and
clinical resolution of the chronic hyperplastic can- normal oral mucosa for their ability to form N-
didal lesions and the reduction in the extent of nitrosobenzylmethylamine, a compound known to
dysplasias after antifungal therapy have empha- be involved in carcinogenesis (Krogh et al. 1987a,
sized a direct etiological role for Candida. It has b; Krogh 1990). It was found that C. albicans had
been demonstrated that a reduction in epithelial the highest nitrosation potential and that strains of
dysplasia can occur in a leukoplakic lesion with C. albicans colonizing leukoplakic lesions differ
concurrent elimination of Candida organisms from those in normal oral mucosa. Furthermore,
using an 11-day course of the antifungal, flucon- these investigators reported that more advanced
azole (Lamey et al. 1989). precancerous lesions were associated with
A study investigated the long-term follow-up C. albicans strains that exhibited a high nitrosation
(mean observation period 9.8 years) of potential (Krogh et al. 1987a, b; Krogh 1990).
670 oral leukoplakias to determine etiological A statistically significant association has been
factors that may influence malignant transfor- shown between fungal infection, determined his-
mation (Banoczy 1977). Although candidal topathologically by periodic acid-Schiff staining,
infection was evident only in 13.5% of the and epithelial dysplasia, with 36/200 (18.0%)
total leukoplakia group (87/670), it occurred cases of moderate epithelial dysplasia and
(63%, 25/40) in patients with oral mucosal squa- 21/138 (15.2%) cases of severe epithelial dyspla-
mous cell carcinoma. The incidence of sia exhibiting fungal infection (Barrett et al.
C. albicans infection in patients with oral 1998). In a separate study, C. albicans was iso-
carcinoma was reported to be second to smoking lated from 8/21 tumor sites in the oral cavity,
(78%) and higher than the incidence of other whereas it was not isolated from control sites
possible etiological factors, including mechani- (Nagy et al. 1998).
cal factors (43%), alcohol (33%), electrical A case report of a 21-year-old female
potential (15%), and syphilis (10%) (Banoczy with candidosis endocrinopathy syndrome (a rare
1977). condition characterized by mucocutaneous
By contrast, a retrospective study that assessed candidosis and multiple endocrinal abnormalities)
biopsies from 235 patients with oral leukoplakias and oral mucosal squamous cell carcinoma
found that cellular atypia was present in 61% supported the concept that C. albicans can act as
of Candida-invaded biopsies of speckled leuko- a promoter in the development of oral squamous
plakias, but was present also in 88% of speckled cell carcinoma (Firth et al. 1997). More recently a
leukoplakias that did not demonstrate candidal study examined the progression of a chronic hyper-
invasion (Renstrup 1970). Furthermore, 3% of plastic candidosis lesion over a 7-year period with
homogeneous leukoplakias demonstrated Can- persistent isolation of C. albicans. After 2 years,
dida invasion, but none exhibited dysplasia the lesion demonstrated progression to squamous
(Renstrup 1970). cell carcinoma (Williams et al. 2001). PCR typing
of C. albicans isolates demonstrated persistence of recently, data from a matched case-control study
a single strain of C. albicans, and further investi- investigating the relative risk of oral Candida col-
gation of this strain on a model of reconstituted onization among other traditional risk factors of
human epithelium indicated it possessed a greater oral cancer showed that both oral Candida carriage
invasive ability than C. albicans isolates from other (OR = 3.242; 95% CI = 1.505, 6.984) and high
patients (Williams et al. 2001). These authors pos- level of colonization (OR = 3.587; 95%
tulated that such findings indicate that C. albicans CI = 1.153, 11.162) were significant risk factors
strains, particularly those with increased invasive- in oral cancer in addition to regular daily alcohol
ness, may have a role in neoplastic change (Wil- consumption (OR = 4.253; 95% CI = 1.351,
liams et al. 2001). A year later, a study showed 13.386) (Alnuaimi et al. 2015). More importantly,
that patients with oral epithelial dysplasia or oral the risk effect was highly additive, but less than
squamous cell carcinomas had a significantly multiplicative when Candida presence was
( p <0.001) higher frequency of oral yeast carriage conjugated with alcohol consumption (OR for
and high colonization in their oral cavity compared Candida presence + current/daily alcohol drink-
to individuals without histopathological evidence ing = 9.288; 95% CI = 2.022, 42.6), suggesting
of dysplasia or neoplasia (McCullough et al. 2002). fungal alcohol metabolism being a probable link
These investigators also observed the amount of (Alnuaimi et al. 2015).
yeast in saliva correlated with the degree of epithe-
lial dysplasia, where yeast levels greater than
1000 CFU/mL were evident for 58.6% (17/29) Experimental Evidence
patients with mild epithelial dysplasia and 83.3%
(40/48) patients with moderate or severe dysplasia The possible carcinogenic action of C. albicans
or squamous cell carcinoma (McCullough et al. and the development of OSCC have been further
2002). Recently, a study compared the amount of investigated by a variety of animal studies that
acetaldehyde production from ethanol and glucose utilized rat and mouse models of candidosis
by oral C. albicans isolates from APECED patients (Field et al. 1989).
and oral cancer patients with control isolates from Extracts of fungi (including C. albicans) and
healthy individuals demonstrated that all isolates fungal metabolites injected subcutaneously
were able to produce mutagenic levels of ACH into the inguinal area of mice have been
(Uittamo et al. 2011). However, C. albicans iso- shown to cause sarcomas, lymphomas, and
lated from healthy and oral cancer patients had primary lung tumors (Blank et al. 1968). Glyco-
significantly higher acetaldehyde production than proteins extracted from C. albicans promoted
those from APECED patients. This study also chemically induced subcutaneous tumor devel-
revealed that C. albicans isolated from APECED opment in newborn rats (Mankowski 1971).
patients were also able to produce carcinogenic When C. albicans-infected tumor cells were
levels of acetaldehyde when incubated with injected into syngeneic mice, they produced
100 mM of glucose (equivalent to 18 g/L, which tumors that grew faster and more aggressively
can commonly be found in food and drinks) and than tumors produced by uninfected tumors at
with significantly higher acetaldehyde levels com- distal sites in the same mice (Ginsburg et al.
pared to a group of patients with oral cancer or 1987). A proposal that Candida infection might
from healthy individuals. The authors suggested a disturb epithelial activity and predispose to
novel microbially mediated mechanism in the path- neoplastic change was supported by observed
ogenesis of oral cancer that could partly explain increased mitotic activity after C. albicans
why chronic oral candidosis is carcinogenic in was injected into the mucosa of Wistar and
APECED patients and why they have a high risk Sprague Dawley rats (Shakir et al. 1986; Reed
for oral cancer at an early age (Uittamo et al. 2009). et al. 1990).
However, in all of these reports, it remains unclear C. albicans has been shown to be as effective
whether C. albicans had a causal role. Most as phorbol-12,13-didecanoate (PDD), a known
promoter of carcinogenesis, in promoting OSCC Increasing numbers of studies support this

in rats with tumors induced by 4-nitroquinolone- hypothesis by demonstrating an association of
1-oxide (4NQO) (O’Grady and Reade 1992). some oral microflora and yeasts with acetalde-
Thus C. albicans infection of dysplastic mucosa hyde production from compounds not considered
appeared to complement the activity of a as carcinogens such as ethanol (Tillonen et al.
known initiator (4NQO), act as a promoter, or 1999; Väkeväinen et al. 2002; Salaspuro 2003;
facilitate progression to malignancy. Similarly, a Kurkivuori et al. 2007).
more recent investigation on the role Recently, there is increased interest in the
of C. albicans as a promoter in oral epithelial mechanisms by which microbial-induced
neoplasia demonstrated that mice exposed to inflammation may have a role in the carcino-
both 4NQO and C. albicans developed genic process, particularly after the classification
dysplastic lesions, while these mice challenged of the bacteria Helicobacter pylori as a class
with C. albicans only developed hyperplastic 1 carcinogen in humans by the World Health
lesions (Dwivedi et al. 2009). The expression Organization International Agency for Research
of p16 and Ki-67, two known cell proliferation on Cancer (IARC) (Peek Jr and Blaser 2002;
and malignancy markers, increased from normal Bjorkholm et al. 2003; Correa and Houghton
to hyperplastic to dysplastic lesions with 2007). One postulated hypothesis on how
the highest expression observed in mice inflammation may influence mucosal carcino-
treated with both 4NQO and C. albicans (Dwivedi genesis is the upregulation of pro-inflammatory
et al. 2009). cytokines and growth factors during chronic
Thus, it can be seen that over a considerable inflammation caused by mucosal microbial
time data accumulated suggest C. albicans may infections (Lax and Thomas 2002; Fantini and
promote OSCC development, but the exact role of Pallone 2008).
this yeast in neoplastic change is yet to be fully Data from a recent study showed that Can-
elucidated. dida isolated from oral cancer patients had
enhanced virulence properties and carcinogenic
acetaldehyde production compared to Candida
isolated from non-oral cancer individuals
Possible Mechanisms (Alnuaimi et al. 2016). The researchers from
this study suggested a significant positive asso-
Several mechanisms by which Candida may pro- ciation between the ability of Candida isolates to
mote oral cancer have been proposed. One of form biofilms, to produce hydrolytic enzymes,
these is the endogenous nitrosamine production and to metabolize alcohol to acetaldehyde and
from precursors that may be already available in their ability to promote oral cancer development.
the oral cavity (Krogh et al. 1987a). This carcin- This positive association between Candida viru-
ogen may directly or indirectly, or in concert lence and cancer presence might, indirectly,
with other carcinogens, activate specific proto- imply a possible role for the inflammatory
oncogenes and initiate the development of malig- response in cancer promotion since previous
nant lesions (Hooper et al. 2009). Nitrosamine studies proved a positive correlation between
compounds like nitrosomethylethylamines have Candida virulence and inflammatory cytokine
been found to be capable of inducing tumors expression (Beausejour et al. 1998; Schaller
in rat esophagus as well as tumors in the stomach et al. 2002, 2005).
and oral cavity (Lijinsky et al. 1982; Fong The link between oral epithelial candidal
et al. 1986). infections and the induction of pro-
The most likely hypothesis as to how yeasts inflammatory cytokines and how this may
and other oral flora promote carcinogenesis relates contribute to the multistep process of carcino-
to the activation of pro-carcinogenic compounds genesis is still unclear and warrants further
into carcinogenic forms (Hooper et al. 2009). investigations.
Conclusions and Future Directions Cross-References
Different fungi may cause oral and maxillofacial ▶ Clinical Evaluation of Oral Diseases
infections that can vary from superficial condi- ▶ Clinical Immunology in Diagnoses of Maxillo-
tions, such as oral candidosis, to invasive and facial Disease
disseminated illness, such as mucormycosis ▶ Head and Neck Tumors
or histoplasmosis. Both healthy and immuno- ▶ Laboratory Medicine and Diagnostic Pathology
compromised patients can be affected by oral ▶ Oral Lichen Planus
fungal infections; however the host’s immune ▶ Oral Manifestations of Systemic Diseases and
defenses play a crucial role in the development Their Treatments
and severity of the diseases. Several local and ▶ Oral Mucosal Malignancies
systemic predisposing factors should be investi- ▶ Oral Ulcerative Lesions
gated in patients affected by oral fungal infec- ▶ Pediatric Oral Medicine
tions, especially for patients who develop ▶ Pharmacotherapeutic Approaches in Oral
chronic disease. Medicine
The presentation of oral candidosis can vary, ▶ White and Red Lesions of the Oral Mucosa
and the diagnosis is generally clinical, based
on signs and symptoms in conjunction with a
careful medical history. Laboratory investiga- References
tions, mainly based on species identification
and antifungal susceptibility tests, can be helpful Abreu e Silva MA, Salum FG, Figueiredo MA,
Cherubini K. Important aspects of oral para-
for infections refractory to initial therapy or in
coccidioidomycosis–a literature review. Mycoses.
patients at risk of developing systemic 2013;56(3):189–99.
infections. Al-Fattani MA, Douglas LJ. Penetration of Candida
The choice of antifungal treatment is based biofilms by antifungal agents. Antimicrob Agents
Chemother. 2004;48(9):3291–7.
on the type of infection (superficial or dissemi-
Al-Karaawi ZM, Manfredi M, Waugh AC, McCullough MJ,
nated), the immunological status of the patient, Jorge J, Scully C, Porter SR. Molecular characteriza-
and the possibility to correct the patient’s tion of Candida spp. isolated from the oral cavities of
underlying predisposing factors. Currently, topi- patients from diverse clinical settings. Oral Microbiol
Immunol. 2002;17:44–9.
cal polyenes (nystatin and amphotericin B) and
Alnuaimi AD, Wiesenfeld D, O’Brien-Simpson NM,
azoles (both in topical and oral systemic Reynolds EC, Peng B, McCullough MJ. The develop-
formulations) are the most frequently used ment and validation of a rapid genetic method for
antifungal agents for localized candidosis in species identification and genotyping of medically
important fungal pathogens using high resolution
patients with normal immune function. Newer
melting curve analysis. Mol Oral Microbiol.
drugs, such as echinocandins, flucytosine, 2014;29:117–30.
and the latest generation of azoles, are Alnuaimi AD, Wiesenfeld D, O’Brien-Simpson NM,
generally reserved for immunocompromised Reynolds EC, McCullough MJ. Oral Candida
colonization in oral cancer patients and its relation-
patients affected by systemic fungal infections.
ship with traditional risk factors of oral cancer: a
Research into new effective agents is necessary matched case-control study. Oral Oncol.
because of increased resistance of NAC 2015;51:139–45.
species and the development of antifungal Alnuaimi AD, Ramdzan AN, Wiesenfeld D, O’Brien-
Simpson NM, Kolev SD, Reynolds EC, McCullough
resistance.
MJ. Candida virulence and ethanol-derived acetalde-
Despite the interest in clinical and experimen- hyde production in oral cancer and non-cancer subjects.
tal studies of the possible role of Candida in the Oral Dis. 2016;22(8):805–14.
development of oral cancerous lesions, the mech- Appleton SS. Candidiasis: pathogenesis, clinical character-
istics, and treatment. J Calif Dent Assoc.
anism through which the yeast could promote oral
2000;28(12):942–8.
carcinogenesis is still unclear and requires further Aras MH, Kara MI, Erkilic S, Ay S. Mandibular
research. mucormycosis in immunocompromised patients: report
of 2 cases and review of the literature. J Oral Maxillofac Borromeo GL, McCullough MJ, Reade PC. Quantitation
Surg. 2012;70(6):1362–8. and morphotyping of Candida albicans from healthy
Arendorf TM, Walker DM. The prevalence and intra-oral mouths and from mouths affected by erythematous
distribution of Candida albicans in man. Arch Oral candidosis. J Med Vet Mycol. 1992;30:477–80.
Biol. 1980;25(1):1–10. Brand A. Hyphal growth in human fungal pathogens and
Arendorf TM, Walker DM. Tobacco smoking and den- its role in virulence. Int J Microbiol.
ture wearing as local aetiological factors in median 2012;2012:517529.
rhomboid glossitis. Int J Oral Surg. Brazao-Silva MT, Andrade MF, Franco T, Ribeiro RI, Silva
1984;13(5):411–5. Wdos S, Faria G, Faria PR, Cardoso SV, Loyola
Axéll T, Holmstrup P, Kramer IRH, Pindborg JJ, Shear M. AM. Paracoccidioidomycosis: a series of 66 patients
International seminar on oral leukoplakia and associ- with oral lesions from an endemic area. Mycoses.
ated lesions related to tobacco habits. Commun Dent 2011;54(4):e189–95.
Oral Epidemiol. 1984;12:145–54. Budtz-Jorgensen E. Candida-associated denture
Azenha MR, Caliento R, Brentegani LG, de Lacerda stomatitis and angular cheilitis. In: Samaranayake LP,
SA. A retrospective study of oral manifestations in MacFarlane TW, editors. Oral candidosis, Chap 9.
patients with paracoccidioidomycosis. Braz Dent J. London: Wright-Butterworth & Co. Ltd; 1990.
2012;23(6):753–7. Burnham R, Bridle C. Aspergillosis of the maxillary sinus
Baillie GS, Douglas LJ. Effect of growth rate on resistance secondary to a foreign body (amalgam) in the maxillary
of Candida albicans biofilms to antifungal agents. antrum. Br J Oral Maxillofac Surg. 2009;47(4):313–5.
Antimicrob Agents Chemother. 1998;42:1900–5. Calderone RA. Candida and candidosis. Washington, DC:
Baillie GS, Douglas LJ. Matrix polymers of candida ASM Press; 2002.
biofilms and their possible role in biofilm resistance Calderone RA, Braun PC. Adherence and receptor
to antifungal agents. J Antimicrob Chemother. relationships of Candida albicans. Microbiol Rev.
2000;46:397–403. 1991;55:1–20.
Banoczy J. Follow-up studies in oral leukoplakia. Calderone RA, Fonzi WA. Virulence factors of Candida
J Maxillofac Surg. 1977;5(1):69–75. albicans. Trends Microbiol. 2001;9(7):327–35.
Bánóczy J, Sugár L. Longitudinal studies in oral Cannon RD, Chaffin WL. Oral colonization by Candida
leukoplakias. J Oral Pathol. 1972;1:265–72. albicans. Crit Rev Oral Biol Med. 1999;10(3):359–83.
Barbosa de Paulo LF, Silva de Faria L, Francisco Cannon RD, Holmes AR, Mason AB, Monk BC. Oral
Durighetto A Jr. Endemic oral paracoccidioi- Candida: clearance, colonization, or candidiasis?
domycosis: clinical presentation, management, and J Dent Res. 1995;74(5):1152–61.
outcomes. Int J Infect Dis. 2014;19:109–10. Cartledge JD, Midgley J, Gazzard BG. Non-albicans oral
Barrett AW, Kingsmill VJ, Speight PM. The frequency of candidosis in HIV-positive patients. J Antimicrob
fungal infection in biopsies of oral mucosal lesions. Chemother. 1999;43(3):419–22.
Oral Dis. 1998;4(1):26–31. Cawson RA, Binnie WH. Candida leukoplakia and carci-
Bartie KL, Williams DW, Wilson MJ, Potts AJ, noma – possible relationship. In: Dabelsteen E,
Lewis MA. Differential invasion of Candida albicans Mackenzie IC, Squier CA, editors. Oral premalignancy.
isolates in an in vitro model of oral candidosis. Oral Iowa City: University of Iowa Press; 1977. p. 59–66.
Microbiol Immunol. 2004;19(5):293–6. Cawson RA, Lehner T. Chronic hyperplastic
Bastiaan RJ, Reade PC. The prevalence of Candida candidiasis–candidal leukoplakia. Br J Dermatol.
albicans in the mouths of tobacco smokers with and 1968;80:9–16.
without oral mucous membrane keratoses. Oral Surg Chandra J, Mukherjee PK, Ghannoum MA. In vitro
Oral Med Oral Pathol. 1982;53:148–51. growth and analysis of Candida biofilms. Nat Protoc.
Beausejour A, Grenier D, Goulet JP, Deslauriers N. Pro- 2008;3(12):1909–24.
teolytic activation of the interleukin-1beta precursor by Chen YC, Wu CC, Chung WL, Lee FJ. Differential secre-
Candida albicans. Infect Immun. 1998;66(2):676–81. tion of Sap4-6 proteins in Candida albicans during
Biswas S, Van Dijck P, Datta A. Environmental sensing hyphae formation. Microbiology. 2002;148(Pt 11):
and signal transduction pathways regulating morpho- 3743–54.
pathogenic determinants of Candida albicans. Micro- Cho H, Lee KH, Colquhoun AN, Evans SA. Invasive oral
biol Mol Biol Rev. 2007;71(2):348–76. aspergillosis in a patient with acute myeloid leukaemia.
Bjorkholm B, Falk P, Engstrand L, Nyren O. Helicobacter Aust Dent J. 2010;55(2):214–8.
pylori: resurrection of the cancer link. J Intern Med. Clarkson JE, Worthington HV, Eden OB. Interventions for
2003;253(2):102–19. preventing oral candidiasis for patients with cancer
Blank F, Chin O, Just G, Meranze DR, Shimkin MB, receiving treatment. Cochrane Database Syst Rev
Weider R. Carcinogens from fungi pathogenic for (Online). 2007;CD003807.
man. Cancer Res. 1968;28:2276–81. Coleman DC, Sullivan DJ, Bennett DE, Moran GP,
Blankenship JR, Mitchell AP. How to build a biofilm: a Barry HJ, Shanley DB. Candidiasis: the emergence
fungal perspective. Curr Opin Microbiol. 2006;9: of a novel species, Candida dubliniensis. AIDS.
588–94. 1997;11(5):557–67.
Coogan MM, Greenspan J, Challacombe SJ. Oral lesions Eyerich K, Foerster S, Rombold S, Seidl HP, Behrendt H,
in infection with human immunodeficiency virus. Bull Hofmann H, Ring J, Traidl-Hoffmann C. Patients with
World Health Organ. 2005;83(9):700–6. chronic mucocutaneous candidiasis exhibit reduced
Correa P, Houghton J. Carcinogenesis of Helicobacter production of Th17-associated cytokines IL-17 and
pylori. Gastroenterology. 2007;133(2):659–72. IL-22. J Invest Dermatol. 2008;128(11):2640–5.
Costa F, Polini F, Zerman N, Robiony M, Toro C, Eyre J, Nally FF. Oral candidosis and carcinoma. Br J
Politi M. Surgical treatment of Aspergillus mycetomas Dermatol. 1971;85:73–5.
of the maxillary sinus: review of the literature. Oral Falworth MS, Herold J. Aspergillosis of the paranasal
Surg Oral Med Oral Pathol Oral Radiol Endod. sinuses. A case report and radiographic review.
2007;103(6):e23–9. Oral Surg Oral Med Oral Pathol Oral Radiol Endod.
Davey ME, O’Toole GA. Microbial biofilms: from ecology 1996;81(2):255–60.
to molecular genetics. Microbiol Mol Biol Rev. Fantini MC, Pallone F. Cytokines: from gut inflammation to
2000;64(4):847–67. colorectal cancer. Curr Drug Targets. 2008;9(5):375–80.
De Bernardis F, Mondello F, San Millan R, Ponton J, Farah CS, Ashman RB, Challacombe SJ. Oral candidosis.
Cassone A. Biotyping and virulence properties of skin Clin Dermatol. 2000;18:553–62.
isolates of Candida parapsilosis. J Clin Microbiol. Farah CS, Lynch N, McCullough MJ. Oral fungal infec-
1999;37(11):3481–6. tions: an update for the general practitioner. Aust Dent
Delgado WA, Romero de Leon E. 14th international con- J. 2010;55(Suppl 1):48–54.
gress IAOP/AAOMP clinical pathology conference Farah CS, Amos K, Leeson R, Porter S. Candida species in
case 6. Head Neck Pathol. 2008;2(4):298–301. patients with oral dysesthesia: a comparison of carriage
Denning DW, Chakrabarti A. Pulmonary and sinus fungal among oral disease states. J Oral Pathol Med.
diseases in non-immunocompromised patients. Lancet 2018;47:281–285. https://doi.org/10.1111/jop.12675.
Infect Dis. 2017;17:e357. Fenn JP, Segal H, Barland B, Denton D, Whisenant J,
Dhiman N, Hall L, Wohlfiel SL, Buckwalter SP, Chun H, Christofferson K, Hamilton L, Carroll K.
Wengenack NL. Performance and cost analysis Comparison of updated Vitek yeast biochemical card
of matrix-assisted laser desorption ionization-time and API 20C yeast identification systems. J Clin Micro-
of flight mass spectrometry for routine biol. 1994;32(5):1184–7.
identification of yeast. J Clin Microbiol. Field EA, Field JK, Martin MV. Does Candida have a role
2011;49(4):1614–6. in oral epithelial neoplasia? J Med Vet Mycol.
do Prado Gomes Pedreira R, de Carli ML, Beijo LA, 1989;27:277–94.
Nonogaki S, Pereira AA, Junior NV, Sperandio FF, Firth NA, O’Grady JF, Reade PC. Oral squamous
Hanemann JA. Oral paracoccidioidomycosis granulo- cell carcinoma in a young person with candidosis
mas are predominantly populated by CD163+ endocrinopathy syndrome: a case report. Int J Oral
multinucleated Giant cells. Mycopathologia. Maxillofac Surg. 1997;26(1):42–4.
2016;181(9–10):709–16. Folk GA, Nelson BL. Oral Histoplasmosis. Head Neck
Dodson TB, Perrott DH, Leonard MS. Nonhealing Pathol. 2017;11(4):513–6.
ulceration of oral mucosa. J Oral Maxillofac Surg. Fong LY, Lui CP, NG WL, Newberne PM. The
1989;47(8):849–52. effect of N-nitrosodimethylamine and N-nitroso-N-
Dojcinovic I, Richter M. Mucormycoses: serious benzylmethylamine on [3H]thymidine incorporation
complication of high-dose corticosteroid therapy for into the DNA of target and non-target tissues in the
traumatic optic neuropathy. Int J Oral Maxillofac zinc-deficient rat. Cancer Lett. 1986;30:61–71.
Surg. 2008;37(4):391–4. Fu Y, Ibrahim AS, Fonzi W, Zhou X, Ramos CF,
Donlan RM. Biofilm formation: a clinically relevant Ghannoum MA. Cloning and characterization of a
microbiological process. Clin Infect Dis. 2001;33(8): gene (LIP1) which encodes a lipase from the patho-
1387–92. genic yeast Candida albicans. Microbiology.
Donlan RM, Costerton JW. Biofilms: survival mechanisms 1997;143:331–40.
of clinically relevant microorganisms. Clin Microbiol Fukayama M, Calderone RA. Adherence of cell surface
Rev. 2002;15(2):167–93. mutants of Candida albicans to buccal epithelial cells
Douglas LJ. Candida proteinases and candidosis. Crit Rev and analyses of the cell surface proteins of the mutants.
Biotechnol. 1988;8(2):121–9. Infect Immun. 1991;59(4):1341–5.
Dwivedi PP, Mallya S, Dongari-Bagtzoglou A. A novel Ganesh P, Nagarjuna M, Shetty S, Kumar P, Bhat V,
immunocompetent murine model for Candida Salins PC. Invasive aspergillosis presenting as swelling
albicans-promoted oral epithelial dysplasia. Med of the buccal mucosa in an immunocompetent individ-
Mycol. 2009;47(2):157–67. ual. Oral Surg Oral Med Oral Pathol Oral Radiol.
Ellepola AN, Morrison CJ. Laboratory diagnosis of inva- 2015;119(2):e60–4.
sive candidiasis. J Microbiol. 2005;43 Spec No: 65–84. Gavito-Higuera J, Mullins CB, Ramos-Duran L,
Ellepola AN, Samaranayake LP. Oral candidal infections Sandoval H, Akle N, Figueroa R. Sinonasal fungal
and antimycotics. Crit Rev Oral Biol Med. 2000;11(2): infections and complications: a pictorial review. J Clin
172–98. Imaging Sci. 2016;6:23.
Gee SF, Joly S, Soll DR, Meis JF, Verweij PE, Polacheck I, immunodeficiency virus-infected patient observed
Sullivan DJ, Coleman DC. Identification of four dis- over a period of 6 years. Mycoses. 1998;41:335–8.
tinct genotypes of Candida dubliniensis and detection Hooper SJ, Wilson MJ, Crean SJ. Exploring the link
of microevolution in vitro and in vivo. J Clin Microbiol. between microorganisms and oral cancer: a systematic
2002;40(2):556–74. review of the literature. Head Neck. 2009;31:1228–39.
Ghannoum MA. Potential role of phospholipases in viru- Hube B, Naglik J. Extracellular hydrolyses. In:
lence and fungal pathogenesis. Clin Microbiol Rev. Calderone RA, editor. Candida and candidiasis.
2000;13(1):122–43. Washington, DC: American Society for Microbiology
Ginsburg I, Fligiel SE, Kunkel RG, Riser BL, Varani J. (ASM) Press; 2002. p. 107–22.
Phagocytosis of Candida albicans enhances Hube B, Stehr F, Bossenz M, Mazur A, Kretschmar M,
malignant behavior of murine tumor cells. Science. Schäfer W. Secreted lipases of Candida albicans: clon-
1987;238(4833):1573–5. ing, characterisation and expression analysis of a new
Glasmacher A, Cornely O, Ullmann AJ, Wedding U, gene family with at least ten members. Arch Microbiol.
Bodenstein H, Wandt H, Boewer C, Pasold R, 2000;174:362–74.
Wolf HH, Hänel M, Dölken G, Junghanss C, Iatta R, Napoli C, Borghi E, Montagna MT. Rare mycoses
Andreesen R, Bertz H, Itraconazole Research Group of the oral cavity: a literature epidemiologic review.
of Germany. An open-label randomized trial comparing Oral Surg Oral Med Oral Pathol Oral Radiol Endod.
itraconazole oral solution with fluconazole oral solu- 2009;108(5):647–55.
tion for primary prophylaxis of fungal infections in Iqbal F, Schifter M, Coleman HG. Oral presentation of
patients with haematological malignancy and profound histoplasmosis in an immunocompetent patient: a diag-
neutropenia. J Antimicrob Chemother. 2006;57: nostic challenge. Aust Dent J. 2014;59(3):386–8.
317–25. Jacobsen ID, Wilson D, Wachtler B, Brunke S, Naglik JR,
Godoy H, Reichart PA. Oral manifestations of para- Hube B. Candida albicans dimorphism as a therapeutic
coccidioidomycosis. Report of 21 cases from target. Expert Rev Anti Infect Ther. 2012;10(1):85–93.
Argentina. Mycoses. 2003;46(9–10):412–7. Klatt JC, Grobe A, Schmelzle R, Atac A, Heiland M,
Goh LC, Shakri ED, Ong HY, Mustakim S, Blessmann M, Pohlenz P. A series of complications
Shaariyah MM, Ng WSJ, Zulkiflee AB. A seven-year after third molar osteotomy in a pancytopenia patient
retrospective analysis of the clinicopathological and and spontaneous healing after bone marrow trans-
mycological manifestations of fungal rhinosinusitis in plantation. J Oral Maxillofac Surg. 2011;69
a single-centre tropical climate hospital. J Laryngol (10):2508–12.
Otol. 2017;131(9):813–6. Klein G, Klein E. Evolution of tumours and the impact of
Gonzalez Ballester D, Gonzalez-Garcia R, Moreno molecular oncology. Nature. 1985;315(6016):190–5.
Garcia C, Ruiz-Laza L, Monje Gil F. Mucormycosis Kojic EM, Darouiche RO. Candida infections of medical
of the head and neck: report of five cases with different devices. Clin Microbiol Rev. 2004;17:255–67.
presentations. J Craniomaxillofac Surg. 2012;40(7): Krogh P. The role of yeasts in oral cancer by means
584–91. of endogenous nitrosation. Acta Odontol Scand.
Gow NA, van de Veerdonk FL, Brown AJ, Netea MG. 1990;48(1):85–8.
Candida albicans morphogenesis and host defence: Krogh P, Hald B, Holmstrup P. Possible mycological eti-
discriminating invasion from colonization. Nat Rev ology of oral mucosal cancer: catalytic potential of
Microbiol. 2012;10(2):112–22. infecting Candida albicans and other yeasts in produc-
Gropp K, Schild L, Schindler S, Hube B, Zipfel PF, tion of N-nitrosobenzylmethylamine. Carcinogenesis.
Skerka C. The yeast Candida albicans evades human 1987a;8(10):1543–8.
complement attack by secretion of aspartic proteases. Krogh P, Holmstrup P, Thorn JJ, Vedtofte P, Pindborg JJ.
Mol Immunol. 2009;47(2–3):465–75. Yeast species and biotypes associated with oral leuko-
Guggenheimer J, Moore PA, Rossie K, Myers D, plakia and lichen planus. Oral Surg Oral Med Oral
Mongelluzzo MB, Block HM, Weyant R, Orchard T. Pathol. 1987b;63(1):48–54.
Insulin-dependent diabetes mellitus and oral soft tissue Kurkivuori J, Salaspuro V, Kaihovaara P, Kari K,
pathologies: II. Prevalence and characteristics of Can- Rautemaa R, Grönroos L, Meurman JH, Salaspuro M.
dida and Candidal lesions. Oral Surg Oral Med Oral Acetyldehyde production from ethanol from by oral
Pathol Oral Radiol Endod. 2000;89(5):570–6. streptococci. Oral Oncol. 2007;43:181–6.
Hattori M, Yoshiura K, Negi M, Ogawa H. Keratinolytic La Vecchia C, Tavani A, Franceschi S, Levi F, Corrao G,
proteinase produced by Candida albicans. Negri E. Epidemiology and prevention of oral cancer.
Sabouraudia. 1984;22(3):175–83. Oral Oncol. 1997;33(5):302–12.
Hazen KC. Participation of yeast cell surface hydropho- LaFleur MD, Kumamoto CA, Lewis K. Candida albicans
bicity in adherence of Candida albicans to human biofilms produce antifungal-tolerant persister
epithelial cells. Infect Immun. 1989;57(7):1894–900. cells. Antimicrob Agents Chemother. 2006;50(11):
Hoegl L, Thoma-Greber E, Röcken M, Korting HC. Per- 3839–46.
sistent oral candidosis by non-albicans Candida strains Lalla RV, Patton LL, Dongari-Bagtzoglou A. Oral candi-
including Candida glabrata in a human diasis: pathogenesis, clinical presentation, diagnosis
and treatment strategies. J Calif Dent Assoc. 2013;41 dubliniensis and Candida stellatoidea. J Clin Micro-
(4):263–8. biol. 1999a;37(2):417–21.
Lamey PJ, Lewis MA, MacDonald DG. Treatment of McCullough MJ, Clemons KV, Stevens DA. Molecular
candidal leukoplakia with fluconazole. Br Dent J. epidemiology of the global and temporal diversity of
1989;166(8):296–8. Candida albicans. Clin Infect Dis. 1999b;29(5):
Lax AJ, Thomas W. How bacteria could cause cancer: one 1220–5.
step at a time. Trends Microbiol. 2002;10:293–9. McCullough MJ, DiSalvo AF, Clemons KV, Park P,
Li L, Redding S, Dongari-Bagtzoglou A. Candida Stevens DA. Molecular epidemiology of Blastomyces
glabrata: an emerging oral opportunistic pathogen. dermatitidis. Clin Infect Dis. 2000;30(2):328–35.
J Dent Res. 2007;86(3):204–15. McCullough M, Jaber M, Barrett AW, Bain L, Speight PM,
Lijinsky W, Saavedra JE, Reuber MD, Singer SS. Esoph- Porter SR. Oral yeast carriage correlates with
ageal carcinogenesis in F344 rats by nitrosomethy- presence of oral epithelial dysplasia. Oral Oncol.
lethylamines substituted in the ethyl group. J Natl 2002;38(4):391–3.
Cancer Inst. 1982;68:681–4. Mehrabi M, Bagheri S, Leonard MK Jr, Perciaccante VJ.
Lilic D, Cant AJ, Abinun M, Calvert JE, Spickett GP. Mucocutaneous manifestation of cryptococcal infec-
Chronic mucocutaneous candidiasis. I. Altered tion: report of a case and review of the literature.
antigen-stimulated IL-2, IL-4, IL-6 and interferon- J Oral Maxillofac Surg. 2005;63(10):1543–9.
gamma (IFN-gamma) production. Clin Exp Immunol. Metzen D, Bohm H, Zimmermann M, Reuther T, Kubler AC,
1996;105(2):205–12. Muller-Richter UD. Mucormycosis of the head and neck.
Liu Y, Filler SG. Candida albicans Als3, a multifunctional J Craniomaxillofac Surg. 2012;40(8):e321–7.
adhesin and invasin. Eukaryot Cell. 2011;10(2): Meyer SA, Aheran DG, Yarrow DG. The genus Candida.
168–73. In: The yeasts: a taxonomic study. Amsterdam:
Liu X, Hua H. Oral manifestation of chronic mucocutane- Elsevier; 1984. p. 585–844.
ous candidiasis: seven case reports. J Oral Pathol Med. Midtvedt T. Ecosystems: development, functions and con-
2007;36(9):528–32. sequences of disturbances, with special reference to the
Mah TF, O’Toole GA. Mechanisms of biofilm resistance to oral cavity. J Clin Periodontol. 1990;17:474–8.
antimicrobial agents. Trends Microbiol. 2001;9(1): Moran GP, Sullivan DJ, Coleman DC. Emergence of non-
34–9. Candida albicans Candida species as pathogens,
Manfredi M, McCullough MJ, Al-Karaawi ZM, Hurel SJ, Chap. 4. In: Calderone RA, editor. Candida and Candi-
Porter SR. The isolation, identification and molecular diasis. 4th ed. Washington, DC: ASM Press; 2002.
analysis of Candida spp. isolated from the oral cavities p. 37–53.
of patients with diabetes mellitus. Oral Microbiol Muadcheingka T, Tantivitayakul P. Distribution of Candida
Immunol. 2002;17:181–5. albicans and non-albicans Candida species in oral can-
Manfredi M, McCullough MJ, Al-Karaawi ZM, Vescovi P, didiasis patients: correlation between cell surface
Porter SR. In vitro evaluation of virulence attributes of hydrophobicity and biofilm forming activities. Arch
Candida spp. isolated from patients affected by diabe- Oral Biol. 2015;60(6):894–901.
tes mellitus. Oral Microbiol Immunol. 2006;21(3): Naglik J, Albrecht A, Bader O, Hube B. Candida albicans
183–9. proteinases and host/pathogen interactions. Cell Micro-
Manfredi M, Polonelli L, Aguirre-Urizar JM, Carrozzo M, biol. 2004;6(10):915–26.
McCullough MJ. Urban legends series: oral candidosis. Nagy KN, Sonkodi I, Szöke I, Nagy E, Newman HN. The
Oral Dis. 2013;19(3):245–61. microflora associated with human oral carcinomas.
Mankowski ZT. Influence of Candida albicans glycopro- Oral Oncol. 1998;34:304–8.
tein on 3-methylcholanthrene induced malignancy Negri M, Martins M, Henriques M, Svidzinski TI,
in newborn rodents. Mycopathol Mycol Appl. Azeredo J, Oliveira R. Examination of potential
1971;44(2):95–100. virulence factors of Candida tropicalis clinical
Mateus C, Crow SA Jr, Ahearn DG. Adherence of Candida isolates from hospitalized patients. Mycopathologia.
albicans to silicone induces immediate enhanced toler- 2010;169(3):175–82.
ance to fluconazole. Antimicrob Agents Chemother. Neppelenbroek K, Seo R, Urban V, Silva S, Dovigo L,
2004;48(9):3358–66. Jorge J, Campanha N. Identification of Candida species
McCullough MJ, Savage NW. Oral candidosis and the in the clinical laboratory: a review of conventional,
therapeutic use of antifungal agents in dentistry. Aust commercial, and molecular techniques. Oral Dis.
Dent J. 2005;50(4 Suppl 2):S36–9. 2013;20:329.
McCullough M, Ross BC, Reade PC. Candida albicans: a Netea MG, Gow NA, Munro CA, Bates S, Collins C,
review of its history, taxonomy, epidemiology, viru- Ferwerda G, Hobson RP, Bertram G, Hughes HB,
lence attributes and methods of strain differentaiation. Jansen T, Jacobs L, Buurman ET, Gijzen K,
Int J Oral Maxillofac Surg. 1996;25:136–44. Williams DL, Torensma R, McKinnon A,
McCullough MJ, Clemons KV, Stevens DA. Molecular MacCallum DM, Odds FC, Van der Meer JW,
and phenotypic characterization of genotypic Candida Brown AJ, Kullberg BJ. Immune sensing of Candida
albicans subgroups and comparison with Candida albicans requires cooperative recognition of mannans
and glucans by lectin and toll-like receptors. J Clin Porter SR, Scully C. Chronic mucocutaneous candidosis
Invest. 2006;116(6):1642–50. and related syndromes, Chap. 11. In: Samaranayake LP,
Nucci M, Marr KA. Emerging fungal diseases. Clin Infect MacFarlane TW, editors. Oral candidosis. London:
Dis. 2005;41(4):521–6. Wright-Butterworth and Co Ltd; 1990.
O’Grady JF, Reade PC. Candida albicans as a promoter Qi QG, Hu T, Zhou XD. Frequency, species and molecular
of oral mucosal neoplasia. Carcinogenesis. 1992;13: characterization of oral Candida in hosts of different
783–6. age in China. J Oral Pathol Med. 2005;34:352–6.
O’Toole GA, Kaplan HB, Kolter R. Biofilm formation as Radford DR, Sweet SP, Challacombe SJ, Walter JD.
microbial development. Annu Rev Microbiol. Adherence of Candida albicans to denture-base mate-
2000;54:49–79. rials with different surface finishes. J Dent.
Odds FC. Candida and candidosis-a review and bibliogra- 1998;26:577–83.
phy. 2nd ed. London: Bailliere Tindall; 1988. Rajendran R, Robertson DP, Hodge PJ, Lappin DF,
Odds FC. Candida albicans, the life and times of a Ramage G. Hydrolytic enzyme production is
pathogenic yeast. J Med Vet Mycol. 1994a;32 associated with Candida albicans biofilm formation
(Suppl 1):1–8. from patients with type 1 diabetes. Mycopathologia.
Odds FC. Pathogenesis of Candida infections. J Am Acad 2010;170:229–35.
Dermatol. 1994b;31(3 Pt 2):S2–5. Rautemaa R, Ramage G. Oral candidosis–clinical chal-
Odds FC, Abbott AB. A simple system for the presumptive lenges of a biofilm disease. Crit Rev Microbiol.
identification of Candida albicans and differentiation 2011;37:328–36.
of strains within the species. Sabouraudia. 1980;18: Rautemaa R, Rusanen P, Richardson M, Meurman JH.
301–17. Optimal sampling site for mucosal candidosis in oral
Oksala E. Factors predisposing to oral yeast infections. cancer patients is the labial sulcus. J Med Microbiol.
Acta Odontol Scand. 1990;48:71–4. 2006;55:1447–51.
Paraje MG, Correa SG, Albesa I, Sotomayor CE. Lipase of Redding SW. The role of yeasts other than Candida
Candida albicans induces activation of NADPH oxi- albicans in oropharyngeal candidiasis. Curr Opin
dase and L-arginine pathways on resting and activated Infect Dis. 2001;14:673–7.
macrophages. Biochem Biophys Res Commun. Redding SW, Kirkpatrick WR, Coco BJ, Sadkowski L,
2009;390(2):263–8. Fothergill AW, Rinaldi MG, Eng TY, Patterson TF.
Patil PM, Bhadani P. Extensive maxillary necrosis Candida glabrata oropharyngeal candidiasis in
following tooth extraction. J Oral Maxillofac Surg. patients receiving radiation treatment for head and
2011;69(9):2387–91. neck cancer. J Clin Microbiol. 2002;40:1879–81.
Patil S, Rao RS, Majumdar B, Anil S. Clinical appearance Reed MF, Scragg MA, Williams DM, Soames JV. In vivo
of oral candida infection and therapeutic strategies. effects of Candida albicans products on rat oral epithe-
Front Microbiol. 2015;6:1391. lium. J Oral Pathol Med. 1990;19(7):326–9.
Pedreira Rdo P, Guimaraes EP, de Carli ML, Magalhaes EM, Reichart PA, Samaranayake LP, Philipsen HP. Pathology
Pereira AA, Hanemann JA. Paracoccidioidomycosis and clinical correlates in oral candidiasis and its vari-
mimicking squamous cell carcinoma on the dorsum of ants: a review. Oral Dis. 2000;6:85–91.
the tongue and review of published literature. Renstrup G. Occurrence of Candida in oral leukoplakias.
Mycopathologia. 2014;177(5–6):325–9. Acta Pathol Microbiol Scand B: Microbiol Immunol.
Peek RM Jr, Blaser MJ. Helicobacter pylori and 1970;78:421–4.
gastrointestinal tract adenocarcinomas. Nat Rev Can- Rex JH, Walsh TJ, Sobel JD, Filler SG, Pappas PG,
cer. 2002;2(1):28–37. Dismukes WE, Edwards JEJ. Practice guidelines for
Peman J, Zaragoza R, Quindos G, Alkorta M, Cuetara MS, the treatment of candidiasis. Infectious Diseases Soci-
Camarena JJ, Ramirez P, Gimenez MJ, Martin- ety of America. Clin Infect Dis. 2000;30:662–78.
Mazuelos E, Linares-Sicilia MJ, Ponton J. Clinical fac- Reznik DA. Oral manifestations of HIV disease. Top HIV
tors associated with a Candida albicans germ tube Med. 2005;13(5):143–8.
antibody positive test in intensive care unit patients. Rindum JL, Stenderup A, Holmstrup P. Identification
BMC Infect Dis. 2011;11:60. of Candida albicans types related to healthy and path-
Pfaller MA. Nosocomial candidiasis: emerging species, ological oral mucosa. J Oral Pathol Med. 1994;23(9):
reservoirs, and modes of transmission. Clin Infect 406–12.
Dis. 1996;22(Suppl 2):S89–94. Romani L. Immunity to fungal infections. Nat Rev
Philip M, Rowley DA, Schreiber H. Inflammation as a Immunol. 2004;4(1):1–23.
tumor promoter in cancer induction. Semin Cancer Romani L, Bistoni F, Puccetti P. Fungi, dendritic cells and
Biol. 2004;14:433–9. receptors: a host perspective of fungal virulence.
Pindborg JJ. Oral cancer and precancer. Bristol: John Trends Microbiol. 2002;10(11):508–14.
Wright and sons; 1980. Ruhnke M, Schmidt-Westhausen A, Morschhäuser J. Devel-
Pinjon E, Moran GP, Coleman DC, Sullivan DJ. Azole opment of simultaneous resistance to fluconazole in Can-
susceptibility and resistance in Candida dubliniensis. dida albicans and Candida dubliniensis in a patient with
Biochem Soc Trans. 2005;33:1210–4. AIDS. J Antimicrob Chemother. 2000;46:291–5.
Ruoslahti E. How cancer spreads. Sci Am. 1996;267:42–7. Shakir BS, Smith CJ, Martin MV. Epithelial mitotic activ-
Salaspuro MP. Acetyldehyde, microbes and cancer of the ity during the induction of palatal candidosis in the
digestive tract. Crit Rev Clin Lab Sci. 2003;40: Wistar rat. J Oral Pathol. 1986;15(7):375–80.
183–208. Shapiro RS, Cowen L. Coupling temperature sensing and
Samaranayake LP. Host factors and oral candidosis. In: development: Hsp90 regulates morphogenetic signal-
Samaranayake LP, MacFarlane TW, editors. Oral ling in Candida albicans. Virulence. 2010;1(1):45–8.
candidosis. London: Wright-Butterworth & Co. Ltd; Sharon V, Fazel N. Oral candidiasis and angular cheilitis.
1990. p. 66–104. Dermatol Ther. 2010;23(3):230–42.
Samaranayake LP. Oral mycoses in HIV infection. Oral Sherman RG, Prusinski L, Ravenel MC, Joralmon RA.
Surg Oral Med Oral Pathol. 1992;73:171–80. Oral candidosis. Quintessence Int. 2002;33:521–32.
Samaranayake LP, Yaacob HB. Classification of oral Silva S, Henriques M, Oliveira R, Williams D, Azeredo J.
candidosis. In: Samaranayake LP, MacFarlane TW, In vitro biofilm activity of non-Candida albicans Can-
editors. Oral candidosis. London: Wright-Butterworth dida species. Curr Microbiol. 2010;61(6):534–40.
and Co. Ltd; 1990. p. 124–32. Simon GB, Berson SD, Young CN. Blastomycosis of
Samaranayake LP, Fidel PL, Naglik JR, Sweet SP, the tongue: a case report. S Afr Med
Teanpaisan R, Coogan MM, Blignaut E, Wanzala P. J. 1977;52(2):82–3.
Fungal infections associated with HIV infection. Oral Singh V, Sharma B, Sen R, Agrawal S, Bhagol A, Bali R.
Disease. 2002;8:151–60. Rhinocerebral mucormycosis: a diagnostic challenge
Samaranayake LP, Keung Leung W, Jin L. Oral mucosal and therapeutic dilemma in immunocompetent host.
fungal infections. Periodontol 2000. 2009;49:39–59. J Oral Maxillofac Surg. 2012;70(6):1369–75.
Sanglard D, Bille J. Current understanding of the modes Singh V, Gupta P, Khatana S, Bhagol A, Gupta A.
of action and resistance mechanisms to conventional A nonhealing ulcer of mandibular alveolar ridge.
and emerging antifungal agents for treatment of Oral Surg Oral Med Oral Pathol Oral Radiol.
Candida infections. In: Calderone RA, editor. Candida 2014;117(3):272–6.
and candidiasis. Washington, DC: American Sitheeque MA, Samaranayake LP. Chronic hyperplastic
Society for Microbiology (ASM) Press; 2002. candidosis/candidiasis (candidal leukoplakia). Crit
p. 349–83. Rev Oral Biol Med. 2003;14(4):253–67.
Sargenti Neto S, Paulo LF, Rosa RR. Oral para- Smith EM, Hoffman HT, Summersgill KS, Kirchner HL,
coccidioidomycosis as a differential diagnosis of oral Turek LP, Haugen TH. Human papillomavirus and risk
cancer. Rev Soc Bras Med Trop. 2012;45(6):777. of oral cancer. Laryngoscope. 1998;108(7):1098–103.
Schaller M, Januschke E, Schackert C, Woerle B, Sohn DS, Lee JK, Shin HI, Choi BJ, An KM. Fungal
Korting HC. Different isoforms of secreted aspartyl infection as a complication of sinus bone grafting and
proteinases (Sap) are expressed by Candida albicans implants: a case report. Oral Surg Oral Med Oral Pathol
during oral and cutaneous candidosis in vivo. J Med Oral Radiol Endod. 2009;107(3):375–80.
Microbiol. 2001;50(8):743–7. Soysa NS, Samaranayake LP, Ellepola AN. Antimicrobials
Schaller M, Mailhammer R, Korting HC. Cytokine expres- as a contributory factor in oral candidosis–a brief over-
sion induced by Candida albicans in a model of cuta- view. Oral Dis. 2008;14:138–43.
neous candidosis based on reconstituted human Spampinato C, Leonardi D. Candida infections, causes,
epidermis. J Med Microbiol. 2002;51:672–6. targets, and resistance mechanisms: traditional and
Schaller M, Borelli C, Korting HC, Hube B. Hydrolytic alternative antifungal agents. Biomed Res Int.
enzymes as virulence factors of Candida albicans. 2013;2013:204237.
Mycoses. 2005;48:365–77. Srivastava N, Bansal V, Kantoor P. Palatal mucormycosis
Schauer F, Hanschke R. [Taxonomy and ecology of the in an infant. J Dent Child (Chic). 2015;82(3):153–6.
genus Candida]. Mycoses. 1999;42 Suppl 1:12–21. Stehr F, Felk A, Gacser A, Kretschmar M, Mahnss B,
Scolozzi P, Perez A, Verdeja R, Courvoisier DS, Lombardi Neuber K, Hube B, Schafer W. Expression analysis of
T. Association between maxillary sinus fungus ball and the Candida albicans lipase gene family during exper-
sinus bone grafting with deproteinized bovine bone imental infections and in patient samples. FEMS Yeast
substitutes: a case-control study. Oral Surg Oral Med Res. 2004;4(4–5):401–8.
Oral Pathol Oral Radiol. 2016;121(6):e143–7. Stevens DA, Odds FC, Scherer S. Application of DNA
Scully C. Candida and candidosis. World workshop on oral typing methods to Candida albicans epidemiology
medicine. 1988. p. 191–7. Chicago, June,1988. and correlations with phenotype. Rev Infect Dis.
Scully C, el-Kabir M, Samaranayake LP. Candida and 1990;12(2):258–66.
oral candidosis: a review. Crit Rev Oral Biol Med. Stokes C, Moran GP, Spiering MJ, Cole GT, Coleman DC,
1994;5(2):125–57. Sullivan DJ. Lower filamentation rates of Candida
Scully C, Flint SR, Porter SR, Moos KF. Oral and maxil- dubliniensis contribute to its lower virulence in com-
lofacial diseases. London: Taylor & Francis; 2004. parison with Candida albicans. Fungal Genet Biol.
Selmecki A, Forche A, Berman J. Genomic plasticity of the 2007;44:920–31.
human fungal pathogen Candida albicans. Eukaryot Strausbaugh LJ, Sewell DL, Ward TT, Pfaller MA,
Cell. 2010;9(7):991–1008. Heitzman T, Tjoelker R. High frequency of yeast
carriage on hands of hospital personnel. J Clin Micro- Umadevi M, Adeyemi O, Patel M, Reichart PA, Robinson
biol. 1994;32(9):2299–300. PG. (B2) periodontal diseases and other bacterial infec-
Sullivan D, Coleman D. Candida dubliniensis: character- tions. Adv Dent Res. 2006;19(1):139–45.
istics and identification. J Clin Microbiol. 1998;36(2): Urs AB, Singh H, Nunia K, Mohanty S, Gupta S. Post
329–34. endodontic Aspergillosis in an immunocompetent indi-
Sullivan DJ, Westerneng TJ, Haynes KA, Bennett vidual. J Clin Exp Dent. 2015;7(4):e535–9.
DE, Coleman DC. Candida dubliniensis sp. nov.: Urs AB, Singh H, Mohanty S, Sharma P. Fungal osteomy-
phenotypic and molecular characterization of a elitis of maxillofacial bones: rare presentation. J Oral
novel species associated with oral candidosis in Maxillofac Pathol. 2016;20(3):546.
HIV-infected individuals. Microbiology. Väkeväinen S, Mentula S, Nuutinen H, Salmela KS,
1995;141:1507–21. Jousimies-Somer H, Färkkilä M, Salaspuro M. Ethanol
Taff HT, Nett JE, Andes DR. Comparative analysis of derived microbial production of carcinogenic
Candida biofilm quantitation assays. Med Mycol. acetyldehyde in achlorhydric atrophic gastritis. Scand
2011;50:214. J Gastroenterol. 2002;37:648–55.
Taschdjian CL, Seelig MS, Kozinn PJ. Serological diagno- van de Veerdonk FL, Plantinga TS, Hoischen A,
sis of candidal infections. CRC Crit Rev Clin Lab Sci. Smeekens SP, Joosten LA, Gilissen C, Arts P,
1973;4(1):19–59. Rosentul DC, Carmichael AJ, Smits-van der
ten Cate JM, Klis FM, Pereira-Cenci T, Crielaard W, de Graaf CA, Kullberg BJ, van der Meer JW, Lilic D,
Groot PW. Molecular and cellular mechanisms that Veltman JA, Netea MG. STAT1 mutations in autosomal
lead to Candida biofilm formation. J Dent Res. dominant chronic mucocutaneous candidiasis. N Engl J
2009;88:105–15. Med. 2011;365(1):54–61.
Thomas J, Munson E, Christianson JC. Unexpected Vazquez JA. Optimal management of oropharyngeal
Blastomyces dermatitidis etiology of fungal sinusitis and esophageal candidiasis in patients living
and erosive palatal infection in a diabetic patient. with HIV infection. HIV AIDS (Auckl).
J Clin Microbiol. 2014;52(8):3130–3. 2010;2:89–101.
Tillonen J, Homann N, Rautio M, Jousimies-Somer H, Vazquez JA, Sanchez V, Dmuchowski C, Dembry LM,
Salaspuro M. Role of yeasts in the salivary acetalde- Sobel JD, Zervos MJ. Nosocomial acquisition of Can-
hyde production from ethanol among risk groups for dida albicans: an epidemiologic study. J Infect Dis.
ethanol-associated oral cavity cancer. Alcohol Clin Exp 1993;168:195–201.
Res. 1999;23:1409–15. Vidya KM, Rao UK, Nittayananta W, Liu H, Owotade
Tsang CS, Chu FC, Leung WK, Jin LJ, Samaranayake FJ. Oral mycoses and other opportunistic infections
LP, Siu SC. Phospholipase, proteinase and in HIV: therapy and emerging problems –
haemolytic activities of Candida albicans isolated a workshop report. Oral Dis. 2016;22
from oral cavities of patients with type (Suppl 1):158–65.
2 diabetes mellitus. J Med Microbiol. 2007;56 Vinay BH, Mohan A, Haritha P, Lakshmi KR.
(Pt 10):1393–8. A rare coexistence of aspergillosis with actinomycosis.
Tumbarello M, Caldarola G, Tacconelli E, Morace G, J Oral Maxillofac Pathol. 2017;21(2):277–81.
Posteraro B, Cauda R, Ortona L. Analysis of the risk Viudes A, Pemán J, Cantón E, Salavert M, Ubeda P, López-
factors associated with the emergence of azole resistant Ribot JL, Gobernado M. Two cases of fungemia due to
oral candidosis in the course of HIV infection. J Anti- Candida lusitaniae and a literature review. Eur J Clin
microb Chemother. 1996;38:691–9. Microbiol Infect Dis. 2002;21:294–9.
Tunnet MM, Gorman SP, Patrick S. Infection associated with Wachtler B, Wilson D, Haedicke K, Dalle F, Hube B. From
medical devices. Rev Med Microbiol. 1996;7:195–205. attachment to damage: defined genes of Candida
Tzerbos F, Kabani S, Booth D. Cryptococcosis as an albicans mediate adhesion, invasion and damage dur-
exclusive oral presentation. J Oral Maxillofac Surg. ing interaction with oral epithelial cells. PLoS One.
1992;50(7):759–60. 2011;6(2):e17046.
Ueta E, Osaki T, Yoneda K, Yamamoto T. Prevalence of Weinberg RA. How cancer arises. Sci Am.
diabetes mellitus in odontogenic infections and oral 1996;275:62–70.
candidiasis: an analysis of neutrophil suppression. Williams D, Lewis M. Pathogenesis and treatment of oral
J Oral Pathol Med. 1993;22(4):168–74. candidosis. J Oral Microbiol. 2011;3:5771–82.
Uittamo J, Siikala E, Kaihovaara P, Salaspuro M, Williams DW, Bartie KL, Potts AJ, Wilson MJ, Fardy MJ,
Rautemaa R. Chronic candidosis and oral cancer in Lewis MA. Strain persistence of invasive Candida
APECED-patients: production of carcinogenic acetal- albicans in chronic hyperplastic candidosis that
dehyde from glucose and ethanol by Candida albicans. underwent malignant change. Gerodontology.
Int J Cancer. 2009;124(3):754–6. 2001;18:73–80.
Uittamo J, Nieminen MT, Kaihovaara P, Bowyer P, Williams DW, Kuriyama T, Silva S, Malic S, Lewis
Salaspuro M, Rautemaa R. Xylitol inhibits carcino- MA. Candida biofilms and oral candidosis:
genic acetaldehyde production by Candida species. treatment and prevention. Periodontol 2000.
Int J Cancer. 2011;129(8):2038–41. 2011;55(1):250–65.
Williamson D. Chronic hyperplastic candidiasis and squa- Yoon SA, Vazquez JA, Steffan PE, Sobel JD, Akins RA.
mous cell carcinoma. Br J Dermatol. 1969;81:125–7. High-frequency, in vitro reversible switching of Can-
Willis AM, Coulter WA, Fulton CR, Hayes JR, Bell PM, dida lusitaniae clinical isolates from amphotericin B
Lamey PJ. Oral candidal carriage and infection in insulin- susceptibility to resistance. Antimicrob Agents
treated diabetic patients. Diabet Med. 1999;16:675–9. Chemother. 1999;43:836–45.
Oral and Maxillofacial Viral Infections
Stephen Porter, Jair C. Leão, and Luiz Alcino Gueiros
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 984
Herpes Viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 984
Herpes Simplex Virus (HSV-1 and HSV-2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 985
Varicella Zoster Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 988
Ramsay Hunt Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 989
Epstein Barr Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 991
Cytomegalovirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 992
Human Herpes Virus 6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 993
Coxsackie Viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 994
Hand, Foot, and Mouth Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 994
Herpangina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 994
Acute Lymphonodular Pharyngitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 994
Rubella . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 995
Human Immunodeficiency Viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 996
Human Papilloma Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 997
Nononcogenic HPV Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 997
Oncogenic HPV Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1001
S. Porter (*)
UCL Eastman Dental Institute, University College
London, London, UK
e-mail: s.porter@ucl.ac.uk
J. C. Leão · L. A. Gueiros
Oral Medicine Unit, Departamento de Clínica e
Odontologia Preventiva, Universidade Federal de
Pernambuco, Recife, PE, Brazil
e-mail: jleao@ufpe.br; luiz.mgueiros@ufpe.br;
lagueiros@gmail.com

https://doi.org/10.1007/978-3-319-72303-7_44
984 S. Porter et al.
Viral Infections of the Salivary Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1001

Mumps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1001
Hepatitis C Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1002
HIV Salivary Gland Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1003
Seasonal Viral Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1004
Emerging Viral Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1004
Conclusions and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1005
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1005
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1005
Abstract discusses viral conditions of the oral cavity,

Awide spectrum of viral infections can affect the including HHV infection, HPV, coxsackievirus,
mouth and allied structures. In most instances, mumps, measles, rubella, and those conditions/
these give rise to short-term local illness (e.g., diseases associated with HIV and HCV infection.
herpes simplex infections in immunocompetent Emerging viral diseases including Ebola and Zika
hosts); however, infections such as Human virus are also briefly discussed.
Immunodeficiency viruses (HIV), Epstein Barr
virus (EBV), and the oncogenic types of Human
Papillomavirus (HPV) can cause significant
orofacial disease that will increase patient mor- Herpes Viruses
bidity and possibly lead to early death. The
present chapter details the viral infections that The human herpesvirus (HHV) are a species-
may commonly affect the oral cavity and/or specific family of DNA virus that includes eight
salivary glands in patients worldwide. The epi- types that can infect humans. The human herpes
demiology of viral infections is ever changing; viruses are classified into three subfamilies (α, β,
hence, health care providers are encouraged to and γ). The α-herpesvirinae viruses are character-
maintain knowledge of virally driven infections ized by a relatively short reproductive cycle and
that may impact upon the health and clinical care irreversible destruction of infected cells, and
of their relevant specialty. include HSV1, HSV2, and VZV. β-Herpesvirinae
viruses (CMV, HHV6, and HHV7) have a long
reproductive cycle and a slow infection process.
Keywords Finally, γ-herpesvirinae (EBV and HHV8) repli-
Viral diseases · Viral infections · cate in lymphoblastoid cells and may establish
Herpesviridae · Enterovirus · HIV · HPV a latent or lytic infection in B or T lymphocytes.
This classification is reflected in the clinical behav-
ior of the associated diseases, as discussed below.
Introduction The human herpes viruses may promote a dis-
ease state in three distinctive ways: (1) direct
The oral mucosa is a common site for primary destruction of cells and tissues, (2) induction of
viral infections particularly those of the human immune responses, and (3) facilitation of neoplas-
herpesvirus (HHV) and human papillomavirus tic transformation. The α-herpesvirinae viruses
(HPV) families. More recently, HPV infections typically present a short reproductive cycle with
have received particular attention as oncogenic irreversible destruction of infected cells, follow-
types etiologically linked to increasing numbers ing the ability to maintain latent infection in the
of cases of oral squamous cell carcinoma. None- sensorial neural ganglion. Herpes simplex virus is
theless, many other viral infections may be found within this subfamily and causes rapid infection of
in the oral cavity of humans. This chapter epithelial cells with subsequent latency state and
Oral and Maxillofacial Viral Infections 985
recurrent flares, characterizing the direct cellular oral illness as a consequence of acquisition via
destruction and specific induction of a latent orogenital contact. Both HSV-1 and HSV-2 lead
immune state. The β-herpesvirinae viruses, on to an initial primary infection with later episodes
the other hand, have a long reproductive cycle of less severe secondary infection in some, but not
and may become latent in lymphoreticular cells. all, infected patients (Arduino and Porter 2008).
CMV is the hallmark of this subfamily, being Primary HSV-1 infection typically affects the
capable of inducing a plethora of clinical disor- mouth and arises within 1–2 weeks of acquisition
ders, particularly in immunocompromised indi- of the virus. The clinical features comprise initial
viduals. Finally, γ-herpesvirinae have an affinity nonspecific features of malaise, pyrexia, and leth-
for T and B lymphocytes, become latent in lym- argy followed by the eruption of widespread
phoid tissues, and are closely associated with ulceration of the oral mucosa and gingiva (Cun-
certain malignant diseases. EBV is the typical ningham et al. 2006).
member of this subfamily, being associated with The ulcers are usually superficial, initially
acute infection (infectious mononucleosis) and small and spherical but may coalesce to give rise
being causative of malignant diseases that in- to large sized, irregular outlined ulcers (Fig. 1).
clude Burkitt’s lymphoma and nasopharyngeal The ulceration can arise on any oral mucosal sur-
carcinoma. face; indeed, typically all sites of the mouth can be
affected. The gingiva becomes swollen, erythem-
atous, and ulcerated, with ulceration affecting the
Herpes Simplex Virus (HSV-1 free and/or attached gingiva (Fig. 2) (and hence
and HSV-2) may mimic acute necrotizing ulcerative gingivitis
– ANUG). The ulceration causes notable pain,
Clinical Features dysphagia, dysarthria, and possibly drooling.
Herpes simplex virus 1 (HSV-1) is transmitted via There is usually bilateral cervical lymphadenopa-
close contact with infected fluids (usually saliva) thy and occasionally a generalized macular cuta-
or lesions, and tends to give rise to disease of the neous rash. The signs and symptoms usually
mouth and surrounding skin. In contrast, HSV-2 is spontaneously resolve within 7–10 days, although
usually transmitted by genital-to-genital contact the disease can be severe and prolonged in immu-
with infected fluids or lesions and predominantly nocompromised individuals (Elad et al. 2010).
gives rise to genital disease. However, HSV-1 can Primary HSV-2 infection of the mouth can give
cause genital disease and HSV-2 can give rise to rise to a similar clinical picture to that of HSV-1
Fig. 1 Initial aspect of intraoral herpes simplex infection, with blister formation involving the hard palate mucosa
(a). Multiple palatal ulcers observed 2–3 days following initial symptoms of intraoral herpes simplex (b)
Fig. 2 Multiple ulcers due to herpes simplex infection Fig. 4 Herpetic gingival ulcer (Image courtesy of Profes-
sor Camile Farah, Perth Oral Medicine & Dental Sleep
Centre, Perth WA, Australia)
Fig. 3 Herpes labialis on the lower lip (Image courtesy of

Professor Camile Farah, Perth Oral Medicine & Dental
Sleep Centre, Perth WA, Australia)
although it has been suggested that the illness may

be less severe and not as prolonged as that caused
by HSV-1.
Secondary HSV-1 infection of the mouth
affects about 30% of patients with a history of
probable primary infection. Many patients present
with a likely secondary disease, however, cannot
recall having the primary disease (Arduino and
Porter 2008; Fatahzadeh and Schwartz 2007).
Fig. 5 Herpetic glossitis in patient under chemotherapy
Secondary HSV-1 infection of the mouth typ- for lung cancer
ically affects the vermillion of the lip termed her-
pes labialis (commonly known as “cold sores”)
(Fig. 3) but can also arise on the perioral or peri- pustule formation, superficial ulceration, and
nasal skin. Sole involvement of the mouth (e.g., eventual spontaneous healing. The complete clin-
small numbers of superficial oral mucosal or gin- ical disease lasts about 5–7 days (Arduino and
gival ulcers) is a very rare manifestation of sec- Porter 2008).
ondary HSV-1 infection (Figs. 4 and 5). Herpes Herpes labialis may often, but not always, be
labialis is characterized by a clinical pattern of precipitated by an identifiable precipitant that may
paraesthesia, followed by erythema, vesiculation, include concomitant illness, (e.g., flu or other
Fig. 6 Atypical and severe herpes simplex infection in a patient with acute myeloid leukemia. Extraoral aspect with
extensive scab formation (a). Extensive intraoral involvement with large ulcers limiting solid food intake (b)
infections) exposure to sunlight or UV light or typically include identification of HSV-1 DNA by

occasionally is associated with particular phases molecular means [e.g., polymerase chain reaction
of the menstrual cycle or pregnancy. Immunosup- (PCR)]. Demonstration of a four-fold or more rise
pression (e.g., iatrogenic, malignancy-associated or in HSV-1 specific IgG antibodies between the acute
HIV-associated) can also lead to the onset of herpes (i.e., ulcerative) and convalescent phase of illness
labialis that may be severe and/or prolonged, but provides a retrospective diagnosis of primary
can also involve intra-oral sites (Fig. 6; Elad et al. HSV-1 infection, although this may not be reliable
2010). Often patients have recurrences at the exact in immunocompromised patients with recurrent
same site each time, presumably reflecting the bouts of severe HSV-1 driven infection. A full
location of residency of the herpes simplex virus blood cell count should be obtained for adults
within the trigeminal ganglion. with likely primary HSV infection to rule out com-
Herpes simplex 1 has been suggested to be a mon causes of immunosuppression (e.g., nonsolid
causative factor of “idiopathic” lower motor neuron hematological malignancies such as leukemia or
palsy of the facial nerve (i.e., Bell’s palsy), although myeloma) or unknown HIV disease (with possible
there is no notably strong evidence to support this. lymphopenia) (Arduino and Porter 2008).
Indeed, antiviral therapy (e.g., acyclovir) is not Herpes labialis does not usually warrant inves-
considered to be a reliable means of resolving tigation, as the clinical picture is so characteristic.
Bell’s palsy. Similarly, HSV-1 has been proposed Where there is some diagnostic confusion, the
to be a precipitant of erythema multiforme minor, as identification of HSV DNA via PCR can be help-
in some instances this has been preceded by herpes ful. The serological investigation is not helpful as
labialis. There is some, albeit limited data, that there is no substantial elevation in IgG anti-HSV
prophylactic acyclovir may lessen outbreaks of antibodies between the acute and convalescent
recurrent erythema multiforme minor. phases of secondary HSV-1 infection.
Diagnosis Management
The diagnosis of primary orofacial HSV-1 Despite the symptoms being distressing, the man-
is typically based upon the clinical features. agement of primary HSV-1 infection can usually
The differential diagnosis would include erythema be based upon symptomatic relief alone. Topical
multiforme (which tends to recur) or anti-inflammatory drugs such as benzydamine
immunobullous disease (which tends to arise in hydrochloride spray or mouthwash, or topical
middle to late age). Confirmatory investigations anesthetics, such as lidocaine (lignocaine) gel,
may reduce painful symptoms and facilitate feed- transmitted via droplets or close contact with
ing. Systemic analgesia and antipyretics such as a lesions (i.e., the cutaneous rash of chickenpox).
nonsteroidal anti-inflammatory agent such as ibu-
profen, or paracetamol can be helpful. Affected Chickenpox
persons, particularly children, should be encour- Chickenpox typically arises in preschool children
aged to drink fluids. Acyclovir should be pre- and is clinically characterized by the appearance
scribed where the symptoms and/or signs are of a macular-papular cutaneous rash that rapidly
“severe” and early, although this will have little evolves into vesicles and later pustules, accompa-
benefit if there is evidence of healing of lesions nied by fever and malaise. Within 3–4 days the
(Mell 2008). Acyclovir should, however, always pustules scab. The fever is generally low and can
be considered for patients with or thought to have be accompanied by mild prodromal symptoms
immunosuppression, and certainly, those with such as anorexia and headache. The incubation
known immunosuppression should be reviewed period of VZV (i.e., time from acquisition until
by their attending specialists (Elad et al. 2010). the initial manifestation of clinical illness) is
The acyclovir prodrug valacyclovir and 7–14 days (Anjos et al. 2009).
famciclovir (the prodrug of penciclovir) are only Complications are uncommon and usually
warranted when there is a need for sustained or involve secondary infection of skin lesions caused
frequent administration of an antiviral. Acyclovir by Staphylococcus aureus and Staphylococcus
may be prescribed as tablets or suspension (e.g., pyogenes, leading to impetigo, cutaneous ab-
200 mg 5 times daily for 7 days). Intravenous scesses, and cellulitis. Rarely, pulmonary or neu-
administration of acyclovir is rarely warranted rological diseases may follow the clinical course
(Arduino and Porter 2008). of chickenpox.
Herpes labialis does not always require treat- Oral lesions are common and may precede
ment. A variety of topical nonantiviral prepara- cutaneous involvement, but as the cutaneous
tions are available as over-the-counter items for symptoms and signs evolve rapidly and dominate
the symptomatic relief of herpes labialis, but these the clinical picture, the oral features may go
are largely untested as to whether they benefit unnoticed by the patient, carers, or attending cli-
patients. Perioral acyclovir cream (5%; applied nicians. The oral manifestations are short lasting
6 hourly) or penciclovir cream (1%; applied small white-opaque vesicles that rupture and
2 hourly) may hasten disease resolution, but ulcerate, usually on the palate and buccal mucosa
these agents should be applied to the affected (Clarkson et al. 2017).
area as soon as possible. Acyclovir is usually Chickenpox can have a seasonal pattern with
only of benefit if applied at the vesicular stage, outbreaks usually occurring in autumn, coincid-
while it is suggested that penciclovir may still ing with the arrival of new populations of suscep-
cause hastening of resolution of symptoms even tible children. Overall, there are no predisposition
if used in the early ulcerative stage. distinctions by age, race, or gender regarding
All patients with primary or secondary HSV infection by VZV. More than 90% of the world
infection should avoid direct contact with other population is infected by 15 years of age.
individuals to lessen the risk of further transmis- Although varicella is usually considered a benign
sion of the causative virus (Mell 2008). disease, it is important to highlight that about
90 children die each year from varicella and its
complications in the United States.
Varicella Zoster Virus
Diagnosis
Clinical Features The diagnosis of chickenpox is usually based
Varicella zoster virus (VZV, HHV-3) gives rise to upon the clinical history and picture. Confirma-
a primary infection termed chickenpox and a sec- tory viral or serological investigations are rarely
ondary infection known as shingles. Infection is warranted.
Management
The treatment of chickenpox is directed toward
lessening of symptoms. The pruritus of the rash
may be reduced by the local use of calamine or
possibly oral antihistamines. Warm baths with
sodium bicarbonate or potassium permanganate
may also be used to relieve the itching. Antivirals
are not routinely indicated.
Shingles
Herpes zoster (HZ) or shingles is caused by
reactivation of the varicella zoster virus (VZV) in
ganglia of the cranial nerves or dorsal roots. This
reactivation and outbreak are more likely to occur Fig. 7 Initial aspect of varizella zoster infection involving
the maxillary branch of trigeminal nerve
when cellular immunity to VZV is impaired, espe-
cially by conditions such as immunosuppression,
HIV disease, and malignancy. Nevertheless, there signs and symptoms may persist for longer periods
is often no identifiable underlying cause for the (Fig. 9). Confusingly, the onset of oral shingles
onset of the viral eruption. The disease is however may be heralded by pain in one or more teeth
most likely to occur in late life (Portella et al. 2013). that have no caries or periapical pathology – the
Shingles typically affect the thoracic derma- toothache diminishing when the oral ulceration
tomes via reactivation within spinal ganglia. It commences (Lopes et al. 1998).
manifests as painful eruptions of vesicles, with
later ulceration and prolonged erythema of skin
supplied by one or more dermatome of one side of Ramsay Hunt Syndrome
the thorax or upper abdomen. The pain is intense
and sharp although with time may become more This is a very rare manifestation of shingles and
ache-like. reflects VZV reactivation within the geniculate
Shingles affecting the trigeminal nerve arises ganglion. It is clinically characterized by otitis
independent of thoracic involvement and can externa, a unilateral lower motor neuron palsy of
affect any branch of (in order of frequency) the the facial nerve, and ulceration of the anterior
ophthalmic, maxillary, or mandibular divisions of two-thirds of the tongue and soft palate – all on
one side (Figs. 7 and 8). Bilateral involvement or the same side (i.e., ipsilateral) as the palsy (Grahn
infection of branches of more than one division of and Studahl 2015). The distribution of the oral
one side is extremely rare. Depending upon the ulceration reflects the branches of chorda tym-
branches that are affected, skin lesions similar to pani. Bilateral Ramsay Hunt syndrome has been
those of thoracic shingles can arise and are nota- described – but is notably rare.
bly painful (Grahn and Studahl 2015). Patients with orofacial shingles are generally
The oral lesions of shingles are akin to those of distressed as a consequence of the severe pain,
primary HSV-1 infection, i.e., vesicles rapidly although do not have substantial systemic upset
evolve into small superficial ulcers that coalesce such as pyrexia or malaise.
to give rise to larger irregular outlined ulcers. The Complications of orofacial shingles can include
site of involvement will clearly depend on the postherpetic neuralgia and meningoencephalitis.
affected branch, but there is usually a distinct uni- The former may affect up to 14% of patients and is
lateral distribution of lesions with minor crossover characterized by pain that persists for 3 or more
in the midline. The painful ulceration may last months after healing of the shingles. It is rare in
5–10 days without therapy in the immunocompe- the mouth but can arise on the face, particularly
tent host. In patients with immunodeficiency, the the forehead. The pain may be an ache, through to
Fig. 8 Herpes zoster in a female patient involving the left face and left buccal mucosa (Images courtesy of Professor
Camile Farah, Perth Oral Medicine & Dental Sleep Centre, Perth WA, Australia)
based on clinical manifestations alone. Identifica-

tion of VZV DNA and retrospective serological
confirmation of VZV infection (i.e., a four-fold or
more rise in specific antibodies between the acute
and convalescent phases) may be possible, but the
antibody levels do not always rise much, particu-
larly in elderly persons and/or those who are
immunocompromised (Sauerbrei 2016). It is
always prudent to assess the full blood cell count
for evidence of unknown neutropenia, leukemia,
or other white blood cell dyscrasia, as occasion-
ally orofacial shingles will be the first manifesta-
tion of an underlying, significant disease.
Fig. 9 Sequelae of herpes zoster infection leading to lim- Management

ited eye closure
Unlike primary HSV infection, antiviral therapy
sharp, and may be particularly worsened by light is almost always warranted for orofacial shin-
touch (Portella et al. 2013). Postherpetic neuralgia gles. Oral acyclovir (e.g., 800 mg, 5 times daily
is discussed in a separate chapter. for 7 days) is a typical therapy but sometimes
valacyclovir or famciclovir can be used, espe-
Diagnosis cially if patients have difficulty in taking medica-
The diagnosis of orofacial shingles (including tion so frequently and/or the disease is atypical or
Ramsay Hunt syndrome) can usually be made prolonged. Topical antivirals are of no benefit for
shingles of the mouth. Patients with shingles may be detected serologically (e.g., liver function
should avoid contact with household members tests) in patients with EBV-related hepatitis as
who are elderly or known to be immunocompro- part of infectious mononucleosis (Luzuriaga and
mised as there is a risk of them acquiring VZVand Sullivan 2010).
developing chickenpox or shingles. All patients Glandular fever describes a similar clinical pat-
with possible ophthalmic shingles should be tern to that of infectious mononucleosis that can
referred for a specialist ophthalmology opinion arise with infection by cytomegalovirus, HIV, and
(Werner et al. 2016). toxoplasmosis. However, unlike infectious mono-
nucleosis, there are no detectable high levels of
anti-EBV antibodies (i.e., these are Paul Bunnell
Epstein Barr Virus negative types of glandular fever) in these disor-
ders, and indeed it may be possible to differentiate
Epstein Barr virus (EBV) is a γ-1 herpes virus that them by the detection of IgG antibodies to HIV or
gives rise to a variety of different clinical illnesses IgM class antibodies to CMV or toxoplasmosis.
that include infectious mononucleosis, oral hairy
leukoplakia, and a number of malignancies that Management
can affect the head and neck (especially extra- The management of infectious mononucleosis is
nodal natural killer T cell lymphoma (ENKTCL), based upon reducing any painful symptoms. The
some other non-Hodgkin lymphomas and naso- lethargy resolves spontaneously, but over several
pharyngeal carcinoma). Epstein Barr virus is weeks. Antiviral therapy is not usually warranted,
transmitted via the salivary route (Cohen 2000). and antibiotics or corticosteroids for pharyngitis
or pharyngeal edema are not typically employed
Infectious Mononucleosis (Oliveira et al. 2012).
This is the primary infection of EBV and arises
about 5 weeks following viral acquisition. It typ- Oral Hairy Leukoplakia
ically occurs in young adults, presumably as a
consequence of close nonsexual contact with Clinical Features
infected persons. The clinical features of infec- Oral hairy leukoplakia (OHL) is a secondary
tious mononucleosis comprise pharyngitis, infection of EBV. It manifests as adherent, homog-
pyrexia, cervical lymphadenopathy, and possibly enous, sometimes hair-like, white patches of the
nausea and abdominal pain due to hepatitis and lateral aspects of the tongue as well as sometimes
hepatosplenomegaly. These can be accompanied the dorsal or ventral surfaces (Fig. 10). The lesions
by a pink maculopapular rash that may be more
profound if patients are prescribed ampicillin-type
antibiotics. There is often profound lethargy that
dominates the clinical symptoms (Luzuriaga and
Sullivan 2010).
Diagnosis
The diagnosis can sometimes be based upon the
clinical picture alone, but as this can also arise
as a consequence of other infections (see below),
formal confirmation is useful. It is confirmed by
the identification of an atypical lymphocytosis
in a full blood cell count and the detection of
anti-EBV antibodies (heterophile antibodies) in
serum (also sometimes termed the monospot test Fig. 10 Oral hairy leukoplakia associated with oral
or Paul Bunnell test). Abnormal hepatic function candidosis in a patient with HIV infection
are nonpainful and not potentially malignant. to body fluids, including saliva, urine, and
Oral hairy leukoplakia arises in individuals who cervicovaginal secretions. Salivary transmission
are immunocompromised (e.g., undiagnosed or within families is common, probably from young
untreated HIV infection, iatrogenic immunosup- children passing it to nonimmune family members.
pression, and rarely a feature of diabetes melli- CMV infection rarely gives rise to oral disease and
tus or secondary to corticosteroid inhaler use) while it has been suggested that it may give rise to
(Stojanov and Woo 2015). salivary gland swelling there is actually little sup-
portive evidence for this claim.
Diagnosis Most perinatally infected infants do not have any
The diagnosis of OHL rests upon histopathologi- symptoms, although immunocompetent adults can
cal examination of lesional tissue, which will sometimes develop glandular fever-like symptoms.
demonstrate hyperkeratosis, acanthosis, possible Of note, however, transplacental transmission of
ballooning koilocytes in the stratum spinosum, CMV can result in fetal damage including
and a lack of any notable inflammatory infiltrate hepatosplenomegaly, jaundice, CNS abnormalities,
in the dermis. Immunohistochemistry is essential and growth retardation (Cannon and Davis 2005).
to confirm the presence of EBV-derived antigen. While the majority of infected newborns will be
asymptomatic, 30% will develop severe hearing
Management impairment. Anodontia of the primary dentition
Given its asymptomatic nature and its lack of can also arise with congenital CMV infection.
any malignant potential, OHL does not warrant In immunocompromised patients (for example,
treatment. In patients whose immune status HIV disease or iatrogenic immunosuppression),
improves [e.g., cessation of iatrogenic immunosup- CMV can cause unusual superficial oral mucosal
pression or antiretroviral therapy (ART; also some- ulcers that may have a star-like (stellate) appear-
times termed ARV-related HIV disease status)], ance, particularly on the tongue (Fig. 11; Torres
lesions often regress (Stojanov and Woo 2015). et al. 2004; Mainville et al. 2015).
Other Disorders Caused by Epstein Barr

Virus
Epstein Barr virus is the cause of several types of
non-Hodgkin’s lymphoma (e.g., Burkitt’s lym-
phoma, and extranodal natural killer T cell lym-
phoma [ENKTCL]) or the nonkeratinizing type of
nasopharyngeal carcinoma. Of relevance to the
mouth, about 50% of B cell type Non-Hodgkins
lymphoma of HIV disease are EBV-associated.
Extranodal natural killer T cell lymphoma usually
arises in the nose or sinus but can cause a notable
destruction of the hard and/or soft palate, upper
gingiva, and posterior tongue (Odumade et al.
2011). These tumors are covered in more detail in
separate chapters on ▶ “Head and Neck Tumors”
and ▶ “Non-odontogenic Bone Pathology.”
Cytomegalovirus
Cytomegalovirus (CMV) is a beta herpesvirus. It is Fig. 11 CMV-related ulcer in a patient with acute myeloid
transmitted both horizontally following exposure leukemia
CMV can cause significant disease in the

immunocompromised host, for example, infec-
tion following renal allografts can cause chronic
rejection while coronary artery stenosis can arise
in patients infected following cardiac transplanta-
tion. CMV pneumonitis is a complication of CMV
infection following lung transplantation, and reti-
nitis (with possible visual loss) can be caused by
CMV infection in HIV disease (Patel et al. 2012).
Ganciclovir and valganciclovir are the antivi-
rals typically used for severe CMV infection.
These should not be prescribed for minor CMV
infection in the immunocompetent patient.
Human Herpes Virus 6

Fig. 12 Oral Kaposi sarcoma presenting as a large ulcer-
Human herpesvirus 6 (HHV-6) is a beta herpes ated erythematous nodule involving upper gingiva and
buccal mucosa in a patient with late stage HIV disease
virus. It gives rise to a disorder termed exanthema
subitum, characterized by pyrexia, skin rash, and
occasionally seizures and encephalitis. It may Kaposi sarcoma of the oral tissues typically mani-
be transmitted via saliva, but as it has no oral man- fests as a red, blue, or purple macule, papule, or
ifestations, it is of little relevance to oral health care. nodule and typically arises at the hard-soft palate
junction of one side. The lesions spread and can be
destructive (Fig. 12). Occasionally KS initially
Human Herpes Virus 7 develops at sites other than the palate, for example,
the maxillary gingiva. As the disease progresses,
Human herpesvirus 7 (HHV-7) is a beta herpes the affected site becomes ulcerated and necrotic
virus that can be transmitted via saliva. It may and gingival involvement can lead to tooth mobil-
give rise to exanthema subitum, but it has no ity and loss (Fatahzadeh and Schwartz 2013).
clinical impact upon oral health care. Occasionally KS can manifest as a nonpigmented
lesion and thus looks like an oral squamous cell
carcinoma or non-Hodgkin’s lymphoma.
Human Herpes Virus 8 The diagnosis of KS rests upon histological and
immunohistochemical examination of lesional tis-
Human herpesvirus 8 (HHV-8) is a gamma sue while staging of disease follows typical radio-
herpes virus that causes Kaposi sarcoma (KS), logical investigation. Certainly, all patients with
pleural effusion lymphoma (PEL), and multi- oral KS require investigation of any unidentified
centric Castleman’s disease. Its predominant rele- underlying immunosuppression – which in almost
vance to oral disease and dentistry is its causative all instances will reveal previously unknown HIV
association with KS. HHV-8 can be transmitted infection (Schneider and Dittmer 2017).
both sexually and less commonly nonsexually In the past, KS was a common oral manifesta-
(e.g., via saliva, other fluids, including blood) tion of HIV disease but as a consequence of the
(Leão et al. 2002). wide increasing availability of effective ART the
Kaposi’s sarcoma of the mouth arises in immu- prevalence of this tumor has greatly reduced in
nocompromised groups, particularly those with HIV-infected groups across the globe. Of note,
HIV disease that has not been identified, or not HIV-associated KS can regress following the
been treated with antiretroviral therapy (ART). introduction of ART, and similarly, the emergence
of oral KS in patients receiving ART can be an The palms of the hand and soles of the feet are
indication that therapy is failing or the patient in usually affected following the oral lesions
not remaining compliant in taking the medication. (Fig. 13b). The eruption consists of vesicles or
The specific management of local or wide- small blisters at the distal flexor aspect of the
spread KS necessitates local radiotherapy and/or fingers or toes (Fig. 13c). Rarely, the skin of the
chemotherapy and is covered elsewhere in knees, elbows, and genital area can be affected
this book. (Aswathyraj et al. 2016).
The diagnosis is typically based upon the clin-
ical picture. Treatment is mainly supportive via
Coxsackie Viruses hydration, topical or systemic analgesics, and
antipyretics (e.g., paracetamol or ibuprofen). The
Hand, Foot, and Mouth Disease disease has no notable long-lasting consequences.
Hand, foot, and mouth disease (HFMD) is a com-

mon viral and exanthematous illness, typically Herpangina
affecting infants and children between 3 and
10 years of age. The most common virus involved Herpangina is caused by a type A coxsackie group
is coxsackie virus A16, but other viruses such as infection. It is most frequent in children. The virus is
coxsackie viruses A5, A7, A9, A10, B2, B5, and typically transmitted via saliva or occasionally via
enterovirus 71 can also cause HFMD (Solomon the fecal-oral route. As with HFMD, infection tends
et al. 2010). The disease usually arises as out- to arise in epidemics. In cold climates, this is often
breaks that are most frequent in the summer in the summer or autumn while in tropical countries
periods. Small epidemics are frequently reported it can occur in any season (Puenpa et al. 2014).
among schoolchildren or those attending nurser- Symptoms arise 2–10 days following exposure
ies. Indeed, it may spread through an entire school to the virus, and comprise fever, sore throat, head-
and also affect parents, carers, and teachers (Shin ache, dysphagia, and malaise. After 24–48 h, a
et al. 2010). diffuse erythema and vesiculation of the posterior
The transmission takes place through fecal-oral region of the oral mucosa and oropharynx occur.
contact or via inhalation of respiratory droplets; There are numerous small vesicles, particularly
however the direct interaction with cutaneous the soft palate and/or tonsillar pillars, which rup-
lesions can also cause disease transmission. The ture quickly to give rise to shallow and painful
incubation period is 3–7 days and the disease is ulcers. The clinical picture resolves spontane-
most contagious in the first week of illness. Never- ously after 7–10 days (Scott and Stone 2003).
theless, some individuals can be contagious for As with HFMD, the diagnosis of herpangina is
days or weeks after resolution of their symptoms usually based upon the clinical picture, while
and signs. The virus is present for about 6–8 weeks therapy is directed toward ensuring adequate
in feces, and about a week in the respiratory system. hydration, appropriate analgesia, and antipyretics.
Hand foot and mouth disease usually presents
with fever, reduced appetite, sore throat, and mal-
aise. After one to two days, numerous vesicles and Acute Lymphonodular Pharyngitis
oral ulcers emerge, varying in number from 1 to
30 lesions. The most commonly affected sites are This is caused by Coxsackie virus A10. It
the buccal mucosa, labial mucosa, and tongue typically affects children and young adults,
(Fig. 13a), but any site of the oral mucosa can although occasionally older individuals can also
be affected. Such vesicles are usually 2–7 mm be included. The infection has an incubation
in diameter, but can be larger than 1 cm, and period of about 5 days following which there is
gradually disappear after a period of about sore throat, pyrexia, mild headache, and anorexia.
1 week (Aswathyraj et al. 2016). Oral lesions develop about 2–3 days after onset of
Fig. 13 Hand Foot and Mouth disease. Lingual ulceration Professors Marcio Lopes and Alan Santos-Silva,
(a), palmar erythematous areas (b), and vesiculation of the Orocentro, FOP/UNICAMP, Brazil)
dorsal surface of the foot (c). (Images courtesy of
the systemic features and comprise a small num- Rubella has an incubation period of 2–3 weeks;
ber of discrete white to yellow papules on the following which a cutaneous rash develops, usu-
uvula, soft palate, palatoglossal folds, and poste- ally on the face, that gradually evolves on all
rior pharyngeal wall. The lesions are self-limiting cutaneous surfaces. The rash is accompanied by
and usually regress in about 10 days without any lymphadenopathy of the cervical region as well
blistering or ulceration. Therapy should be aimed as headache, low-grade fever, malaise and mild
at reducing any pyrexia and ensuring adequate conjunctivitis, and rarely transient arthralgia of
hydration (Steigman et al. 1962). the hands and multiple petechiae of the torso or
extremities.
Oral lesions can arise in about 20% of affected
Rubella individuals as dark-red macules or petechiae
(Forchheimer sign) on the soft palate. The oral
Rubella virus (RV) is a member of the Togaviridae features appear simultaneously with cutaneous
family. The virus is transmitted via the droplet eruptions (Tyor and Harrison 2014).
route, but of concern is vertical transmission from In most instances, the acute illness of rubella
an infected mother transplacentally during the first is of little clinical significance. However, con-
semester of pregnancy which can cause congenital genital rubella syndrome is significant – causing
rubella syndrome (CRS). The risk of rubella infec- malformations, premature birth or spontane-
tion is however low in view of the high uptake of ous abortion in severe cases. Newborns with con-
vaccination (together with mumps and measles genital rubella are extremely contagious. Clinical
immunization) (Tyor and Harrison 2014). features in infants may include microcephaly,
intellectual disability, developmental delay, cloudy to cell-mediated immunity. The fall in CD4+ T
corneas, and seizures, among other severe devel- lymphocytes increases the risk of opportunistic
opmental limitations (Tyor and Harrison 2014). infection particularly by viruses, mycobacteria,
Treatment of the acute disease is generally not and fungi. As a result, patients without appropri-
required. Antipyretic and antipruritic agents may ate ART can manifest a spectrum of systemic
be helpful in patients with significant fever and infections that include Pneumocystis pneumonia,
symptomatic skin involvement. Passive immunity mucocutaneous and visceral Kaposi’s sarcoma,
can be provided by administration of rubella herpes zoster infection and candidal infection as
human immunoglobulin. If the immunoglobulin well as a very wide range of other infections,
is administered during the first days of exposure, virally driven malignancies, and neurological dis-
it will lessen the severity of the infection. Double orders (Northfield et al. 2005).
dose vaccination is recommended with measles, A wide range of oral disorders can arise in HIV
mumps, and rubella, the first dose being between disease, these reflecting the failure of cell-mediated
12 and 15 months of age and the second between immunity. Indeed prior to the availability of ART, it
4 and 6 years. was likely that all individuals infected with HIV
would ultimately develop oral disease (Ficarra
1997). However, as ART is increasingly available
Human Immunodeficiency Viruses (90% of all HIV-infected individuals in many
countries now have access to this) and is highly
Human immunodeficiency virus (HIV) comprises effective in lessening HIV burden, the frequency
2 main RNA viruses (HIV-1 and HIV-2) that tend to and severity of oral disorders likely to be observed
give rise to a similar clinical picture. This infection in HIV-infected individuals have dramatically
came to clinical and public attention in the early fallen over the past decade (Patton et al. 2013). In
1980s and since then has gone on to infect, and kill, turn, a spectrum of oral symptoms and signs can
many millions of individuals across the globe. occur as a consequence of adverse side effects of
However, in the past decade the numbers of per- ART. Nevertheless, not all individuals with HIV
sons acquiring infection has begun to fall as a disease are aware that they are infected, and not all
consequence of changing lifestyle and/or aware- patients can tolerate or take ART, hence there will
ness of methods of avoiding acquisition (i.e., bar- always remain individuals who develop oral fea-
rier methods of contraception), while increasing tures of HIV disease.
availability of effective therapy (antiretroviral ther- The most common oral manifestations of
apy – ART) has led to a fall in the mortality rate of HIV disease are candidosis (usually pseudo-
infected persons (Patton et al. 2013). Nevertheless, membranous) (Fig. 14), hairy leukoplakia, and
as of 2015, there are 37 million individuals across Kaposi’s sarcoma. Each of these is detailed in
the globe living with HIV disease. other sections of this book. The likelihood of
The virus is principally transmitted by sexual, each of these arising in the mouth is directly
parenteral, or vertical (transplacental) routes linked to the degree of immune dysfunction that
(Pinheiro et al. 2009). While infection was ini- occurs (typically determined by peripheral blood
tially observed in gay men and recipients of blood CD4+ T cell count).
and blood products, the majority of new infections Recall also that early HIV infection (usually at
arise as a consequence of heterosexual transmis- the time of generating of anti-HIV antibodies –
sion, although sex between men remains a risk termed seroconversion) can give rise to glandular
factor. Vertical transmission has greatly decreased fever-like symptoms and signs.
in the past two decades as a consequence of The oral manifestations that are potentially
improved HIV disease surveillance (Patton 2016). possible if HIV disease either goes undertreated
Human immunodeficiency virus gives rise to or fails to be treated for different reasons are wide
clinical disease principally as a result of infection ranging and are summarized in Table 1. The char-
and later loss of CD4+ T lymphocytes that are key acter, severity, and frequency of the oral disorders
dermatotropic and mucosotropic. They can also

be classified as oncogenic (i.e., cancer causing)
and nononcogenic. Human papilloma virus infec-
tion gives rise to a wide range of usually benign
skin or squamous mucosal lesions. These include
plantar warts, flat warts, genital condyloma
acuminata and oral papillomas.
Human papilloma virus is typically transmitted
by direct contact with an infected lesion, for
example, squamous papillomas may arise as a
result of autoinoculation following biting of a
wart of the skin. Similarly, oral or genital condy-
loma may arise as a consequence of oral sex
(Beder Ribeiro et al. 2014). Nonsexual transmis-
sion via oral fluids or food utensils may account
for the acquisition of multifocal epithelial hyper-
plasia (see later).
Fig. 14 Pseudomembranous candidosis in HIV disease.
Erythematous plaque intermingled with white patch as a
clinical presentation of oral candidosis in a patient with Nononcogenic HPV Disease
HIV infection under ART
that can arise are dependent upon the stage of Squamous Papilloma and Related
disease, and the type of ART a patient may be Lesions
receiving (Patton 2016). The most common oral HPV lesion is squamous
The management of the underlying HIV infec- papilloma (SP). These manifest as small finger-like
tion is out of the spectrum of an oral medicine projections resulting in a lesion with a rough or
specialist, as is the management of the vast major- cauliflower-like surface (Fig. 15). HPV 6 and
ity of infections and tumors of HIV disease. HPV 11 are the most commonly isolated genotypes
Certainly however, all patients with known HIV in these lesions (Stojanov and Woo 2015). Condy-
should be given appropriate advice to prevent loma acuminata – warts possibly acquired sexually
common oral diseases such as caries, gingivitis, (e.g., via oral sex and possibly maternal transmis-
and periodontitis. They should also be encouraged sion) gives rise to similar lesions to those of SP
to consult a clinician if they develop unusual (Fig. 16). HPV types 2, 6, and 11 seem to be the
symptoms or signs (e.g., painful ulceration, more commonly isolated genotypes of condyloma
lumps in the mouth, or salivary gland swellings) acuminata. HPV 1 and 57 (sometimes also 6 and 11)
that persist for 2 or more weeks. Finally, all oral associated verucca vulgaris, often clinically indis-
health care workers should be aware of the com- tinguishable from SP and condyloma acuminata,
mon oral manifestations of HIV disease as these may also arise on the oral mucosa (Fig. 17).
may be the first and only manifestation of The diagnosis of HPV-related isolated warty-
unknown or undiagnosed HIV infection. like masses can be confirmed by histopathology
of lesional tissue (Figs. 18 and 19) with the viral
proteins being identified by immunohistochemi-
Human Papilloma Virus cal studies. Genotyping of the virus is possible,
but it is not a routine diagnostic investiga-
Human papilloma viruses (HPV) comprise a tion (Pinheiro et al. 2011).
group of DNA viruses of approximately 200 dif- Squamous papillomas of the oral mucosa
ferent sub-types. These viruses are classified require removal either via scalpel surgery or laser
according to their tissue tropism into surgery (Stojanov and Woo 2015) incorporating a
Table 1 Oral mucosal disease in HIV infection

Tissue Clinical presentation Disease
Oral mucosal Ulceration Herpes simplex
disease Herpes zoster
Cytomegalovirus
Mycobacterium tuberculosis
Mycobacteria other than tuberculosis (MOTT)
Treponema pallidum (e.g., lues maligna)
Gram negative bacterial infection
Toxoplasmosis
Aspergillosis
Erythema multiforme secondary to drug therapy
Kaposi’s sarcoma
Non-Hodgkin’s lymphoma
Recurrent oral ulceration of unknown cause
White patches Pseudomembranous candidosis
Chronic hyperplastic candidosis
Mucormycosis
Oral hairy leukoplakia
Condylomata (i.e., HPV infection)
Koilocytic dysplasia (probable HPV infection)
Pigmented lesions Addisonian pigmentation – secondary to adrenal cortex hypofunction
(e.g., by CMV, histoplasmosis, or mycobacteria) or drug therapy (e.g.,
ketoconazole)
Hypermelanotic pigmentation secondary to nucleoside reverse
transcriptase inhibitor therapy
Borrelia hanselae infection (Cat scratch disease)
Kaposi’s sarcoma
Gingival and Severe acute gingivitis
periodontal Acute necrotizing ulcerative gingivitis
disease Aggressive periodontitis (necrotizing periodontitis)
Salivary gland Salivary gland HIV salivary gland disease (i.e., BK virus infection)
disease enlargement due to: Parotid lymphadenopathy
Intra-glandular malignancy (e.g., non-Hodgkin’s lymphoma, Kaposi’s
sarcoma)
Acute suppurative sialadenitis
Sialolithiasis secondary to ART
Xerostomia due to: HIV salivary gland disease
Protease inhibitors or other drug therapy (e.g., anxiolytics and
antidepressants)
Altered sensation Dysgeusia (e.g., due to protease inhibitors)
Trigeminal neuropathy
Other cranial nerve anomalies
rim of normal mucosa in the excisional biopsy. A Multifocal Epithelial Hyperplasia

search for the possible source of the causative Multifocal epithelial hyperplasia (MEH), some-
virus is rarely helpful, but patients should be times termed Heck’s disease, gives rise to multiple
advised to have any other warts managed by soft, flat, or rounded elevated nodules and is prob-
appropriate specialists – and to avoid biting any ably the most clinically significant HPV disorder
existing ones that they may have on their skin. of the mouth (Fig. 20). The lesions develop in
Fig. 15 Squamous papilloma on the soft palate (Image

courtesy of Professor Camile Farah, Perth Oral Medicine &
Dental Sleep Centre, Perth WA, Australia)
Fig. 17 Verruca vulgaris on the buccal mucosa (Image

courtesy of Professor Camile Farah, Perth Oral Medicine &
Fig. 16 Notable HPV-induced condylomata of the upper
gingivae
early childhood, are asymptomatic, persist for Eskimos MEH may be more common in adults
several years, and regress spontaneously. The than in children (Said et al. 2013).
lesions of MEH occur exclusively on the oral Many HPV genotypes have been detected in
mucosa, being commonly located on the mucosa MEH lesions although types 13 and 32 are the
of the lower lip and the buccal mucosa (Said et al. most commonly associated types, representing
2013). Lesions can arise at other sites, but the 75–100% of the isolated HPV (Padayachee and
involvement of the floor of the mouth, soft palate, van Wyk 1991). The clustering of MEH in socio-
and oropharynx is unusual. economically deprived groups and ethnically
Multifocal epithelial hyperplasia is rare but related cohorts suggest that both acquired and
tends only to occur in certain ethnic and racial genetic factors may underlie transmission and
groups. It is particularly found among Inuit acquisition of causative HPV genotypes.
Indians resident in North, Central and South The diagnosis of MEH can usually be based
America, Eskimos from Greenland and North upon the clinical picture, sometimes aided by
Canada, and descendants of Khoi-San in South a review of the patient’s genetic background.
Africa. Multifocal epithelial hyperplasia is more Histopathology will confirm the presence of epi-
common in children and adolescents than in adults thelial proliferation typical of HPV and immuno-
in most examined populations, although in histochemistry of lesional tissue can identify
Fig. 18 Squamous papilloma at low magnification (a) courtesy of Professor Camile Farah, Perth Oral Medicine
and higher magnifciation (b) demonstrating fibrovascular & Dental Sleep Centre, Perth WA, Australia)
cores surrounded by benign squamous epithelium (Images
Fig. 19 Verruca vulgaris at low magnification (a) and Farah, Perth Oral Medicine & Dental Sleep Centre, Perth
higher magnificaiton (b) with clear koilocytes in upper WA, Australia)
epithelial layers (Images courtesy of Professor Camile
has climbed greatly in the past 30 years, in some

instances by 225%. The exact reason for this
change in the epidemiology of OPSCC is unclear.
The causative genotypes of HPV-related
OPSCC are HPV 16 and sometimes HPV 18. Of
note HPV 16 is the predominant genotype associ-
ated with cervical cancer of females and
anogenital cancers of males. It is suggested that
the HPV causing oropharyngeal malignancy has
been acquired sexually and may reflect numbers
of sexual partners (more than four may increase
the likelihood of malignancy), but there is no
Fig. 20 Multifocal epithelial hyperplasia presenting with
extensive labial involvement in a patient with HIV infection striking evidence that the virus is acquired via
orogenital or oroanal contact (despite both being
HPV-derived proteins. Genotyping may be possi- likely). The precise reason why HPV-related
ble but is not a routine investigation and not likely malignancy has emerged over the past three
to be helpful to the management of the disease. decades is unknown, but it does not seem to reflect
There is no specific management protocol for any change in the sexual lifestyle of individuals
MEH, although unsightly lesions and those that or populations. It is quite possible that HPV-
lessen oral function should be removed. Topical associated OPSCC is simply behaving like any
therapies such as imiquimod or interferon-2α may other sexually transmitted disease – the more an
be of some benefit, but there are no detailed stud- infection is within a population the greater the
ies of the precise efficacy for this disorder. It is chance that an individual will ultimately develop
however important to inform patients and their clinically detectable disease. In view of the nota-
carers that lesions usually spontaneously regress ble rise in the number of persons developing
with time and that the disease is not known to be HPV-related oral and pharyngeal cancer, it
potentially malignant (Said et al. 2013). would perhaps seem appropriate that vaccination
in both boys and girls against the oncogenic types
of HPV (particularly 16 and 18) be undertaken
Oncogenic HPV Disease across all populations. HPV-related oropharyn-
geal carcinoma is discussed in more detail in a
Oncogenic types of HPV are now recognized as a separate chapter on ▶ Head and Neck Tumors.
cause of some squamous cell carcinoma, particu-
larly of the posterior tongue, tonsillar area, and
upper pharynx. HPV-related oropharyngeal squa- Viral Infections of the Salivary Glands
mous cell carcinoma (OPSCC) seems to be a
distinct disease differing to head and neck carci- Mumps
nomas associated with tobacco and alcohol intake
(Sedghizadeh et al. 2016; Mazul et al. 2017). Mumps, sometimes known as epidemic parotitis,
Affected patients tend to be male, under 50 years is an acute self-limiting disease caused by the
of age and have no history of notable tobacco mumps virus – a member of the Rubulavirus
and/or alcohol use. Furthermore, the outcome of genus of RNA Paramyxoviruses. In view of the
treatment of HPV-related OPSCC is better (80% availability of an appropriate vaccine, the out-
survival at 5 years) compared with oropharyngeal breaks of disease are much less common than in
cancer due to alcohol and tobacco (40–50% 5-year the past. Prior to this, mumps was likely to arise as
survival rate). In the US, Finland, Sweden, Den- outbreaks in kindergartens and schools and thus
mark, Netherlands, UK, Canada, Australia, and clinical infection was most likely in 5–16-year-old
elsewhere, the incidence of HPV-positive OPSCC children. The virus is transmitted via the droplet
route with patients being infectious about 48 h suggested as useful, there are no supportive data
before the onset of the salivary gland swelling that systemic corticosteroids will reduce any pain-
and for a further 9–10 days. The infection has an ful salivary gland swelling.
incubation period of 15–21 days. Mumps is a preventable infection, with vacci-
Infected individuals develop an initial pyrexia nation being provided at the same time as that for
and malaise that is soon followed by swelling of measles and rubella. The clinical and economic
one or both parotid glands. The submandibular benefits of the mumps, measles, and rubella vac-
glands, and rarely the sublingual glands, can cination are unfortunately well illustrated by the
become swollen and together with cervical instance of non-immunized children and adults
lymphadenopathy can cause notable swelling of who have developed mumps-related neurological
the neck. Rarely sublingual gland enlargement disease necessitating hospitalization (Tyor and
can cause an elevation of the floor of the mouth Harrison 2014).
and tongue with resultant dysarthria and/or dys-
phagia (Wilson et al. 2014). All salivary gland
swelling diminishes after about 9 days. Of note, Hepatitis C Virus
but rare, there can be a reversible weakening of
the facial nerve in association with parotid Hepatitis C virus (HCV) is an RNA virus trans-
enlargement of mumps. mitted primarily by parenteral and sometimes via
Mumps can give rise to a multitude of systemic sexual (although not orogenital) or vertical routes.
manifestations. Orchitis (i.e., infection of the Persons who inject drugs (PWID) are at notable
testicles) can arise 4–5 days after the onset of risk of acquiring HCV.
parotid enlargement, causing local usually unilat- Unlike other hepatotropic viruses, HCV fre-
eral pain that resolves after a few days. Orchitis quently gives rise to a wide spectrum of extrahe-
tends to occur in postpubertal boys but is not a patic manifestations that include salivary gland
common cause of late infertility. A lymphocytic disease. Hepatitis C virus-associated salivary
or viral meningitis giving rise to headache and gland disease arises in as many as 80% of infected
photophobia can either arise in the absence of any patients (Sherman and Sherman 2015).
parotid enlargement or follow salivary gland swell- Xerostomia is the predominant symptom of
ing. Rarely mumps causes retrobulbar neuritis or HCV-associated salivary gland disease although
encephalitis. Deafness is a rare but possible com- patients may develop painless or painful swelling
plication of mumps. Mumps-associated pancreati- of one or both parotid glands (Fig. 21).
tis can cause transient upper abdominal pain while The histopathological features of HCV-
hepatic, breast, cardiac, or joint infections are pos- associated sialadenitis have similarities to those
sible. These are uncommon and not likely to give of Sjögren’s syndrome, there being lymphocytic
rise to long-term complications (Tyor and Harrison infiltrate of salivary tissue in both. However,
2014). Although rare now as a consequence of whereas the infiltrate is periductal in the latter, in
effective vaccination, mumps in the first trimester HCV sialadenitis it is pericapillary (Ko et al.
of pregnancy can lead to spontaneous abortion. 2012). In addition, there is a more dominant cyto-
The diagnosis of mumps is almost always toxic T cell infiltrate in HCV disease than in
based on the clinical picture. The detection of Sjögren’s syndrome. Nevertheless, the precise
mumps-specific IgM or IgA class antibodies pathogenesis of HCV-related salivary gland dis-
can provide confirmatory evidence of recent ease remains unclear, particularly as the presence
infection while viral culture from saliva, urine, of HCV RNA in saliva does not correlate with
or cerebrospinal fluid (CSF) is possible but it is clinical or histopathological evidence of salivary
rarely justified (Tyor and Harrison 2014). gland dysfunction.
There is no specific therapy for mumps. Treat- HCV infection may occasionally give rise to
ment is directed toward lessening any pain and/or non-Hodgkin’s lymphoma (usually low-grade B
pyrexia. Fluid intake should be maintained. While cell malignancies), indeed the salivary glands are a
infection and include HIV salivary gland disease

per se, bacterial sialadenitis, intraparotid lymph-
adenopathy, primary or metastatic non-Hodgkin’s
lymphoma, or Kaposi’s sarcoma. There have been
rare reports of sialolithiasis possibly secondary
to atazanavir (that has been linked to renal and
biliary lithiasis) (Lê et al. 2013), ranula formation
of the sublingual gland, and submandibular gland
swelling due to cytomegalovirus infection as
part of Immune Reconstitution Inflammatory
Syndrome (IRIS) (Sheikh et al. 2013).
HIV salivary gland disease is a distinct disor-
der characterized by recurrent and/or persistent
major salivary gland enlargement and xerostomia.
The parotid glands are most frequently affected,
there often being a profound bilateral enlargement
(Schiödt et al. 1992). Salivary gland disease tends
to arise in late HIV infection, although occasion-
ally can be the first manifestation of unknown
HIV infection. It is usually part of a more gener-
Fig. 21 Bilateral parotid gland enlargement in Hepatitis C
virus disease alized disorder termed Diffuse Infiltrative Lym-
phocytosis Syndrome (DILS) characterized by
CD8+ T cell infiltration of the lungs, salivary
common site of lymphoma in HCV-infected indi- glands, and lacrimal glands (Ghrenassia et al.
viduals with sicca-like symptoms (Sherman and 2015). There is increasing evidence that the sali-
Sherman 2015). There is however, no association vary gland inflammation is driven by infection
between HCV infection and the pathogenesis of with BK polyomavirus (BKV) and thus HIV sal-
Sjögren’s syndrome. Association between HCV ivary gland disease might be considered to be a
infection and the development of oral lichen planus virally driven opportunistic infection (Burger-
has been suggested for many years but at present Calderon and Webster-Cyriaque 2015).
there remains no substantial evidence that lichen There is little information regarding the spe-
planus is driven by HCV. Certainly, interferon cific management of HIV salivary gland disease
gamma therapy for HCV infection can cause the and associated cystic swellings. Clinical signs are
emergence of oral and cutaneous lichen planus. usually nonprogressive, and hence therapy is only
The management of HCV infection is out with indicated if there is notable cosmetic deformity or
the remit of the oral medicine specialist although xerostomia. Antiretroviral therapy may cause
the management of xerostomia should be similar some reduction in swelling, and while it has
to that of other causes of oral dryness and is cov- been suggested that ART will reduce the swelling
ered in great detail in the chapter on ▶ “Salivary of HIV salivary gland disease, there is some evi-
Gland Disorders and Diseases.” dence that protease inhibitors of ART may
increase swelling (sometimes as a consequence
of fat accumulation within the gland) and lessen
HIV Salivary Gland Disease salivary secretion (Syebele 2010; Ghrenassia et al.
2015). Other therapies that have been suggested
Salivary gland manifestations can arise in up to include repeated aspiration, tetracycline sclerosis,
10% of adults and children with untreated HIV or surgical removal of the enlarged gland. Exter-
infection (Rath et al. 2015). A variety of lesions nal radiation (e.g., 8–10Gy) can cause transient
can underlie the salivary gland disease of HIV improvement, although higher doses (e.g., 24Gy)
can cause resolution of swelling for at least several asymptomatic red appearance. Severe cases may
years – without causing severe xerostomia. present cervical lymph node enlargement and high
fever, and viral pneumonia is an uncommon but
severe complication of the infection. Considering
Seasonal Viral Infections its high transmissibility, dental practices may
become a place of spreading the disease, so good
Influenza, commonly known as flu, is usually a clinical practice should include avoiding regular
benign and self-limiting viral febrile disease care of infected individuals, and urgent dental
caused by a RNA virus, Myxovirus influenzae. attention should be provided under rigorous bio-
Symptoms often present an acute onset and safety measures. On the other hand, dental units
include fever, headaches, myalgia, anorexia, shiv- have an important role in disseminating health-
ering, and chills, as well as respiratory symptoms related information to patients outside the realm
such as cough, sore throat, and coryza. Disease of oral health (Glick 2009).
usually lasts for 7 days, fever being usually the
most significant symptom.
There are three main types of influenza Emerging Viral Infections
virus: A, B, and C. Influenza C virus is associated
with mild respiratory symptoms and is not asso- Just as the incidence of some infections has or will
ciated with epidemics. The influenza A and B lessen as a consequence of vaccines and antiviral
virus are associated with seasonal outbreaks, and therapies, so will new viral infections continue to
the later can eventually cause major pandemics emerge, some of which can have implications for
(SteelFisher et al. 2010). The influenza A virus oral health and/or oral health care. Similarly, some
presents with high variability and can be classified infections that were previously localized to certain
according to surface proteins hemagglutinin geographical regions will spread across the globe
and neuraminidase; the subtypes A(H1N1) and as a consequence of migration and/or travel. For
A(H3N2) are currently more common in humans. example, the Ebola virus, an RNA filovirus easily
The virus replicates in the epithelial columnar transmitted nonsexually, principally infected per-
cells of the respiratory tract, mix with respiratory sons from certain African countries but there have
secretions and spread into small aerosol particles been instances of this arising in individuals who
generated during talking, coughing, and sneezing, have travelled out of these areas. This disorder
so one infected individual may transmit the virus (Ebola Virus Disease; EVD) causes sudden onset
to several other people. In addition, the influenza of high fever, headache, anorexia, nausea, abdom-
viruses present a significantly elevated variability, inal pain, and later hemorrhagic disease – includ-
which turn them into a unique cause of recurrent ing spontaneous gingival bleeding (Scully and
annual epidemics, and eventually, pandemics. Samaranayake 2016). Similarly, the RNA Zika
Because of this variability, previous exposition Virus (ZIKV), transmitted by the female genre
to one virus does not offer protection to a new of the Aedes mosquito, was initially described in
viral challenge. the Ugandan Zika forest in Africa but there have
Clinically, the disease presents with an acute been recent outbreaks in Micronesia and Brazil,
onset fever, usually above 38 C (100.4 F)., fol- with affected persons being reported in the USA.
lowing myalgia, sore throat, fatigue, headache, and This infection, among other features, can give rise
cough. Fever usually lasts for 3 days and is to Guillain Barre-like disease that may affect
followed by respiratory symptoms, such as dry facial motor function as well as microcephaly as
throat, hoarseness, and retrosternal burning when a consequence of in utero acquisition of the virus
coughing. Furthermore, red eyes, tearing, and (Ioos et al. 2014, Leão et al. 2017). Finally, the
widespread redness of the mucosa are observed, Chikungunya virus (CHIKV), an RNA alphavirus
together with nasal secretion. The mouth is of the Togavirus family that originated from
also involved, presenting with a diffuse and Africa, has infected persons in Asia and South
America and has been reported to give rise to oral several countries, and oral involvement is yet not
ulceration, gingival inflammation, and oral muco- adequately recognized. There is ongoing research
sal pigmentation (Pialoux et al. 2007; Nasci 2014; aiming to determine if a less intense treatment is
Scully and Samaranayake 2016). A detailed dis- an adequate strategy for HPV+ head and neck
cussion of each of these infections is beyond the cancer. However, the management strategies for
scope of this chapter, but they are reminders that viral infections in severely immunosuppressed
infection is ever changing and that all health care individuals should also be a focus of clinical
workers should attempt to maintain an under- training and research efforts.
standing of how infection may impact upon the
clinical care of patients.
Cross-References
Conclusions and Future Directions ▶ Clinical Evaluation of Oral Diseases
▶ Clinical Immunology in Diagnoses of Maxillo-
Viral infections are common causes of oral illness facial Disease
that can affect persons of all ages. Common infec- ▶ Cutaneous Pathology of the Head and Neck
tions such as herpes simplex and coxsackie ▶ Head and Neck Tumors
viruses usually give rise to nonlife threatening ▶ Laboratory Medicine and Diagnostic Pathology
acute illness, often localized to the mouth. How- ▶ Non-odontogenic Bone Pathology
ever, immunosuppression can greatly increase the ▶ Oral and Maxillofacial Fungal Infections
risk of severe orofacial viral infection (e.g., vari- ▶ Oral Lichen Planus
cella zoster) and possibly life changing (e.g., ▶ Oral Manifestations of Systemic Diseases and
CMV retinitis) or fatal disease (e.g., HHV-8 asso- Their Treatments
ciated Kaposi’s sarcoma). Prompt recognition of ▶ Oral Mucosal Malignancies
the clinical features of possible viral infection can ▶ Oral Ulcerative Lesions
greatly reduce disease morbidity or mortality. ▶ Oral Vesicular and Bullous Lesions
The risk of some viral infections may be ▶ Pediatric Oral Medicine
influenced by ethnicity and/or socioeconomic sta- ▶ Pharmacotherapeutic Approaches in Oral
tus (e.g., MEH), lifestyle factors such as injecting Medicine
drug use (e.g., HCV and HIV disease) or sexual ▶ Salivary Gland Disorders and Diseases
activity (e.g., HPV, HIV, and perhaps HCV) and ▶ White and Red Lesions of the Oral Mucosa
immunocompetency hence a review of the social
and medical histories of people with suspected
viral infection can be diagnostically helpful. The References
treatment of viral infections continues to improve
thanks to the availability of a widening range of Anjos KS, Ferreira MME, Arruda MC, Ramos KS,
antiviral agents, although over -prescribing of Magalhães AP. Epidemiological characterization of var-
icella cases in patients of a university hospital located in
such agents will undoubtedly increase the spread Recife. Rev Bras Epidemiol. 2009;12(4):523–32.
emergence and spread of antiviral resistant Arduino PG, Porter SR. Herpes simplex virus type 1 infec-
infections. Similarly, while vaccines for viral tion: overview on relevant clinico-pathological fea-
infections continue to become available (e.g., tures. J Oral Pathol Med. 2008;37(2):107–21.
Aswathyraj S, Arunkumar G, Alidjinou EK, Hober D.
varicella zoster and oncogenic types of HPV) Hand, foot and mouth disease (HFMD): emerging epi-
there remains no vaccines for HIV or HCV demiology and the need for a vaccine strategy. Med
and any fall in publicly funded immunization Microbiol Immunol. 2016;205:397–407.
programs can lead to the re-emergence of Beder Ribeiro CM, Ferrer I, Santos de Farias AB,
Fonseca DD, Morais Silva IH, Monteiro Gueiros LA,
life-threatening (preventable) infections (e.g., Carvalho AT, Porter SR, Leao JC. Oral and genital HPV
mumps). Lastly, several emerging viral diseases genotypic concordance between sexual partners. Clin
represent a significant public health problem in Oral Investig. 2014;18(1):261–8.
Burger-Calderon R, Webster-Cyriaque J. Human BK Luzuriaga K, Sullivan JL. Infectious mononucleosis.

polyomavirus-the potential for head and neck malig- N Engl J Med. 2010;362(21):1993–2000.
nancy and disease. Cancers (Basel). 2015;7(3):1244–70. Mainville GN, Marsh WL, Allen CM. Oral ulceration
Cannon MJ, Davis KF. Washing our hands of the congen- associated with concurrent herpes simplex virus, cyto-
ital cytomegalovirus disease epidemic. BMC Public megalovirus, and Epstein-Barr virus infection in an
Health. 2005;5:70. immunocompromised patient. Oral Surg Oral Med
Clarkson E, Mashkoor F, Abdulateef S. Oral viral infec- Oral Pathol Oral Radiol. 2015;119:e306–14.
tions. Diagn Manag Dent Clin N Am. 2017;61:351–63. Mazul AL, Taylor JM, Divaris K, Weissler MC, Brennan P,
Cohen JI. Epstein–Barr virus infection. N Engl J Med. Anantharaman D, Abedi-Ardekani B, Olshan AF,
2000;343:481–92. Zevallos JP. Oral health and human papillomavirus-
Cunningham AL, Diefenbach RJ, Miranda-Sakesena M. associated head and neck squamous cell carcinoma.
The cycle of human herpes simplex virus infection: Cancer. 2017;123(1):71–80.
virus transport and immune control. J Infect Dis. Mell HK. Management of oral and genital herpes in the
2006;194(1):11–8. emergency department. Emerg Med Clin North Am.
Elad S, Zadik Y, Hewson I, Hovan A, Correa ME, Logan R, 2008;26:457–73.
Elting LS, Spijkervet FK, Brennan MT. A systematic Nasci RS. Movement of chikungunya virus into the west-
review of viral infections associated with oral involve- ern hemisphere. Emerg Infect Dis. 2014;20:1394–5.
ment in cancer patients: a spotlight on Herpesviridea. Northfield JW, Harcourt G, Lucas M, Klenerman P. Immu-
Support Care Cancer. 2010;18(8):993–1006. nology of viral co-infections with HIV. Arch Immunol
Fatahzadeh M, Schwartz RA. Human herpes simplex Ther Exp. 2005;53(1):3–12.
labialis. Clin Exp Dermatol. 2007;32(6):625–30. Odumade OA, Hogquist KA, Balfour HH Jr. Progress
Fatahzadeh M, Schwartz RA. Oral Kaposi’s sarcoma: a and problems in understanding and managing primary
review and update. Int J Dermatol. 2013;52:666–72. Epstein-Barr virus infections. Clin Microbiol Rev.
Ficarra G. Oral ulcers in HIV-infected patients: an update 2011;24(1):193–209.
on epidemiology and diagnosis. Oral Dis. 1997;3 Oliveira JL, Freitas RT, Arcuri LJ, Gomes AP. Epstein-Barr
(Suppl 1):S183–9. virus and infectious mononucleosis. Rev Bras Clin
Ghrenassia E, Martis N, Boyer J, Burel-Vandenbos F, Med. 2012;10(6):535–43.
Mekinian A, Coppo P. The diffuse infiltrative lympho- Padayachee A, van Wyk CW. Human papillomavirus
cytosis syndrome (DILS). A comprehensive review. (HPV) DNA in focal epithelial hyperplasia by in situ
J Autoimmun. 2015;59:19–25. hybridization. J Oral Pathol Med. 1991;20:210–4.
Glick M. Do dentists have a role in fighting the latest H1N1 Patel N, Snyder LD, Finlen-Copeland A, Palmer SM.
pandemic? J Am Dent Assoc. 2009;140:1072–4. Is prevention the best treatment? CMV after lung trans-
Grahn A, Studahl M. Varicella-zoster virus infections of plantation. Am J Transplant. 2012;12:539–44.
the central nervous system – prognosis, diagnostics and Patton LL. Current strategies for prevention of oral mani-
treatment. J Infect. 2015;71(3):281–93. festations of human immunodeficiency virus. Oral Surg
Ioos S, Mallet HP, Leparc Goffart I, Gauthier V, Cardoso T, Oral Med Oral Pathol Oral Radiol. 2016;121(1):29–38.
Herida M. Current Zika virus epidemiology and recent Patton LL, Ramirez-Amador V, Anaya-Saavedra G,
epidemics. Med Mal Infect. 2014;44:302–7. Nittayananta W, Carrozzo M, Ranganathan K. Urban
Ko HM, Hernandez-Prera JC, Zhu H, Dikman SH, legends series: oral manifestations of HIV infection.
Sidhu HK, Ward SC, Thung SN. Morphologic features Oral Dis. 2013;19:533–50.
of extrahepatic manifestations of hepatitis C virus Pialoux G, et al. Chikungunya, an epidemic arbovirosis.
infection. Clin Dev Immunol. 2012;2012:1. 740138 Lancet Infect Dis. 2007;7(5):319–27.
Korostil IA, Regan DG. Varicella-zoster virus in Perth, Pinheiro R, França TT, Ribeiro CM, Leão JC, de Souza IP,
Western Australia: seasonality and reactivation. PLoS Castro GF. Oral manifestations in human immunodefi-
One. 2016;11(3):1–13. ciency virus infected children in highly active antire-
Lê MP, Stitou H, Soulie C, Katlama C, Peytavin G. troviral therapy era. J Oral Pathol Med. 2009;38(8):
Sialolithiasis in an HIV-1-infected patient treated 613–22.
with atazanavir/ritonavir monotherapy. J Antimicrob Pinheiro R, de França TR, Ferreira D de C, Ribeiro CM,
Chemother. 2013;68(3):727–9. Leão JC, Castro GF. Human papillomavirus in the oral
Leão JC, Caterino-De-Araújo A, Porter SR, Scully C. cavity of children. J Oral Pathol Med. 2011;40(2):121–6.
Human herpesvirus 8 (HHV-8) and the Portella AVT, Souza LCB, Gomens JMA. Herpes-zoster and
etiopathogenesis of Kaposi’s sarcoma. Rev Hosp Clin post-herpetic neuralgia. Rev Dor. 2013;14(3):210–5.
Fac Med Sao Paulo. 2002;57:175–86. Puenpa J, Mauleekoonphairoj J, Linsuwanon P,
Leão JC, Gueiros LA, Lodi G, Robinson NA, Scully C. Suwannakarn K, Chieochansin T, Korkong S,
Zika virus: oral healthcare implications. Oral Dis. Theamboonlers A, Poovorawan Y. Prevalence and
2017;23:12–7. characterization of enterovirus infections among pedi-
Lopes MA, de Souza Filho FJ, Jorge Júnior J, atric patients with hand foot mouth disease, herpangina
de Almeida OP. Herpes zoster infection as a differential and influenza like illness in Thailand, 2012. PLoS One.
diagnosis of acute pulpitis. J Endod. 1998;24:143–4. 2014;9(6):e98888.
Rath IB, Beltrame AP, Carvalho AP, Schaeffer MB, Solomon T, Lewthwaite P, Perera D, Cardosa MJ,
Almeida IC. HIV-associated salivary gland disease– McMinn P, Ooi MH. Virology, epidemiology, patho-
clinical or imaging diagnosis? Int J Paediatr Dent. genesis, and control of enterovirus 71. Lancet Infect
2015;25(4):233–8. Dis. 2010;10:778–90.
Said AK, Leao JC, Fedele S, Porter SR. Focal epithelial SteelFisher GK, Blendon RJ, Bekheit MM, Lubell K. The
hyperplasia – an update. J Oral Pathol Med. public’s response to the 2009 H1N1 influenza pan-
2013;42(6):435–42. demic. N Engl J Med. 2010;362:e65.
Sauerbrei A. Diagnosis, antiviral therapy, and prophylaxis Steigman AJ, Lipton MM, Braspennickx H. Acute
of varicella-zoster virus infections. Eur J Clin Micro- lymphonodular pharyngitis: a newly described condi-
biol Infect Dis. 2016;35(5):723–34. tion due to Coxsackie A virus. J Pediatr.
Schiödt M, Dodd CL, Greenspan D, Daniels TE, 1962;61:331–6.
Chernof D, Hollander H, Wara D, Greenspan JS. Nat- Stojanov IJ, Woo SB. Human papillomavirus and Epstein-
ural history of HIV-associated salivary gland disease. Barr virus associated conditions of the oral mucosa.
Oral Surg Oral Med Oral Pathol. 1992;74:326–31. Semin Diagn Pathol. 2015;32(1):3–11.
Schneider JW, Dittmer DP. Diagnosis and treatment of Kaposi Syebele K. Regression of both oral mucocele and parotid
sarcoma. Am J Clin Dermatol. 2017;18:529. in press swellings, following antiretroviral therapy. Int J Pediatr
Scott LA, Stone MS. Viral exanthems. Dermatol Online J. Otorhinolaryngol. 2010;74(1):89–92.
2003;9:4. Torres R, Cottrell D, Reebye UN. Ulcerative tongue lesion
Scully C, Samaranayake LP. Emerging and changing secondary to cytomegalovirus. J Mass Dent Soc.
viral diseases in the new millennium. Oral Dis. 2004;53(3):36–7.
2016;22(3):171–9. Tyor W, Harrison T. Mumps and rubella. Handb Clin
Sedghizadeh PP, Billington WD, Paxton D, Ebeed R, Neurol. 2014;123:591–600.
Mahabady S, Clark GT, Enciso R. Is p16-positive oro- Werner RN, Nikkels AF, Marinović B, Schäfer M,
pharyngeal squamous cell carcinoma associated with Czarnecka-Operacz M, Agius AM, Bata-Csörgő Z,
favorable prognosis? A systematic review and meta- Breuer J, Girolomoni G, Gross GE, Langan S, Lapid-
analysis. Oral Oncol. 2016;54:15–27. Gortzak R, Lesser TH, Pleyer U, Sellner J, Verjans GM,
Sheikh V, Caplan M, Wilson EM, Papadi B, Rosenberg AZ, Wutzler P, Dressler C, Erdmann R, Rosumeck S,
Higgins J, Driscoll B, Filie AC, Sereti I. Cytomegalo- Nast A. European consensus-based (S2k) guideline on
virus immune reconstitution inflammatory syndrome the Management of Herpes Zoster – guided by the
manifesting as sialadenitis in an HIV-infected patient. European dermatology forum (EDF) in cooperation
AIDS. 2013;27(11):1833–5. with the European academy of dermatology and
Sherman AC, Sherman KE. Extrahepatic manifestations venereology (EADV), Part 2: treatment. J Eur Acad
of hepatitis C infection: navigating CHASM. Curr Dermatol Venereol. 2016;31:20. https://doi.org/10.11
HIV/AIDS Rep. 2015;12(3):353–61. 11/jdv.13957.
Shin JU, Oh SH, Lee JH. A case of hand-foot-mouth Wilson KF, Meier JD, Ward PD. Salivary gland disorders.
disease in an immunocompetent adult. Ann Dermatol. Am Fam Physician. 2014;89(11):882–8.
2010;22(2):216–8.
Oral Ulcerative Lesions
Giovanni Lodi, Elena Varoni, Jairo Robledo-Sierra,

Alessandro Villa, and Mats Jontell
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1010
Ulcerative Lesions of the Mouth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1013
Reactive Ulcerative Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1013
Immunological Ulcerative Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1014
Infective Ulcerative Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1015
Neoplastic Ulcerative Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1015
Recurrent Aphthous Stomatitis (RAS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1015
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1016
Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1017
Diagnosis and Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1018
Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1019
Aphthous Stomatitis Associated with Systemic Conditions . . . . . . . . . . . . . . . . . . . . . . . 1021
Gastrointestinal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1021
Behçet Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1028
Food Allergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1031
G. Lodi (*) · E. Varoni

Dipartimento di Scienze Biomediche, Chirurgiche e
Odontoiatriche, Università degli Studi di Milano, Milan,
Italy
e-mail: giovanni.lodi@unimi.it; elena.varoni@unimi.it
J. Robledo-Sierra · M. Jontell
Department of Oral Medicine and Pathology, Sahlgrenska
Academy, University of Gothenburg, Gothenburg, Sweden
e-mail: jairo.robledo@odontologi.gu.se;
robledosierra@gmail.com; mats.jontell@odontologi.gu.se
A. Villa
e-mail: avilla@bwh.harvard.edu; avilla@partners.org

https://doi.org/10.1007/978-3-319-72303-7_12
1010 G. Lodi et al.
Recurrent Aphthous Stomatitis and Micronutrient Deficiency . . . . . . . . . . . . . . . . . . . 1033

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1037
Abstract Keywords
Ulcers are the most common lesions affecting Oral ulcer · Oral ulcerative disease · Oral
the oral mucosa, and they can be ascribed to ulcerative conditions · Recurrent aphthous
a plethora of local or systemic conditions, ulceration · Recurrent aphthous stomatitis ·
making differential diagnosis pivotal and Aphthous-like ulcers · Crohn’s disease · Celiac
often difficult. As oral ulcers dŁ can be a man- disease · Inflammatory bowel disease · Behçet
ifestation of local or systemic conditions of syndrome · Food allergy · Micronutrient
very different nature and severity, including deficiency
trauma (mechanical, chemical, thermal), drug
reactions, immune-mediated diseases, infec-
tions, and neoplasms; a careful differential Introduction
diagnosis is mandatory. Recurrent aphthous
stomatitis (RAS) is the most frequent ulcera- An ulcer of the mouth results from the complete
tive disorder of the oral cavity, affecting 10–20% loss of epithelium which exposes the underlying
of the general population. RAS lesions typically connective tissues. When the loss is limited to the
present as round or oval shallow ulcers of the epithelial layers, the term erosion is preferred,
nonkeratinized mucosa, with a yellow-grayish although such distinction can be difficult on the
fibrin pseudomembrane and a characteristic basis of clinical investigation only.
erythematous halo. They usually appear first As indicated by a number of epidemiological
in childhood or adolescence, in subjects without studies (Axéll 1976; Carrard et al. 2011; García-
other systemic signs. RAS may present in four Pola Vallejo et al. 2002; Pentenero et al. 2008;
main forms based on its clinical appearance Shulman et al. 2004), ulcerations are among the
(minor, major, herpetiform, and severe), and most common lesions affecting the oral mucosa.
its management depends on the frequency and This is probably due to the fact that not only do
severity of the lesions. RAS episodes are self- many of the most common oral conditions present
limiting and in most cases do not need treat- as ulcerative lesions (see other chapters on
ment. For severe and painful cases, the aim of ▶ “Oral Lichen Planus,” ▶ “Oral Vesicular and
therapy is to control pain and to reduce the Bullous Lesions,” and ▶ “Oral and Maxillofacial
frequency of episodes. Topical corticosteroids Viral Infections”) but also that an ulcer can be the
are typically first-line treatment, but they do not manifestation of a large number of local and sys-
affect the rate of recurrence. Less frequently, temic conditions, including viral, bacterial,
aphthous stomatitis can be associated with a parasite and fungal infections, immune-mediated
number of systemic conditions, including gas- diseases, neoplasms, hematological disorders,
trointestinal disorders, in particular inflamma- trauma (mechanical, chemical, thermal), and
tory bowel diseases and celiac disease, Behçet drug reactions (Table 1). In addition, an ulcerative
syndrome, food allergy, and deficiencies of lesion can result from different processes and
micronutrients, mainly vitamin B12, folate, fer- etiopathogenic mechanisms, such as bullae or
ritin, and iron. In all these cases, the detection vesicle formation and rupture, external forces,
of oral lesions can lead to an early diagnosis host-related factors, or alteration of epithelial pro-
of the underlying condition, the management of liferation and differentiation (Fig. 1). Thus, differ-
which requires a multi-specialist approach. ential diagnosis of an oral ulcer is a key skill in
Oral Ulcerative Lesions 1011
Table 1 Causes of oral ulcers (Modified from Scully and Table 1 (continued)
Felix 2005)
Gastrointestinal disease
Local causes Celiac disease
Trauma Crohn’s disease
Oral appliances Ulcerative colitis
Iatrogenic Miscellaneous uncommon diseases
Non-accidental injury Eosinophilic ulcer
Self-inflicted Giant cell arteritis
Sharp teeth or restorations Hypereosinophilic syndrome
Burns Lupus erythematosus
Chemical Necrotizing sialometaplasia
Cold Periarteritis nodosa
Electric Reiter’s syndrome
Heat Sweet’s syndrome
Radiation Wegener’s granulomatosis
Recurrent aphthae
Infections
Acute necrotizing gingivitis
oral medicine practice, since similar lesions can
Chickenpox
have a deeply different impact on the well-being
Deep mycoses
Hand, foot, and mouth disease
of patients, and a misdiagnosis can bring very
Herpangina serious consequences. This is the case with a
Herpetic stomatitis chronic traumatic ulcer of the tongue, a very com-
HIV mon lesion that can share a number of features
Infectious mononucleosis with a squamous cell carcinoma of the same site,
Syphilis as they are both long-lasting, pauci-symptomatic,
Tuberculosis indurated, single lesions (Fig. 2). While the
Drugs first resolves spontaneously once the traumatic
Cytotoxic drugs cause has been removed, the latter is potentially
Nicorandil, NSAIDs lethal (see chapters on ▶ “White and Red Lesions
Many others of the Oral Mucosa” and ▶ “Oral Mucosal
Malignant neoplasms Malignancies”).
Oral Although histological examination and spe-
Encroaching from antrum cific laboratory tests are often mandatory, a careful
Systemic disease
clinical examination, associated with thorough
Mucocutaneous disease
history taking, can provide insights into the nature
Behçet syndrome
of an oral ulcer. Important clinical features in
Chronic ulcerative stomatitis
investigating a patient affected by ulcer(s) of the
Epidermolysis bullosa
Erythema multiforme
mouth range from:
Lichen planus
Pemphigus vulgaris • Number of lesions, single as for oral cancer or
Subepithelial immune blistering diseases (pemphigoid multiple as for herpetic infection
and variants, dermatitis herpetiformis, linear IgA disease)
• Specific localization, as for aphthae which pre-
Hematological disorders
fer nonkeratinized mucosa or chronic trau-
Anemia
matic ulcer, in relation with a scabrous or
Gammopathies
rough surface
Hematinic deficiencies
Leukemia and myelodysplastic syndrome
• Duration, with a recent onset typical of acute
Neutropenia and other white cell dyscrasias conditions, or extensive length for chronic
(continued) lesions, including oral cancer
1012 G. Lodi et al.
Normal mucous membrane
Epithelium
Lamina propria
a b c d
Mucosal ulcer
Complete breach of epithelium
Fig. 1 Mechanisms leading to the formation of a muco- of different origin affecting the mucosa, and (d) distur-
sal ulcer. Oral ulcers can be the result of (a) external bances of epithelial proliferation and differentiation,
trauma of different nature (mechanical, thermal, chemi- leading to architectural abnormalities of the mucosa
cal, radiant), (b) inflammatory processes leading to atro- (Original drawing by Dr Hala Al Janaby, Perth WA,
phy of the mucosal lining, (c) rupture of vesicles or bullae Australia)
Fig. 2 Two persistent lesions of different nature: a chronic traumatic ulcer (a) and an oral squamous cell carcinoma (b)
(i) Traumatic ulcer

Acute solitary ulcers (ii) Necrotizing sialometaplasia
Acute ulcers
Acute multiple ulcers (i) Primary herpetic gingivostomatitis

(ii) Varicella-Zoster Virus infection
(iii) Herpangina
(i) Long-standing traumatic ulcers (iv) Hand-foot-and-mouth disease
(ii) Necrotizing sialometaplasia (v) Erythema multiforme
(iii) Eosinophilic ulcer (vi) Necrotizing ulcerative gingivitis
Chronic solitary ulcers (iv) Ulcerative squamous cell carcinoma (vii) Oral hypersentivity reactions
(v) Cytomegalovirus-associated ulceration (viii) Plasma cell gingivostomatitis
(vi) Tuberculous ulcer (ix) Chemotherapy-related ulcers
Oral Ulcers Chronic ulcers (vii) Syphilitic ulceration (chancre)
(viii) Deep fungal ulceration
(Histoplasmosis, Blastomycosis, and
Mucormycosis)
(i) Pemphigus vulgaris

(ii) Mucous membrane pemphigoid
Chronic multiple ulcers (iii) Bullous pemphigoid
(iv) Lichen planus
(v) Linear IgA disease
(i) Recurrent aphthous stomatitis

Recurrent ulcers Solitary/multiple ulcers (ii) Recurrent herpes stomatitis
(iii) Herpes-associated erythema multiforme
(iv) Cyclic neutropenia
(v) Behçet’s disease
Fig. 3 Diagnostic flowchart for oral ulcerative lesions (Mortazavi et al. 2016)
• Presence of a blister preceding the ulcer,

a feature of immune-mediated conditions Ulcerative Lesions of the Mouth
(bulla) or viral infection (vesicle)
• Presence of other mucosal changes, as for oral Reactive Ulcerative Conditions
lichen planus, which ulcers are always associ-
ated with other manifestations of the disease, Reactive oral ulcerations are those resulting from
and extraoral signs, as for mucocutaneous con- trauma affecting the mucosal lining of the mouth
ditions with frequent skin involvement (i.e., and represent a large group of conditions of dif-
pemphigus, erythema multiforme) ferent origin and nature, including self-inflicted
lesions, iatrogenic disorders, and drug-related
adverse effects. Reactive oral ulcerations are diag-
In addition, some conditions allow a diagnosis nosed on the basis of clinical presentation, history,
based on pattern recognition (Sackett et al. 1991), and identification of the trauma responsible, and
which is based on a very distinctive presentation they resolve spontaneously once the causative
of lesions. This is the case of recurrent aphthous factor has been identified and removed.
stomatitis, probably the most common ulcerative Mechanical trauma, mostly chronic, can result
condition affecting the oral mucosa (Fig. 3) from sharp margins of teeth or a prosthesis, an
(Mortazavi et al. 2016). incongruous denture flange, or self-biting, including
1014 G. Lodi et al.
Fig. 4 Self-inflicted ulcer of the tongue in a child (a) and teenager (b) with psychiatric disorders
factitious injuries, which are more common

in subjects with psychological or psychiatric prob-
lems (Fig. 4). Thermal lesions are also common; in
most cases they are the consequence of contact of
the oral mucosa, especially of the palate, with par-
ticularly hot drinks or solid food, particularly when
heated in a microwave oven (Cowan et al. 2013).
The so-called pizza burn is the most typical lesion of
this kind (Nahlieli et al. 1999). Chemicals can also
cause oral ulceration. Caustic agents, either acidic or
alkaline, responsible for damage of the oral mucosa
include dental materials (hydrogen peroxide or
Fig. 5 Tongue ulceration as an adverse effect to heart
whitening gels), local or systemic medications arrhythmia medication (sotalol) (Image courtesy of Profes-
such as aspirin, bisphosphonates, antipsychotic sor Camile Farah, Perth Oral Medicine and Dental Sleep
drugs, antihypertensive medications, mouthwashes, Centre, Perth WA, Australia)
recreational drugs, and non-pharmaceutical sub-
stances (hair products, battery acid) (Figs. 5 and 6)
(Gilvetti 2010). Exposure to ionizing radiation for
the treatment of head and neck cancer almost invari-
ably leads to mucositis, a diffuse and painful ulcer-
ation of the oral mucosa (Fig. 7).
Immunological Ulcerative Conditions
Immunological conditions affecting the oral

mucosa are a group of diseases which are
common causes of oral ulcerations, comprising
aphthous stomatitis, oral lichen planus, mucous
membrane pemphigoid, pemphigus vulgaris,
erythema multiforme, lupus erythematosus, and
other less common disorders. Although ulcers
can be a distinctive feature, they are never, with Fig. 6 Chemical burn on buccal mucosa caused by local
the exception of aphthous stomatitis, the only application of aspirin tablets
particular herpes simplex virus 1 and 2

(or HHV1 and HHV2) and varicella zoster virus
(or HHV3), are the most common causes of infec-
tive ulcers of the mouth. Herpes simplex infection
of the oral mucosa, either primary or recurrent,
presents with oral ulcerations which, although
different in severity and extension, have some
characteristic features which allow a clinical diag-
nosis in most cases (Balasubramaniam et al.
2014). These ulcers appear as small (few millime-
ters) shallow round lesions, originating from ves-
icles, surrounded by an erythematous halo, which
Fig. 7 Mucositis in a patient undergoing head and neck
radiotherapy can coalesce to form larger and irregular ulcers
(Fig. 8). Often painful, they have a predilection for
sign of the disease but part of a more complex keratinized surfaces, although they can affect any
picture, which can comprise other oral manifesta- oral mucosa. Secondary infection of varicella zos-
tions, such as white striae in oral lichen planus ter virus, which is less common and often associ-
(Alrashdan et al. 2016) and lupus erythematosus ated with immunocompromised status, causes
(Brennan et al. 2005), blisters in pemphigoid and similar lesions, often with a unilateral distribution.
pemphigus (McMillan et al. 2015; Taylor et al. Although less common, bacterial and mycotic
2015), lip crusting in erythema multiforme infections can also cause ulcerative lesions of
(Samim et al. 2013), and desquamative gingivitis the mouth. Among them the most common
(Lo Russo et al. 2008) in most of the aforemen- causal agents are Treponema pallidum (syphilis),
tioned conditions. Additionally, extraoral signs Toxoplasma gondii (toxoplasmosis), Mycobacte-
can be part of the clinical presentation of immu- rium tuberculosis (tuberculosis), and Neisseria
nological conditions causing oral ulcers, and often gonorrhoeae (see chapters on ▶ “Oral and Maxillo-
they are a key feature of differential diagnosis. In facial Fungal Infections” and ▶ “Non-odontogenic
particular, cutaneous lesions can be pathogno- Bacterial Infections” for more detail).
monic as in the case of target lesions in erythema
multiforme or strongly suggestive as in papulae
for lichen planus or blisters in pemphigus vulgaris Neoplastic Ulcerative Conditions
(Fig. 8). More detailed discussion around these
conditions can be found in chapters on ▶ “Oral A single, indurated ulcer is a common presentation
Lichen Planus,” ▶ “Oral Vesicular and Bullous of oral cancer and must be carefully differentiated
Lesions,” and ▶ “Oral and Maxillofacial Viral from traumatic or bacterial ulcers. Oral squamous
Infections,” ▶ “White and Red Lesions of the cell carcinoma represents more than 90% of can-
Oral Mucosa” and ▶ “Oral Manifestations of Sys- cer of the mouth (Chi et al. 2015); however a range
temic Diseases and Their Treatments.” of other malignancies of the oral cavity may also
present as ulcers, including neoplasms of the sal-
ivary glands, hematologic malignancies, meta-
Infective Ulcerative Conditions static neoplasms, and Kaposi sarcoma (Fig. 9).
Many infections of the oral mucosa, either viral,

bacterial, or mycotic, can present as ulcerative Recurrent Aphthous Stomatitis (RAS)
conditions affecting the oral cavity.
Among viral infections, those caused by Recurrent aphthous stomatitis (RAS), or “canker
some of the human herpesviruses (HHV), the sores,” is a common oral mucosal disease affect-
Herpesviridae known to infect humans, in ing 10–20% of the general population. It is
1016 G. Lodi et al.
Fig. 8 Immunological ulcerative conditions. (a) Lichen planus, (b) pemphigus vulgaris, (c) mucous membrane
pemphigoid, and (d) erythema multiforme
characterized by recurring ulcers of the oral Epidemiology

mucosa usually manifesting first in childhood or
adolescence in patients with no other systemic RAS usually initially develops in individuals
diseases. RAS may present in four main forms between 10 and 19 years of age and becomes
based on its clinical appearance: minor, major, less common with time (Ship et al. 2000). Cases
herpetiform, and severe (Table 2). of RAS that become more severe with age may be
Fig. 9 Neoplastic ulcerative conditions. (a) Low-grade salivary adenocarcinoma and (b) diffuse large B cell lymphoma
Table 2 Types of recurrent aphthous stomatitis infections, such as varicella zoster virus (VZV),
Type Size Duration cytomegalovirus (CMV), and human herpes
Minor <1.0 cm 7–10 days virus (HHV) 6 and 7, oral streptococci, and
Major >1.0 cm Weeks, often Helicobacter pylori, although none of these have
with scarring been confirmed and data remain inconclusive (Lin
Herpetiform Few mm (usually 7–10 days et al. 2005; Pedersen and Hornsleth 1993; Victoria
>10 ulcers)
et al. 2003).
Severe <1.0 cm (same as Continuously
minor)
Common risk and triggering factors associated
with RAS include local factors (e.g., smoking
cessation and trauma), hematologic or immuno-
indicative of an underlying systemic condition logic defects, and genetics. Heredity may play a
(e.g., Behçet disease, connective tissue disorders, role as both twins and children with parents
hematologic diseases) and merit further investiga- affected by RAS are more prone to develop the
tion. The incidence of RAS ranges between 5% disease (Miller et al. 1980). Several specific
and 50% and is dependent on the socioeconomic human leukocyte antigens (HLAs) have been
status and ethnicity of patients (Ship 1962). The associated in RAS patients (HLA-A2, HLA-B5,
prevalence of RAS in children has been reported HLA-B12, HLA-B44, HLA-B51, HLA-B52,
to be as high as 40% (Miller et al. 1980) and is HLA-DR2, HLA-DR7, and HLA-DQ series)
influenced by family history; individuals whose confirming the inherited nature of this disease
parents have a history of RAS are at higher risk of (Albanidou-Farmaki et al. 2008).
developing RAS compared to those who have a RAS is considered an immuno-mediated
negative family history (90% vs. 20%) (Ship condition; however specific abnormalities of the
1972). In addition, children with a high socioeco- immune system have not yet been identified
nomic status are five times more likely to develop (Baccaglini et al. 2008). Immunoglobulin serum
RAS (Crivelli et al. 1988; Gallo et al. 2009). levels and natural killer cells are usually within
normal ranges in patients with RAS. Studies have
shown defects of cell-mediated immunity with an
Etiopathogenesis alteration in the CD4+:CD8+ T lymphocyte ratio
(Preeti et al. 2011). Specifically, CD4+ cells are
The etiology of RAS is multifactorial and not more frequent in the pre-ulcer and healing phases,
yet well understood. Theories in the past have while CD8+ cell levels are higher when the ulcer
associated RAS with several bacterial and viral is present (Bachtiar et al. 1998; Sun et al. 2000).
1018 G. Lodi et al.
A dysfunction of the mucosal cytokine cascade Minor aphthous stomatitis (Fig. 10) represents
has been associated with RAS with a subsequent the most common form; minor aphthae are less
increased cell-mediated immune response and than 1 cm in diameter and can be single or multi-
local ulceration of the oral mucosa. Increased ple. The ulcers are round, shallow, and often sym-
levels of interleukin-2 (IL-2), IL-4, IL-5, inter- metric. Once present, they can be painful (mainly
feron-γ, and tumor necrosis factor-α in aphthous during the first 3–4 days, exacerbated with oral
ulcers and raised levels of circulating IL-6 have function), usually last 7–10 days, and heal without
been found in patients with RAS (Boras et al. scarring. The majority of patients with RAS report
2006; Buno et al. 1998; Pekiner et al. 2012; Yama- one to six lesions at a time with few recurring
moto et al. 1994). In addition, RAS has been episodes in 1 year.
linked to genetic factors, specifically those genes Major aphthous ulcers (Fig. 11) are larger (usu-
controlling the release of pro-inflammatory cyto- ally >1.0 cm in diameter), deep, extremely painful
kines IL-1B and IL-6 (Bazrafshani et al. 2002).
Other possible precipitating factors for RAS
include nutritional deficiencies, psychological
stress, anxiety, hormonal fluctuations, allergy
to certain foods, and sodium lauryl sulfate-
containing toothpaste (Akintoye and Greenberg
2014). Conditions that may present with RAS
include micronutrient deficiencies, Behçet dis-
ease, celiac disease, inflammatory bowel disease,
and HIV disease (see below).
Diagnosis and Clinical Presentation
The diagnosis of RAS is generally made through

the patient’s history and clinical presentation.
Biopsy is not indicated, although it may be helpful
in atypical cases to rule out other conditions. Oral
ulcers typically develop in the first two decades of
life, and the frequency of developing recurrent
Fig. 10 Minor recurrent aphthous stomatitis on the buccal
lesions decreases during the third decade. In some
mucosa
rare cases, the severity and frequency of RAS can
increase in the elderly. RAS typically presents as
round or oval shallow ulcers of the nonkeratinized
mucosa with a yellow-grayish fibrin pseudo-
membrane with a characteristic erythematous halo.
The labial and buccal mucosae are the most com-
monly affected sites. Major RAS may also involve
other sites such as the tongue dorsum, hard palate,
soft palate, and palatoglossal and palatopharyngeal
arches. Sometimes a burning sensation or tingling
may precede the development of oral ulcers with
localized erythema. Crunchy, spicy, acidic food and
certain beverages may make eating, speaking, and
swallowing uncomfortable. Four main forms exist: Fig. 11 Major recurrent aphthous stomatitis on the soft
minor, herpetiform, major, and severe (Table 2). palate
Fig. 12 Herpetiform recurrent aphthous stomatitis on the soft palate (a) and lower labial mucosa (b)
lesions, which interfere with speech and eating, and

last for weeks or months. In some cases, major
aphthae may be misdiagnosed as a vesiculobullous
disorder, squamous cell carcinoma, or granuloma-
tous disease. The lesions may heal with scar for-
mation. In the most severe cases, hospitalization for
intravenous feeding may be required.
Herpetiform aphthous stomatitis (Fig. 12) is a
rare variant, with multiple small ulcers, measuring
few millimeters, with a crop-like appearance that
usually coalesce to form a large lesion with irreg-
ular margin similar to HSV-related ulcers. The
overall appearance is identical to the minor Fig. 13 Severe recurrent aphthous stomatitis on the uvula,
palatoglossal arches, and soft palate
aphthous ulcers (although smaller in size), and
these also heal within 7–10 days.
Severe aphthous ulcers (Fig. 13) are a variant membrane pemphigoid or pemphigus) or granu-
in which patients are almost never ulcer-free, lomatous diseases (e.g., sarcoidosis or Crohn’s
and they are often associated with chronic pain, disease).
malnutrition, and weight loss. Patients typically
develop new ulcers when the previous ones are
healing. Both the keratinized and nonkeratinized Management
mucosa may be affected. In HIV patients, severe
recurrent aphthous ulcers are often larger than The management of RAS depends on the fre-
1.0 cm in diameter. quency and severity of the lesions. In many
In cases of atypical RAS (such as in older cases (especially for the minor form) treatment is
individuals with new episodes or in patients with not necessary as the pain is tolerable and does
other/new systemic symptoms), laboratory tests not interfere with the daily life activities of
may be helpful. A blood workup might be indi- the patient (Fig. 14). The main therapeutic goal
cated if hematologic deficiencies are suspected for severe and painful cases is to reduce the
(e.g., low serum levels of vitamin B12, folate, frequency of the episodes and control the pain.
ferritin, and iron) or in HIV patients with a Patients who report one to two outbreaks a year
CD4 count below 100/mm3 (Crivelli et al. may be instructed to use over-the-counter local
1988). Tissue biopsies may be obtained to rule anesthetics (such as 10% benzocaine), viscous
out vesiculobullous disorders (e.g., mucous lidocaine, or mucoadhesive agents such as
1020 G. Lodi et al.
Fig. 14 Spontaneous healing of an aphthous lesion on the buccal mucosa at initial presentation (a) and 10 days later (b)
polyvinylpyrrolidone sodium hyaluronate Table 3 Topical anesthetics and immunosuppressive

(Gelclair ®, Helsinn Healthcare SA, Lugano, Swit- agents used for management of recurrent aphthous
zerland) and methylcellulose paste (Orabase stomatitis
Paste ® Colgate, Colgate-Palmolive Company, Topical anesthetics for Instructions
New York). Amlexanox is a prescription medica- pain control
tion with anti-inflammatory properties incorpo- Benzocaine 10% Apply to the affected site,
3–4 times a day
rated in a mucoadhesive agent that has shown
Benzydamine Swish 5–15 mL and spit
some effectiveness (OraDisc A™, Access Phar- hydrochloride 0.15% out, 3–4 times a day
maceuticals Inc., Addison, TX). Reassurance Dyclonine hydrochloride
and patient education on the condition are also 1%
indicated. Patients with more frequent and Viscous lidocaine 2% Viscous lidocaine may be
severe episodes may be treated with topical mixed in equal volume with
diphenhydramine,
corticosteroids and other immunosuppressive
aluminum/magnesium, and
agents to shorten the duration and size of bismuth subsalicylate
the ulcers (Baccaglini et al. 2011; Scully Topical Instructions
et al. 2003). High-potency topical steroids immunosuppressive
(betamethasone, clobetasol, or fluocinonide) are agents
usually applied on the affected area two to three Triamcinolone 0.1% in Apply to affected site 2–3
methylcellulose paste times daily; no drink or
times daily after meals. Larger and recalcitrant Clobetasol 0.05% gel food intake for 20–30 min
ulcers (such as the ones observed in the major Betamethasone 0.05% afterward
form) can be treated by intralesional therapy gel
such as triamcinolone injections at 10 mg per Fluocinolone 0.05% gel
cm2 of ulceration (Table 3). Systemic therapy Dexamethasone elixir Dispense 300 mL; swish
0.5 mg/5 mL 5 mL for 3–4 min (timed)
for severe outbreaks that do not respond to top- Clobetasol 0.05% and spit out, 3–4 times a
ical measures can be managed with prednisone solution (compounded) day; no drink or food intake
(usually at 1 mg/kg), pentoxifylline, dapsone, for 20–30 min afterward
colchicine, azathioprine, or thalidomide. Due to Steroid injection with 5–10 mg triamcinolone per
triamcinolone (into the cm2 of ulceration
possible side effects with these medications,
ulcer)
patients should be carefully monitored long
term. Thalidomide is indicated for patients with
severe or major RAS cases who failed other of contraception. In the United States, clinicians
treatments (Hello et al. 2010). Thalidomide prescribing thalidomide must be registered in the
causes severe birth defects, and as such women REMS (Risk Evaluation and Mitigation Strat-
of childbearing age must agree to use two forms egy) program for thalidomide. Noteworthy, the
evidence supporting such treatments are scarce, involvement of IBD, pediatricians and dentists
as showed by a Cochrane review in 2012 play a critical role in the diagnosis of oral mani-
(Table 4). festations as an early sign of IBD. The prevalence
of IBD is increasing worldwide, and it is higher in
industrialized countries. In particular, the preva-
Aphthous Stomatitis Associated lence of Crohn’s disease has been estimated to be
with Systemic Conditions around 30–50 cases in 100,000 inhabitants in
Western countries (Laranjeira et al. 2015). In
Gastrointestinal Disorders Europe, the prevalence has been attested around
6.3 in 100,000 individuals (Burisch et al. 2013),
Aphthous lesions are often reported as common in while in the United States is 201 per 100,000
inflammatory bowel diseases (IBD) and celiac adults (National Center for Chronic Disease Pre-
disease (CD); thus it is not unusual that a patient vention and Health Promotion 2015). For ulcera-
with an established gastrointestinal disorder tive colitis, in Europe, the prevalence is 11.4 per
reports recurring oral ulcers with an aspect 100,000 individuals (Burisch et al. 2013), while in
recalling common aphthae. In addition, aphthous the United States is 238 per 100,000 adults, with-
lesions can represent early features of these intes- out significant difference between sexes (National
tinal conditions and thus suggestive of these dis- Center for Chronic Disease Prevention and Health
eases (Fasano and Catassi 2012; Kalla et al. 2014). Promotion 2015).
For such reasons, when a patient reports abdom- Etiology of IBD, most likely multifactorial, is
inal pain, persistent diarrhea, and weight loss, still unknown, although several factors such as
together with oral aphthous lesions, the clinical smoking habit, diet, and geographic and social
suspicion of IBD or CD should be considered environment play a pivotal, triggering role
(Scully 2006). In these patients, aphthous lesions (Lankarani et al. 2013). Though not clearly eluci-
can be either proper extraintestinal manifestations dated yet, the pathogenesis appears related to
of the gastrointestinal disturbance or signs of overly aggressive acquired immune responses to
nutritional and hematological deficiencies due to a subset of commensal enteric bacteria developed
the malabsorption of micronutrients, a typical in genetically susceptible hosts and environmen-
complication of such conditions (Slebioda et al. tal factors which precipitate the onset or
2014) (Table 5). reactivation of disease (Lankarani et al. 2013).
Inflammatory Bowel Disease (IBD) • Genetics – Four genes (CARD15, SLC22A4

Inflammatory bowel disease (IBD) is a broad term and SLC22A5, DLG5, PPARG) have been
to define chronic or recurring inflammation of the associated with Crohn’s disease and one with
gastrointestinal tract, due to the dysregulation of ulcerative colitis (MDR1), which regulate
mucosa immune cells. IBD include two types of innate immune responses, bacterial killing,
chronic intestinal disorders, Crohn’s disease and and immune responses to microbial antigens
ulcerative colitis, two chronic inflammatory dis- and epithelial function (Sartor 2006).
eases of the digestive tract likely to originate from • Immune response – Crohn’s disease and ulcer-
an inappropriate inflammatory response to intes- ative colitis show enhanced local recruitment
tinal microbes in a genetically susceptible host and retention of effector macrophages, neutro-
which can be differentiated by means of the loca- phils, and T cells and then activated and able
tion of lesions along the gastrointestinal tract, as to release pro-inflammatory cytokines (Sartor
well as histological features (Abraham and Cho 2006). Crohn’s disease is mainly a TH1- and
2009). About one-third of IBD patients also dis- TH17-mediated process, while ulcerative coli-
play a wide range of extraintestinal manifesta- tis is an atypical TH2 disorder: although direct
tions, which mainly involve the joints, skin, oral evidence of defective regulatory T-cell func-
mucosa, eyes, and liver. Focusing on oral tion is lacking in either disease, a plethora of
1022 G. Lodi et al.
Table 4 Systemic treatments for recurrent aphthous stomatitis (Adapted from Brocklehurst et al. 2012)
Cochrane
Drug Dose conclusions Adverse effects
Immunomodulatory/ 1.3–1.6 beta- 10 mg twice per day for Insufficient No reporting of
anti-inflammatory glucan 20 days evidence to adverse effects
support or refute
the use
Clofazimine 100 mg daily for 30 days, Insufficient An increase in
then 100 mg every other evidence to cutaneous adverse
day support or refute effects
the use
Colchicine 0.5 mg three times per day Insufficient Gastrointestinal
evidence to adverse effects
support or refute
the use
Levamisole 150 mg per day Inconsistent Headache, nausea,
evidence heartburn/weakness,
regarding the diarrhea, metallic taste
effectiveness of
levamisole
Leukotriene 10 mg montelukast orally Insufficient Equal drug-related
receptor daily for 1 month evidence to adverse effect for
antagonist followed by alternate days support or refute those treated with
for the second month the use montelukast and
placebo
Pentoxifylline 400 mg three times daily Insufficient Dizziness, headaches,
for 60 days evidence to stomach upset,
support or refute increased heart rate,
the use and nausea
Prednisone 25 mg with a phased dose Insufficient Gastritis
reduction over a 2-month evidence to
period support or refute
the use
Sulodexide 250 units twice per day for Insufficient No reporting of
40 days and then once a evidence to adverse effects
day for a further 40 days support or refute
the use
Other treatments Camel thorn 40 ml mouthwash Insufficient No reporting of
distillate evidence to adverse effects
support or refute
the use
Individualized n.a. Insufficient No participant needed
homeopathic evidence to to discontinue
medicine support or refute treatment due to
the use adverse events
LongoVital Three tablets per day for Insufficient Adverse events were
(herbal + 4 months evidence to minor
vitamin) support or refute
the use
LongoVital Three tablets per day for Insufficient Very few and mostly
(herbal alone) 4 months evidence to harmless side effects
support or refute
the use
Multivitamin 100 percent of the US Insufficient No reporting of
reference daily intake of evidence to adverse effects
essential vitamin for support or refute
12 months the use
(continued)
Table 4 (continued)
Cochrane
Drug Dose conclusions Adverse effects
Propolis 500 mg per day Insufficient Low rates of minimal
evidence to side effects
support or refute
the use
Sub- 20 mg twice daily for Insufficient No differences in
antimicrobial 90 days evidence to adverse events
doxycycline support or refute compared with
the use placebo
Tetracycline 25 mg four times per day Insufficient No differences in
suspension for 5 days evidence to adverse events
support or refute compared with
the use placebo
Vitamin B12 1000 mcg daily for Insufficient No reporting of
6 months evidence to adverse effects
support or refute
the use
Table 5 Clinical manifestations of inflammatory bowel diseases (IBD), i.e., Crohn’s disease and ulcerative colitis.
Extraintestinal manifestations occur more frequently in patients affected by Crohn’s disease than ulcerative colitis
Gastrointestinal Extraintestinal
manifestations manifestations
Abdominal pain – altered Joint (arthritis, spondylitis,
bowel habits back pain)
Bloody diarrhea, weight Liver (hepatobiliary
loss disorders, fatty liver)
Fever, occasionally Eye (uveitis)
Skin (pyoderma
gangrenosum)
Oral mucosa
Specific Indurated tag-like lesions
Cobblestoning
Orofacial Crohn’s disease (granulomatosis)
Granular cheilitis
Lip swelling with vertical fissures
Pyostomatitis vegetans
Non specific Aphthous stomatitis
Angular cheilitis
Persistent submandibular lymphadenopathy
Recurrent buccal abscesses
Perioral erythema
Malabsorption-related oral changes (glossitis, oral
candidosis, angular cheilitis)
studies support deficiency in innate immune innate immune responses (such as dendritic
responses in Crohn’s disease (Sartor 2006). cells) or antigens, or stimulating the clonal
• Commensal microbial stimulants – Enteric expansion of T cells that selectively recog-
microflora can stimulate immune responses nize the antigen through their T-cell receptor
either by functioning as adjuvants, activating (Sartor 2006).
1024 G. Lodi et al.
• Environmental triggers – These factors include ulcerative colitis (Katsanos et al. 2015; Lankarani
smoking, which is protective in ulcerative coli- et al. 2013; Pittock et al. 2001).
tis but detrimental in Crohn’s disease, diet, Aphthae may occur in 10–30% of adult
the use of antibiotics and nonsteroidal anti- patients with Crohn’s disease and in a signifi-
inflammatory drugs (NSAIDs), stress, and cantly smaller proportion of subjects with ulcera-
infection (Sartor 2006). tive colitis (Akintoye and Greenberg 2014;
Katsanos et al. 2015; Lankarani et al. 2013; Singh
Even if mechanisms which initiate the onset of et al. 2015). This frequency is not significantly
disease or reactivate quiescent IBD are not well different than in the unaffected population
understood, from a broad perspective, these trig- (Bradley et al. 2004). However, in a recent
gering factors alter mucosal barrier integrity, Turkish study, aphthous stomatitis (40.2%) was
immune responses, or the luminal microenviron- the most common mucocutaneous manifestation
ment, each of which has an impact on susceptibil- reported in both ulcerative colitis (44.6%) and
ity to inflammation (Sartor 2006). Crohn’s disease (33.3%), and no relationship
The basis of an accurate diagnosis of IBD was found between mucocutaneous manifesta-
is focused on clinical presentation, colonoscopy, tions and age, duration of disease, activity indices,
and biopsy of ulcer tissue (Scully 2006), in com- or location of IBD (Topaloğlu Demir et al. 2014).
bination, because there is no unique manifesta-
tion of IBD. Colonoscopy reveals inflammatory Etiopathogenesis
lesions surrounded by normal mucosa, which The pathogenesis of the IBD oral manifestations
initially appear as spherical aphthoid erosions, is still unclear. In Crohn’s disease, pathological
then persisting invariant or progressing to form features of aphthae include, as highlighted by oral
ulcers (Jung 2012). If mucosal inflammation and mucosa biopsies: (i) granuloma formation, simi-
edema increase in correlation to activity of IBD, larly to that observed in intestinal lesions, (ii) the
the intestinal mucosa shows a nodular surface presence of lymphocytes around vessels in the
with a cobblestone appearance (Jung 2012). subepithelial tissue and of plasma cells con-
Crohn’s disease can affect any part of the diges- taining IgM, and (iii) a decreased heat shock pro-
tive tract, while ulcerative colitis is limited to the tein 27 (HSP27) expression compared to controls
colon and rectum (Baumgart and Sandborn (Katsanos et al. 2015).
2007). Biopsy is usually performed on areas Only weak evidence supports a genetic pre-
beyond erosions or ulcers, which has the highest disposition for oral manifestations, though studies
potential for detecting granuloma, in turn difficult show altered patterns of T-cell cytokine pro-
to find in the cobblestone mucosa (Jung 2012). duction leading to loss of tolerance to oral anti-
Histologically, ulcerative colitis displays chronic gens, association between HLA-B27 and IBD
inflammatory lesions restricted to the mucosal extraintestinal symptoms, and DRB1*0103 allele
epithelium, while Crohn’s disease affects the full increase in patients with ulcerative colitis com-
thickness of the bowel wall (Baumgart and plaining of oral ulcers (Katsanos et al. 2015).
Sandborn 2007). Increased frequency of oral manifestations
among IBD patients has been recently correlated
Epidemiology with aberrations in the oral salivary microbiota,
The global prevalence of the oral manifestation of where Bacteroidetes was significantly increased
IBD in adults varies from 5% to 50% (Katsanos with a concurrent decrease in Proteobacteria
et al. 2015; Lankarani et al. 2013); this wide range (Katsanos et al. 2015).
results from several reports that also include non-
specific oral manifestations of IBD, which might Clinical Presentation
be related to medical treatment or derived from Crohn’s oral ulcers can resemble RAS (Fig. 15),
other etiologies. IBD prevalence is higher in chil- but they may also have distinct characteristics
dren than in adults and in Crohn’s disease than in such as indurated borders and histological
Fig. 15 Aphthous-like lesions in the mouth of patients suffering from Crohn’s disease involving the buccal mucosa and
sulcus (a) and buccal mucosa in separate patients (b)
features of granulomatous nature (Akintoye and primary sclerosing cholangitis (Veloso et al.
Greenberg 2014). In addition, they appear more 1996). In addition, aphthous ulcers, as extra-
extensive and painful than those seen in other intestinal manifestations of IBD, usually parallel
aphthous forms (Bradley et al. 2004). Although the disease activity of IBD, occurring during
the oral lesions might be more severe at the time active intestinal disease and responding favorably
of active disease, the association between oral to its treatment (Veloso et al. 1996).
aphthosis and IBD disease activity is not clear,
and data are still controversial (Akintoye and Oral Lesions in the Diagnosis of IBD
Greenberg 2014; Katsanos et al. 2015). Normally, intestinal involvement precedes oral
IBD can display other oral lesions different manifestations; however in 5–10% of IBD cases
from aphthous ulcers (Katsanos et al. 2015; and in up to 60% in patients with Crohn’s disease
Lankarani et al. 2013), which are more common (Lankarani et al. 2013), the specific oral mani-
in patients suffering from Crohn’s disease than festations may precede gastrointestinal symp-
in subjects with ulcerative colitis, particularly toms by many years. It has been estimated that
in Crohn’s disease patients with proximal 10–37% of children who receive a diagnosis
gastrointestinal tract and/or perianal involve- of orofacial granulomatosis may start suffering
ment (Lankarani et al. 2013) These include cob- from Crohn’s disease in the following years
blestoned buccal mucosa, granular cheilitis, (Katsanos et al. 2015). In the presence of
and granular gingival swelling, similar to oro- oral manifestations, histological examination is
facial granulomatosis (Katsanos et al. 2015). only recommended for lesions suggestive of
Pyostomatitis vegetans is another specific finding, granulomatosis. Although it is not possible to
which can be typically associated with both distinguish orofacial granulomatosis and oral
Crohn’s disease and ulcerative colitis (Katsanos Crohn’s disease just on the basis of histolo-
et al. 2015). gical features, referral to a gastroenterologist is
Subjects with extraintestinal manifestations recommended when the presence of granulomatosis
of IBD seem to be more likely to suffer from is confirmed in a patient with bowel features sug-
a combination of these; thus IBD patients with gestive of IBD (such as persistent diarrhea).
aphthae may have concomitantly extraintestinal To date, it is not possible to distinguish patients
manifestations including peripheral and axial with RAS from those with aphthous-like ulcers of
arthropathies, erythema nodosum, uveitis, and the mouth who are likely to develop IBD. Since
1026 G. Lodi et al.
the buccal epithelium of children with Crohn’s genetically predisposed individuals by exposure
disease appears immunologically more reactive to dietary gluten, particularly to gliadin, a specific
when compared to that of adult patients, showing gluten protein which belongs to the group of pro-
overproduction of certain chemokines (CXCL-8, lamins (Gujral et al. 2012). The latter are plant
CXCL-9, and CXCL-10), it has been hypothe- storage proline-rich proteins present in wheat, rye,
sized that these could be used as a screening tool and barley. Originally thought to affect white
for children with IBD and RAS (Katsanos et al. Europeans solely, CD is nowadays widely distrib-
2015). Similarly, levels of tumor necrosis factor-α uted globally, becoming a frequent food intoler-
(TNF-α), found to be higher in the mucosa of ance. The worldwide mean prevalence of CD
patients with Crohn’s disease and oral aphthae, has been reported to range from 0.5% to 1%,
could also contribute to recognize immune- depending on the population under investigation.
mediated oral ulcers associated with this condition The prevalence of 1% reflects figures in Europe
(Bradley et al. 2004). and North America (Gujral et al. 2012). In the
general population, high-risk groups for CD
Patient Management are those with familial history of biopsy-proven
Management of Crohn’s disease is based mainly CD or affected by type 1 diabetes or systemic
on anti-inflammatory and immunosuppressive autoimmune disorders such as thyroiditis (Gujral
topical and systemic therapies as well as dietary et al. 2012).
advice, including elimination of cinnamon, ben- The pathogenesis of CD is dependent on both a
zoate, glutaminate, cocoa, and with micronu- strong genetic predisposition and environmental
trient supplementation. The medical therapies triggers. The primary environmental factor is the
for Crohn’s disease are usually sufficient for ingestion of food containing gluten, while the
the control of oral manifestations of the disease main genetic factor is the class II major histo-
(Veloso et al. 1996). Oral aphthosis usually compatibility complex HLA- DQ2 or DQ8
resolves in most treated children, despite that up genes, also shared in patients with type 1 diabetes
to 30% of affected patients, especially pediatric and other systemic autoimmune disorders (Gujral
ones, may continue to manifest oral lesions after et al. 2012; Lionetti et al. 2014). A recent random-
disease control (Lankarani et al. 2013). In such ized clinical trial on infants at high risk of CD
cases where specific oral manifestations, such indicated that a high-risk HLA genotype was a
as cobblestoned mucosa, granulomatosis, and pivotal predictor of disease, while the delayed
lip and facial swelling, are refractory and uncom- introduction of gluten in the diet did not modify
fortable, as well as in those cases where oral risk of developing the disease, although it was
aphthae are recurrent and severe, local treatment associated with a delayed onset of disease
for pain and discomfort relief is indicated. It can (Lionetti et al. 2014).
be easily achieved by topical application Several pathways have been involved in CD
of anesthetic drugs (lidocaine gel) and anti- pathogenesis. Besides the direct toxicity of gliadin
inflammatory drugs, mainly steroids, such as tri- against the enterocytes, gliadin peptides appeared
amcinolone or dexamethasone ointments, up to to upregulate stress molecules in intraepithelial
three times/day for about 10 days (Akintoye and lymphocytes, promoting a lymphocyte-mediated
Greenberg 2014). Systemic or intralesional ste- cytotoxic response against enterocytes (Barker
roids and other immunomodulators are also and Liu 2008). Moreover, the structure of gliadin
recommended for severe refractory and/or persis- itself, unusually rich in proline residues, results
tent cases not responding to topical therapies in an intrinsic resistance to gastrointestinal diges-
(Akintoye and Greenberg 2014). tion, along with a preference for binding to
DQ2 molecules, further mediating autoimmune
Celiac Disease (CD) inflammation (Barker and Liu 2008). An additio-
CD is a chronic, multisystem, immune-mediated nal, pivotal pathway for CD development involves
disease of the small intestine triggered in transglutaminase (tTG), a calcium-dependent
enzyme. tTG has the main molecular role of cross- studies on the prevalence of RAS in patients with
linking and deamidation of gliadin, producing an CD show that the number of subjects who have
epitope that binds efficiently to DQ2 RAS ranges from 3% to 61% (Baccaglini et al.
and is recognized by gut-derived gliadin-reactive 2011), while in a large survey of a Canadian
CD-4+ T cells (Barker and Liu 2008). tTG auto- population with biopsy-proven CD, 16% of chil-
antibodies, as immunoglobulin A (IgA), occur dren and 26% of adults reported suffering from
because antigen-presenting cells “inadvertently” recurrent oral ulcers (Rashid et al. 2011).
target tTG-gliadin complexes, resulting in an
immune reaction against both gliadin and tTG Etiopathogenesis
(Barker and Liu 2008). tTG IgA, detectable in The exact cause of aphthous ulcers in CD is
the serum of almost all CD individuals is also unknown, although they have been related mainly
associated to extraintestinal symptoms of CD, with hematinic deficiencies, including low serum
which can deposit in the liver, kidney, lymph iron, folic acid, and vitamin B12 due to malab-
nodes, and muscles (Gujral et al. 2012). tTG IgA sorption in patients with untreated CD (see recur-
disappears slowly from the bloodstream, when the rent aphthous stomatitis and deficiencies of
patient is under a gluten-free diet. micronutrients). Similarly, the exact mechanism
leading to dental defects is largely unclear.
Epidemiology Immune-mediated damage has been proposed
Weight loss or other signs of malabsorption may to be the primary cause, though nutritional dis-
be suggestive of the presence of CD in a patient turbances, putatively producing hypocalcemia
with oral aphthae, even though this disease has and vitamin insufficiencies, as well as gluten-
been detected in less than 5 percent of patients dependent stimulation of oral naïve lymphocytes
with RAS referred to a hospital clinic for exami- cannot be completely ruled out (Rashid et al. 2011).
nation (Scully 2006).
Dental enamel defects and oral aphthae repre- Clinical Presentation
sent the two most common oral manifestations Aphthous ulcers and dental enamel defects belong
associated with CD. The prevalence of dental to a group of well-documented dental and oral
enamel defects in CD patients with mixed or per- mucosa manifestations of CD (Table 6). The pres-
manent dentition ranges widely, from 9.5% to ence of recurrent aphthous lesions, especially in
95.9%, while in patients with deciduous teeth, it individuals with dental enamel defects, is now
decreases to 5.8–13.3% (Rashid et al. 2011). Such considered a significant condition for suspecting
difference is due to the difference in time of erup- CD. Interestingly, in around one-fifth of cases,
tion, and the fact that crowns of permanent teeth oral ulcers can represent the first sign of CD;
develop within the seventh year of age after the several authors have reported cases of patients
introduction of dietary gluten in the child, and the presenting with recurrent oral ulceration who sub-
development of deciduous teeth occurs primarily sequently received a diagnosis of CD (Baccaglini
in utero, in the absence of gluten gastrointestinal et al. 2011). Clinically, the features of oral
exposure of the fetus. Regarding oral aphthae, aphthous lesions in CD are not far from the
figures are difficult to extrapolate, since several classical picture of idiopathic oral aphthae; they
reports fail to specify the exact diagnostic criteria have been mostly described as minor RAS
used. Some controlled studies, however, although, as mentioned above, most studies have
suggested a higher frequency of recurrent oral not reported well-defined criteria for diagnosis of
ulcers in CD patients compared with control RAS (Baccaglini et al. 2011).
groups (Baccaglini et al. 2011; de Carvalho et al. If CD appears in children, when permanent
2015). Excluding case reports, studies investigat- teeth are developing, abnormalities in the struc-
ing the prevalence of CD in patients with RAS ture of the dental enamel can arise, usually
provide a broad range of estimates, ranging from symmetrically and chronologically in all four
4% to 40% (Baccaglini et al. 2011). Conversely, quadrants. Typical aspects include enamel
1028 G. Lodi et al.
Table 6 Oral and dental lesions associated with celiac confirmation of CD, the clinician should not rec-
disease ommend a gluten-free diet for the patient (Rashid
Oral mucosa lesions Dental lesions et al. 2011).
Recurrent aphthous ulcers Delayed dental eruption Oral health-care providers play an important
Cheilosis Enamel defects role in detecting both classical and atypical cases
Atrophic glossitis (classification according to
Aine (de Carvalho et al. of CD, contributing to decreasing diagnostic
2015): delay, which is still high. Delay in CD diagnosis
Grade I: defects in color can lead to a plethora of complications, from
of enamel – single or anemia to osteoporosis and, in worse cases, repro-
multiple cream, yellow or
brown opacities ductive disorders and increased risk of developing
Grade II: slight intestinal malignancies such as small intestine
structural defects – rough adenocarcinoma and lymphoma (Green and
enamel surface, horizontal Cellier 2007; Rashid et al. 2011).
grooves, shallow pits
Grade III: evident
structural defects – deep Patient Management
horizontal grooves and Currently, the main therapeutic intervention for
vertical pits CD is a gluten-free diet. Adherence to a gluten-
Grade III: severe
structural defects – shape free diet improves gastrointestinal symptoms
changes and may also reduce frequency and severity of
aphthous ulcers, although this has not been con-
firmed in all reports (de Carvalho et al. 2015). The
hypoplasia and hypomineralization, with pitting, response to therapy is poor in up 30% of patients
grooving, and sometimes complete loss of enamel (refractory form of CD), mainly due to lack of
(Rashid et al. 2011). A classification of these CD compliance with diet (Green and Cellier 2007).
dental defects has been developed (Table 6) (Aine Severe and persistent aphthae can often
et al. 1990), which are less frequent in adults with be managed as idiopathic forms of RAS, using
CD, due to the fact that CD onset may have topical antiseptic and steroid medicaments
occurred after dentition development or may and reserving systemic therapies for severe,
have had affected restored or extracted teeth non-respondent cases.
(Rashid et al. 2011).
Oral Lesions in the Diagnosis of Celiac Behçet Syndrome

Disease
The clinician should always consider CD among Behçet syndrome or Behçet disease (BD) is an
differential diagnosis in any patient presenting inflammatory multisystemic disorder with vascu-
with dental enamel defects and recurrent aphthous lar, articular, gastrointestinal, neurologic, urogen-
lesions, since their association is considered spe- ital, pulmonary, and cardiac involvement. The
cific to CD. The presence of a hereditary case of disease was first described in 1937 by the Turkish
CD or concomitant autoimmune diseases, espe- dermatologist, Hulusi Behçet, as a triad of symp-
cially type 1 diabetes, will further increase the toms, namely, recurrent oral ulcers, genital ulcers,
probability of CD. and uveitis (Behçet 1937).
Children with a documented history of RAS
and signs of malabsorption should undergo a den- Epidemiology
tal examination and, if presenting with enamel The onset of BD usually occurs in the third or
defects, should be referred to a gastroenterologist fourth decade of life. BD is seen worldwide,
who may confirm the diagnosis of CD by per- although it is a rare condition. It has a typical
forming laboratory and instrumental evaluations geographic distribution, with an increased preva-
(Marty et al. 2016). While awaiting diagnostic lence in people with ancestors who lived in the Silk
Route, which extended from Japan to the Middle patients with BD compared to controls. However,
East and Mediterranean countries. Turkey has the their role in the etiology of the disease remains to
highest prevalence, with a prevalence in the popu- be determined. A clinical hypothesis is that infec-
lation aged 12 years or older of 420/100,000 tious agents and associated stress proteins found
(Azizlerli et al. 2003). The disease is rarely in the oral cavity of patients with BD induce cross-
observed in Western countries: the prevalence of reactivity with host cells and stimulate the prolif-
BD is approximately 0.64/100,000 in the United eration of autoreactive T-cell clones. Heat shock
Kingdom and 0.12–0.33/100,000 in the United proteins can be recognized by pattern recognition
States (Sakane et al. 1999). The overall gender receptors as an endogenous “danger” signal, lead-
distribution has been reported to be roughly equal, ing to activation of innate and adaptive immune
but some regional variability also exists. BD shows responses. They also increase the expression of
a male predominance in certain Middle East and adhesion molecules on endothelial cells. Over-
Mediterranean countries and a female predomi- expression of pro-inflammatory cytokines (mainly
nance in Japan and South Korea (Bang et al. 2003). IL-17, IL-23, and interferon-γ) appears to be
There is a strong association between the responsible for the enhanced inflammatory reac-
geographic distribution of human leukocyte tion. Increased neutrophil activity and neutrophil
antigen HLA-B51 and the prevalence of BD. infiltration in affected organs may be caused by
The frequency of HLA-B51 along the Silk Route increased IL-17 response. This inflammatory pro-
ranges between 20% and 25% among the gen- cess eventually results in tissue damage and vas-
eral population and 50–80% among patients culitis (Keogan 2009).
with BD (Alpsoy 2016). In contrast, the fre-
quency of HLA-B51 in Northern Europe and the Clinical Presentation
United States is around 2–8% in the general pop- BD is characterized by unpredictable exacerba-
ulation and 15% among patients with BD (Dalvi tions and remissions and presents with a wide
et al. 2012). spectrum of clinical manifestations. It is associ-
ated with increased mortality due to involvement
Etiopathogenesis of the central nervous system, lungs and large
The etiology of BD is unknown. The most widely vessels, bowel perforation, and gastrointestinal
accepted theory behind its pathogenesis is that hemorrhage (Keogan 2009). Mucocutaneous
an environmental stimulus elicits an abnormal lesions constitute the hallmark of BD. Oral ulcers
immune response in a genetically susceptible are the most common feature, affecting 92–100%
host. The presence of HLA-B51 is still considered of the patients, followed by genital ulcers
the strongest susceptibility factor for BD, as (57–93%) and cutaneous lesions (38–99%)
subjects carrying this gene have a signifi- (Alpsoy et al. 2007). Ocular and articular involve-
cantly increased risk of developing this condition ments are also frequent traits of the disease.
(de Menthon et al. 2009). The presence of No specific histopathological features have
HLA-B51 alone is not sufficient to explain the been described in BD. Large vessel involvement
etiology of the disease in all cases; only 60% of is generally characterized by vasculitis with
patients with BD express HLA-B51, and this thrombosis or aneurysm, while the mucocutane-
HLA allele is seen frequently in the absence of ous lesions often display leukocytoclastic vascu-
the disease (Keogan 2009). These data suggest litis or a neutrophilic vascular reaction.
that other susceptibility genes or genetic varia- Oral ulcers – This is usually the first manifes-
tions may also be involved. tation of BD. They are characterized by recurrent
It has also been suggested that environmental and debilitating ulcerations of the oral mucosa,
factors may play a pivotal role in the pathogenesis clinically indistinguishable from RAS. They can
of BD. The presence of HSV-1-infected cells and be found anywhere in the oral cavity, but the
the load of Streptococcus species, particularly most commonly affected sites are the labial and
S. sanguinis, have been found to be higher in buccal mucosa, tongue, soft palate, and
1030 G. Lodi et al.
Severity may differ between the eyes. Panuveitis,

posterior uveitis, anterior uveitis, retinal vasculi-
tis, optic neuritis, and retinal vein occlusion are
the most common features and cause significant
morbidity. Formation of a hypopyon, a visible
layer of pus in the anterior chamber, is seen in
12% of patients and rarely in other conditions
(Tugal-Tutkun et al. 2004) (Fig. 17).
Cutaneous lesions – Skin lesions are described
in approximately 80% of patients with
BD. Erythema nodosum-like lesions are seen in
30% of patients, mainly on the lower extremities
but also on the face, neck, and buttocks. Lesions
Fig. 16 Aphthous-like lesion in the mouth of a patient
rarely ulcerate, resolve within 2–3 weeks, and
with Behçet syndrome involving the lateral dorsal tongue
can cause post-inflammatory hyperpigmentation.
While clinically similar to classical erythema
oropharynx. The minor form is by far the most nodosum, lesions of BD differ histologically, with
common, followed by the major and herpetiform evidence of vasculitis (Kim and LeBoit 2000).
variants in decreasing order, as described in a Other common skin lesions include papulopustular
large study which reported a high frequency of lesions, superficial thrombophlebitis, and pathergy.
mixed forms (Gurler et al. 1997). Patients with
BD tend to have a higher number of simultaneous Diagnosis
ulcers, more frequent recurrences (Main and Since there are no pathognomonic signs nor any
Chamberlain 1992), higher incidence of major specific laboratory, radiologic, or histologic find-
aphthae (Krause et al. 1999), and more involve- ings for BD, the diagnosis is purely based on
ment of the soft palate and oropharynx (Alpsoy the recognition of clinical findings together with
et al. 2007) than patients with RAS (Fig. 16). the exclusion of other conditions. Despite large
Genital ulcers – Genital ulcers are rarely the research efforts over the past few decades, no uni-
presenting feature of BD. The ulcerations may be versally accepted diagnostic criteria exist for BD, as
preceded by a papule or pustule and appear similar documented by the existence of 17 sets of diagno-
to oral aphthae but occur less often and scar more sis/classification criteria (Davatchi et al. 2015). The
frequently. Associated pain may cause difficulty criteria proposed in 1990 by the International Study
with micturition, dyspareunia, and even hinder Group (ISG) for Behçet Disease (International
walking (Senusi et al. 2015). In women, ulcers Study Group for Behçet Disease 1990) remain the
most commonly affect the labia, but lesions in the most widely used among experts (Table 7).
vaginal mucosa and cervix may also occur. In Recently, the International Team for the Revision
men, the scrotum is regularly involved, although of the International Criteria for Behçet Disease
involvement of the shaft and glans penis is also (ICBD) published new criteria (International
frequent. Ulcers in the groin, perineum, and peri- Team for the Revision of the International Criteria
anal area are seen in both genders. for Behçet Disease 2014), where oral ulcers, genital
Ocular lesions – Ocular disease is seen in ulcers, and ocular lesions receive two points each
30–70% of patients and is more frequent and and other manifestations (cutaneous lesions, neuro-
severe in men. Typically, ocular symptoms begin logic and vascular involvement, and positive skin
after the onset of oral ulceration. However, intra- pathergy test) receive one point each. If a patient
ocular inflammation is the presenting feature in receives four points or more, the patient is diag-
approximately 20% of cases. Ocular disease is nosed with BD. It has been shown that the ICBD
bilateral in 85% of patients and runs a relapsing criteria are more sensitive but less specific than the
course in 95% of cases (Kitaichi et al. 2007). ISG criteria, which may cause overdiagnosis.
Fig. 17 Ocular lesions of Behçet syndrome. (a) Mild vasculitis (demonstrated by fluorescein angiography)
conjunctival injection and hypopyon, (b) retinal hemor- (Images courtesy of Dr Hiroshi Goto, Tokyo Medical Uni-
rhage associated with retinal vasculitis, and (c) retinal versity, Japan)
Patient Management Systemic therapy with colchicine, pentoxifylline,

No curative therapy is currently available for and dapsone is often useful when mucocutaneous
BD. The ultimate goals of treatment are to prevent lesions are frequent or severe. In refractory cases
irreversible organ damage, which occurs especially thalidomide, azathioprine, or biological agents, such
in the early stage and active phases of the disease, as tumor necrosis factor-α antagonists (infliximab,
and to alleviate symptoms. As for RAS, the treat- etanercept) and interferon-α, may be necessary.
ment of oral ulcers and other mucocutaneous lesions
in patients with BD consists mainly in the use of
topical agents, particularly steroids. However, the Food Allergy
number of randomized controlled trials for targeted
therapy is scarce. A recent systematic review on the Food allergy has been investigated as a putative
management of oral ulcers in BD concluded that cause of aphthous-like lesions, though scientific evi-
there was insufficient evidence to support or refute dence to support this association is still sparse. Since
the use of any topical or systemic intervention with the oral cavity is subjected to a wide spectrum of
regard to pain, episode duration, or episode fre- antigenic agents, including food, allergic reactions to
quency associated with lesions (Taylor et al. 2014). such antigens might manifest as ulcerative lesions.
1032 G. Lodi et al.
Table 7 Diagnostic criteria for Behçet disease by the Etiopathogenesis

International Study Group for Behçet Disease Although causality between a certain food and
Recurrent oral Minor aphthous, major aphthous, aphthous-like lesions cannot be definitely stated,
ulceration or herpetiform ulceration observed the association between allergy and RAS can be
by the physician/dentist or patient
that recurred at least three times in hypothesized on the basis of RAS pathogenesis.
one 12-month period The latter includes immediate type I reactions or
Plus, two of the delayed type IV reactions, similar to IgE-mediated
following: and cell-mediated food hypersensitivity, as is
Recurrent Aphthous ulceration or scarring also supported by histological findings of lesions
genital observed by the physician or
(Wardhana and Datau 2010).
ulceration patient
Eye lesions Anterior uveitis, posterior uveitis,
Among possible etiological factors, the associ-
cells in the vitreous on slit lamp ation between immunity to cow’s milk proteins
examination, or retinal vasculitis (CMP) and RAS has been investigated. A strong
observed by an ophthalmologist association between high levels of serum anti-
Cutaneous Erythema nodosum observed by CMP IgA, IgG, and IgE antibodies and clinical
lesions physician or patient,
pseudofolliculitis or manifestations of RAS has been reported (Besu
papulopustular lesions, or et al. 2009). In one study, 50 subjects with RAS
acneiform nodules observed by (36 with proven increased immunity to CMP
physician in postadolescent and 14 without this increased immunity) were
patients not receiving
corticosteroids enrolled, and data showed that levels of serum
Positive Read by the physician at 24–48 h anti-fresh cow’s milk IgA, IgG, and IgE anti-
pathergy test bodies were significantly higher than levels of
Findings applicable only in the absence of other clinical serum anti-fresh goat’s milk in subjects with
explanation RAS with proven increased immunoreactivity to
CMP (Besu et al. 2009). These results indicate
that patients with RAS with increased immunity
to CMP could consider the use of goat’s milk as
Epidemiology the alternative protein source. The same group
A recent epidemiological study, “National of authors further provided evidence of an etio-
Health and Nutrition Examination Survey logical role for cow’s milk proteins in RAS deter-
(NHANES),” investigated food allergy preva- mining the prevalence of increased levels of
lence in US children in 1988–1994 and in serum antibodies to specific cow’s milk proteins
2005–2006, stratified by race and/or ethnicity (SCMP), constituents of cheese or whey in sub-
(McGowan et al. 2016). Nearly 8,000 subjects jects with RAS. Results indicated a strong associ-
were included, and the prevalence of food sensi- ation between high levels of serum anti-SCMP
tization was 24.3%, with no significant differ- IgA, IgG, and IgE antibodies, especially to
ences between the two-time periods for milk, caseins: α-, β-, and κ-casein from cow’s milk and
egg, or peanut sensitization, while shrimp sensi- clinical manifestations of RAS (Besu et al. 2013).
tization decreased markedly (McGowan et al.
2016). One of the first studies suggesting a puta- Clinical Presentation
tive role of food allergy or intolerance in RAS Food allergic reactions in adult patients are
was a small case series published in 1986, show- similar to those in children, and they can range
ing a significant improvement in 6 out 15 patients in severity from local and very mild symptoms to
following dietary withdrawal (Wright et al. systemic symptoms involving different organs,
1986). Subsequent reports that explored sensitiv- up to a fatal outcome (Ballmer-Weber 2015).
ity to foods, preservatives, or other agents in After oral mucosal ulcerations (Fig. 18), other
patients with a diagnosis of RAS reported a prev- putative oral manifestations of food allergy
alence of 35–50% (Wardhana and Datau 2010). include cheilitis, perioral dermatitis, and contact
between food allergy and RAS in a single patient

is probably to verify the resolution or a significant
improvement of aphthous lesions following the
withdrawal of the suspected food from the diet
(elimination diet) and the relapse of the oral ulcers
following rechallenge with the same food. Diet
elimination is not always successful regardless
of whether leukocytes released histamine after
exposure to food antigens is noted or not (Wray
et al. 1982).
Patient Management
Reduction in frequency and severity of recur-
Fig. 18 Oral ulceration in a patient suffering from food rences and maintenance of remission are among
allergy involving the buccal mucosa
the goals of therapies to treat RAS. Elimination
diets are frequently utilized in both diagnosis and
stomatitis (Collet et al. 2013). Orofacial management of RAS caused by food allergy, i.e.,
granulomatosis has also been associated with once certain foods are suspected of triggering the
intake of certain foods (McCartan et al. 2011), as allergic reactions, they are completely omitted
well as RAS, although without a strong cause- from the diet. Strict exclusion diets result in
effect correlation (Wardhana and Datau 2010). improvement and/or resolution of ulcers in a
Oral allergy syndrome (or pollen food hypersen- wide range of cases, from 25% to 75% of patients
sitivity syndrome) is considered to be the (Wardhana and Datau 2010). The success of such
commonest form of food allergy in adults. It dietary intervention depends on the correct iden-
occurs in pollen-sensitized subjects after ingestion tification of the food allergens and on the ability
of fruits, nuts, and vegetables containing allergens of the patient to avoid them during daily life
sharing homology with pollen allergens. It is lim- (Wardhana and Datau 2010).
ited to the oropharynx in pruritus, and clinical Besides dietary approaches, treatment of RAS
presentation may include tingling, erythema, and associated with food allergy involves, once more,
swelling of the lip, oral mucosa, palate, and throat the use of topical and/or systemic treatments,
(Ho et al. 2014). mainly based on steroid agents, following the
Clinical history and physical examination are same posology used for idiopathic RAS
the foundation for the diagnosis of RAS caused by (Wardhana and Datau 2010).
food allergy. Aphthous lesions, however, do not
differ from the clinical presentation of idiopathic
RAS; thus further elements are required to achieve Recurrent Aphthous Stomatitis
a diagnosis of food allergy. and Micronutrient Deficiency
Diagnosis The WHO definition of micronutrients states that

In a patient with a clinical history suggesting food “these substances are the magic wands that enable
allergy, first-line diagnostic testing consists of the body to produce enzymes, hormones and other
skin testing or measurement of serum food- substances essential for proper growth and devel-
specific IgE levels or both. However, sensitization opment. As tiny as the amounts are, however, the
often does not equate to clinical allergy, and a consequences of their absence are severe” (World
medically supervised oral food challenge is the Health Organization 2016). The association of
diagnostic gold standard (Abrams and Sicherer RAS with deficiencies of different micronutrients
2016). Once the suspected food has been identi- (i.e., vitamin B12, iron, folate, and, more recently,
fied, the best way to demonstrate the association zinc), as well as the putative role of these
1034 G. Lodi et al.
substances in its pathogenesis, has been the sub- can represent up to 51% of patients suffering from
ject of a number of studies since the 1960s (Ship RAS (Table 8). In a recent meta-analysis including
1962). At the time, early reports of RAS patients data of over 1100 subjects from 8 case-control
who improved or even healed following vitamin studies published between 1975 and 2014, the
supplementation led to the idea that RAS could be a rate of vitamin B12 and folic acid deficiencies
deficiency syndrome, at least in some cases. Since was significantly higher in RAS patients, compared
then, many studies have investigated the frequency with controls (vitamin B12: odds ratio = 3.75, 95%
of different micronutrient deficiencies among RAS confidence interval, 2.38–5.94; folic acid, odds
patients. Nevertheless, a definitive conclusion has ratio = 7.55, 95% confidence interval,
not yet been reached. In fact, differences in terms of 3.91–14.60) (Chen et al. 2015).
diagnostic criteria, patient and control selection, Similar data are available for iron deficiency
laboratory technique, and normal value range and anemia. Although sideremia, transferrin, and
make data hardly comparable and to certain extent total iron binding capacity have been the subject
explain conflicting results (Table 8). of investigation, ferritin (a protein that stores iron)
The deficiency of vitamin B12, a coenzyme for is the indicator more commonly used in studies
fat and carbohydrate metabolism, protein synthe- exploring the association of RAS and iron
sis, and hematopoiesis, is responsible for megalo- deficiency, which has been found below normal
blastic anemia, neurological symptoms, chronic values in a proportion of patients ranging between
tiredness, and mood disturbance (Vidal-Alaball 7% and 40% (Table 8). In the aforementioned
et al. 2005). The association of RAS and deficiency meta-analysis, ferritin below normal values was
of vitamin B12 has been investigated in a number more common in 687 patients with RAS than in
of controlled and noncontrolled studies that found a the 583 controls (odds ratio 2.62, 95%; confidence
frequency of vitamin B12 deficiency among RAS interval 1.69–4.06) (Chen et al. 2015). Similarly,
patients to range between 0% and 45% (Fig. 19). although diagnostic criteria for anemia varied
Another micronutrient of the vitamin B group often among studies, up to 60% of patients with RAS
investigated among RAS patients is folic acid, a may have hemoglobin values below normal
vitamin necessary for purine and pyrimidine syn- range, and pooled data from controlled studies
thesis, erythropoiesis, and methionine regenera- shows a significant association (odds ratio 1.77,
tion, the deficiency of which causes effects 95%; confidence interval 1.12–2.80).
similar to that of vitamin B12 (Fairfield and When vitamin B12, folic acid, and iron are
Fletcher 2002). Patients with folic acid deficiency taken together, the proportion of patients suffering
from aphthae, with one or more micronutrient
deficiency, can be as high as 50% (Compilato
et al. 2010) and the difference with control sub-
jects statistically significant (Lopez-Jornet et al.
2014). Notably, anemia and deficiencies of serum
ferritin and folate may be more common in female
patients with RAS, but the same is not true for
vitamin B12 (Burgan et al. 2006).
Little is known about the prevalence of oral
mucosal lesions among subjects with hematinic
deficiencies, although a recent study reported a
22% prevalence of aphthous lesions in patients
deficient in vitamin B12 and vitamin B9 (Andrès
et al. 2016).
Fig. 19 Oral ulcers involving the lateral and dorsal sur-
Clinical form (minor, major, herpetic, severe),
faces of the tongue in a patient suffering from vitamin B12 localization, and severity of lesions do not seem
deficiency to be useful in identifying RAS patients with
Table 8 Frequency of micronutrient deficiencies among patients affected by recurrent aphthous stomatitis
Study RAS patients Controls Lower reference value
Vitamin B12
Burgan et al. 2006 38/143 (27%) 18/143 (13%) 180 pg/mL
Challacombe et al. 1977 1/40 (2%) 0/26 (0%) 200 ng/L
Compilato et al. 2010 5/32 (15%) 0/29 (0%) 226 pg ⁄mL
Khan et al. 2013 27/60 (45%) 9/60 (15%) 220 pg/mL
Koybasi et al. 2006 12/34 (35%) 0/32 (0%) Not reported
Lopez-Jornet et al. 2014 5/92 (5%) 1/94 (1%) 200 pg/mL
Olson et al. 1982 0/90 (0%) 0/23 (0%) 160 pg/mL
Piskin et al. 2002 8/35 (23%) 0/26 (0%) 200 pg/mL
Porter et al. 1988 2/69 (3%) 2/75 (3%) Not reported
Rogers and Hutton 1986 0/102 (0%) – Not reported
Sun et al. 2015 13/273 (5%) 0/273 (0%) 200 pg/mL
Thongprasom et al. 2002 0/23 (0%) 0/19 (0%) 150 pg/mL
Wray et al. 1975 5/130 (4%) 1/130 (1%) 120 ng/L
Folic acid
Burgan et al. 2006 7/143 (5%) 0/143 (0%) 2.5 ng/mL
Challacombe et al. 1977 7/40 (17%) 4/26 (15%) 5 μg/L
Compilato et al. 2010 6/32 (19%) 0/29 (0%) 2.3 ng ⁄mL
Khan et al. 2013 31/60 (51%) 6/60 (10%) 1.5 ng/mL
Lopez-Jornet et al. 2014 4/92 (4%) 1/94 (1%) 2.7 ng/mL
Piskin et al. 2002 4/35 (11%) 0/26 (0%) 3 μg/L
Sun et al. 2015 7/273 (3%) 0/273 (0%) 4 ng/mL
Wray et al. 1975 7/130 (5%) 3/130 (2%) 2.5 μg/L
Ferritin
Burgan et al. 2006 24/143 (17%) 14/143 (10%) 12 (female) and 14 (male) ng/mL
Compilato et al. 2010 13/32 (40%) 0/29 (0%) 10 (female) and 22 (male) ng⁄mL
Lopez-Jornet et al. 2014 6/92 (7%) 5/94 (5%) 12 ng/mL
Piskin et al. 2002 6/35 (17%) 3/26 (11%) 9 (female) and 18 (male) ng⁄mL
Hemoglobin
Babaee et al. 2016 17/28 (60%) 9/28 (32%) 14 (female) and 17 (male) g/dL
Burgan et al. 2006 20/143 (14%) 15/143 (10%)
Challacombe et al. 1977 14/193 (7%) 2/100 (2%) 11.5 (female) and 13 (male) g/dL
Compilato et al. 2010 11/32 (34%) 2/29 (7%) 12.0 (female) and 12.5 (male) g⁄dL
Khan et al. 2013 35/60 (58%) 26/60 (43%) 12 (female) and 14 (male) g/dL
Olson et al. 1982 6/90 (7%) 2/23 (9%) 11 (female) and 13 (male) g/dL
Sun et al. 2015 57/273 (21%) 0/273 (0%) 12 (female) and 13 (male) g/dL
Zinc
Bao et al. 2016 33/156 (21.2%) – 70 μg/dL (10.7 μmol/L)
Orbak et al. 2003 17/40 (42.5%) – 95 μg/dL
Ozler 2014 7/25 (28%) 1/25 (4%) 95 μg/dL
Wray 1982 0/20 (0%) – 55 μg/dL
1036 G. Lodi et al.
hematinic deficiencies. In fact, as stated in one of least three episodes in the previous 12 months,
the first studies investigating this association, “it irrespective of their vitamin serum level, and com-
was not possible by clinical examination of the pared a multivitamin supplement containing the
ulcers to separate patients with an underlying US reference daily intake of vitamins A, B1, B2,
deficiency or disease from those with no such B3, B5, B6, B9, B12, C, D, and E with placebo (Lalla
abnormality” (Wray et al. 1975). In fact, clinical et al. 2012). Noteworthy, the multivitamin supple-
features are similarly distributed in deficient and ment showed no benefit either in the subgroup of
non-deficient subjects (Lopez-Jornet et al. 2014; participants with low baseline levels of B12 or in
Rogers and Hutton 1986; Sun et al. 2015; Wray those with a highly frequent form. The trial was
et al. 1978). judged at low risk of bias by a Cochrane review and
The role played by diet in RAS onset has been showed no differences in number or duration of
investigated by comparing nutritional habits RAS episodes between the two groups
among RAS patients and controls, with reported (Brocklehurst et al. 2012). A separate placebo-
significant differences in vitamin B12 and folate controlled randomized trial tested the effects of a
intakes (Kozlak et al. 2010), but not in specific 6-month monotherapy with vitamin B12 (1000 mcg
food categories (Ogura et al. 2001; Ship 1962). sublingual daily) in patients with RAS. Again,
Noteworthy, single or multiple deficiencies of patients were selected on the basis of the frequency
such micronutrients can be a consequence of of aphthous episodes (at least one outbreak every
insufficient absorption in the gastrointestinal 2 months in the last year), and more than 80% had
tract, a common consequence of chronic inflam- normal levels of serum vitamin B12. At completion
matory conditions of the bowel, including of the trial, the treatment group reported less pain, a
Crohn’s disease and celiac disease, disorders shorter duration of RAS episodes, and lower fre-
often associated with RAS. quency of episodes, and during the last 2 months of
More recently, zinc has been the subject of treatment, more participants in the same group
investigation in groups of patients affected by were free from ulcers (Volkov et al. 2009). How-
RAS. Zinc is an essential micronutrient for ever, the Cochrane review assessed the study as
humans. It is a constituent of a large number of unclear risk of bias and concluded that the evidence
enzymes, fundamental for cell growth, collagen provided was insufficient to support or refute the
synthesis, wound healing, and normal function of use of vitamin B12 for the treatment of RAS
reproductive, neurologic, immune, dermatologic, (Brocklehurst et al. 2012).
and gastrointestinal systems. The features of mild In conclusion, although a number of patients
zinc deficiency are frequently nonspecific and with RAS can be affected by micronutrient defi-
include diarrhea, cognitive and behavioral prob- ciencies, the evidence presently available does not
lems, hair loss, eye problems, growth retardation, offer strong support for routine testing of RAS
and recurrent infections (Bao et al. 2016; Shah et al. patients or treatment with supplements in the
2016). Patients with RAS may have lower mean absence of a demonstrated deficiency (in which
levels of zinc in serum compared with controls case improvement of the oral condition is not
(Ozturk et al. 2013), as well as higher rate of zinc guaranteed).
deficiency (Table 8). In addition, studies on animal
models, specifically in rats, have shown that a zinc-
deficient diet is associated with aphthous ulcers and Conclusions and Future Directions
other alterations of the oral mucosa (Orbak et al.
2007; Seyedmajidi et al. 2014). An ulcer of the mouth can represent a mani-
On the basis of anecdotal reports of RAS festation of a number of local and systemic
patients with documented clinical improvements conditions ranging from self-limiting lesions to
following replacement therapy, few randomized life-threatening diseases. Histological examina-
controlled trials have been conducted. One study tion and specific laboratory tests are often essen-
treated RAS patients who had experienced at tial elements in the differential diagnosis;
however, clinical features, such as number, local- Aine L, Mäki M, Collin P, Keyriläinen O. Dental
ization, duration, and aspect, are fundamental in enamel defects in celiac disease. J Oral Pathol Med.
1990;19(6):241–5.
the distinguishing of oral ulcerative lesions, and Akintoye SO, Greenberg MS. Recurrent aphthous stoma-
in many cases they can be sufficient to establish titis. Dent Clin N Am. 2014;58(2):281–97.
a definitive diagnosis and start treatment. A Albanidou-Farmaki E, Deligiannidis A, Markopoulos AK,
proper management of a patient with oral ulcera- Katsares V, Farmakis K, Parapanissiou E. HLA -
haplotypes in recurrent aphthous stomatitis: a mode of
tion needs an appropriate knowledge of the inheritance? Int J Immunogenet. 2008;35(6):427–32.
different mechanisms able to lead to the onset of Alpsoy E, Zouboulis CC, Ehrlich GE. Mucocutaneous
such mucosal lesion and, ideally, of the lesions of Behcet’s disease. Yonsei Med J. 2007;48
etiopathogenesis of the underlining diseases. (4):573–85.
Alpsoy E. Behcet’s disease: a comprehensive review with a
Unfortunately, for many of them, including com- focus on epidemiology, etiology and clinical features,
mon disorders as recurrent aphthous stomatitis and management of mucocutaneous lesions.
and immunological conditions, very little is J Dermatol. 2016; 43(6):620–32.
known, and for this reason, treatment is essen- Alrashdan MS, Cirillo N, McCullough M. Oral lichen
planus: a literature review and update. Arch Dermatol
tially palliative, while a better understanding of Res. 2016;308(8):539–51.
the causes and pathological mechanisms respon- Andrès E, Nachit M, Guillet-Thibault J. Oral manifesta-
sible for them would warrant a far better manage- tions of vitamin B12 and B9 deficiencies: a prospective
ment of affected subjects. study. J Oral Pathol Med. 2016;45(2):154.
Axéll T. A prevalence study of oral mucosal lesions in
an adult Swedish population. Odontol Revy Suppl.
1976;36:1–103.
Cross-References Azizlerli G, Kose AA, Sarica R. Prevalence of Behcet’s
disease in Istanbul, Turkey. Int J Dermatol. 2003;42
(10):803–6.
Babaee N, Hosseinkazemi H, Pouramir M, Khakbaz
▶ Clinical Immunology in Diagnoses of Maxillo- Baboli O, Salehi M, Khadir F, Bijani A, Mehryari M.
facial Disease Salivary oxidant/antioxidant status and haematological
▶ Gingival Pathology parameters in patients with recurrent aphthous stomati-
tis. Caspian J Int Med. 2016;7(1):13–8.
▶ Interface Between Oral and Systemic Disease
Baccaglini L, Lalla RV, Bruce AJ, Sartori-Valinotti JC,
▶ Laboratory Medicine and Diagnostic Pathology Latortue MC, Carrozzo M, Rogers RS 3rd. Urban
▶ Non-odontogenic Bacterial Infections legends: recurrent aphthous stomatitis. Oral Dis.
▶ Oral and Maxillofacial Fungal Infections 2011;17(8):755–70.
Bachtiar EW, Cornain S, Siregar B, Raharjo TW.
Decreased CD4+/CD8+ ratio in major type of
▶ Oral Lichen Planus recurrent aphthous ulcers: comparing major to minor
▶ Oral Manifestations of Systemic Diseases and types of ulcers. Asian Pac J Allergy Immunol.
Their Treatments 1998;16(2–3):75–9.
Balasubramaniam R, Kuperstein AS, Stoopler ET.
▶ Oral Mucosal Malignancies
Update on oral herpes virus infections. Dent Clin N
▶ Oral Vesicular and Bullous Lesions Am. 2014;58(2):265–80.
▶ Pediatric Oral Medicine Ballmer-Weber BK. Food allergy in adolescence and adult-
▶ Pharmacotherapeutic Approaches in Oral hood. Chem Immunol Allergy. 2015;101:51–8.
Bang DS, Oh SH, Lee KH. Influence of sex on patients
Medicine
with Behcet’s disease in Korea. J Korean Med Sci.
▶ Soft and Hard Tissue Operative Investigations 2003;18(2):231–5.
in the Diagnosis and Treatment of Oral Disease Bao ZX, Yang XW, Shi J, Liu LX. Serum zinc levels
in 368 patients with oral mucosal diseases: a prelimi-
nary study. Med Oral Patol Oral Cir Bucal. 2016;21(3):
e335–40.
References Barker JM, Liu E. Celiac disease: pathophysiology, clinical
manifestations, and associated autoimmune conditions.
Abraham C, Cho JH. Inflammatory bowel disease. N Engl Adv Pediatr Infect Dis. 2008;55:349–65.
J Med. 2009;361(21):2066–78. Baumgart DC, Sandborn WJ. Inflammatory bowel disease:
Abrams EM, Sicherer SH. Diagnosis and management of clinical aspects and established and evolving therapies.
food allergy. CMAJ. 2016;188(15):1087–93. Lancet. 2007;369(9573):1641–57.
1038 G. Lodi et al.
Bazrafshani MR, Hajeer AH, Ollier WE, Thornhill MH. Compilato D, Carroccio A, Calvino F, Di Fede G,
IL-1B and IL-6 gene polymorphisms encode significant Campisi G. Haematological deficiencies in patients
risk for the development of recurrent aphthous stoma- with recurrent aphthosis. J Eur Acad Dermatol
titis (RAS). Genes Immun. 2002;3(5):302–5. Venereol. 2010;24(6):667–73.
Behçet H. Uber rezidivierende aphthöse, durch ein Cowan D, Ho B, Sykes KJ, Wei JL. Pediatric oral burns: a
Virus verursachte Geschwure, am Mund, am Auge, ten-year review of patient characteristics, etiologies and
und an den Genitalien. Dermatol Wochenschr. treatment outcomes. Int J Pediatr Otorhinolaryngol.
1937;36:1152–7. 2013;77(8):1325–8.
Besu I, Jankovic L, Magdu IU, Konic-Ristic A, Crivelli MR, Aguas S, Adler I, Quarracino C, Bazerque P.
Raskovic S, Juranic Z. Humoral immunity to cow’s Influence of socioeconomic status on oral mucosa
milk proteins and gliadin within the etiology of recur- lesion prevalence in schoolchildren. Community Dent
rent aphthous ulcers? Oral Dis. 2009;15(8):560–4. Oral Epidemiol. 1988;16(1):58–60.
Besu I, Jankovic L, Konic-Ristic A, Raskovic S, Besu V, Dalvi SR, Yildirim R, Yazici Y. Behcet’s syndrome. Drugs.
Djuric M, Cakic S, Magdu IU, Juranic Z. The 2012;72(17):2223–41.
role of specific cow’s milk proteins in the etiology Davatchi F, Sadeghi Abdollahi B, Chams-Davatchi C,
of recurrent aphthous ulcers. J Oral Pathol Med. Shahram F, Shams H, Nadji A, Faezi T, Akhlaghi M,
2013;42(1):82–8. Ghodsi Z, Mohtasham N, Ashofteh F. The saga of
Boras VV, Lukac J, Brailo V, Picek P, Kordic D, Zilic IA. diagnostic/classification criteria in Behcet’s disease.
Salivary interleukin-6 and tumor necrosis factor-alpha Int J Rheum Dis. 2015;18(6):594–605.
in patients with recurrent aphthous ulceration. J Oral de Carvalho FK, de Queiroz AM, Bezerra da Silva RA,
Pathol Med. 2006;35(4):241–3. Sawamura R, Bachmann L, Bezerra da Silva LA,
Bradley PJ, Ferlito A, Devaney KO, Rinaldo A. Crohn’s Nelson-Filho P. Oral aspects in celiac disease children:
disease manifesting in the head and neck. Acta clinical and dental enamel chemical evaluation. Oral Surg
Otolaryngol. 2004;124(3):237–41. Oral Med Oral Pathol Oral Radiol. 2015;119(6):636–43.
Brennan MT, Valerin MA, Napeñas JJ, Lockhart PB. Oral de Menthon M, Lavalley MP, Maldini C, et al. HLA-B51/
manifestations of patients with lupus erythematosus. B5 and the risk of Behcet’s disease: a systematic review
Dent Clin N Am. 2005;49(1):127–41. and meta-analysis of case–control genetic association
Brocklehurst P, Tickle M, Glenny AM, Lewis MA, studies. Arthritis Rheum. 2009;61(10):1287–96.
Pemberton MN, Taylor J, Walsh T, Riley P, Yates JM. Fairfield KM, Fletcher RH. Vitamins for chronic disease
Systemic interventions for recurrent aphthous stomati- prevention in adults: scientific review. JAMA.
tis (mouth ulcers). Cochrane Database Syst Rev. 2002;287(23):3116–26.
2012;9:CD005411. Fasano A, Catassi C. Clinical practice. Celiac disease.
Buno IJ, Huff JC, Weston WL, Cook DT, Brice SL. N Engl J Med. 2012;367(25):2419–26.
Elevated levels of interferon gamma, tumor necrosis Gallo C d B, Mimura MA, Sugaya NN. Psychological
factor alpha, interleukins 2, 4, and 5, but not interleukin stress and recurrent aphthous stomatitis. Clinics (Sao
10, are present in recurrent aphthous stomatitis. Arch Paulo). 2009;64(7):645–8.
Dermatol. 1998;134(7):827–31. García-Pola Vallejo MJ, Martínez Díaz-Canel AI, García
Burgan SZ, Sawair FA, Amarin ZO. Hematologic status in Martín JM, González García M. Risk factors for oral
patients with recurrent aphthous stomatitis in Jordan. soft tissue lesions in an adult Spanish population. Com-
Saudi Med J. 2006;27(3):381–4. munity Dent Oral Epidemiol. 2002;30(4):277–85.
Burisch J, Jess T, Martinato M, Lakatos PL, ECCO Gilvetti C, Porter SR, Fedele S. Traumatic chemical oral
-EpiCom. The burden of inflammatory bowel disease ulceration: a case report and review of the literature.
in Europe. J Crohns Colitis. 2013;7(4):322–37. Br Dent J. 2010;208(7):297–300.
Carrard V, Haas A, Rados P, Filho M, Oppermann R, Green PHR, Cellier C. Celiac disease. N Engl J Med.
Albandar J, Susin C. Prevalence and risk indicators of 2007;357(17):1731–43.
oral mucosal lesions in an urban population from South Gurler A, Boyvat A, Tursen U. Clinical manifestations of
Brazil. Oral Dis. 2011;17(2):171–9. Behcet’s disease: an analysis of 2147 patients. Yonsei
Challacombe SJ, Barkhan P, Lehner T. Haematological Med J. 1997;38(6):423–7.
features and differentiation of recurrent oral ulceration. Gujral N, Freeman HJ, Thomson AB. Celiac disease: prev-
Br J Oral Surg. 1977;15(1):37–48. alence, diagnosis, pathogenesis and treatment. World J
Chen H, Sui Q, Chen Y, Ge L, Lin M. Impact Gastroenterol. 2012;18(42):6036–59.
of haematologic deficiencies on recurrent aphthous Hello M, Barbarot S, Bastuji-Garin S, Revuz J, Chosidow O.
ulceration: a meta-analysis. Br Dent J. 2015;218(4):E8. Use of thalidomide for severe recurrent aphthous
Chi AC, Day TA, Neville BW. Oral cavity and oropharyn- stomatitis: a multicenter cohort analysis. Medicine
geal squamous cell carcinoma–an update. CA Cancer J (Baltimore). 2010;89(3):176–82.
Clin. 2015;65(5):401–21. Ho MH, Wong WH, Chang C. Clinical spectrum of food
Collet E, Jeudy G, Dalac S. Cheilitis, perioral dermatitis allergies: a comprehensive review. Clin Rev Allergy
and contact allergy. Eur J Dermatol. 2013;23(3):303–7. Immunol. 2014;46(3):225–40.
International Study Group for Behçet Disease. Criteria associated with recurrent aphthous ulceration.
for diagnosis of Behçet disease. Lancet. Microbes Infect. 2005;7(4):635–44.
1990;335(8697):1078–80. Lionetti E, Castellaneta S, Francavilla R, Pulvirenti A,
International Team for the Revision of the International Tonutti E, Amarri S, Barbato M, Barbera C, Barera G,
Criteria for Behçet Disease (ITR-ICBD). Bellantoni A, Castellano E, Guariso G, Limongelli
The international criteria for Behçet disease (ICBD): a MG, Pellegrino S, Polloni C, Ughi C, Zuin G,
collaborative study of 27 countries on the sensitivity Fasano A, Catassi C, SIGENP (Italian Society of Pedi-
and specificity of the new criteria. J Eur Acad Dermatol atric Gastroenterology, Hepatology, and Nutrition)
Venereol. 2014;28(3):338–47. Working Group on Weaning and CD Risk. Introduction
Jung SA. Differential diagnosis of inflammatory bowel of gluten, HLA status, and the risk of celiac disease in
disease: what is the role of colonoscopy? Clin Endosc. children. N Engl J Med. 2014;371(14):1295–303.
2012;45(3):254–62. Lo Russo L, Fedele S, Guiglia R, Ciavarella D, Lo
Kalla R, Ventham NT, Satsangi J, Arnott ID. Crohn’s dis- Muzio L, Gallo P, Di Liberto C, Campisi G. Diagnostic
ease. BMJ. 2014;349:g6670. pathways and clinical significance of desquamative
Katsanos KH, Torres J, Roda G, Brygo A, Delaporte E, gingivitis. J Periodontol. 2008;79(1):4–24.
Colombel JF. Review article: non-malignant oral man- Lopez-Jornet P, Camacho-Alonso F, Martos N. Hemato-
ifestations in inflammatory bowel diseases. Aliment logical study of patients with aphthous stomatitis. Int J
Pharmacol Ther. 2015;42(1):40–60. Dermatol. 2014;53(2):159–63.
Khan NF, Saeed M, Chaudhary S, Khan NF. Main DM, Chamberlain MA. Clinical differentiation of
Haematological parameters and recurrent aphthous oral ulceration in Behcet’s disease. Br J Rheumatol.
stomatitis. J Coll Physicians Surg Pak. 2013;23(2): 1992;31(11):767–70.
124–7. Marty M, Bailleul-Forestier I, Vaysse F. Recurrent
Keogan MT. Clinical Immunology Review Series: an Aphthous stomatitis as a marker of celiac disease in
approach to the patient with recurrent orogenital ulcer- children. Pediatr Dermatol. 2016;33(2):241.
ation, including Behcet’s syndrome. Clin Exp McCartan BE, Healy CM, McCreary CE, Flint SR,
Immunol. 2009;156(1):1–11. Rogers S, Toner ME. Characteristics of patients
Kim B, LeBoit PE. Histopathologic features of erythema with orofacial granulomatosis. Oral Dis.
nodosum – like lesions in Behcet disease: a comparison 2011;17(7):696–704.
with erythema nodosum focusing on the role of vascu- McGowan EC, Peng RD, Salo PM, Zeldin DC, Keet CA.
litis. Am J Dermatopathol. 2000;22(5):379–90. Changes in food-specific IgE over time in the National
Kitaichi N, Miyazaki A, Iwata D, et al. Ocular features of Health and nutrition examination survey (NHANES).
Behcet’s disease: an international collaborative study. J Allergy Clin Immunol Pract. 2016;4(4):713–20.
Br J Ophthalmol. 2007;91(12):1579–82. McMillan R, Taylor J, Shephard M, Ahmed R,
Krause I, Rosen Y, Kaplan I, et al. Recurrent aphthous Carrozzo M, Setterfield J, Grando S, Mignogna M,
stomatitis in Behcet’s disease: clinical features and Kuten-Shorrer M, Musbah T, Elia A, McGowan R,
correlation with systemic disease expression and sever- Kerr AR, Greenberg MS, Hodgson T, Sirois D.
ity. J Oral Pathol Med. 1999;28(5):193–6. World workshop on oral medicine VI: a systematic
Koybasi S, Parlak AH, Serin E, Yilmaz F, Serin D. Recur- review of the treatment of mucocutaneous pemphigus
rent aphthous stomatitis: investigation of possible etio- vulgaris. Oral Surg Oral Med Oral Pathol Oral Radiol.
logic factors. Am J Otolaryngol. 2006;27(4):229–32. 2015;120(2):132–42.
Kozlak ST, Walsh SJ, Lalla RV. Reduced dietary intake Miller MF, Garfunkel AA, Ram CA, Ship II. The inheri-
of vitamin B12 and folate in patients with tance of recurrent aphthous stomatitis. Observations
recurrent aphthous stomatitis. J Oral Pathol Med. on susceptibility. Oral Surg Oral Med Oral Pathol.
2010;39(5):420–3. 1980;49(5):409–12.
Lalla RV, Choquette LE, Feinn RS, Zawistowski H, Mortazavi H, Safi Y, Baharvand M, Rahmani S. Diagnostic
Latortue MC, Kelly ET, Baccaglini L. Multivitamin features of common oral ulcerative lesions: an updated
therapy for recurrent aphthous stomatitis: a random- decision tree. Int J Dent. 2016;2016:7278925.
ized, double-masked, placebo-controlled trial. J Am Nahlieli O, Eliav E, Shapira Y, Baruchin AM. Central
Dent Assoc. 2012;143(4):370–6. palatal burns associated with the eating of microwaved
Lankarani KB, Sivandzadeh GR, Hassanpour S. Oral man- pizzas. Burns. 1999;25(5):465–6.
ifestation in inflammatory bowel disease: a review. National Center for Chronic Disease Prevention and Health
World J Gastroenterol. 2013;19:8571–9. Promotion, Centers for Disease Control and Prevention
Laranjeira N, Fonseca J, Meira T, Freitas J, Valido S, Leitão J. – Epidemiology of the IBD – Inflammatory Bowel
Oral mucosa lesions and oral symptoms in inflam- Disease. [Internet] 2015 [page last updated: March
matory bowel disease patients. Arq Gastroenterol. 31, 2015]. Available from: www.cdc.gov/ibd/ibd-epide
2015;52(2):105–10. miology.htm. Accessed 19 Aug 2016.
Lin SS, Chou MY, Ho CC, Kao CT, Tsai CH, Wang L, Ogura M, Yamamoto T, Morita M, Watanabe T. A case-
Yang CC. Study of the viral infections and cytokines control study on food intake of patients with recurrent
1040 G. Lodi et al.
aphthous stomatitis. Oral Surg Oral Med Oral Pathol clinical features, and treatment. Dent Clin North Am.
Oral Radiol Endod. 2001;91(1):45–9. 2013;57(4):583–96.
Olson JA, Feinberg I, Silverman S Jr, Abrams D, Green- Sartor RB. Mechanisms of disease: pathogenesis of
span JS. Serum vitamin B12, folate, and iron levels in Crohn’s disease and ulcerative colitis. Nat Clin Pract
recurrent aphthous ulceration. Oral Surg Oral Med Oral Gastroenterol Hepatol. 2006;3(7):390–407.
Pathol. 1982;54(5):517–20. Scully C. Clinical practice. Aphthous ulceration. N Engl J
Orbak R, Cicek Y, Tezel A, Dogru Y. Effects of zinc Med. 2006;355(2):165–72.
treatment in patients with recurrent aphthous stomatitis. Ship II. Epidemiologic aspects of recurrent aphthous
Dent Mater J. 2003;22(1):21–9. ulcerations. Oral Surg Oral Med Oral Pathol.
Orbak R, Kara C, Ozbek E, Tezel A, Demir T. Effects of 1972;33(3):400–6.
zinc deficiency on oral and periodontal diseases in rats. Scully C, Felix DH. Oral medicine–update for the dental
J Periodontal Res. 2007;42(2):138–43. practitioner. Aphthous and other common ulcers.
Ozler GS. Zinc deficiency in patients with recurrent Br Dent J. 2005;199(5):259–64.
aphthous stomatitis: a pilot study. J Laryngol Otol. Scully C, Gorsky M, Lozada-Nur F. The diagnosis
2014;128(6):531–3. and management of recurrent aphthous stomatitis:
Ozturk P, Belge Kurutas E, Ataseven A. Copper/zinc and a consensus approach. J Am Dent Assoc.
copper/selenium ratios, and oxidative stress as bio- 2003;134(2):200–7.
chemical markers in recurrent aphthous stomatitis. J Senusi A, Seoudi N, Bergmeier LA, et al. Genital ulcer
Trace Elem Med Biol. 2013;27(4):312–6. severity score and genital health quality of life in
Pedersen A, Hornsleth A. Recurrent aphthous ulceration: a Behcet’s disease. Orphanet J Rare Dis. 2015;10:117.
possible clinical manifestation of reactivation of vari- Seyedmajidi SA, Seyedmajidi M, Moghadamnia A,
cella zoster or cytomegalovirus infection. J Oral Pathol Khani Z, Zahedpasha S, Jenabian N, Jorsaraei G,
Med. 1993;22(2):64–8. Halalkhor S, Motallebnejad M. Effect of zinc-deficient
Pekiner FN, Aytugar E, Demirel GY, Borahan MO. Inter- diet on oral tissues and periodontal indices in rats. Int J
leukin-2, interleukin-6 and T regulatory cells in periph- Mol Cell Med. 2014;3(2):81–7.
eral blood of patients with Behçet’s disease and Shah D, Sachdev HS, Gera T, De-Regil LM, Peña-
recurrent aphthous ulcerations. J Oral Pathol Med. Rosas JP. Fortification of staple foods with zinc for
2012;41(1):73–9. improving zinc status and other health outcomes in
Pentenero M, Broccoletti R, Carbone M, Conrotto D, the general population. Cochrane Database Syst Rev.
Gandolfo S. The prevalence of oral mucosal lesions in 2016;6:CD010697.
adults from the Turin area. Oral Dis. 2008;14(4):356–66. Ship II. Nutrition and food intake in aphthous ulcerations.
Piskin S, Sayan C, Durukan N, Senol M. Serum iron, Arch Environ Health. 1962;5:158–66.
ferritin, folic acid, and vitamin B12 levels in recurrent Ship JA, Chavez EM, Doerr PA, Henson BS, Sarmadi M.
aphthous stomatitis. J Eur Acad Dermatol Venereol. Recurrent aphthous stomatitis. Quintessence Int.
2002;16(1):66–7. 2000;31(2):95–112.
Pittock S, Drumm B, Fleming P, McDermott M, Imrie C, Shulman JD, Beach MM, Rivera-Hidalgo F. The preva-
Flint S, Bourke B. The oral cavity in Crohn’s disease. lence of oral mucosal lesions in U.S. adults: data
J Pediatr. 2001;138:767–71. from the third National Health and nutrition
Porter SR, Scully C, Flint S. Hematologic status in examination survey, 1988–1994. J Am Dent Assoc.
recurrent aphthous stomatitis compared with other 2004;135(9):1279–86.
oral disease. Oral Surg Oral Med Oral Pathol. Singh B, Kedia S, Konijeti G, Mouli VP, Dhingra R,
1988;66(1):41–4. Kurrey L, Srivastava S, Pradhan R, Makharia G,
Preeti L, Magesh KT, Rajkumar K, Karthik R. Ahuja V. Extra-intestinal manifestations of inflamma-
Recurrent aphthous stomatitis. J Oral Maxillofac tory bowel disease and intestinal tuberculosis: fre-
Pathol. 2011;15(3):252–6. quency and relation with disease phenotype. Indian J
Rashid M, Zarkadas M, Anca A, Limeback H. Oral man- Gastroenterol. 2015;34:43–50.
ifestations of celiac disease: a clinical guide for den- Slebioda Z, Szponar E, Kowalska A. Etiopathogenesis of
tists. J Can Dent Assoc. 2011;77:b39. recurrent aphthous stomatitis and the role of immuno-
Rogers RS 3rd, Hutton KP. Screening for haematinic defi- logic aspects: literature review. Arch Immunol Ther
ciencies in patients with recurrent aphthous stomatitis. Exp. 2014;62(3):205–15.
Australas J Dermatol. 1986;27(3):98–103. Sun A, Chen HM, Cheng SJ, Wang YP, Chang JY, YC W,
Sackett DL, Haynes RB, Guyatt GH, Tugwell P. Clinical Chiang CP. Significant association of deficiencies of
epidemiology: a basic science for clinical medicine. hemoglobin, iron, vitamin B12, and folic acid and high
2nd ed. Boston: Little, Brown; 1991. homocysteine level with recurrent aphthous stomatitis.
Sakane T, Takeno M, Suzuki N, et al. Behcet’s disease. N J Oral Pathol Med. 2015;44(4):300–5.
Engl J Med. 1999;341(17):1284–91. Sun A, Chu CT, Liu BY, Wang JT, Leu JS, Chiang CP.
Samim F, Auluck A, Zed C, Williams PM. Erythema Expression of interleukin-2 receptor by activated
multiforme: a review of epidemiology, pathogenesis, peripheral blood lymphocytes upregulated by the
plasma level of interleukin-2 in patients with recurrent vitamin B12 deficiency. Cochrane Database Syst Rev.
aphthous ulcers. Proc Natl Sci Counc Repub China B. 2005;3:CD004655.
2000;24(3):116–22. Volkov I, Rudoy I, Freud T, Sardal G, Naimer S, Peleg R,
Taylor J, Glenny AM, Walsh T, et al. Interventions for the Press Y. Effectiveness of vitamin B12 in treating recur-
management of oral ulcers in Behcet’s disease. rent aphthous stomatitis: a randomized, double-blind,
Cochrane Database Syst Rev. 2014;9:CD011018. placebo-controlled trial. J Am Board Fam Med.
Taylor J, McMillan R, Shephard M, Setterfield J, 2009;22(1):9–16.
Ahmed R, Carrozzo M, Grando S, Mignogna M, Wardhana, Datau EA. Recurrent aphthous stomatitis
Kuten-Shorrer M, Musbah T, Elia A, McGowan R, caused by food allergy. Acta Med Indones.
Kerr AR, Greenberg MS, Hodgson T, Sirois D. 2010;42(4):236–40.
World workshop on oral medicine VI: a systematic World Health Organization. Nutrition. Micronutrients.
review of the treatment of mucous membrane [Internet] 2016. Available from: www.who.int/nutri
pemphigoid. Oral Surg Oral Med Oral Pathol Oral tion/topics/micronutrients/en/#. Accessed 19 Aug 2016.
Radiol. 2015;120(2):161–71. Wray D. A double-blind trial of systemic zinc sulfate in
Thongprasom K, Youngnak P, Aneksuk V. Hematologic recurrent aphthous stomatitis. Oral Surg Oral Med Oral
abnormalities in recurrent oral ulceration. Pathol. 1982;53(5):469–72.
Southeast Asian J Trop Med Public Health. 2002;33 Wray D, Ferguson MM, Mason DK, Hutcheon AW,
(4):872–7. Dagg JH. Recurrent aphthae: treatment with
Topaloğlu Demir F, Kocatürk E, Yorulmaz E, Adalı G, vitamin B12, folic acid, and iron. Br Med J.
Kavala M. Mucocutaneous manifestations of inflam- 1975;2(5969):490–3.
matory bowel disease in Turkey. J Cutan Med Surg. Wray D, Ferguson MM, Hutcheon AW, Dagg JH. Nutri-
2014;18(6):397–404. tional deficiencies in recurrent aphthae. J Oral Pathol
Tugal-Tutkun I, Onal S, Altan-Yaycioglu R, et al. Uveitis Med. 1978;7(6):418–23.
in Behcet disease: an analysis of 880 patients. Am J Wray D, Vlagopoulos TP, Siraganian RP. Food allergens
Ophthalmol. 2004;138(3):373–80. and basophil histamine release in recurrent aphthous
Veloso FT, Carvalho J, Magro F. Immune-related systemic stomatitis. Oral Surg Oral Med Oral Pathol.
manifestations of inflammatory bowel disease. A pro- 1982;54(4):388–95.
spective study of 792 patients. J Clin Gastroenterol. Wright A, Ryan FP, Willingham SE, Holt S, Page AC,
1996;23(1):29–34. Hindle MO, Franklin CD. Food allergy or intolerance
Victoria JM, Kalapothakis E, Silva Jde F, Gomez RS. in severe recurrent aphthous ulceration of the mouth. Br
Helicobacter pylori DNA in recurrent aphthous stoma- Med J (Clin Res Ed). 1986;292(6530):1237–8.
titis. J Oral Pathol Med. 2003;32(4):219–23. Yamamoto T, Yoneda K, Ueta E, Osaki T. Serum cyto-
Vidal-Alaball J, Butler CC, Cannings-John R, Goringe A, kines, interleukin-2 receptor, and soluble intercellular
Hood K, McCaddon A, McDowell I, Papaioannou A. adhesion molecule-1 in oral disorders. Oral Surg Oral
Oral vitamin B12 versus intramuscular vitamin B12 for Med Oral Pathol. 1994;78(6):727–35.
Oral Lichen Planus
Michael J. McCullough, Mohammad S. Alrashdan, and

Nicola Cirillo
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1044
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1045
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1045
Genetic Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1045
Infectious Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1046
Psychological Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1046
Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1047
Systemic Associations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1047
Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1048
The Immunology of the Oral Cavity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1049
Pathogenic Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1050
Clinical-Pathologic Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1055
Clinical Appearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1055
Signs, Symptoms, Clinical Behavior and Scoring Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . 1057
Histopathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1058
M. J. McCullough (*)
Oral Anatomy, Medicine, and Surgery Section, Melbourne
Dental School, Faculty of Medicine, Dentistry and Health
Sciences, The University of Melbourne, Carlton, VIC,
Australia
e-mail: m.mccullough@unimelb.edu.au
M. S. Alrashdan
Faculty of Dentistry, Department of Oral Medicine and
Oral Surgery, Jordan University of Science and
Technology, Irbid, Jordan
e-mail: msalrashdan3@just.edu.jo
N. Cirillo
Melbourne Dental School and Oral Health CRC, Faculty of
Medicine, Dentistry and Health Sciences, The University
of Melbourne, Carlton, VIC, Australia
e-mail: nicola.cirillo@unimelb.edu.au

https://doi.org/10.1007/978-3-319-72303-7_14
1044 M. J. McCullough et al.
Oral Lichenoid Reactions (OLR) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1059

Cutaneous Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1061
Other Mucosal Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1061
Malignant Potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1061
OLL and Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1063
Tumors Developing in OLP and their
Carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1064
Patient Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1067
Topical Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1068
Systemic Drug Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1072
Miscellaneous Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1073
Follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1074
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1075
Abstract ongoing debate regarding the malignant trans-

Lichen planus (LP) is a chronic, inflammatory, formation potential of OLLs, a long-term fol-
mucocutaneous, immune-mediated condition low-up protocol is essential.
with variable clinical presentations. Oral lichen
planus (OLP) is the oral variant and affects Keywords
about 1–2% of the general adult population Oral lichen planus · Oral lichenoid lesions ·
with characteristic relapses and remissions. Oral lichenoid reactions · Malignant
OLP is about twice as common in females as transformation
in males. The most commonly involved oral
sites are the buccal mucosa, lateral surfaces of
the tongue, and gingivae, respectively. Six Introduction
clinical patterns of OLP are described in liter-
ature: reticular, plaque-like, erythematous, ero- The term lichen planus (LP) is derived from the
sive/ulcerative, papular, and bullous. Helper Greek word leichen meaning tree moss and the
and cytotoxic T lymphocytes, in addition to Latin planus meaning flat. Erasmus Wilson first
antigen-presenting cells, represent the key described the condition LP in 1869, as a chronic
cells in the inflammatory infiltrate in OLP and inflammatory disease affecting the skin, scalp,
play an essential role in its pathogenesis. The nails, and mucosa, with possible rare malignant
diagnosis of OLP is usually made by clinical transformation (Farhi and Dupin 2010). LP may
and histological examinations. Lesions similar involve the hair follicles (lichen planopilaris,
to OLP may develop as a reaction to dental resulting in scarring alopecia), nails, esophagus,
restorative materials or systemic medications and, more seldom, the eyes, urinary tract, nasal
or conditions and are called oral lichenoid mucosa, and larynx (Parashar 2011).
reactions (OLR). OLP and OLR may collec- The oral variant, oral lichen planus (OLP), is a
tively be referred to as oral lichenoid lesions chronic inflammatory disease affecting the oral
(OLLs). Management of symptomatic OLLs mucosa with characteristic relapses and remis-
varies considerably and ranges from elimina- sions (Scully et al. 1998; Eisen et al. 2005; Lodi
tion of precipitating factors – local or systemic et al. 2005a). While cutaneous lesions of LP are
to long-term pharmacological interventions, generally self-limiting and pruritic, oral lesions
mainly with topical immunosuppressants, cor- are commonly chronic, non-remissive, and can
ticosteroids in particular. In the light of the be a source of morbidity (Scully et al. 1998).
Oral Lichen Planus 1045
The diagnosis of OLP is usually made by clin- There is a slight female predisposition (female/
ical and histological examinations. However, in male sex ratio is 1.5–2:1), and the age of onset is
classical lesions (bilateral, reticular pattern), it is generally between 30 and 60 years (Scully et al.
possible to make a diagnosis based on their clinical 1998; Al-Hashimi et al. 2007; Farhi and Dupin
appearance alone (Epstein et al. 2003). Addition- 2010). However, there have been case reports of
ally, there is a spectrum of oral lichenoid lesions OLP occurring in children, with a 17% prevalence
(OLLs) that may confuse the differential diagnosis. of oral involvement in a population of 100 children
These include lichenoid contact lesions, lichenoid diagnosed with LP at a mean age of 8.7 years in
drug reactions, and lichenoid lesions of graft- one report (Kanwar and De 2010).
versus-host disease. Systemic medications, such Genital and cutaneous LP are associated with
as nonsteroidal anti-inflammatory drugs, antihy- approximately 20% and 15% of OLP cases,
pertensives, and oral hypoglycemics, can contrib- respectively, while it is estimated that OLP occurs
ute to the development of oral lichenoid reactions in 70–77% of patients with cutaneous LP (Scully
(OLRs) (Ismail et al. 2007). Dental restorative et al. 1998; Farhi and Dupin 2010; Kanwar and De
materials, including amalgam, gold, and nickel, 2010).
may also be related to localized OLRs in a number
of patients (Epstein et al. 2003).
Treatment is not always necessary, unless Etiology
OLLs are symptomatic (Scully et al. 1998). Man-
agement of symptomatic OLLs varies consider- OLP is not a classical autoimmune disorder, and
ably and ranges from elimination of precipitating the precise etiology of this condition is unknown.
or provoking local and systemic factors, psycho- However, given that cell-mediated immune
social interventions, to long-term pharmacologi- dysregulation targeting the stratified squamous
cal therapies. Thus, although OLP localizes to the epithelia has been shown to be associated with
oral cavity, there are broader implications in terms the pathogenesis of OLP (Epstein et al. 2003;
of patient management that warrant careful con- Eisen et al. 2005; Lodi et al. 2005a), it is possible
sideration. The ongoing controversy as to whether that a LP-specific epidermal antigen is present in
OLP is associated with an increased risk of malig- some epithelial cells. The nature of the antigen,
nant transformation adds further complexity to however, remains uncertain. Several predisposing
this disease. factors have been reported to be associated with
OLP and OLLs.
Epidemiology
Genetic Background
The estimated prevalence of OLP in general adult
population is 0.5–2% (Scully et al. 1998; Eisen Genetic background seems to play a role in OLP
et al. 2005). However, because of a lack of stan- pathogenesis as several familial cases have been
dardized approaches to the clinical diagnosis of reported (Bermejo-Fenoll and Lopez-Jornet
OLP and OLL, it is difficult to draw accurate fig- 2006); however the association has not been con-
ures about the prevalence of OLP. In a demographic sistent. In terms of HLA associations, an increase
study from Sweden, 20,333 people aged 15 and in HLA-B15, Bw57, B5, B7, BX, DR2 and a
above were examined for signs of OLP. The prev- decrease in the frequency of HLA-DQ1, DR4,
alence reported was 1.9%, 1.6% in men, and 2.2% and B18 has been noted for OLP (Roitberg-
in women (Axell and Rundquist 1987). Another Tambur et al. 1994). On the other hand, in a
demographic study from India showed a preva- comprehensive review of literature, Porter et al.
lence of 2.6% (Murti et al. 1986). A report from reported no significant association with any
Malaysia showed a relatively low prevalence of particular HLA types in familial LP (Porter
0.38% (Zain et al. 1997). et al. 1997).
Genetic polymorphisms of several cytokines (HIV) have all been postulated in different studies
have been postulated to be associated with the to have an association with an increased incidence
clinical presentation of LP. Interferon-gamma of OLP, yet definitive evidence for the association
(IFN-γ) UTR 5644 genotype frequencies showed is lacking (Lodi et al. 2005a; Farhi and Dupin
a significant increase in number of T/T homozy- 2010).
gotes in a sample of OLP patients (n = 44) com- For example, the receptor for EBV (CD21) was
pared with controls (n = 140) (40.9% vs. 22.9%; shown to be upregulated in OLP, and a signifi-
p = 0.0022) (Carrozzo et al. 2004). It has been cantly higher optometric density of EBV anti-
suggested that genetic polymorphism of the first earlier antigen (EA) IgG positivity has been
intron of the promoter gene of IFN-gamma may reported in a sample of OLP patients (n = 22)
be an important risk factor to develop oral lesions compared with controls (n = 22), despite no dif-
of LP, whereas an increase in the frequency of ference in the frequency of both EBV IgG and
308A TNF-alpha allele may best contribute to IgM for EA and nuclear antigen-1 (EBNA)
the development of additional skin involvement. (Pedersen 1996).
More recently, the concept that a particular In summary, while association between OLP
genetic background may be important in a subset and infectious agents has been reported, at present
of patients with OLP has been presented there is no evidence for a causative role of these
(Carrozzo et al. 2011). In particular, this study microorganisms in OLP.
suggested that those patients who had both OLP
and chronic hepatitis C infection may well have
particular HLA-Cw* alleles (Carrozzo et al. Psychological Factors
2011).
Nevertheless, the overall statement that OLP is Psychological factors are thought to play a role in
a genetically determined disease has not been the pathogenesis of OLP. A group of OLP patients
confirmed, and further studies in different geo- (n = 9) exhibited higher levels of anxiety, greater
graphic areas are required. depression, and increased vulnerability to psycho-
logical disorders, as opposed to a group of
20 healthy controls (Soto Araya et al. 2004).
Infectious Agents In another study that involved 100 OLP
patients, those with erosive LP were shown to
Many infectious agents, principally viruses, have exhibit higher depression scores than patients
been studied in association with OLP, but the with nonerosive LP (Rojo-Moreno et al. 1998).
evidence is generally sparse. Other infectious In addition to the chronic discomfort that can
agents, such as Helicobacter pylori, were also result in stress, patients with OLP were shown to
suggested to have a link to OLP by some authors be concerned about the possibility of malignancy,
(Shimoyama et al. 2000). the contagious nature of the disease, and the lack
The viruses for which an association with OLP of available patient educational materials
has been suspected can be classified in two (Burkhart et al. 1997).
groups: (1) viruses for which an association with Exacerbations of OLP have been linked to
OLP has been anecdotally suggested and periods of psychological stress and anxiety in
(2) viruses for which there is abundant documen- some studies (Rojo-Moreno et al. 1998).
tation of an association with OLP, although with In a study that involved 40 OLP patients
marked geographic disparities (discussed in sec- (20 reticular and 20 erosive OLP) assessed against
tion “Systemic Associations”). 25 healthy controls using the psychological Min-
Varicella zoster virus (VZV), Epstein-Barr nesota Multiphasic Personality Inventory
virus (EBV), cytomegalovirus (CMV), human (MMPI)-202 test, Ivanovski et al. hypothesized
herpesvirus 6 (HHV6), human papillomavirus that prolonged emotive stress in many OLP
(HPV), and human immunodeficiency virus patients may lead to psychosomatization
(as shown by significantly higher mean scores of dermatologic diseases that have been most fre-
internalization ratio index in OLP groups) which quently reported in patients infected with HCV
in turn may contribute to the initiation and clinical (Farhi and Dupin 2010). The first report appeared
expression of OLP (Ivanovski et al. 2005). How- in 1991 (Mokni et al. 1991) and suggested an
ever, as a common issue in studies of this type, the association between OLP and HCV seropositivity.
authors were unable to determine whether the Since then, the association has been well
observed psychological alterations constitute a documented in some Mediterranean populations
direct cause or a consequence of OLP. (Carrozzo et al. 1996; Erkek et al. 2001), in Japan
When the levels of anxiety and salivary corti- (Nagao et al. 1995), and in a United States metro-
sol were measured in a group of OLP patients politan population (Beaird et al. 2001). Neverthe-
(n = 40), the scores were statistically correlated less, an association between OLP and HCV
and significantly higher than a control group seropositivity could not be demonstrated in
(mean state anxiety level = 49 vs. 40, cortisol France (Dupin et al. 1997), the United Kingdom
levels = 1.46 vs. 0.93 μg/dl) (Koray et al. 2003). (Ingafou et al. 1998), and in countries with high
In conclusion, in spite of the presence of higher HCV prevalence, such as Egypt (HCV prevalence
levels of psychological stress and anxiety among estimated at 14.7%) (Ibrahim et al. 1999), and
OLP patients, the question remains whether the Nigeria (HCV prevalence estimated to range
psychological factors contribute to the etiology of from 5% to 20%) (Daramola et al. 2002).
OLP or represent a part of resulting morbidity. A systematic review of HCV prevalence in LP
patients and in matched controls without LP
yielded 25 relevant studies, including eight with
Trauma only OLP (Lodi et al. 2004). A significantly
higher proportion of HCV seropositivity was
Trauma as such has not been reported as an etio- documented in patients with OLP, with an odds
logical factor in OLP, although it has been postu- ratio (OR) of 5.7 (95% confidence interval,
lated as a mechanism by which other etiological 3.5–9.4). This association was stronger in Medi-
factors may exert their effects (Scully et al. 1998). terranean countries (OR 6.63, 95% CI, 4.7–9.4)
However, no studies were conducted to verify this but disappeared in Northern Europe such as in
hypothesis. Germany and the United Kingdom (OR 2.14,
The Koebner phenomenon (isomorphic 95% CI, 0.6–7.7). Three more recent independent
response), whereby OLP lesions develop in meta-analyses (Shengyuan et al. 2009; Lodi et al.
response to mechanical trauma, may partially 2010; Petti et al. 2011) have provided robust evi-
explain why OLP lesions develop commonly in dence that LP and HCV are associated. Overall,
sites prone to trauma, i.e., the buccal mucosa or there is a significant positive association noted in
lateral surfaces of the tongue (Eisen et al. 2005). studies across the world, although the association
is more homogeneous in studies from East and
Southeast Asia and South America than in studies
Systemic Associations from the Middle East and Europe (Baccaglini
et al. 2013).
OLP may be associated with some systemic dis- In HCV-positive patients, the estimated preva-
eases; however, few have been thoroughly inves- lence of LP is 1.6–20% (Farhi and Dupin 2010)
tigated. The most studied are the associations with being higher than expected in the respective geo-
hepatitis C, hypertension, diabetes, thyroid dis- graphic areas. In a study from Italy, 44 OLP
ease, and graft versus host disease. patients positive for HCV were compared to a
group of 144 OLP patients negative for HCV.
Hepatitis C Virus (HCV) HCV-related OLP group showed a significantly
Along with porphyria cutanea tarda and higher association with HLA class II allele
cryoglobulinemia, OLP is one of the three HLA-DR6 (52% vs. 18%), which may partially
explain the peculiar geographical heterogeneity of enteritis, and hepatitis with immunosuppression
the association between HCV and OLP, probably and cachexia. Chronic GVHD develops after day
depending on the presence of certain HLA sub- 100 and comprises an autoimmune-like syndrome
types (Carrozzo et al. 2001). comparable to ulcerative colitis, primary biliary
cirrhosis, Sjögren’s syndrome, rheumatoid arthri-
Hypertension and Diabetes Mellitus tis, and lupus-like disease with glomerulonephri-
Although OLP patients do not seem to have an tis. The skin is a primary target in chronic GVHD
increased risk of diabetes, diabetics who develop and exhibits either a lichenoid eruption or
OLP were reported to have an increased fre- sclerodermatous changes (Lodi et al. 2005a).
quency of atrophic-erosive lesions, especially Oral involvement occurs in 33–75% of patients
affecting the tongue (Bagan et al. 1993). How- with acute GVHD and up to 80% of patients with
ever, this was not confirmed in any further studies. chronic GVHD (Imanguli et al. 2008). Oral muco-
An association between OLP, diabetes sal GVHD resembles OLP both clinically and
mellitus, and hypertension was first described by histologically.
Grinspan in a small series of seven patients Squamous cell carcinoma (SCC) may develop
(Grinspan et al. 1966). The triad was later named in oral and cutaneous chronic GVHD, as reported
as Grinspan’s syndrome. Although Grinspan’s in few case reports (Lodi et al. 2005b). Most
syndrome may be seen clinically, the association patients who undergo allogeneic HSCT receive
between the three conditions may represent a stem cells from MHC-identical donors. In these
coincidental finding or probably an OLR to med- patients, GVHD is initiated by donor T cells that
ications used to manage hypertension or diabetes recognize a subset of host peptides called minor
rather than a true syndrome (Scully et al. 1998). histocompatibility antigens (miHAs). Although
the antigen specificity of LP and mucocutaneous
Thyroid Dysfunction GVHD is probably distinct, it is likely that they
The association between OLP and thyroid dys- share similar immunological effector mechanisms
function was recently investigated in a retrospec- resulting in T-cell infiltration, epithelial basement
tive Finnish study that confirmed a link between membrane disruption, basal keratinocyte apopto-
OLP and hypothyroidism in particular (Siponen sis, and clinical disease (Lodi et al. 2005a).
et al. 2010). This study compared data of 222 OLP The role of TNF-alpha as a major effector
patients with 222 age- and sex-matched controls molecule in GVHD has been confirmed in a num-
and revealed that 10% of OLP patients (n = 15) ber of experimental systems. Importantly, neutral-
versus 5% of the controls (n = 11) had hypothy- izing anti-TNF-alpha antibodies have been shown
roidism (OR 2.39, 1.05–5.61, CI 95%). to alleviate cutaneous and intestinal GVHD in
Other studies suggested a relationship between both mice and humans (Herve et al. 1992;
OLP and hyperthyroidism. Overall, more well- Brown et al. 1999).
designed, large population-based studies are
required to confirm whether an association
between OLP and thyroid disorders does exist. Pathogenesis
Graft Versus Host Disease (GVHD) Much is still not known about the
Nearly 15,000 patients worldwide receive allo- etiopathogenesis of OLP. OLP is characterized
genic hematopoietic cell transplants (HSCT) by a chronic T-cell inflammatory infiltrate with
each year, and GVHD will eventually develop in basal cell degeneration including vacuolar degen-
about 40–70% and will represent the leading eration, hyperkeratosis or parakeratosis, and saw-
cause of death in such patients (Imanguli et al. tooth rete ridges (Sugerman et al. 1993, 2002;
2008). Zhou et al. 2002). The mechanism that irrevers-
Acute GVHD occurs within the first 100 days ibly switches on this process resulting in the
of transplantation and comprises dermatitis, chronic disease state is currently unknown.
There are multiple theories on OLP pathogenesis (eosinophils) while also being involved in the
and the mechanisms that underpin the ongoing host allergic reactions. Mast cells especially are
chronic inflammatory process. In order to better thought to play an important immunological role
understand the pathobiological events that under- in OLP (Zhou et al. 2002). Natural killer
lie the development of OLP lesions, it is important (NK) cells target and destroy tumor cells as well
to recall some basic concepts of oral immunology. as viruses as part of the oral innate immune
response by recognizing peptides presented in
the context of major histocompatibility complex
The Immunology of the Oral Cavity (MHC) class I molecules. The complement sys-
tem is a series of 20 serum glycoproteins that form
The oral cavity immune system consists of innate membrane attack complexes; opsonization and
and adaptive immune system components. The chemoattractants work to upregulate phagocytosis
innate immune system consists of all the immune and mobilize the host immune system to clear
defenses that lack an immunologic memory pathogens (Delves and Roitt 2000).
(Delves and Roitt 2000). In the oral cavity the The adaptive immune response in the oral cavity
oral mucosa serves as a mechanical barrier to consists of antigen-presenting cells (APC), T cells
microbial colonization. Loss of tissue integrity and B cells. The main difference between the adap-
places the oral cavity at risk of opportunistic tive and innate immune system is the adaptive
microbial infection. immune system’s ability to tailor the response to
Saliva makes up another portion of the oral suit different pathogens as well as remember past
innate immune system. Saliva is rich in water microbial and viral challenges. The adaptive
and mucin that acts to provide a moist barrier immune system also uses MHC molecules, specif-
that helps to limit microbial colonization. It also ically MHC I and II, to distinguish self from nonself
consists of numerous ions, such as bicarbonate, to allow for a targeted immune response (Delves
phosphate, etc., that neutralize pH and keep the and Roitt 2000). The APCs of the adaptive immune
saliva supersaturated to prevent tooth deminerali- system recognize foreign, nonhost proteins, known
zation. Salivary antibodies, specifically secretory as antigens. APC of the adaptive immune system
IgA, exist in saliva and act as a first line of defense includes macrophages, B cells, dendritic cells, and
by limiting colonization and invasion of microor- Langerhans cells. Langerhans cells reside in the
ganisms into the epithelium (Brandtzaeg 2007; epidermis with the highest counts found in the
Feller et al. 2013). Saliva contains numerous non- nonkeratinized oral mucosal tissues including the
immune innate factors such as salivary peroxi- ventral tongue, soft palate, lip, and floor of mouth
dase, myeloperoxidase, lysozyme, cystatins, (Daniels 1984). Langerhans cells are thought to
proline-rich proteins, mucin, peroxidase, potentially play a role in the pathogenesis of OLP
lactoferrin, and statherin which also work to pre- (Sugerman et al. 2002; Roopashree et al. 2010;
vent microbial colonization through antifungal, Gueiros et al. 2012).
antibacterial, antiviral, and antiparasitic properties The major task of plasma cells (which are
(Tenovuo 1998). terminally differentiated B lymphocytes), is to
The oral innate immune response also consists produce immunoglobulins, specifically IgA, IgG,
of phagocytic cells such as macrophages and neu- IgM, IgE, and IgD. Secretory IgA is the primary
trophils. Macrophages are phagocytic cells antibody of the oral cavity found in present in
derived from monocytes, while neutrophils are saliva which acts as the first line of defense
polymorphonuclear granulocytes. Both work to (Brandtzaeg 2007; Feller et al. 2013). The other
detect infections organisms and destroy infectious major task of B cells is the production of memory
organisms through the process of phagocytosis B cells whose function is to circulate through
(Aderem 2003). Eosinophils, basophils, and the body and mount a rapid response against
mast cells also constitute part of the oral innate previously recognized antigens (Delves and
response working to protect against parasites Roitt 2000).
T cells are the major effector cell in cell- by keratinocyte-derived chemokines (“directed
mediated immunity. They consist of helper migration” hypothesis) (Sugerman et al. 2002).
T cells (CD4+) which recognize MHC class II The migration of activated T cells in the OLP
molecules, cytotoxic T cells (CD8+) which recog- infiltrate to oral epithelium can be mediated by
nize MHC class I molecules present on all cells, intercellular and vascular adhesion molecules
regulatory T cells which are essential for pre- (ICAM-1 and VCAM) (Eisen et al. 1990).
venting autoimmune diseases while also limiting Upregulation of ELAM-1, ICAM-1, and
chronic inflammation, NK cells, and memory T VCAM-1, especially by endothelial cells in the
cells (Delves and Roitt 2000; Vignali et al. 2008). subepithelial vascular plexus in OLP, was demon-
Helper T cells play an important role in coordinat- strated in an immunohistochemical study that
ing the adaptive immune response by promoting assessed various endothelial-associated adhesion
cellular (cytotoxic T-cell-mediated, via activation molecules in frozen sections from 12 OLP cases
of TH1) or humoral (B-cell-mediated, via TH2 and nine normal controls (Regezi et al. 1996).
activation) types of response. Cytotoxic T cells Biopsy specimens from patients with OLP con-
on recognition of a foreign antigen induce apo- sistently showed significantly higher levels of
ptosis in the infected cell. OLP is characterized by expression of the three molecules. The prolonged
T-cell accumulation, specifically cytotoxic T-cell overexpression of adhesion molecules on endo-
accumulation, within the superficial lamina pro- thelial cells may represent the molecular basis for
pria that is directed at the basal cell layer the so-called reactive isomorphism seen in OLP
(Sugerman et al. 2002; Roopashree et al. 2010). patients. Previous studies have shown that in OLP
It is this chronic cytotoxic T-cell inflammatory there is an upregulation of epithelial basement
process which defines the chronicity of OLP. membrane extracellular matrix (ECM) proteins,
including collagen types IV and VII, laminin and
certain integrins – possibly serving as pathways
Pathogenic Mechanisms for T-cell migration (Eversole 1997). Finally,
cytokines (IL-1, IL-8, IL-10, IL-12, and TNF-α),
The work of Sugerman and colleagues in the secreted by keratinocytes in OLP, are also chemo-
1990s and early 2000s in the field of OLP patho- tactic for lymphocytes ultimately leading to tissue
genesis and disease mechanisms established the destruction in OLP (Sugermann et al. 1996).
basis of most research conducted thereafter The cell-mediated immunological response
(Sugerman et al. 1994, 1995, 1996, 2000, 2000, seen in OLP, possibly initiated by endogenous or
2002; Khan et al. 2003). In general these mecha- exogenous factors, is thought to result in the pro-
nisms can be divided into specific and nonspecific duction of TNF-α and IFN-γ and keratinocyte/T-
ones, which involve T cells and dendritic cells cell/antigen-presenting dendritic cell associations
activated by specific (yet unknown) antigens and (Eisen et al. 2005; Lodi et al. 2005; Payeras et al.
MMPs, cytokines and other immune cells, 2013). The increased production of TH1 cyto-
respectively. kines is a key and early event in LP. This event
A number of biochemical changes, including is, at least in part, genetically controlled, and
altered keratinocyte antigen expression and genetic polymorphism of cytokines seems to gov-
altered keratinocyte function, have been previ- ern whether lesions develop in the mouth alone
ously suggested to be early events in OLP patho- (IFN-γ associated) or in the mouth and skin
genesis (Holmstrup and Dabelsteen 1979). It was (TNF-α associated) (Carrozzo et al. 2004, Scully
originally proposed that following altered and Carrozzo 2008).
keratinocyte antigen expression, a CD8+ T cell TNF-α may stimulate the activation of nuclear
on routine surveillance in the epithelium may factor kappa B (NF-κB) whose increased expres-
encounter the keratinocyte antigen by chance sion has been seen in OLP (Santoro et al. 2003).
(“chance encounter” hypothesis). Alternatively, Because NF-κB translocation in keratinocytes
the CD8+ T cell may be attracted to the epithelium may induce the production of several
inflammatory cytokines, it could be partially T-cell antigen receptors and Ag2 in the context
responsible for the characteristic, chronic course of MHC class II engaged by CD4+ T-cell antigen
of OLP similar to other chronic inflammatory receptors. To date, sound experimental evidence
diseases such as psoriasis and rheumatoid arthritis to support this theory is lacking.
(Eisen et al. 2005).
The cellular and molecular constituents of Cell-Mediated Immunity
these pathogenic events will be discussed in detail
in the following paragraphs. CD8+ T Cells
An early immunohistochemical study assessing
Putative OLP Antigens the lymphocytic infiltrate in OLP showed this to
While OLP is not considered to be a typical auto- be composed almost exclusively of T cells, and
immune disease, it is believed that one or more the majority of T cells within the epithelium and
epithelial antigens are present in basal adjacent to damaged basal keratinocytes were
keratinocytes. Antigens that are presented by activated CD8+ lymphocytes (Kilpi 1988). CD8+
MHC class II receptor are processed through an T cells were also co-localized with apoptotic
endosomal cellular pathway, while antigens that keratinocytes in OLP lesions (Sugerman et al.
are presented by MHC class I are processed 2000). The dominant role of CD8+ T cells and
through a cytosolic cellular pathway (Sugerman CD4+ T cells in OLP pathogenesis was further
et al. 2002). Hence, the putative antigen presented confirmed by the expression of the chemokines
by MHC class II to CD4+ helper T cells in OLP CCR5 and CXCR3, known to be selectively
may differ from that presented by MHC class I to expressed by TH1, in the infiltrating lymphocytes,
CD8+ cytotoxic T cells. Alternatively, a single in addition to the CD8+ T-cell respective ligand
antigen may gain access to both the endosomal RANTES/CCL5 and IP-10/CXCL10 (Iijima et al.
and cytosolic cellular pathways of antigen presen- 2003).
tation (Sugerman et al. 2002; Roopashree et al. Analysis of these previous data suggests that
2010). CD8+ T cells are involved in disease pathogenesis
Whether one or more different antigens are and that activated CD8+ T cells may trigger
involved in disease pathogenesis, it has been keratinocyte apoptosis in OLP. T-cell lines and
suggested that simultaneous antigen presentation clones isolated in vitro from LP lesions were
to CD8+ and CD4+ T cells in the context of MHC more cytotoxic against autologous lesional
classes I and II, respectively, is required to keratinocytes than T cells from the clinically nor-
develop persistent T-cell infiltration and CD8+ mal skin of LP patients, and the majority of non-
cytotoxic T-cell activity in OLP (Sugerman et al. cytotoxic clones were CD4+ (helper/inducer
2002). clones) (Sugerman et al. 2000).
A unifying hypothesis of the specific mecha- Furthermore, the cytotoxic activity of CD8+
nisms thought to play a role in the pathogenesis of lesional T-cell clones was partially blocked with
OLP was introduced by Sugerman et al. (2002). anti-MHC class I monoclonal antibody
The hypothesis is based on a theoretical interac- (Sugerman et al. 2000). Hence, early in OLP
tion between CD8+ T cells and CD4+ T cells lesion formation, CD8+ lesional T cells may rec-
through a “request cytotoxic activity” (RCA) cell ognize an antigen associated with MHC class I on
surface molecule expressed by CD8+ T cells and a lesional keratinocytes. Following antigen recog-
RCA receptor expressed by the CD4+ T cells to nition and activation, CD8+ cytotoxic T cells are
allow confirmation and initiation of cytotoxic thought to trigger keratinocyte apoptosis
activity by CD8+ T cells. The hypothesis stresses (Sugerman et al. 2002).
that this interaction can only take place after each Activated CD8+ T cells (and possibly
type of the T-cell antigen receptors is engaged keratinocytes) may release chemokines that
with a related foreign antigen (Ag), i.e., Ag1 in attract additional lymphocytes and other immune
the context of MHC class I engaged by CD8+ cells into the developing OLP lesion. This has
been suggested by studies that found significantly T-cell-derived IL-2 and IFN-γ. Activated CD8+
higher chemokine production within OLP lesions cytotoxic T cells may then trigger basal
when compared to normal or chronically inflamed keratinocyte apoptosis in OLP (Sugerman et al.
gingival tissues (Yamamoto and Osaki 1995). 2002). However, it is essential to note that this
hypothesis has never been proven by robust
CD4+ T Cells evidence.
The majority of intraepithelial lymphocytes in A recently discovered subgroup of CD4+ T
OLP have been shown to be CD8+ cytotoxic T cells, namely, TH17 CD4+ subgroup, has been
cells (Sugerman et al. 2002), while studies have shown to produce IL-26 and IL-22, in addition
shown that most lymphocytes in the lamina pro- to IL-17, which are known to be, when
pria are CD4+ helper T cells (Ishii 1987; Kilpi uncontrolled, inducers of the inflammatory
1988). A mixed helper and suppressor activity response in different autoimmune conditions,
among OLP lesional T-cell clones in vitro was such as multiple sclerosis, psoriasis, and lupus
identified, suggesting that the balance between (Payeras et al. 2013).
immunological help and suppression may deter- The proportion of lesional Th1 and Th17 cells
mine the clinical behavior of the disease and serum IL-17 levels in patients with OLP
(Sugerman et al. 1994). In this interesting report, (n = 40) were shown to be significantly greater
Sugerman et al. reported that the majority of T than controls (n = 15), especially in the atrophic-
lymphocyte lines extracted from six biopsy spec- erosive OLP patients compared with those pre-
imens of OLP (n = 13) expressed the α/β T-cell senting with reticular OLP, suggesting that Th17
receptor of which 11 were CD8+ and two were cells and their cytokine Th17 might play an impor-
CD4+ (Sugerman et al. 1994). tant role in OLP pathogenesis (Xie et al. 2012).
Hence, an early event in OLP lesion formation
may be a presentation of a MHC class II antigen to Dendritic Cells (DCs)
CD4+ helper T cells, followed by keratinocyte DCs have an important role in the immunological
apoptosis triggered by CD8+ cytotoxic T cells. response as they activate T cells through antigenic
MHC class II antigen presentation in OLP may stimulation (Banchereau et al. 2000). Studies have
be mediated by Langerhans cells (LCs) or revealed an increase in the number of DCs in OLP,
keratinocytes. Furthermore, increased numbers indicating that they may be associated with its
of LCs have been reported in OLP lesions with pathogenesis (Santoro et al. 2005; Gueiros et al.
upregulated MHC class II expression (Villarroel 2012). According to Santoro et al., the increase of
Dorrego et al. 2002). different subsets of DCs, such as Langerhans cells
Keratinocytes in OLP have also been shown to (LCs), stromal DCs, and plasmacytoid dendritic
express MHC class II (Ichimura et al. 2006). High cells (PDCs), may promote the inflammatory
levels of antigen expression, CD40 and CD80 response in OLP (Santoro et al. 2005).
expression, and IL-12 secretion by MHC class II Among these, LCs have been the most studied
+ antigen-presenting cells (APC) in OLP are DCs. These cells reside in the supra-basal layers
thought to promote a TH1 CD4+ T-cell response of the stratified epithelium of the skin and oral
with IL-2 and IFN-γ secretion (Sugerman et al. mucosa and have the principle function of captur-
2002). ing and presenting antigens. When LCs capture
Analysis of these data together suggests that antigen, they are activated, migrate to the regional
LCs or keratinocytes in OLP may present antigen lymph nodes, and are introduced to the T lympho-
associated with MHC class II to CD4+ helper cytes, producing a primary immune response
T cells that are stimulated to secrete the TH1 (Payeras et al. 2013). Subsequently, when LCs
cytokines IL-2 and IFN-γ. Subsequently, CD8+ recapture antigen, this antigen will be presented
cytotoxic T cells may be activated by the and recognized by T lymphocytes circulating
combination of (i) antigen associated with MHC memory and will induce a secondary immune
class I on basal keratinocytes and (ii) TH1 CD4+ response (Barrett and Raja 1997).
In the OLP lesions, a large number of LCs are stimulate mast cells to release TNF-α and
present in the basal layer of the epithelium chymase. This cyclical activity has been
(Villarroel Dorrego et al. 2002). It has been pos- suggested to contribute to the chronicity of OLP
tulated that in these lesions the LCs play an impor- (Roopashree et al. 2010).
tant role in presenting antigen to the T lymphocyte
through class II MHC molecules, introducing not Macrophages
only an initial sensitivity to the antigen (primary Macrophages are phagocyte cells derived from
immune response) but also a subsequent second- blood monocytes, recruited in the tissues in the
ary immune response and thus the appearance of presence of chemotactic signals. They are present
the clinical signs of the disease (Payeras et al. in the healthy oral mucosa and in larger numbers
2013). during pathological processes (Merry et al. 2012).
Macrophages are classified as M1
Mast Cells (pro-inflammatory) or M2 (anti-inflammatory)
Mast cells are preferentially located in the lamina according to the functions of their effectors
propria, near blood vessels and nerves. They are (Mantovani et al. 2004). The M1 macrophages
derived from the CD34+ hematopoietic progeni- might exacerbate OLP manifestation through the
tor that has the ability to activate T lymphocyte, production of pro-inflammatory agents such as
undergo degranulation, and release a series of TNF-α or IL-1b. These agents, in turn, regulate
mediators that modulate the inflammatory the presence of adhesion molecules on the endo-
response (Payeras et al. 2013). Studies have thelial cell surface inducing the production of
shown an increased mast cell density in OLP chemokines (RANTES) by the keratinocytes and
with approximately 60% of them being resulting in an increase in the lesional inflamma-
degranulated, compared with 20% in normal buc- tory cells recruitment. Furthermore, it has been
cal mucosa (Sugerman et al. 2002). shown that the production of TNF-α by the mac-
Utilizing IHC, mast cell density in OLP was rophages can initiate the basal keratinocyte apo-
found to be markedly higher in the basement ptosis and indirectly increase the disruption rate of
membrane rupture sites as compared to intact the basement membrane by MMP-9, produced by
sites, suggesting that this cell might play a direct T cells (Merry et al. 2012).
role in the basement membrane destruction, as
well as in the T CD8+ lymphocyte migration to Soluble Factors
the intraepithelial region (Zhou et al. 2002). Thus,
mast cells have been proposed to be involved in Matrix Metalloproteinases (MMPs)
the pathogenesis of OLP. Mast cell degranulation MMPs are a family of zinc-containing endo-pro-
in OLP releases a range of pro-inflammatory teinases with at least 20 members with the prin-
mediators such as TNF-α, chymase, and tryptase. cipal function of proteolytic degradation of
TNF-α has been shown to upregulate endothelial connective tissue matrix proteins. MMPs share
cell adhesion molecule (CD62E, CD54, and biochemical properties but retain distinct sub-
CD106) expression in OLP that is required for strate specificities (Zhou et al. 2001). MMP pro-
lymphocyte adhesion to the luminal surfaces of teolysis is regulated by the action of endogenous
blood vessels and subsequent extravasation (Zhao inhibitors, including the tissue inhibitors of
et al. 1997). Chymase, a mast cell protease, is a metalloproteinases (TIMPs), which are thought
known activator of MMP-9 (Fang et al. 1997). to form stable inactive enzyme-inhibitor com-
It has been proposed that basement membrane plexes with MMPs or pro-MMPs (Sugerman
disruption in OLP may be mediated by mast cell et al. 2002). An imbalance between MMPs and
proteases directly or indirectly via activation of T- TIMPs can be associated with the process of
cell-secreted MMP-9 (Sugerman et al. 2002). tissue destruction seen in some pathologies,
Both TNF-α and chymase stimulate secretion of including cancer, arthritis, and cardiovascular
RANTES by T lymphocytes which in turn diseases (Bode 2003).
The primary source of MMPs in OLP is prob- fibroblasts, oral keratinocytes, and mast cells.
ably the immune infiltrate. In one study, culture RANTES plays a critical role in the recruitment
supernatants from OLP lesional T cells contained of lymphocytes, monocytes, natural killer cells,
a higher concentration of MMP-9 and TIMP-1 eosinophils, basophils, and mast cells in OLP
than those obtained from peripheral blood T cells (Roopashree et al. 2010). This chemokine has a
in both the same OLP patients group and the number of cell surface receptors (CCR1, CCR3,
healthy controls, suggesting the presence of addi- CCR4, CCR5, CCR9, and CCR10) that have been
tional MMP-9 activators in the OLP lesional identified in OLP (Sugerman et al. 2002).
T-cell supernatants (Zhou et al. 2001). The role that RANTES may play in OLP path-
MMP-9 activators released from the OLP T cell ogenesis was hypothesized by Sugerman and col-
are believed to help in activating pro-MMP-9, leagues (2002) who suggested that RANTES
resulting in basement membrane disruption secreted by OLP lesional T cells may attract
(Roopashree et al. 2010). Rubaci et al. (2012) mast cells into the developing OLP lesion and
showed that the expression of MMP-2 (1.3 subsequently stimulate mast cell degranulation.
vs. 0.7) and MMP-7 (1.7 vs. 0.6) in epithelium Degranulating mast cells in OLP would release
and connective tissues from OLP lesions was TNF-α and chymase which in turn upregulates
greater than normal oral mucosa (P < 0.05). This OLP lesional T-cell RANTES secretion.
IHC study was undertaken on a cohort of 29 OLP According to this hypothesis, such a cyclical
patients and ten healthy controls. Likewise, the mechanism may underlie OLP chronicity.
study revealed that MMP-2/TIMP-1 and MMP-7/ Ichimura et al. (2006) analyzed the
TIMP-1 ratios were higher in the OLP patient chemokines and their receptors expressed in the
group than in the control group (P < 0.05). These epithelium of OLP by means of DNA microarray.
results support the view that increased MMP The study found that high levels of MIP-3a/
expression and imbalance between MMPs and LARC/CCL20, and its receptor CCR6, are
TIMPs may play a role in the pathology of OLP. expressed on the lesional epithelium. Further-
more, DC-CK1/CCL18, ELC/CCL19, SDF-1/
Chemokines CXCL12, and CXCR4 expressions were also
Chemokines are a family of small cytokines (pro- increased. Immunohistological analysis showed
teins that are involved in cell signaling and medi- that high numbers of LCs were present in the
ating immune reactions), which were initially epithelium of OLP. Lesional epithelium also
identified by their modulator action on the inflam- expressed high levels of the ligands specific for
matory response (Payeras et al. 2013). More atten- CXCR3 and CCR5 (e.g., RANTES/CCL5).
tion has been given to these proteins recently, Based on these results, it was suggested that infil-
especially due to their potential function on endo- tration of LCs may be regulated by CCR6
thelial cells and possible involvement in chronic (as these receptors are expressed by LCs) and
inflammation and tumor progression (Kiefer and that LCs residing in the lesional epithelia may
Siekmann 2011). Moreover, evidence has shown represent a mature phenotype. Moreover, infiltra-
the role chemokines play in different autoimmune tion of T cells in OLP could be mediated by
diseases, such as rheumatoid arthritis and multiple signaling pathways through CXCR3 and CCR5.
sclerosis, through lymphocyte recruitment and Thus, it would appear that there is a
establishment of ectopic lymphoid structures in dysregulation of specific chemokines, and chemo-
the target organs in affected individuals kine receptors, and that this would appear to be
(Godessart and Kunkel 2001). related to expression of chemokine receptors on
RANTES (regulated on activation, normal T LCs. Similar to the observed dysregulation of
cell expressed and secreted) is a member of the MMPs/TIMPs and keratinocyte/basement mem-
CC chemokine family and is produced by various brane noted above, this may be either involved
cells, including activated T lymphocytes, bron- in the etiopathogenesis of OLP or a byproduct of
chial epithelial cells, rheumatoid synovial the disease.
Epithelial Components perforin-induced membrane pores (Sugerman

et al. 2002). All of these mechanisms may activate
The Epithelial Basement Membrane the keratinocyte caspase cascade, resulting in
Keratinocytes contribute to the structure of the keratinocyte apoptosis. Elevated levels of TNF-α
epithelial basement membrane by secreting colla- in the serum of OLP patients were identified
gen IV and laminin V into the basement mem- (Sugermann et al. 1996).
brane zone (Marinkovich et al. 1993). Evidence In summary, while it is well established that
from mouse models suggests that keratinocytes apoptosis of basal keratinocytes is a key feature of
require a basement membrane-derived cell sur- OLP, the exact pathogenic mechanisms have not
vival signal to prevent the onset of apoptosis yet been elucidated.
(Pullan et al. 1996). Similarly, lack of appropriate
ECM anchorage results in a form of cell death
called “anoikis.” Thus, an intact basement mem- Clinical-Pathologic Features
brane is required for keratinocytes survival, and
reciprocally healthy keratinocytes are necessary OLP is the most common mucocutaneous con-
for normal basement membrane integrity. dition in the mouth and affects approximately
Keratinocytes undergoing cell death are no 1–2% of the population (Axell and Rundquist
longer able to perform this reciprocal function, 1987). Areas which are typically affected
and as such keratinocyte apoptosis triggered by include the buccal mucosa, tongue, alveolar
intraepithelial CD8+ cytotoxic T cells may result ridge, and gingival tissues (Axell and Rundquist
in epithelial basement membrane disruption in 1987).
OLP, thus fueling anoikis and allowing for non-
specific T lymphocytes present in the sub-
epithelial zone to migrate into the epithelium Clinical Appearance
(Chainani-Wu et al. 2001). Both keratinocyte apo-
ptosis and basement membrane disruption may be OLP classically presents in a bilateral, symmetri-
involved in the pathogenesis of OLP, and such a cal pattern with the buccal mucosa (bilaterally)
cyclical mechanism has been postulated to under- being the most typical site of involvement
lie disease chronicity (Sugerman et al. 2002; (Fig. 1); however, any other oral mucosal sites
Lodi et al. 2005a). and the lips can also be involved (Al-Hashimi
et al. 2007; Ismail et al. 2007; Scully and Carrozzo
Keratinocyte Apoptosis 2008). Other common sites of involvement
Keratinocyte apoptosis is a common and key include the tongue (Fig. 1c), gingival (Fig. 1d),
feature in the histopathological findings of labial mucosa, and vermilion of the lower lip
OLP lesions and is considered a major diagnostic (Eisen et al. 2005; Al-Hashimi et al. 2007; Scully
criterion (Ismail et al. 2007; Eisen et al. 2005; and Carrozzo 2008; Parashar 2011). Patients with
Scully et al. 1998). Therefore, keratinocyte apo- isolated lip lesions and tongue lesions have been
ptosis has been postulated to be intentionally described although many patients who present
involved in the etiopathogenesis of OLP with isolated lesions eventually develop more
(Sugerman et al. 2002). widespread disease (Eisen et al. 2005). Lesions
A number of mechanisms have been suggested of OLP affecting the palate, floor of the mouth,
by which CD8+ cytotoxic T cells can trigger and upper lip are not common.
keratinocyte apoptosis in OLP. These include The oral manifestations of OLP have been
(i) T-cell-secreted TNF-α binding to TNF receptor described in many large studies. Clinically, there
1 (TNFR1) on the keratinocyte surface, (ii) T-cell are six clinical subtypes of OLP that can be seen
surface CD95L (Fas ligand) binding CD95 (Fas) individually or in combination: reticular, plaque-
on the keratinocyte surface, or (iii) T-cell-secreted like, atrophic, erosive, papular, and bullous
granzyme B entering the keratinocyte via (Ismail et al. 2007; Scully and Carrozzo 2008;
Fig. 1 Clinical presentation of patients with OLP: (a) reticular, (b) erosive/ulcerative, (c) atrophic and plaque-like, and
(d) desquamative gingivitis (atrophic and erosive forms)
Farhi and Dupin 2010). The most common of reticular keratotic striae (Ismail et al. 2007). Atro-
these are the reticular, erosive, and plaque-like phic and erosive OLP lesions result in varying
subtypes, and these variants can coexist within degrees of discomfort. The number of ulcerations
the same patient (Fig. 1). is variable as are their size and location; rarely,
The reticular lesions, the most recognized form bullae that rupture easily may be observed in the
of OLP, encompass white lesions, which appear as erosive form of OLP (Eisen et al. 2005). If the
a network of connecting and overlapping lines erosive subtype of OLP only affects the gingival
referred to as Wickham striae, papules, or plaques tissue, the descriptive clinical term desquamative
(Eisen et al. 2005). Although some patients may gingivitis is often used (Fig. 1d). OLP is confined
display an impressive array of diffuse and wide- to the gingiva in about 10% of patients (Mignogna
spread reticulated lesions, they rarely complain of et al. 2005; Scully and Carrozzo 2008). Erosive
symptoms and often are unaware of their pres- lesions resembling those observed in other vesicu-
ence. In the absence of the classic reticular pattern lobullous diseases including pemphigoid, pem-
on oral mucosal surfaces, it is challenging to clin- phigus, linear IgA disease, and foreign body
ically diagnose non-reticular types (Fig. 1b, d) gingivitis can also produce desquamative gingivi-
(Scully and Carrozzo 2008). Histologic confirma- tis not easily identified as OLP unless there are
tion of the diagnosis is thus required. The erosive coexistent reticular lesions on the gingiva or else-
form of OLP (Fig. 1b) may present with erythema where in the oral cavity. Two recent cohort studies
caused by inflammation or epithelial thinning, or found OLP to be the most common cause of
both, and ulceration/pseudomembrane formation desquamative gingivitis (71% and 75%), while
with periphery of the lesion surrounded by pemphigoid and pemphigus were next in
frequency (Leao et al. 2008; Lo Russo et al. 2003 (Table 2), which resulted in a substantial
2009). OLP isolated to a single oral site other increase in consensus and clinicopathologic cor-
than the gingiva is uncommon. relation (Epstein et al. 2003; van der Meij and van
In general, bullous and papular forms are rare der Waal 2003). In addition, knowledge about
in the oral mucosa (Parashar 2011). The erosive history of systemic diseases, history of drug use,
lesions hardly ever remit spontaneously and may and cutaneous lesions can be helpful in arriving at
lead to confusion with other vesiculobullous dis- a definite diagnosis.
eases, which share similar clinical features (Eisen
et al. 2005).
The plaque form of OLP mimics leukoplakia Signs, Symptoms, Clinical Behavior
in that it appears as a white, homogeneous, and Scoring Systems
slightly elevated, multifocal, smooth lesion.
The plaque form of OLP commonly affects the The clinical signs and symptoms of OLP vary. In
dorsum of the tongue and buccal mucosa (Ismail many patients, the onset of OLP is insidious, and
et al. 2007). patients are unaware of their oral condition. Some
OLL and OLR have similar features, clinically
and histologically, to OLP, but have a less charac-
teristic morphology or have a distinct cause, unlike Table 2 Modified WHO diagnostic criteria of OLP and
OLL (van der Meij and van der Waal 2003)
OLP. OLL therefore needs to be distinguished
because treatment modalities are different from Clinical criteria
those for OLP (Al-Hashimi et al. 2007). Presence of bilateral, more or less symmetrical lesions
To better define the criteria for diagnosis of Presence of a lacelike network of slightly raised gray-
white lines (reticular pattern)
OLP, the World Health Organization (WHO)
Erosive, atrophic, bullous, and plaque-like lesions are
devised a set of clinicopathologic criteria in only accepted as a subtype in the presence of reticular
1978 (Table 1) (Kramer et al. 1978). However, lesions elsewhere in the oral mucosa
these criteria lacked consensus regarding a clini- In all other lesions that resemble OLP but not complete
cal and histologic diagnosis of OLP, and so mod- with the aforementioned criteria, the term “clinically
compatible with” should be used
ifications were proposed to the WHO criteria in
Histopathological criteria
Presence of well-defined band-like zone of cellular
Table 1 Original WHO diagnostic criteria of OLP infiltration that is confined to the superficial part of the
(Kramer et al. 1978) connective tissue, consisting mainly of lymphocytes
Clinical criteria Signs of “liquefaction degeneration” in the basal cell
Presence of white papule, reticular, annular, plaque- layer
type lesions, gray-white lines radiating from the Absence of epithelial dysplasia
papules When the histopathological features are less obvious, the
Presence of lacelike network of slightly raised gray- term “histopathologically compatible with” should be
white lines (reticular pattern) used
Presence of atrophic lesions, with or without erosion, Final diagnosis of OLP or OLL
and possibly also bullae To achieve a final diagnosis, clinical as well as
Histopathological criteria histopathological criteria should be included
Presence of thickened ortho- or parakeratinized layer OLP: a diagnosis of OLP requires fulfillment of both
in sites that are normally keratinized, and if site is clinical and histopathological criteria
normally nonkeratinized, this layer may be thin OLL: the term OLL will be used under the following
Presence of Civatte bodies in basal layer, epithelium, conditions
and superficial part of connective tissue (1) Clinically typical of OLP but histopathologically
Presence of a well-defined band-like zone of cellular only “compatible with” OLP
infiltration that is confined to the superficial part of the (2) Histopathologically typical of OLP but clinically
connective tissue, consisting mainly of lymphocytes only “compatible with” OLP
Signs of liquefaction degeneration in the basal cell (3) Clinically “compatible with” OLP and
layer histopathologically “compatible with” OLP
patients report roughness of the lining of the Some of the more detailed scoring systems
mouth, sensitivity of the oral mucosa to hot or have worked to split OLP into three clinical sub-
spicy foods, painful oral mucosa, red or white types, reticular, atrophic/erythematous, and ero-
patches on the oral mucosa, or oral ulcerations sive/ulcerative (Escudier et al. 2007). For some
(Ismail et al. 2007). of these studies the oral cavity is divided into
Symptoms and signs can range from patients different subsites so each site is given an activ-
being unaware of the disease, with lesions that are ity/severity score which can be totaled to give an
completely asymptomatic as in reticular OLP, to entire oral cavity score (Chainani-Wu et al. 2001;
those experiencing mucosal sensitivity and burning Piboonniyom et al. 2005; Escudier et al. 2007). In
and debilitating pain. Approximately two-thirds of some of these scoring systems, presence of ery-
the patients affected with OLP experience some thema, erosions, or ulceration is graded higher
degree of oral discomfort (Parashar 2011). than the presence of reticular lesions alone
OLP has periods of relapses and remissions. (Piboonniyom et al. 2005; Escudier et al. 2007).
During a period of exacerbation there will be One of the main advantages of using a detailed
an increase in symptoms and clinical signs, scoring system is the ability to objectively measure
while during periods of quiescence, symptoms disease activity baseline and changes in disease
and signs of OLP are diminished (Ismail activity for the entire oral cavity and specific sites.
et al. 2007). Factors such as stress may aggravate Recently attempts have been made to validate some
the clinical presentation of the disease. Precipi- of the more detailed scoring systems (Chainani-Wu
tating factors similar to the Koebner phenome- et al. 2012). Time has also been taken with these
non, which is characteristic of cutaneous LP scoring systems to add subjective measures of the
whereby lesions develop in response to trauma, patient’s pain and symptoms making this a complete
can also affect the oral cavity where sharp cusps disease scoring system (Chainani-Wu et al. 2012).
and ill-fitting dental prosthesis may be the Currently there are many available disease
triggers. scoring systems which systems in place to mea-
Accumulation of plaque and calculus can also sure changes in subjective and objective disease
exacerbate OLP, probably because of the Koebner activity in OLP. At this stage no one system has
phenomenon (Mignogna et al. 2005). Gingival been universally accepted for use.
OLP can eventually lead to gingival recession,
advanced periodontal disease, and so forth, and
therapeutic periodontal procedures may aggravate Histopathology
these conditions (Eisen et al. 2005; Scully and
Carrozzo 2008). The histologic features of OLP were first
Oral post-inflammatory pigmentation (OPP) described by Dubreuill in 1906 and later revised
has been described in patients with OLP and by Shklar in 1972 (Parashar 2011). The WHO
OLR as diffuse brown or black pigmentation fol- developed a set of histopathologic criteria for
lowing the lichenoid lesions distribution OLP in 1978, which was most recently modified
(Mergoni et al. 2011). in 2003 (Tables 1 and 2). Definite diagnostic his-
Currently there is no universally accepted scor- tologic findings include liquefactive degeneration
ing system for OLP; however many have been of the basal cells, colloid bodies (Civatte, hyaline,
proposed to objectively and even subjectively cytoid), homogeneous infiltrate of lymphocytes
measure OLP disease severity. Several studies and histiocytes in a dense, band-like pattern
have proposed using scoring systems with the along the epithelium-connective tissue interface
earlier systems based upon a three- or five-point in the superficial dermis, cytologically normal
scale from no disease to severe disease (Eisen et al. maturation of the epithelium, sawtooth rete ridges,
1990; Thongprasom et al. 1992). Other scoring and hyperkeratosis (orthokeratosis or para-
systems base severity on the level of site involve- keratosis) (Fig. 2) (Eisenberg 2000; Eisen et al.
ment (<> 50% site) (Malhotra et al. 2008). 2005; Ismail et al. 2007; Parashar 2011). In
Fig. 2 Histopathology of
OLP. (a) Low power
parakeratosis, band-like
subepithelial chronic
inflammatory infiltrate, and
sawtooth rete ridges
stain, original magnification
x100). (b) High-power
several colloid bodies
(arrows) and liquefactive
degeneration of basal
keratinocytes (arrowheads)
stain, original magnification
x200)
addition, the surface epithelium may show signs sensitivity to amalgam (Koch and Bahmer 1995;
of ulceration, typically seen in erosive LP. Ostman et al. 1996; Thornhill et al. 2003; Issa
Several histologic criteria are considered as et al. 2004; Eisen et al. 2005; Ismail et al. 2007).
exclusionary in diagnosing OLP, including the As with OLP, OLRs present clinically with a
absence of basal cell liquefaction degeneration, range of different features ranging from asymp-
polyclonal inflammatory infiltrate, abnormal tomatic striae and plaque-like lesions to painful
cytology suggestive of dysplasia, abnormal kera- erythematous and ulcerative lesions. Histopatho-
tinization, flat rete ridges, and absence of colloid logically OLRs align with OLP showing a band-
bodies (Eisenberg 2000; Ismail et al. 2007). like lymphohistiocytic infiltrate (mainly T cell)
within the lamina propria as well as liquefactive
degeneration of the basal cell layer.
Oral Lichenoid Reactions (OLR) Cases of OLRs related to restorative materials
will typically present in a direct topographic
There are various lesions that may resemble OLP relationship with the restorative material. The
both clinically and histopathologically. These allergens thought to be responsible for amalgam-
lesions are collectively termed OLR and encom- contact sensitivity include mercury, amalgam
pass lichenoid drug reactions (LDR) and OLR to alloying metal zinc, copper, silver, gold, or palla-
dental materials, most notably allergic contact dium (Koch and Bahmer 1995; Suter and
Warnakulasuriya 2016). There has been some in two patients (total n = 15) after amalgam
evidence to suggest that some patients with replacement and a mean follow-up of 3.2 years
amalgam-associated OLRs represent a true (Laine et al. 1992). In another trial, Thornhill et al.
delayed hypersensitivity reaction as a result reported that amalgam replacement resulted in
of metal haptens released from dental restorative improvement in 93% of patients (28 out of 30)
materials (Laine et al. 1999). LDRs will typically who had amalgam-contact hypersensitivity
arise with a direct temporal association lesions (Thornhill et al. 2003). Gingival OLR
when taking certain medications including non- lesions, in particular, were reported to be non-
steroidal anti-inflammatory medications responsive to amalgam replacement for unknown
(NSAIDs), some antihypertensive medications, reasons (Henriksson et al. 1995).
oral hypoglycemics, penicillamine, and antima- Diagnosis of OLR will commonly depend on the
larial medications (Epstein et al. 2003; topography and distribution of the lesions as in most
Bagan et al. 2004; Al-Hashimi et al. 2007; Ismail cases, OLR are indistinguishable from idiopathic
et al. 2007). OLP, clinically or histologically (Thornhill et al.
No specific criteria exist for the diagnosis of 2003). Cutaneous patch testing may also play a
LDR; however withdrawal and reexposure to the role in differentiating these lesions (Scully and
drug resulting in resolution and recurrence can be Carrozzo 2008; Ismail et al. 2007). Thornhill et al.
considered diagnostic. Patch testing may be a found that 70% of amalgam-contact hypersensitivity
valuable diagnostic tool for OLR as a result of a lesions (presented as lichenoid reactions) were patch
contact sensitivity to dental materials (Suter and test positive for amalgam or mercury compared with
Warnakulasuriya 2016). In cases of a suspected only 3.9% of OLP cases (Thornhill et al. 2003).
OLR as a result of amalgam dental restorations, To date, OLP and OLR lack internationally
there is evidence to suggest that replacement of accepted distinguishing features, and the diagno-
amalgam can result in resolution or improvement sis of OLR can be challenging as the pathogno-
of OLR; in some cases this is irrespective of a monic features of OLR are yet to be identified
positive patch testing result (Laine et al. 1992; (Ismail et al. 2007).
Ostman et al. 1996; Thornhill et al. 2003; Issa Recent findings have suggested that OLR
et al. 2004). Thus in cases of suspected OLRs, it appears to be the result of cell-mediated contact
is essential that proper testing including histopa- hypersensitivity to dental materials, in susceptible
thology and patch testing be undertaken to ensure individuals who have been sensitized through
a correct diagnosis is made as OLP and OLR long exposure (Ismail et al. 2007).
benefit from different management protocols.
Systemic Medications
Dental Materials Medications, such as antihypertensives ( in par-
OLR as an allergic reaction to dental materials has ticular beta-blockers and ACE inhibitors),
been widely reported, with many studies dapsone, oral hypoglycemics, NSAIDs, penicilla-
documenting contact hypersensitivity to dental mine, phenothiazines, antimalarials, sulfonyl-
materials such as amalgam (Lind et al. 1986; ureas, and gold salts, have been associated with
Thornhill et al. 2003), composite (Lind 1988), OLRs (Scully et al. 1998; Al-Hashimi et al. 2007;
dental acrylics (van Loon et al. 1992), cobalt Ismail et al. 2007).
(Torresani et al. 1994), and nickel (Ismail et al. More recently, OLR induced by antiretroviral
2007) presenting as OLR. Some studies also medications for treatment of human immunodefi-
showed resolution of OLR following replacement ciency virus (HIV) has been reported (Scully and
of causative restorations. Laine et al. reported a Diz Dios 2001). Clinical identification of LDR
complete remission of OLR lesions associated has been based largely on subjective criteria
with amalgam in a small cohort of seven patients, although there may sometimes be a tendency for
a marked remission in six patients, and no change the oral lesions to be unilateral and erosive (Eisen
et al. 2005). Histology may be beneficial as lesions are commonly pruritic but self-limiting
lichenoid lesions may have a more diffuse lym- (Eisen et al. 2005).
phocytic infiltrate and contain eosinophils and
plasma cells, and there may be more colloid bod-
ies than in classical OLP (Eisen et al. 2005; Scully Other Mucosal Lesions
and Carrozzo 2008).
The most reliable method to diagnose LDRs is Undoubtedly, the most frequent extraoral site of
to note if the reaction resolves after the offending involvement in female patients with OLP is the
drug is withdrawn and if it returns when the genital mucosa with lesions developing in 20% of
patient is challenged again. As this is both imprac- women with OLP compared with only 2–4% of
tical and potentially unsafe, empiric withdrawal of men with OLP (Ismail et al. 2007; Scully and
a potentially offending drug and substitution with Carrozzo 2008; Farhi and Dupin 2010). The asso-
another agent may not be warranted. After the ciation of LP of the vulva, vagina, and gingiva is
offending drug is withdrawn, it may be months recognized as the vulvovaginal-gingival syn-
before the LDR resolves. Interestingly, it was drome (Pelisse 1989), and the male counterpart
reported that LDR may develop months or even is known as penogingival syndrome (Bain and
years after a patient takes a drug (Eisen et al. 2005). Geronemus 1989).
When LP affects the genital mucosa, the ero-
sive form of the disease is the predominant type
Cutaneous Lesions although asymptomatic reticular lesions can be
identified in about a quarter of all patients (Eisen
LP may affect the hair follicles, nails, esophagus, et al. 2005). Various symptoms including burning,
and, less frequently, the eyes, urinary tract, geni- pain, vaginal discharge, and dyspareunia are fre-
tals, nasal mucosa, and larynx. Scalp involvement quent and are noted in patients with erythematous
causes pruritic, follicular and perifollicular, scaly, and erosive disease.
violaceous papules, referred to as lichen Reports of malignant transformation of genital
planopilaris, and can also lead to permanent LP in women (Dwyer et al. 1995) underscore the
patchy hair loss known as scarring alopecia. need for an early diagnosis and the institution of
When LP affects nails, it causes pitting, subungual prompt treatment for these patients. Although the
hyperkeratosis, and permanent nail loss (Farhi and concomitant involvement of oral and genital LP is
Dupin 2010). much less common in males than females, recog-
Skin lesions characteristically present as flat- nition and treatment of the disease are important
topped, polygonal, violaceous papules regularly as malignant transformation of penile LP has also
covered by a network of fine lines affecting the been reported (Bain and Geronemus 1989).
wrists, ankles, and genitalia (Bornstein et al. The clinical features of esophageal LP have
2006). Cutaneous LP may also appear in several been well documented, and the disease appears
atypical forms that are not easily recognizable. As to develop most commonly in patients with OLP
previously mentioned, approximately 15% of (Evans et al. 2000), while conjunctival, laryngeal,
patients with OLP develop cutaneous lesions, or other mucosal involvement is rarely reported
while OLP occurs in 70–77% of patients with (Eisen et al. 2005).
cutaneous LP (Eisen 1999; Farhi and Dupin 2010).
Typically, cutaneous lesions develop within
several months after the appearance of the oral Malignant Potential
lesions, and the severity of the oral lesions does
not seem to correlate with the extent of cutaneous Since the first report of malignant transformation
involvement, i.e., while OLP is chronic and rep- of OLP (Hallopeau 1910), numerous studies have
resents a common cause of morbidity, cutaneous attempted to address this issue. Malignant
transformation rates ranging from 0% to 12.5% After applying these new criteria, they concluded
were reported (Gonzalez-Moles et al. 2008). that only 15 of the 223 cases reported in the
Although these findings appear to support the literature should be unquestionably accepted as
potentially malignant character of OLP, it remains malignant transformation in OLP. The remaining
a controversial topic. cases were excluded for at least one of the follow-
Several authors agreed to a frequency of malig- ing reasons: (1) insufficient data to support the
nant transformation between 0.4% and 5%, over OLP diagnosis, (2) appearance of oral cancer in
periods of observation from 0.5 to over 20 years an area anatomically distant from the OLP, and
with an annual rate between 0.2% and 0.5%. (van (3) inadequate historical data on previous expo-
der Meij et al. 2003; Al-Hashimi et al. 2007; sure to carcinogens. The authors commented: “If
Scully and Carrozzo 2008). However, reviews OLP prevalence is accepted to be 1–2% of general
limited to selected studies on malignant potential population over 15 years, and if malignant trans-
of OLP with a follow-up of more than 2 years formation rate is 1% in a mean period of 5 years,
showed that when strict criteria were applied, the then, 10 to 20 patients per 100 000 inhabitants
malignant transformation rate is 0–2% (Ismail should develop oral cancer in a mean period of
et al. 2007). 5 years. This would indicate that in many parts of
It has been thought that the increased risk of the world all oral carcinomas should develop on
oral cancer appears to be independent of the clin- an OLP, which is rather improbable” (Krutchkoff
ical type of OLP and therapy administered et al. 1978). They further drew the conclusion that
(Gandolfo et al. 2004). there was insufficient evidence to accept an inher-
The first critical review regarding OLP malig- ent biological potential of OLP to progress to
nant transformation appeared in the Journal of cancer, but they acknowledged that OLP patients
Oral Pathology about four decades ago have a slightly higher tendency to develop carci-
(Krutchkoff et al. 1978), included data published nomas compared to individuals without OLP
up to 1977, and the authors recommended strict (Krutchkoff et al. 1978).
criteria (Table 3) to be adopted to definitively Almost 20 years later, van der Meij et al.
accept the malignant transformation in OLP. (1999a, b) reviewed studies on the malignant
transformation of OLP published from 1977 to
Table 3 Criteria for malignant transformation of OLP 1999, applying the Krutchkoff criteria. During
(Krutchkoff et al. 1978) this period, 98 new malignant transformations
A. Original diagnosis must have been properly verified, were reported, of which 33 (34%) met the pro-
with histological evidence demonstrating at least the last posed criteria. According to the authors, the high
two of these four features
incidence of malignant transformation described
Hyperkeratosis or parakeratosis
in many studies may be due to the misdiagnosis of
Sawtoothed rete ridges
some lesions as OLP or to the analysis of a highly
Superficial infiltrate of lymphocytes
Basal cell liquefaction
selected study population (e.g., predominance of
B. History and follow-up patients referred to specialists). This investigation
Clinical and histological features of the alleged concluded that nearly all of the case reports lacked
transformation must have been adequately described precise documentation and that still no consensus
(information on age and sex of patient and on the precise had been established about the criteria for the
location and clinical description of the lesion) histopathologic diagnosis of OLP (van der Meij
The reported transformation should have had proper
et al. 1999a).
follow-up (minimum of 2 years) with all changes in
clinical features properly recorded van der Meij et al. further emphasized the need
C. Tobacco exposure for standard criteria for a firm diagnosis of OLP to
Tobacco habits should have been properly documented be universally adopted (van der Meij et al. 1999a, b).
to help distinguish between true malignant The designation OLL was later proposed for
transformation and conventional carcinomas occurring in cases that are clinically characteristic and histo-
the mouths of patients who happened to have OLP
logically compatible, clinically compatible and
histologically characteristic, or clinically and his- (unilateral distribution, absence of reticular

tologically compatible with OLP (Table 2) (van lesions) (Lodi et al. 2005b). The former could
der Meij and van der Waal 2003). It is currently represent an early phase in the malignant transfor-
proposed by some key authors that OLL rather mation of OLP, while the latter could represent an
than OLP is at high risk of developing cancer OLL with underlying various clinical conditions
(Bornstein et al. 2006; van der Meij et al. 2007; that may have lichenoid histopathology including
Gonzalez-Moles et al. 2008). lichenoid reactions, lupus erythematosus, leuko-
On the other hand, a review by Mattsson et al. plakia, erythroleukoplakia, and proliferative
largely based on follow-up studies reported a verrucous leukoplakia (PVL). PVL, particularly
higher incidence of oral cancer in OLP patients in the early stages, can have features, both clinical
and concluded that OLP should be considered a and histologic, that can be confused with OLP,
potentially malignant condition with a transfor- frequently shows dysplastic changes, and is char-
mation rate of 0.5–2% (Mattsson et al. 2002). acterized by a high malignant transformation rate
Many other studies using strict diagnostic criteria (Lodi et al. 2005b).
have shown a significant risk of malignant trans-
formation of OLP to squamous cell carcinoma
(SCC) (Holmstrup et al. 1988; Gandolfo et al. OLL and Cancer
2004; Rodstrom et al. 2004).
Finally, the World Health Organization, (Gale A very interesting, and potentially informative,
et al. 2005), has recommended the development of group of patients regarding OLL and oral malig-
diagnostic criteria to differentiate between OLP nancies are those who underwent allogeneic bone
and OLL but declared that both lesions should be marrow transplantation and developed oral
considered at risk of malignant transformation GVHD. Oral GVHD is clinically and histologi-
until such criteria become available. cally indistinguishable from OLP. Case reports
In 1985, Krutchkoff and Eisenberg (1985) (Abdelsayed et al. 2002) and large studies (Deeg
coined the term lichenoid dysplasia (LD) to et al. 1996; Curtis et al. 1997) describe numerous
describe lesions that resemble OLP histologically episodes of oral cancers (mainly SCC) in patients
and also show features of dysplasia. They with oral GVHD. A large study that investigated
suggested that OLP has no inherent predisposition the incidence of solid tumors in 20,000 bone
to become malignant and that reported cases of marrow transplantation patients found that oral
malignant transformation in OLP lesions were due cancer had the highest risk among cancers, being
to lack of discrimination between OLP and LD or 11.1 times more frequent than expected (Curtis
failure to identify a concomitant exposure to known et al. 1997). The significant risk factors for OSCC
carcinogens (Krutchkoff and Eisenberg 1985). were chronic GVHD, limited-field irradiation, and
The assumption for the proposal of malignant male sex. In one of these studies, head and neck
potential in LD rather than OLP was that any cancer was the only solid cancer observed in a
departure from normal epithelial maturation and group of 78 patients undergoing bone marrow
growth altogether excludes a diagnosis of OLP transplantation for Fanconi anemia, with the fre-
(Eisenberg 2000), although consensus on such quency of such tumors was 167 times higher than
criteria has never been reached, and some authors expected (Deeg et al. 1996).
consider dysplasia a very common feature of OLP Clearly, bone marrow transplantation patients
(Lodi et al. 2005b). have numerous risk factors that may enhance
The entity LD might correspond to two groups their likelihood of developing malignancies (pri-
of conditions: those with clinical features similar mary immunodeficiencies, immunosuppressive
to OLP but dysplastic at the histological level and treatments, viral infections, and probably genetic
those with lichenoid microscopic features (band- predisposition to cancer) that do not allow a com-
like lymphocytic infiltration in particular) and clin- parison with OLP patients; however, the similarity
ical features which do not resemble classic OLP of the oral conditions and the apparent common
tendency to transform are worthy of careful con- of transformation – rather they considered the loss
sideration (Lodi et al. 2005b). Other lichenoid of lesion homogeneity at a specific site to be most
lesions that can undergo malignant transformation relevant. This clinical sign is especially useful
include discoid lupus erythematosus, in particular when only a small area is involved, as OLP usu-
of the lip (Voigtlander and Boonen 1990) and ally affects various areas or a large area.
amalgam-associated OLR (Ostman et al. 1996). An important reported feature of the presen-
Interestingly, in a prospective study on prema- tation and clinical course of carcinomas that
lignant potential of OLP, all cases of malignant arise on OLP is their tendency of multiplicity.
transformation involved lesions that the authors Mignogna et al. (2002) found that 29% of
included in the group of OLL because they did not patients developing carcinomas in OLP had two
fulfill both clinical and histologic criteria for OLP or more independent neoplastic lesions (19%
(van der Meij et al. 2003). In 2007, van der Meij with a second tumor, 10% with >2 metachronous
et al. (2007) also studied the number of expected tumors) (Fig. 3b, c). This finding confirmed pre-
oral carcinomas in 67 patients with OLP and vious reports by Duffey et al. (1996) (20% of
125 patients with OLL. All malignant transforma- patients with second primary tumors) and Lo
tions (4 of 192, 2.1%) appeared in OLL patients, Muzio et al. (1998) (35.7% of patients with sec-
i.e., an annual OLL malignant transformation rate ond primary tumors).
of 0.71%. Hence, there was no increase in oral The relatively high frequency of multiple
cancer risk for patients with OLP but a 142-fold intraoral localizations of second primary tumors
increase for patients with OLL (P = 0.04). in previously diagnosed OLP may be attributed to
There may be considerable overlap between the the field cancerization phenomenon and indicates
clinical and microscopic features of OLR and OLP. that OLP may have an intrinsic predisposition to
Although no association has been established tumor development (Mignogna et al. 2007).
between OLR and malignant transformation The metastatic capacity of carcinomas devel-
(Mattsson et al. 2002), Larsson and Warfvinge oping in OLP has been addressed by an earlier
proposed that there may be a similar rate of malig- report by Mignogna et al. (2002) who showed
nant transformation in OLR to that observed in that 24% of these patients had detectable lymph
OLP, especially in lesions at the lateral border of node metastases at the time of diagnosis. In their
the tongue, a frequent site for OLR due to the close more recent work, the same authors (Mignogna
contact with silver amalgam restorations. They et al. 2007) reported that 94% of 97 neoplastic
reported that the cancer had developed on an events observed were TisN0M0 or T1N0M0
OLR in 4 of 724 patients with tongue cancer (intraepithelial neoplasia or microinvasive carci-
(Larsson and Warfvinge 2005). noma <1 mm) and 6% were stage III (three
tumors) or IV (three tumors).
Histopathologically, most tumors detected in
Tumors Developing in OLP and their OLP are well-differentiated SCCs [70% in the
Carcinogenesis study by Lo Muzio et al. (1998); 100% in the
study by Markopoulos et al. (1997)]. Finally,
Clinically, carcinomas that develop in previously there are conflicting results on the prognosis of
diagnosed OLP lesions have been reported to be patients with neoplasia in OLP, some indicating a
exophytic keratotic lesions (Lo Muzio et al. 1998; poor prognosis (Hietanen et al. 1999; Mignogna
Fatahzadeh et al. 2004) (Fig. 3a), but some may et al. 2001; Mignogna et al. 2002), but Mignogna
also show endophytic growth patterns (Lo Muzio et al. (2007) reported 100% 3-year and 97%
et al. 1998). Markopoulos et al. (1997) suggested 5-year survival, although there may have been a
that rapid expansion of OLP lesion should raise bias in this study as the neoplastic events
suspicion of malignant transformation, but corresponded to severe dysplasias ⁄carcinomas in
Mignogna et al. (2001) found neither the exten- situ in most patients, due to a meticulous follow-
sion nor severity of symptoms a useful indicator up program.
Fig. 3 Oral squamous cell carcinoma in OLP. Clinical carcinomas in an OLP patient whose right buccal mucosa
presentation of patients with OLP and who subsequently had previously shown histopathological evidence of OLP.
developed OSCC: (a) An exophytic squamous cell carci- Subsequently developed a more florid erythematous
noma that developed on the right lateral tongue in a patient mucosa in the same area (pictured) that was biopsied and
who previously had histopathologically diagnosed OLP in diagnosed as OSCC. (c) Eight years later, the same patient
the same area. (b) An example of metachronous developed a second OSCC, controlaterally
Numerous studies (Silverman et al. 1985; differentiate between the transformation caused
Markopoulos et al. 1997; Hietanen et al. 1999; by tobacco and that secondary to OLP. For this
van der Meij et al. 2003; Mignogna et al. 2006) reason, some authors recommend the exclusion of
have been unable to identify risk factors for cancer smokers with OLP from studies (van der Meij
development in patients with OLP. It has therefore et al. 1999a, b, Lozada-Nur 2000). However,
been proposed by some authors that carcinoma- according to Lodi et al. (2005b), although some
tous transformation is part of the natural history of cases described may be mainly related to tobacco
the disease or is attributable to unknown risk consumption, the exclusion of one putative risk
factors (van der Meij et al. 2003). factor based on the presence of another appears
Several risk factors for malignant transforma- inappropriate and could prevent the identification
tions in OLP have been proposed. These include of new risk factors. Thus, for example, this
erosive forms, tongue lesions, women more than approach would have impeded identification of
men, and sixth to seventh decades of life, but none the super-multiplicative risk of combined tobacco
of them gained significant agreement among and alcohol consumption for oral and oropharyn-
researchers (Gonzalez-Moles et al. 2008). geal cancer development.
Another relevant issue in the context of malignant Therefore, the putative role in OLP transfor-
transformation of OLP is whether to include mation of well-known risk factors for oral cancer
patients with chronic oral exposure to carcino- (tobacco and alcohol) has not been properly eval-
gens, as it will probably be impossible to uated in most studies (Lodi et al. 2005b). In a
single study, in which this interaction was Regarding gender and age, there appears to be
addressed, it was suggested that alcohol and a general consensus that the risk is higher in
tobacco, or their interaction, cannot explain the women than in men (Gonzalez-Moles et al.
excess risk for oral cancer found in OLP 2008). Some authors reported that an oral cancer
(Gandolfo et al. 2004). most frequently develops on an OLP between the
However, many authors (Murti et al. 1986; sixth and seventh decade of life (Barnard et al.
Barnard et al. 1993; Eisen 2002; van der Meij 1993; Hietanen et al. 1999).
et al. 2003; Gandolfo et al. 2004) found no rela- The mean interval between OLP diagnosis and
tionship between tobacco and alcohol consump- cancer diagnosis ranges widely from 20.8 months
tion on one side and malignant transformation on to 10.1 years, although the maximum risk is
the other side in OLP patients. reportedly between 3 and 6 years after OLP diag-
Results published by Rajentheran et al. (1999) nosis (Gonzalez-Moles et al. 2008). The risk of
indicate that tobacco and alcohol consumption malignant progression may also increase with the
may even be lower in these patients than in use of immunosuppressive agents. Although no
patients developing oral cancer in the absence of specific data are available in OLP patients, it is
OLP. In a cohort of 24 OLP patients with subse- well known that immunosuppressive treatment,
quent OSCC, Mignogna et al. (Mignogna et al. which generally includes corticosteroids, cyclo-
2001) found only three patients to be smokers and sporine, and tacrolimus, is a risk factor for cancer,
none to be alcoholic. Munoz et al. (2007) reported including OSCC (Kruse and Gratz 2009). A grow-
that only two out of ten OLP patients who devel- ing body of evidence now suggests that glucocor-
oped OSCC were smokers, none was an alcoholic ticoids can act as antiapoptotic agents in epithelial
abuser. cells to promote cancer progression (Azher et al.
With respect to the clinical form of OLP, 2016). The discovery that corticosteroids can
numerous authors (Silverman et al. 1985; Barnard directly target the oral mucosa via GR expressed
et al. 1993; Markopoulos et al. 1997; Hietanen by oral keratinocytes (Cirillo et al. 2012) may
et al. 1999; Rajentheran et al. 1999; Eisen 2002; have salient clinical implications in the under-
van der Meij et al. 2003) found that atrophic- standing of the malignant potential of OLP.
erosive forms predisposed to cancer development, However, other authors consider that immuno-
but this remains a controversial issue. In some suppressant therapy does not increase the risk of
series (Hietanen et al. 1999; Mignogna et al. transformation (Hietanen et al. 1999; Rajentheran
2001, 2007), plaque-like OLP lesions were also et al. 1999; Gandolfo et al. 2004; Mignogna et al.
relevant, both when they appeared alone and 2007) and might even reduce it. Thus, it has been
when associated with atrophic-erosive lesions. proposed that a microenvironment rich in
Analyses of malignant transformation risk fac- pro-inflammatory cytokines may be especially
tors have also considered the different intraoral favorable for neoplastic promotion, suggesting
sites of OLP. The tongue appears to be the pre- that more aggressive immunosuppressant treat-
ferred site for the emergence of cancer (Holmstrup ments against the inflammatory response in OLP
et al. 1988; Barnard et al. 1993; Markopoulos might restore normal immune surveillance and
et al. 1997; Munoz et al. 2007). interrupt neoplastic progression (Eisen 2002). In
Other studies, however, have reported sites a study of OLP patients treated mostly with topi-
other than the tongue to have a higher risk of cal and/or systemic steroids, therapeutic modali-
malignant transformation in OLP. Mignogna ties did not affect the risk of malignant
et al. (2001) found a significantly higher fre- transformation (Gandolfo et al. 2004).
quency of carcinomas at the midline of the palate, Malignant transformation of OLP has been
gingivae, and lips in a cohort of 502 OLP patients suggested to be related to, or dependent upon, a
who were followed up for periods from 4 months series of molecular stimuli originating in the inflam-
to 12 years and an overall malignant transforma- matory infiltrate (Mignogna et al. 2004). Chronic
tion rate of 3.7%. inflammation has been associated with various
types of cancer (Clevers 2004), and it has been potentially premalignant or malignant lesions
widely reported that the inflammatory infiltrate including oral leukoplakia and OSCC (Zeng
can be a strong risk factor for cancer development et al. 2009; Masaki et al. 2011). Candida spp.
in ulcerative colitis, atrophic gastritis, and Barret’s has been shown to present higher frequency and
esophagitis, among other diseases (Balkwill and colonization in those with OSCC compared to
Mantovani 2001). In fact, it was proposed by controls ( p = 0.001 and 0.033, respectively)
some authors that OLP could be included in this (Alnuaimi et al. 2015). With reference to OLP,
group of diseases (Mignogna et al. 2004). Some studies have shown the presence of oral yeast to
molecules and radicals generated by inflammatory be anywhere between 40% and 80% for patients
cells can act as mutagenic agents for epithelial cells with OLP and around 20% and 40% for controls
or influence important cell cycle regulation mecha- (Jainkittivong et al. 2007; Lodi et al. 2007;
nisms (Gonzalez-Moles et al. 2008). Masaki et al. 2011).
Most studies on cell proliferation in OLP have In relation to the association of Candida spp.
reported a marked increase in the proliferation rate and OLP, the evidence is conflicting. Specifically
of basal epithelial cells (Valente et al. 2001; the evidence is conflicting in terms of whether
Gonzalez-Moles et al. 2006), and some authors there is a significant relationship between Can-
have proposed that this might be an important dida spp. and erosive OLP, specifically whether
event in the development of cancer in OLP this relationship plays a role which enhances
(Taniguchi et al. 2002). inflammation to aggravate the pathogenic condi-
Mignogna et al. (2004) presented the possible tion (Zeng et al. 2009).
role of each type of inflammatory cells in the Similarly, there is conflicting evidence with
malignant transformation of OLP. According to regard to Candida invasion in OLP. At this stage
their hypothesis, macrophages, mast cells, lym- it is not certain if the presence of Candida in OLP
phocytes, and fibroblasts can contribute to the and other premalignant and malignant conditions
process of carcinogenesis in OLP by secreting is simply a coincidental finding and whether
cytokines, chemokines, MMPs, and RANTES changes in the local environment as a result of
molecules which have the ability to cause DNA OLP, such as roughness of the mucosal surface
damage, bypass p53 tumor suppression function, and hyperkeratosis, create an ideal environment
induce immortalization, and influence growth, which simply favors colonization and overgrowth
survival, angiogenesis, and invasion. of Candida spp. (McCullough et al. 2002).
In addition to the proposal that OLP-related
inflammatory microenvironment is able to initiate
tumorigenesis in normal epithelium, this microen- Patient Management
vironment has also been suggested to represent a
predisposing and enhancing factor toward the The characteristic clinical aspects of OLP (sym-
molecular changes caused by conventional envi- metry, bilateral distribution) are thought by some
ronmental carcinogens, such as tobacco and alco- researchers to be sufficient to make a correct diag-
hol (Mignogna et al. 2004). Interestingly, nosis especially if there are classic skin lesions
smoking was recently shown to alter the inflam- present (Eisen et al. 2005).
matory infiltrate in OLL, reducing the expression However, an oral biopsy with histopathologic
of macrophages, which may in turn affect the study is usually recommended to confirm the
immune surveillance and theoretically the mech- clinical diagnosis and mainly to exclude
anisms of malignant transformation (Alrashdan dysplasia and malignancy (Eisen et al. 2005;
et al. 2016). Al-Hashimi et al. 2007; Ismail et al. 2007; Scully
The role of Candida spp. in the symptomatol- and Carrozzo 2008).
ogy and malignant potential of OLP is unclear. The histopathologic assessment of OLP has
Candida spp. is frequently identified in patients been described as a subjective and insufficiently
with intraoral lesions of OLP and other oral reproducible process (van der Meij et al. 1999a),
and in about 50% of OLP cases, there is a lack of total of 1,158 patients (27% males and 73%
clinicopathologic correlation in the diagnostic females, age range 23–79 years) with OLR asso-
assessment of OLP (van der Meij and van der ciated with amalgam, 16–91% of patients were
Waal 2003). Gingival LP may be more difficult patch test positive for at least one mercury
to diagnose, and direct immunofluorescence of compound (Issa et al. 2004).
perilesional mucosa may facilitate the diagnosis Treatment of OLP should be directed at achiev-
and exclude other causes such as vesiculobullous ing specific goals after considering the degree of
diseases (Eisen et al. 2005). The value of direct clinical involvement, the predominant clinical
immunofluorescence for confirmation of the dis- type of lesions, the patient’s symptoms, and age.
ease is well accepted, especially with non- Reticular lesions that are asymptomatic generally
diagnostic histopathologic features and for the require no therapy but only observation for
desquamative gingivitis form of OLP (Eisen change. In general, all treatment should be aimed
et al. 2005; Scully and Carrozzo 2008). at managing atrophic and ulcerative lesions,
Direct immunofluorescence studies of OLP alleviating symptoms, and potentially decreasing
have shown a linear pattern and intense positive the risk of malignant transformation (Eisen et al.
fluorescence with antifibrogen outlining the base- 2005; Lodi et al. 2005; Al-Hashimi et al. 2007;
ment membrane zone and cytoid-like bodies with Scully and Carrozzo 2008).
positive immunoglobulin M labeling (Eisen et al. Mechanical trauma or irritants such as
2005; Ismail et al. 2007; Scully and Carrozzo sharp filling margins, rough surfaces, or badly
2008). Indirect immunofluorescence studies are fitting dentures should receive attention. A drug
not routinely used in the clinical diagnosis of OLP. history should be obtained to identify reversible
It has been proposed that allergy to dental causes of lichenoid eruptions as discontinuation
materials is common in patients with OLR. Cuta- of the offending agent can be curative (Eisen
neous patch testing is a recognized and accepted et al. 2005).
method to identify allergens responsible for type I Hypersensitivity reactions should be suspected
and IV allergic reactions with Dental Series when OLLs are confined to oral mucosal sites in
Epicutaneous Test Battery (Trolab) of patch test close proximity to dental restorations. An optimal
allergens being commonly used. The test sub- oral hygiene program should be instituted in
stances are applied to normal skin of the back patients with gingival disease (Eisen et al. 2005).
and read after 72 h. The patient is considered a Many therapeutic modalities have been
patch test positive to an allergen if they develop suggested in the treatment of OLP, with the most
erythematous vesicular or ulcerative reaction at currently accepted and reliable modality being the
the site of contact (Ismail et al. 2007). use of topical steroids with consideration to be
Skin patch testing to investigate contact sensi- given for use of systemic steroids in cases of
tivity responses to mercury and amalgam pro- severe widespread disease and/or refractory
duced conflicting results with variable numbers cases of OLP (Vincent et al. 1990; Al-Hashimi
of patients being positive in different studies. In et al. 2007).
one study, Laine et al. (1992) studied 118 patients
with OLR topographically associated with dental
fillings, 68% of such patients were patch test Topical Agents
positive to metals of fillings materials, particularly
mercury and silver nitrate. In another trial, Glucocorticoids
Wong et al. reported a positive patch test in 39% The most commonly employed and useful agents
of a total of 84 patients who presented with for the treatment of OLP are topical corticoste-
OLR related to amalgam fillings (Wong and roids. A response to treatment with midpotency
Freeman 2003). corticosteroids such as triamcinolone, potent fluo-
In a systematic review that analyzed data from rinated corticosteroids such as fluocinolone
14 cohort and five case-controlled studies with a acetonide and fluocinonide, and superpotent
halogenated corticosteroids such as clobetasol has (Lo Muzio et al. 2001). Elixir forms of corticoste-
been reported in 30–100% of treated patients roids, such as dexamethasone, triamcinolone, and
(Carbone et al. 1999; Thongprasom et al. 2003; clobetasol, have been used as an oral rinse for
Eisen et al. 2005). patients with diffuse oral involvement or for
Al-Hashimi et al. (2007) reviewed 12 clinical elderly patients who may find it technically diffi-
trials in the context of corticosteroid use for OLP cult to apply medication to various active loca-
(four were placebo controlled, one assessed sys- tions of the oral cavity. Careful consideration
temic corticosteroids). Most studies were not should be given to the vehicle as unlike skin
focused on investigating the value of corticoste- compounds, which have been well studied, clini-
roids in the treatment of OLP per se but compared cal trials that have compared the strength of corti-
the effectiveness of different formulations, differ- costeroids in various bases in the oral cavity are
ent classes of corticosteroid, different strengths of generally lacking (Eisen et al. 2005).
topical steroids, and different frequency of appli- Few serious side effects arise with topical cor-
cation. The specific medications included in the ticosteroids as they are generally well tolerated.
review were fluocinonide, fluocinolone acetonide, Side effects reported include secondary
triamcinolone acetonide, clobetasol propionate, candidosis, nausea, oral use not tolerated, refrac-
fluticasone propionate, and betamethasone valer- tory response, mucosal atrophy, oral dryness, sore
ate/sodium phosphate for topical therapy, with throat, bad taste, delayed healing, and systemic
dosages ranging from 0.025%, 0.1%, to 0.5% absorption (Savage and McCullough 2005;
and the frequency of application varying from Thongprasom and Dhanuthai 2008).
two, three, to four times a day. The average dura- Given the high rate of commensal oral yeast
tion of the studies was between 4 and 8 weeks, carriage in the community, it is expected that some
except for one, which was for 6 months, and the patients will develop a secondary erythematous
overall conclusion suggests that corticosteroids candidosis or pseudomembranous candidosis
are effective in the management of OLP and are (thrush) (Thongprasom and Dhanuthai 2008). As
unlikely to cause serious side effects (Al-Hashimi many as one-third of OLP patients treated with
et al. 2007). There were no studies determining if topical corticosteroids have been reported to
adhesive vehicles are better than mouth rinses. develop secondary candidosis (Vincent et al.
However, empirical evidence seems to suggest 1990) which necessitates treatment or instituting
that mouth rinses are of value in patients with antifungal therapy before the patient begins using
widespread symptomatic OLP where the lesions topical steroids. Many of these patients can be
are not easily accessible to the placement of identified prior to commencing corticosteroids
ointments or gels. The evidence also suggests and preventive treatment initiated coincident or
that higher potency corticosteroids, such as immediately prior to the initial applications. Com-
clobetasol, are probably more effective mon conditions that have been proposed to predis-
(Al-Hashimi et al. 2007). There was insufficient pose to candidal overgrowth include xerostomia;
evidence regarding different dosages, formula- systemic and/or topical use of antibiotics, cortico-
tions, or modes of delivery of topical steroids steroid asthma inhalants, prostheses, and cigarette
(e.g., paste, spray, mouthwash) to make an smoking (Savage and McCullough 2005).
evidence-based recommendation (Al-Hashimi Development of candidosis often leads to
et al. 2007). immediate interruption to treatment, prolonged
The greatest obstacle in using topical cortico- and amplified morbidity, additional treatment for
steroids in the mouth is the lack of adherence to the infection, delayed management of the original
the mucosa for a sufficient length of time. For this condition, and clouding of the baseline pathosis
reason, some investigators prefer using topical present. Wherever possible, anticipation and pre-
corticosteroids in adhesive pastes although there vention are preferable to a reactive response.
is no data that topical steroids in adhesive bases A refractory response, described by some as
are more effective than as base preparations tachyphylaxis, is characterized by decreasing
efficacy of corticosteroids during continued treat- methylprednisolone have been used (Eisen et al.
ment (Hengge et al. 2006) and may result from a 2005). Frequent injections of steroids, however,
number of areas, including poor patient compli- are painful, not invariably effective, and may
ance, inappropriate instruction and patient use, result in an unwanted systemic dose (Eisen et al.
inappropriate application, for example, a carrier 2005).
may be helpful for the gingiva, agent of insuffi-
cient potency, incorrect diagnosis, and failure to Calcineurin Inhibitors
remove any local cause, for example, a corroded Calcineurin inhibitors are microbially derived
amalgam restoration causing a OLR (Savage and immunosuppressive agents that have been primar-
McCullough 2005). ily used in transplant medicine and in the treat-
Systemic absorption has been reported, and it ment of immune-mediated diseases with the
is thought that absorption of small amounts principle agents being tacrolimus, pimecrolimus,
through the oral mucosa can take place, but clin- and cyclosporine (Al Johani et al. 2009).
ical experience and laboratory studies have shown Calcineurin inhibitors bind to different cyto-
this not to be of clinical significance in almost all plasmic proteins of T lymphocytes (cyclosporine
cases (Savage and McCullough 2005). to cyclophilin, tacrolimus, and pimecrolimus to
Interestingly, although systemic absorption FK506-binding protein) to form complexes that
and adrenal suppression were reported with in turn inhibit calcineurin leading to suppression
long-term use of superpotent corticosteroids for of transcription and production of many cyto-
chronic skin diseases (Levin and Maibach 2002), kines. Calcineurin inhibitors have been suggested
this does not seem to be the case with oral corti- to be of clinical benefit in the management of
costeroids used for OLP (Thongprasom and some immunologically mediated oral mucosal
Dhanuthai 2008). Exceptions arise, and this is an disorders including OLP (Al Johani et al. 2009).
issue that should receive consideration with par- There are now numerous reports of the efficacy
ticular patient groups along with the occasional of calcineurin inhibitors in the management of
idiosyncratic response. Patients with medical con- OLP, and effectiveness has been assessed via
ditions that are of particular concern include dia- open-label prospective studies, randomized trials,
betes, hypertension, and tuberculosis. Steroid retrospective studies, case series, and described in
mouth rinses in patients with extensive areas of several case reports (Lodi et al. 2005; Al-Hashimi
disease and excessive and unmonitored usage are et al. 2007; Al Johani et al. 2009). Initial studies
also a concern. focused on patients with symptomatic OLP that
Therefore, careful and frequent follow-up had not responded to topical corticosteroids or
examinations are necessary especially with who were at risk of adverse side effects from
chronic use of topical corticosteroids. Temporary corticosteroids. In their review, Al-Hashimi et al.
burning or stinging at the site of application has (2007) assessed four studies regarding cyclospor-
also been reported with triamcinolone acetonide ine use for OLP (three used 500 mg mouthwash
0.1% ointment (Laeijendecker et al. 2006). and one used adhesive gel form). In all of the
In general, it has been recommended that ther- studies, the side effects were minimal and mainly
apy should be initiated with a potent preparation consisted of a transient burning sensation, bad
to achieve a rapid response, particularly in erosive taste, and high cost. In OLP patients, systemic
OLP lesions, and then lowering the strength with absorption is probably low, and most studies did
healing, and eventually once the disease becomes not detect cyclosporin in peripheral blood. The
inactive and there is either an absence of lesions or results of all of the studies showed a marked
the presence of only white reticular lesions, therapy improvement in the oral symptoms. However,
may be temporarily discontinued (Eisen et al. 2005). cyclosporine mouth rinse was not significantly
For intractable erosive OLP lesions, better than 0.1% triamcinolone paste in a con-
intralesional injections of hydrocortisone, dexa- trolled, randomized prospective trial that involved
methasone, triamcinolone acetonide, and 13 OLP patients randomly assigned to treatment
with cyclosporine rinse or triamcinolone paste for and well tolerated, some OLP patients have
6 weeks (Sieg et al. 1995). noted flare-ups soon after stopping the treatment.
In general, cyclosporin can be an alternative to The treatment of chronic erosive oral LP with low
conventional treatments for initial control of OLP. concentrations of tacrolimus was found to yield a
However, it should not be considered as a first rapid and important palliative effect in an open-
drug of choice because of the high cost of long- label prospective study that included eight erosive
term treatment and the availability of effective OLP with 6 months of treatment; however, all
alternatives. Severe side effects of systemic cyclo- patients relapsed after 12-month follow-up (Oliv-
sporin, such as hypertension and nephrotoxicity, ier et al. 2002). Currently, there remains little
preclude its long-term use for OLP (Lodi evidence demonstrating that tacrolimus is notably
et al. 2005). superior to topical corticosteroids for the treat-
Tacrolimus is a macrolide immunosuppressant ment of OLP (Al Johani et al. 2009).
derived from Streptomyces tsukubaensis. It is a Pimecrolimus is derived from the macrolide
relatively selective inhibitor of calcineurin and ascomycin and shares the same cellular binding
was initially developed as a systemic agent to protein (FK506-binding protein-12) as tacrolimus
lessen allograft rejection. Tacrolimus has the abil- and blocks the transcription of cytokines by
ity to inhibit T-cell activation at 10–100 times inhibiting the calcineurin pathway. Topical
lower concentration than cyclosporin. Notably, pimecrolimus is a cream developed specifically
topical tacrolimus seems to penetrate skin better for the treatment of AD and approved for the
than topical cyclosporin (Lodi et al. 2005; Al treatment of patients with mild to moderate AD
Johani et al. 2009). Formulated for topical appli- disease in patients older than 2 years. There is
cation in the management of atopic dermatitis currently limited data on the potential use of topical
(AD), it was approved in 2000 by the United pimecrolimus for the treatment of oral mucosal
States Food and Drug Administration (FDA) to disease, with few reports suggesting it to be effec-
be used in moderate to severe AD for patients tive in the management of symptoms and erosions/
older than 2 years. Topical tacrolimus has proven ulcerations of OLP (Dissemond et al. 2004).
to be of benefit in the treatment of other disorders In a recent study, Arduino et al. (2014) found
including cutaneous psoriasis, contact allergy, no difference between pimecrolimus 1% cream
corticosteroid-induced rosacea, pyoderma and tacrolimus 0.1% ointment in managing recal-
gangrenosum, alopecia areata, mucocutaneous citrant atrophic-erosive OLP in an 8-week ran-
LP, and GVHD (Al Johani et al. 2009). Topical domized, double-blind controlled trial, followed
tacrolimus is available in different concentrations by a 6-month follow-up period in 30 unresponsive
(0.03%, 0.1%). OLP patients. Both agents were effective in induc-
Systemic tacrolimus is substantially less ing clinical improvement; however, pimecrolimus
expensive and 10–100 times more potent than showed better stability in therapeutic effective-
cyclosporine, even though relative potency of ness with statistically significant higher number
topical preparations has never been evaluated. of patients (10 vs. 4) not requiring any further
Tacrolimus used topically can control symptoms treatment at the end of the follow-up period.
and significantly improve refractory erosive OLP The theoretical increased risk of developing
(Hodgson et al. 2003). Local irritation is the most malignancy with use of either tacrolimus or
common adverse effect reported (Lodi et al. 2005; pimecrolimus has been raised with the FDA; in
Al Johani et al. 2009). Other side effects include the USA “Black Box” warning attached to these
transient taste disturbance and sore throat. agents is based on theoretical increased risk of
Tacrolimus ointment 0.1% was shown to be well malignancy (SCC and lymphoma) in patients
tolerated and appeared to be effective in erosive using these agents for cutaneous psoriasis. In a
OLP that did not respond to topical steroids in a recent case report of a patient with OLP, the top-
small cohort of six erosive OLP (Morrison et al. ical use of tacrolimus 0.1% was suggested to be
2002). Although topical tacrolimus is effective the cause of the development of an SCC of the
tongue (Becker et al. 2006). Therefore, some clobetasol propionate with and without topical
authors believe that the use of these agents should miconazole in patients with symptomatic OLP.
be restricted and patients should be made aware of Results showed significant improvement in both
these concerns (Al-Hashimi et al. 2007). On the the test ( p = 0.0020) and control ( p < 0.001)
other hand, other researchers find that although groups, and it was concluded while miconazole
systemic tacrolimus may increase the risk of prevented secondary candidosis, which occurred
malignancy, there is no strong evidence that top- in 30% of control subjects; however adjunctive
ical application of tacrolimus is associated with topical antifungal treatment did not affect the effi-
such an increased risk (Al Johani et al. 2009). In cacy of treatment or improve outcomes such as
support of this view, a recent case-control study pain or lesion extension (Lodi et al. 2007). Due to
that involved 294 patients did not find any the current lack of controlled studies and literature
increased risk of lymphoma in patients with AD in this particular area, recent systemic review by
treated with topical calcineurin inhibitors Lodi et al. (2012) and Cochrane review by
(Arellano et al. 2007). Thongprasom et al. (2011) concluded that there
Overall, there remains little information of the is currently insufficient evidence to determine
carcinogenic potential of tacrolimus or whether adjunctive antifungal therapy is effective
pimecrolimus, and the new recommendations from in the treatment of oral lichen planus
the European Medicines Agency state that the ben- (Thongprasom et al. 2011; Lodi et al. 2012).
efits of these calcineurin inhibitors outweigh the
risks. The European Medicines Agency, however,
recommends intermittent use of topical tacrolimus Systemic Drug Treatment
with the lowest strength possible and only for short
periods of time (Al Johani et al. 2009). Several studies have reported that systemic corti-
costeroids are the most effective treatment for
Retinoids OLP; however, a comparative study that involved
Systemic and topical forms of retinoids have been a total of 49 OLP patients did not find differences
used in the treatment of OLP (Lodi et al. 2005; in response between systemic prednisone (1 mg/
Al-Hashimi et al. 2007). Topical tretinoin or kg/day) with topical clobetasol in an adhesive
isotretinoin has been used to treat OLP, particu- base (n = 26) and topical clobetasol alone
larly atrophic-erosive forms, with considerable (n = 23) after a mean follow-up period of
improvement (Scardina et al. 2006), but retinoids 36 months (Carbone et al. 2003). Complete remis-
often cause adverse effects and are less effective sion was achieved in 68% of the prednisone group
than topical corticosteroids (Scully and Carrozzo and 705 of the topical clobetasol group
2008). (P = 0.94).
Systemic corticosteroids are, therefore, usually
Topical Antifungal Therapy reserved for cases where topical approaches have
The role Candida plays in the symptomatology of failed, where there is recalcitrant, erosive, or ery-
OLP is currently unknown. Based on the current thematous OLP, or for widespread OLP when the
evidence, a question therefore arises as to whether skin, genitals, esophagus, or scalp is also involved
antifungals are required to treat symptomatic OLP (Al-Hashimi et al. 2007; Scully and Carrozzo
along with corticosteroids, not only prevent sec- 2008). Prednisolone 40–80 mg daily is usually
ondary candidosis and the symptoms associated sufficient to achieve a response: its toxicity
with this but also as a prophylactic treatment to requires that it should be used only when neces-
reduce Candida spp. overgrowth and the associ- sary, at the lowest dose, and for the shortest time
ated factors which may encourage a carcinogenic possible with recommendation of (5–7 days) and
event. A randomized double-blinded clinical trial then withdrawn abruptly, or the dose should be
undertaken by Lodi et al. (2007) with 35 patients reduced by 5–10 mg/day gradually over
reviewed the efficacy of topically applied 2–4 weeks (Scully and Carrozzo 2008). Adverse
effects are possible even with short courses but 2003). In a recent retrospective review of clinical
may be minimized if patients can tolerate the same responses of ten patients with severe ulcerative LP
total dose on alternate days. (vulvovaginal with gingival involvement, n = 8;
Systemic calcineurin inhibitors are associated penogingival, n = 1; oral, n = 1) treated with
with significant adverse effects including hyper- mycophenolate, Wee et al. (2012) showed remis-
tension, nephrotoxicity, and infections second- sion in six patients, well-controlled disease in one,
ary to immunosuppressive status of the patients and partially controlled in the other three. The
which correlated with the dosage, blood levels, mean duration for mycophenolate treatment was
and duration of therapy (Al Johani et al. 2009). 3.7 years, and the mean follow-up was 4.2 years.
Moreover, systemic tacrolimus can increase the Mycophenolate was well tolerated in all patients
risk of malignancy (e.g., oropharyngeal and skin except in two who reported mild headaches and
cancers) by suppressing immune surveillance tiredness (Wee et al. 2012).
and inhibiting DNA repair and apoptosis (Yarosh
et al. 2005). Therefore, systemic calcineurin Aloe vera
inhibitors are not recommended for OLP Aloe vera (AV) is a cactus-like plant that belongs
treatment. to the Liliaceae family. The reported pharmaco-
logical actions of AV include anti-inflammatory,
antibacterial, antiviral, and antifungal properties
Miscellaneous Agents and hypoglycemic effects (Yagi et al. 2002). Top-
ical Aloe vera is an emerging new modality in the
Azathioprine treatment of OLP that has been recently investi-
Azathioprine has been reportedly successful as a gated. In a randomized double-blind study, AV
“steroid-sparing agent” for cutaneous LP, and mouthwash significantly improved the oral qual-
there is limited published evidence suggesting it ity of life for 32 OLP patients over a period of
may have a similar role in recalcitrant OLP 3 months as compared to a placebo group
(Silverman et al. 1991). In general, the results (Salazar-Sanchez et al. 2010). In another study,
are no better than systemic steroids alone or sys- comparable effects of AV mouthwash were
temic steroids in conjunction with topical steroids reported when compared to 0.1% triamcinolone
(Lodi et al. 2005b). acetonide paste in a group of OLP patients (n = 23
each) in terms of VAS of pain, burning sensation,
Dapsone clinical presentation, and healing of the OLP
Dapsone has been used in the treatment of lesions after 2 months from the beginning of treat-
erosive OLP with some benefit (Beck and ment (Mansourian et al. 2011).
Brandrup 1986). It should be considered in According to a recent Cochrane review
resistant cases, particularly when severe erosive (Thongprasom et al. 2011), there is weak evidence
lesions are present. Significant adverse effects from two placebo-controlled RCTs, using differ-
such as hemolysis have been reported, and ent formulations, that AV may be associated with
thus the use of dapsone in the treatment OLP a reduction in pain in OLP (Choonhakarn et al.
is generally not recommended (Matthews et al. 2008; Salazar-Sanchez et al. 2010). It should be
1989). emphasized that the above trials used different AV
formulations and the amount of active drug sub-
Mycophenolate Mofetil stance in AV varies depending also on the age of
Mycophenolate has shown promise as an alterna- the plant, the growing and harvesting conditions,
tive to azathioprine as an immunomodulatory the parts of the plant, and the extraction methods
agent with a better safety profile in the manage- used. The great level of variability could have
ment of graft rejection in organ transplant recipi- affected the results of the published studies and
ents, and GVHD, and therefore may be a represents a challenge for future research
candidate for use in recalcitrant OLP (Eisen (Thongprasom et al. 2013).
Biologics for the rarity of reports of use of TNF antagonists

The management of various immune-mediated in LP to date and may be a barrier to further
disorders has changed dramatically by the advent use. Additional concerns center around the
of biologic therapies. Biologics are designed by potential for reactivation of viral infections
recombinant biotechnology to target particular with concern about those patients with LP
steps in the pathogenesis of immunoinflammatory who have concomitant HCV infection
diseases. Structurally, biologics include receptor (Lodi et al. 2010). The potential risk of
fusion proteins, monoclonal antibodies, and malignancy in LP and those reports of the devel-
recombinant cytokines. Functionally, biologics opment of oral cancer in patients receiving
can be divided into T-cell or cytokine modulators TNF-α blockers may be an additional reason to
(Zhang et al. 2011). Various immunobiologics use these agents with caution (O’Neill and
have been recently applied in the treatment of Scully 2013).
psoriasis and rheumatic diseases as biologic
immunomodulators may represent a more effec-
tive and targeted approach than conventional Other Agents and Treatment Modalities
treatment modalities (Shirota et al. 2008). Other agents have been suggested for OLP treat-
Various diseases including Behcet’s disease, ment but with weaker evidence. These include
recurrent aphthous stomatitis, benign mucous levamisole, amitriptyline, amlexanox,
membrane pemphigoid, and LP are considered hyaluronic acid, thalidomide, ignatia,
potential candidates for the use of biologics curcuminoids, lycopene, phototherapy, lasers,
(O’Neill 2008). surgery, and cryosurgery (Lodi et al. 2005;
After the pathogenesis of OLP has been thor- Al-Hashimi et al. 2007; Thongprasom et al.
oughly investigated, several biologic agents, 2013).
especially those targeting T cells such as TNF-α In conclusion, it appears that although a wide
inhibitors, are suggested as a future alternative to range of treatment options is available for patients
steroid therapy. However, possible reactions and with OLP, the level of clinical efficacy is incon-
side effects will always be a major concern (Zhang sistent, and individualized protocols are required
et al. 2011). in cases with recalcitrant OLP.
TNF-α inhibitors currently available are Recently, Lodi et al. (2012) reviewed 28
etanercept, infliximab, and adalimumab, all of randomized controlled trials (RCTs) in the
which are FDA approved for psoriasis. The clin- context of interventions for OLP. Although
ical feasibility has been demonstrated not only topical corticosteroids are considered to be the
by a successful treatment of LP with etanercept first-line treatment, no RCTs were identified
(Yarom 2007) but also by the efficacy of that compared topical corticosteroids with
adalimumab for the treatment of cutaneous and placebo in patients with symptomatic OLP. From
OLP (Chao 2009). Moreover, there are several the 28 trials included in this systematic review, the
ongoing clinical trials to evaluate the safety and wide range of interventions compared means
effectiveness of etanercept in treating oral and there is insufficient evidence to support the supe-
cutaneous LP. According to a recent review by rior effectiveness of any specific treatment (Lodi
O’Neill and Scully (2013), the best data, et al. 2012).
although limited, are for the use of the T-cell
modulator alefacept in OLP. Limitations on
future studies with such agents include the Follow-up
need for continuous or intermittent use of anti-
TNF-α therapy for long-term control of OLP Patient follow-up ranging from every 2 months to
and the fact that TNF-α blockers have the annually is accepted as part of long-term care for
potential for initiating lichenoid eruptions patients with OLP largely to screen for changes
(Asarch et al. 2009).This possibly accounts that may indicate malignant transformation
(Mignogna et al. 2006). At a minimum, annual there is much that remains unknown regarding
monitoring is recommended (Al-Hashimi et al. oral mucosal lichen planus, such as the exact
2007; Parashar 2011) and favorably two to four cause, pathogenic mechanism involved, and pro-
reviews (Scully et al. 1998; Mattsson et al. 2002; cess by which malignant transformation occurs.
van der Meij et al. 2007). More frequent exami- Further directed research is required so that we
nations are recommended for patients with OLL may be able to best advise and treat our patients.
with dysplasia.
If changes are noted in a lesion at follow-up
visits, then an additional biopsy or biopsies should Cross-References
be performed and the follow-up intervals short-
ened (Ismail et al. 2007). ▶ Clinical Evaluation of Oral Diseases
For those OLP patients who develop OSSC, ▶ Clinical Immunology in Diagnoses of Maxillo-
Mignogna et al. (2002) proposed the strict follow- facial Disease
up of patients with oral and neck examinations ▶ Cutaneous Pathology of the Head and Neck
every 2 months during the 5- to 9-month period ▶ Gingival Pathology
after the diagnosis of oral carcinoma, when the ▶ Interface Between Oral and Systemic Disease
risk of metastasis or second primary tumor is ▶ Laboratory Medicine and Diagnostic Pathology
maximum. The same authors subsequently ▶ Normal Variation in the Anatomy, Biology, and
reported that a program of three follow-up exam- Histology of the Maxillofacial Region
inations a year enables detection of malignant ▶ Oral and Maxillofacial Fungal Infections
transformation in early or microinvasive ▶ Oral Manifestations of Systemic Diseases and
intraepithelial states, which generally have a their Treatments
very good prognosis (Mignogna et al. 2006). ▶ Oral Mucosal Malignancies
▶ Oral Vesicular and Bullous Lesions
Conclusions and Future Directions ▶ Orofacial Pain in Patients with Cancer and
Mucosal Diseases
LP is a common chronic inflammatory disease of ▶ Pharmacotherapeutic Approaches in Oral
the skin and oral mucosa with an estimated prev- Medicine
alence of 0.5–2%. Although the cause of OLP is ▶ White and Red Lesions of the Oral Mucosa
unknown, it is thought to result from the complex
interplay of host, lifestyle, and environmental fac-
tors resulting in cell-mediated immune References
dysregulation. The oral appearance of OLP has
been described as six clinical subtypes seen indi- Abdelsayed RA, Sumner T, Allen CM, Treadway A, Ness
vidually or in combination (reticular, plaque-like, GM, Penza SL. Oral precancerous and malignant
atrophic, erosive, papular, and bullous), with the lesions associated with graft-versus-host disease: report
of 2 cases. Oral Surg Oral Med Oral Pathol Oral Radiol
most common being reticular occurring bilaterally Endod. 2002;93(1):75–80.
in the posterior buccal mucosa. Aderem A. Phagocytosis and the inflammatory response.
Symptoms and signs can range from patients J Infect Dis. 2003;187(Suppl 2):S340–5.
being unaware of the disease, with lesions that are Al Johani KA, Hegarty AM, Porter SR, Fedele
S. Calcineurin inhibitors in oral medicine. J Am Acad
completely asymptomatic as in reticular OLP, to Dermatol. 2009;61(5):829–40.
those experiencing mucosal sensitivity and burn- Al-Hashimi I, Schifter M, Lockhart PB, Wray D,
ing and debilitating pain. Treatment generally Brennan M, Migliorati CA, Axell T, Bruce AJ,
consists of the topical use of anti-inflammatory Carpenter W, Eisenberg E, Epstein JB, Holmstrup P,
Jontell M, Lozada-Nur F, Nair R, Silverman B,
agents for symptomatic relief. Malignant transfor- Thongprasom K, Thornhill M, Warnakulasuriya S,
mation of OLP remains a controversy and vari- van der Waal I. Oral lichen planus and oral lichenoid
ably reported between 0% and 5%. Obviously, lesions: diagnostic and therapeutic considerations. Oral
Surg Oral Med Oral Pathol Oral Radiol Endod. Barrett AW, Raja AM. The immunohistochemical identifi-
2007;103(Suppl):S25 e21–12. cation of human oral mucosal melanocytes. Arch Oral
Alnuaimi AD, Wiesenfeld D, O’Brien-Simpson NM, Biol. 1997;42(1):77–81.
Reynolds EC, McCullough MJ. Oral Candida coloni- Beaird LM, Kahloon N, Franco J, Fairley JA. Incidence of
zation in oral cancer patients and its relationship with hepatitis C in lichen planus. J Am Acad Dermatol.
traditional risk factors of oral cancer: a matched case- 2001;44(2):311–2.
control study. Oral Oncol. 2015;51(2):139–45. Beck HI, Brandrup F. Treatment of erosive lichen planus
Alrashdan MS, Angel C, Cirillo N, McCullough with dapsone. Acta Derm Venereol. 1986;66(4):366–7.
M. Smoking habits and clinical patterns can alter the Becker JC, Houben R, Vetter CS, Brocker EB. The carci-
inflammatory infiltrate in oral lichenoid lesions. Oral nogenic potential of tacrolimus ointment beyond
Surg Oral Med Oral Pathol Oral Radiol. 2016;121 immune suppression: a hypothesis creating case report.
(1):49–57. BMC Cancer. 2006;6:7.
Arduino PG, Carbone M, Della Ferrera F, Elia A, Bermejo-Fenoll A, Lopez-Jornet P. Familial oral lichen
Conrotto D, Gambino A, Comba A, Calogiuri PL, planus: presentation of six families. Oral Surg Oral
Broccoletti R. Pimecrolimus vs. tacrolimus for the top- Med Oral Pathol Oral Radiol Endod. 2006;102(2):
ical treatment of unresponsive oral erosive lichen e12–5.
planus: a 8 week randomized double-blind controlled Bode W. Structural basis of matrix metalloproteinase func-
study. J Eur Acad Dermatol Venereol. 2014;28 tion. Biochem Soc Symp. 2003;70:1–14.
(4):475–82. Bornstein MM, Kalas L, Lemp S, Altermatt HJ, Rees TD,
Arellano FM, Wentworth CE, Arana A, Fernandez C, Paul Buser D. Oral lichen planus and malignant transforma-
CF. Risk of lymphoma following exposure to tion: a retrospective follow-up study of clinical and
calcineurin inhibitors and topical steroids in patients histopathologic data. Quintessence Int. 2006;37
with atopic dermatitis. J Invest Dermatol. 2007;127 (4):261–71.
(4):808–16. Brandtzaeg P. Do salivary antibodies reliably reflect both
Asarch A, Gottlieb AB, Lee J, Masterpol KS, Scheinman mucosal and systemic immunity? Ann N Y Acad Sci.
PL, Stadecker MJ, Massarotti EM, Bush ML. Lichen 2007;1098:288–311.
planus-like eruptions: an emerging side effect of tumor Brown GR, Lindberg G, Meddings J, Silva M, Beutler B,
necrosis factor-alpha antagonists. J Am Acad Thiele D. Tumor necrosis factor inhibitor ameliorates
Dermatol. 2009;61(1):104–11. murine intestinal graft-versus-host disease. Gastroen-
Axell T, Rundquist L. Oral lichen planus – a demographic terology. 1999;116(3):593–601.
study. Community Dent Oral Epidemiol. 1987;15 Burkhart NW, Burkes EJ, Burker EJ. Meeting the educa-
(1):52–6. tional needs of patients with oral lichen planus. Gen
Azher S, Azami O, Amato C, McCullough M, Dent. 1997;45(2):126–32; quiz 143–24.
Celentano A, Cirillo N. The non-conventional effects Carbone M, Conrotto D, Carrozzo M, Broccoletti R,
of glucocorticoids in cancer. J Cell Physiol. Gandolfo S, Scully C. Topical corticosteroids in asso-
2016;231:2368–73. ciation with miconazole and chlorhexidine in the long-
Baccaglini L, Thongprasom K, Carrozzo M, Bigby term management of atrophic-erosive oral lichen
M. Urban legends series: lichen planus. Oral Dis. planus: a placebo-controlled and comparative study
2013;19(2):128–43. between clobetasol and fluocinonide. Oral Dis. 1999;5
Bagan JV, Donat JS, Penarrocha M, Milian MA, Sanchis (1):44–9.
JM. Oral lichen planus and diabetes mellitus. a clinico- Carbone M, Goss E, Carrozzo M, Castellano S,
pathological study. Bull Group Int Rech Sci Stomatol Conrotto D, Broccoletti R, Gandolfo S. Systemic and
Odontol. 1993;36(1–2):3–6. topical corticosteroid treatment of oral lichen planus: a
Bagan JV, Thongprasom K, Scully C. Adverse oral reac- comparative study with long-term follow-up. J Oral
tions associated with the COX-2 inhibitor rofecoxib. Pathol Med. 2003;32(6):323–9.
Oral Dis. 2004;10(6):401–3. Carrozzo M, Elia A, Mereu V, Dametto E, Fasano M,
Bain L, Geronemus R. The association of lichen planus of Broccoletti R, Rendine S, Amoroso A. HLA-C/KIR
the penis with squamous cell carcinoma in situ and with genotypes in oral lichen planus patients infected or
verrucous squamous carcinoma. J Dermatol Surg non-infected with hepatitis C virus. Oral Dis. 2011;17
Oncol. 1989;15(4):413–7. (3):309–13.
Balkwill F, Mantovani A. Inflammation and cancer: back Carrozzo M, Francia Di Celle P, Gandolfo S, Carbone M,
to Virchow? Lancet. 2001;357(9255):539–45. Conrotto D, Fasano ME, Roggero S, Rendine S,
Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Ghisetti V. Increased frequency of HLA-DR6 allele in
Liu YJ, Pulendran B, Palucka K. Immunobiology of Italian patients with hepatitis C virus-associated oral
dendritic cells. Annu Rev Immunol. 2000;18:767–811. lichen planus. Br J Dermatol. 2001;144(4):803–8.
Barnard NA, Scully C, Eveson JW, Cunningham S, Porter Carrozzo M, Gandolfo S, Carbone M, Colombatto P,
SR. Oral cancer development in patients with oral Broccoletti R, Garzino-Demo P, Ghisetti V. Hepatitis
lichen planus. J Oral Pathol Med. 1993;22(9):421–4. C virus infection in Italian patients with oral lichen
planus: a prospective case-control study. J Oral Pathol infection: a fortuitous association? Arch Dermatol.
Med. 1996;25(10):527–33. 1997;133(8):1052–3.
Carrozzo M, Uboldi de Capei M, Dametto E, Fasano ME, Dwyer CM, Kerr RE, Millan DW. Squamous carcinoma
Arduino P, Broccoletti R, Vezza D, Rendine S, Curtoni following lichen planus of the vulva. Clin Exp
ES, Gandolfo S. Tumor necrosis factor-alpha and Dermatol. 1995;20(2):171–2.
interferon-gamma polymorphisms contribute to sus- Eisen D. The evaluation of cutaneous, genital, scalp, nail,
ceptibility to oral lichen planus. J Invest Dermatol. esophageal, and ocular involvement in patients with
2004;122(1):87–94. oral lichen planus. Oral Surg Oral Med Oral Pathol
Chainani-Wu N, Madden E, Lozada-Nur F, Silverman Jr Oral Radiol Endod. 1999;88(4):431–6.
S. High-dose curcuminoids are efficacious in the Eisen D. The clinical features, malignant potential, and
reduction in symptoms and signs of oral lichen planus. systemic associations of oral lichen planus: a study of
J Am Acad Dermatol. 2012;66(5):752–60. 723 patients. J Am Acad Dermatol. 2002;46
Chainani-Wu N, Silverman Jr SOL, Lozada-Nur F, May- (2):207–14.
er P, Watson JJ. Oral lichen planus: patient profile, Eisen D. The clinical manifestations and treatment of oral
disease progression and treatment responses. J Am lichen planus. Dermatol Clin. 2003;21(1):79–89.
Dent Assoc. 2001;132(7):901–9. Eisen D, Ellis CN, Duell EA, Griffiths CE, Voorhees
Chao TJ. Adalimumab in the management of cutaneous JJ. Effect of topical cyclosporine rinse on oral lichen
and oral lichen planus. Cutis. 2009;84(6):325–8. planus. A double-blind analysis. N Engl J Med.
Choonhakarn C, Busaracome P, Sripanidkulchai B, 1990a;323(5):290–4.
Sarakarn P. The efficacy of Aloe vera gel in the treat- Eisen D, Griffiths CE, Ellis CN, Nickoloff BJ, Voorhees
ment of oral lichen planus: a randomized controlled JJ. Cyclosporin wash for oral lichen planus. Lancet.
trial. Br J Dermatol. 2008;158(3):573–7. 1990b;335(8688):535–6.
Cirillo N, Hassona Y, Pignatelli M, Gasparoto TH, Morgan Eisen D, Carrozzo M, Bagan Sebastian JV, Thongprasom
DJ, Prime SS. Characterization of a novel oral gluco- K. Number V Oral lichen planus: clinical features and
corticoid system and its possible role in disease. J Dent management. Oral Dis. 2005;11(6):338–49.
Res. 2012;91(1):97–103. Eisenberg E. Oral lichen planus: a benign lesion. J Oral
Clevers H. At the crossroads of inflammation and cancer. Maxillofac Surg. 2000;58(11):1278–85.
Cell. 2004;118(6):671–4. Epstein JB, Wan LS, Gorsky M, Zhang L. Oral lichen
Curtis RE, Rowlings PA, Deeg HJ, Shriner DA, Socie G, planus: progress in understanding its malignant poten-
Travis LB, Horowitz MM, Witherspoon RP, Hoover tial and the implications for clinical management. Oral
RN, Sobocinski KA, Fraumeni Jr JF, Boice Jr Surg Oral Med Oral Pathol Oral Radiol Endod. 2003;96
JD. Solid cancers after bone marrow transplantation. (1):32–7.
N Engl J Med. 1997;336(13):897–904. Erkek E, Bozdogan O, Olut AI. Hepatitis C virus infec-
Daniels TE. Human mucosal Langerhans cells: postmor- tion prevalence in lichen planus: examination of
tem identification of regional variations in oral mucosa. lesional and normal skin of hepatitis C virus-infected
J Invest Dermatol. 1984;82(1):21–4. patients with lichen planus for the presence of hepati-
Daramola OO, George AO, Ogunbiyi AO. Hepatitis C tis C virus RNA. Clin Exp Dermatol. 2001;26
virus and lichen planus in Nigerians: any relationship? (6):540–4.
Int J Dermatol. 2002;41(4):217–9. Escudier M, Ahmed N, Shirlaw P, Setterfield J, Tappuni A,
Deeg HJ, Socie G, Schoch G, Henry-Amar M, Black MM, Challacombe SJ. A scoring system for
Witherspoon RP, Devergie A, Sullivan KM, mucosal disease severity with special reference to oral
Gluckman E, Storb R. Malignancies after lichen planus. Br J Dermatol. 2007;157(4):765–70.
marrow transplantation for aplastic anemia and Evans AV, Fletcher CL, Owen WJ, Hay RJ. Oesophageal
fanconi anemia: a joint Seattle and Paris lichen planus. Clin Exp Dermatol. 2000;25(1):36–7.
analysis of results in 700 patients. Blood. Eversole LR. Immunopathogenesis of oral lichen planus
1996;87(1):386–92. and recurrent aphthous stomatitis. Semin Cutan Med
Delves PJ, Roitt IM. The immune system. First of two Surg. 1997;16(4):284–94.
parts. N Engl J Med. 2000;343(1):37–49. Fang KC, Raymond WW, Blount JL, Caughey GH. Dog
Dissemond J, Schroter S, Franckson T, Herbig S, Goos mast cell alpha-chymase activates progelatinase B by
M. Pimecrolimus in an adhesive ointment as a new cleaving the Phe88-Gln89 and Phe91-Glu92 bonds of
treatment option for oral lichen planus. Br J Dermatol. the catalytic domain. J Biol Chem. 1997;272
2004;150(4):782–4. (41):25628–35.
Duffey DC, Eversole LR, Abemayor E. Oral lichen planus Farhi D, Dupin N. Pathophysiology, etiologic factors, and
and its association with squamous cell carcinoma: an clinical management of oral lichen planus, part I: facts
update on pathogenesis and treatment implications. and controversies. Clin Dermatol. 2010;28(1):100–8.
Laryngoscope. 1996;106(3 Pt 1):357–62. Fatahzadeh M, Rinaggio J, Chiodo T. Squamous cell car-
Dupin N, Chosidow O, Lunel F, Fretz C, Szpirglas H, cinoma arising in an oral lichenoid lesion. J Am Dent
Frances C. Oral lichen planus and hepatitis C virus Assoc. 2004;135(6):754–9; quiz 796.
Feller L, Altini M, Khammissa RA, Chandran R, Holmstrup P, Thorn JJ, Rindum J, Pindborg JJ. Malignant
Bouckaert M, Lemmer J. Oral mucosal immunity. development of lichen planus-affected oral mucosa. J
Oral Surg Oral Med Oral Pathol Oral Radiol. Oral Pathol. 1988;17(5):219–25.
2013;116(5):576–83. Hallopeau H. Sur um cãs de lichen de Wilson gingival avec
Gale N, Pilch BZ, Sidransky D, Westra WH, Califano neoplasicvoisinedans la region maxillaire. Bull Soc Fr
J. Epithelial precursor lesions. In: Barnes L, Evenson DermatolSyphiligr. 1910;17: 33.
JW, Reichart P, Sidransky D, editors. Pathology & Ibrahim HA, Baddour MM, Morsi MG, Abdelkader
genetics. Head and neck tumours. Lyon: IARC; 2005. AA. Should we routinely check for hepatitis B and C
p. 177–81. in patients with lichen planus or cutaneous vasculitis?
Gandolfo S, Richiardi L, Carrozzo M, Broccoletti R, East Mediterr Health J. 1999;5(1):71–8.
Carbone M, Pagano M, Vestita C, Rosso S, Merletti Ichimura M, Hiratsuka K, Ogura N, Utsunomiya T,
F. Risk of oral squamous cell carcinoma in 402 patients Sakamaki H, Kondoh T, Abiko Y, Otake S, Yamamoto
with oral lichen planus: a follow-up study in an Italian M. Expression profile of chemokines and chemokine
population. Oral Oncol. 2004;40(1):77–83. receptors in epithelial cell layers of oral lichen planus. J
Godessart N, Kunkel SL. Chemokines in autoimmune Oral Pathol Med. 2006;35(3):167–74.
disease. Curr Opin Immunol. 2001;13(6):670–5. Iijima W, Ohtani H, Nakayama T, Sugawara Y, Sato E,
Gonzalez-Moles MA, Bascones-Ilundain C, Gil Montoya Nagura H, Yoshie O, Sasano T. Infiltrating CD8+ T
JA, Ruiz-Avila I, Delgado-Rodriguez M, Bascones- cells in oral lichen planus predominantly express CCR5
Martinez A. Cell cycle regulating mechanisms in oral and CXCR3 and carry respective chemokine ligands
lichen planus: molecular bases in epithelium pre- RANTES/CCL5 and IP-10/CXCL10 in their cytolytic
disposed to malignant transformation. Arch Oral Biol. granules: a potential self-recruiting mechanism. Am J
2006;51(12):1093–103. Pathol. 2003;163(1):261–8.
Gonzalez-Moles MA, Scully C, Gil-Montoya JA. Oral Imanguli MM, Alevizos I, Brown R, Pavletic SZ, Atkinson
lichen planus: controversies surrounding malignant JC. Oral graft-versus-host disease. Oral Dis. 2008;14
transformation. Oral Dis. 2008;14(3):229–43. (5):396–412.
Grinspan D, Diaz J, Abulafia J, Villapol L, Schneiderman Ingafou M, Porter SR, Scully C, Teo CG. No evidence of
J, Palese D, Berdichesky R. Our experience with lichen HCV infection or liver disease in British patients with
ruber planus of the buccal mucosa. Ann Dermatol oral lichen planus. Int J Oral Maxillofac Surg. 1998;27
Syphiligr (Paris). 1966;93(5):531–42. (1):65–6.
Gueiros LA, Gondak R, Jorge Junior J, Coletta RD, Ishii T. Immunohistochemical demonstration of T cell sub-
Carvalho Ade A, Leao JC, de Almeida OP, Vargas sets and accessory cells in oral lichen planus. J Oral
PA. Increased number of Langerhans cells in oral Pathol. 1987;16(7):356–61.
lichen planus and oral lichenoid lesions. Oral Surg Ismail SB, Kumar SK, Zain RB. Oral lichen planus and
Oral Med Oral Pathol Oral Radiol. lichenoid reactions: etiopathogenesis, diagnosis, man-
2012;113(5):661–6. agement and malignant transformation. J Oral Sci.
Hengge UR, Ruzicka T, Schwartz RA, Cork MJ. Adverse 2007;49(2):89–106.
effects of topical glucocorticosteroids. J Am Acad Issa Y, Brunton PA, Glenny AM, Duxbury AJ. Healing of
Dermatol. 2006;54(1):1–15; quiz 16–18. oral lichenoid lesions after replacing amalgam restora-
Henriksson E, Mattsson U, Hakansson J. Healing of tions: a systematic review. Oral Surg Oral Med Oral
lichenoid reactions following removal of amalgam. A Pathol Oral Radiol Endod. 2004;98(5):553–65.
clinical follow-up. J Clin Periodontol. 1995;22 Ivanovski K, Nakova M, Warburton G, Pesevska S,
(4):287–94. Filipovska A, Nares S, Nunn ME, Angelova D,
Herve P, Flesch M, Tiberghien P, Wijdenes J, Racadot E, Angelov N. Psychological profile in oral lichen planus.
Bordigoni P, Plouvier E, Stephan JL, Bourdeau H, J Clin Periodontol. 2005;32(10):1034–40.
Holler E, et al. Phase I-II trial of a monoclonal anti- Jainkittivong A, Kuvatanasuchati J, Pipattanagovit P,
tumor necrosis factor alpha antibody for the treatment Sinheng W. Candida in oral lichen planus patients under-
of refractory severe acute graft-versus-host disease. going topical steroid therapy. Oral Surg Oral Med Oral
Blood. 1992;79(12):3362–8. Pathol Oral Radiol Endod. 2007;104(1):61–6.
Hietanen J, Paasonen MR, Kuhlefelt M, Malmstrom M. A Kanwar AJ, De D. Lichen planus in childhood: report of
retrospective study of oral lichen planus patients with 100 cases. Clin Exp Dermatol. 2010;35(3):257–62.
concurrent or subsequent development of malignancy. Khan A, Farah CS, Savage NW, Walsh LJ, Harbrow DJ,
Oral Oncol. 1999;35(3):278–82. Sugerman PB. Th1 cytokines in oral lichen planus.
Hodgson TA, Sahni N, Kaliakatsou F, Buchanan JA, Porter J Oral Pathol Med. 2003;32(2):77–83.
SR. Long-term efficacy and safety of topical tacrolimus Kiefer F, Siekmann AF. The role of chemokines and
in the management of ulcerative/erosive oral lichen their receptors in angiogenesis. Cell Mol Life Sci.
planus. Eur J Dermatol. 2003;13(5):466–70. 2011;68(17):2811–30.
Holmstrup P, Dabelsteen E. Changes in carbohydrate Kilpi A. Characterization of mononuclear cells of inflam-
expression of lichen planus affected oral epithelial cell matory infiltrates in oral tissues. A histochemical and
membranes. J Invest Dermatol. 1979;73(5):364–7. immunohistochemical study of labial salivary glands in
Sjogren’s syndrome and of oral lesions in systemic Lo Muzio L, della Valle A, Mignogna MD, Pannone G,
lupus erythematosus and in lichen planus. Proc Finn Bucci P, Bucci E, Sciubba J. The treatment of oral
Dent Soc. 1988;84(Suppl 3):1–93. aphthous ulceration or erosive lichen planus with top-
Koch P, Bahmer FA. Oral lichenoid lesions, mercury ical clobetasol propionate in three preparations: a clin-
hypersensitivity and combined hypersensitivity to mer- ical and pilot study on 54 patients. J Oral Pathol Med.
cury and other metals: histologically-proven reproduc- 2001;30(10):611–7.
tion of the reaction by patch testing with metal salts. Lo Russo L, Fierro G, Guiglia R, Compilato D, Testa NF, Lo
Contact Dermatitis. 1995;33(5):323–8. Muzio L, Campisi G. Epidemiology of desquamative
Koray M, Dulger O, Ak G, Horasanli S, Ucok A, gingivitis: evaluation of 125 patients and review of the
Tanyeri H, Badur S. The evaluation of anxiety and literature. Int J Dermatol. 2009;48(10):1049–52.
salivary cortisol levels in patients with oral lichen Lodi G, Giuliani M, Majorana A, Sardella A, Bez C,
planus. Oral Dis. 2003;9(6):298–301. Demarosi F, Carrassi A. Lichen planus and hepatitis C
Kramer IR, Lucas RB, Pindborg JJ, Sobin LH. Definition virus: a multicentre study of patients with oral lesions
of leukoplakia and related lesions: an aid to studies on and a systematic review. Br J Dermatol. 2004;151
oral precancer. Oral Surg Oral Med Oral Pathol. (6):1172–81.
1978;46(4):518–39. Lodi G, Scully C, Carrozzo M, Griffiths M, Sugerman PB,
Kruse AL, Gratz KW. Oral carcinoma after hematopoietic Thongprasom K. Current controversies in oral lichen
stem cell transplantation – a new classification based on planus: report of an international consensus meeting.
a literature review over 30 years. Head Neck Oncol. Part 1. Viral infections and etiopathogenesis. Oral Surg
2009;1:29. Oral Med Oral Pathol Oral Radiol Endod.
Krutchkoff DJ, Eisenberg E. Lichenoid dysplasia: a dis- 2005a;100(1):40–51.
tinct histopathologic entity. Oral Surg Oral Med Oral Lodi G, Scully C, Carrozzo M, Griffiths M, Sugerman PB,
Pathol. 1985;60(3):308–15. Thongprasom K. Current controversies in oral lichen
Krutchkoff DJ, Cutler L, Laskowski S. Oral lichen planus: planus: report of an international consensus meeting.
the evidence regarding potential malignant transforma- Part 2. Clinical management and malignant transforma-
tion. J Oral Pathol. 1978;7(1):1–7. tion. Oral Surg Oral Med Oral Pathol Oral Radiol
Laeijendecker R, Tank B, Dekker SK, Neumann HA. A Endod. 2005b;100(2):164–78.
comparison of treatment of oral lichen planus with Lodi G, Tarozzi M, Sardella A, Demarosi F, Canegallo L,
topical tacrolimus and triamcinolone acetonide oint- Di Benedetto D, Carrassi A. Miconazole as adjuvant
ment. Acta Derm Venereol. 2006;86(3):227–9. therapy for oral lichen planus: a double-blind random-
Laine J, Kalimo K, Forssell H, Happonen RP. Resolution ized controlled trial. Br J Dermatol.
of oral lichenoid lesions after replacement of amalgam 2007;156(6):1336–41.
restorations in patients allergic to mercury compounds. Lodi G, Pellicano R, Carrozzo M. Hepatitis C virus infec-
Br J Dermatol. 1992;126(1):10–5. tion and lichen planus: a systematic review with meta-
Laine J, Konttinen YT, Beliaev N, Happonen analysis. Oral Dis. 2010;16(7):601–12.
RP. Immunocompetent cells in amalgam-associated Lodi G, Carrozzo M, Furness S, Thongprasom
oral lichenoid contact lesions. J Oral Pathol Med. K. Interventions for treating oral lichen planus: a sys-
1999;28(3):117–21. tematic review. Br J Dermatol. 2012;166(5):938–47.
Larsson A, Warfvinge G. Oral lichenoid contact reactions Lozada-Nur F. Oral lichen planus and oral cancer: is there
may occasionally transform into malignancy. Eur J enough epidemiologic evidence? Oral Surg Oral Med
Cancer Prev. 2005;14(6):525–9. Oral Pathol Oral Radiol Endod. 2000;89(3):265–6.
Leao JC, Ingafou M, Khan A, Scully C, Porter Malhotra AK, Khaitan BK, Sethuraman G, Sharma
S. Desquamative gingivitis: retrospective analysis of VK. Betamethasone oral mini-pulse therapy compared
disease associations of a large cohort. Oral Dis. with topical triamcinolone acetonide (0.1%) paste in
2008;14(6):556–60. oral lichen planus: a randomized comparative study. J
Levin C, Maibach HI. Topical corticosteroid-induced adre- Am Acad Dermatol. 2008;58(4):596–602.
nocortical insufficiency: clinical implications. Am J Mansourian A, Momen-Heravi F, Saheb-Jamee M,
Clin Dermatol. 2002;3(3):141–7. Esfehani M, Khalilzadeh O, Momen-Beitollahi
Lind PO. Oral lichenoid reactions related to composite J. Comparison of Aloe vera mouthwash with triamcin-
restorations. Preliminary report. Acta Odontol Scand. olone acetonide 0.1% on oral lichen planus: a random-
1988;46(1):63–5. ized double-blinded clinical trial. Am J Med Sci.
Lind PO, Hurlen B, Lyberg T, Aas E. Amalgam-related 2011;342(6):447–51.
oral lichenoid reaction. Scand J Dent Res. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A,
1986;94(5):448–51. Locati M. The chemokine system in diverse forms of
Lo Muzio L, Mignogna MD, Favia G, Procaccini M, Testa macrophage activation and polarization. Trends
NF, Bucci E. The possible association between oral Immunol. 2004;25(12):677–86.
lichen planus and oral squamous cell carcinoma: a Marinkovich MP, Keene DR, Rimberg CS, Burgeson
clinical evaluation on 14 cases and a review of the RE. Cellular origin of the dermal-epidermal basement
literature. Oral Oncol. 1998;34(4):239–46. membrane. Dev Dyn. 1993;197(4):255–67.
Markopoulos AK, Antoniades D, Papanayotou P, Tri- observations in 722 patients from India. J Oral Pathol.
gonidis G. Malignant potential of oral lichen planus; a 1986;15(2):71–7.
follow-up study of 326 patients. Oral Oncol. 1997;33 Nagao Y, Sata M, Tanikawa K, Itoh K, Kameyama
(4):263–9. T. Lichen planus and hepatitis C virus in the northern
Masaki M, Sato T, Sugawara Y, Sasano T, Takahashi Kyushu region of Japan. Eur J Clin Investig. 1995;25
N. Detection and identification of non-Candida (12):910–4.
albicans species in human oral lichen planus. Micro- O’Neill ID. Off-label use of biologicals in the management
biol Immunol. 2011;55(1):66–70. of inflammatory oral mucosal disease. J Oral Pathol
Matthews RW, Pinkney RC, Scully C. The management of Med. 2008;37(10):575–81.
intransigent desquamative gingivitis with Dapsone. O’Neill ID, Scully C. Biologics in oral medicine: ulcerative
Ann Dent. 1989;48(1):41–3. disorders. Oral Dis. 2013;19(1):37–45.
Mattsson U, Jontell M, Holmstrup P. Oral lichen planus Olivier V, Lacour JP, Mousnier A, Garraffo R, Monteil RA,
and malignant transformation: is a recall of patients Ortonne JP. Treatment of chronic erosive oral lichen
justified? Crit Rev Oral Biol Med. 2002;13(5):390–6. planus with low concentrations of topical tacrolimus:
McCullough M, Jaber M, Barrett AW, Bain L, Speight PM, an open prospective study. Arch Dermatol. 2002;138
Porter SR. Oral yeast carriage correlates with presence (10):1335–8.
of oral epithelial dysplasia. Oral Oncol. 2002;38 Ostman PO, Anneroth G, Skoglund A. Amalgam-
(4):391–3. associated oral lichenoid reactions. Clinical and histo-
Mergoni G, Ergun S, Vescovi P, Mete O, Tanyeri H, Meleti logic changes after removal of amalgam fillings. Oral
M. Oral postinflammatory pigmentation: an analysis of Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;81
7 cases. Med Oral Patol Oral Cir Bucal. 2011;16(1):e11–4. (4):459–65.
Merry R, Belfield L, McArdle P, McLennan A, Crean S, Parashar P. Oral lichen planus. Otolaryngol Clin N
Foey A. Oral health and pathology: a macrophage Am. 2011;44(1): 89–107, vi.
account. Br J Oral Maxillofac Surg. 2012;50(1):2–7. Payeras MR, Cherubini K, Figueiredo MA, Salum
Mignogna MD, Lo Muzio L, Lo Russo L, Fedele S, FG. Oral lichen planus: focus on etiopathogenesis.
Ruoppo E, Bucci E. Clinical guidelines in early detec- Arch Oral Biol. 2013;58(9):1057–69.
tion of oral squamous cell carcinoma arising in oral Pedersen A. Abnormal EBV immune status in oral lichen
lichen planus: a 5-year experience. Oral Oncol. planus. Oral Dis. 1996;2(2):125–8.
2001;37(3):262–7. Pelisse M. The vulvo-vaginal-gingival syndrome. A new
Mignogna MD, Lo Russo L, Fedele S, Ruoppo E, form of erosive lichen planus. Int J Dermatol. 1989;28
Califano L, Lo Muzio L. Clinical behaviour of malig- (6):381–4.
nant transforming oral lichen planus. Eur J Surg Oncol. Petti S, Rabiei M, De Luca M, Scully C. The magnitude of
2002;28(8):838–43. the association between hepatitis C virus infection and
Mignogna MD, Fedele S, Lo Russo L, Lo Muzio L, Bucci oral lichen planus: meta-analysis and case control
E. Immune activation and chronic inflammation as the study. Odontology. 2011;99(2):168–78.
cause of malignancy in oral lichen planus: is there any Piboonniyom SO, Treister N, Pitiphat W, Woo SB. Scoring
evidence ? Oral Oncol. 2004;40(2):120–30. system for monitoring oral lichenoid lesions: a prelim-
Mignogna MD, Lo Russo L, Fedele S. Gingival involve- inary study. Oral Surg Oral Med Oral Pathol Oral
ment of oral lichen planus in a series of 700 patients. Radiol Endod. 2005;99(6):696–703.
J Clin Periodontol. 2005;32(10):1029–33. Porter SR, Kirby A, Olsen I, Barrett W. Immunologic
Mignogna MD, Fedele S, Lo Russo L. Dysplasia/neoplasia aspects of dermal and oral lichen planus: a review.
surveillance in oral lichen planus patients: a description Oral Surg Oral Med Oral Pathol Oral Radiol Endod.
of clinical criteria adopted at a single centre and their 1997;83(3):358–66.
impact on prognosis. Oral Oncol. 2006;42(8):819–24. Pullan S, Wilson J, Metcalfe A, Edwards GM,
Mignogna MD, Fedele S, Lo Russo L, Mignogna C, de Goberdhan N, Tilly J, Hickman JA, Dive C,
Rosa G, Porter SR. Field cancerization in oral lichen Streuli CH. Requirement of basement membrane
planus. Eur J Surg Oncol. 2007;33(3):383–9. for the suppression of programmed cell death in
Mokni M, Rybojad M, Puppin Jr D, Catala S, Venezia F, mammary epithelium. J Cell Sci. 1996;109(Pt 3):
Djian R, Morel P. Lichen planus and hepatitis C virus. J 631–42.
Am Acad Dermatol. 1991;24(5 Pt 1):792. Rajentheran R, McLean NR, Kelly CG, Reed MF, Nolan
Morrison L, Kratochvil 3rd FJ, Gorman A. An open trial of A. Malignant transformation of oral lichen planus. Eur
topical tacrolimus for erosive oral lichen planus. J Am J Surg Oncol. 1999;25(5):520–3.
Acad Dermatol. 2002;47(4):617–20. Regezi JA, Dekker NP, MacPhail LA, Lozada-Nur F,
Munoz AA, Haddad RI, Woo SB, Bhattacharyya McCalmont TH. Vascular adhesion molecules in oral
N. Behavior of oral squamous cell carcinoma in sub- lichen planus. Oral Surg Oral Med Oral Pathol Oral
jects with prior lichen planus. Otolaryngol Head Neck Radiol Endod. 1996;81(6):682–90.
Surg. 2007;136(3):401–4. Rodstrom PO, Jontell M, Mattsson U, Holmberg E. Cancer
Murti PR, Daftary DK, Bhonsle RB, Gupta PC, Mehta FS, and oral lichen planus in a Swedish population. Oral
Pindborg JJ. Malignant potential of oral lichen planus: Oncol. 2004;40(2):131–8.
Roitberg-Tambur A, Friedmann A, Korn S, Markitziu A, Silverman Jr S, Gorsky M, Lozada-Nur F. A prospective

Pisanti S, Safirman C, Nelken D, Brautbar C. Serologic follow-up study of 570 patients with oral lichen planus:
and molecular analysis of the HLA system in Israeli persistence, remission, and malignant association. Oral
Jewish patients with oral erosive lichen planus. Tissue Surg Oral Med Oral Pathol. 1985;60(1):30–4.
Antigens. 1994;43(4):219–23. Silverman Jr S, Gorsky M, Lozada-Nur F, Giannotti K. A
Rojo-Moreno JL, Bagan JV, Rojo-Moreno J, Donat JS, prospective study of findings and management in
Milian MA, Jimenez Y. Psychologic factors and oral 214 patients with oral lichen planus. Oral Surg Oral
lichen planus. A psychometric evaluation of 100 cases. Med Oral Pathol. 1991;72(6):665–70.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. Siponen M, Huuskonen L, Laara E, Salo T. Association of
1998;86(6):687–91. oral lichen planus with thyroid disease in a Finnish
Roopashree MR, Gondhalekar RV, Shashikanth MC, population: a retrospective case-control study. Oral
George J, Thippeswamy SH, Shukla A. Pathogenesis Surg Oral Med Oral Pathol Oral Radiol Endod.
of oral lichen planus – a review. J Oral Pathol Med. 2010;110(3):319–24.
2010;39(10):729–34. Soto Araya M, Rojas Alcayaga G, Esguep A. Association
Rubaci AH, Kazancioglu HO, Olgac V, Ak G. The roles of between psychological disorders and the presence of
matrix metalloproteinases-2, -7, -10 and tissue oral lichen planus, burning mouth syndrome and recur-
inhibitor of metalloproteinase-1 in the pathogenesis of rent aphthous stomatitis. Med Oral. 2004;9(1):1–7.
oral lichen planus. J Oral Pathol Med. 2012;41 Sugerman PB, Savage NW, Walsh LJ, Seymour
(9):689–96. GJ. Disease mechanisms in oral lichen planus. A pos-
Salazar-Sanchez N, Lopez-Jornet P, Camacho-Alonso F, sible role for autoimmunity. Australas J Dermatol.
Sanchez-Siles M. Efficacy of topical Aloe vera in 1993;34(2):63–9.
patients with oral lichen planus: a randomized double- Sugerman PB, Savage NW, Seymour GJ. Phenotype and
blind study. J Oral Pathol Med. 2010;39(10):735–40. suppressor activity of T-lymphocyte clones extracted
Santoro A, Majorana A, Bardellini E, Festa S, Sapelli P, from lesions of oral lichen planus. Br J Dermatol.
Facchetti F. NF-kappaB expression in oral and cutane- 1994;131(3):319–24.
ous lichen planus. J Pathol. 2003;201(3):466–72. Sugerman PB, Savage NW, Xu LJ, Walsh LJ, Seymour
Santoro A, Majorana A, Roversi L, Gentili F, Marrelli S, GJ. Heat shock protein expression in oral lichen planus.
Vermi W, Bardellini E, Sapelli P, Facchetti J Oral Pathol Med. 1995;24(1):1–8.
F. Recruitment of dendritic cells in oral lichen planus. Sugerman PB, Satterwhite K, Bigby M. Autocytotoxic
J Pathol. 2005;205(4):426–34. T-cell clones in lichen planus. Br J Dermatol.
Savage NW, McCullough MJ. Topical corticosteroids in 2000a;142(3):449–56.
dental practice. Aust Dent J. 2005;50(4 Suppl 2):S40–4. Sugerman PB, Savage NW, Zhou X, Walsh LJ, Bigby
Scardina GA, Messina P, Carini F, Maresi E. A randomized M. Oral lichen planus. Clin Dermatol. 2000b;18
trial assessing the effectiveness of different concentra- (5):533–9.
tions of isotretinoin in the management of lichen Sugerman PB, Savage NW, Walsh LJ, Zhao ZZ, Zhou XJ,
planus. Int J Oral Maxillofac Surg. 2006;35(1):67–71. Khan A, Seymour GJ, Bigby M. The pathogenesis of
Scully C, Carrozzo M. Oral mucosal disease: lichen planus. oral lichen planus. Crit Rev Oral Biol Med. 2002;13
Br J Oral Maxillofac Surg. 2008;46(1):15–21. (4):350–65.
Scully C, Diz Dios P. Orofacial effects of antiretroviral Sugermann PB, Savage NW, Seymour GJ, Walsh LJ. Is
therapies. Oral Dis. 2001;7(4):205–10. there a role for tumor necrosis factor-alpha
Scully C, Beyli M, Ferreiro MC, Ficarra G, Gill Y, (TNF-alpha) in oral lichen planus? J Oral Pathol Med.
Griffiths M, Holmstrup P, Mutlu S, Porter S, Wray 1996;25(5):219–24.
D. Update on oral lichen planus: etiopathogenesis and Suter VG, Warnakulasuriya S. The role of patch testing in
management. Crit Rev Oral Biol Med. 1998;9 the management of oral lichenoid reactions. J Oral
(1):86–122. Pathol Med. 2016;45(1):48-57.
Shengyuan L, Songpo Y, Wen W, Wenjing T, Haitao Z, Taniguchi Y, Nagao T, Maeda H, Kameyama Y,
Binyou W. Hepatitis C virus and lichen planus: a recip- Warnakulasuriya KA. Epithelial cell proliferation in
rocal association determined by a meta-analysis. Arch oral lichen planus. Cell Prolif. 2002;35(Suppl
Dermatol. 2009;145(9):1040–7. 1):103–9.
Shimoyama T, Horie N, Kato T, Kaneko T, Komiyama Tenovuo J. Antimicrobial function of human saliva – how
K. Helicobacter pylori in oral ulcerations. J Oral Sci. important is it for oral health? Acta Odontol Scand.
2000;42(4):225–9. 1998;56(5):250–6.
Shirota Y, Illei GG, Nikolov NP. Biologic treatments for Thongprasom K, Dhanuthai K. Steriods in the treatment of
systemic rheumatic diseases. Oral Dis. 2008;14 lichen planus: a review. J Oral Sci. 2008;50(4):377–85.
(3):206–16. Thongprasom K, Luangjarmekorn L, Sererat T, Taweesap
Sieg P, Von Domarus H, Von Zitzewitz V, Iven H, Farber W. Relative efficacy of fluocinolone acetonide
L. Topical cyclosporin in oral lichen planus: a con- compared with triamcinolone acetonide in treatment
trolled, randomized, prospective trial. Br J Dermatol. of oral lichen planus. J Oral Pathol Med.
1995;132(5):790–4. 1992;21(10):456–8.
Thongprasom K, Luengvisut P, Wongwatanakij A, Vincent SD, Fotos PG, Baker KA, Williams TP. Oral lichen
Boonjatturus C. Clinical evaluation in treatment of planus: the clinical, historical, and therapeutic features
oral lichen planus with topical fluocinolone acetonide: of 100 cases. Oral Surg Oral Med Oral Pathol.
a 2-year follow-up. J Oral Pathol Med. 1990;70(2):165–71.
2003;32(6):315–22. Voigtlander V, Boonen H. Squamous cell carcinoma of the
Thongprasom K, Carrozzo M, Furness S, Lodi lower lip in discoid lupus erythematosus associated
G. Interventions for treating oral lichen planus. with hereditary deficiency of complement 2. Z Hautkr.
Cochrane Database Syst Rev. 2011;(7):Cd001168. 1990;65(9):836–7.
Thongprasom K, Prapinjumrune C, Carrozzo M. Novel Wee JS, Shirlaw PJ, Challacombe SJ, Setterfield
therapies for oral lichen planus. J Oral Pathol Med. JF. Efficacy of mycophenolate mofetil in severe muco-
2013;42:721–7. cutaneous lichen planus: a retrospective review of
Thornhill MH, Pemberton MN, Simmons RK, Theaker 10 patients. Br J Dermatol. 2012;167(1):36–43.
ED. Amalgam-contact hypersensitivity lesions and Wong L, Freeman S. Oral lichenoid lesions (OLL) and
oral lichen planus. Oral Surg Oral Med Oral Pathol mercury in amalgam fillings. Contact Dermatitis.
Torresani C, Nannini R, Bondi A, Guadagni M, Manara Xie S, Ding L, Xiong Z, Zhu S. Implications of Th1 and
GC. Erosive oral lichen planus due to sensitization to Th17 cells in pathogenesis of oral lichen planus. J
cobalt chloride. Clin Exp Dermatol. 1994;19(6):535–6. Huazhong Univ Sci Technolog Med Sci.
Valente G, Pagano M, Carrozzo M, Carbone M, Bobba V, 2012;32(3):451–7.
Palestro G, Gandolfo S. Sequential immunohistochem- Yagi A, Kabash A, Okamura N, Haraguchi H, Moustafa
ical p53 expression in biopsies of oral lichen planus SM, Khalifa TI. Antioxidant, free radical scavenging
undergoing malignant evolution. J Oral Pathol Med. and anti-inflammatory effects of aloesin derivatives in
2001;30(3):135–40. Aloe vera. Planta Med. 2002;68(11):957–60.
van der Meij EH, van der Waal I. Lack of clinicopathologic Yamamoto T, Osaki T. Characteristic cytokines generated
correlation in the diagnosis of oral lichen planus based by keratinocytes and mononuclear infiltrates in
on the presently available diagnostic criteria and sug- oral lichen planus. J Invest Dermatol.
gestions for modifications. J Oral Pathol Med. 1995;104(5):784–8.
2003;32(9):507–12. Yarom N. Etanercept for the management of oral lichen
van der Meij EH, Reibel J, Slootweg PJ, van der Wal JE, de planus. Am J Clin Dermatol. 2007;8(2):121.
Jong WF, van der Waal I. Interobserver and Yarosh DB, Pena AV, Nay SL, Canning MT, Brown
intraobserver variability in the histologic assessment DA. Calcineurin inhibitors decrease DNA repair
of oral lichen planus. J Oral Pathol Med. and apoptosis in human keratinocytes following ultra-
1999a;28(6):274–7. violet B irradiation. J Invest Dermatol. 2005;125
van der Meij EH, Schepman KP, Smeele LE, van der (5):1020–5.
Wal JE, Bezemer PD, van der Waal I. A review of the Zain RB, Ikeda N, Razak IA, Axell T, Majid ZA, Gupta
recent literature regarding malignant transformation of PC, Yaacob M. A national epidemiological survey of
oral lichen planus. Oral Surg Oral Med Oral Pathol Oral oral mucosal lesions in Malaysia. Community Dent
Radiol Endod. 1999b;88(3):307–10. Oral Epidemiol. 1997;25(5):377–83.
van der Meij EH, Schepman KP, van der Waal I. The Zeng X, Hou X, Wang Z, Jiang L, Xiong C, Zhou M, Chen
possible premalignant character of oral lichen planus Q. Carriage rate and virulence attributes of oral Can-
and oral lichenoid lesions: a prospective study. Oral dida albicans isolates from patients with oral lichen
Surg Oral Med Oral Pathol Oral Radiol Endod. planus: a study in an ethnic Chinese cohort. Mycoses.
2003;96(2):164–71. 2009;52(2):161–5.
van der Meij EH, Mast H, van der Waal I. The possible Zhang J, Zhou G, Du GF, Xu XY, Zhou HM. Biologics, an
premalignant character of oral lichen planus and alternative therapeutic approach for oral lichen planus.
oral lichenoid lesions: a prospective five-year follow-up J Oral Pathol Med. 2011;40(7):521–4.
study of 192 patients. Oral Oncol. 2007;43(8):742–8. Zhao ZZ, Savage NW, Pujic Z, Walsh
van Loon LA, Bos JD, Davidson CL. Clinical evaluation of LJ. Immunohistochemical localization of mast cells
fifty-six patients referred with symptoms tentatively and mast cell-nerve interactions in oral lichen planus.
related to allergic contact stomatitis. Oral Surg Oral Oral Dis. 1997;3(2):71–6.
Med Oral Pathol. 1992;74(5):572–5. Zhou XJ, Sugerman PB, Savage NW, Walsh LJ. Matrix
Vignali DA, Collison LW, Workman CJ. How metalloproteinases and their inhibitors in oral lichen
regulatory T cells work. Nat Rev Immunol. planus. J Cutan Pathol. 2001;28(2):72–82.
2008;8(7):523–32. Zhou XJ, Sugerman PB, Savage NW, Walsh LJ, Seymour
Villarroel Dorrego M, Correnti M, Delgado R, Tapia GJ. Intra-epithelial CD8+ T cells and basement mem-
FJ. Oral lichen planus: immunohistology of mucosal brane disruption in oral lichen planus. J Oral Pathol
lesions. J Oral Pathol Med. 2002;31(7):410–4. Med. 2002;31(1):23–7.
Oral Vesicular and Bullous Lesions
Stephen J. Challacombe and Jane F. Setterfield
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1086
Epithelial and Basement Membrane Structure and Antigens . . . . . . . . . . . . . . . . . . . . . . . . . 1086
Pemphigus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1087
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1089
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1090
Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1090
Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1093
Pathologic Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1093
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1095
Paraneoplastic Pemphigus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1103
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1103
Etiology and Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1104
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1105
Erythema Multiforme . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1106
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1107
S. J. Challacombe (*)
Department of Oral Medicine, King’s College London,
London, UK
Guys and St Thomas’ Hospital NHS Foundation Trust,
London, UK
e-mail: stephen.challacombe@kcl.ac.uk
J. F. Setterfield
Department of Oral Medicine, King’s College London,
London, UK
Department of Dermatology, King’s College London,
London, UK
Guys and St Thomas’ Hospital NHS Foundation Trust,
London, UK
e-mail: jane.setterfield@kcl.ac.uk

https://doi.org/10.1007/978-3-319-72303-7_13
1084 S. J. Challacombe and J. F. Setterfield
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1107
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1110
Mucous Membrane Pemphigoid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1111
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1111
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1111
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1118
Bullous Pemphigoid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1122
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1123
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1123
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1124
Anti-P200 Pemphigoid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1124
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1124
Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1125
Linear IgA Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1125
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1125
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1125
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1126
Epidermolysis Bullosa Acquisita . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1127
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1127
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1127
Dermatitis Herpetiformis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1129
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1129
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1129
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1130
Bullous Lichen Planus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1131
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1131
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1131
Oral Vesicular and Bullous Lesions 1085
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1132
Angina Bullosa Hemorrhagica . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1133
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1133
Etiology and Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1133
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1134
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1135
Abstract group of diseases in particular, which partially

Vesiculobullous disorders involving the oral elucidates the question of antigen specificity
cavity may also affect the skin and other and clinical phenotypes. At long last, the oral
mucous membranes. They may thus reflect medicine field has begun to embrace disease
the oral manifestations of dermatological severity scoring and clinical outcome mea-
conditions, especially those which are sures. This has allowed an evidence base to
immune mediated. Several different types of the efficacy of immunosuppressive therapies
vesiculobullous disorders may present or be in the treatment of vesiculobullous diseases.
seen in the oral cavity, and it is important that The continued development of biologics has
they be recognized as distinct from the many led to consideration of monoclonal antibody
other types of oral ulceration since they may therapy as a first-line treatment in pemphigus
represent systemic disease. Successful man- and other conditions.
agement depends on this recognition. Thus, Modern laboratory techniques have allowed
careful histories, clinical examination, an much investigation into both target antigens and
understanding of the pathogenesis, and appro- isotype specificity of antibodies. These have allo-
priate investigations are essential. wed the identification of new disease phenotypes
Several of the vesiculobullous lesions are which in turn, with application of disease severity
immune mediated. The most common and scoring, has given an evidence base to treat-
serious are mucous membrane pemphigoid ments. There has been much investigation of
(MMP) and pemphigus vulgaris, both of the use of saliva in diagnostics of vesicular bul-
which are type II, antibody-mediated condi- lous lesions which suggest that saliva will be
tions. In contrast erythema multiforme is useful as an adjunct fluid to serum and in some
thought to be an immune complex-mediated cases as an alternative. Pemphigus and MMP are
condition (type III), and bullous lichen planus reported in detail as archetypal examples of
is a cell-mediated initiated condition (type IV). immune-bullous conditions.
The etiology of angina bullosa hemorrhagica
remains enigmatic but does not appear to be Keywords
immune mediated, whereas those of dermatitis Vesicular conditions · Bullous disease ·
herpetiformis and linear IgA disease are Vesiculobullous lesions · Pemphigus vulgaris ·
immune related, one showing deposition of Paraneoplastic pemphigus · Mucous
dimeric IgA linked to gut disease and the other membrane pemphigoid · Erythema
monomeric IgA and not related to gut disease. multiforme · Linear IgA disease · Angina
There have been recent advances in the bullosa hemorrhagica · Epidermolysis bullosa
understanding of target antigens in the MMP acquisita · Bullous lichen planus · Dermatitis
herpetiformis · Disease severity scoring · Table 1 Differential diagnoses of vesiculo-bullous

Evidence- based treatment · Clinical diseases of the oral mucosa
outcomes · Basement membrane zone · Epidermal
Desmogleins · BP180 · Desmosomes · Pemphigus vulgaris
Hemidesmosomes Pemphigus foliaceus
Subepidermal
Introduction Bullous pemphigoid
Epidermolysis bullosa acquisita
Linear IgA disease
Vesiculobullous disorders involving the oral cavity
Nonspecific/epithelial
may also affect the skin and other mucous mem-
Erythema multiforme
branes. The two main conditions discussed in detail
Bullous lichen planus
in this chapter are pemphigus vulgaris (PV) as an Angina bullosa hemorrhagica
archetypal epidermal disease and mucous mem-
brane pemphigoid (MMP) as a subepidermal disor-
der, but we have included summaries of the less adherence of cells to adjacent structures, and cell-
frequently encountered blistering diseases pre- cell recognition and signaling (Fig. 1). The basement
senting to oral medicine, namely, bullous membrane zone comprises the basal cell plasma
pemphigoid, epidermolysis bullosa acquisita, linear membrane, the lamina lucida, the lamina densa,
IgA disease, bullous lichen planus, angina bullosa and the sub-lamina densa. On the ventral surface of
hemorrhagica, and erythema multiforme (EM). All basal keratinocytes are small electron dense domains
may present orally with similar bullous or ulcerative of the plasma membrane, the hemidesmosomes
lesions, but the mechanisms of damage, the histo- (HD). These are specialized junctional complexes
pathology, and the clinical history are different that contribute to the attachment of epithelial cells to
(Challacombe et al. 2017). PV and MMP are type the underlying basement membrane.
II antibody-mediated diseases directed at Epithelial cell-cell contact is via occludens
desmogleins and basement membrane antigens, (tight junctions), adherens (desmosomes and adhe-
respectively, while EM is a type III immune com- sion plaques), and nexus junctions (gap
plex disease with no specific target yet identified but junctions), each having a complex structure.
usually with a microbial or drug association. Differ- Desmosomes guarantee the integrity of the epider-
ential diagnoses of vesiculobullous diseases of the mis, by functioning both as an adhesive complex
oral mucosa are shown in Table 1. Target antigens and as a cell-surface attachment site for the keratin
may be those in the desmosome (e.g., pemphigus), intermediate filaments of the cytoskeleton (Fig. 1).
in the basement membrane zone (e.g., pemphigoid), Desmosomes are adhesion protein complexes that
or as yet unidentified antigens of epithelial cells contain a series of proteins, particularly
(e.g., bullous lichen planus) (Table 1). desmogleins and desmocollins, glycoproteins of
the cadherin family that link to cytokeratins via
desmoplakins and plakoglobin (Syed et al. 2002).
Epithelial and Basement Membrane Cell to basement membrane contact is largely via
Structure and Antigens hemidesmosomes, which have a complex structure
and contact the superficial part of the basement
The oral epithelium is a complex structure membrane (the lamina lucida). A number of pro-
consisting of a range of cells, mainly keratinocytes, teins that are implicated in the pathogenesis of sub-
adherent to each other by desmosomes, and via epidermal blistering diseases are associated with the
hemidesmosomes and an epithelial basement mem- HD and include the bullous pemphigoid antigens
brane to the underlying lamina propria. Each com- BP230 and BP180 and the α6ß4 integrin (Borradori
ponent is itself complex and consists of several and Sonnenberg 1999). The lamina lucida is the
proteins with important functions, not least the electron lucent zone adjacent to the basal cell plasma
Fig. 1 Structure of desmosome and hemidesmosome antigens targeted in both PV and MMP, respectively. Pem-
(Modified from Taghipour et al. 2009 and Ali 2016a). An phigus targets antigens in the desmosome including
overview of the structure of basal epithelial cells and the desmogleins, but also desmoplakins or desmocollins.
basement membrane in oral epithelium. Autoimmune Pemphigoid diseases target antigens in the
vesiculo bullous diseases target antigens in this area. The hemidesmosome including BP180, a6b4, type VII colla-
figure displays the basal cell and underlying connective gen, and laminin 5 (also known as laminin 332)
tissue. The desmosome and hemidesmosome are home to
membrane and is 20–40 nanometers thick. Anchor- that easily rupture, resulting in ulceration of
ing filaments transverse the lamina lucida perpen- mucosal and/or cutaneous sites. The two main
dicularly from the basal cell membrane to the subtypes are PV and pemphigus foliaceus (PF),
underlying lamina densa. Hemidesmosomes are of which PV is the most common and clinically
found above the lamina lucida, and the anchoring the most aggressive variant, being associated with
filaments may be the link between the significant morbidity and mortality, composing
hemidesmosomes and the anchoring fibrils. The 70% of all reported cases of skin pemphigus and
lamina densa is the electron dense layer below the over 96% of oral cases of pemphigus. Less com-
lamina lucida and is thought to be thinner in female mon forms and variants include paraneoplastic
than in male skin and possibly mucosal epithelium. pemphigus, drug-induced pemphigus, and IgA
pemphigus (Table 2).
Pemphigus was first named by Wichman in
Pemphigus 1791 when all blistering diseases were grouped
together under one term, pemphigus (Korman
Pemphigus is a group of potentially life- 1988). Lever, in 1953, characterized PV based
threatening autoimmune diseases characterized on its histopathological picture, clinical criteria,
by epithelial blistering affecting cutaneous and the course of the disease as a distinct entity
and/or mucosal surfaces, the term being derived from bullous pemphigoid (see Korman 1988).
from the Greek pemphix (bubble or blister). This was an important finding as it provided the
Pemphigus is characterized by intraepithelial blis- base for separating the distinct clinical diseases,
tering, resulting in superficial vesicles or bullae bullous pemphigoid, and MMP, which form
Table 2 Target adhesion molecules/autoantigens in bullous disorders. Modified from Otten et al. (2014) and based on
data from Amagai et al. (2006), Harman et al. (2000a), Capon et al. (2009), and Schmidt and Zillikens (2013)
Pemphigus diseases
Pemphigus vulgaris Desmoglein 3, desmoglein 1
Pemphigus foliaceus Desmoglein 1
Pemphigus erythematosus Desmoglein 1, 3, ANAs
Paraneoplastic pemphigus Desmoglein 1, desmoglein 3, desmoplakin, envoplakin, periplakin, BP230,
alpha-2-macroglobulin-like-1, plectin, desmocollins 1–3
IgA pemphigus Desmocollin 1–3, desmoglein 3
Subset with the clinical spectrum of Desmoplakins I and II
erythema multiforme
Pemphigoid diseases
Bullous pemphigoid BP180 BP180, BP230
Pemphigoid gestationis BP180, BP230
Mucous membrane pemphigoid Laminin 332, α6β4 integrin
Linear IgA disease LAD-1 (BP180), BP230
Anti-p200 pemphigoid p200 antigen (laminin γ1)
Epidermolysis bullosa acquisita Collagen VII
Dermatitis herpetiformis Tissue/epidermal transglutaminase
subepithelial clefts, from pemphigus, which pro- PV is the most common form and involves the
duces intraepithelial clefts. Also whereas PV mouth in most cases, while other types of pem-
shows suprabasal clefts, PF was associated with phigus, such as PF and pemphigus vegetans, only
clefts in the sub-corneal layer (i.e., more superfi- rarely affect the oral mucosae (Scully and
cial in the epithelium). The first suggestion of the Challacombe 2002). Apart from PV, an important
mechanism of pathogenesis in pemphigus was form affecting the oral mucosa is paraneoplastic
made in the 1960s by Beutner and Jordon, who pemphigus, usually associated with lymphoproli-
demonstrated that sera from patients with pemphi- ferative disease (Wieczorek and Czernik 2016),
gus contained autoantibodies that could bind to although cases with oral squamous carcinoma
autoantigens present intercellularly in the skin and have been reported. Oral lesions have also been
mucosa (Beutner et al. 1967). This work paved the seen in all reported cases of paraneoplastic pem-
way to our current understanding of desmogleins phigus (Laskaris et al. 1982) and may be the sole
as the main target antigens in pemphigus manifestation (Wieczorek and Czernik 2016).
(Figs. 1, 2, Table 2). PV is the most common form of pemphigus
There are several variants of pemphigus with and involves the mouth in over 90% of cases
different autoantibody profiles and clinical mani- (Harman et al. 2001). In contrast, other types of
festations (Table 2); the main antigen in PV pemphigus such as PF and pemphigus vegetans
is desmoglein 3 (Dsg 3) (Amagai 2000; Harman only rarely affect the oral mucosae. The peak age
et al. 2000a), whereas that in pemphigus foliaceus of onset is 55–60, and females are affected more
is Dsg 1 (Amagai et al. 2006; Amagai and Stanley than males. Oral lesions are common early mani-
2012). However, 50% of PV patients with anti- festations, and many patients may have oral
bodies to Dsg3 also have autoantibodies to Dsg1, lesions without skin lesions. Initially
and the proportion of Dsg1 and Dsg3 antibodies vesiculobullous lesions, the lesions readily rup-
appears to be related to the clinical severity ture, new bullae developing as the older ones
(Harman et al. 2000b, 2001) and whether predom- rupture and ulcerate, and thus erosions and ulcers
inantly skin or mucosal (Fig. 1). Those PV cases are the main features and seen mainly in the buc-
that are predominantly oral have only Dsg3 anti- cal mucosa, palate, and lips. Ulcers heal slowly,
bodies (Harman et al. 2001). but scarring is rare. Gingival lesions usually
Pemphigus vulgaris
Intra-epithelial cleft Stratified squamous epithelium
Desmosomes
Lamina lucida Basement

Lamina densa membrane
Hemidesmosomes
Sub-epithelial cleft
Fig. 2 Difference between a cleft within the epithelium (pemphigus) and beneath the epithelium (pemphigoid) (Original
drawing by Dr Hala Al Janaby, Perth WA, Australia)
comprise severe desquamative or erosive gingivi- affects 3–15 patients per million population per
tis, where bullae have ruptured to leave flaps of year with a preponderance of females (Murrell
peeling tissue with red erosions or deep ulcerative et al. 2008; Chams-Davatchi et al. 2005; Baum
craters mainly on the attached gingivae et al. 2016). Recent studies from Israel indicate
(Challacombe et al. 2001). Whereas skin lesions an incidence of about six per million, with those
of PVand PF are associated with IgG antibodies to of Jewish origin having three times greater inci-
Dsg1, oral PV is associated with antibodies to dence than those of Arabic origin (Kridin et al.
Dsg3 (Harman et al. 2001). Antibodies can be 2016, 2017) indicating a genetic linkage (see
found in saliva but appear to be mainly serum below). Nevertheless, PV can be found all round
transudate and of the IgG isotype (Ali et al. the world (Baum et al. 2016). A similar incidence
2016a,b). Treatment can be considered in two per million population of about 4.5 for both PVand
stages: the induction of remission and then the MMP has been reported in Europe (Milinković
maintenance of remission. Primary treatment is et al. 2016). Despite the frequency of oral involve-
still with systemic steroids, followed by immuno- ment, there are relatively few recent studies either
suppressive drugs (azathioprine or MMF). Bio- of the oral manifestations of pemphigus or their
logics including rituximab are increasingly management, and delays in diagnosis are still com-
effective. It is now realistic to aim to reduce sys- mon (Harman et al. 2000a; Kumar et al. 2017;
temic therapy and to maintain with local therapy Sultan et al. 2017). PV is generally at least five
orally. times as prevalent as PF. However, there is regional
variation (Uzun et al. 2006), and PF is more com-
mon in Finland and South Africa (Aboobaker et al.
Epidemiology 2001), and an endemic variety of PF affects up to
3% of the population in affected rural regions in
Pemphigus remains a potentially lethal chronic Brazil, Columbia, and Tunisia (Culton et al. 2008;
bullous disease of the stratified squamous mucosa Abreu-Velez et al. 2003). This strongly suggests
and skin, occurring mainly in adults over the age of that genetics play a role in disease manifestations
60 but sometimes in young adults. Pemphigus (see below).
Etiology protein complexes that contain a series of pro-

teins, particularly Dsg and Dsc, that link to
The typical histopathological picture in PV is of cytokeratins via desmoplakins and plakoglobin
acantholysis with intraepithelial bullae formation. (Buxton and Magee 1992). Oral epithelium is
Serum IgG, IgM, or sometimes IgA autoanti- closely similar to the skin but differs in several
bodies to desmogleins (Dsg) in the skin and essentials; for example, desmoglein 1 (Dsg 1) and
mucosa are found in nearly all cases of pemphi- Dsg 3 are expressed in the skin, but oral epithe-
gus. Desmoglein 1 predominates in the skin and lium expresses predominantly Dsg 3 (Shirakata
desmoglein 3 in mucosa. Thus, antibodies against et al. 1998). This has consequences in terms of
Dsg1 will result in skin lesions, those against disease manifestations, as discussed below, as
Dsg3 cause oral lesions, and if antibodies well as in antibody detection (Harman et al.
against both Dsg1 and 3 are present, the patient 2000a; Elias et al. 2001).
may have a combination of skin and mucosal
lesions (Harman et al. 2001). The autoantibody
titer is correlated with the severity of pemphigus, Pathophysiology
and serum antibody reduces or even disappears as
the lesions heal (Harman et al. 2001). Antibodies Anti-desmoglein pathogenic antibodies are usu-
to pemphigus antigens may be present in saliva ally the culprit of cell-tissue attachment distur-
and may be of both IgG and IgA isotypes bances that clinically result in mucocutaneous
(Ali et al. 2016a). lesions (Culton et al. 2015). Dsg1 is a 160 KDa
Desmosomes are multiprotein complexes and transmembrane molecule. The mature form con-
are the target in PV (Fig. 1). They form the sists of five extracellular domains EC1–EC4 and
intercellular attachment structures that are linked an extracellular anchor domain attached to the
to the intercellular intermediate filament network. transmembrane region. The intracellular portion
They are expressed mainly by epithelial cells and is made up of five domains (Fig. 3). It is abundant
are most commonly present in tissue undergoing in stratified epithelium of the epidermis, tongue,
mechanical stresses such as the skin, heart, and esophagus. Dsg 1 is considered to be the PF
and bladder (Kowalczyk and Green 2013). They antigen (Gniadecki 2006; Eyre and Stanley 1988).
maintain cell cohesion. They are disc-shaped Dsg 3, although similar in structure to Dsg 1,
organelles of 0.1–0.5 um diameter. Cadherins has been identified as the PV antigen (Eyre and
(calcium-dependent cell adhesion molecules) are Stanley 1988; Mahoney et al. 1999). Dsg 3, 130
transmembrane components of the desmosome. KDa, is also a transmembrane protein belonging
They are responsible for intercellular adhesion to the cadherin family. It comprises of five extra-
and interact with intermediate filaments (Schmidt cellular domains, a transmembrane domain, and
and Koch 2007). an intracellular portion (Fig. 3). The major anti-
There are two main groups of cadherins genic regions of Dsg 3 are EC1, EC2, and EC4
identified that contain an extracellular portion: (Gniadecki 2006). Dsg 3 and Dsc 1 are implicated
desmogleins (Dsg) and desmocollins (Dsc). in the IgA subtype of pemphigus. Other antigens
They bind to the desmosomal plaque through the may be targeted such as cholinergic keratinocyte
intracellular fragments. Epithelial cell-cell contact receptor, desmoplakin, endoplakin, periplakin,
is via occludens (tight junctions), adherens (des- and plectin (Tchernev and Orfanos 2006).
mosomes and adhesion plaques), and nexus junc-
tions (gap junctions), each having a complex Immunopathogenesis
structure. Desmosomes guarantee the integrity of PV is a type II autoimmune disorder in which there
the epidermis, by functioning both as an adhesive is damage to desmosomes by antibodies directed
complex and as a cell-surface attachment site for against cadherin-type epithelial cell adhesion mole-
the keratin intermediate filaments of the cytoskel- cules particularly Dsg3 (Hammers and Stanley
eton (see Fig. 1). Desmosomes are adhesion 2016). Any of the desmosomal proteins can be
TM
a EC1 EC2 EC3 EC4 EA IA ICS IPL RUD DTD
Desmoglein 1
160kD
Desmoglein 3
130kD
Extracellular domain Intracellular domain
Fig. 3 Structure of desmoglein 1 and 3 modified from intracellular domains and is therefore smaller than Dsg1.
Gniadecki (2006) (a). Both are transmembrane proteins Electron photomicrograph showing a desmosome between
with five extracellular domains, but Dsg 3 has only four two epithelial cells (b)
defective or damaged, and this can result in loss of There is direct evidence that autoantibodies
cell-cell adhesion leading to the clinical result of against Dsg3 are critical in the pathogenesis
vesiculation, erosions, or ulcers, which characterize since the transfer of PV serum IgG antibodies
pemphigus. Since oral epithelium expresses largely against Dsg3 into newborn mice induces a bullous
Dsg 3, but the skin expresses Dsg 1 as well as Dsg 3, skin disease resembling PV (Amagai et al. 1998),
damage by antibodies to Dsg 3 as in PV results in and recombinant desmoglein (rDsg) 1 and rDsg 3
oral lesions at an early stage, whereas skin integrity absorb the antibodies that cause PV-like skin blis-
is maintained by Dsg 1; however, if Dsg 1 antibodies ters in neonatal mice. Mucosal IgG anti-Dsg3
appear, cutaneous lesions appear to result, and antibodies can induce oral mucosal lesions in
the disease is more severe (Harman et al. humanized mice (Culton et al. 2015).
2000a). The Dsg autoantibodies in active PV are The precise mechanism of the acantholysis after
reported to be predominantly IgG4 polyclonal anti- pemphigus IgG binds to Dsg 3 on the cell surface
bodies that co-localize with Dsg3 in oral PV (Abé is unknown. In cell lines, the IgG antibodies cause
et al. 2015) but are IgG1 while in remission (Bhol a transient increase in intracellular calcium and
et al. 1995). inositol 1,4,5-trisphosphate concentration and
subsequent activation of protein kinase C (PKC). indicates that IgG autoantibody-induced Dsg3
The phosphatidylcholine (PC)-specific phospholi- cleavage is inhibited by anti-FasL antibodies,
pase C (PLC) pathway plays a major role in P-IgG- suggesting a role for FasL in pemphigus (Sajda
induced transmembrane signaling by causing long- et al. 2016).
term activation of PKC (Seishima et al. 1999).
Possible mechanisms leading to loss of cell adhe-
Antigens Other than Desmogleins
sion resulting in acantholysis include the effects of
Non-desmoglein antibodies have been shown
altered desmosome turnover (Schmidt et al. 2017).
to induce pemphigus-like lesions in neonatal
Depletion of Dsg begins in the lower epidermis,
mice inducing gross skin blisters with PV-like
and the desmosomes become reduced in size and
suprabasal acantholysis and staining perilesional
number in both PV and PF.
epithelium in a fishnet-like pattern (Nguyen et al.
The appearance of antibodies to Dsg 1 in PV
2000). This indicates that the PV phenotype can
correlates with disease progression and severity
be induced without anti-Dsg 3 or anti-Dsg 1 anti-
(Miyagawa et al. 1999a; Harman et al. 2000b);
body. A possible role of herpes and coxsackie
PV patients can carry a variant of the ST18 gene
viruses as triggering agents has been examined
that enhances susceptibility of keratinocytes to the
by a number of groups (Ghalayani et al. 2015;
deleterious effects of autoantibodies, indicating
Kurata et al. 2014; Kaçar et al. 2014), but the
that autoantibody pathogenicity may be genetically
evidence remains unconvincing.
modulated (Vodo et al. 2016). The lineage relation-
ships of the IgG1-, IgG4-, IgA1-, and IgA2-specific
B-cell repertoires directed against Dsgs have been Cellular Immunity in PV
examined. The results indicated that anti-Dsg Although PV autoantibodies on their own are
IgG1, IgG4, and IgA B-cell repertoires largely pathogenic, any role of the cellular immune sys-
evolve independently from one another or arise tem in acantholysis is unclear. There is a sparse
from common precursors but through divergent cellular infiltrate at the basement membrane zone.
pathways of somatic mutation (Chen et al. 2017). However, autoreactive T-cell responses to Dsg 3
may be critical to the pathogenesis since antibody
Role of Anti-Desmoglein Versus Non- production generally requires T-cell help (Hertl
anti-Desmoglein Antibodies and Veldman 2003). The strong association with
Much data supports the notion that anti-Dsg anti- distinct HLA class II alleles (see below) suggests
bodies are pathogenic. Immunoabsorption of anti- the involvement of CD4+ T lymphocytes. There is
bodies targeting Dsg1 and Dsg3 abrogates the general agreement that T helper (Th) cells (Th1,
pathogenic effects of patients’ IgG, and Dsg3- Th17) are critically involved in regulating the
deficient mice show pemphigus-like lesions in formation of autoantibodies in the pathogenesis
epidermis and conjunctiva. Dsg3-specific autoan- of pemphigus and IL-21-producing Th17 cells
tibodies induce loss of keratinocyte cohesion, and and T follicular helper (Tfh) cells are augmented
targeting Dsg3 was paralleled by activation of in PV (Hennerici et al. 2016). These T cells rec-
p38MAPK, the inhibition of which reduced loss ognize epitopes of Dsg 3. Most of the T cells are
of cohesion (Egu et al. 2017). It has been proposed CD45RO (Hertl and Riechers 2001) that help
that desmogleins form signaling hubs regulating autoreactive B lymphocytes to produce autoanti-
keratinocyte adhesion and migration (Rötzer et al. bodies. Interestingly, CD28-deficient mice
2015) and that signaling patterns may correlate (lacking a costimulatory signal for T lymphocyte
with clinical phenotypes. activation) are much more sensitive to the devel-
It has been suggested that autoantibodies opment of PV than wild-type mice (Toto et al.
directed against other cell-membrane and intracel- 2000). T-cell recognition of epitopes of Dsg
lular antigens, such as mitochondrial proteins, 3 may be crucial for the initiation and perpetuation
may synergize with anti-desmoglein antibodies to of the production of Dsg 3-specific autoantibodies
cause pemphigus (Schmidt et al. 2017). Recent data by B lymphocytes (Hertl and Riechers 2001).
It has been shown that activation of auto- The disease affects males and females, usually
reactive T cells responsive to Dsg 1 and 3 in the over the age of 50 years. Painful, fluid-filled blis-
context of HLA-DRB1*04:02 led, via B cells, to ters or bullae may appear in the mouth and burst
the induction of IgG autoantibodies and, eventu- within a few hours, resulting in shallow irregular
ally, loss of epidermal adhesion (Schmidt et al. ulcers. These persist for weeks or months, but new
2017). Utilizing this model, they showed that T lesions recur throughout the disease process. Oral
regulatory (Treg) cells downregulate autoreactive manifestations of the disease may persist for many
T cells, suggesting that T cells might be exploited months without overt ill-health, but skin lesions,
therapeutically (Schmidt et al. 2017). A novel malaise, and loss of weight may occur at a later
approach to treating autoimmunity in pemphigus stage. Mucosal surfaces involved may include the
using chimeric immunoreceptors adapted from oral cavity, conjunctiva, genitalia, and upper respi-
those that have been used to successfully treat ratory tract (Scully and Challacombe 2002). Clas-
B-cell leukemias has recently been studied sically, lesions appear to be flaccid, thin-walled
(Ellebrecht et al. 2016). Using Dsg3 as the extra- bullae that may form on normal or erythematous
cellular domain of a “chimeric autoantibody mucous membranes or skin. They break leaving
receptor” or CAAR, they showed that Dsg3 partially denuded areas of variable size that enlarge
CAAR T cells specifically kill anti-Dsg3 B cells as the epithelium detaches from the periphery.
in a PV mouse model, even in the presence of Commonly, skin lesions are seen as erosions
soluble anti-Dsg3 antibodies, thus providing a and heal without scarring. Skin areas affected are
potent and feasible strategy for targeted B-cell usually the trunk, pressure areas, groin, and axil-
depletion in pemphigus, which could potentially lae (Saha et al. 2014). The first signs of PV in over
be extended to any autoantibody-mediated dis- 60% of the cases are oral lesions. At some point
ease (Ellebrecht et al. 2016). This also provides over the course of their disease, over 95% of the
proof of principle for anti-B cell therapy in patients will develop oral lesions. The most
humans (Ran and Payne 2017). predominant site of involvement is the buccal
mucosa, followed by palatal, lingual, labial
mucosa, and finally gingivae (Fig. 4).
Clinical Features With regard to age and sex distribution, PV has
a wide range of onset and peaks at 50–60 years. It
Clinically the oral lesions of pemphigus can be is only rarely reported in children and among
easily differentiated from recurrent aphthous these has a mean age of presentation of 12 years
ulcers by the presence of bullae and when these (Lara-Corrales and Pope 2010). Furthermore, PV
ulcerate the edges lack the well-defined character is rarer still in neonates. Neonatal PV, which is
of aphthous ulcers. PV ulcers are therefore irreg- caused by the passive transfer of autoantibodies
ular in outline. The ulceration of PV is persistent, (IgG1) from the mother, is a transitory condition
in contrast to intermittent of RAS, and the age of (Fainaru et al. 2000; Kardos et al. 2009). Sex
onset is much later. Only occasionally is the predilection is also variable, some reporting a
Nikolsky sign helpful (by rubbing the mucosa female predilection (Saha et al. 2014), while
to induce a bulla). The most important diagnostic others report a male dominance mainly in Middle
test is the presence of acantholytic cells on Eastern countries (Alpsoy et al. 2015).
microscopic examination of direct scrapings
from the lesion, and a biopsy must always be
taken. Both direct and indirect immunofluores- Pathologic Features
cence are usually positive, and specific anti-
bodies to Dsg1 and 3 may also assist in the Biopsy of perilesional tissue with histological and
diagnosis. Pemphigus must be differentiated immunostaining examination is essential to the
from pemphigoid, erythema multiforme, and diagnosis. Assay of serum antibody titers by indirect
dermatitis herpetiformis. immunofluorescence (IIF) may also help guide
Fig. 4 Shallow irregular ulcers of pemphigus vulgaris involving palate (a), buccal mucosa (b), lower lip (c), the upper
gingivae (d), and ventral tongue showing epithelial shedding (e)
prognostication and therapy. A recent critical eval- antibodies but would aid in the differentiation of
uation of two ELISAs for the detection of antibodies PV from PF (Harman et al. 2000a). This strongly
to Dsg 1 and 3 comparing two substrates, normal suggests that both substrates should be used in the
human skin and monkey esophagus, showed that diagnosis of PV since patients with predominantly
using PV serum the sensitivity of IIF was 83% on oral disease may only have Dsg3 antibodies which
human skin and 90% on monkey esophagus and are not always detectable using human skin.
that this combination of substrates should not only Other types of pemphigus, such as PF and
increase the sensitivity of detecting pemphigus pemphigus vegetans, only rarely affect the oral
Fig. 5 The epidermis shows acanthosis and a suprabasal 100). Higher magnification depicting eosinophilic
cleft containing numerous eosinophils forming micro- microabscesses within the suprabasal split and the dermal
abscesses (a). The superficial dermis shows a perivascular papillae (Hematoxylin and eosin, 200) (b) (Khullar et al.
infiltrate rich in eosinophils (Hematoxylin and eosin, 2015; permission granted)
mucosae. In vegetans, vegetation-type lesions may alleles appear critical to T lymphocyte recognition
be found on the oral mucosa and lips, and histolog- of Dsg 3 peptides (Amber et al. 2013; Eming et al.
ical examination shows intraepithelial abscesses 2014). Two kinds of Dsg 3-derived peptides may
containing numerous eosinophils (Fig. 5). Apart be presented by HLA-DR according to the HLA
from PV, the other important form affecting the polymorphism (DRB1*0402 or DRB1*14/0406).
oral mucosa is paraneoplastic pemphigus, usually The DRB1*14/0406 PV-related molecules may
associated with lymphoproliferative diseases. Oral be able to present both Dsg 1 and Dsg 3 peptides,
lesions have also been seen in all reported cases of providing one explanation for cases of PV with
paraneoplastic pemphigus and may be the sole combined responses to Dsg1 and to Dsg3
manifestation (Kartan et al. 2017). which are typified by a mucocutaneous clinical
Dsg 1 autoantibodies are found in over 50% of phenotype (Loiseau et al. 2000). The
cases of PV, and the frequency may differ with HLA-DRB1*04:02 and *14:01 alleles and the
race since they are found in significantly greater HLA-DRB1*14-DQA1*01-DQB1*05 haplotype
proportion of patients of Indian origin than white appear to be associated with PV patients in Brazil
northern Europeans (Harman et al. 2000b). Dsg1 (Brochado et al. 2016).
antibodies in the presence of Dsg3 antibodies are
associated with more severe phenotypes of PV
(Harman et al. 2000a). PV-IgG subclasses are Diagnosis
detectable not only in patients but sometimes
also in their first-degree relatives (Kricheli et al. Essential components of a diagnosis of pemphi-
2000), supporting a genetic linkage. gus include:
HLA class II allele associations in PV are
found with HLA-DR4 (DRB1*0402), DRw14 (a) A full history and examination
(DRB1*1041), and DQB1*0503 (Miyagawa (b) Biopsy with appropriate histopathological
et al. 1999b; Roujeau and Charron 2000; Svecova and immunological investigations
et al. 2015). HLA DRB1* and DQB1* alleles are (c) Serology
associated with disease severity in patients with
pemphigus vulgaris (Svecova et al. 2015; The oral disease severity score (ODSS) is a
Harfouch and Daoud 2014). These HLA class II comprehensive scoring methodology devised by
Fig. 6 Oral pemphigus Site Site Score Activity score (0-3).

severity scoring system. An Add score for each 50% or side
oral disease severity scoring
system for assessing the
disease severity of oral Outer lips 1
pemphigus. Seventeen oral Inner lips 1
sites are assessed for the
L Buccal mucosa <50% = 1, >50%=2
presence or absence of
lesions, and activity at each R Buccal mucosa <50% = 1, >50%=2
site given as mild Gingiva:
involvement (=1),
moderate involvement Lower R distal 1
(=2), or ulcerated (=3). The Lower central 1 1 (mild)
total numbers of sites are Lower L distal 1
added to the total activity
and a subjective pain score Upper R distal 1
out of 10 to give the oral Upper central 1
disease severity score at that
Upper L distal 1
visit
Dorsum of tongue One side= 1, both=2 2 (moderate)
R ventral tongue 1
L ventral tongue 1
Floor of mouth One side= 1, both=2
Hard palate One side= 1, both=2
3 (ulcerated)
Soft palate One side= 1, both=2
Oropharynx One side= 1, both=2
the Oral Medicine group at Guy’s Hospital as part of involvement and allocated a site score of 0–2.
a strategy of having disease severity scores applica- The sites include the outer/inner lips, left and
ble to most, if not all, oral mucosal diseases. It was right buccal mucosa, six gingival segments, hard
first developed from a scoring system devised for palate (left/right or both), soft palate (left/right or
multisite MMP (Setterfield et al. 1998) and has now both), dorsum tongue (left/right or both), left ven-
been validated for use in PV (Ormond et al. 2018) tral tongue, right ventral tongue, floor of mouth
and for MMP (unpublished). The ODSS records the (left/right or both), and oropharynx. Individual
presence of lesions and degree of activity at multiple sites (or units of a site) are then allocated an
oral sites. Additionally, it includes a subjective activity score (0–3), reflecting mild inflammation
assessment of the patient’s degree of oral pain over (minimal erythema or a white “healing” mucosa),
the preceding 2 weeks. Other studies have demon- 1; moderate inflammation (marked erythema but
strated that the ODSS has good inter- and intra- no ulceration), 2; and ulceration, 3 (Fig. 6). Addi-
observer reliability in both lichen planus (LP) and tionally, a subjective assessment of the patient’s
MMP (Escudier et al. 2007; Reeves et al. 2012). In oral pain over the preceding 2 weeks is included
addition, it has been shown to be valuable in the (visual analogue score of 0–10). The theoretical
assessment of therapeutic response in severe muco- maximum total score is 106; however, greater
sal LP and PV (Wee et al. 2012; Greenblatt et al. than 95% of patients would be expected to fall in
2016). It was formally validated in a multi-clinician the range from 0 to 60 representing a clinical
study which showed that the scoring took on aver- range from remission to severe disease.
age less than 90 s per patient (Ormond et al. 2018). Routine investigations for the diagnosis of
The ODSS divides the mouth into 17 sites pemphigus include biopsy and serum for indirect
weighted according to area of possible immunofluorescent or ELISA studies as well as
Fig. 7 Histopathology of
oral pemphigus vulgaris
showing separation of the
epithelium from the basal
cell layer (a), and an intra-
epithelial cleft with higher
power showing
acantholytic cells in the
supra-basilar cleft (b)
complete blood picture and hematinics. In a clas- Indirect immunofluorescence: It is also essen-
sical histopathological picture, suprabasilar clefts tial to take serum that can be analyzed for indirect
and separation of the epithelium from the basal immunofluorescence, for specific ELISA to
cell layer will be seen. Within the blister/bullae desmogleins or other cell adhesion molecules
separated area, acantholytic cells may be present. and for determining the antibody titer. The sub-
Careful cytology of affected epithelium will also strate can be human skin (rich in Dsg1) or monkey
reveal acantholytic cells in the smear. Since PV is esophagus (rich in Dsg3, Fig. 9). Sequential sam-
an antibody-mediated disease, there are relatively ples can be used to assay the antibody titer. IIF
few intraepithelial lymphocytes or indeed in the titer is semiquantitative and related to the intensity
connective tissue beneath the epithelium (Fig. 7). of fluorescence, but that determined by ELISA is
Biopsies ideally include the ulcerated and adja- quantitative and can prove very useful to enable
cent apparently unaffected tissue, but it is essen- comparison between the clinical severity score
tial that the biopsy contains epithelium. and the antibody titer. In general, the serum anti-
Direct immunofluorescence: The biopsy can be body titer to Dsg3 in oral pemphigus shows a
hemisected and one half frozen for IIF studies good correlation with the disease severity
(Challacombe et al. 2001). Direct immunofluores- (Fig. 10).
cence can show different patterns representing Target antigens and enzyme-linked immuno-
different epithelial layers (Fig. 8) suggestive of sorbent assay (ELISA): The indirect ELISA tech-
differential expression of desmosomal antigens nique involves the binding of serum antibody to a
or specificity of the serum autoantibodies. specific antigen on a microtiter plate. This type of
Fig. 8 Direct immunofluorescence of an oral biopsy showing intercellular “chicken-wire” immunofluorescence within the
epithelium in the stratum corneum (a), within the basal cell layer (b), and in the superficial epithelial cells (c)
Fig. 9 Indirect immunofluorescence of oral epithelium human epithelium (a), and monkey esophagus (b) showing
intercellular IgG antibodies
Fig. 10 Serum antibodies

to Dsg3 in relation to oral
disease activity in
pemphigus. There was a
clear relationship between
the antibody titer to Dsg
3 and oral disease activity,
but not skin disease activity
(Harman et al. 2001;
permission granted)
ELISA is used in detecting class-specific autoan- (Mortazavi et al. 2015; Ali et al. 2016a). Further
tibodies targeted against specific antigens in PV studies are now indicated to study paired salivary
and MMP. ELISAs are now much more sensitive and serum titers and their potential use in disease
than IIF and more reproducible as they are less monitoring. Detection of salivary antibodies appears
technique sensitive (Harman et al. 2000b). to provide a practical alternative to serum in diag-
Serum antibodies: ELISA is a well-established nosis of PV and can be used for the monitoring of
method of measuring serum autoantibody titers disease activity in PV patients (Ali et al. 2016a).
to Dsg 3 and Dsg 1, which directly correlate Both IgG and IgA salivary antibodies to Dsg3 and
with mucosal involvement and skin involvement, Dsg peptides can be detected (Ali et al. 2016a), and
respectively, in PV (Harman et al. 2000a, 2001). it appears that antibodies in whole saliva closely
These studies have shown a strong relationship reflect those in serum. No antibodies have been
between serum antibodies to Dsg3 and oral dis- reported in parotid saliva, suggesting the absence
ease severity but not skin severity, (Fig. 10), of any locally produced mucosal antibodies and that
whereas serum antibodies to Dsg1 showed the antibodies in whole saliva are derived from serum.
inverse, a strong relationship with the skin but Further investigation is needed to understand the
not oral disease severity (Harman et al. 2001). role of IgA in the pathogenesis of PV.
ELISA is also used to monitor sequential serum
antibody levels over the course of the disease
(Schmidt and Zillikens 2010) showing that an Patient Management
improvement in disease severity is related to a
decrease in serum antibody levels. PV is an uncommon and potentially life-
Salivary antibodies: There are few published threatening disease requiring immunosuppressive
studies thus far using saliva in the diagnosis of treatment. It should be managed by secondary
PV. Salivary anti-Dsg 1 and 3 IgG ELISA is both care physicians such as immunologists and
sensitive and specific, thus suitable for the diagnosis dermatologists experienced in the treatment
of pemphigus (Andreadis et al. 2006; Hallaji et al. of autoimmune mucocutaneous diseases. Current
2010). Assay of salivary antibodies may become a treatment is largely based on systemic immuno-
noninvasive alternative to serum antibodies suppression using systemic corticosteroids,
with azathioprine, dapsone, methotrexate, cyclo- Remission induction: The initial aim of treat-
phosphamide, gold, and cyclosporin as adjuvants ment is to induce disease control, defined as new
or alternatives (McMillan et al. 2016). The lesions ceasing to form and established lesions
recognition that the severity of the disease is beginning to heal. Corticosteroids are the most
related to the proportion of Dsg3 and Dsg1 effective and rapidly acting treatment for PV
antibodies (Harman et al. 2000a) and to the titer and, hence, are critical in this phase. Using corti-
of each (Harman et al. 2001) suggests that costeroids, disease control typically takes several
sequential assays to monitor the specificity and weeks to achieve, median 3 weeks (Murrell et al.
titer of antibodies, along with the clinical 2008). During this phase, the intensity of treat-
features, may be useful in determining the degree ment may need to be built up rapidly to suppress
of immunosuppression needed. Localized oral disease activity. Although adjuvant drugs are ini-
lesions, with low titer antibodies, may be some- tiated during this phase in general, their immedi-
times treated with topical corticosteroids alone ate therapeutic benefit is relatively limited
(see below). because of their slower onset. They are rarely
Newer therapies such as biologics, myco- used alone to induce remission in PV.
phenolate mofetil, or intravenous immunoglobu- After disease control is achieved, there follows
lin therapy may prove in the longer term to offer a consolidation phase during which drug doses
significant advantages over the systemic cortico- used to induce disease control are continued.
steroids (Ellebrecht and Payne 2017). Work using The end of this consolidation phase is defined
proteinase inhibitors as adjuvant therapy (Dobrev arbitrarily as being reached when 80% of lesions
et al. 1996) does not appear to have been devel- have healed, both the mucosa and skin, and there
oped further. Meanwhile, emerging therapies have been no new lesions for at least 2 weeks
include the possible development of chimeric (Murrell et al. 2008). It can be suggested that
molecules for specific recognition and elimination this might equate to a two thirds reduction in the
of the autoimmune B cells (Proby et al. 2000) and oral disease severity score (see above). Healing of
suggestions for targeting Dsg 3-specific T cells to oral ulceration tends to take longer than that for
eventually modulate the T-cell-dependent produc- the skin, with the oral cavity often the last site to
tion of pathogenic autoantibodies in PV (Hertl and clear in those with mucocutaneous PV. The end of
Riechers 2001). The anti-acantholytic activity of the consolidation phase is the point at which most
cholinergic agonists suggests a further novel ave- clinicians would begin to taper treatment, usually
nue for the development of a nonhormonal treat- the corticosteroid dose. Premature tapering of cor-
ment for PV (Grando et al. 2006). ticosteroids, before disease control is established
The ultimate aim of treatment is for there to and consolidated, is not recommended.
be no active clinical disease and patients fully Remission maintenance: After consolidation,
weaned off their corticosteroids, immunosuppres- there follows a maintenance phase during which
sives, or other immunomodulators. Disease sever- treatment is gradually reduced, in order to mini-
ity should be assessed at presentation using an oral mize side effects, to the minimum required for
disease severity score, and this is repeated at each disease control. The ultimate goal of treatment
visit (McMillan et al. 2015). The identification of should be to maintain remission on 10 mg pred-
successful therapies or of recalcitrant disease can nisolone daily or less, with 10 mg being the dose
be more easily determined using sequential oral designated arbitrarily as “minimal therapy” by
pemphigus severity scores (Fig. 11). international consensus (Murrell et al. 2008).
The British Association of Dermatologists has Occasional blisters are acceptable and indicate
recently published guidelines for the management that the patient is not being overtreated, but PV
of pemphigus (Harman et al. 2017) (Table 3). The is a chronic disease, and patients may require at
management of PV can be considered in two main least 10 years of treatment.
phases: induction of remission and maintenance Systemic corticosteroids are the most important
of remission. element of remission induction and consolidation.
a b
c 70
60
Mean disease severity score
50
40
30
20
10
0
1 2 3 4 5 6 7 8 9
Visit Number
Fig. 11 Example of oral disease severity in a patient with score 0 (b). Visits were at 3–4 month intervals. Disease
pemphigus vulgaris treated with systemic steroids and severity scored at each visit using the mucosal disease
azathioprine. Clinical appearance at baseline visit ODSS severity scoring system (c). Systemic therapy discontinued
score 68 (a). Clinical appearance at visit 9 ODSS at visit 9 (2 years), maintained on local steroid therapy only
In general, adjuvant drugs are slower in onset than Davatchi et al. 2007; Martin et al. 2009). Despite
corticosteroids, and their main role is in the sparsity of evidence, it is commonly believed
maintaining remission. Adjuvant drugs are com- that adjuvant drugs are likely to be beneficial, as
bined commonly with corticosteroids with the aim proven in other areas of autoimmunity, and most
of increasing efficacy and reducing maintenance centers use them as standard practice.
corticosteroid doses and corticosteroid side effects. Steroids may need to be maintained for life,
Although mortality and complete remission rates but clinical improvement along with reduction in
have improved since the introduction of adjuvant circulating antibody titer allows the dose to be
drugs, it should be noted that there are no prospec- reduced to minimal levels. Patients rarely die
tive, high-quality controlled studies that demon- now from the disease, but they may develop the
strate conclusively the presumed benefits of side effects of steroid therapy. Treatment with-
adjuvant drugs in PV. However, some trials have drawal is a realistic aim, with one study reporting
demonstrated lower cumulative corticosteroid rates of complete remission off therapy of 38%,
doses, but without a difference in primary disease 50%, and 75% achieved in 3, 5, and 10 years from
outcome measures, for azathioprine, cyclophos- diagnosis, respectively. However, withdrawal of
phamide, and mycophenolate mofetil (Chams- treatment should be cautious and not done
Table 3 An overview of the management of pemphigus vulgaris reproduced from the British Association of Dermatol-
ogists 2017 (Harman et al. 2017)
First-line Corticosteroids
therapy Oral prednisolone – Optimal dose not established but suggest start with prednisolone
1 mg/kg/day (or equivalent) in most cases, 0.5–1 mg/kg in milder cases
Increase in 50–100% increments every 5–7 days if blistering continues
Consider pulsed intravenous corticosteroids if >1 mg/kg oral prednisolone required, or as initial
treatment in severe disease followed by 1 mg/kg/day oral prednisolone
Taper dose once remission induced and maintained, with absence of new blisters and healing of
the majority of lesions (skin and mucosal). Aim to reduce to 10 mg daily or less
Assess risk of osteoporosis immediately
Effective in all stages of disease, including remission induction
Combine corticosteroids with an adjuvant immunosuppressant more important for remission
maintenance than induction, due to delayed therapeutic onset
Azathioprine 2–3 mg/kg/day (if TPMT normal)
Mycophenolate mofetil 2–3 g/day
Rituximab** (RA protocol, 1 g 2 infusions, 2 weeks apart)
Good oral care is essential
**Rituximab is currently approved by NHS England as a third-line treatment for pemphigus.
Regulatory authorities in many other countries have not yet approved rituximab as a first-line
treatment
Second-line Consider switching to alternate corticosteroid sparing agent if treatment failure with first-line
therapy adjuvant drug*: azathioprine or mycophenolate mofetil or rituximab
Third-line Consider choice of additional treatment options based on assessment of individual patient need and
therapy consensus of MDT
Options include:
Cyclophosphamide
Immunoadsorption
Intravenous immunoglobulin (IVIG)
Methotrexate
Plasmapheresis or plasma exchange
*Treatment failure
Defined by international consensus (Murrell et al. 2008) as continued disease activity or failure to heal despite 3 weeks
of prednisolone 1.5 mg/kg/day, or equivalent, or any of the following, given for 12 weeks:
Azathioprine 2.5 mg/kg/day (assuming normal TPMT)
Mycophenolate mofetil 1.5 g twice daily
Cyclophosphamide 2 mg/kg/day
Methotrexate 20 mg/week
Abbreviations: TPMT, thiopurine methyl transferase; GI, gastrointestinal; MDT, multidisciplinary team; RA, rheumatoid
arthritis
prematurely; relapse rates can be high especially if (5 mg) can be used in the same way. Although
treatment is stopped after 1 year (Sharma and there are no clinical trials formally assessing the
Khandpur 2013). A suggested treatment algo- clinical outcome using local steroid mouthwashes,
rithm for oral PV management is summarized in it is a widely used therapy initially in conjunction
Table 4. with systemic therapy as above and, with clinical
Local therapy: Soluble steroids used as a improvement allied to a decrease in antibody titers,
mouthwash are the mainstay of local therapy in can be used as sole maintenance therapy once the
the oral cavity. Betamethasone phosphate tablets systemic therapy is reduced (Fig. 11).
(0.5 mg) are effervescent and easily dissolved in Biologics: Rituximab has emerged as an effec-
10 ml water. The mouthwash can be used four tive therapeutic option for pemphigus patients
times a day, holding the solution in the oral cavity (Ahmed et al. 2006, Schmidt 2017). Nearly all
for at least 2 min each time, and can then be spat patients (95–100%) experience initial disease con-
out. Alternatively, soluble prednisolone tablets trol (Ran and Payne 2017; Ahmed and Shetty
Table 4 Suggested treatment algorithm for oral pemphigus

1 Diagnosis of PV by
Clinical features
Biopsy (histopathology)
Direct immunofluorescence and indirect serology for Dsg1 and Dsg3 antibodies
2 Assessment of disease severity by ODSS
3 Prednisolone 0.5–1 mg/kg bodyweight, add in 50 mg azathioprine daily or mycophenolate 1000 mg (or up to 1.5 g)
bd
Continue until clinical lesions improve (remembering that MMF and Aza take 8–12 weeks to reach good
therapeutic levels), then tail off steroids
Assess for osteoporosis, consider proton pump inhibitor
4 Keep on immunosuppressives for up to 2 years
Monitor clinical response by ODSS and antibody response by IIF or ELISA
5 If both ODSS and antibodies have fallen, then stop immunosuppressives and monitor twice yearly
6 Use local steroid therapy for the occasional bullous lesion
7 For refractory disease, infusion of rituximab 500 mg or 1000 mg and second infusion 2 weeks later (noting that
rituximab may take 8–12 weeks to be effective (monitor CD19 B-cell counts)
Maintain systemic steroids during this period
Also consider paraneoplastic pemphigus
2015). A recent meta-analysis of 578 cases showed depletion, since relapse is associated with an
a complete remission in 76% of patients after increase in anti-Dsg B cells (Hammers et al.
rituximab (Wang et al. 2015), which included 2015). It is likely that higher-dose regimens may
those remaining on systemic immunosuppressive be needed to achieve complete B-cell depletion
therapies. Relapse increases with time since treat- and long-term remission.
ment with rates of 41–80% reported. Long-term
rates of complete remission after rituximab therapy
were observed in 39–45% of patients (Wang et al. Paraneoplastic Pemphigus
2015; Ran and Payne 2017). Data from a large
clinical trial suggest that first-line use of rituximab Paraneoplastic pemphigus (PNP), a subset of
plus short-term prednisone for patients with pem- pemphigus, is a life-threatening, usually fatal,
phigus is more effective than using prednisone autoimmune blistering disease associated with
alone, with fewer adverse events (Joly et al. 2017). an underlying malignancy, most commonly of
The optimal dosing for rituximab in pemphi- lymphoproliferative origin (see Wieczorek and
gus has not been established. Rituximab was Czernik 2016). PNP is a unique autoimmune blis-
initially approved for lymphoma, and so early tering condition that can affect multiple organs
pemphigus treatment protocols often used the other than the skin (Anhalt 2004). PNP shows
lymphoma dosing regimen (375 mg/m2 weekly clinically intractable ulcerative stomatitis and
for 4 weeks). However, because the B-cell burden conjunctivitis with polymorphous-cutaneous
in autoimmune disease is much lower than that lesions (Anhalt et al. 1990; Hashimoto 2001).
in lymphoma, several studies have evaluated a
lower-dose regimen (two 1,000 mg doses given
2 weeks apart). A meta-analysis found no signif- Epidemiology
icant difference in complete remission rates
between the two treatment regimens, although PNP is a rare disease whose incidence is still not
higher-dose protocols were associated with a sig- fully documented, probably due to lack of recog-
nificantly longer duration of disease remission nition of the diagnosis. PNP was first described by
(Wang et al. 2015). Additionally, relapse after Anhalt et al. (1990) who reported five cases of
rituximab may be due to incomplete B-cell patients with a rare form of atypical pemphigus
Table 5 Relative frequencies of paraneoplastic pemphi-

gus and associated neoplasms (After Wieczorek and
Czernik 2016)
Associated malignancy Occurrence (%)
Non-Hodgkin lymphoma 39
Chronic lymphocytic leukemia 18
Castleman’s disease 18
Carcinoma 9
Thymoma 6
Sarcomas 6
Waldenström’s macroglobulinemia 1
Hodgkin lymphoma <1
Monoclonal gammopathy <1
Melanoma <1 Fig. 12 Widespead superficial ulceration. Paraneoplastic
pemphigus secondary to a thymoma
that were all associated with lymphoproliferative

diseases (Anhalt et al. 1990). PNP is rare, and Castleman’s disease, Waldenstrom’s macroglobu-
perhaps the best evidence of its frequency comes linemia, and thymoma (with or without myasthe-
from the US Food and Drug Administration who nia gravis) (Table 5). However, the precise
reported 12 cases of PNP in 100,000 cases of mechanisms remain unclear.
non-Hodgkin’s lymphoma and chronic lympho-
cytic leukemia. PNP mostly affects adults
between 45 and 70 years of age, but it may also Clinical Features
be found in children, particularly when associated
with Castleman’s disease. There is no known cor- The clinical picture may resemble pemphigus,
relation between incidence of the disease and spe- pemphigoid, erythema multiforme, graft-versus-
cific sex, race, or place of origin. host disease, or lichen planus (Fig. 12). The earliest
and most consistent finding is a painful, severe,
chronic, and often recalcitrant oral ulceration. It pre-
Etiology and Pathophysiology sents most frequently between 45 and 70 years old
but can also occur in children and adolescents. A
Tumors can express antigens that are normally wide variety of lesions, including florid oral muco-
hidden and induce epitope spreading with recog- sal lesions, a generalized polymorphous cutaneous
nition of antigens and epitopes not normally eruption, and pulmonary involvement, may occur in
exposed to the immune system or which may patients with PNP. At least five clinical variants with
cross-react with epithelial antigens. Skin lesions different morphology have been reported, all with
are thought to be caused by an autoimmune oral ulceration (Wieczorek and Czernik 2016).
response generated by antibodies to tumor anti-
gens that cross-react with epithelial antigens. 1. Pemphigus-like: superficial vesicles, flaccid
Thus, interactions between the immune system vesicles, erosions, crusts, and erythema
and neoplasms seem to be the basis of pathogen- 2. Bullous pemphigoid-like: scaly erythematous
esis, with autoantibodies directed against both papules and irregular ulceration
desmosomal and hemidesmosomal antigens. In 3. Erythema multiforme-like: polymorphic alter-
PNP, the vast majority of patients have autoanti- ations, mainly erythematous peeling areas with
bodies to periplakins and envoplakins. The most erosions and sometimes with hard-to-heal
frequently reported associated malignancies are ulceration
lymphomatoid and hematological, e.g., B-cell 4. Graft-versus-host disease: disseminated dusky
lymphoma, chronic lymphocytic leukemia, red scaly papules
5. Lichen planus-like: small flat scaly papules and than PV, MMP, or other bullous disorders. The
intense mucous membrane involvement histopathology shows acantholysis and therefore
defines pemphigus rather than PNP. Occasionally
there may be positive immunofluorescence for
Pathologic Features both BMZ and epithelial cells, indicating more
than one antibody specificity. Immunofluores-
The histological findings are very variable, and cence using rat bladder testing is thought to
often diagnosis of the disease necessitates multi- have the highest sensitivity (75%) in diagnosis.
ple biopsies. Usually intraepidermal-acantholytic Immunoprecipitation using rat bladder extract is
bullae and keratinocyte apoptosis are seen. The usually informative since sera from PNP patients
most common features revealed by direct immu- will show more than one precipitation line,
nofluorescence (DIF) are deposition of IgG to confirming the presence of antibodies to antigens
keratinocyte cell surfaces and C3 to basement in addition to Dsg. Immunoblotting can demon-
membrane zone (BMZ) (Anhalt et al. 1990; strate antibodies to all desmosomal proteins:
Hashimoto 2001). Acantholysis occurs over the desmoglein 3 (130 kD), desmoplakin 1
basal layer in blisters. Additionally, there might be (250 kD), BP230, desmoplakin 2 (210 kD),
vacuolar degeneration of the basal layer associ- envoplakin (210 kD), plectin (>400 kD), peri-
ated with band-like infiltrate of lymphocytes in plakin (190 kD), epiplakin, and occasionally
the lamina propria, similar to that which might be desmoglein 1 (160 kD).
expected in lesions that are clinically and histo- PNP is thus characterized by the presence of a
pathologically lichenoid. wide range of autoantibodies against antigens
including desmoplakin I (250 kD), bullous
pemphigoid antigen I (230 kD), desmoplakin II
Diagnosis (210 kD), envoplakin (210 kD), periplakin
(190 kD), plectin (500 kD), and a 170 kD protein.
The diagnosis is made based on clinical, histolog- Anti-BP180 autoantibodies are relatively fre-
ical, and immunofluorescent findings. Investiga- quently detected. A study of 102 cases of PNP
tions to diagnose PNP should include checking using novel ELISAs for desmocollins (Dscs),
for systemic complications (to identify the tumor), found that 19 (18.6%), 42 (41.2%), and 62
skin biopsies (for histopathological and immuno- (60.8%) of PNP patients showed antibodies to
fluorescence studies), and serum for immunolog- Dsc1, Dsc2, and Dsc3, respectively. Thirty-two
ical studies. Unlike other forms of pemphigus, (60%) of fifty-three patients had antibodies to
PNP can affect other types of epithelia, such as alpha-2-macroglobulin-like protein 1 (A2ML1).
gastrointestinal and respiratory tract. A statistically significant correlation was found
There is no consensus regarding the diagnostic between positive desmoglein 3 reactivity and gen-
criteria for PNP. The first set of criteria were ital lesions (Ohzono et al. 2015).
established by Anhalt (1997, 2004) and included:
1. Characteristic clinical appearance and Patient Management

histopathology
2. Detection of tissue bound autoantibodies via Treatment of PNP is difficult, and the best out-
direct immunofluorescence comes have been reported with benign neoplasms
3. Detection of circulating autoantibodies via that have been surgically excised. The first-line
indirect immunofluorescence and immunopre- treatment is high-dose corticosteroids with the
cipitation studies addition of steroid-sparing agents. Treatment fail-
ures are often managed with rituximab with or
However, the clinical appearance can be varied without concomitant intravenous immunoglobu-
and certainly not characteristic of PNP rather lin. In general, the prognosis is poor, not only
because of eventual progression of malignant eruption with or without oral or other lesions of
tumors but also because treatment with aggressive the mucous membrane (Fig. 13).
immunosuppression therapy often results in EM has been classified into a number of vari-
infectious complications, which unfortunately is ants, based on the degree of mucosal involvement
still the most common cause of death in and the nature and distribution of the skin lesions.
PNP (Wieczorek and Czernik 2016; Yong and EM minor typically affects only one mucosa and
Tey 2013). may be associated with symmetrical target skin
lesions on the extremities. EM major typically
involves two or more mucous membranes with
Erythema Multiforme more variable skin involvement. A severe variant
of EM major is Stevens-Johnson syndrome (SJS),
Erythema multiforme (EM) is an uncommon which typically extensively involves the skin.
mucocutaneous disease characterized by typical Both EM major and SJS can involve internal
target skin lesions, with oral or ocular involve- organs and produce systemic symptoms (see
ment in some cases and a marked tendency to Ayangco and Rogers 2003; Farthing et al. 2005).
recur. EM can be triggered by a range of factors, The most severe cutaneous relative is toxic epi-
but the best-documented association is with pre- dermal necrolysis (TEN), and all variants share
ceding infection with herpes simplex virus (HSV). two common features: typical or less typical cuta-
Most other cases are initiated by drugs. EM may neous target lesions and satellite cell or more
involve the mouth alone or present as a skin widespread necrosis of the epithelium.
Fig. 13 Clinical manifestations of erythema multiforme. (b), irregular ulceration of the lips with crusting along the
Intraoral ulceration of erythema multiforme (a), swollen vermillion border (c), and target lesions on the skin with
hemorrhagic crusted lips typical of erythema multiforme characteristic concentric circles of inflammation (d)
Epidemiology allopurinol, antibiotics, anticonvulsants, and

NSAIDs of the oxicam type are the main cause
EM continues to be an underestimated disease of EM/SJS in most cases (Halevy et al. 2008).
with a lack of strict classification and diagnostic Possibly 1% of patients prescribed allopurinol
criteria. The oral EM variant is an under- may develop either EM or SJS (Halevy et al.
recognized form of EM, and there is little infor- 2008). The strong association observed in
mation on the incidence of the disorder. EM Han Chinese between the human leukocyte
usually affects apparently healthy young adults, antigen HLA-B*1502 and SJS induced by allopu-
and the peak age at presentation is between 20 and rinol (Park et al. 2016) suggests a genetic
40 years, although 20% of cases occur in children. susceptibility.
Several reports suggest that males are affected A range of usually exogenous factors trigger
more than females. However, in a large what appears to be an immunologically related
European series, 52% of patients were male, and reaction with sub- and intraepithelial vesiculation.
48% were female, with a mean age of 38 years A wide range of drugs may be responsible,
(Celentano et al. 2015). The frequency of previous especially the barbiturates, phenylbutazone, sul-
occurrences ranged from 0 to 10 (mean SD: fonamides, carbamazepine, allopurinol, and peni-
1.4 2.0), but 48% had no previous occurrence. cillin. The anticonvulsant drugs of the hydantoin
Medications (particularly antipyretics, food addi- and succinimide groups may cause a severe bul-
tives, and antibiotics) were the suspected precipi- lous form of EM (Scully and Bagan 2008).
tants in half the patients, whereas herpes simplex Certain infections including herpes simplex,
virus infection was suspected in 30%. The disease Mycoplasma, Histoplasma, and Trichomonas
is often recurrent and is precipitated by preceding may also be associated with EM with a time gap
herpes infection in up to 70% of cases (Scully and between infection and disease suggestive of an
Bagan 2008; Carrozzo et al. 1999). immune complex disease. Herpes can be identi-
Patients have involvement of multiple oral fied as a trigger in 15–20% of cases, and recurrent
sites, with the buccal mucosa being the most com- EM is almost always associated with HSV (Wetter
monly involved oral site (75%), followed by the and Davis 2010). HSV is usually not isolated from
vermillion border (72%) (Celentano et al. 2015). the lesions or demonstrable in biopsy specimens,
EM has reported associations of recurrent EM but EM can be induced by challenge with a vac-
with HLA-B15 (B62), HLA-B35, HLA-A33, cine of HSV. The time frame of a herpes virus
HLA-DR53, and HLA-DQB1*0301 (Farthing infection, a latent period of 7–10 days, and then
et al. 2005). In contrast, SJS secondary to drugs the onset of vesiculobullous lesions are strongly
shows a strong HLA linkage with HLA-A*24:02, suggestive of an immune complex reaction.
HLA-B*44:03, and HLA-Cw*01:02 of the A variety of other infectious agents have been
HLA-A, HLA-B, and HLA-C genes, respectively reported to trigger EM but are less commonly
(Park et al. 2016). implicated and include Mycoplasma pneumoniae,
borreliosis, cat scratch disease, diphtheria,
hemolytic streptococci, legionellosis, leprosy,
Etiology Neisseria meningitidis, Mycobacterium avium
complex, pneumococcus, Proteus, Pseudomonas,
EM, SJS and TEN are considered to be sequelae Rickettsia, Salmonella, Staphylococcus, syphilis,
of a cytotoxic immunologic attack on tuberculosis, tularemia, typhoid, Vibrio para-
keratinocytes expressing non-self-antigens. The haemolyticus, Yersinia, Chlamydia, and psittaco-
etiology of oral EM has not formally been sis (Farthing et al. 2005; Ayangco and Rogers
established, but many agents have been impli- 2003). Immune conditions such as Bacillus
cated, primarily microbial (viruses) or drugs Calmette-Guérin (BCG) or hepatitis B immuniza-
(Ayangco and Rogers 2003). Drugs including tion, sarcoidosis, graft-versus-host disease,
inflammatory bowel disease, polyarteritis nodosa, HSV has not been recovered from the lesions
or systemic lupus erythematosus may be impli- but HSV-DNA has been detected in over 60%
cated. Food additives or chemicals such as benzo- (Kokuba et al. 1999). These findings, together
ates, nitrobenzene, perfumes, or terpenes have with the observation that antiviral drugs are suc-
also been reported as etiological agents (Ayangco cessful in treating some patients with recurrent
and Rogers 2003). lesions without a clinical association of HSV,
In general, there appears to be a general asso- suggest that some cases of idiopathic EM may
ciation between the type of etiological agent and actually be related to a subclinical HSV infection
the severity of the disease. Thus, viral infections or reactivation (see Farthing et al. 2005). A study
appear to trigger EM minor or major, but drug using nested PCR found HSV-1 in 66%, HSV-2 in
ingestion tends to trigger more severe SJS or 28%, and both HSV-1 and HSV-2 in 6% of the
TEN. However, this is not absolute, and in clinical HSV-associated EM patients (Sun et al. 2003).
practice, in most instances, no causal factor is
found, and there is little evidence for an allergic
cause. In practice, the etiology of EM is unclear in Pathophysiology
most patients but appears to be an immunological
hypersensitivity reaction with the appearance of EM is characterized by more or less extensive
cytotoxic effector cells, CD8+ T lymphocytes, in painful erythematous and ulcerative lesions of
epithelium, inducing apoptosis of scattered the mucous membranes with the appearance of
keratinocytes and leading to satellite cell necrosis cytotoxic T lymphocytes in the epithelium that
(Ayangco and Rogers 2003). No abnormalities of induce apoptosis in keratinocytes, which leads to
immunoglobulin levels, lymphocyte transforma- satellite cell necrosis. It is considered to be one
tion, or skin testing have been reported, but there end of a spectrum of severe epidermolytic adverse
is an increase in macrophage aggregation. It is mucocutaneous drug reactions, differing only by
possible that immune complexes activate the clas- their extent of skin detachment and sites involved.
sical pathway of complement to initiate bulla The cellular infiltrate in both EM and SJS/TEN
formation. lesions is composed mainly of T lymphocytes and
There may be a genetic predisposition to EM, CD68+ macrophages along with large numbers of
with reported associations of recurrent EM neutrophils.
with HLA-B15 (B62), HLA-B35, HLA-A33, Herpes-associated EM appears to be the result
HLA-DR53, and HLA-DQB1*0301. HLA DQ3 of a cell-mediated immune reaction to the precip-
has been proven to be especially related to recur- itating agent. In those triggered by HSV, DNA
rent EM and may be a helpful marker for fragments in the skin or mucosa may precipitate
distinguishing herpes-associated EM from other the disease. Such HSV-DNA fragments and DNA
diseases with EM-like lesions. Patients with polymerase (PoL) have been detected in the basal
extensive mucosal involvement may have the and suprabasal cell layers of the epidermis in
rare HLA allele DQB1*0402 (Farthing et al. lesions as well as healed lesions for up to 3 months
2005). (Farthing et al. 2005). T cells in active lesions are
The best-documented association is between CD4+ (Vβ2+) cells which respond to HSV anti-
HSV infection and EM minor/major. In single gens in vitro (Kokuba et al. 1999). In addition,
episode and recurrent EM, many patients give a there is a good correlation between PoL expres-
history of a preceding herpes infection 2 weeks or sion in lesions and the duration of clinical symp-
less before onset of the disease (Farthing et al. toms (Kokuba et al. 1999). Mononuclear cells in
2005), and the antiviral agent acyclovir is success- EM lesional skin tissues stain positively for the
ful in treating a high proportion of patients with pro-inflammatory cytokine IFN-γ,
recurrent EM. A number of studies have sought probably produced by CD4+ T helper 1 (Th1)
HSV or HSV-DNA in lesions of EM. Infectious lymphocytes. IFN-γ induces adhesion molecule
expression on keratinocytes. Thus, it seems likely Other mucosal surfaces including ocular, nasal,
that the HSV-DNA fragments in the skin pharyngeal, laryngeal, upper respiratory, and
or mucosa initiate a specific T-cell-mediated anogenital may be involved. Scarring from ocu-
DTH response resulting in the presence of lar and pharyngeal involvement may cause sig-
HSV-specific T cells, which generate IFN-γ. This nificant post-episode clinical problems. SJS is
cytokine then amplifies the immune response and more severe, involves several sites, and affects
stimulates the production of additional cytokines mainly young adult men although children can
and chemokines, which aids the recruitment of also be affected (Léauté-Labrèze et al. 2000).
further reactive T cells to the area. These cytotoxic SJS has a seasonal incidence and mainly occurs
T cells, NK cells, or chemokines can all induce in spring or autumn.
epithelial damage (Farthing et al. 2005). EM tends to affect the anterior part of
The mechanisms of tissue damage in drug- the mouth with irregular shallow ulcers and
associated EM appear to differ between virally crusting of the lips (Fig. 13). However, any
induced and drug-induced EM, as well as differ- part of the mouth can be affected including the
ing from those in SJS and TEN, particularly those buccal mucosae and tongue. Frequently,
that are characterized by widespread epithelial classical “target” lesions can be found on the
damage but with a sparse inflammatory infiltrate. skin (Fig. 13), ears, and chest, so called
In drug-induced EM, it is thought that reactive because of apparent concentric rings of inflam-
metabolites of the initiating drug induce the dis- mation. Occasionally, the condition may affect
ease, but the mechanisms of damage are variable the eyes and genitals leading to a diagnosis of
and, unlike HSV-induced EM, do not appear to be Stevens-Johnson syndrome. EM can be
the result of a DTH response. T cells do not appear recurrent, especially when a viral trigger such
to produce IFN-γ in drug-induced lesions, but as HSV is evident.
rather the lesions are characterized by tumor
necrosis factor alpha (TNF-α) present in
keratinocytes and also produced by macrophages
and monocytes. TNF-α may have been shown to Pathologic Features
mediate keratinocyte apoptosis, and much of the
tissue damage in drug-induced lesions appears to Lesions of EM are similar histopathologically
be due to apoptosis. It is possible this mechanism both in the oral mucosa and the skin. They are
plays a role in the milder forms of drug-induced characterized by a lichenoid infiltrate in the base-
EM (Ayangco and Rogers 2003). ment membrane zone of the epidermis or epithe-
Some cases of EM show antibodies to epithelium. T lymphocytes and mononuclear cells are
lial antigens including desmoplakins, but whether present in the dermis and lamina propria and
they are directly involved in amplifying the dis- extend into the epithelium or epidermis obscur-
ease process or as a response to epitope spreading ing the basement membrane zone. The degree of
as a result of epithelial damage is not clear mononuclear cell infiltration is variable and
(Cozzani et al. 2011). tends to be less in those lesions resembling
TEN. The epithelium or epidermis may appear
edematous and spongiotic, and there is necrosis
Clinical Features both of basal and suprabasal epithelial cells,
resulting in both intra- and subepithelial bullae
EM is characterized by extensive painful ery- formation. Not infrequently the bullae contain
thematous and ulcerative lesions of the mucous mononuclear cells (Fig. 14). Immunofluores-
membranes. The oral manifestations of the spec- cence shows granular staining for C3 at the base-
trum of EM range from tender superficial ery- ment membrane zone and occasionally within
thematous and hyperkeratotic plaques to painful vessels or apoptotic keratinocytes (Ayangco
deep hemorrhagic bullae, ulcers, and erosions. and Rogers 2003).
Fig. 14 Histopathology of erythema multiforme extensive keratinocyte apoptosis (b). There are degenera-
(EM) minor (a). The epithelium is edematous and intra- tive changes at the epithelial connective tissue junction,
and subepithelial vesicles are present. An infiltration of with bullae either sub- or intra-epithelially: the
lymphocytes and macrophages is seen in the lamina pro- degenerating oral epithelium is strikingly eosinophilic,
pria and within the epithelium. EM major showing destruc- and there is a lymphohistiocytic infiltration in the lamina
tion and necrolysis of most of the epithelium due to propria (Farthing et al. 2005; permission granted)
Diagnosis evidence that antivirals may be helpful in pre-

venting new attacks in the recurrent form of EM
Diagnosis relies mainly on clinical signs together (Ayangco and Rogers 2003). A 5-day course of
with the history and histological analysis of an acyclovir at the first sign of lesions or 400 mg qds
oral mucosal biopsy. The diagnosis of oral EM is for 6 months is useful for prophylaxis. Continuous
one of exclusion. Careful clinical evaluation for therapy of valacyclovir, 500 mg twice a day, has
other chronic mucocutaneous diseases, such as also been reported to be effective in preventing
pemphigus, PNP, MMP, and LP, is a necessary new attacks.
component of the diagnosis. A biopsy specimen The usefulness of corticosteroids remains
examined by both routine histopathological and unclear. Minor EM may respond to topical corti-
immunopathological methods is fundamental to costeroids, though systemic corticosteroids may
excluding the other causes for this variant of EM be required and patients with major EM or SJS
(Ayangco and Rogers 2003). may need to be admitted for hospital care and
should be treated with systemic corticosteroids
(prednisolone 0.5–1.0 mg kg 1 day 1 tapered
Patient Management over 7–10 days) and/or azathioprine or other
immunomodulatory drugs. Other treatments
Treatment of EM remains controversial, as used may include cyclophosphamide, dapsone,
there are no reliable evidence-based outcomes. cyclosporine, azathioprine, levamisole, and
Spontaneous healing of EM can be slow taking thalidomide (Conejo-Mir et al. 2003), and more
2–3 weeks in minor EM and up to 6 weeks in recently rituximab has been used with some
major EM. In severe cases, corticosteroids may be success (Hirsch et al. 2016), perhaps confirming
needed. In HSV-associated EM, antivirals such as a role for B cells or their products in the patho-
acyclovir may be prescribed, but since the lesions genesis of EM.
occur some days after a viral infection, there is For the drug-induced EM, no specific treat-
little expectation or evidence that antivirals pre- ment is available, but in addition to immunosup-
scribed at this stage result in reduced longevity of pressives, supportive care is important and a
the condition. In contrast, there appears to be good liquid diet and intravenous fluid therapy may be
necessary. Similarly, in SJS, the oral ulceration in 1972 (Bean et al. 1972), and circulating auto-
can be so severe as to require supplemental hydra- antibodies were demonstrated using indirect
tion or liquid food because patients are unable to immunofluorescence on intact skin in 1973
drink or swallow. Aqueous chlorhexidine 0.2% (Dantzig 1973). These immunofluorescence stud-
mouthwashes may be useful in maintaining oral ies introduced the concept that BMMP/CP might
hygiene. be an autoimmune disease. In 2002, the first Inter-
national Consensus meeting agreed the term
mucous membrane pemphigoid be used instead
Mucous Membrane Pemphigoid of CP as not all cases show scarring but all are
predominantly mucosal (Chan et al. 2002). To
Mucous membrane pemphigoid (MMP) is a rare date investigators have focused upon the identifi-
predominantly mucosal subepidermal blistering cation of specific target antigens and potential
disorder involving the oral mucosa, conjunctiva, pathogenic mechanisms.
anogenital tissues, and upper aerodigestive tract.
In some patients, there may be additional skin
involvement. Conjunctival lesions may lead to Epidemiology
impaired vision and, finally, blindness. It is char-
acterized by linear BMZ autoantibody deposition MMP has a reported annual incidence of between
with binding to a range of autoantigens in the 1.16 and 0.87 per million population in France
BMZ. There is wide variation in disease severity and Germany, respectively (Bernard et al. 1995;
ranging from minimal painless oral involvement Zillikens et al. 1995), and a prevalence in
to severe blistering with scarring sequelae leading Germany of 24.64 per million inhabitants
to esophageal or laryngeal strictures or blindness. (Hubner et al. 2016). It has been estimated to be
Early recognition, careful disease monitoring, and ten times less prevalent than BP and almost four
a multidisciplinary team approach to management times less prevalent than PV in Germany (Hubner
are essential to an optimal outcome. et al. 2016). In the USA, an estimate for incidence
The diagnosis of MMP has been evolving was between 1 in 12,000 and 1 in 20,000 of the
over more than 200 years. Wichmann in 1794 general population and 1 in 20,000 to 1 in 40,000
published the first description of a female patient patients seen by ophthalmologists (Mondino and
with a chronic bullous skin disease with oral and Brown 1981).
ocular involvement (Wichmann 1794). In 1878 The disease generally affects the middle-aged
von Kries described “essential shrinkage of the and elderly although childhood cases have been
conjunctiva” (Von Kries 1878). Civatte and Lever reported. In a review of 16 studies in the literature,
on the basis of their histopathologic studies sepa- the reported mean age of onset among a total of
rated “benign mucous membrane pemphigoid” 457 patients was 62 years with a female predom-
(BMMP) from pemphigus (Civatte 1949; Lever inance of 2.27:1 (Ahmed and Hombal 1986). In
1951). In 1957, a case series described seven a case series of 140 UK patients presenting to
patients (six male and one female) all of whom clinicians in oral medicine, dermatology, and oph-
had cutaneous scarring lesions involving mainly thalmology, the mean age was 57.8 (range
the head and neck. Five also had transient wider 23–86 years) (Setterfield 2009). No geographical
cutaneous lesions, and one had oral and conjunc- or racial predilection has been reported.
tival lesions (Brunsting and Perry 1957). Lever, in
a commentary on these cases, suggested the term
“cicatricial pemphigoid” (CP) (Lever 1957). In Etiology
1971, clinical and laboratory data on the first
large series of patients with BMMP provided The cause of MMP is unclear. However, it is likely
insights into the clinical spectrum of the disease to be due to a combination of genetic, immuno-
(Hardy et al. 1971). DIF studies were first reported logical, and environmental factors. The HLA
DQB1*0301 allele with DRB*04 and DRB*11 the treatment of rheumatoid arthritis has been
allele in linkage disequilibrium has been shown associated with MMP in three cases (Shuttleworth
in many studies to be strongly associated with et al. 1985). Ocular MMP has been reported in
MMP (Setterfield et al. 2001). DQB1*0301 has association with topical glaucoma medications
been shown to be increased in North American (Tauber et al. 1989) and as a sequel to SJS
Caucasian patients with OCP (Ahmed et al. 1991; (De Rojas et al. 2007; Chan et al. 1991).
Chan et al. 1994; Delgado et al. 1996) in those
with both ocular and oral MMP (Yunis et al. 1994)
and in predominantly oral MMP in an Italian
population (Carrozzo et al. 2001). Analysis of Pathophysiology
DRB1 genes and haplotype frequencies have
shown an increased frequency of DRB1*04 in The pathogenic potential of anti-BMZ autoanti-
OCP (n = 17) and the DRB1*04, DRB4*0101, bodies in MMP suggested by the clinicopatholog-
DQA1*03, and DQB1*0301 haplotype with oral ical associations described above has not yet been
pemphigoid (n = 22) and OCP (Yunis et al. 1994; fully explained in MMP. Several basement mem-
Chan et al. 1994). In a further study among French brane antigens are associated with autoantibody
Caucasian patients (n = 25), the DRB1*1101/ reactivity including BP180, BP230, both subunits
DQB1*0301 haplotype was associated with oral, of a6b4 integrin, laminin 332, and type VII colla-
ocular, and cutaneous subgroups (Yunis et al. gen (Schmidt and Zillikens 2013).
1994; Drouet et al. 1998). The most frequently targeted antigen is
The question of whether there might be BP180 identified in up to 75% patient sera
other genetic polymorphisms that impact upon (Oyama et al. 2006; Schmidt et al. 2001).
disease susceptibility was studied where the The NC16A domain is immunodominant albeit
IL-4RA-1902 SNP was associated with oral less so than is seen in BP and is targeted by
MMP in a North Italian cohort (Carrozzo et al. IgG and/or IgA autoantibodies in up to 50%
2014). Similarly a genome-wide association study of patients with MMP (Schmidt et al. 2001;
(GWAS) on 95 UK MMP patient samples was Hayakawa et al. 2014). More recent studies
undertaken. Thirty-eight SNPs in twenty-eight using ELISA have shown that saliva can
haploblocks were associated with MMP. improve the diagnostic sensitivity of serum by
A novel association was found with polymor- 30% with a combined positivity of 67%
phisms in GALC, the gene encoding for when tested on plates with the BP180 NC16a
β-galactocerebrosidase (EC3.2.1.46) (Sadik et al. immuno-dominant peptide (Ali et al. 2016b)
2017). Studies in mice and in lysosomal storage (Fig. 15). The presence of NC16A-specific anti-
diseases have shown immunoregulatory dysfunc- bodies additionally detected in parotid saliva
tion with a pro-inflammatory activation state char- may indicate a potential role for the mucosal
acterized by an increased release of TNF-α upon immune system in disease induction and patho-
stimulation. It is hypothesized that this among genesis and may in part explain the mucosal
other pathways may contribute to disease predominance of this variant of pemphigoid
pathogenesis. (Ali et al. 2016b). Evidence for the pathogenic
Immunological factors are discussed in detail relevance for anti-BP180 antibodies can be
below. However, due to a loss of self-tolerance, extrapolated from animal studies in BP (see sec-
patients develop autoantibodies to the BMZ tion on BP). In addition to the NC16A domain,
which are detectable on tissue biopsies and may epitopes may be targeted on the C-terminal
also be detectable in serum and saliva. Patient may domain by both IgG and IgA (Murakami et al.
have detectable IgG, IgA, IgM, or complement 1998). Since both the titre of anti-BMZ IgG and
binding to the BMZ. The trigger for loss of toler- the detection of combined IgG and IgA anti-
ance is unknown; however, there have been rare BMZ antibodies has been associated with a
reports of drug-induced MMP. Penicillamine in more severe disease, epitope specificity may be
a 250000 b 100000
200000
IgG antibody units against
IgA antibody units against

80000
BP180-NC16a in serum
BP180-NC16a in serum
150000 60000
100000 40000
50000 20000
0 0
MMP Healthy controls Disease controls MMP Healthy controls Disease controls
sample groups tested sample groups tested
c 15000
IgA antibody units against
BP180-NC16a in saliva
10000 d
0.4
Optical Density
0.3
5000 0.2
0.1
0 0.0
MMP Healthy controls Disease controls
MMP HC PV/ LP
sample groups tested
sample groups tested
Fig. 15 Results of BP180-NC16a ELISA testing in the horizontal bar depicts 1 SD of the group and the horizontal
three subgroups (MMP, healthy controls, and disease con- I bar shows the cut-off point. Controls were negative in all.
trols which include LP and PV) for variables specific IgG (a) Serum IgG antibody units against BP180-NC16a in
and IgA antibody in serum, whole saliva, and parotid MMP 42% (27/64) positive. (b) Serum IgA antibody
saliva. For (a), (b), and (c) results are shown as unit units against BP180-NC16a in MMP 28% (18/64) posi-
while for (d) results are reported in optical density. tive. (c) Whole saliva IgA antibody units against BP180-
Positivity was established as lying above the mean + 2 NC16a in MMP 36% (23/64) positive. (d) Parotid saliva
SD of the healthy controls. The middle horizontal bar SIgA antibody OD against BP180-NC16a in MMP 44%
corresponds to the mean value of the group, while the top (8/18) positive
relevant to MMP phenotype (Setterfield et al. patient sera often targeting more than one antigen
1998, 1999a). and there being no clear correlation between anti-
The B4 integrin has been associated in some gen specificity and clinical phenotype (Oyama
studies with ocular MMP (Tyagi et al. 1996; Li et al. 2006).
et al. 2016), while a6 has been suggested to be However autoantibody-induced BMZ separa-
associated with oral MMP (Bhol et al. 2001). tion is just part of the immunological response.
An association was reported in 78 Italian The propensity for scarring in MMP distinguishes
patients between BP180 antibodies and oral and it from bullous pemphigoid. Scarring may be medi-
cutaneous lesions (Cozzani et al. 2016). Laminin ated by a range of cytokines including IL-2, IL-4,
332 is detected in 5–15% patients and is associ- IL-5, IL-13, IFN-γ, TNFα, TGFβ, and HSP47;
ated with a more severe disease with a greater ALDH/RA (aldehyde dehydrogenase/retinoic
than expected association with solid organ acid)-mediated paracrine and autocrine effects initi-
tumors (Egan et al. 2001). While antibodies to ate and perpetuate fibroblast activation (Dart 2017).
one target antigen may lead to MMP, there have MMP is characterized by a gradual onset and
also been several studies showing individual slower progression than, for example, bullous
Fig. 16 Gingival lesions in mucous membrane pemphigoid with erythema, blistering, and ulceration (desquamative
gingivitis) involving maxillary and mandibular gingivae in (a) and mostly maxillary gingivae in (b)
pemphigoid or PV, punctuated by periods of acute Clinical Features

exacerbation or remission. The site of onset is
variable but in the majority of patients will Oral Involvement
involve the oral mucosa, with other sites often The oral mucosa is the most frequently involved
additionally involved. While the oral epithelium site. In the combined data from 16 studies of
has a rapid turnover and is therefore relatively MMP, oral lesions were present in 85% patients
resistant to scarring, the conjunctiva and other (Ahmed and Hombal 1986). Characteristic
mucosal sites, e.g., larynx or esophagus, have a intraoral sites are the gingiva (80%), buccal
much higher risk of scarring. The duration of the mucosa (58%), palate (26%), alveolar ridge
disease is not well documented; however, in an (16%), tongue (15%), and lower lip (7%)
18-year retrospective study of 81 patients treated (Laskaris et al. 1982). There are three broad pat-
only with topical or systemic steroids, there were terns of intraoral involvement, desquamative gin-
no spontaneous remissions and no prolonged givitis (DG), extra-gingival lesions, and a
remission if effective therapy was interrupted combination of the two. Notably, the gingivae
(Hardy et al. 1971). are the most frequently affected site, while the
Due to the diverse clinical spectrum with lip, tongue, and floor of mouth are much less
patients presenting to a range of specialists, affected (Setterfield 2009).
the reported frequency of involved sites has var-
ied in the literature. While the majority of Desquamative Gingivitis
patients have lesions in more than one site, This is the most frequent oral presentation and may
there are subgroups of patients who appear to range from mild or localized gingival erythema to
have single site involvement, such that they generalized DG with blistering, erosions, or ulcer-
have pure ocular disease or pure oral disease. In ation (Fig. 16). The labial gingivae are always
contrast to those with pure ocular disease, involved, with lingual and palatal gingivae less
patients with pure oral disease frequently have frequently affected. The reason for this is unclear.
a mild disorder, usually localized to the gingivae, Gingival bleeding often results in suboptimal oral
and with little associated morbidity. Two further hygiene with subsequent plaque-related marginal
clinical subgroups have been described, those gingivitis leading to chronic periodontitis as a rec-
patients with oral and skin only and those with ognized complication (Foster 1986). Gingival
multisite disease (Chan et al. 1993). However, lesions in MMP may be indistinguishable from
there is a broad spectrum of site involvement in LP, PV, or epidermolysis bullosa acquisita (EBA),
many patients (Setterfield 2009; Ahmed and and therefore histology and immunofluorescence
Hombal 1986). are essential for diagnosis (Setterfield et al. 2000).
PV and EBA, however, tend to produce more gin- disorders, PNP, EM, bullous or ulcerative LP,
gival tip or marginal inflammation, respectively. bullous lupus erythematosus, and EBA.
Extra-Gingival Lesions Ocular Lesions

Lesions in other sites within the oral mucosa The conjunctiva is the second most frequent site of
appear as erythematous patches or blisters that involvement in MMP. The earliest manifestation of
subsequently develop into erosions. The buccal ocular pemphigoid (OCP) is a chronic conjuncti-
mucosa and soft palate are most frequently vitis, which may be bilateral or unilateral. Patients
involved, with additional ulcers sometimes pre- may complain of burning, irritation, and tearing or
sent on the lateral borders of the tongue, hard mucous production. Periods of exacerbation and
palate, sublingual areas, and rarely the lips remission result eventually in subepithelial
(Fig. 17). Ulcers are frequently chronic and may conjunctival fibrosis. The conjunctivae become
occasionally be associated with scarring. During scarred, and adhesions or symblepharon develop
the healing phase, fibrosis is often seen as white, between the bulbar and palpebral conjunctivae
reticulated striations that resemble LP (Gallagher (Fig. 18) or between the superior and inferior pal-
and Shklar 1987). There is a broad differential pebral conjunctivae with limitation of movement
diagnosis for extra-gingival oral lesions in MMP, of the globe termed ankyloblepharon. The contrac-
which includes the spectrum of immunobullous tion of the conjunctivae (forniceal foreshortening)
and inversion of the eyelid margins (entropion)
lead to inversion of the lashes onto the corneal
surface (trichiasis).
Inflammation and fibrosis can also lead to
destruction of the tear ducts and mucous glands
leading to xerosis. Superficial corneal trauma can
then result in corneal ulceration (Foster 1986).
There may be inability to completely close
the lids further exacerbating corneal exposure.
Keratinization of the cornea and neo-
vascularization lead to corneal opacification and
eventual blindness. These changes are not exclu-
sive to OCP but may also be seen as a result of a
Fig. 17 Extensive ulceration on the hard and soft palate
and anterior arch of the fauces in mucous membrane broad range of disease that includes drug-induced
pemphigoid ocular pseudo-pemphigoid (often unilateral) (Butt
Fig. 18 Ocular mucous membrane pemphigoid with fore-shortening of the lower fornix and symblepharon
formation (a), and keratinization of the cornea leading to blindness (b)
Fig. 19 Ulceration and

scarring alopecia in mucous
membrane pemphigoid
et al. 1998). Thus, diagnosis should ideally be mucosal predominant disease. Lesions frequently
supported by positive DIF. heal with an atrophic scar but may relapse inter-
In terms of the overall risk of disease progres- mittently over several years.
sion, in a study of 130 OCP patients (of whom
116/130 were DIF positive), 1/3 were reported to Nasopharyngeal Lesions
have a severe reduction in visual acuity (Foster Nasal lesions may be associated with extensive
1986). However, studies such as these with potential involvement of the upper aerodigestive tract. In a
selection bias may overemphasize the risk of visual prospective study of upper aerodigestive tract
loss compared to other subgroups of patients such as involvement, 38/110 (38%) of MMP patients
those attending dermatology or oral medicine were symptomatic, and 33 (30%) had clinical
clinics. Among these cohorts, patients are signifi- lesions; of these, 30 (79%) had nasal, 6 (16%)
cantly symptomatic when they have sight- pharyngeal, and 19 (50%) laryngeal lesions
threatening disease. It is recommended therefore detected (Alexandre et al. 2006). Epistaxis,
that patients with ocular symptoms be screened by fibrous adhesions, and stenosis have been
an ophthalmologist with expertise in MMP. reported with dysphagia or odynophagia as rec-
ognized sequelae (Ahmed and Hombal 1986).
Skin Lesions
Skin lesions occur in 10–43% patients with sev- Laryngeal and Tracheobronchial Lesions
eral types described (Ahmed et al. 1991). Patients Laryngotracheal involvement occurs in 8% (range
may present with a transient generalized BP-type 0–29%) of patients (Ahmed and Hombal 1986).
eruption followed by persistent mucosal lesions or Erosions on the vocal cords may be associated
more scattered recurrent blisters similar to those with hoarseness or dysphonia. Direct laryngos-
seen in BP that rupture and heal without signifi- copy may show erosions of the epiglottis and
cant scarring. A second pattern, which predomi- aryepiglottic folds, and severe laryngeal scarring
nantly involves the head and neck, has been may lead to stenosis necessitating a tracheostomy.
referred to as the “Brunsting-Perry” type. These Combined upper and lower airway involvement
lesions are often localized and heal with scarring has rarely resulted in death.
(Brunsting and Perry 1957) sometimes associated
with scarring alopecia (Fig. 19) but must have a Anogenital Lesions
predominantly mucosal disease. In other patients, Vesicles or erosions of the glans penis and
there may be a few localized, recurrent skin foreskin, urethra, vulva, or vagina can lead to
lesions on the limbs and trunk or in the peri- fibrosis and stricture formation. In males, chronic
umbilical region but again on a background of a blistering on the glans penis may result in loss of
Fig. 20 Genital mucous

membrane pemphigoid
leading to balanoposthitis
(a) with loss of the coronal
sulcus (b)
Fig. 21 Esophageal
scarring leading to a cork- Esophageal Lesions
screw esophagus Esophageal lesions are reported to occur in
approximately 5% of patients (Fig. 21) (Ahmed
and Hombal 1986). The hypopharynx and cervi-
cal esophagus are most commonly involved.
Patients complain of dysphagia or odynophagia.
A careful history should elicit these symptoms
and appropriate investigations either a barium
swallow or upper endoscopy undertaken.
Strictures and stenoses are longer-term sequelae
and may necessitate frequent dilatations.
Pathologic Features
The histology typically shows a subepidermal/

subepithelial cleft with a mixed inflammatory
infiltrate (Fig. 22). DIF will show IgG, IgA,
IgM, and/or C3 at the basement membrane. In
patients with predominantly ocular MMP, con-
junctival positivity may be low, and therefore an
additional oral biopsy is recommended (Grau
et al. 2013) (Fig. 23).
Serum samples may be tested on 1 M salt-split
the coronal sulcus and fusion of foreskin to the skin to identify the titer of circulating IgG and/or
glans penis (Bunker 2004) (Fig. 20). Anal lesions IgA anti-basement membrane zone antibodies.
may also result in scarring and stricture formation, Antibodies may be epidermal and dermal, or
in one case with delayed diagnosis leading to a dual binding IgG autoantibodies are detected in
defunctioning colostomy (Harman et al. 2003). 50–80% patients and/or IgA autoantibodies in
about 60% patients directed against a variety of of IgG reduce as the clinical scores reduce
proteins in the anchoring complex of the skin and (Setterfield et al. 1999a; Ali et al. 2016b).
mucosal BMZ when tested on salt-split skin sub-
strate (Setterfield et al. 1998; Schmidt et al.
2001;). While antibody titers are often low, serial Diagnosis
IgG titers have been shown to correlate with dis-
ease severity. Furthermore, the detection of both The diagnosis of MMP is based upon the combi-
IgG and IgA is associated with a more severe nation of clinical, histological, and immunopath-
disease than with IgG alone (Setterfield et al. ological findings. Clinically patients must have a
1998). Sequential studies have shown that titers predominantly mucosal disease. Histology dem-
onstrates a subepithelial split with a mixed inflam-
matory cell infiltrate. The current gold standard
diagnostic test for MMP is positive DIF for IgG,
IgA, IgM, or C3 at the BMZ (Chan et al. 2002).
Where DIF is negative but IIF is strongly positive,
this would be accepted as an equivalent diagnostic
test. In the initial weeks or months, MMP may be
hard to distinguish from BP where there are wide-
spread skin lesions. However in BP, the oral
lesions soon settle, and ocular disease is not an
important feature. Thus, as soon as the disease is
mucosally predominant, the diagnosis of MMP is
confirmed. Historically some cases with pure IgA
on IF were classified as having linear IgA disease.
However, since the First Consensus meeting on
MMP in 2001, these patients were brought under
the umbrella of MMP where the disease was
mucosally predominant (Chan et al. 2002).
Fig. 22 Mucosa with mild features of pemphigoid, with a
subepithelial split at the biopsy margin where trauma has
DIF is positive in almost all cases of oral and
induced the split. Separation of dermal papillae and pres- multisite MMP. The lack of detection of anti-BMZ
ervation of basal cells aid distinction from traumatic sepa- antibodies in pure ocular pemphigoid (OCP)
ration and lichen planus (detected in approximately 50% conjunctival
Fig. 23 Linear IgG (a) and linear IgA (b) at the basement membrane zone (BMZ) in skin biopsies of mucous membrane
pemphigoid
biopsies) is difficult to explain, and there is an with multisite disease (in particular where there
ongoing debate as to whether non-autoantibody- is ocular, genital, esophageal and/or laryngeal
mediated immunological mechanisms predomi- lesions or where patients have progressive pure
nate in these patients and therefore whether the ocular disease). These would be classified as hav-
diagnostic criteria need to be modified. The ocular ing high-risk disease (Chan et al. 2002). Figure 24
clinical phenotype in these cases is indistinguish- shows an algorithm modified from Taylor et al.
able from DIF-positive OCP, and the patients (2015) with a detailed overview of possible ther-
respond in the same way to immunosuppressive apeutic options in MMP in both low- and high-
therapy. Thus, in practice DIF-negative cases of risk patient subgroups.
OCP are managed by ophthalmologists in the
same way. It is nevertheless important to empha- Disease Severity
size that for oral and multisite MMP-positive lin- In order to assess disease severity at presentation
ear BMZ, IF is essential to distinguish patients and subsequent response to treatment, an objec-
from LP and PV. tive scoring methodology is needed. One
Two biopsy sites should be sampled: one from proposed method included all clinical sites
perilesional tissue for histology and DIF and a (Setterfield et al. 1998) and was later modified to
second from unaffected buccal mucosa also for more accurately assess oral lesions. It has been
direct immunofluorescence. As DIF is the gold validated for LP (Escudier et al. 2007), PV
standard diagnostic test for MMP, the combined (Ormond et al. 2018), and MMP (Fig. 25).
sampling methodology will ensure at least one Recently the MMP disease activity index
tissue sample has intact epithelium and therefore (MMPDAI) (Murrell et al. 2015) has been pro-
an accurate diagnosis from the outset. In the posed as a new scoring methodology to include all
mouth, the perilesional sample is ideally taken sites but awaits validation. It includes a score for
from the buccal mucosa if involved or reflected ocular disease, but generally this is undertaken by
alveolar mucosa as in the case of pure gingival ophthalmologists, and several specific methodol-
MMP. Avoidance of the gingival papilla and lip is ogies are in use already for detailed scoring of
advisable as both have fragile epithelium which is ocular MMP (Dart 2017).
easily separated from the underlying corium.
Serum is routinely tested for circulating anti- Treatments
BMZ antibodies as above. When positive, further There is a limited evidence base upon which to
testing with ELISA for BP180 and BP230 may be guide therapy in MMP (Di Zenzo et al. 2014;
undertaken for epidermal binding sera and type Taylor et al. 2015). An International Consensus
VII collagen or, with immunoblotting studies, guideline published in 2002 (Chan et al. 2002)
laminin 332 for dermal binding sera. Diagnosis made recommendations based upon risk of pro-
of laminin 332 patients is important as there is a gression in MMP. A Cochrane systematic review
risk of an underlying solid tumor in up to a third of published in 2003 (Kirtschig et al. 2003) identi-
cases (Setterfield et al. 1999a; Egan et al. 2001). fied just two RCTs providing limited evidence for
Immunoblot studies can also be undertaken. treatment of OCP (Foster 1986) with one further
RCT identified in a subsequent review (Taylor
et al. 2015). It is vital that a multidisciplinary
Patient Management approach to management is used for this often
multisite disease.
It is important to adopt a multidisciplinary team
approach to carefully assess each affected site and Topical Treatment
then to stratify patients according to their risk. It is Topical treatments can control mild to moderate
generally agreed that patients with disease local- disease in the oral cavity. These may be used as
ized to the mouth with or without skin involve- mouthwashes, combined with adhesive pastes
ment are at a relatively low risk compared to those such as Orabase or applied in custom-made
Algorithm for treatment of MMP
LOW Risk
HIGH Risk
• Oral Mucosa only
• Oral Mucosa + limited skin MILD • Severe oral mucosa and/or
• No ocular, genital, esophageal, e.g Ocular or • Ocular, genital,
laryngeal genital esophageal, laryngeal
• Moderate-high potency topical CS SEVERE disease

+/- • CS (0.5-1.0 mg/kg/d) +/-
• Dapsone (50-150 mg/day) • Azathioprine (1-2 mg/kg/d)
• Sulphapyridine* (0.25-1 g/d) • MMF (1-2 g/d)
• Tetracycline (1-2 g/d) + nicatinamide (2-2.5 g/d) +/-
(*not universally available) • Dapsone/sulphapyridine
Partial Complete
Complete Partial Response Response
response Response
Progressive
• Rituximab
• IVIG monthly pulses
• Prednisolone +/- or rarely oral cyclophosphamide (1-2 mg/kg/d) or
• Azathioprine IV 500-1000 mg 3-4 weekly (mainly ocular lesions)
(1-2 mg/kg/d)
• MMF (1-2 g/d)
Maintenance Complete
Response
CS: corticosteroid; MMF; mycophenolate mofetil
H&E: hematoxylin and eosin; DIF: direct Surgery as needed Taper and maintain
Immunofluorescence for OCP topical CS/ dapsone/
IIF: indirect immunofluorescence low dose IS
Fig. 24 An algorithm for treatment of patients with MMP (Modified from Taylor et al. 2015)
trays allowing close approximation to the gingi- pemphigoid, extra-gingival+/ skin, and pure
vae (Lee et al. 1991). Betamethasone 0.5 mg in ocular (OCP), the localized oral and pure ocular
10 mL of water as a 3-min rinse and spit 1–4/day subgroups were more responsive to therapy than
and fluticasone propionate 400 micrograms more extensive disease (Rogers 1986). Among
(1 mg/ml) in 10 mL as a mouthwash twice daily localized oral MMP, 15/30 were in remission at
are examples of frequently used preparations. 5-year follow-up, whereas in those with mixed
Clobetasol propionate in Orabase as a 50% mix oral/skin or OCP, only 13/47 were in remission
can be applied either directly or in a custom-made at a mean 4-year follow-up. Fifty-five of seventy-
tray for short periods of time. seven patients were treated with dapsone (up to
Maintenance of good oral hygiene is paramount 150 mg daily) and/or sulfapyridine, and of these
as plaque is likely to compound gingival inflamma- 85% had successful clinical courses.
tion (Arduino et al. 2011; Arduino et al. 2012). In a further later study of 29 patients with pure
Furthermore, the clinician should be aware of the oral pemphigoid, regression analysis of treatment
increased risk of oral candidosis where topical or suggested that the longer the delay before diagno-
systemic corticosteroids are used on a regular basis. sis, the longer the duration of treatment (Mobini
et al. 1998).
Systemic Treatment In a retrospective review of our own series of
For mild to moderate disease, case series have 64 cases, 30 stopped due to side effects that
suggested that dapsone or tetracycline and nico- included anemia, a rash, myalgia, nausea, and
tinamide are helpful if tolerated. In a review of dizziness, and 2 stopped due to treatment failure.
77 cases of MMP divided into localized oral When the drug was tolerated, it gradually
Fig. 25 The oral disease Site Site Score Acvity score (0-3).
severity score for use in
Add score for each 50% or side
MMP. It combines a site
score, activity score and
subjective pain score Outer lips 1
Inner lips 1
L Buccal mucosa <50% = 1, >50%=2
R Buccal mucosa <50% = 1, >50%=2
Gingiva:
Lower R distal 1 1 (mild)
Lower central 1
Lower L distal 1
Upper R distal 1
Upper central 1
Upper L distal 1
Dorsum of tongue One side= 1, both=2 2 (moderate)
R ventral tongue 1
L ventral tongue 1
Floor of mouth One side= 1, both=2
Hard palate One side= 1, both=2
Soft palate One side= 1, both=2 3 (ulcerated)
Oropharynx One side= 1, both=2
improved oral disease as shown in Fig. 26. It is prednisolone (1.0–1.5 mg.kg/day) plus cyclo-
worth noting that maximum effect however took phosphamide (1–2 mg/kg/day) orally or
18 months. 500–1000 mg IV every 3–4 weeks (Chan et al.
For moderate to more severe disease, MMP is 2002). However, cyclophosphamide is not used as
managed with mycophenolate mofetil or azathio- a long-term drug due to its risk of toxicity, partic-
prine. This may be added to a sulfa drug with ularly in the elderly with a high risk of infections
or without additional short-term prednisolone. related to lymphopenia and neutropenia. In refrac-
A recommended approach to management is a tory disease monthly IVIG infusions have been of
step-up (adding immunosuppressive agents to benefit usually as a combination therapy.
sulfa drugs) and as the patient improves a step- Finally, there is emerging evidence in case
down approach adding sulfa drugs to immuno- series for rituximab. In a retrospective cohort
suppressive agents with a view to withdrawing study of ocular MMP, 61 eyes in 32 patients
immunosuppressives (Saw et al. 2008). In a recent were reviewed. All had received rituximab either
systematic review, an RCT was identified that as monotherapy or in combination with immuno-
showed limited evidence for pentoxifylline was suppression. Twenty-six patients achieved clinical
identified in OCP (Taylor et al. 2015). However, remission (defined as absence of progressive scar-
this is not used in clinical practice. ring and active ocular inflammation for
For more severe ocular disease, Cochrane > = 2 months) with an average sustained remis-
identified one RCT which suggested that cyclo- sion of 24.5 months (range 9–84 m) (You et al.
phosphamide plus prednisolone was more effec- 2017). This is often prescribed as two infusions
tive than prednisolone alone. This may be used as of 1 mg on day 1 and day 15 with a reduction
a 30
25
Mean disease severity score

20
15
10
0
0 5 10 15 20 25 30
Dapsone therapy (months)
Fig. 26 Objective assessment of mean therapeutic (b) and after (c) treatment with dapsone. Pretreatment
response to dapsone over 28 months in 20 patients with ODSS (site score 6, activity score 18, pain score 6, total
mucous membrane pemphigoid using the disease severity score = 30) and posttreatment ODSS (site score 5, activity
score (ODSS) (a). Clinical appearance of a patient before score 7, pain score 1, total score = 13)
in concurrent immunosuppressive medication applicable for assessment of oral PV and oral

(by 50% in our practice) while continuing with lichen planus. Use of a careful clinical disease
oral prednisolone. Subsequent courses may be scoring methodology combined with serological
given depending upon clinical response, circulat- and/or salivary biomarkers will confirm a clinical
ing B-cell levels and antibody titers. The timing of and immunological response to therapy.
a second course has been at 4 months (Le Roux-
Villet et al. 2011) or later (Maley et al. 2016).
Repeat cycles have been effective in most patients Bullous Pemphigoid
not responding to one cycle.
A recent review of therapies highlighted the Bullous pemphigoid (BP) is the most common
frequent serious adverse effects from these medi- subepidermal blistering disease. It is characterized
cations, the need for more RCTs, but the lack of by linear BMZ binding of IgG and C3 on DIF. The
validated methods of assessing disease activity majority of patients will have generalized cutane-
and outcomes (Di Zenzo et al. 2014). The ODSS ous blisters associated with pruritus, but in
described here is a validated method of assessing approximately 20%, the presentation may be
oral disease with the added benefit of being atypical with either localized blisters or a
non-blistering more eczematous rash. There is a non-collagenous extracellular portion of BP180 is

significant mortality (20–40% in the first year) the immunodominant epitope for IgG autoanti-
associated with the condition in part on account bodies. IgG reactivity with C-terminal epitopes
of the age of presentation but additionally associ- are associated with severe skin disease and muco-
ated with comorbidities (Karnofsky score) and sal lesions. The predominant immunoglobulin
complications of treatment. Infectious complica- isotypes are IgG, IgA, and/or IgE. Some studies
tions are the leading cause of death. have demonstrated that anti-BP180 titers may act
as a serologic marker of clinical disease activity.
However, presentation and disease course will
Epidemiology be influenced by many factors including gene
polymorphisms, immunological response mole-
It is associated with old age (usually >70 years). cules, and a variety of environmental factors.
The incidence of BP is reported to be 2.4–21.7 There is good evidence for the pathogenic rel-
new cases per million inhabitants/year (Amber evance of humoral and cellular immunity against
et al. 2017) increasing to 42.8/million UK inhab- BP180. Studies have shown correlation between
itants in a retrospective study (Langan et al. 2008). disease activity and serum titers of IgG antibodies
BP is present in both genders equally and affects against the NC16A domain and other epitopes on
the elderly. BP180. Animal models have shown the impor-
tance of complement activation at the BMZ, neu-
trophils, mast cells, macrophages, and a variety of
Etiology proteases including matrix metalloproteinase 9,
plasmin, α1 proteinase inhibitor, and mast cell
The major histocompatibility class II allele proteinase 4 for blister formation (Bieber et al.
DQB1*03:01 is associated with BP (Delgado 2009; Schmidt and Zillikens 2013). Transgenic
et al. 1996). It is involved in the presentation of mouse models have replicated the human disease
antigens to CD4+ lymphocytes and in particular successfully. In addition, mouse models have
the NC16a epitope of BP180. In addition, many demonstrated the role of autoreactive T cells, spe-
drugs have been implicated in the onset of BP cifically the NC16A- reactive CD4 T cells to the
including antibiotics, antihypertensives, bio- HLA DQB1*03O1 allele (Thoma-Uszynski et al.
logics, loop diuretics, nonsteroidal anti- 2006). There is some evidence from mouse
inflammatory drugs, etc. (Amber et al. 2017). models for a pathogenic role for IgE BP180
More recently the antidiabetic, dipeptidyl NC16A-specific antibodies but little evidence to
peptidase-IV inhibitors (Izumi et al. 2016) have support the pathogenicity of BP230-specific
been implicated. Several neurologic and psychi- autoantibodies.
atric disorders, e.g., Parkinson’s disease, stroke, Immunological mediators such as IL-1β, IL-5,
epilepsy, and multiple sclerosis, have been asso- IL-6, IL-8, IL-10, IL-15, and TNF-α and
ciated. The latter observation is of interest as the chemokines CCL2, CCL5, CCL11, CCL13, and
BP180 molecule is expressed in hippocampus, CCL18 have been detected in serum and blister
thalamus, midbrain, and basal forebrain. Further- fluid and may parallel disease activity (Schmidt
more, serum levels of anti-BP180 correlate with and Zillikens 2013).
more severe dementia and Alzheimer’s disease
(Kokkonen et al. 2017).
Clinical Features
Pathophysiology Patients may present with an itchy urticated

erythematous rash within which tense blisters
The main target antigens are BP180 and BP230. develop. Blisters may appear weeks to months
As in MMP, the NC16a domain localized on the after initial pruritus. Lesions may be localized
Fig. 27 Intact blisters on the hand appearing on an ery-

thematous base in patient with bullous pemphigoid Fig. 28 Direct immunofluorescence showing strongly
positive fluorescence along the roof of a subepidermal
blister in bullous pemphigoid
often to the limbs or may be generalized favoring
flexural sites and the trunk (Fig. 27).
Oral lesions are mild, transient, and seen in Patient Management
10–20% patients. They are not usually associated
with involvement of other mucosal sites (Schmidt Therapeutic intervention is determined by
et al. 2011). They may affect the buccal mucosae, disease severity and a careful assessment of
palate, tongue, or lips and heal without scarring. comorbidities. For mild or localized disease, ultra-
When oral lesions persist in the context of a gener- potent topical corticosteroids may suffice (e.g.,
alized blistering skin rash that resolves, the patient clobetasol propionate 20–30 g/day). In a recent
will have MMP. There can therefore be some early prospective controlled trial, doxycycline 200 mg
confusion as to the diagnosis (Setterfield et al. 1997). daily was considered to be non-inferior to tapering
doses of prednisolone 0.5 mg/kg daily at 6 weeks
for short-term blister control and superior in terms
Pathologic Features of long-term safety (Williams et al. 2017). For
moderate to severe disease, oral prednisolone at
Histology typically shows a subepidermal blister a dose of 0.5 mg/kg with or without adjuvant
with an inflammatory infiltrate comprising lym- therapy (mycophenolate mofetil 2–3 g/day, aza-
phocytes and eosinophils. DIF typically shows thioprine 1.5–2.5 mg/kg/day) may be required.
linear BMZ deposition of IgG and or complement
(Fig. 28).
Anti-P200 Pemphigoid
Diagnosis This entity was initially reported in 1996 by

Zillikens and Hashimoto (Zillikens et al. 1996).
This is made on the clinical presentation of a
predominantly cutaneous disease and histological
findings. A biopsy is taken across the edge of an Diagnosis
active lesion ensuring that the sample remains
intact. The perilesional tissue is sent for DIF. DIF shows linear IgG/C3 and occasionally IgA.
Serum is collected for IIF on intact human skin Circulating antibodies bind to the floor of 1 M
and 1 M salt-split skin. Typically binding of anti- salt-split skin (similar to anti-laminin 332 MMP
BMZ antibodies is to the roof of the split. and EBA). Immunoblotting or ELISA is required
to make the distinction. Sera target the C-terminus >60 years and may be associated with an under-
of laminin γ1 in 90% cases (Dainichi et al. 2009). lying medication. There is no racial or gender
While there is some evidence for a pathogenic role predilection. It is associated with HLA-B8,
for these antibodies, further work is needed to HLA-CW7, and HLA-DR3 and where all three
define their relevance. are present may be associated with an earlier age
of onset. In the older group, the disease has a more
benign course compared with childhood onset
Clinical Presentation where it may lead to scarring in some patients
with a more chronic form of the disease.
The mean age of presentation is 69 years (range
50–91) and has a male predominance. Patients
typically present with a BP-like rash with tense Etiology
blisters appearing on an erythematous base but
may be variable. Involvement of the hands and The etiology is unknown. However, in the elderly
feet is frequent. Mucosal lesions have been population may be triggered by various drugs
reported in 20–57% cases (Commin et al. 2016). typically by IV vancomycin, amiodarone, nonste-
roidal anti-inflammatory drugs, captopril, and
ceftriaxone-metronidazole. It is associated with
Patient Management systemic diseases including ulcerative colitis and
systemic lupus erythematosus.
The disease usually responds well to treatment
that is aligned with BP.
Pathophysiology
Linear IgA Disease IgA autoantibodies have been shown to target

a wide variety of potential BMZ antigens in
Linear IgA disease (linear IgA bullous disease; LAD (Fortuna and Marinkovich 2012). The
linear IgA bullous dermatosis; LAD) is rare blis- majority of patients autoantibodies target LABD-
tering disease characterized by spontaneous blis- 97 (a 97 kDa antigen) and LAD-1 (a 120 kDa
tering and the present of linear deposits of IgA antigen), both being proteolytic cleavage products
in the basement membrane zone of clinical of the BP180 ectodomain. Cellular immune
uninvolved skin. This entity was classified as responses include activation of memory CD4+ T
distinct from BP and DH in 1979 (Chorzelski helper cells and polymorphs.
and Jablonska 1979). However, since that time,
it has been recognized that there is broad overlap
with MMP, BP, and EBA in terms of clinical Clinical Features
presentation and immunopathological features.
LAD has two peaks of onset: childhood and adult-
hood. It is the most common autoimmune blister-
Epidemiology ing disease in childhood. The clinical presentation
may be heterogeneous and may mimic bullous
The incidence has been reported as 0.25–1.0/mil- pemphigoid or dermatitis herpetiformis. Skin
lion/year in Europe, Singapore, and Kuwait with lesions typically may be urticated plaques, ero-
higher incidences reported in parts of Africa and sions, or blisters arranged in a ring as in Fig. 29. In
Malaysia. There are two peaks in age of presenta- children, the lesions are predominantly on the
tion. It is the most common subepidermal blister- lower abdomen and anogenital skin, whereas in
ing disease in children usually over the age of adults, the lesions may occur on the face, extensor
6 years. It then tends to present in older patients surfaces, and hands and feet. Early studies which
Fig. 29 Linear IgA disease. Blisters, erosions, and ulcers seen on mid-dorsal tongue (a), lateral border of tongue (b), and
skin (c)
included patients now categorized as having infiltrate in the upper dermis. Neutrophilic micro-
MMP estimated that mucosal lesions occurred in abscesses may be present in the papillary dermis.
70% patients (Wojnarowska et al. 1988). How- DIF characteristically shows a linear band of IgA
ever, while any mucosal site can be affected, there sometimes with additional IgG. Binding is usually
is no systematic study of the type, frequency, and to the roof of a blister though occasionally to the
distribution of oral lesions in LAD per se. Ulcers base. IIF may show circulating IgA anti-BMZ
or blisters may occur on the palate, buccal antibodies in 30–50% usually epidermal binding
mucosa, or tongue but are less frequent on the but occasionally dermal binding (Fig. 30).
lips or gingivae.
Diagnosis
Pathologic Features
The diagnosis therefore is based upon the com-
Routine histology and DIF do not differentiate bined clinical features with consistent histology
between IgA disease and benign MMP or and IF. Immunoblotting studies may help to iden-
BP. Histology typically shows a subepidermal tify the 120 or 97 kDa antigens shed ectodomain
separation with a predominant neutrophilic of BP180.
Fig. 30 Hematoxylin and eosin stained section showing microabscesses beneath the epidermis (a). Direct immuno-
incipient dermo-epidermal separation and a neutrophil fluorescence typically shows linear IgA deposition; how-
rich inflammation in the papillary dermis with small ever, IgG, IgM, or C3 may additionally be detected (b)
Patient Management Etiology
As the majority of patients will have a disease EBA is a prototypical autoimmune disease with a
triggered by drugs, removal of the offending well-characterized pathogenic relevance of auto-
drug will usually resolve the condition. A multi- antibody binding to the target antigen type VII
disciplinary approach may be needed if the disease collagen (COL7). This collagen anchors the epi-
is mucocutaneous. Topical corticosteroids are thelial cells and BMZ to the underlying connec-
helpful and may be the sole treatment required. tive tissue, so functional absence of COL7 leads to
Sulfone drugs (dapsone) are first line, or sulfon- separation of the mucosa and sub-basilar bullae.
amides (sulfapyridine) as second line are
very effective. Occasionally third-line agents are
needed such as corticosteroids or mycophenolate
Pathophysiology
mofetil although a wide range of drugs have
been used.
EBA is characterized by the presence of IgG auto-
antibodies targeting the non-collagenous (NC1)
domain of type VII collagen. A subset of patients
Epidermolysis Bullosa Acquisita have variations in which either IgG autoantibodies
bind the central triple-helical collagenous (NC2)
Epidemiology domain of type VII collagen, or immunoglobulin
A (IgA), rather than IgG, targets type VII collagen.
EBA is a chronic mucocutaneous autoimmune The targeting of the NC2 domain by autoantibodies
skin blistering disease (Ludwig 2013). It may destabilize anchoring fibrils by interfering
presents a similar clinical appearance to other with antiparallel dimer formation, leading to
blistering conditions and presents usually in dermoepidermal disadherence (Chen et al. 2001).
middle age. EBA is a rare disease with an IgG autoantibodies specific for anchoring fibrils
incidence of 0.2 new cases per million and (type VII collagen) of the skin basement membrane
per year (Ludwig 2013). The disease usually have a heterogeneous subclass and light-chain
affects adults with no gender or racial composition, and their complement-activating
predilection. capacities do not correlate with the inflammatory
phenotype (Gandhi et al. 2000). These antibodies oral mucosa including lips (Fig. 31) and tongue
compromise the strength of the BMZ, leading to (Fig. 31). Lesions heal with scarring that may lead
skin fragility and trauma-induced blister formation. to ankyloglossia, a reduction in the oral aperture and
The pathogenic relevance of autoantibodies microstomia. Gingivitis may be present but is less
targeting type VII collagen has been well- prominent than seen in MMP.
documented. The recent development of novel
in vitro and in vivo models of EBA has allowed
understanding of the critical role of the genetic Pathologic Features
background, T cells, and cytokines for mediating
the loss of normal immune tolerance toward EBA can be differentiated from other subepidermal
COL7. Neutrophils, complement activation, Fc bullous diseases by sophisticated techniques such
gamma receptor engagement, cytokines, several as immunoelectron microscopy, salt-split skin anti-
molecules involved in cell signaling, release gen mapping, fluorescence overlay antigen map-
of reactive oxygen species, and matrix meta- ping, immunoblot, and enzyme-linked
lloproteinases are crucial for autoantibody- immunosorbent assay. Diagnosis is usually made
induced tissue injury in EBA (Ludwig 2013). by a combination of clinical, histological, DIF, and
serological investigations. Histologically, there is
subepidermal separation of the epithelium from
Clinical Features the underlying connective tissue, but this cannot
usually be confidently distinguished from other
The clinical pattern may be a BP-type presentation subepidermal lesions. However, DIF in a biopsy
with widespread inflammatory skin lesions, or there taken from an area of blistering will typically dem-
may be a more mechano-bullous presentation with onstrate a dermal binding pattern with a U-serrated
blisters on trauma-prone sites, e.g., elbows, knees, pattern on DIF compared with the n-serrated pat-
hands, and feet. Oral lesions may be seen in both. tern in all other types of pemphigoid disorders
The pathogenic effect is similar to that of children (Vodegel et al. 2004). Serology is only positive in
who have a genetic absence of collagen VII that 50% sera and thus diagnosis can be difficult to
results in an unstable mucosa and severe mucosal confirm. ELISA to detect antibodies against type
ulceration (Epidermolysis Bullosa Dystrophica). VII collagen is definitive but available only in
Irregular ulceration can appear anywhere in the specialist laboratories.
Fig. 31 Oral manifestations of epidermolysis bullosa acquisita. Bullae and ulcers on the lower lip (a), and ulceration of
the side of tongue (b)
Patient Management gluten leads to activation of CD4+ T cells in

intestinal mucosa leading to production of B
The current treatment of EBA relies on general lymphocytes predominantly of the IgA class.
immunosuppressive therapy and is similar to that IgA1 antibodies are directed against peptides
described for MMP above. Unfortunately, immu- present in gluten, e.g., gliadin and against auto-
nosuppressive treatment does not lead to remission antigens such as the intestinal enzyme trans-
in all cases (Mehren and Gniadecki 2011), and glutaminase (TGT), which deposit in the skin
treatment is generally more challenging than with and cross-react with epidermal transglutaminase
MMP. EBA appears to be responsive to rituximab (transglutaminase 3, TG3).
antibody to CD20 (which supports the role of B
cells). However, there remains a need for the devel-
opment of further therapeutic options in EBA. Pathophysiology
Immunological findings in tissue include the char-

Dermatitis Herpetiformis acteristic presence of granular IgA deposits along
or near the basement membrane of both involved
Dermatitis herpetiformis (DH) is an uncommon, and uninvolved skin and mucosa including oral.
chronic, intensely itchy, symmetrical papulo- There is evidence that the IgA deposits are
vesicular eruption mainly involving the skin and dimeric and thus of mucosal origin. In a small
which is associated with gluten-sensitive enterop- percentage <5%, a fibrillar pattern may be seen
athy occurring in patients with known celiac though may be higher in Japanese patients.
disease, as well as in patients without symptom- Immune reactants are also detected in the vessel
atic intestinal disease. It was first described as a walls of the papillary and reticular dermis, in the
clinical entity by Louis Duhring in 1884. elastic fibers, in the arrector pili muscle, around
hair follicles, and at the basement membrane of
the sweat glands and sweat ducts (Barnados
Epidemiology 2016).
There is an increased frequency of HLA DQ2 and

DQ8 in DH. DH and celiac disease have been Clinical Features
shown to cluster in the same families. Gender
differences suggest that male patients dominate Lesions are usually distributed symmetrically
(approximately 2:1) in DH, whereas female on extensor surfaces, especially the elbows,
patients dominate in celiac disease. A minority knees, shoulders, and buttocks, but oral lesions
of patients with DH present with prominent gas- can also occur though rarely. They can
trointestinal symptoms or signs of malabsorption, present before any skin manifestations
and a quarter of DH patients have no villous (Fig. 32). If present they may appear as erythem-
atrophy in the small bowel. The ratio of coeliac atous, vesicular, purpuric, or erosive more
to DH is in the order of 8 to 1 (Mansikka et al. visible in sites of trauma, for example, along
2017). The prevalence of DH in the UK has been the bite line.
estimated at 30/100,000 population and
11/100,000 in the USA (Collina et al. 2017).
Pathologic Features
Etiology Histologically the typical features of DH consist

of accumulations of neutrophils and eosinophils
The pathogenic mechanism leading to DH is at the tips of connective tissue papillae (Fig. 33).
unclear. However, intestinal intolerance to As lesions develop, these microabscesses
Fig. 32 Erythematous
papular-type lesions of
dermatitis herpetiformis on
the skin
Fig. 33 Dermatitis herpetiformis. Histopathology (Hematoxylin and eosin stain) demonstrates papillary tip micro-
abscesses (a), and direct immunofluorescence showing a granular deposition of IgA in the papillary dermis (b)
increase in size, become confluent, and form 2016). Serology is undertaken for IgA antibody
large fluid-filled bullae at the level of the base- to transglutaminase 3 using ELISA and has a high
ment membrane. specificity but lower sensitivity than in coeliac
disease.
Diagnosis
Patient Management
Histology from lesional skin and DIF from peri-
lesional or normal tissue together confirm diagno- The treatment of celiac disease is gluten-free
sis. DIF typically show a granular pattern of IgA diet (GFD) which means avoidance of foods
deposition although in some biopsies additional containing wheat, rye and barley. Reduction in
IgG, IgM, C0 3, C1q, and fibrinogen – although in itch may take months to years and usually
a lower percentage may be detected (Barnados requires dapsone to gain rapid control. Dapsone
is then slowly withdrawn over 2–3 years. Etiology

There is an increased risk of B-cell lymphomas
in DH, but this risk returns to normal after BOLP, as a subtype of OLP, is considered a type
5 years of a strict gluten-free diet. TG3 anti- IV immunologically cell-mediated disorder. There
bodies are detectable only in the presence of is no evidence that the basic mechanisms of dam-
gluten and therefore become negative with a age differ from those leading to other types of
strict diet. OLP, even though the oral manifestation differs.
The initial trigger seems to be the expression of
keratinocyte basal antigen (Zhou et al. 2002).
Bullous Lichen Planus T cells migrate to the epithelium either by random
encounter of the keratinocyte basal antigen during
Bullous lichen planus is a rare variant of lichen routine surveillance or by a cytokine-mediated
planus. It is characterized by vesicles or bullae, process. Subsequently, there is extensive lympho-
which usually develop in the context of cytic infiltrate consisting mainly of CD4+ and
preexisting LP lesions. It is often misdiagnosed CD8+ T cells (Zhou et al. 2002). The activation
and should be differentiated from other subepi- of CD8+ cells appear to play a pivotal role to the
dermal bullous diseases. This is evident on disease process either directly by recognition of
histology, with alteration of the dermoepidermal an antigen binding to the MHC class I on lesional
junction and intra-basal bullae as a con- keratinocytes or through activation from CD4+
sequence of extensive inflammation. Bullous cells (Liakopoulou and Rallis 2017).
oral lichen planus (BOLP) is the least common
clinical subtype of OLP. BOLP lesions are
most commonly seen on the buccal mucosa, Pathophysiology
less frequently on the gingivae and rarely the
lips. The bullae are generally short-lived and A plausible hypothesis for the mechanism of dam-
leave ulcerated lesions on rupturing. Most com- age (Roopashree et al. 2010) is that CD4+ cells are
monly they are accompanied by other signs activated by antigens associated with MHC class
of lichen planus, such as striae, elsewhere in II molecules that are present in Langerhans cells
the oral cavity. More information on this topic and keratinocytes. Increased numbers of CD4+
is detailed in a separate chapter on ▶ “Oral and Langerhans cells are found in the lamina
Lichen Planus”. propria and in the epithelium in OLP (Zhou et al.
2002; Liakopoulou and Rallis 2017). CD4+
T cells then activate CD8+ cells through receptor
Epidemiology interaction and by the concurrent action of IL-2
and IFN-γ (Roopashree et al. 2010).
The prevalence of OLP has been reported as IFN-γ in turn induces the production of TNF-α
affecting between 0.5% and 2% of the adult from keratinocytes as well as an increase in class
population. BOLP is the least common of the II MHC resulting in increased interaction with
clinical variants of OLP affecting perhaps 1 in helper T cells. Furthermore, it induces the produc-
100 OLP patients, thus 5 to 10 per 100,000 tion of VCAM-1 and ICAM-1 by keratinocytes
population. The exact prevalence of BLP and dendritic/Langerhans cells, which facilitates
remains unknown. The disease is usually spo- lymphocyte adhesion to keratinocytes and results
radic. However, familial cases of skin BLP in keratinocyte apoptosis (Nogueira et al. 2015).
have also been described in literature (Huang This apoptosis may be induced by a number of
et al. 2005). The role of hereditary factors in possible mechanisms: a) release of cytotoxic mol-
the development of BOLP warrants further ecules like perforin and granzymes B that work
investigation and may shed further light on its together to trigger cell lysis, b) TNF-α secretion
etiology. by T cells which binds to TNF-α receptor on
Fig. 34 Bullous oral lichen planus showing intact bullous on the left buccal mucosa (a) (arrow) and burst bullous on the
palate (b) (arrow). Few signs of lichen planus are otherwise evident
specific keratinocytes and induces apoptosis, and acanthosis and increased numbers of intra-
c) expression of Fas-ligand on T-cell surface that epithelial lymphocytes. These features in con-
binds to FAS on keratinocytes (Roopashree et al. junction with negative immunofluorescence
2010; Nogueira et al. 2015). suggest that bullous lichen planus is a form of
“hyperreactive lichen planus” rather than a dis-
tinct entity, though the reason histologically for a
Clinical Features different clinical appearance is unclear.
The clinical features of bullous oral lichen planus

include typical lichen planus lesions, accompa- Diagnosis
nied by the formation of bullae on the affected
areas. Lesions appear as vesicles or bullae within Clinical presentation, histology, and DIF are
typical lichenoid lesions ranging from a few mil- required for the diagnosis. There are no serum
limeters to a centimeter or more. Blisters burst markers. The clinical diagnosis of BOLP can be
leaving painful ulcers. Common sites are the buc- extremely difficult, especially in the apparent
cal mucosa, palate (Fig. 34), and less frequently absence of other signs of OLP, and histopathology
the lateral borders of the tongue and gingivae. is usually required to make a definitive diagnosis.
However, any oral site may be affected. The skin The diagnosis is based on history and clinical
can be concurrently affected and nail beds may suspicion and is confirmed by positive OLP his-
show signs of LP. topathology and negative immunofluorescence.
Pathologic Features Patient Management
In spite of the expectation that histologically Patients are managed in the usual way as for OLP
BOLP might show increased evidence of epithe- as detailed in the chapter on ▶ “Oral Lichen
lial damage subsequent to apoptosis, the histolog- Planus”. There is no standard treatment of bullous
ical features do not appear to differ significantly lichen planus. Topical and systemic corticoste-
from other types of LP. There is a subepithelial roids, dapsone, and acitretin have been described
cellular infiltrate that is almost entirely lympho- as effective choices based on case reports rather
cytic, a mixture of epithelial atrophy and than clinical trials.
Angina Bullosa Hemorrhagica
Angina bullosa hemorrhagica (ABH) is the term

used to describe benign subepithelial oral mucosal
blisters filled with blood in the absence of an
identifiable cause or systemic disorder. It is a
very rare condition. Elderly patients are usually
affected, and lesions heal spontaneously without
scarring. ABH is a benign phenomenon that is
characterized by the sudden appearance of blood
blisters on the oral mucosa, especially the soft
palate. It is important that ABH is distinguished
from immune-bullous disorders even though clin-
ical presentation of burst bullae may be similar.
Fig. 35 Angina bullosa hemorrhagica. A 5 mm 3 mm
blood blister is noted on the right side of tongue (arrow)
Epidemiology
masticatory keratinized mucosa of the hard palate
ABH affects mainly middle-aged and elderly peo- and gingivae do not seem to be affected. ABH
ple. There is no strong predilection for either men patients have been mainly the middle-aged and
or women. There are no data on the prevalence of elderly, and ABH lesions have not been
ABH, but the literature contains many case series documented in children less than 10 years of
from around the world suggesting both that ABH age. ABH lesions can also occur down the esoph-
is not restricted genetically but is rare. agus and pharynx. The hemorrhagic bullae spon-
taneously burst after a short time resulting in
ragged, often painless, superficial erosions that
Etiology and Pathophysiology heal spontaneously within 1 week without scar-
ring. The intact bulla is red to purple in color
The pathogenesis is unknown, although it may be (Fig. 35). Blisters can reach 2–3 cm in diameter
a multifactorial phenomenon. Trauma seems to be and burst spontaneously, leaving ragged ulcers
the major provoking factor, and long-term use of that heal without scarring. Clinically, the lesions
steroid inhalers has also been implicated in the may recur.
disease. No underlying hematological or immu-
nological disorders have been found, although
zinc deficiency and hypertension have been Pathologic Features
claimed to be associated.
The histopathological features of ABH include
the parakeratotic epithelium with a subepithelial
Clinical Features separation from the underlying lamina propria.
Superficially located bullae filled with erythro-
ABH are acute and sometimes painful oral blood- cytes and fibrin are seen. The inflammatory cell
filled vesicles and bullae not attributable to blood infiltrate, if present, consists primarily of lympho-
dyscrasias, vesiculobullous disorders, systemic cytes. Neutrophils and eosinophils are not present.
diseases, or other known causes (Stephenson Immunofluorescence demonstrates no evidence of
et al. 1987; Singh et al. 2013). ABH mainly affects IgG, IgM, IgA, or C3 antibodies within the epi-
the soft palate, but lesions can also develop on thelium or the BMZ. No underlying hematologi-
other oral sites including the buccal mucosa, lip, cal or immunological disorders have been found
and the lateral surface of the tongue. The though zinc deficiency and hypertension have
been claimed to be associated. Cytological smears lesions should be symptomatic. Long-term fol-
do not reveal any abnormal cells, and biopsies low-up is recommended to definitively exclude
have not revealed any specific features or cellular other conditions that may present with oral blood
infiltrate. containing bullae.
Diagnosis Conclusions and Future Directions
The diagnosis of ABH is largely clinical and Pemphigus and MMP are autoantibody-mediated
includes the elimination of other disease processes blistering skin diseases. In pemphigus, kera-
at histology. ABH seems to be a multifactorial tinocytes in epidermis and mucous membranes
phenomenon: dental or functional trauma seems lose cell-cell adhesion, and in pemphigoid, the
to be the major provoking factor. The lesions of basal keratinocytes lose adhesion to the basement
ABH can be easily confused with other mucosal membrane. Pemphigus lesions can be mediated
diseases. It is important that the presentation of directly by the autoantibodies, whereas the auto-
this benign disorder is distinguished from other antibodies in pemphigoid fix complement and
more serious disorders with similar presenting mediate inflammation. In both diseases, the auto-
features, including EM, bullous LP, pemphigus, antigens have been characterized; pemphigus
pemphigoid, and epidermolysis bullosa. Even if antigens are desmogleins (cell adhesion mole-
there is a typical history of rapid blistering, the cules in desmosomes), and pemphigoid antigens
absence of any dermatological, hematological, or are found in hemidesmosomes (which mediate
systemic signs and normal healing of the ulcers adhesion to the basement membrane) with the
generally lead to a diagnosis of ABH. Patients predominant target of BP180. Understanding
with bleeding disorders (thrombocytopenia and these mechanisms of disease has led to rational
von Willebrand’s disease) can present with targeted therapeutic strategies which require both
intraoral blood-filled lesions, but a hemostatic careful clinical phenotyping and assessment of
function test will distinguish between these clinical outcomes in response to treatment. The
conditions. role of cell-mediated immunity in these antibody-
mediated diseases remains to be fully determined.
Interestingly, proteomic analysis of pemphigus
Patient Management autoantibodies indicates a larger, more diverse,
and changing repertoire than determined by
The management of a patient presenting with oral B-cell genetics (Chen et al. 2017) suggesting
blood-filled bullae should start with a detailed that modern molecular techniques may reveal a
medical history and careful examination to differ- hitherto unsuspected dynamism in the pattern of
entiate ABH from other more serious diseases. autoantibody responses.
The lesion should be biopsied to perform histol- In the oral cavity, several subtypes of MMP
ogy and direct immunofluorescence in order to have been recognized which may respond to dif-
exclude more serious diseases. A complete blood ferent treatments, and so clinical recognition and
picture and baseline coagulation tests should disease severity scoring are essential in disease
always be performed to exclude blood disorders. management. The target antigens responsible for
The patient should be reassured of the benign the different clinical phenotypes of MMP have not
nature of the blisters. A large palatal or pharyngeal so far been identified, and more work is required
blister causing a choking sensation should be sur- to answer the question of the role of mucosal
gically treated if still intact since although this is a immunity in MMP. In general, the standard ther-
benign condition, it may theoretically result in apies of immune suppression may give way to the
acute airway obstruction. Management of these greater application of biologics. Determining the
role of various pathological mechanisms, includ- Ahmed AR, Kurgis BS, Rogers IR. Cicatricial
ing direct inhibition of cell adhesion, antibody- pemphigoid. J Am Acad Dermatol. 1991;24:987–1001.
Ahmed AR, Spigelman Z, Cavacini LA, Posner MR. Treat-
induced internalization of antigen, and cell signal- ment of pemphigus vulgaris with rituximab and intra-
ing, may help us to understand the disease pro- venous immune globulin. N Engl J Med. 2006;355(17):
cesses further and lead to more targeted treatment 1772–9.
in the future. Alexandre M, Brette MD, Pascal F, Tsianakas P, Fraitag S,
Doan S, Caux F, Dupuy A, Heller M, Lievre N,
Lepage V, Dubertret L, Laroche L, Prost-Squarcioni
C. A prospective study of upper aerodigestive tract
manifestations of mucous membrane pemphigoid.
Cross-References Medicine. 2006;85:239–52.
Ali S, Kelly C, Challacombe SJ, Donaldson AN, Bhogal
BS, Setterfield JF. Serum and salivary IgG and IgA
antibodies to Dsg3 in mucosal pemphigus vulgaris.
▶ Clinical Immunology in Diagnoses of Maxillo- Br J Dermatol. 2016a;175:113–21.
facial Disease Ali S, Kelly C, Challacombe SJ, Donaldson AN, Dart JK,
▶ Cutaneous Pathology of the Head and Neck Gleeson M, MMP Study Group 2009-14, Setterfield J.
Detection of salivary IgA and IgG antibodies to BP180-
▶ Gingival Pathology
NC16a in mucous membrane pemphigoid patients as
▶ Interface between Oral and Systemic Disease a diagnostic biomarker. Br J Dermatol. 2016b;174:
▶ Laboratory Medicine and Diagnostic Pathology 956–7.
▶ Oral and Maxillofacial Fungal Infections Allen CM, Camisa C. Paraneoplastic pemphigus: a review
of the literature. Oral Dis. 2000;6:208–14.
Alpsoy E, Akman-Karakas A, Uzun S. Geographic varia-
▶ Oral Lichen Planus tions in epidemiology of two autoimmune bullous
▶ Oral Manifestations of Systemic Diseases and diseases: pemphigus and bullous pemphigoid. Arch
their Treatments Dermatol Res. 2015;307(4):291–8.
Amagai M. Towards a better understanding of pemphigus
▶ Oral Mucosal Malignancies
autoimmunity. Br J Dermatol. 2000;143:237–8.
▶ Oral Ulcerative Lesions Amagai M, Stanley JR. Desmoglein as a target in
▶ Pediatric Oral Medicine skin disease and beyond. J Invest Dermatol.
▶ Pharmacotherapeutic Approaches in Oral 2012;132(3 pt 2):776–84.
Amagai M, Nishikawa T, Nousari HC, Anhalt GJ, Hashi-
Medicine
moto T. Antibodies against desmoglein 3 (pemphigus
▶ Soft and Hard Tissue Operative Investigations vulgaris antigen) are present in sera from patients
in the Diagnosis and Treatment of Oral Disease with paraneoplastic pemphigus and cause acantholysis
in vivo in neonatal mice. J Clin Invest. 1998;102(4):
775–82.
Amagai M, Ahmed AR, Kitajima Y, Bystryn JC, Milner Y,
References Gniadecki R, et al. Are desmoglein autoantibodies
essential for the immunopathogenesis of pemphigus
Abé T, Maruyama S, Babkair H, Yamazaki M, Cheng J, vulgaris, or just “witnesses of disease”? Exp Dermatol.
Saku T. Simultaneous immunolocalization of 2006;15(10):815–31.
desmoglein 3 and IgG4 in oral pemphigus vulgaris: Amber KT, Staropoli P, Shiman MI, Elgart GW, Hertl M,
IgG4 predominant autoantibodies in its pathogenesis. Autoreactive T. Cells in the immune pathogenesis of
J Oral Pathol Med. 2015;44(10):850–6. pemphigus vulgaris. Exp Dermatol. 2013;22(11):
Aboobaker J, Morar N, Ramdial PK, Hammond MG. 699–704.
Pemphigus in South Africa. Int J Dermatol. Amber KT, Murrell DF, Schmidt E, Joly P, Borradori L.
2001;40:115–9. Autoimmune subepidermal bullous diseases of the skin
Abreu-Velez AM, Hashimoto T, Bollag WB, et al. and mucosae: clinical features, diagnosis, and manage-
A unique form of endemic pemphigus in northern ment. Clin Rev Allergy Immunol. 2017.
Colombia. J Am Acad Dermatol. 2003;49:599–608. Andreadis D, Lorenzini G, Drakoulakos D, Belazi M,
Ahmed AR, Hombal SM. Cicatricial pemphigoid. Int J Mihailidou E, Velkos G, Mourellou-Tsatsou O,
Dermatol. 1986;25:90–6. Antoniades D. Detection of pemphigus
Ahmed AR, Shetty SA. Comprehensive analysis of treat- desmoglein 1 and desmoglein 3 autoantibodies
ment outcomes in patients with pemphigus vulgaris and pemphigoid BP180 autoantibodies in saliva and
treated with rituximab. Autoimmun Rev. 2015;14(4): comparison with serum values. Eur J Oral Sci.
323–31. 2006;114(5):374–80.
Anhalt GJ. Paraneoplastic pemphigus. Adv Dermatol. pemphigus vulgaris patients from a prevalent south-
1997;12:77. eastern Brazilian region. J Autoimmun. 2016;72:
Anhalt GJ. Paraneoplastic pemphigus. J Investig Dermatol 19–24.
Symp Proc. 2004;9:29–33. Brunsting L, Perry H. Benign Pemphigoid? A report of
Anhalt GJ, Kim SC, et al. Paraneoplastic pemphigus. An seven cases with chronic scarring, herpetiform plaques
autoimmune mucocutaneous disease associated with about the head and neck. Arch Dermatol. 1957;75:
neoplasia. N Engl J Med. 1990;323:1729–35. 489–501.
Arduino PG, Farci V, D’Aiuto F, et al. Periodontal status in Bunker CB. Male genital skin disease. Edinburgh:
oral mucous membrane pemphigoid: initial results of a Saunders; 2004.
case-control study. Oral Dis. 2011;17(1):90–4. Butt Z, Kaufman D, McNab A, McKelvie P. Drug-induced
Arduino PG, Lopetuso E, Carcieri P, et al. Professional oral ocular cicatricial pemphigoid: a series of clinicopatho-
hygiene treatment and detailed oral hygiene instruc- logical reports. Eye. 1998;12(Pt 2):285–90.
tions in patients affected by mucous membrane Buxton RS, Magee AI. Structure and interactions of des-
pemphigoid with specific gingival localization: a pilot mosomal and other cadherins. Semin Cell Biol. 1992;
study in 12 patients. Int J Dent Hyg. 2012;10(2): 3(3):157–67. Review.
138–41. Capon F, Boulding H, Quaranta M, et al. Genetic analysis
Ayangco L, Rogers RS 3rd. Oral manifestations of of desmoglein 3 (DSG3) sequence variants in patients
erythema multiforme. Dermatol Clin. 2003;21(1): with pemphigus vulgaris. Br J Dermatol. 2009;161(6):
195–205. 1403–5.
Barnados MA. Dermatitis herpetiformis: a review of direct Carrozzo M, Gandolfo S, Lodi G, Carbone M, Garzino-
immunofluorescence findings. Am J Dermatopathol. Demo P, Carbonero C, et al. Oral lichen planus in
2016;38(4):283–8. patients infected or non infected with the hepatitis C
Baum S, Astman N, Berco E, Solomon M, Trau H, virus: the role of autoimmunity. J Oral Pathol Med.
Barzilai A. Epidemiological data of 290 pemphigus 1999;28:16–19.
vulgaris patients: a 29-year retrospective study. Eur J Carrozzo M, Fasano ME, Broccoletti R, Carbone M,
Dermatol. 2016;26(4):382–7. Cozzani E, Rendine S, Roggero S, Parodi A,
Bean SF, Waisman M, Michel B, Thomas CI, Knox JM, Gandolfo S. HLA-DQB1 alleles in Italian patients
Levine M. Cicatricial pemphigoid. Immunofluorescent with mucous membrane pemphigoid predominantly
studies. Arch Dermatol. 1972;106:195–9. affecting the oral cavity. Br J Dermatol. 2001;145:
Bernard P, Vaillant L, Labeille B, Bedane C, Arbeille B, 805–8.
Denoeux JP, Lorette G, Bonnetblanc JM, Prost C. Carrozzo M, Dametto E, Fasano ME, et al. Interleukin-
Incidence and distribution of subepidermal autoim- 4RA gene polymorphism is associated with oral
mune bullous skin diseases in three French regions. mucous membrane pemphigoid. Oral Dis. 2014;20:
Bullous Diseases French Study Group. Arch Dermatol. 275–80.
1995;131:48–52. Celentano A, Tovaru S, Yap T, Adamo D, Aria M,
Beutner EH, Rhodes EL, Holborow EJ. Autoimmunity in Mignogna MD. Oral erythema multiforme: trends and
chronic bullous skin diseases. Immunofluorescent clinical findings of a large retrospective European case
demonstration of three types of antibodies to skin in series. Oral Surg Oral Med Oral Pathol Oral Radiol.
sera of patients with pemphigus, bullous pemphigoid 2015;120(6):707–16.
and in other human sera. Clin Exp Immunol. 1967;2(2): Challacombe SJ, Setterfield J, Shirlaw P, Harman K,
141–51. Scully C, Black MM. Immunodiagnosis of pemphigus
Bhol K, Natarajan K, Nagarwalla N, Mohimen A, Aoki V, and mucous membrane pemphigoid. Acta Odontol
Ahmed AR. Correlation of peptide specificity and IgG Scand. 2001;59:226–34.
subclass with pathogenic and nonpathogenic autoanti- Challacombe SJ, Shirlaw PJ, Thornhill MH. Immunology
bodies in pemphigus vulgaris: a model for autoimmu- of diseases of the oral cavity. Chapter 102. In:
nity. Proc Natl Acad Sci USA. 1995;92(11):5239–43. Mestecky J, Strober W, Russell MW, Kelsall BL,
Bhol KC, Goss L, Kumari S, Colon JE, Ahmed AR. Cheroutre H, Lambrecht BN, editors. Mucosal immu-
Autoantibodies to human alpha6 integrin in patients nology. 4th ed. St Louis: Elsevier Ltd; 2016.
with oral pemphigoid. J Dent Res. 2001;80:1711–5. p. 1943–83.
Bieber K, Sun S, Ishii N, Kasperkiewicz M, Schmidt E, Chams-Davatchi C, Valikhani M, Daneshpazhooh M, et al.
Hirose M, Westermann J, Yu X, Zillikens D, Ludwig R. Pemphigus: analysis of 1209 cases of pemphigus
Animal models for autoimmune bulous dermatoses. vulgaris and pemphigus foliaceus. Int J Dermatol.
Exp Dermatol. 2009;19:2–11. 2005;44:470–6.
Borradori L, Sonnenberg A. Structure and function of Chams-Davatchi C, Esmaili N, Daneshpazhooh M, et al.
hemidesmosomes: more than simple adhesion com- Randomized controlled open label trial of four treat-
plexes. J Invest Dermatol. 1999;112:411–8. ment regimens for pemphigus vulgaris. J Am Acad
Brochado MJ, Nascimento DF, Campos W, Deghaide NH, Dermatol. 2007;57:622–8.
Donadi EA, Roselino AM, Differential HLA. Class I Chan LS, Soong HK, Foster CS, Hammerberg C,
and class II associations in pemphigus foliaceus and Cooper KD. Ocular cicatricial pemphigoid occurring
as a sequela of Stevens-Johnson syndrome. JAMA. Autoantibody profile of a cohort of 78 Italian patients

1991;266:1543–6. with mucous membrane pemphigoid: correlation
Chan LS, Yancey KB, Hammerberg C, Soong HK, between reactivity profile and clinical involvement.
Regezi JA, Johnson K, Cooper KD. Immune-mediated Acta Derm Venereol. 2016;96(6):768–73.
subepithelial blistering diseases of mucous membranes: Culton DA, Qian Y, Li N, et al. Advances in pemphigus
pure ocular cicatricial pemphigoid is a unique clinical and its endemic pemphigus foliaceus (Fogo Selvagem)
and immunopathological entity distinct from bullous phenotype: a paradigm of human autoimmunity.
pemphigoid and other subsets identified by antigenic J Autoimmun. 2008;31:311–24.
specificity of autoantibodies. Arch Dermatol. Culton DA, McCray SK, Park M, Roberts JC, Li N,
1993;129:448–55. Zedek DC, Anhalt GJ, Cowley DO, Liu Z, Diaz LA.
Chan LS, Wang T, Wang XS, Hammerberg C, Cooper KD. Mucosal pemphigus vulgaris anti-Dsg3 IgG is patho-
High frequency of HLA-DQB1*0301 allele in patients genic to the oral mucosa of humanized Dsg3 mice.
with pure ocular cicatricial pemphigoid. Dermatology. J Invest Dermatol. 2015;135(6):1590–7.
1994;189(Suppl 1):99–101. Dainichi T, Kurono S, Ohyama B, Ishii N, Sanzen N,
Chan LS, Ahmed AR, Anhalt GJ, Bernauer W, Cooper KD, Hayashi M, Shimono C, Taniguchi Y, Koga H,
et al. The first international consensus mucous mem- Karashima T, Yasumoto S, Zillikens D, Sekiguchi K,
brane pemphigoid: definition, diagnostic criteria, path- Hashimoto T. Anti-laminin gamma-1 pemphigoid.
ogenetic factors, medical treatment and prognostic Proc Natl Acad Sci USA. 2009;106:2800–5.
indicators. Arch Dermatol. 2002;138(3):370–9. Dantzig P. Circulating antibodies in cicatricial pemphigoid.
Chen M, Keene DR, Costa FK, Tahk SH, Woodley DT. Arch Dermatol. 1973;108:264–6.
The carboxyl terminus of type VII collagen mediates Dart JK. The 2016 Bowman lecture conjunctival curses:
antiparallel dimer formation and constitutes a new anti- scarring conjunctivitis 30 years on. Eye (Lond).
genic epitope for epidermolysis Bullosa acquisita auto- 2017;31:301–32.
antibodies. J Biol Chem. 2001;276(24):21649–55. De Rojas MV, Dart JK, Saw VP. The natural history of
Chen J, Zheng Q, Hammers CM, Ellebrecht CT, Stevens Johnson syndrome: patterns of chronic ocular
Mukherjee EM, Tang HY, Lin C, Yuan H, Pan M, disease and the role of systemic immunosuppressive
Langenhan J, Komorowski L, Siegel DL, Payne AS, therapy. Br J Ophthalmol. 2007;91:1048–53.
Stanley JR. Proteomic analysis of pemphigus autoanti- Delgado JC, Turbay D, Yunis EJ, Yunis JJ, Morton ED,
bodies indicates a larger, more diverse, and more Bhol K, Norman R, Alper CA, Good RA, Ahmed R.
dynamic repertoire than determined by B cell genetics. A common major histocompatibility complex class II
Cell Rep. 2017;18(1):237–47. allele HLA-DQB1*0301 is present in clinical variants of
Chorzelski TP, Jablonska S. IgA linear dermatosis of child- pemphigoid. Proc Natl Acad Sci USA. 1996;93:8569–71.
hood (chronic bullous disease of childhood). Br J Di Zenzo G, Carrozzo M, Chan LS. Urban legend series:
Dermatol. 1979;101:535–42. mucous membrane pemphigoid. Oral Dis. 2014;20(1):
Civatte A. Le diagnostic des dermatoses bulleuses au 35–54.
laboratoire. Arch Belg Dermatol Syphiligr. 1949;5: Dobrev H, Popova L, Vlashev D. Proteinase inhibitors and
273–5. pemphigus vulgaris. An in vitro and in vivo study. Arch
Collina P, Salmi TT, Hervonen K, Kaukinen K, Reunala T. Dermatol Res. 1996;288(11):648–55.
Dermatitis herpetiformis: a cutaneous manifestation of Drouet M, Delpuget-Bertin N, Vaillant L, Chauchaix S,
coeliac disease. Ann Med. 2017;49(1):23–31. Boulanger MD, Bonnetblanc JM, Bernard P.
Commin MH, Schmidt E, Duvert-Lehembre S, Lasek A, HLA-DRB1 and HLA-DQB1 genes in susceptibility
Morice C, Estival JL, Debarbieux S, Rigal E, and resistance to cicatricial pemphigoid in French Cau-
Pauwels C, De Quatrebarbes J, Roussel A, Goujon E, casians. Eur J Dermatol. 1998;8:330–3.
Stoebner PE, Jouen F, Joly P. Clinical and immunolog- Egan CA, Lazarova Z, Darling TN, Yee C, Cote T,
ical features and outcome of anti-p200pemphigoid. Br J Yancey KB. Anti-epiligrin cicatricial pemphigoid and
Dermatol. 2016;175:776–81. relative risk for cancer. Lancet. 2001;357:1850–1.
Conejo-Mir JS, del Canto S, Muñoz MA, Rodríguez- Egu DT, Walter E, Spindler V, Waschke J. Inhibition of
Freire L, Serrano A, Hernandez C, Pulpillo A. Thalid- p38MAPK signalling prevents epidermal blistering and
omide as elective treatment in persistent erythema alterations of desmosome structure induced by pemphi-
multiforme; report of two cases. J Drugs Dermatol. gus autoantibodies in human epidermis. Br J Dermatol.
2003;2(1):40–4. 2017
Cozzani E, Di Zenzo G, Calabresi V, Caproni M, Schena D, Elias PM, Matsuyoshi N, Wu H, et al. Desmoglein isoform
Quaglino P, Marzano AV, Fabbri P, Rebora A, Parodi A. distribution affects stratum corneum structure and func-
Anti-desmoplakin antibodies in erythema multiforme tion. J Cell Biol. 2001;153(2):243–50.
and Stevens-Johnson syndrome sera: pathogenic or Ellebrecht CT, Payne AS. Setting the target for pemphigus
epiphenomenon? Eur J Dermatol. 2011;21(1):32–6. vulgaris therapy. JCI Insight. 2017;2(5):e92021.
Cozzani E, Di Zenzo G, Calabresi V, Carrozzo M, Review.
Burlando M, Longanesi L, Cerri A, Caproni M, Ellebrecht CT, Bhoj VG, Nace A, Choi EJ, Mao X,
Sera F, Antiga E, Quaglino P, Marzano AV, Parodi A. Cho MJ, Di Zenzo G, Lanzavecchia A, Seykora JT,
Cotsarelis G, Milone MC, Payne AS. Reengineering Allopurinol is the most common cause of Stevens-
chimeric antigen receptor T cells for targeted therapy Johnson syndrome and toxic epidermal necrolysis in
of autoimmune disease. Science. 2016;353(6295): Europe and Israel. J Am Acad Dermatol. 2008;58
179–84. (1):25–32.
Eming R, Hennerici T, Bäcklund J, Feliciani C, Hallaji Z, Mortazavi H, Lajevardi V, Tamizifar B,
Visconti KC, Willenborg S, Wohde J, Holmdahl R, AmirZargar A, Daneshpazhooh M, Chams-Davatchi C.
Sønderstrup G, Hertl M. Pathogenic IgG antibodies Serum and salivary desmoglein 1 and 3 enzyme-linked
against desmoglein 3 in pemphigus vulgaris are immunosorbent assay in pemphigus vulgaris: correla-
regulated by HLA-DRB1*04:02-restricted T cells. tion with phenotype and severity. J Eur Acad Dermatol
J Immunol. 2014;193(9):4391–9. Venereol. 2010;24(3):275–80.
Escudier M, Ahmed N, Shirlaw P, et al. A scoring system Hammers CM, Stanley JR. Mechanisms of disease: pem-
for mucosal disease severity with special reference to phigus and bullous pemphigoid. Annu Rev Pathol.
oral lichen planus. Br J Dermatol. 2007;157(4):765–70. 2016;11:175–97.
Eyre RW, Stanley JR. Identification of pemphigus vulgaris Hammers CM, Chen J, Lin C, et al. Persistence of anti-
antigen extracted from normal human epidermis and desmoglein 3 IgG + B-cell clones in pemphigus patients
comparison with pemphigus foliaceus antigen. J Clin over years. J Invest Dermatol. 2015;135(3):742–9.
Investig. 1988;81(3):807–12. Hardy KM, Perry HO, Pingree GC, Kirby TJ Jr. Benign
Fainaru O, Mashiach R, Kupferminc M, Shenhav M, mucous membrane pemphigoid. Arch Dermatol.
Pauzner D, Lessing JB. Pemphigus vulgaris in preg- 1971;104:467–75.
nancy: a case report and review of literature. Hum Harfouch E, Daoud S. Allelic variation in HLA-DRB1*
Reprod. 2000;15(5):1195–7. Review. loci in Syrian pemphigus vulgaris patients. Int J
Farthing P, Bagan JV, Scully C. Mucosal disease Dermatol. 2014;53(12):1460–3.
series. Number IV. Erythema multiforme. Oral Dis. Harman KE, Gratian MJ, Seed PT, Bhogal BS,
2005;11(5):261–7. Challacombe SJ, Black MM. An evaluation of ELISA
Fortuna G, Marinkovich P. Linear immunoglobulin A bul- for detection of antibodies to the major pemphigus
lous dermatosis. Clin Dermatol. 2012;30:38–50. antigens, desmoglein 1 and 3: a sensitive tool to
Foster CS. Cicatricial pemphigoid. Trans Am Ophthalmol aid the diagnosis and differentiation of pemphigus
Soc. 1986;84:527–663. vulgaris and foliaceus. Clin Exp Dermatol.
Gallagher G, Shklar G. Oral involvement in mucous mem- 2000a;25:236–40.
brane pemphigoid. Clin Dermatol. 1987;5:18–27. Harman KE, Gratian MJ, Bhogal BS, Challacombe SJ,
Gandhi K, Chen M, Aasi S, Lapiere JC, Woodley DT, Black MM. A study of desmoglein 1 autoantibodies
Chan LS. Autoantibodies to type VII collagen have in pemphigus vulgaris: racial differences in frequency
heterogeneous subclass and light chain compositions and the association with a more severe phenotype. Br J
and their complement-activating capacities do not cor- Dermatol. 2000b;142:343–8.
relate with the inflammatory clinical phenotype. J Clin Harman KE, Seed PT, Gratian MJ, Bhogal BS,
Immunol. 2000;20(6):416–23. Challacombe SJ, Black MM. The severity of cutaneous
Ghalayani P, Rashidi F, Saberi Z. Assessment of IgG anti- and oral pemphigus is related to desmoglein 1 and
bodies against HSV1, HSV2, CMV and EBV in 3 antibody levels. Br J Dermatol. 2001;144:775–80.
patients with pemphigus vulgaris versus healthy peo- Harman KE, Setterfield JF, Shirlaw PJ, Black MM,
ple. J Dent (Tehran). 2015;12(11):835–40. Challacombe SJ. Clinicopathological case 1: mucous
Gniadecki R. Desmoglein autoimmunity in the pathogen- membrane pemphigoid, epidermolysis bullosa
esis of pemphigus. Autoimmunity. 2006;39(7):541–7. acquisita and linear immunoglobulin A disease. Clin
Review. Exp Dermatol. 2003;28:461–2.
Grando SA, Pittelkow MR, Schallreuter KU. Adrenergic Harman KE, Brown D, Exton LS, Groves RW,
and cholinergic control in the biology of epidermis: Hampton PJ, Mohd Mustapa MF, Setterfield JF,
physiological and clinical significance. J Invest Yesudian PD. British Association of Dermatologists’
Dermatol. 2006;126(9):1948–65. guidelines for the management of pemphigus vulgaris
Grau AE, Setterfield J, Saw VPJ. How to do conjunctival 2017. Br J Dermatol. 2017;177:1170–1201.
and buccal biopsies to investigate cicatrising conjunc- Hashimoto T. Immunopathology of paraneoplastic pem-
tivitis: improving the diagnosis of ocular mucous mem- phigus. Clin Dermatol. 2001;19:675–82.
brane pemphigoid. Br J Ophthalmol. 2013;97:530–1 Hayakawa T, Furumura M, Fukano H, et al. Diagnosis of
and 537–8. oral mucous membrane pemphigoid by means of com-
Greenblatt DT, Benton EC, Groves RW, Setterfield JF. bined serologic testing. Oral Surg Oral Med Oral Pathol
Crescendo response to rituximab in oral pemphigus Oral Radiol. 2014;117:483–96.
vulgaris: a case with 7-year follow-up. Clin Exp Hennerici T, Pollmann R, Schmidt T, Seipelt M,
Dermatol. 2016;41(5):529–32. Tackenberg B, Möbs C, Ghoreschi K, Hertl M, Eming R.
Halevy S, Ghislain PD, Mockenhaupt M, Fagot JP, Increased frequency of T follicular helper cells and
Bouwes Bavinck JN, Sidoroff A, Naldi L, Dunant A, elevated Interleukin-27 plasma levels in patients with
Viboud C, Roujeau JC, EuroSCAR study group. pemphigus. PLoS One. 2016;11(2):e0148919.
Herbst A, Bystryn JC. Patterns of remission in pemphigus associated with more severe dementia in Alzheimer’s
vulgaris.J Am Acad Dermatol. 2000;42(3):422–7. disease. J Invest Dermatol. 2017;137:71–6.
Hertl M, Riechers R. Autoreactive T cells as potential Kokuba H, Aurelian L, Burnett J. Herpes simplex
targets for immunotherapy of autoimmune bullous virus associated erythema multiforme (HAEM) is
skin diseases. Clin Dermatol. 2001;19(5):592–7. mechanistically distinct from drug-induced erythema
Review. multiforme: interferon-gamma is expressed in HAEM
Hertl M, Veldman C. T-cellular autoimmunity against lesions and tumor necrosis factor-alpha in drug-
desmogleins in pemphigus, an autoantibody-mediated induced erythema multiforme lesions. J Invest
bullous disorder of the skin. Autoimmun Rev. Dermatol. 1999;113(5):808–15.
2003;2(5):278–83. Review. Korman N. Pemphigus. J Am Acad Dermatol. 1988;
Hirsch G, Ingen-Housz-Oro S, Fite C, Valeyrie-Allanore L, 18(6):1219–38. Review.
Ortonne N, Buffard V, Verlinde-Carvalho M, Korman N. Pemphigus. J Am Acad Dermatol. 1988;
Marinho E, Martinet J, Grootenboer-Mignot S, 18(6):1219–38. Review. PMID: 3290286.
Descamps V, Wolkenstein P, Joly P, Chosidow O. Kowalczyk AP, Green KJ. Structure, function and regula-
Rituximab, a new treatment for difficult-to-treat tion of desmosomes. Prog Mol Biol Transl Sci.
chronic erythema multiforme major? Five cases. J Eur 2013;116:95–118.
Acad Dermatol Venereol. 2016;30(7):1140–3. Kricheli D, David M, Frusic-Zlotkin M, Goldsmith D,
Huang C, Chen S, Liu Z, Tao J, Wang C, Zhou Y. Familial Rabinov M, Sulkes J, Milner Y. The distribution of
bullous lichen planus (FBLP): pedigree analysis pemphigus vulgaris-IgG subclasses and their reactivity
and clinical characteristics. J Cutan Med Surg. with desmoglein 3 and 1 in pemphigus patients
2005;9:217–22. and their first-degree relatives. Br J Dermatol.
Hübner F, Recke A, Zillikens D, Linder R, Schmidt E. 2000;143(2):337–42.
Prevalence and age distribution of pemphigus and Kridin K, Zelber-Sagi S, Khamaisi M, Cohen AD,
pemphigoid diseases in Germany. J Invest Dermatol. Bergman R. Remarkable differences in the epidemiol-
2016;136:2495–8. ogy of pemphigus among two ethnic populations in
Izumi K, Nishie W, Mai Y, Wada M, Natsuga K,Ujiie H, the same geographic region. J Am Acad Dermatol.
et al. Autoantibody profile differentiates between 2016;75(5):925–30.
inflammatory and noninflammatory bullous Kridin K, Zelber-Sagi S, Bergman R. Pemphigus vulgaris
pemphigoid. J Invest Dermatol. 2016;136:2201e10. and pemphigus foliaceus: differences in epidemiology
Joly P, Maho-Vaillant M, Prost-Squarcioni C, Hebert V, and mortality. Acta Derm Venereol. 2017.
French study group on autoimmune bullous skin Kumar S, De D, Handa S, Ratho RK, Bhandari S, Pal A,
diseases, et al. First-line rituximab combined with Kamboj P, Sarkar S. Identification of factors associated
short-term prednisone versus prednisone alone for the with treatment refractoriness of oral lesions in pemphi-
treatment of pemphigus (Ritux 3): a prospective, multi- gus vulgaris. Br J Dermatol. 2017.
centre, parallel-group, open-label randomised trial. Kurata M, Mizukawa Y, Aoyama Y, Shiohara T. Herpes
Lancet. 2017;389(10083):2031–40. simplex virus reactivation as a trigger of mucous
Kaçar N, Cevahir N, Demirkan N, Şanlı B. The investiga- lesions in pemphigus vulgaris. Br J Dermatol.
tion of the possible relationship between Coxsackie 2014;171(3):554–60.
viruses and pemphigus. Int J Dermatol. 2014;53(3): Langan SM, Smeeth L, Hubbard R, Fleming KM,
312–5. Smith CJ, West J. Bullous pemphigoid and pemphigus
Kardos M, Levine D, Gürcan HM, Ahmed RA. Pemphigus vulgaris – incidence and mortality in the UK: popula-
vulgaris in pregnancy: analysis of current data on the tion based cohort study. BMJ. 2008;337:a180.
management and outcomes. Obstet Gynecol Surv. Lara-Corrales I, Pope E. Autoimmune blistering diseases
2009;64(11):739–49. in children. Semin Cutan Med Surg. 2010;29(2):85–91.
Kartan S, Shi VY, Clark AK, Chan LS. Paraneoplastic Laskaris G, Sklavounou A, Stratigos J. Bullous
pemphigus and autoimmune blistering diseases associ- pemphigoid, cicatricial pemphigoid, and pemphigus
ated with neoplasm: characteristics, diagnosis, associ- vulgaris. A comparative clinical survey of 278 cases.
ated neoplasms, proposed pathogenesis, treatment. Am Oral Surg Oral Med Oral Pathol. 1982;54:656–62.
J Clin Dermatol. 2017;18(1):105–26. Le Roux-Villet C, Prost-Squarcioni C, Alexandre M,
Khullar G, De D, Narang T, Saikia UN, Handa S. Pemphi- Caux F, Pascal F, Doan S, et al. Rituximab for patients
gus vegetans localized to unusual sites. Indian J with refractory mucous membrane pemphigoid. Arch
Dermatol Venereol Leprol. 2015;81(5):509–11. Dermatol. 2011;147:843–9.
Kirtschig G, Murrell D, Wojnarowska F, Khumalo N. Léauté-Labrèze C, Lamireau T, Chawki D, Maleville J,
Interventions for mucous membrane pemphigoid and Taïeb A. Diagnosis, classification, and management of
epidermolysis bullosa acquisita. Cochrane Database erythema multiforme and Stevens-Johnson syndrome.
Syst Rev. 2003;(1):CD004056. Review Arch Dis Child. 2000;83(4):347–52.
Kokkonen N, Herukka SK, Huilaja L, Kokki M, Lee MS, Wakefield PE, Konzelman JL Jr, James WD. Oral
Koivisto AM, Hartikainen P, et al. Increased levels of insertable prosthetic device as an aid in treating oral
the bullous pemphigoid BP180 autoantibody are ulcers. Arch Dermatol. 1991;127(4):479–80.
Lever W. Pemphigus: a histopathologic study. Arch responses to desmogleins in Japanese patients with
Dermatol. 1951;64:727–53. pemphigus. Tissue Antigens. 1999b;54(4):333–40.
Lever W. Commentary on Brunsting LA, Perry HO. Mobini N, Nagarwalla N, Ahmed AR. Oral pemphigoid.
Benign pemphigoid? A report of seven cases with Subset of cicatricial pemphigoid? Oral Surg Oral Med
chronic, scarring, herpetiform plaques about the head Oral Pathol Oral Radiol Endod. 1998;85(1):37–43.
and neck. Arch Dermatol. 1957;75:489–501. Mondino BJ, Brown SI. Ocular cicatricial pemphigoid.
Li X, Qian H, Sogame R, et al. Integrin β4 is a major target Ophthalmology. 1981;88:95–100.
antigen in pure ocular mucous membrane pemphigoid. Mortazavi H, Khatami A, Seyedin Z, Vasheghani Farahani I,
European Journal of Dermatology. 2016;1;26(3): Daneshpazhooh M. Salivary desmoglein enzyme-linked
247–53. immunosorbent assay for diagnosis of pemphigus
Liakopoulou A, Rallis E. Bullous lichen planus – a review. vulgaris: a noninvasive alternative test to serum assess-
J Dermatol Case Rep. 2017;11(1):1–4. ment. Biomed Res Int. 2015;2015:698310.
Loiseau P, Lecleach L, Prost C, Lepage V, Busson M, Murakami H, Nishioka S, Setterfield J, Bhogal BS,
Bastuji-Garin S, Roujeau JC, Charron D. HLA class Black MM, et al. Analysis of antigens targeted by
II polymorphism contributes to specify desmoglein circulating IgG and IgA autoantibodies in 50 patients
derived peptides in pemphigus vulgaris and pemphigus with cicatricial pemphigoid. J Dermatol Sci. 1998;17:
foliaceus. J Autoimmun. 2000;15(1):67–73. 39–44.
Ludwig RJ. Clinical presentation, pathogenesis, diagnosis, Murrell DF, Dick S, Ahmed AR, et al. Consensus statement
and treatment of epidermolysis bullosa acquisita. ISRN on definitions of disease, end points and therapeutic
Dermatol. 2013;2013:812029. response for pemphigus. J Am Acad Dermatol.
Mahoney MG, Wang Z, Rothenberger K, Koch PJ, 2008;58:1043–6.
Amagai M, Stanley JR. Explanations for the clinical Murrell DF, et al. Definitions and outcome measures for
and microscopic localization of lesions in pemphigus mucous membrane pemphigoid (MMP): recommenda-
foliaceus and vulgaris. J Clin Investig. 1999;103(4): tions of a panel of experts. JAAD. 2015;72(1):168–74.
461–8. Nguyen VT, Ndoye A, Shultz LD, Pittelkow MR,
Maley A, Warren M, Haberman I, Swerlick R, Kharod- Grando SA. Antibodies against keratinocyte antigens
Dholakia B, Feldman R. Rituximab combined with other than desmogleins 1 and 3 can induce pemphigus
conventional therapy versus conventional therapy vulgaris-like lesions. J Clin Invest. 2000;106(12):
alone for the treatment of mucous membrane 1467–79.
pemphigoid (MMP). J Am Acad Dermatol. Nogueira PA, Carneiro S, Ramos-e-Silva M. Oral lichen
2016;74:835–40. planus: an update on its pathogenesis. Int J Dermatol.
Mansikka E, Hervonen K, Salmi TT, Kautiainen H, 2015;54:1005–10.
Kaukinen K, Collin P, Reunala T. The decreasing prev- Ohzono A, Sogame R, Li X, et al. Clinical and immuno-
alence of severe villous atrophy in dermatitis logical findings in 104 cases of paraneoplastic pemphi-
herpetiformis. A 45-year experience in 393 patients. gus. Br J Dermatol. 2015;173:1447.
J Clin Gastroenterol. 2017;51:235–9. Ormond M, McParland H, Donaldson ANA, Andiappan
Martin LK, Werth V, Villanueva E, et al. Interventions for M, Cook RJ, Escudier M, Hullah E, Higham J, McMil-
pemphigus vulgaris and pemphigus foliaceus. lan R, Taylor J, Shirlaw PJ, Challacombe SJ, Setterfield
Cochrane Database Syst Rev. 2009;(1):CD006263. JF. An Oral Disease Severity Score (ODSS) validated
McMillan R, Taylor J, Shephard M, Ahmed R, for use in oral pemphigus vulgaris. Br J Dermatol. 2018
Carrozzo M, Setterfield J, et al. World workshop on [Epub ahead of print].
oral medicine VI: a systematic review of the treatment Otten JV, Hashimoto T, Hertl M, Payne AS, Sitaru C.
of mucocutaneous pemphigus vulgaris. Oral Surg Oral Molecular diagnosis in autoimmune skin blistering
Med Oral Pathol Oral Radiol. 2015;120(2):132–42. conditions. Curr Mol Med. 2014;14:69–95.
Mehren CR, Gniadecki R. Epidermolysis bullosa Oyama N, Setterfield JF, Powell AM, Sakuma-Oyama Y,
acquisita: current diagnosis and therapy. Dermatol Albert S, Bhogal BS, Vaughan RW, Kaneko F,
Reports. 2011;3(3):e38. Challacombe SJ, Black MM. Bullous Pemphigoid anti-
Milinković MV, Janković S, Medenica L, Nikolić M, gen II (BP180) and its soluble extracellular domains are
Reljić V, Popadić S, Janković J. Incidence of autoim- major autoantigens in mucous membrane pemphigoid:
mune bullous diseases in Serbia: a 20-year retrospective the pathogenic relevance to HLA class II alleles and
study. J Dtsch Dermatol Ges. 2016;14(10):995–1005. disease severity. Br J Dermatol. 2006;154:90–8.
Miyagawa S, Amagai M, Iida T, Yamamoto Y, Park HJ, Young JK, Dong HK, Junho K, Park KH, Park J-W,
Nishikawa T, Shirai T. Late development of anti- Lee J-H. HLA allele frequencies in 5802 Koreans: varied
desmoglein 1 antibodies in pemphigus vulgaris: corre- allele types associated with SJS/TEN according to culprit
lation with disease progression. Br J Dermatol. drugs. Yonsei Med J. 2016;57(1):118–26.
1999a;141(6):1084–7. Proby CM, Ota T, Suzuki H, Koyasu S, Gamou S,
Miyagawa S, Amagai M, Niizeki H, Yamashina Y, Shimizu N, Wahl JK, Wheelock MJ, Nishikawa T,
Kaneshige T, Nishikawa T, Shirai T, Inoko H. Amagai M. Development of chimeric molecules for
HLA-DRB1 polymorphisms and autoimmune recognition and targeting of antigen-specific B cells in
pemphigus vulgaris. Br J Dermatol. 2000;142(2): Schmidt E, della Torre R, Borradori L. Clinical features
321–30. and practical diagnosis of bullous pemphigoid.
Ran NA, Payne AS. Rituximab therapy in pemphigus Dermatol Clin 2011;29:427–38
and other autoantibody-mediated diseases. F1000Res. Schmidt E, Spindler V, Eming R, Amagai M, Antonicelli F,
2017;6:83. et al. Meeting report of the pathogenesis of pemphigus
Reeves GMB, Lloyd M, Rajlawat BP, et al. Ocular and oral and pemphigoid meeting in Munich, September 2016.
grading of mucous membrane pemphigoid. Graefes J Invest Dermatol. 2017;137(6):1199–203.
Arch Clin Exp Ophthalmol. 2012;250:611–8. Scully C, Bagan J. Oral mucosal diseases: erythema multi-
Rogers RS 3rd. Dapsone and sulfapyridine therapy of forme. Br J Oral Maxillofac Surg. 2008;46(2):90–5.
pemphigoid diseases. Australas J Dermatol. Scully CS, Challacombe SJ. Pemphigus vulgaris: update
1986;27:58–63. on etiopathogenesis, oral manifestations, and manage-
Roopashree MR, Gondhalekar RV, Shashikanth MC, ment. Crit Rev Oral Biol Med. 2002;13:397–408.
George J, Thippeswamy SH, Shukla A. Pathogenesis Seishima M, Iwasaki-Bessho Y, Itoh Y, Nozawa Y,
of oral lichen planus–a review. J Oral Pathol Med. Amagai M, Kitajima Y. Phosphatidylcholine-specific
2010;39:729–34. phospholipase C, but not phospholipase D, is involved
Rötzer V, Hartlieb E, Vielmuth F, Gliem M, Spindler V, in pemphigus IgG-induced signal transduction. Arch
Waschke J. E-cadherin and Src associate with extra- Dermatol Res. 1999;291(11):606–13.
desmosomal Dsg3 and modulate desmosome assembly Setterfield J. Clinicopathological associations in mucous
and adhesion. Cell Mol Life Sci. 2015;72(24): membrane pemphigoid. MD thesis, University of
4885–97. London; 2009.
Roujeau JC, Charron D. HLA class II polymorphism con- Setterfield J, Challacombe SJ, Black MM. Oral mucosal
tributes to specify desmoglein derived peptides in pemphigoid. Br J Dermatol 1997;137:825.
pemphigus vulgaris and pemphigus foliaceus. J Auto- Setterfield J, Shirlaw PH, Kerr-Muir M, Bhogal BS, Mor-
immun. 2000;15:67–73. gan PR, Challacombe SJ, Tilling K, Black MM.
Sadik CD, Bischof J, van Beek N, Benoit S, Sárdy M, Mucous membrane pemphigoid: a dual circulating anti-
Worm M, Meller S, Gläser R, Zillikens D, Homey B, body response with IgG and IgA signifies a more
Setterfield J, Minassian D, Schmidt E, Dart J, MMP severe and persistent disease. Br. J Dermatol.
study group 2009–2014, Autoimmune Bullous Dis- 1998;138:602–10.
eases Study Group, Ibrahim SM. Genome-wide asso- Setterfield J, Shirlaw PJ, Bhogal BS, Tilling K,
ciation study identifies GALC as susceptibility gene for Challacombe SJ, Black MM. Cicatricial pemphigoid:
mucous membrane pemphigoid. Exp Dermatol. 2017. serial titres of circulating IgG and IgA antibasement
Saha M, Bhogal B, Black MM, Cooper D, Vaughan RW, membrane antibodies correlate with disease activity.
Groves RW. Prognostic factors in pemphigus Br J Dermatol. 1999a;140(4):645–50.
vulgaris and pemphigus foliaceus. Br J Dermatol. Setterfield J, Shirlaw PJ, Lazarova Z, Bryant BM, Bhogal
2014;170(1):116–22. BS, Harman K, Challacombe SJ, Black MM. Para-
Sajda T, Hazelton J, Patel M, Seiffert-Sinha K, Steinman L, neoplastic cicatricial pemphigoid. Br J Dermatol.
Robinson W, Haab BB, Sinha AA. Multiplexed auto- 1999b;141:127–31.
antigen microarrays identify HLA as a key driver of Setterfield JF, Black MM, Challacombe SJ. The manage-
anti-desmoglein and -non-desmoglein reactivities in ment of oral lichen planus. Clin Exp Dermatol.
pemphigus. Proc Natl Acad Sci USA. 2016;113(7): 2000;25:176–82.
1859–64. Setterfield J, Theron J, Welsh K, Vaughan R, Shirlaw P,
Saw VP, Dart JK, Rauz S, Ramsay A, Bunce C, Xing W, Wojnarowska F, Challacombe SJ, Black
Maddison PG, Phillips M. Immunosuppressive therapy MM. Mucous membrane pemphigoid: HLA
for ocular mucous membrane pemphigoid strategies DQB1*0301 allele is associated with all clinical
and outcomes. Ophthalmology. 2008;115:253–61. sites of involvement and may be linked to anti-
Schmidt A, Koch PJ. Desmosomes: just cell adhesion or is basement membrane IgG production. Br J Dermatol.
there more? Cell Adhes Migr. 2007;1(1):28–32. 2001;145:406–14.
Schmidt E. Rituximab as first-line treatment of pemphigus. Sharma VK, Khandpur S. Evaluation of cyclophospha-
Lancet. 2017;389(10083):1956–8. mide pulse therapy as an adjuvant to oral corticosteroid
Schmidt E, Zillikens D. Modern diagnosis of autoimmune in the management of pemphigus vulgaris. Clin Exp
blistering skin diseases. Autoimmun Rev. 2010;10:84–9. Dermatol. 2013;38:659–64.
Schmidt E, Zillikens D. Pemphigoid diseases. Lancet. Shirakata Y, Amagai M, Hanakawa Y, Nishikawa T,
2013;381:320–32. Hashimoto K. Lack of mucosal involvement in pem-
Schmidt E, Skrobek C, Kromminga A, Hashimoto T, phigus foliaceus may be due to low expression of
Messer G, Bröcker EB, Yancey KB, Zillikens D. Cic- desmoglein 1. J Invest Dermatol. 1998;110:76–8.
atricial pemphigoid: IgA and IgG autoantibodies target Shuttleworth D, Graham-Brown RA, Hutchinson PE,
epitopes on both intra- and extracellular domains of Jolliffe DS. Cicatricial pemphigoid in D-penicillamine
bullous pemphigoid antigen 180. Br J Dermatol. treated patients with rheumatoid arthritis–a report of
2001;145(5):778–83. three cases. Clin Exp Dermatol. 1985;10:392–7.
Singh D, Misra N, Agrawal S, Misra P. Angina bullosa Von Kries N. Cauistsche Mittheilungen aus der
haemorrhagica. BMJ Case Rep. 2013;2013: Augenklinik zu Halle: V. Essentielle Schrumpfung
bcr2012008505. der Conjunctiva. Arch Ophthalmol (Berlin).
Stephenson P, Lamey P-J, Scully C, et al. Angina bullosa 1878;24:157–8.
haemorrhagica: clinical and laboratory features Wang HH, Liu CW, Li YC, et al. Efficacy of rituximab for
in 30 patients. Oral Surg Oral Med Oral Pathol. pemphigus: a systematic review and meta-analysis of
1987;63(5):560–5. different regimens. Acta Derm Venereol. 2015;95(8):
Sultan AS, Villa A, Saavedra AP, Treister NS, Woo SB. 928–32.
Oral mucous membrane pemphigoid and pemphigus Wee J, Shirlaw PJ, Challacombe SJ, Setterfield JF. Efficacy
vulgaris-a retrospective two-center cohort study. Oral of mycophenolate mofetil in severe mucocutaneous
Dis. 2017;23(4):498–504. lichen planus: a retrospective review of 10 patients.
Sun Y, Chan RK, Tan SH, Ng PP. Detection and Br J Dermatol. 2012;167:36–43.
genotyping of human herpes simplex viruses in cuta- Wetter DA, Davis MD. Recurrent erythema multiforme:
neous lesions of erythema multiforme by nested PCR. clinical characteristics, etiologic associations, and treat-
J Med Virol. 2003;71(3):423–8. ment in a series of 48 patients at Mayo Clinic, 2000 to
Svecova D, Parnicka Z, Pastyrikova L, Urbancek S, 2007. J Am Acad Dermatol. 2010;62(1):45–53.
Luha J, Buc M. HLA DRB1* and DQB1* alleles are Wichmann J. Ideen zur Diagnostik: Beobachtenden
associated with disease severity in patients with pem- Aerzten Mitgetheilet. Hanover: Helwing; 1794.
phigus vulgaris. Int J Dermatol. 2015;54(2):168–73. Wieczorek M, Czernik A. Paraneoplastic pemphigus:
Syed S-H, Trinnaman B, Martin S, Major S, Hutchinson J, a short review. Clin Cosmet Investig Dermatol.
Magee AI. Molecular interactions between desmo- 2016;9:291–5.
somal cadherins. Biochem J. 2002;362(Pt 2):317–27. Williams HC, Wojnarowska F, Kirtschig G, Mason J, et al.
Tauber J, Melamed S, Foster CS. Glaucoma in patients And clinical trials network BLISTER study group.
with ocular cicatricial pemphigoid. Ophthalmology. Doxycycline versus prednisolone as an initial treatment
1989;96:33–7. strategy for bullous pemphigoid: a pragmatic,
Taylor J, McMillan R, Shephard M, Setterfield J, non-inferiority, randomised controlled trial. Lancet.
Ahmed R, et al. World workshop on oral medicine 2017;389(10079):1630–8.
VI: a systematic review of the treatment of mucous Wojnarowska F, Marsden RA, Bhogal B, Black MM.
membrane pemphigoid. Oral Surg Oral Med Oral Chronic bullous disease of childhood, childhood cica-
Pathol Oral Radiol. 2015;120(2):161–71. tricial pemphigoid, and linear IgA disease of adults.
Tchernev G, Orfanos CE. Antigen mimicry, epitope A comparative study demonstrating clinical and immu-
spreading and the pathogenesis of pemphigus. Tissue nopathologic overlap. J Am Acad Dermatol. 1988;19:
Antigens. 2006;68(4):280–6. Review. 792–805.
Thoma-Uszynski S, Uter W, Schwietzke S, Schuler G, Yong AA, Tey HL. Paraneoplastic pemphigus. Australas J
Borradori L, Hertl M. Autoreactive T and B cells from Dermatol. 2013;54(4):241–50. Review.
bullous pemphigoid (BP) patients recognize epitopes You C, Lamba N, Lasave AF, Ma L, Diaz MH, Foster CS.
clustered in distinct regions of BP180 and BP230. Rituximab in the treatment of ocular cicatricial
J Immunol. 2006;176(3):2015–23. pemphigoid: a retrospective cohort study. Graefes
Toto P, Feliciani C, Amerio P, Suzuki H, Wang B, Shivji Arch Clin Exp Ophthalmol. 2017;255(6):1221–8.
GM, Woodley D, Sauder DN. Immune modulation in Yunis JJ, Mobini N, Yunis EJ, Alper CA, Deulofeut R,
pemphigus vulgaris: role of CD28 and IL-10. Rodriguez A, Foster CS, Marcus-Bagley D, Good RA,
J Immunol. 2000;164(1):522–9. Ahmed AR. Common major histocompatibility com-
Taghipour K, et al. Autoimmune and other blistering dis- plex class II markers in clinical variants of cicatricial
eases. Medicine 2009;37(6):291–297. pemphigoid. Proc Natl Acad Sci USA. 1994;91:
Tyagi S, Bhol K, Natarajan K, et al. Ocular cicatricial 7747–51.
pemphigoid antigen: partial sequence and biochemical Zhou XJ, Sugerman PB, Savage NW, Walsh LJ,
characterization. Proc Natl Acad Sci USA Seymour GJ. Intra-epithelial CD8+ T cells and base-
1996;93:14714–19. ment membrane disruption in oral lichen planus. J Oral
Uzun S, Durdu M, Akman A, et al. Pemphigus in the Pathol Med. 2002;31:23–7.
Mediterranean region of Turkey: a study of 148 cases. Zillikens D, Wever S, Roth A, Weidenthaler-Barth B,
Int J Dermatol. 2006;45:523–8. Hashimoto T, Brocker EB. Incidence of autoimmune
Vodegel RM, Jonkman MF, Pas HH, de Jong MC. subepidermal blistering dermatoses in a region of Cen-
U-serrated immunodeposition pattern differentiates tral Germany. Arch Dermatol. 1995;131:957–8.
type VII collagen targeting bullous diseases from Zillikens D, Kawahara Y, Ishiko A, Shimizu H, Mayer J,
other subepidermal bullous autoimmune diseases. Br J Rank CV, Liu Z, Giudice GJ, Tran HH,
Dermatol. 2004;151(1):112–8. Marinkovich MP, Brocker EB, Hashimoto T. A novel
Vodo D, Sarig O, Geller S, Ben-Asher E, et al. Identifica- subepidermal blistering disease with autoantibodies
tion of a functional risk variant for pemphigus vulgaris to a 200-kDa antigen of the basement membrane
in the ST18 gene. PLoS Genet. 2016;12(5):e1006008. zone. J Invest Dermatol. 1996;106:1333–8.
Gingival Pathology
Anne Hegarty and Alison Rich
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1144
Gingival Lesions of Developmental/Genetic
Origin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1144
Hereditary Gingival Fibromatosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1144
Ligneous Gingivitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1146
Gingival Hamartoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1147
Reactive Gingival Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1148
Gingival Epulides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1148
Localized Juvenile Spongiotic Gingival
Hyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1149
Peripheral Giant Cell Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1149
Drug-Induced Gingival Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1152
Gingival Lesions of Infectious Origin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1153
Viral Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1153
Human Immunodeficiency Virus (HIV) Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1154
Immune-Mediated Gingival Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1155
Oral Lichen Planus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1155
Mucous Membrane Pemphigoid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1157
Linear IgA Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1158
Pemphigus Vulgaris . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1158
Orofacial Granulomatosis and Oral Crohn’s
Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1160
Granulomatosis with Polyangiitis (Wegener’s Granulomatosis) . . . . . . . . . . . . . . . . . . . . . . 1161
Pyostomatitis Vegetans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1161
Plasma Cell Gingivitis/Gingivostomatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1161
A. Hegarty
Oral Medicine, Sheffield Teaching Hospitals, Sheffield,
UK
e-mail: Anne.Hegarty@sth.nhs.uk
A. Rich (*)
The Department of Oral Diagnostic and Surgical Sciences,
University of Otago, Dunedin, Otago, New Zealand
e-mail: alison.rich@otago.ac.nz

https://doi.org/10.1007/978-3-319-72303-7_15
1144 A. Hegarty and A. Rich
Cysts, Potentially Neoplastic and Neoplastic Gingival Lesions . . . . . . . . . . . . . . . . . . . 1163

Odontogenic Cysts and Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1163
Leukoplakia and Erythroplakia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1164
Oral Squamous Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1166
Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1166
Other Primary Malignant Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1167
Metastases to the Gingiva . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1169
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1170
Abstract benign, malignant, and metastatic. This chapter out-

The normal anatomy and physiology of the peri- lines these conditions, describing them in terms of
odontium is well known to dentists and dental four categories related to their pathogenesis:
specialists, as are the effects on the periodontium Genetic, Reactive, Immunological, and Neoplastic.
of plaque-associated bacterial infections. How- Using this framework, and with careful consider-
ever, the gingivae may be involved in many other ation of both the clinical features and use of appro-
local and systemic conditions. The purpose of priate special tests, should enable the clinician to
this chapter is to describe some of the less com- make a timely and accurate diagnosis. Plaque-
mon pathological conditions that may affect one related gingival and periodontal conditions are cov-
or more of the components of the periodontium ered in more detail in separate chapters on
and to discuss how clinicians can ensure these ▶ “Odontogenic Bacterial Infections” and
lesions are diagnosed and managed in a timely ▶ “Odontogenic Pathology”. Given the wide spread
manner. of conditions affecting the gingival tissues, more
detailed exploration of conditions covered in this
Keywords chapter can also be found in separate chapters on
Gingival lesions · Periodontium · Periodontal ▶ “Oral Lichen Planus”, ▶ “White and Red Lesions
diseases and conditions · Non-plaque gingival of the Oral Mucosa”, ▶ “Oral Mucosal Malignan-
pathology · Immunological · Lichen planus · cies”, ▶ “Oral Ulcerative Lesions”, ▶ “Oral and
Infectious · Drug-induced · Leukoplakia · Maxillofacial Viral Infections”, and ▶ “Oral Vesic-
Erythroplakia · Neoplastic ular and Bullous Lesions” among others. Readers
are also directed to the 2017 new classification
Introduction scheme for periodontal and peri-implant diseases
and conditions for more detail (Caton et al. 2018).
A wide variety of lesions may arise from the oral
mucosa, fibrous connective tissue, bone, and
cementum of the periodontium. The most common Gingival Lesions of Developmental/
pathology is a result of bacterial infection and is very Genetic Origin
well known to dental practitioners and is covered in
other chapters of this text and detailed in the classi- Hereditary Gingival Fibromatosis
fication of periodontal diseases and conditions
(Table 1) (Armitage 1999), and which have recently Hereditary gingival fibromatosis is an uncommon
been updated (Caton et al. 2018). Rarer conditions, condition characterized by generalized extensive
however, also present as gingival pathology. The fibrous enlargement of the gingivae which have a
pathogenesis of these non-plaque-related lesions normal or slightly paler color and are firm to touch
and conditions comprises genetic, traumatic, immu- (Fig. 1). It is inherited, usually as an autosomal
nological, and neoplastic etiologies including dominant trait, and is associated with mutation of
Gingival Pathology 1145
Table 1 Classification of periodontal diseases and conditions (Armitage 1999)

I. Gingival diseases 3. Gingival diseases of fungal origin
A. Dental plaque-induced gingival diseasesa a. Candida-species infections
1. Gingivitis associated with dental plaque only 1. Generalized gingival candidosis
a. Without other local contributing factors b. Linear gingival erythema
b. With local contributing factors (see VIII A) c. Histoplasmosis
2. Gingival diseases modified by systemic factors d. Other
a. Associated with the endocrine system 4. Gingival lesions of genetic origin
1. Puberty-associated gingivitis a. Hereditary gingival fibromatosis
2. Menstrual cycle-associated gingivitis b. Other
3. Pregnancy associated 5. Gingival manifestations of systemic conditions
a. Gingivitis a. Mucocutaneous disorders
b. Pyogenic granuloma 1. Lichen planus
4. Diabetes mellitus-associated gingivitis 2. Pemphigoid
b. Associated with blood dyscrasias 3. Pemphigus vulgaris
1. Leukemia-associated gingivitis 4. Erythema multiforme
2. Other 5. Lupus erythematosus
3. Gingival diseases modified by medications 6. Drug-induced
a. Drug-influenced gingival diseases 7. Other
1. Drug-influenced gingival enlargements b. Allergic reactions
2. Drug-influenced gingivitis 1. Dental restorative materials
a. Oral contraceptive-associated gingivitis a. Mercury
b. Other b. Nickel
4. Gingival diseases modified by malnutrition c. Acrylic
a. Ascorbic acid-deficiency gingivitis d. Other
b. Other 2. Reactions attributable to
B. Non-plaque-induced gingival lesions a. Toothpastes/dentifrices
1. Gingival diseases of specific bacterial origin b. Mouthrinses/mouthwashes
a. Neisseria gonorrhea-associated lesions c. Chewing gum additives
b. Treponema pallidum-associated lesions 3. Other
c. Streptococcal species-associated lesions 6. Traumatic lesions (factitious, iatrogenic,
accidental)
d. Other a. Chemical injury
2. Gingival diseases of viral origin b. Physical injury
a. Herpesvirus infections c. Thermal injury
1. Primary herpetic gingivostomatitis 7. Foreign body reactions
2. Recurrent oral herpes 8. Not otherwise specified (NOS)
3. Varicella-zoster infections
b. Other
II. Chronic periodontitisb VII. Periodontitis associated with endodontic lesions
A. Localized A. Combined periodontic-endodontic lesions
B. Generalized VIII. Developmental or acquired deformities and
conditions
III. Aggressive periodontitisb A. Localized tooth-related factors that modify or
predispose to plaque-induced gingival diseases/
periodontitis
A. Localized 1. Tooth anatomic factors
B. Generalized 2. Dental restorations/appliances
IV. Periodontitis as a manifestation of systemic diseases 3. Root fractures
A. Associated with hematological disorders 4. Cervical root resorption and cemental tears
(continued)
Table 1 (continued)
1. Acquired neutropenia B. Mucogingival deformities and conditions
around teeth
2. Leukemias 1. Gingival/soft tissue recession
3. Other a. Facial or lingual surfaces
B. Associated with genetic disorders b. Interproximal (papillary)
1. Familial and cyclic neutropenia 2. Lack of keratinized gingiva
2. Down syndrome 3. Decreased vestibular
3. Leukocyte adhesion deficiency syndromes 4. Aberrant frenum/muscle position
4. Papillon-Lefèvre syndrome 5. Gingival excess
5. Chediak-Higashi syndrome a. Pseudopocket
6. Histiocytosis syndromes b. Inconsistent gingival margin
7. Glycogen storage disease c. Excessive gingival display
8. Infantile genetic agranulocytosis d. Gingival enlargement (see I.A.3 and I.B.4)
9. Cohen syndrome 6. Abnormal color
10. Ehlers-Danlos syndrome (Types IV and VIII) C. Mucogingival deformities and conditions on
edentulous ridges
11. Hypophosphatasia 1. Vertical and/or horizontal ridge deficiency
12. Other 2. Lack of gingiva/keratinized tissue
C. Not otherwise specified (NOS) 3. Gingival/soft tissue enlargement
V. Necrotizing periodontal diseases 4. Aberrant frenum/muscle position
A. Necrotizing ulcerative gingivitis (NUG) 5. Decreased vestibular depth
B. Necrotizing ulcerative periodontitis (NUP) 6. Abnormal color
VI. Abscesses of the periodontium D. Occlusal trauma
A. Gingival abscess 1. Primary occlusal trauma
B. Periodontal abscess 2. Secondary occlusal trauma
C. Pericoronal abscess

Readers are directed to the 2017 new classification scheme for periodontal and peri-implant diseases and conditions for
more detail (Caton et al. 2018)
a
Can occur on a periodontium with no attachment loss or on a periodontium with attachment loss that is not progressing
b
Can be further classified on the basis of extent and severity. As a general guide, extent can be characterized as Localized = 30%
of sites involved and Generalized = >30% of sites involved. Severity can be characterized on the basis of the amount of clinical
attachment loss (CAL) as follows: Slight = 1 or 2 mm CAL, Moderate = 3 or 4 mm CAL, and Severe = 5 mm CAL
(Hart et al. 2002; Poulopoulos et al. 2011). It may

be associated with hypertrichosis and/or sensori-
neural hearing loss (Hartsfield et al. 1985) with or
without learning disability and/or epilepsy (Witkop
1971). Care with oral hygiene may be all that is
required for treatment, but surgical reduction may
be necessary with recurrences to be expected.
Ligneous Gingivitis
Fig. 1 Generalized extensive fibrous enlargement of the
gingivae which may impede the eruption of teeth Ligneous gingivitis, also known as destructive
membranous periodontal disease or (erroneously)
the son-of-sevenless (SOS-1) gene which encodes a amyloidaceous gingival hyperplasia, is another
guanine-nucleotide exchange factor that is impor- rare disorder that should be included in the differ-
tant for Ras activation and hence activation of ential diagnoses for patients presenting with
various receptors relating to cell proliferation generalized or focal gingival enlargement in the
absence of the use of medications. Females are of patients have similar conjunctival lesions,
affected more frequently than males (F:M ratio known as ligneous (woody) conjunctivitis.
3:1), and while the initial cases were reported in These patients should be investigated to exclude
people of Turkish ethnicity, it is now clear there is an association with inherited type 1 plasminogen
a worldwide distribution (Sivolella et al. 2012). deficiency since hypoplasminogenemia is pre-
The gingival enlargement has a generalized nod- sent in a high proportion of cases (Schuster
ular appearance with surface ulceration which et al. 1997; Scully et al. 2007; Sivolella
may begin in childhood (Fig. 2). The soft tissue et al. 2012). In cases with or without hypo-
hyperplasia may be associated with significant plasminogenemia, surgical removal of the hyper-
alveolar bone loss and severe periodontal dis- plastic gingival tissue tends to be followed by
ease. Histological examination shows the depo- recurrence (Kurtulus et al. 2007; Sivolella et al.
sition of eosinophilic acellular material, 2012). Topical and/or systemic plasminogen sup-
demonstrated to be fibrin, in the connective tissue plementation has been attempted with variable
(Fig. 3). Amyloid is not present. A small number success (Sivolella et al. 2012).
Gingival Hamartoma
Odontogenic gingival epithelial hamartoma

(OGEH) is a rare benign hamartoma believed to
arise from epithelial remnants of the dental lamina
(rests of Serres) (Kitano et al. 1991). It usually
presents as an asymptomatic gingival lump in
adults, mostly females. Histologically OGEH
shows multiple islands and clusters of bland epi-
thelial cells surrounded by condensed fibrous con-
nective tissue, without significant hyalinization
typical of epithelial-mesenchymal inductive inter-
actions seen in odontogenic neoplasms (Fig. 4). It
Fig. 2 Irregular nodular gingival hyperplasia with super-
ficial ulceration and erythema in a patient being investi-
gated for ligneous gingivitis (destructive membranous
periodontal disease)
Fig. 4 Islands of bland epithelial cells within the fibrous

Fig. 3 Photomicrograph showing eosinophilic acellular connective tissue of an odontogenic gingival epithelial
Congo-red negative material, mostly fibrin, in the gingival hamartoma. These lesions usually present as an asymptom-
connective tissue (arrow) in ligneous gingivitis atic gingival lump
is a completely innocuous lesion but is an impor- of the gingival tissues to the use of some systemic
tant differential histological diagnosis for local- medications.
ized gingival lesions containing odontogenic
epithelium when a diagnosis of a peripheral odon-
togenic tumour is being considered (see below). Gingival Epulides
Gingival epulis refers to a lump on the gingiva and

Reactive Gingival Lesions includes angiogranuloma (also known as vascular
epulis or erroneously as pyogenic granuloma)
Acute physical trauma to the gingiva is common (Fig. 5), pregnancy epulis (Fig. 6) and fibrous
and is easily recognized by the patient and clini- epulis (sometimes known as peripheral fibroma
cian, although low-level chronic trauma may not despite the fact the lesion is traumatic in origin)
elicit a clear history. The first part of this section (Fig. 7). Angiogranuloma is a relatively common
will describe gingival reactions to various local tissue response to localized irritation or trauma
irritants. The second part will describe reactions often seen in the gingiva and presents as a
Fig. 5 Angiogranuloma presenting as a large gingival central incisors with a semi-lunar bone defect along the
palatal lump associated with the upper central incisor alveolar crest (c). (Images courtesy of Professor Camile
teeth (11 and 21) in a 35-year-old female (a) with extension Farah, Perth Oral Medicine & Dental Sleep Centre, Perth
to the labial aspect (b) causing separation of the upper WA, Australia)
Localized Juvenile Spongiotic Gingival

Hyperplasia
Localized juvenile spongiotic gingival hyperpla-

sia (LJSGH) is a painless solitary localized sessile
or pedunculated swelling of the attached gingivae
with a characteristic bright red color (Fig. 9a). It
bleeds easily and usually affects the maxillary
anterior labial gingivae in children and adoles-
cents. Histologically the lesion is covered by
nonkeratinized epithelium with elongated rete
ridges with pronounced edema of the stratum
Fig. 6 With pregnancy hormones circulating, vascular
epulides can become extensive. In this situation, the term spinosum and neutrophil exocytosis. Numerous
pregnancy epulis is often applied small dilated blood vessels and a mixed inflam-
matory cell infiltrate are conspicuous in the con-
nective tissue papilla (Fig. 9b). Sometimes the
localized swelling. It is a reactive inflammatory surface has a granular or papillary texture.
process filled with proliferating vascular chan- LJSGH is considered to be a reactive lesion, but
nels, immature fibroblastic connective tissue, it is not simply a response to plaque (Darling et al.
and scattered inflammatory cells. Pregnancy can 2007), and there is no convincing evidence to
predispose the patient to gingival hyperplasia and support a viral etiology (Argyris et al. 2015).
induce a large localized vascular lesion (preg- The histological features and pattern of cyto-
nancy epulis), particularly when oral hygiene is keratin expression in the epithelium of LJSGH
poor. A fibrous epulis, a localized hyperplastic are similar to that of junctional epithelium, rather
fibrous gingival mass formed as a response to than mature gingival epithelium, leading to the
chronic irritation, shows much less vascularity suggestion that these lesions might represent exte-
histolologically with more mature fibrous tissue riorized junctional epithelium from the gingival
and little inflammation. Mineralization within a sulcus (Chang et al. 2008; Allon et al. 2016). The
fibrous epulis is relatively common and, in these exposed junctional-type epithelium is then vulner-
cases, the surface is often ulcerated. There may be able to local irritants and the reactive LJSGH
dystrophic calcification or recognizable woven ensues. Localized surgical excision with careful
bone or cementum (Fig. 7c). These are known as scaling and root planning of the adjacent teeth is
mineralizing or ossifying fibrous epulides to the treatment of choice (Chang et al. 2008).
reflect their reactive nonneoplastic nature.
For all gingival epulides management involves
treating the cause and usually requires excisional Peripheral Giant Cell Lesions
biopsy as definitive treatment and to confirm
the diagnosis. The excision should extend to peri- Peripheral giant cell lesions (giant cell epulis) are
osteum, and the region should be thoroughly scaled relatively common and present as a red, bluish, or
and root planed (Fig. 8). This is usually curative, purple gingival mass, sometimes ulcerated. Ini-
but recurrences do occur. Although many of these tially they usually involve the buccal interdental
lesions can be excised without extensive periodon- papillae but they may extend lingually/palatally
tal surgery with adequate healing, occasionally and separate the adjacent teeth (Fig. 10a). They
coronally repositioned flaps are required to provide occur over a wide age range with a reasonably
adequate tissue coverage, healing, and esthetics. even gender distribution. Peripheral giant cell
For pregnancy epulis, treatment is best deferred lesions are considered to be derived from cells
until after parturition when the vascularity of the in the periosteum or periodontal ligament as a
lesion will regress. reactive response to local trauma (Lester et al.
Fig. 7 Fibrous epulis between the lower left canine and teeth (36 and 37), in a 14-year-old female. Histologically
first premolar teeth (33 and 34) (a). The surface mucosa this was shown to contain mineralized areas within the
is of the same color and texture as surrounding tissue. connective tissue similar to that shown in (c). (Images a
(b) shows another fibrous epulis, in this case involving and b courtesy of Professor Camile Farah, Queensland
the labial gingiva of the lower left first and second molar Oral Medicine & Pathology, Brisbane QLD, Australia)
2014). There have been reports of their develop- reports describing the immunohistochemical pro-
ment adjacent to dental implants (Hirshberg files of mononuclear cells and giant cells in
et al. 2003; Brown et al. 2015). Histological peripheral and central giant cell lesions in antici-
examination shows mononuclear cells and numer- pation of variation in expression reflecting differ-
ous multinucleated giant cells, thought to be of ences in behavior and response to treatment
osteoclastic origin, in vascular cellular connective modalities such as calcitonin, interferons, and
tissue (Fig. 10b). There have been numerous bone resorption inhibitors (Tobón-Arroyave
Fig. 8 Surgical removal and debridement of without raising a flap (b). Healing at 2 weeks
angiogranuloma. Angiogranuloma involving labial gingi- post-surgery (c). (Images courtesy of Professor Camile
val margin between upper left central and lateral incisor Farah, Queensland Oral Medicine & Pathology, Brisbane
teeth (21 and 22) (a). Lesion is excised completely down to QLD, Australia)
periosteum and periodontal tissues debrided thoroughly
Fig. 9 Clinical presentation of localized juvenile Medicine & Pathology, Brisbane QLD, Australia). The
spongiotic gingival hyperplasia involving the labial gin- small vessels in the superficial connective tissue are typi-
giva of the upper right first and second incisors and canine cally dilated and engorged in this condition, contributing to
teeth (11, 12, 13) in a 12-year-old female (a). (Image the clinical appearance (b)
courtesy of Professor Camile Farah, Queensland Oral
et al. 2005; Kujan et al. 2015; Martins et al. 2015). with peripheral extension. A peripheral giant cell
It is important that radiographs of the region are lesion should be treated in the same way as a
obtained since, while these lesions can cause fibrous epulis. Clinical review is recommended
minor resorption “cupping” of the adjacent corti- since recurrences do occur. The clinical and his-
cal bone, more extensive bony involvement indi- tological appearance of the “brown tumors” of
cates the presence of a central giant cell lesion hyperparathyroidism (Fig. 11) may be the same
Fig. 10 Peripheral giant cell granuloma of the gingiva Numerous multinucleate giant cells are present in vascular
between the lower left lateral incisor and canine (32 and immature fibrous connective tissue, typical of a giant cell
33) causing displacement of tooth 32 lingually. (a) The lesion (b). More mature fibrous tissue containing hemosid-
surface mucosa is erythematous and easily traumatized erin and a mild chronic inflammatory cell infiltrate is
(Image courtesy of Professor Camile Farah, Queensland present in the top right side of the photomicrograph
Oral Medicine & Pathology, Brisbane QLD, Australia).
as that of giant cell lesions and hence hyperpara- physician if possible, but regression of the gingival
thyroidism should be excluded for central giant hyperplasia is often slow. Surgical debulking may
cell lesions and for multiple or recurrent periph- assist but should not be performed until after the
eral lesions. The oral lesions in these cases may drug has been ceased for some months. If the drug
not need surgical intervention once the parathy- cannot be altered, gingival recontouring, either by
roid hormone levels are stabilized. conventional surgery or laser, may be helpful but is
likely to relapse. Despite a number of reports
recommending the use of topical or systemic
Drug-Induced Gingival Lesions folic acid supplementation, or azithromycin to
manage drug-induced gingival enlargement, there
One of the most troublesome drug-induced gingi- is currently insufficient evidence to confirm their
val lesions is gingival enlargement, which may value (Brown and Arany 2014).
be so marked as to interfere with mastication Drug-induced hyposalivation may be associated
and cause esthetic problems. Agents associated with increased susceptibility to cervical caries and
with gingival enlargement include phenytoin gingivitis/periodontitis due to prolonged adherence
(Fig. 12a), calcineurin inhibitors such as cyclo- of plaque at the tooth-gingival interface (Lam et al.
sporine (Fig. 12b) and tacrolimus, and calcium 2009). Drug-induced hyposalivation may be associ-
channel blockers (Fig. 12c) such as nifedipine, ated with many medications, particularly antide-
diltiazem, oxidipine, and amlodipine. A common pressants and diuretics. Mouth-breathing has been
link between these drugs is cation flux inhibition, associated with higher levels of plaque and gingival
leading to decreased uptake of folate by gingival inflammation (Wagaiyu and Ashley 1991).
fibroblasts and subsequent changes in matrix Drug-induced oral ulceration has been reported
metalloproteinase metabolism and lack of collage- with numerous medications (Scully and Bagan
nase activation. Thus, the excess collagen formed 2004) and, in more recent times, secondary to
in association with inflammatory gingivitis cannot nicorandil, a potassium channel activator used in
be degraded effectively (Brown et al. 1991; Brown the treatment of unstable angina (Yamamoto et al.
and Arany 2014). Careful attention to oral hygiene 2011). Although more common on the tongue,
remains an important treatment modality. The lesions may affect the gingivae and edentulous
putative drug should be withdrawn by the treating ridge mucosa (Fig. 13).
Fig. 11 Brown’s tumour of hyperparathyroidism pre- extending into the nasopalatine canal and into the overly-
senting as a gingival lump on the maxillary alveolus (a). ing gingiva on MDCT (b) and MRI (c). (Images courtesy
The lesion demonstrates a strongly enhancing soft tissue of Professor Camile Farah, Perth Oral Medicine & Dental
mass eroding bone within the right anterior maxilla Sleep Centre, Perth WA, Australia)
symptomatic, ensuring adequate hydration, while an

Gingival Lesions of Infectious Origin
antiviral agent such as acyclovir (also known as
aciclovir) may be necessary in immunocompro-
Viral Infections
mised hosts. Acyclovir is prescribed for primary
herpetic gingivostomatitis at a dose of 200 mg five
Herpes Simplex Infection
times daily for 5 days in adults and for a child,
Primary herpetic gingivostomatitis presents usually
1 month to 2 years old, half the adult dose is
in young children as a painful acute viral illness with
given. Potential adverse effects include nausea,
intraoral vesicles and erythematous, swollen gingiva
vomiting, rash and photosensitivity and very rarely
(Fig. 14). The generalized gingival involvement is a
hepatitis, acute renal failure, neurological reactions,
fairly constant and conspicuous clinical feature of
and hematological effects. Valaciclovir, a pro-drug
primary herpetic gingivostomatitis and may assist in
of acyclovir, may be used if there are adverse effects
distinguishing it from other viral infections that
to acyclovir or it is ineffective. A usual dose for
involve the oral mucosa such as herpangina and
adults is 500 mg twice daily for 5 days, and for
hand, foot and mouth disease. Treatment is usually
Fig. 12 Extensive gingival enlargement associated with and calcium channel blockers (c). (Image c courtesy of
the use of phenytoin (a). Other drugs capable of inducing Professor Camile Farah, Perth Oral Medicine & Dental
profound gingival enlargement include cyclosporine (b) Sleep Centre, Perth WA, Australia).
Fig. 13 An area of ulceration in the maxillary buccal Fig. 14 Pronounced gingival erythema with ulceration
sulcus associated with the use of the potassium channel around the gingival margins in a patient with primary
activator nicorandil herpetic gingivostomatitis
children consultation with pediatric medical special- immunocompromised patients (Mendieta et al.
ists is advised. Adverse reactions are similar to 2005; Jain et al. 2010).
those related to acyclovir but neurological reactions
are more likely with higher doses. Other herpesvi-
ruses, e.g., varicella-zoster rarely affects the gingiva, Human Immunodeficiency Virus (HIV)
but if gingival herpes zoster does occur, treatment Infection
should take into account the possibility of
post-zoster osteonecrosis, since alveolar bone Antiretroviral therapy (ART) has dramatically
necrosis and tooth exfoliation is a rare complication improved the management of patients infected
of intraoral herpes zoster infection, particularly in with human immunodeficiency virus and has
Fig. 15 Multiple gingival papillomas in a patient Fig. 16 Plaque-like lichen planus involving the posterior
with AIDS mandibular gingivae
reduced the incidence and severity of linear gingi- edema, the term “desquamative gingivitis” may
val erythema and necrotizing periodontitis as well be used (Fig. 17). This is a general term describing
as intraoral neoplasms associated with acquired a clinical situation and is not a diagnosis. Because
immunodeficiency syndrome (AIDS). Human pap- other conditions can have a similar clinical
illomaviruses may induce a number of lesions in appearance, biopsy is recommended to confirm
patients with HIV/AIDS including gingival papil- the diagnosis, but it is advisable to avoid a gingi-
lomas, warts, condyloma acuminatum, and focal val biopsy if there are other sites of involvement,
epithelial hyperplasia (Fig. 15). Carbon dioxide since the inflammatory infiltrate associated with
laser treatment may reduce the HPV-related lesions concomitant gingivitis may disrupt the typical
but the underlying immune impairment reduces its histological features of OLP (Fig. 18) leading to
effectiveness (Limeres Posse and Scully 2016). difficulties in obtaining a definite diagnosis. The
Malignant transformation in gingival papillary cause of OLP is not fully understood, but it is
lesions in HIV/AIDS is rare. It is interesting to thought to represent a T cell-mediated immune
note that the incidence of HPV-associated malig- response to an unknown trigger, whereby cyto-
nancies in other sites, specifically anus and cervix, toxic T-cells damage basal epithelial keratinocytes
has not declined since the introduction of ART, (Zhou et al. 2002), in a microenvironment where
indicating that ART confers little benefit in the there is an altered balance of immune regulatory
prevention and management of HPV-related cells and signalling pathways (Firth et al. 2015;
pathology (Palefsky 2017). Sinon et al. 2016). OLP is considered a potentially
malignant condition (Al-Hashimi et al. 2007), and
it is prudent that patients be reviewed at regular
Immune-Mediated Gingival Lesions intervals by an oral medicine specialist because of
an increased likelihood of oral squamous cell
Oral Lichen Planus carcinoma occurring in association with OLP,
particularly of the atrophic or ulcerative variety.
Oral lichen planus (OLP) can present as white, Treatment is aimed at relieving symptoms and is
red, and/or ulcerative lesions usually appearing usually provided to patients with painful, erosive,
bilaterally on the buccal mucosa, the lateral mar- and ulcerative forms of disease (Hegarty 2012;
gins of the tongue or the gingivae. White striated, Ryan et al. 2014). Maintenance of good oral
papular, or plaque-like forms (Fig. 16) are often hygiene and attention to routine dental care should
asymptomatic, but the atrophic and ulcerative be reinforced to patients. Due to the paucity of
forms may cause significant discomfort. When randomized controlled clinical trials to evaluate
OLP affects the gingivae and gives rise to gener- therapies, there is a lack of strong evidence
alized gingival erythema, desquamation, and supporting the effectiveness of any palliative
Fig. 17 Another manifestation of gingival lichen planus of gingival lichen planus manifesting as desquamative
is desquamative gingivitis. Usually there is buccal involve- gingivitis. Histological examination of representative tis-
ment but occasionally desquamative gingivitis may be the sue is necessary to confirm the diagnosis
only sign of oral lichen planus (a). (b) is another example
betamethasone sodium phosphate as a

mouthrinse, fluticasone propionate as spray,
mouth rinse, or cream, beclomethasone spray,
fluocinolone cream, and clobetasol ointment or
cream, or dexamethasone mouth rinse. As OLP
can present as desquamative gingivitis, improve-
ment and maintenance of oral hygiene should be a
priority in the management of this disease, but
pain may be a limiting factor to good oral hygiene
measures and therefore must be taken into account
when designing a preventive program for these
patients (Scattarella et al. 2011; Hegarty 2012).
Topical immunomodulators such as tacrolimus
and cyclosporine may be useful second line
therapies in recalcitrant OLP (Elad et al.
2010; Thongprasom et al. 2011). Systemic immu-
nosuppressants that have been used successfully
in the treatment of recalcitrant symptomatic OLP
include azathioprine, mycophenolate mofetil, and
systemic corticosteroids (Al-Hashimi et al. 2007;
Ryan et al. 2014). The use of laser therapy and
ultraviolet light phototherapy has been reported
Fig. 18 This photomicrograph shows the important diag- less frequently in the treatment of OLP with lim-
nostic features of basal cell damage with the ingress of ited effectiveness (Ryan et al. 2014). Topical aloe
lymphocytes into the basal layers of the epithelium. The
inflammatory infiltrate is confined to the superficial connec-
vera, topical pimecrolimus, and oral curcuminoids
tive tissue and is composed of lymphocytes and macrophages are the most promising of the new therapies
reported (Thongprasom et al. 2013). Other inter-
therapy for symptomatic OLP (Chan et al. 2000; esting modalities are topically applied thalido-
Zakrzewska et al. 2005). Topical corticoste- mide and amlexanox. Regular monitoring of
roids are still considered first line therapy patients with OLP is recommended due to the
(Thongprasom et al. 2011). Preparations include potentially malignant nature of the condition
Fig. 19 When mucous membrane pemphigoid involves brushing. Careful attention to oral hygiene in conjunction
the gingiva, the clinical appearance is frequently of with a dental hygienist is an important component of the
desquamative gingivitis (a, b). It is exacerbated by plaque, management plan
but the painful gingivae cause difficulty with tooth
although the optimum frequency of review

appointments is uncertain (Mattsson et al. 2002;
Ryan et al. 2014).
Mucous Membrane Pemphigoid
Mucous membrane pemphigoid (MMP) is a rare

chronic blistering autoimmune disease, where
autoantibodies are formed against components of
hemidesmosomes. Target antigens in MMP
include bullous pemphigoid antigen 1 (BP 230)
and 2 (BP180), and laminins (Chan et al. 2002)
with antibodies to human α6 integrin being iden-
tified as important in the pathogenesis of oral
MMP (Rashid et al. 2006). The condition com-
monly affects middle-aged and elderly females
and the usual presentation is oral mucosal vesi-
cle/bulla formation with or without gingival
involvement. Gingival involvement usually man-
ifests as painful erythema with desquamation
(Fig. 19), either spontaneously or following
Fig. 20 Biopsy from a perilesional area in mucous mem-
minor trauma such as tooth-brushing. Blood or brane pemphigoid shows separation of the entire epithe-
fluid-filled blisters may be seen. The diagnosis lium from the underlying connective tissue, with an intact
should be confirmed by biopsy for routine layer of basal keratinocytes on the epithelial aspect of the
split
microscopic evaluation and immunofluorescence
where possible, understanding that a biopsy of an
already ulcerated region is likely to provide a (Fig. 20). Perilesional and lesions early in their
nonspecific result and the typical subepithelial evolution will show linear deposition of IgG
split, with intact basal keratinocytes remaining and/or C3 in the basement membrane zone
on the epithelial surface, will not be seen (Fig. 21). Because of potential ocular involvement,
Fig. 21 Part of a biopsy from a perilesional region may

also be used for direct immunofluorescence or, as in this Fig. 22 Some forms of mucous membrane pemphigoid
photomicrograph, immunohistochemistry, where a linear induce conjunctival scarring (ocular cicatricial
deposit of IgG and/or C3 may be observed in the basement pemphigoid), which, if untreated, can lead to blindness
membrane zone
as shown in Fig. 22, an ophthalmological exami- 2005). Tetracyclines which have anti-inflammatory
nation should be organized given the risk for blind- and immunosuppressive activity and nicotinamide
ness. Treatment of MMP may be difficult due to the have also been used successfully in managing oral
complexity of the disease, diversity of pathogenic MMP (Chan et al. 2002; Bagan et al. 2005). Sys-
pathways seen, and the lack of large scale, well- temic corticosteroids either alone or combined with
controlled studies regarding therapy for MMP other systemic therapy are effective in achieving
(Chan et al. 2002; Di Zenzo et al. 2014; Taylor rapid control of severe disease; however, the
et al. 2015). Patients with oral disease including adverse effects tend to limit their long-term use
involvement of the gingivae can often be managed (Bagan et al. 2005; Taylor et al. 2015).
with local therapies, namely, topical corticosteroids
and calcineurin inhibitors (Taylor et al. 2015). With
gingival involvement, avoidance of trauma and Linear IgA Disease
improvement of oral hygiene should be part of
the management regime (Bagan et al. 2005). For Linear IgA disease is a rare chronic, subepithelial
gingival lesions application of topical therapy in a blistering disease that is associated with the pres-
vacuum-formed custom tray may be more effective ence of linear deposits of IgA along the basement
(Bagan et al. 2005). The choice of medication use membrane zone. Oral mucosal lesions may occur
in the treatment of MMP depends on the site, similarly to oral MMP with gingival involvement
severity, and rapidity of progression. If gingival rarely seen (Fig. 23). Management is similar to
MMP is recalcitrant to local measures and that of MMP but should include exclusion of
topical therapies, systemic immunosuppressants inflammatory bowel disease (IBD), because of
and immunomodulators may be required. Azathio- its occasional association with linear IgA disease
prine, mycophenolate mofetil, methotrexate, cyclo- (Shipman et al. 2012).
sporine, and cyclophosphamide have been used in
the management of severe disease to reduce inflam-
mation, and biological agents such as rituximab are Pemphigus Vulgaris
used to reduce autoantibody production (Taylor
et al. 2015). Dapsone and other sulphonamides Pemphigus vulgaris (PV) is a rare but important
which suppress neutrophil adherence modulate autoimmune disease, which frequently first occurs
severe vesiculobullous disease (Bagan et al. intraorally. Gingival involvement may be in the
form of mild erythema, desquamative gingivitis, (Fig. 25) and with direct immunofluorescence, a
and/or ulceration (Fig. 24). Antibodies are formed rim of IgG may be seen around the suprabasal
against cell adhesion molecules, particularly cells (Fig. 26). Early diagnosis of oral lesions
desmoglein 3 in the case of oral mucosal disease, and hence early initiation of appropriate therapy
leading to progressive bulla formation and subse- appears to minimize the chance of later severe
quent ulceration and desquamation. A biopsy is cutaneous disease in some instances, in part by
mandatory to confirm the diagnosis prior to the reducing the likelihood of epitope spread and
institution of systemic and topical immunosup- introduction of antibodies to desmoglein 1 (Endo
pressive therapy, but care should be taken with et al. 2008). Treatment usually involves use of
obtaining an adequate specimen since the tissue is systemic immunosuppressants and benefits
fragile and the epithelium can easily be lost. A have been reported from use of systemic cortico-
perilesional site, not directly involving the gingi- steroids, azathioprine, mycophenolate mofetil,
vae, should be chosen if possible. Histology will plasmapheresis, intravenous immunoglobulins,
show an intraepithelial split with acantholysis methotrexate, and the monoclonal antibody to
CD20 on B cells, rituximab (Black et al. 2005;
McMillan et al. 2015; Cholera and Chainani-Wu
2016). There is still a lack of evidence from good
quality clinical studies regarding best interven-
tions for PV (McMillan et al. 2015; Cholera and
Chainani-Wu 2016). The response to treatment
varies and the incidence of remissions in pemphi-
gus is unclear (Black et al. 2005). If there is
gingival involvement, local measures must be
included in the management plan and attention
to improving and maintaining good oral hygiene
and minimizing irritation is essential along with
the adjuvant use of topical immunosuppressive
Fig. 23 The clinical presentation of linear IgA disease, as therapies in the form of corticosteroids and/or
seen in this clinical photograph, may involve the gingivae
calcineurin inhibitors (Black et al. 2005).
in a similar manner to mucous membrane pemphigoid
Fig. 24 The oral manifestations of pemphigus vulgaris effective treatment is instigated. As noted in relation to
may be relatively localized in the early stages of the mucous membrane pemphigoid, careful control of oral
disease, as in (a), but are very likely to become more hygiene is very important and may reduce the amount of
widespread (b) with extensive oral mucosal involvement topical and/or systemic medication required for disease
and involvement of other mucosae and skin unless control
Orofacial Granulomatosis and Oral

Crohn’s Disease
Orofacial granulomatosis (OFG) is a term used to

describe a group of conditions with a clinical
presentation of diffuse swelling of the lower half
of the face, particularly the lips, hyperplastic
mucosal tags in the buccal mucosa, and diffuse
gingival enlargement and/or erythema (Fig. 27).
Biopsy shows non-caseating granulomata. A pro-
portion of these patients have underlying Crohn’s
Fig. 25 The histological features of intraoral pemphigus disease or sarcoidosis. While the oral lesions may
vulgaris include intraepithelial clefting with acantholysis, pre-date gastrointestinal Crohn’s disease where
leaving one to three layers of keratinocytes on the base- investigations have ruled out Crohn’s disease or
ment membrane
sarcoidosis, a search for an allergic etiology, par-
ticularly to cinnamonaldehyde and benzoates,
should be undertaken. Management of OFG
and oral Crohn’s disease is challenging. Topical
and systemic immunosuppressants including
intralesional injections of triamcinolone have
been used successfully but many patients require
systemic interventions to achieve partial or com-
plete remission of signs and symptoms. Topical
corticosteroids and tacrolimus have been reported
to be beneficial, and systemic therapies include
systemic corticosteroids, azathioprine, thalido-
mide, methotrexate, and in recalcitrant cases bio-
logic agents such as infliximab and adamilumab
Fig. 26 Direct immunofluorescence in pemphigus (monoclonal antibodies against TNF-alpha) have
vulgaris shows intercellular binding of IgG been used (Hegarty et al. 2003; Kolho et al. 2011;
Zbar et al. 2012; O’Neill and Scully 2012).
Fig. 27 Friable erythematous maxillary gingival tissues swelling of the upper and lower lips in a 4-year-old male
extending to involve the attached mucosa in a 33-year-old with orofacial granulomatosis. (Images courtesy of Profes-
male with biopsy proven Crohn’s disease (a). (b) shows sor Camile Farah, Queensland Oral Medicine & Pathology,
hyperplastic inflamed mandibular labial gingiva with Brisbane QLD, Australia)
A cinnamon and benzoate-free diet has been Pyostomatitis Vegetans

reported to be beneficial and plays a role in man-
agement of OFG (Campbell et al. 2011). Gingival Pyostomatitis vegetans (PyoV) is a rare oral disor-
erythema and enlargement can be managed addi- der that may affect the gingivae and is associated
tionally by attention to oral hygiene and dental with Inflammatory Bowel Disease (IBD), in par-
scaling and debridement. If gingival enlargement ticular ulcerative colitis (Hegarty et al. 2004). It is
persists following treatment of the condition, then considered a specific marker of disease activity in
surgical intervention may be appropriate in some ulcerative colitis (Lankarani et al. 2013). The term
cases (Bansal et al. 2015). Pyostomatitis vegetans was first introduced by
McCarthy in 1949 and considered the oral coun-
terpart of pyoderma vegetans and since then more
Granulomatosis with Polyangiitis than 50 cases have been reported (Hegarty et al.
(Wegener’s Granulomatosis) 2004; Clark et al. 2016). Males are affected two to
three times more often than females with an aver-
Granulomatosis with polyangiitis (GPA), previ- age age at presentation of 34 years (Lankarani et al.
ously known as Wegener’s granulomatosis, is a 2013). Bowel disease may precede the onset of
severe systemic vasculitis affecting medium and oral lesions by months or years. The condition
small arteries (Falk et al. 2011; Wojciechowska presents as erythematous, thickened oral mucosa
et al. 2016). It is characterized by necrotizing with multiple pustules and superficial erosions and
granulomatous inflammation of the upper and may involve the gingivae (Fig. 29), labial and
lower respiratory tract with glomerulonephritis, buccal mucosae, and palate. As vegetating lesions
although many systems may be involved. progress, the mucosa may develop thickened folds
Approximately one third of patients with GPA particularly in the labial and buccal mucosa
will have oral involvement, which, in a small (Hegarty et al. 2004). Immunological and micro-
number of cases, can first manifest in the oral bial factors have been suggested as possible etio-
mucosa (Almouhawis et al. 2013). The gingivae logical factors (Femiano et al. 2009). Skin lesions
are the usual site of oral involvement, with the of pyoderma vegetans may appear at the same time
development of a characteristic reddish purple as oral lesions, and liver dysfunction has also been
granular hyperplasia, known as “strawberry gin- reported in association with PyoV (Hegarty et al.
givitis” (Fig. 28) (Cohen and Meltzer 1981; 2004). Histopathologically, PyoV is characterized
Almouhawis et al. 2013). Diagnosis in clinical by intraepithelial and/or subepithelial abscesses
practice is based on a combination of the clinical containing large numbers of eosinophils
manifestations suggestive of a vasculitis, a (Fig. 30). Peripheral eosinophilia is seen in up to
biopsy of the affected organ showing necrotizing 90% of cases (Lankarani et al. 2013; Wu et al.
granulomatous inflammation with vasculitis 2015). Topical and systemic corticosteroids are
and the presence in serum of anti-neutrophil the mainstay of treatment but medical and/or sur-
cytoplasmic antibodies (ANCA) (Lutalo and gical treatment of any coexisting bowel disease
D’Cruz 2014; Wojciechowska et al. 2016). may be effective in controlling oral lesions
The particular pattern of ANCA in GPA is (Hegarty et al. 2004; Femiano et al. 2009;
cytoplasmic (c-ANCA), where the antibody Lankarani et al. 2013).
binds to proteinase 3 (Relle et al. 2016). Immu-
nosuppression with corticosteroids and cyclo-
phosphamide is used to induce remission with Plasma Cell Gingivitis/
azathioprine and methotrexate for remission Gingivostomatitis
maintenance. Rituximab (monoclonal antibody
against CD20) is used for severe GPA (Relle Plasma cell gingivitis is a rare condition which
et al. 2016). presents as diffuse or more localized erythema and
Fig. 28 Granulomatosis with polyangiitis presenting as histopathological specimen demonstrating widespread

friable erythematous gingiva in a 63-year-old female on nonspecific inflammatory infiltrate with extravasated red
initial presentation (a), post-systemic prednisolone therapy blood cells (d). (Images courtesy of Professor Camile
(b), and post-systemic methotrexate and cyclophospha- Farah, Perth Oral Medicine & Dental Sleep Centre, Perth
mide therapy (c). Hematoxylin and eosin stained WA, Australia)
swelling of the gingiva (Fig. 31) characterized plasmacytosis are more appropriate (Tong et al.
by infiltration of polyclonal plasma cells into 2008; Madhavarajan and Tighe 2015). The etiol-
the subepithelial gingival tissues (Fig. 32). ogy is uncertain but thought to represent an immu-
Occasionally the plasma cell proliferation may nological reaction to an allergen (Joshi and Shukla
extend beyond the gingiva in which case the 2015) such as components of toothpastes and tooth
terms plasma cell gingivostomatitis, orofacial powders, chewing gum, and certain foods. Treat-
plasmacytosis, or oropharyngeal mucosal ment is with topical and/or systemic
Fig. 29 Erythema of the gingivae with small irregular Fig. 31 The typical features of gingival erythema and swell-
ulcers and superficial necrosis in pyostomatitis vegetans ing are seen in this clinical photograph of plasma cell gingivos-
tomatitis (Image courtesy of Professor Camile Farah,
Queensland Oral Medicine & Pathology, Brisbane QLD,
Australia)
Fig. 30 The histological features of pyostomatitis vegetans

include both epithelial hyperplasia and ulceration with char-
acteristic microabscesses containing eosinophils and neutro- Fig. 32 Photomicrograph showing the intense plasma cell
phils at the tips of the connective tissue papillae and within infiltrate seen in the connective tissue in plasma cell
the epithelium, as shown in the photomicrograph gingivostomatitis
immunosuppression, in addition to identification of adult (Fig. 33). These occur most often as an
offending agent and its exclusion where possible. asymptomatic elevated dome-like lesion in the
mandibular canine and premolar gingivae, with-
out underlying bony involvement. The histology
Cysts, Potentially Neoplastic shows a cyst with a thin epithelial lining, usually
and Neoplastic Gingival Lesions with focal epithelial thickenings known as
plaques. Excision is curative.
Odontogenic Cysts and Neoplasms Peripheral ameloblastoma (PA), also known
as extraosseous ameloblastoma is a type of
Cysts and neoplasms peculiar to the odontogenic ameloblastoma that occurs exclusively in the soft
tissues may present with gingival involvement tissues of the gingiva or edentulous alveolar areas,
when they arise in an intrabony site and expand showing microscopic features of ameloblastoma
or erode the cortical plate. Less commonly these and without bone involvement (Vered et al.
lesions can arise within the soft tissues of the 2017). It has a predilection for the lingual
gingival complex such as the gingival cyst of the gingiva in the premolar region of the mandible
Fig. 33 A raised dome-

shaped lump involving the
attached mucosa between
the upper right first and
second incisor teeth (11 and
12) (a). Surgical removal of
the lump reveals exposed
root of tooth 12 (b).
Histologically the lesion
demonstrates a cyst with a
thin epithelial lining
consistent with a gingival
cyst of the adult (c). (Images
Camile Farah, Perth Oral
Medicine & Dental Sleep
Centre, Perth WA,
Australia)
(Philipsen et al. 2001). PA can mimic nonspecific cementoblastoma and cemento-ossifying fibroma,
ulceration and/or pyogenic granuloma/ as well as non-neoplastic bone lesions such as
angiogranuloma clinically (Fig. 34a). It shares fibrous dysplasia and the osseous dysplasias, may
similar histological features with intraosseous also present as a diffuse swelling of the alveolar
ameloblastomas and retains an unencapsulated bone. These lesions are covered in more detail in
and infiltrative histopathological growth pattern separate chapters on ▶ “Odontogenic Pathology”
(Fig. 34b). However, the recurrence rate is and ▶ “Non-odontogenic Bone Pathology”.
lower, and PA is generally regarded to be less
aggressive than intrabony ameloblastomas.
Other benign odontogenic tumours such as cal- Leukoplakia and Erythroplakia
cifying epithelial odontogenic tumour and
adenomatoid odontogenic tumour very rarely Oral potentially malignant lesions of the gingiva
have peripheral counterparts in the absence include leukoplakia, erythroleukoplakia, and
of an intrabony component. Benign cementum- erythroplakia. Homogeneous and non-
producing neoplasms such as benign homogeneous leukoplakia may develop on the
Fig. 34 Biopsy proven peripheral ameloblastoma pre- ameloblastoma in direct continuity with surface epithelium
senting as a gingival lump on the lingual aspect of the (b). (Images courtesy of Professor Camile Farah, Perth
lower left second premolar suggestive of an Oral Medicine & Dental Sleep Centre, Perth WA,
angiogranuloma (a). Hematoxylin and eosin stained Australia)
histopathological specimen demonstrates islands of
Fig. 35 Diffuse leukoplakia involving the maxillary alve- Fig. 36 Erythroplakia is relatively uncommon but is a
olar mucosa and the labial mucosa lesion with a high malignant potential. The clinical photo-
graph shows an erythroplakia involving the maxillary
gingivae
gingiva (Fig. 35) and are considered to be at risk adherent lesions which frequently involve the gin-
of malignant transformation. Less commonly, giva (Fig. 37), in addition to the palate and buccal
erythroplakia may be diagnosed which has a mucosa (Bagan et al. 2003; Gondalfo et al. 2009).
higher malignant potential than leukoplakia The diagnosis can only be made retrospectively
(Fig. 36). Biopsy is necessary to establish the and the underlying etiopathogenesis is poorly
degree of epithelial dysplasia (Warnakulasuriya understood. PVL requires close monitoring, and
et al. 2011). Proliferative verrucous leukoplakia adequate management is difficult. There is some
(PVL) is a rare form of leukoplakia which pro- evidence to suggest carcinoma arising in PVL
gresses, often over many years, from a single have a better prognosis than other intraoral carci-
localized homogeneous leukoplakia to multiple nomas (Akrish et al. 2015). Oral potentially
widespread nonhomogeneous verrucous leuko- malignant lesions are covered in more detail in
plakic lesions with a high rate of change to separate chapters on ▶ “White and Red Lesions
verrucous and/or squamous cell carcinoma. It is of the Oral Mucosa” and ▶ “Oral Mucosal
characterized by extensive and multifocal white Malignancies”.
Oral Squamous Cell Carcinoma and alcohol use, although the gingivae are a rela-
tively frequent site of carcinoma in elderly
Over 90% of oral cancers are squamous cell car- females who have never smoked or drank alcohol
cinomas and the gingivae or edentulous alveolar (Dahlstrom et al. 2008). Any lesion on the gingi-
mucosa are sites that may be involved. Oral squa- vae which does not show significant resolution
mous cell carcinoma (OSCC) may present as a following elimination of possible causes should
persistent nonhealing ulcer (Fig. 38a), a persistent be biopsied within 3 weeks. A degree of urgency
white, red, or mixed white and red patch or an in management is advisable, because, while early
exophytic mass (Fig. 38b). Patients may be gingival SCC can usually be treated successfully
asymptomatic or present with pain, bleeding, by local surgery, the proximity of the gingival soft
altered sensation, difficulty eating, speaking, tissues to alveolar bone can lead to early bone
swallowing and/or cervical lymphadenopathy. involvement. Invasion of the underlying bone,
OSCC, including gingival SCC, is seen most particularly invasion of the mandibular canal, pre-
frequently in patients with a history of tobacco sents a difficult surgical problem and poor 5-year
survival (Okura et al. 2016).
Lymphoma
Lymphoma is a term used to describe a heteroge-

neous group of malignant disorders derived from
lymphoid cells and their precursors. Extranodal
Hodgkin’s lymphoma is uncommon and most pri-
mary oral lymphomas are B-cell non-Hodgkin’s
lymphoma (NHL), particularly diffuse large B cell
NHL (Iguchi et al. 2012; Silva et al. 2016).
Lymphoma is the second most common intraoral
Fig. 37 Proliferative verrucous leukoplakia is a term used malignancy after SCC (Epstein et al. 2001).
to describe leukoplakias that progress from being solitary Waldeyer’s ring is the most frequent oropharyn-
with a relatively homogeneous surface to a verrucous sur-
face, as shown in this Figure and then to verrucous and/or
geal site involved, but gingival lesions occur in
squamous cell carcinoma. There are no particular clinical otherwise healthy people (Fig. 39a, b), as well as
or histological features that are specific to this condition; it in those with immunodeficiencies. A study of
is a diagnosis that is made retrospectively 68 extranodal B cell NHL in the head and neck
Fig. 38 Persistent gingival ulcer which histologically was teeth. Gingival squamous cell carcinomas can present in a
found to be a squamous cell carcinoma (a). Note the variety of forms including as an erythematous somewhat
leukoplakia around the gingival margin of the adjacent exophytic lesion as shown in (b)
Fig. 39 Intraoral
lymphomas may be part of
disseminated disease, but
the first indication of
lymphoma may be
presentation with a painless
soft tissue swelling
involving the gingivae, as
shown in a, b, or posterior
hard palate
Fig. 40 (a) is a photomicrograph from an incisional which were CD3 positive (b). The diagnosis was diffuse
biopsy of a gingival mass in a 63-year-old female and large B-cell lymphoma
shows a dense infiltrate of neoplastic lymphoid cells
reported that 30 were intraoral; and the most fre- Other Primary Malignant Neoplasms
quent intraoral location was the gingiva (Bagan
et al. 2015). Gingival NHL may be associated Rarely other primary oral malignant neoplasms
with alveolar bone loss, edema, and pain mimick- may involve the gingivae. Oral malignant mela-
ing dental periapical and/or periodontal infec- noma usually presents as a pigmented lesion on
tions, leading to a delay in diagnosis (Spatafore the gingivae or palate (Fig. 41a). It is an aggres-
et al. 1989; Jessri et al. 2013). The conventional sive neoplasm derived from malignant transfor-
histopathology findings need to be interpreted mation of oral mucosal melanocytes. Early in its
along with immunohistochemistry with a panel evolution, it is likely to be a dark brown to black
of appropriate antibodies and molecular investi- irregular macule which progresses to a raised
gations for various translocations (Fig. 40a, b). nodule with ulceration and soon involves the
Prognosis is grade-dependent and ranges from underlying alveolar bone (Fig. 41b, c). An obser-
sustained long-term survival to a 5-year mortality vational study of 46 new cases involving intraoral
rate of around 60%. Hematologists are the pri- malignant melanoma emphasized their clinical
mary specialists involved in provision of treat- and histological diversity. The greater majority
ment for lymphoma. of these were found in the maxillary mucosa
Fig. 41 Malignant
melanoma, confirmed
histologically from an
incisional biopsy, involving
the maxillary labial
gingivae, with margins
marked for excision (a) and
corresponding surgical
resection specimen (b). The
photomicrograph shows
sheets of malignant
melanocytes with bone
involvement (c)
with clinicians’ impressions of these varying from brown, or purple macules and/or swellings
benign fibrous growths to high grade malignan- which may affect the gingivae (Fig. 43). Kaposi
cies. The histopathological features also varied sarcoma-associated herpesvirus (KSHV) is neces-
widely among cases, with two cell types pre- sary for the development of KS which usually
dominating, namely, epithelioid cells and spindle occurs in a setting of immunosuppression
cells, often in combination. Only 53.1% demon- (Chang et al. 1994; Dittmer and Damania 2016).
strated melanin pigmentation (Housley Smith This virus also causes other diseases in AIDS
et al. 2016). patients, including multicentric Castleman’s dis-
Leukemia, a group of malignancies of hemo- ease, a B cell lymphoproliferative disorder, and
poietic stem cells, may occasionally manifest as specific lymphomas (Goncalves et al. 2017). Most
diffuse gingival swelling when leukaemic cells primary KSHV infections are asymptomatic. The
infiltrate the gingival soft tissues (Fig. 42a, b). virus infects endothelial cells, epithelial cells, B
As the normal hemopoietic stem cells in the cells, monocytes and dendritic cells where it
bone marrow are displaced by malignant cells, becomes latent, but it can be reactivated and
the oral mucosa, including the gingivae, may induced to replicate in certain circumstances in
show evidence of neutropenia with increased sus- response to severe T cell depletion or inactivation
ceptibility to infection and ulceration and throm- (Dittmer and Damania 2016; Goncalves et al.
bocytopenia with petechial hemorrhages and a 2017). The diagnosis is made by demonstrating
tendency to spontaneous or prolonged bleeding. KSHV in lesional spindle cells in a biopsy sample.
Kaposi sarcoma (KS), an AIDS defining While the incidence and mortality from Kaposi
malignancy, may present as oral mucosal red, sarcoma has dropped significantly since the use of
Fig. 42 Widespread gingival hyperplasia involving the periodontal disease complicated by chronic leukemic infil-
maxillary and mandibular labial (a) and mandibular lingual trates. (Images courtesy of Dr Marie Matias, Western Peri-
(b) gingiva in a 48-year-old female patient with chronic odontics, Perth WA, Australia)
circulating tumor cells to thrive (Allon et al. 2014;

Hirshberg et al. 2014). The most common clinical
presentation of a gingival metastasis is a painful
swelling, with or without surface ulceration, which
rapidly increases in size. If bone is involved and the
lesion is located in the vicinity of the inferior alve-
olar nerve, labial paresthesia or anesthesia may
develop. In these instances, radiographs are likely
to show radiolucency with poorly defined margins.
Fig. 43 Prior to effective antiretroviral treatment innova- In males, the most common primary sites that
tions, intraoral Kaposi sarcoma was a relatively frequent
oral manifestation of AIDS, usually involving the gingivae metastasize to the oral region are lung, kidney,
or palate liver, and prostate, and in females, metastases are
most likely to be from breast, female genital organs,
ART, it remains the most common AIDS- kidney, and colorectum (Hirshberg et al. 2014).
associated malignancy in both developed and
developing nations (Wen and Damania 2010).
Metastases to the Gingiva Gingival lesions may be of a simple local nature or

may be an indication of severe local or systemic
Metastases to the oral regions are rare and are disease. Recognizing the signs and/or symptoms of
usually associated with widespread metastatic dis- gingival pathology will ensure prompt and appro-
ease. Bony metastases are the most likely, particu- priate management for the patient. Careful clinical
larly to the mandible, but soft tissue metastases do observation will continue to be critical to the devel-
occur, and in these instances the gingival mucosa is opment of a clinical diagnosis for gingival pathol-
the most common oral mucosal site involved ogy. However diagnostic techniques are changing.
(Allon et al. 2014). An association has been noted Biopsy of a lesion for conventional histopathology
between gingival metastases and the presence of remains the gold standard for most diagnoses, but
teeth, leading to the suggestion that cytokines this is often interpreted in conjunction with the
related to periapical and periodontal inflammation results of immunofluorescence and immunohisto-
facilitate the development of a suitable niche for chemistry studies. We are increasingly looking
beyond the tissue architecture and cellular features Al-Hashimi I, Schifter M, Lockhart PB, Wray D,
to study genetic and protein-related biomarkers Brennan M, Migliorati CA, et al. Oral lichen planus
and oral lichenoid lesions: diagnostic and therapeutic
from lesional tissue, blood, and potentially saliva. considerations. Oral Surg Oral Med Oral Pathol Oral
The diagnostic applications of saliva as a biofluid Radiol Endod. 2007;103:e1–12.
are beginning to be understood but reliable cost- Allon I, Pessing A, Kaplan I, Allon DM, Hirshberg A.
effective technology is not yet available. The sig- Metastatic tumors to the gingiva and the presence
of teeth as a contributing factor: a literature analysis.
nificance and clinical impact of the 2017 new clas- J Periodontol. 2014;85:132–9.
sification scheme for periodontal and peri-implant Allon I, Lammert KM, Iwase R, Spears R, Wright JM,
diseases and conditions (Caton et al. 2018) remains Naidu A. Localised juvenile spongiotic gingival
to be realized, and has not affected our approach to hyperplasia possibly originates from the junc-
tional epithelium-an immunohistochemcial study.
characterization of gingival pathology. Histopathology. 2016;68:549–55.
Almouhawis HA, Leao JC, Fedele S, Porter SR. Wegener’s
granulomatosis: a review of clinical features and an
Cross-References update in diagnosis and treatment. J Oral Pathol Med.
2013;42:507–16.
▶ Clinical Evaluation of Oral Diseases Argyris PP, Nelson AC, Papanakou S, Merkourea S,
Tosios KI, Koutlas IG. Localised juvenile spongiotic
▶ Clinical Immunology in Diagnoses of gingival hyperplasia featuring unusual p16INK4A
Maxillofacial Disease labelling and negative human papillomavirus status
▶ Diagnostic Imaging Principles and by polymerase chain reaction. J Oral Pathol Med.
Applications in Head and Neck Pathology 2015;44:37–44.
Armitage G. Development of a classification system for
▶ Head and Neck Tumors periodontal diseases and conditions. Ann Periodontol.
▶ Laboratory Medicine and Diagnostic Pathology 1999;4:1–6.
▶ Non-odontogenic Bone Pathology Bagan JV, Jimenez Y, Sanchis JM, Poveda R, Milian MA,
▶ Normal Variation in the Anatomy, Biology, and Murillo J, et al. Proliferative verrucous leukoplakia:
high incidence of gingival squamous cell carcinoma.
Histology of the Maxillofacial Region J Oral Pathol Med. 2003;32:379–82.
▶ Odontogenic Bacterial Infections Bagan J, Lo Muzio L, Scully C. Mucosal disease series.
▶ Odontogenic Pathology Number III. Mucous membrane pemphigoid. Oral Dis.
▶ Oral and Maxillofacial Viral Infections 2005;11:197–218.
Bagan JV, Carbonell F, Gómez MJ, Sánchez NA,
▶ Oral Lichen Planus Leopoldo M, et al. Extra-nodal B-cell non-Hodgkin’s
▶ Oral Manifestations of Systemic Diseases and lymphomas of the head and neck: a study of 68 cases.
Their Treatments Am J Otolaryngol. 2015;36:57–62.
▶ Oral Mucosal Malignancies Bansal M, Singh N, Patne S, Singh SK. Orofacial
granulomatosis affecting lip and gingiva in a 15-year-
▶ Oral Ulcerative Lesions old patient: a rare case report. Contemp Clin
▶ Oral Vesicular and Bullous Lesions Dent. 2015;6(Suppl 1):S94–6. https://doi.org/10.4103/
▶ Pediatric Oral Medicine 0976-237X.152958.
▶ Pharmacotherapeutic Approaches in Oral Black M, Mignogna MD, Scully C. Number II. Pemphigus
vulgaris. Oral Dis. 2005;11:119–30.
Medicine Brown RS, Arany PR. Mechanism of drug-induced gingi-
▶ Pigmented Lesions of the Oral Mucosa val overgrowth revisited: a unifying hypothesis. Oral
▶ White and Red Lesions of the Oral Mucosa Dis. 2014;21:e51–61.
Brown RS, Beaver WT, Bottomley WK. On the mecha-
nism of drug-induced gingival hyperplasia. J Oral
Pathol Med. 1991;20:201–9.
References Brown AL, Camargo de Moraes P, Sperandio M,
Borges Soares A, Cavalcanti Araújo V, Passador-
Akrish S, Ben-Izhak OF, Sabo E, Rachmiel A. Oral squa- Santos F. Peripheral giant cell granuloma associated
mous cell carcinoma associated with proliferative with a dental implant: a case report and review of
verrucous leukoplakia compared with conventional the literature. Case Rep Dent. 2015;2015:697673.
squamous cell carcinoma-a clinical, histologic and https://doi.org/10.1155/2015/697673.
immunohistochemical study. Oral Surg Oral Med Oral Campbell H, Escudier M, Patel P, Nunes C, Elliott TR,
Pathol Oral Radiol Endod. 2015;119:318–25. Barnard K, et al. Distinguishing orofacial
granulomatosis from Crohn’s disease: two separate Falk RJ, Gross WL, Guillevin L, Hoffman G, Jayne DR,
disease entities? Inflamm Bowel Dis. Jennette JC, et al. Granulomatosis with polyangiitis
2011;17:2109–15. (Wegener’s): an alternative name for Wegener’s
Caton JG, Armitage G, Berglundh T, Chapple ILC, Jepsen granulomatosis. Ann Rheum Dis. 2011;70:704.
S, Kornman KS, et al. A new classification scheme for Femiano F, Lanza A, Buonaiuto C, Perillo L, Dell’Ermo A,
periodontal and peri-implant diseases and conditions - Cirillo N. Pyostomatits vegetans: a review of the liter-
Introduction and key changes from the 1999 classifica- ature. Med Oral Patol Oral Cir Bucal. 2009;14:E114–7.
tion. J Periodontol. 2018;89 (1 Suppl):S1–S8. https:// Firth FA, Friedlander LT, Parachuru VPB, Kardos TB, Sey-
doi.org/10.1002/JPER.18-0157. mour GJ, Rich AM. Regulation of immune cells in oral
Chan ES, Thornhill M, Zakrzewska J. Interventions for lichen planus. Arch Dermatol Res. 2015;307:333–9.
treating oral lichen planus. J Cochrane Database Syst Goncalves PH, Ziegelbauer J, Uldrick TS, Yarchoan R.
Rev. 2000;2:CD001168. Kaposi sarcoma herpesvirus-associated cancers and
Chan LS, Ahmed AR, Anhalt GJ, Bernauer W, Cooper KD, related diseases. Curr Opin HIVAIDS. 2017;12:47–56.
Elder MJ, et al. The first international consensus Gondalfo S, Castellani R, Pentenero M. Proliferative
on mucous membrane pemphigoid. Definition, verrucous leukoplakia: a potentially malignant
diagnostic criteria, pathogenic factors, medical treat- disorder involving periodontal sites. J Periodontol.
ment, and prognostic indicators. Arch Dermatol. 2009;80:274–81.
2002;138:370–9. Hart TC, Zhang Y, Gorry MC, Hart PS, Cooper M,
Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Marazita ML, Marks JM, et al. A mutation in the
Knowles DM, et al. Identification of herpesvirus-like SOS1 gene causes hereditary gingival fibromatosis
DNA sequences in AIDS-associated Kaposi’s sarcoma. type 1. Am J Hum Genet. 2002;70:943–95.
Science. 1994;266:1865–9. Hartsfield JK Jr, Bixler D, Hazen RH. Gingival fibromatosis
Chang JY, Kessler HP, Wright JM. Localised juvenile with sensorineural hearing loss: an autosomal dominant
spongiotic gingival hyperplasia. Oral Surg Oral Med trait. Am J Med Genet. 1985;22:623–7.
Oral Pathol Oral Radiol Endod. 2008;106:411–8. Hegarty AM. Oral lichen planus: aetiology, diagnosis and
Cholera M, Chainani-Wu N. Management of pemphigus treatment. Dent Nurs. 2012;8:14–20.
vulgaris. Adv Ther. 2016;33:910–58. Hegarty A, Hodgson T, Porter S. Thalidomide for the
Clark LG, Tolkachjov SN, Bridges AG, Camilleri MJ. treatment of recalcitrant oral Crohn’s disease and
Pyostomatitis vegetans (PSV)-pyodermatitis vegetans orofacial granulomatosis. Oral Surg Oral Med Oral
(PDV): a clinicopathologic study of 7 cases at a tertiary Pathol Oral Radiol Endod. 2003;95:576–85.
referral center. J Am Acad Dermatol. 2016;75:578–84. Hegarty AM, Barrett AW, Scully C. Pyostomatitis
Cohen PS, Meltzer JA. Strawberry gums. A sign of vegetans. Clin Exp Dermatol. 2004;29:1–7.
Wegener’s granulomatosis. JAMA. 1981;246:2610–1. Hirshberg A, Kozlovsky A, Schwartz-Arad D,
Dahlstrom KR, Little JA, Zafereo ME, Lung M, Wei Q, Mardinger O, Kaplan I. Peripheral giant cell granuloma
Sturgis EM. Squamous cell carcinoma of the head and associated with dental implants. J Periodontol.
neck in never smoker-never drinkers: a descriptive 2003;74:1381–4.
epidemiologic study. Head Neck. 2008;30:75–84. Hirshberg A, Berger R, Allon I, Kaplan I. Metastatic
Darling MR, Daley TD, Wilson A, Wysocki GP. Juvenile tumors to the jaws and mouth. Head Neck Pathol.
spongiotic gingivitis. J Periodontol. 2007;78:1235–40. 2014;8:463–74.
Di Zenzo G, Carrozzo M, Chan LS. Urban legend Housley Smith M, Bhattacharyya I, Cohen DM, Islam NM,
series: mucous membrane pemphigoid. Oral Dis. Fitzpatrick SG, Montague LJ. Melanoma of the oral
2014;20:35–54. cavity: an analysis of 46 new cases with emphasis on
Dittmer DP, Damania B. Kaposi sarcoma-associated clinical and histopathologic characteristics. Head Neck
herpesvirus: immunobiology, oncogenesis, and ther- Pathol. 2016;10:298–305.
apy. J Clin Invest. 2016;126:3165–75. Iguchi H, Wada T, Matsushita N, Oishi M, Yamane
Elad S, Epstein JB, Yarom N, Drucker S, Tzach R, von H. Anatomic distribution of hematolymphoid
Bültzingslöwen I. Topical immunomodulators for malignancies in the head and neck: 7 years experi-
management of oral mucosal conditions, a systematic ence in a single institution. Acta Otolaryngol.
review; part 2: calcineurin inhibitors. Expert Opin 2012;132:1224–31.
Emerg Drugs. 2010;15:713–26. Jain MK, Manjunath KS, Jagadish SN. Unusual oral com-
Endo H, Rees TD, Hallmon WW, Kuyama K, Nakadai M, plications of herpes zoster infection: report of a case
Kato T, et al. Disease progression from mucosal to and review of literature. Oral Surg Oral Med Oral
mucocutaneous involvement in a patient with Pathol Oral Radiol Endod. 2010;110:e37–41.
desquamative gingivitis associated with pemphigus Jessri M, AbdulMajeed AA, Matias MA, Farah CS. A case
vulgaris. J Periodontol. 2008;79:369–75. of primary diffuse large B-cell non-Hodgkin’s lym-
Epstein JB, Epstein JD, Le ND, Gorsky M. Characteristics phoma misdiagnosed as chronic periapical periodonti-
of oral and paraoral malignant lymphoma: a tis. Aust Dent J. 2013;58:250–5.
population-based review of 361 cases. Oral Surg Oral Joshi C, Shukla P. Plasma cell gingivitis. J Indian Soc
Med Oral Pathol Oral Radiol Endod. 2001;92:519–25. Periodontol. 2015;19:221–3.
Kitano M, Landini G, Urago A, Okubo A, Mukai H, mandibular canal invasion in lower gingival squamous
Yamashita S. Odontogenic epithelial hamartoma of cell carcinoma. Cancer Med. 2016. https://doi.org/
the gingiva: a case report. J Periodontol. 10.1002/cam4.899.
1991;62:452–7. Palefsky JM. Human papillomavirus-associated anal
Kolho KL, Heiskanen K, Verkasalo M, Pitkäranta A. and cervical cancers in HIV-infected individuals: inci-
Orofacial granulomatosis in children-a challenge for dence and prevention in the antiretroviral therapy
diagnosis and treatment. Int J Pediatr Otorhinolaryngol. era. Curr Opin HIV AIDS. 2017;12(1):26–30.
2011;75:864–7. Philipsen HP, Reichart PA, Nikai H, Takata T, Kudo Y.
Kujan O, Al-Shawaf AZ, Azzeghaiby S, AlManadille A, Peripheral ameloblastoma: biological profile based
Aziz K, Raheel SA. Immunohistochemical comparison on 160 cases from the literature. Oral Oncol.
of p53, Ki-67, CD68, vimentin, α-smooth muscle actin 2001;37:17–27.
and alpha-1-antichymotrypsin in oral peripheral and Poulopoulos A, Kittas D, Sarigelou A. Current concepts on
central giant cell granuloma. J Contemp Dent Pract. gingival fibromatosis-related syndromes. J Investig
2015;16:20–4. Clin Dent. 2011;2:156–61.
Kurtulus I, Gokbuget A, Efeoglu A, Cintan S, Tefs K, Rashid KA, Stern JNH, Ahmed AR. Identification of
Schuster V, et al. Hypoplasminogenemia with ligneous an epitope within human integrin α6 subunit for the
periodontitis: a failed local therapeutic approach. binding of autoantibody and its role in basement
J Periodontol. 2007;78:1164–75. membrane separation in oral pemphigoid. J Immunol.
Lam A, Kiyak A, Gossett AM, McCormick L. Assessment 2006;176:1968–77.
of the use of xerogenic medications for chronic medical Relle M, Föhr B, Fasola F, Schwarting A. Genetics and
and dental conditions among adult day health partici- pathophysiology of granulomatosis with polyangiitis
pants. Consult Pharm. 2009;24:755–64. (GPA) and its main autoantigen proteinase 3. Mol
Lankarani KB, Sivandzadeh GR, Hassanpour S. Oral man- Cell Probes. 2016;30:366–73.
ifestation in inflammatory bowel disease: a review. Ryan K, Hegarty AM, Hodgson T. Aetiology, diagnosis
World J Gastroenterol. 2013;19:8571–9. and treatment of oral lichen planus. Br J Hosp Med.
Lester SR, Cordell KG, Rosebush MS, Palaiologou AA, 2014;75:492–6.
Maney P. Peripheral giant cell granulomas: a series of Scattarella A, Petruzzi M, Ballini A, Grassi F, Nardi G.
279 cases. Oral Surg Oral Med Oral Pathol Oral Radiol. Oral lichen planus and dental hygiene: a case report. Int
2014;118:475–82. J Dent Hyg. 2011;9:163–6.
Limeres Posse J, Scully C. Oral HPV-associated Schuster V, Mingers AM, Seidenspinner S, Nüssgens Z,
papillomatosis in AIDS. N Engl J Med. 2016;374:2585. Pukrop T, Kreth HW. Homozygous mutations in the
Lutalo PMK, D’Cruz DP. Diagnosis and classification of plasminogen gene of two unrelated girls with ligneous
granulomatosis with polyangiitis (aka Wegener’s conjunctivitis. Blood. 1997;90:958–66.
granulomatosis). J Autoimmun. 2014;48–49:94–8. Scully C, Bagan JV. Adverse drug reactions in the orofacial
Madhavarajan S, Tighe J. Orofacial plasmacytosis: a man- region. Crit Rev Oral Biol Med. 2004;15:221–39.
agement conundrum. Br J Oral Maxillofac Surg. Scully C, Gokbuget A, Kurtulus I. Hypoplasminogenaemia,
2015;53:399–402. gingival swelling and ulceration. Oral Dis. 2007;
Martins AF, Souza PO, Rege IC, Morais MO, Mendonça EF. 13:515–8.
Glucocorticoids, calcitonin, and osteocalcin cannot dif- Shipman AR, Reddy H, Wojnarowska F. Association
ferentiate between aggressive and nonaggressive central between the subepidermal autoimmune blistering
giant cell lesions of the jaws. Oral Surg Oral Med Oral diseases linear IgA disease and the pemphigoid
Pathol Oral Radiol. 2015;120:386–95. group and inflammatory bowel disease: two case reports
Mattsson U, Jontell M, Holmstrup P. Oral lichen planus and literature review. Clin Exp Dermatol. 2012;37:461–8.
and malignant transformation: is a recall of patients Silva TDB, Ferreira CBT, Leite GB, Pontes JRdM,
justified? Crit Rev Oral Biol Med. 2002;13:390–6. Antunes HS. Oral manifestations of lymphoma: a
McMillan R, Taylor J, Shephard M, Ahmed R, systemic review. Ecancermedicalscience. 2016;10.
Carrozzo M, Setterfield J, et al. World workshop on https://doi.org/10.3332/ecancer.2016.665.
oral medicine VI: a systematic review of the treatment Sinon S, Rich AM, Parachuru VPB, Firth FA, Milne T,
of mucocutaneous pemphigus vulgaris. Oral Surg Seymour GJ. Downregulation of toll-like receptor-
Oral Med Oral Pathol Oral Radiol. 2015;120:132–42. mediated signalling pathways in oral lichen planus.
Mendieta C, Miranda J, Brunet LI, Gargallo J, Berini L. J Oral Pathol Med. 2016;45:28–34.
Alveolar bone necrosis and tooth exfoliation following Sivolella S, De Biagi M, Sartori MT, Berengo M,
herpes zoster infection: a review of the literature and Bressan E. Destructive membranous periodontal
case report. J Periodontol. 2005;76:148–53. disease (ligneous gingivitis): a literature review.
O’Neill ID, Scully C. Biologics in oral medicine: oral J Periodontol. 2012;83:465–76.
Crohn’s disease and orofacial granulomatosis. Oral Spatafore CM, Keyes G, Skidmore AE. Lymphoma: an
Dis. 2012;18:633–8. unusual oral presentation. J Endod. 1989;15:438–41.
Okura M, Yanamoto S, Umeda M, Otsuru M, Ota Y, Taylor J, McMillan R, Shephard M, Setterfield J,
Kurita H. Prognostic and staging implications of Ahmed R, Carrozzo M, et al. World workshop on oral
medicine VI: a systematic review of the treatment of disorders among patients accrued over a 10-year period
mucous membrane pemphigoid. Oral Surg Oral Med in South East England. J Oral Pathol Med.
Oral Pathol Oral Radiol. 2015;120:161–71. 2011;40:677–83.
Thongprasom K, Carrozzo M, Furness S, Lodi G. Inter- Wen KW, Damania B. Kaposi sarcoma-associated herpes-
ventions for treating oral lichen planus. Cochrane virus (KSHV): molecular biology and oncogenesis.
Database Syst Rev. 2011. https://doi.org/10.1002/ Cancer Lett. 2010;289:140–50.
14651858.CD001168.pub2. Witkop CJ Jr. Heterogeneity in gingival fibromatosis. Birth
Thongprasom K, Prapinjumrune C, Carrozzo M. Novel Defects Orig Artic Ser. 1971;7:210–21.
therapies for oral lichen planus. J Oral Pathol Med. Wojciechowska J, Krajewski W, Krajewski P, Kręcicki T.
2013;42:721–7. Granulomatosis with polyangiitis in otolaryngologist
Tobón-Arroyave SI, Franco-González LM, Isaza- practice: a review of current knowledge. Clin Exp
Guzmán DM, Floréz-Moreno GA, Bravo-Vásquez T, Otorhinolaryngol. 2016;9:8–13.
Castañeda-Peláez DA, et al. Immunohistochemical Wu YH, Chang JY, Chen HM, Wang YP. Pyostomatitis
expression of RANK, GRalpha and CTR in central vegetans: an oral manifestation of inflammatory bowel
giant cell granuloma of the jaws. Oral Oncol. disease. J Formos Med Assoc. 2015;114:672–3.
2005;41:480–8. Yamamoto K, Matsusue Y, Horita S, Minamiguchi M,
Tong DC, Leaper MR, Colquhoun AN, Rich AM. An Komatsu Y, Kirita T. Nicorandil-induced oral ulcera-
unusual presentation of oropharyngeal mucosal tion: report of 3 cases and review of the Japanese
plasmacytosis related to toothpaste. J Laryngol Otol. literature. Oral Surg Oral Med Oral Pathol Oral Radiol
2008;122:1112–4. Endod. 2011;112:754–9.
Vered M, Muller S, Heikinheimo K. Ameloblastoma, Zakrzewska JM, Chan ES, Thornhill MH. A systematic
extraosseous/peripheral type. In: El-Nagger AK, review of placebo-controlled randomized clinical trials
Chan JKC, Grandid JR, Takata T, Slootweg PJ, editors. of treatments used in oral lichen planus. Br J Dermatol.
WHO classification of head and neck tumours. Lyon, 2005;153:336–41.
France: International Agency for Research on Cancer Zbar AP, Ben-Horin S, Beer-Gabel M, Eliakim R. Oral
(IARC); 2017. p. 218. Crohn’s disease: is it a separable disease from orofacial
Wagaiyu EG, Ashley FP. Mouthbreathing, lip seal and granulomatosis? A review. J Crohns Colitis.
upper lip coverage and their relationship with gingival 2012;2:135–42.
inflammation in 11–14 year-old schoolchildren. J Clin Zhou XJ, Sugerman PB, Savage NW, Walsh LJ,
Periodontol. 1991;18:698–702. Seymour GJ. Intra-epithelial CD8+ T cell and basement
Warnakulasuriya S, Kovacevic T, Madden P, Coupland membrane disruption in oral lichen planus. J Oral
Sperandio M, Odell E, et al. Factors predicting malig- Pathol Med. 2002;31:23–7.
nant transformation in oral potentially malignant
Pigmented Lesions of the Oral Mucosa
Eric T. Stoopler and Faizan Alawi
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1176
Focal Pigmentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1177
Freckle/Ephelis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1177
Oral/Labial Melanotic Macule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1178
Oral Melanoacanthoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1179
Melanocytic Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1181
Malignant Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1183
Multifocal/Diffuse Pigmentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1188
Physiologic Pigmentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1188
Drug-Induced Melanosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1190
Smoker’s Melanosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1191
Post-inflammatory (Inflammatory) Hyperpigmentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1192
Laugier-Hunziker Pigmentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1193
Pigmentation Associated with Systemic or Genetic Disorders . . . . . . . . . . . . . . . . . . . . 1194
Adrenal Insufficiency (Addison Disease) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1194
Cushing Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1196
Human Immunodeficiency Virus (HIV): Associated Pigmentation . . . . . . . . . . . . . . . . . . . 1197
Peutz-Jeghers Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1199
Exogenous Causes of Clinical Pigmentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1200
Tattoos: Amalgam, Graphite, and Ornamental . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1200
Metal-induced Discoloration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1202
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1203
E. T. Stoopler (*) Abstract

Department of Oral Medicine, University of Pennsylvania Pigmented lesions of the oral mucosa are
School of Dental Medicine, Philadelphia, PA, USA
e-mail: ets@upenn.edu
encountered on a routine basis in clinical prac-
tice. Oral health-care providers must assess
F. Alawi
Department of Pathology, University of Pennsylvania
several parameters associated with pigmented
School of Dental Medicine, Philadelphia, PA, USA lesions, such as location, shape, color, and size.
e-mail: falawi@upenn.edu

https://doi.org/10.1007/978-3-319-72303-7_17
1176 E. T. Stoopler and F. Alawi
Etiology of pigmented lesions may be attrib- traumatic or iatrogenic events that result in deposi-
uted to a local phenomenon and/or associated tion of foreign material directly into the mucosal
with an underlying systemic disorder. Diag- tissues. Several parameters associated with
nostic and therapeutic modalities must be care- pigmented lesions, such as location, shape, color,
fully considered as these lesions encompass the and size, must be assessed in order for clinicians to
spectrum of clinical pathology, ranging from appropriately evaluate and manage the condition, as
benign to malignant. Clinicians should conduct pathology of pigmented lesions ranges from benign
a thorough medical history and relevant phys- to malignant. Clinicians should conduct a thorough
ical examination for patients with pigmented medical, family, and social history, as well as a
lesions to identify possible adrenal, gastroin- relevant physical examination for patients with
testinal, or genetic disorders that are commonly pigmented lesions, to identify possible adrenal, gas-
associated with these types of lesions. If a trointestinal, or genetic disorders that are commonly
systemic disorder is suspected, the patient associated with these types of lesions. If a systemic
should be promptly referred to the appropriate disorder is suspected, the patient should be
health-care provider for further evaluation and promptly referred to the appropriate health-care
management. Multidisciplinary care is often provider for further evaluation and management.
necessary to effectively manage patients with Multidisciplinary care is often necessary to effec-
these conditions. This chapter provides a con- tively manage patients with these conditions. This
temporary perspective of pigmented lesions of chapter provides a contemporary perspective of
the oral mucosa and is intended to serve as a pigmented lesions of the oral mucosa focusing on
practical clinical resource for oral health-care those associated with melanin and will discuss focal
providers. pigmentation conditions, multifocal or diffuse pig-
mentation conditions, pigmentation associated with
Keywords systemic or genetic disorders, and exogenous
Oral mucosa · Pigmentation · Melanin · Focal · causes of clinical pigmentation (Table 1).
Multifocal · Diffuse · Systemic · Genetic ·
Exogenous Table 1 Pigmented lesions of the oral mucosa
I. Focal pigmentation conditions
a. Freckle/ephelis
Introduction b. Oral/labial melanotic macule
c. Oral melanoacanthoma
The mucous membranes lining the oral cavity are d. Melanocytic nevus
e. Malignant melanoma
not uniformly colored and dependent upon the spe-
II. Multifocal/diffuse pigmentation conditions
cific anatomic location; healthy tissue commonly
a. Physiologic pigmentation
ranges in color from white to red-purple. This is due
b. Drug-induced melanosis
to the interaction of various tissues that compose the
c. Smoker’s melanosis
mucosal lining, including presence or absence of d. Post-inflammatory (inflammatory) hyperpigmentation
keratin on the surface epithelium, location and pres- e. Laugier-Hunziker pigmentation
ence of vascular structures in the stroma, existence III. Pigmentation associated with systemic or genetic
of adipocytes, and the lack of melanin pigmentation disorders
in the basal cell layer of the epithelium. Pigment a. Adrenal insufficiency (Addison disease)
deposition, whether physiologic or pathologic, or b. Cushing disease
attributed to endogenous or exogenous substances, c. Human immunodeficiency virus (HIV) – associated
will impart gray, blue, brown and/or black color pigmentation
changes to the oral mucosa. The most common d. Peutz-Jeghers syndrome
IV. Exogenous causes of clinical pigmentation
endogenous sources of pigmentation are melanin,
a. Tattoos – amalgam, graphite and ornamental
hemoglobin, and hemosiderin, while exogenous
b. Metal – induced discoloration
sources of pigmentation are usually attributed to
Pigmented Lesions of the Oral Mucosa 1177
Melanocytes are derived from neural crest cells Etiology

and are located in the basal epithelial layer Freckles are thought to be developmental in origin
of squamous mucous membranes (Meleti et al. (Gaeta et al. 2002; Hatch 2005). Genetic poly-
2008). The functions of melanocytes are not morphisms associated with the melanocortin-1
fully understood, but the melanin produced receptor (MC1R) gene and chromosome 4q32-
by these cells absorb ultraviolet light, scavenge q34 have been strongly associated with freckle
reactive oxygen species, and determine skin, hair, development (Bastiaens et al. 2001).
and eye color (Meleti et al. 2008; Feller et al.
2014a, b). Oral melanocytes are regularly inter- Pathophysiology
spersed between basal keratinocytes, and melanin Freckles are due to an increase in melanin produc-
from the melanocytes are transported and trans- tion without an increase in the number of melano-
mitted to epithelial cells via dendritic migration of cytes and become more pronounced after sun
melanosomes (melanin-containing vesicles). The exposure. They are also associated closely with a
ratio of melanocytes to keratinocytes in the basal history of symptomatic childhood sunburns (Bliss
epithelial layer ranges from 1:10 to 1:15 (Feller et al. 1995).
et al. 2014a, b). Two chemically distinct types of
melanin exist, eumelanin (brown-black) and Clinical-Pathologic Features
pheomelanin (red/yellow), and melanogenesis is Freckles appear as a uniformly tan- or brown-
considered a mixed process between these mela- colored, oval or round macule, between 1 and
nin types, with proportions of eumelanin and 3 mm in size on sun-exposed cutaneous surfaces
pheomelanin being genetically determined (Feller (Gaeta et al. 2002; Hatch 2005) (Fig. 1). They
et al. 2014a, b). There are no numerical or struc- have regularly defined borders, are not elevated
tural differences in oral melanocytes between above the skin surface, and are asymptomatic
light-skinned and dark-skinned individuals except (Gaeta et al. 2002; Hatch 2005). They often
that in the latter, the melanosomes are larger and appear on the perioral skin and vermillion border
more numerous (Feller et al. 2014a, b). Several of the lips with increased frequency on the lower
factors likely determine intraoral mucosal color, lip (Hatch 2005). Although many individuals
including number and melanogenic activity of have less than ten lesions, due to the great vari-
melanocytes, differences in number, size and disability in the number of lesions present, some may
tribution of melanosomes, difference in the type have hundreds of freckles (Gaeta et al. 2002;
of melanin, and the masking effect of heavily Hatch 2005). Histopathologically, freckles exhibit
keratinized epithelium (Feller et al. 2014a, b). abundant melanin deposition in the basal cell
Focal Pigmentation
Freckle/Ephelis
Epidemiology
A freckle (ephelis) is a hyperpigmented macule
commonly observed on the facial and perioral
skin. They usually develop during the first decade
of life and are more common in light-skinned
individuals with blonde or red hair (Gaeta et al.
2002; Hatch 2005). There is no gender predilec-
tion, and the color intensity and frequency of
freckles typically decrease after adolescence
(Gaeta et al. 2002; Hatch 2005). Fig. 1 Freckle (ephelis) [arrow] on the facial skin
layer of the epidermis without elongation of rete 2004). They are uniformly tan to dark brown,
ridges (Hatch 2005). round or oval, and asymptomatic (Kaugars et al.
1993; Shen et al. 2011). Overall, labial melanotic
Patient Management macules are the most common type of macules
Treatment is typically not indicated for freckles in observed with the lower lip vermillion border pre-
childhood or adolescence (Hatch 2005). Sun- dominantly affected (Kaugars et al. 1993; Shen et al.
screens may help prevent darkening of existing 2011). In contrast to freckles, labial melanotic mac-
lesions and prevent the appearance of new lesions ules do not darken after exposure to the sun (Lim
(Bliss et al. 1995). Freckles of cosmetic concern et al. 2014; Meleti et al. 2008). Oral melanotic
may be treated with chemical peels, laser therapy, macules may appear on any surface but are most
and/or cryotherapy. MC1R gene variants have commonly observed on the buccal mucosa, gingiva,
been associated with an increased risk for spo- and palate (Kauzman et al. 2004) (Figs. 2, 3, 4,
radic cutaneous melanoma (Pasquali et al. 2015).
Oral/Labial Melanotic Macule
Epidemiology
A melanotic macule is a benign pigmented lesion
that may occur on intraoral mucosal surfaces (oral
melanotic macule) or on the lips (labial melanotic
macule) (Tarakji et al. 2014). They are considered
to be the most common oral mucosal lesions of
melanocytic origin and are also termed focal
melanosis (Alawi 2013; Muller 2010). Oral/labial
melanotic macules are present in up to 3% of the
population, are typically observed in patients in Fig. 2 Biopsy-proven gingival melanotic macule
the fourth and fifth decades, and have a 2:1 female appearing as brown pigmented lesion involving the inter-
predilection (Hatch 2005; Meleti et al. 2008; dental gingiva between 41 and 42 (Image courtesy of
Muller 2010). Professor Camile Farah, Perth Oral Medicine & Dental
Sleep Centre, Perth WA, Australia)
Etiology
The etiology of oral/labial melanotic macules has
not been definitively determined but may repre-
sent a reactive or a physiologic process (Meleti
et al. 2008).
Pathophysiology
Oral/labial melanotic macules are caused by an
increased production and deposition of melanin
within the basal cell layer, the lamina propria, or
both (Meleti et al. 2008). The etiology of these
lesions is unclear; however, sun exposure does not
appear to be a precipitating factor.
Clinical-Pathologic Features Fig. 3 Biopsy-proven melanotic macule appearing as an

irregular brown pigmented lesion along the edentulous
Oral/labial melanotic macules are solitary, well-
mandibular alveolar ridge (Image courtesy of Professor
circumscribed lesions that are typically less than Camile Farah, Perth Oral Medicine & Dental Sleep Centre,
1 cm in diameter (Alawi 2013; Kauzman et al. Perth WA, Australia)
and 5a, b). Intraoral lesions are often larger than or may be free (incontinence) in the subepithelial
those located on the lips (Meleti et al. 2008). Histo- connective tissue, and these lesions do not typically
pathological analysis of melanotic macules reveals demonstrate elongated rete ridges (Alawi 2013).
an increase in melanin in the basal and parabasal
layers of normal stratified squamous epithelium Patient Management
without an increase in number of melanocytes Oral/labial melanotic macules are considered
(Kaugars et al. 1993; Shen et al. 2011) (Fig. 6). benign lesions without malignant potential
Melanin may also be observed within melanophages (Kauzman et al. 2004). Since early malignant
melanoma may have a similar clinical appearance
and exhibits a predilection for the maxillary alve-
olar mucosa and palate, it is strongly advisable to
perform an excisional biopsy for any suspected
oral/labial melanotic macule for histopathologic
analysis (Kauzman et al. 2004). Labial melanotic
macules may be of cosmetic concern, and removal
of these lesions may be accomplished by scalpel,
cryosurgery, electrocautery, or laser ablation
(Alawi 2013; Lim et al. 2014).
Oral Melanoacanthoma
Epidemiology
Oral melanoacanthoma represents a benign
melanocytic lesion that is most commonly
observed in dark-complexioned females between
Fig. 4 Biopsy-proven melanotic macule appearing as a
30 and 50 years of age (Arava-Parastatidis
faint brown lesion on the right soft palate (Image courtesy
of Professor Camile Farah, Perth Oral Medicine & Dental et al. 2011). This condition has been reported
Sleep Centre, Perth WA, Australia) in Hispanic, Asian, and Caucasian patients and
Fig. 5 Biopsy-proven melanotic macule involving the fluorescence limited to lesion with no diascopy (Images
hard palate demonstrating irregular pigmentation and bor- courtesy of Professor Camile Farah, Perth Oral Medicine &
der viewed with white light (a) and with optical fluores- Dental Sleep Centre, Perth WA, Australia)
cence imaging VELscope Vx (b) showing loss of
Fig. 7 Oral melanoacanthoma affecting the buccal

mucosa
Fig. 6 Melanotic macule. Melanin pigmentation is noted

in the basal epithelial layer (Hematoxylin and eosin stain,
200)
has an overall female predilection (Arava-

Parastatidis et al. 2011).
Etiology
Oral melanoacanthoma is of unknown etiology
(Gondak et al. 2012; Muller 2010).
Fig. 8 Dendritic melanocyte (arrow) within the stratum
spinosum
Pathophysiology
The pathophysiologic mechanism for oral
melanoacanthoma is most consistently associated
with acute regional trauma or chronic irritation on the buccal mucosa followed by the palate,
(Alawi 2013; Arava-Parastatidis et al. 2011). lips, gingiva, and tongue and may present unilat-
erally or bilaterally (Alawi 2013; Arava-
Clinical-Pathologic Features Parastatidis et al. 2011). This condition is primar-
Oral melanoacanthoma typically presents as ily asymptomatic; however, some patients report
a diffuse, rapidly enlarging area of macular pig- burning sensations and/or pruritus associated with
mentation that may range in size from a few these lesions (Cantudo-Sanagustín et al. 2016).
millimeters to several centimeters (Alawi 2013; Histologically, oral melanoacanthoma is charac-
Arava-Parastatidis et al. 2011) (Fig. 7). The lesion terized by spongiotic epithelium containing den-
is typically brown to black in color with possible dritic pigmented melanocytes throughout the
heterogeneity of color throughout the lesion. lesional epithelium (Alawi 2013) (Fig. 8). A
Oral melanoacanthoma usually manifests as a mild to moderate inflammatory infiltrate com-
solitary lesion, but multifocal lesions have been posed of lymphocytes and occasional eosinophils
reported (Arava-Parastatidis et al. 2011). Oral is observed in the underlying connective tissue
melanoacanthoma is most frequently observed (Alawi 2013).
Patient Management oncogenes (Alawi 2013; Meleti et al. 2008). It

Treatment of oral melanoacanthoma is typically remains unclear if similar mutations are impli-
not indicated after diagnosis has been established. cated as the etiology of oral melanocytic nevi
An incisional biopsy is necessary to rule out (Alawi 2013).
malignant melanoma as it is considered in the
differential diagnosis of these lesions due to its Pathophysiology
ominous clinical presentation (Alawi 2013). The pathogenesis of melanocytic nevi, including
Spontaneous regression of oral melanoacanthoma oral melanocytic nevi, is poorly understood
has been observed after biopsy, and recurrence of (Meleti et al. 2008). Acquired melanocytic nevi
these lesions is rare (Alawi 2013; Arava- evolve through several developmental stages
Parastatidis et al. 2011). Malignant transformation although not all nevi pass through each stage
of oral melanoacanthoma has not been reported (Meleti et al. 2008). It has been postulated that
(Kauzman et al. 2004). junctional nevi evolve into compound nevi and
ultimately into intramucosal nevi, with differenti-
ating clinical and histologic features (Alawi
Melanocytic Nevus 2013). Melanocytic proliferation can be consid-
ered in three phases that correspond to each of the
Epidemiology aforementioned nevi types: (1) proliferation of
Melanocytic nevi, commonly referred to as benign neoplastic melanocytes along the
“moles,” represent a group of benign tumors that epithelial-mesenchymal junction (i.e., junctional
develop due to melanocytic growth and prolifera- nevus), (2) migration of these cells into the mes-
tion (Alawi 2013; Hatch 2005). Cutaneous nevi enchymal compartment (i.e., compound nevus),
are common and typically develop during child- and (3) loss of the junctional component of the
hood with most cutaneous lesions present before nevus so all remaining cells are located within the
the age of 35 (Marangon Junior et al. 2015). In subepithelial compartment (intramucosal nevi)
addition, Caucasians tend to develop cutaneous (Meleti et al. 2008). Blue nevi are melanocytic
nevi more frequently than blacks or Asians lesions that typically appear slate blue to blue
(Marangon Junior et al. 2015). The intramucosal black and account for up to 35% of all oral nevi
nevus is the most frequently observed type of oral (Pinto et al. 2003). They are categorized into the
nevus followed by the blue nevus, compound common type and the less frequently encountered
nevus, junctional nevus, and combined nevus, in cellular type, and while each has specific charac-
decreasing order of frequency (Alawi 2013). Oral teristic histopathologic features, both types harbor
melanocytic nevi are frequently observed in the melanin particles deep to the surface so that
third to fourth decades of life, and while the total reflected light appears blue to the observer (Pinto
number of nevi tends to be higher in males, oral et al. 2003). Darkly pigmented blue nevi may be
melanocytic nevi are more common in females clinically indistinguishable from other types of
(Alawi 2013). melanocytic nevi.
Etiology Clinical-Pathologic Features

In general, melanocytic nevi are acquired lesions Cutaneous junctional nevi commonly appear as a
with both environmental and genetic factors sharply demarcated macule less than 6 mm in
thought to play a role in the development of diameter with brown or blue coloration (Alawi
cutaneous lesions (Alawi 2013; Muller 2010). 2013). Compound nevi may be macular or slightly
Sun exposure is a well-recognized environmental elevated, soft with a relatively smooth surface,
factor for development of cutaneous nevi (Lim while intradermal (cutaneous counterpart to
et al. 2014). Recent studies have demonstrated intramucosal) nevi exhibits loss of pigmentation
cutaneous nevi exhibiting somatic, activating and a papillomatous surface with possible central
mutations in the BRAF, HRAS, and NRAS proto- hair growth (Alawi 2013). Oral melanocytic nevi
Fig. 9 Intramucosal nevus (arrow) located on the palate

(Image courtesy of Dr Edward Marcus, Yardley, Pennsyl-
vania, USA) Fig. 11 Intramucosal nevus. Nests of benign nevus cells
are identified within the lamina propria (Hematoxylin and
eosin stain, 200)
Fig. 10 Blue nevus (arrow) identified on the palate
have no distinguishing clinical characteristics;

however, they are usually asymptomatic, solitary,
well circumscribed, less than 1 cm, macular or
nodular in appearance, and brown or blue in
color (Alawi 2013) (Figs. 9 and 10). It is impor-
tant to note that up to 15% of oral nevi may not
exhibit any evidence of clinical pigmentation
(Alawi 2013; Muller 2010). The most commonly
affected intraoral surfaces are the hard palate,
buccal and labial mucosae, and gingiva, respec-
Fig. 12 Intramucosal nevus composed of heavily
tively (Alawi 2013; Meleti et al. 2008). pigmented nevus cells (Hematoxylin and eosin stain,
Histopathologically, nevus cells confined to 200)
the basal layer at the junction of the epithelium
and connective tissue, especially at the tips of the epithelial-connective tissue surface, all of which
rete ridges are characteristic of junctional nevi are characteristic of the compound nevus (Alawi
(Alawi 2013). As the junctional nevus evolves, 2013). Intramucosal nevi demonstrate nevus cells
clustered melanocytes proliferate down into the separated from the epithelial layer and found only
connective tissue, forming nests of various sizes, in the connective tissue (Alawi 2013) (Figs. 11
while some nevus cells are still seen at the and 12). The common blue nevus is characterized
four- to fivefold (Lim et al. 2014). Overall, the

risk of malignant transformation of cutaneous
nevi to melanoma is low, and current evidence
does not suggest that oral melanocytic nevi are
markers for development of oral malignant mela-
noma (Meleti et al. 2008).
Malignant Melanoma
Epidemiology
Malignant melanoma is a neoplasm of
melanocytic origin with most cases occurring on
the skin. While the incidence of malignant mela-
noma is lower compared to nonmelanoma skin
cancers, it accounts for the vast majority of skin
cancer deaths (Lee et al. 2017). Malignant mela-
noma is most common among white populations
residing in Sunbelt regions of the world (Berwick
et al. 2016). International incidence of melanoma
varies depending on geographic regions with the
highest rates of malignant melanoma occurring in
Fig. 13 Blue nevus. Spindle-shaped melanocytes New Zealand, Australia, and the United States
(arrows) are embedded within a densely fibrotic lamina (Jiang et al. 2015). It is estimated that 1 in 50 per-
propria (Hematoxylin and eosin stain, 200)
sons in the United States will be diagnosed with
malignant melanoma during his or her lifetime
by an intramucosal proliferation of pigment- (Lim et al. 2014). It accounts for approximately
laden, spindle-shaped melanocytes (Fig. 13), 4.6% of all new cancers and 1.7% of all cancer-
while the cellular blue nevus demonstrates sub- related deaths in the United States (Gandhi and
mucosal proliferation of both spindle-shaped and Kampp 2015). Incidence of malignant melanoma
larger, round- or ovoid-shaped melanocytes (Pinto in European countries varies widely with approx-
et al. 2003). imately 2 to 20 cases diagnosed per 100,000
annually (Jiang et al. 2015). Malignant melanoma
Patient Management incidence in Asia, Africa, and Central and South
Treatment of cutaneous lesions are typically not America is considered low; however, the overall
indicated unless a cosmetic concern exists and international incidence trends of malignant mela-
there is a tendency for lesion regression with noma suggest it is continuing to increase (Jiang
advancing age (Alawi 2013). A biopsy is neces- et al. 2015). Median age of diagnosis is 64 years;
sary to confirm the diagnosis of oral melanocytic however, incidence of malignant melanoma
nevi as the clinical presentation resembles other increases with age, reaching a peak between
focally pigmented lesions, such as malignant mel- 80 and 84 years (Gandhi and Kampp 2015). Over-
anoma (Felix et al. 2013). Oral melanocytic nevi all, there is a male predilection for the condition,
are indicated for complete, conservative surgical but incidence is increasing in younger women of
excision with recurrence rarely reported (Felix child-bearing age (Lim et al. 2014). Prognosis of
et al. 2013). The number of melanocytic nevi malignant melanoma is dependent on depth of
represents an independent risk factor for develop- invasion, lesion thickness, and stage of disease at
ment of melanoma, with greater than 50 nevi diagnosis utilizing the Clark system, the Breslow
increasing the risk of melanoma approximately classification, and the tumor node metastasis
(TNM) staging criteria, respectively (Lim et al. There is a relationship between a prior personal
2014). Thicker lesions and advanced-stage dis- or family history and malignant melanoma risk
ease have a much lower 5-year survival rate, and with approximately 10% of malignant melanomas
metastatic melanoma is associated with a median occurring in familial clusters (Lim et al. 2014).
survival time of 6 to 9 months (Lim et al. 2014). Mutations have been identified in two high-
Oral malignant melanoma occurs much less penetrance susceptibility genes, the cyclin-
frequently than its cutaneous counterpart; it com- dependent kinase inhibitor 2A (CDKN2A) on
prises less than 1% of all malignant melanomas in chromosome 19p21 and cyclin-dependent kinase
the United States and 0.26% of all oral cavity 4 (CDK4) on chromosome 12q14 (Lim et al.
cancers worldwide (Hashemi Pour 2008). Data 2014). The MC1R gene has been identified as a
suggests oral malignant melanoma may occur low penetrance malignant melanoma susceptibil-
more frequently in certain countries, such as ity gene, and alterations of the BRAF, HRAS, and
Japan and Uganda, and dark-skinned races have NRAS proto-oncogenes, and alteration or loss of
a greater relative incidence of oral malignant mel- PTEN function, have been associated with malig-
anoma and higher mortality rate associated with nant melanoma development (Lim et al. 2014).
this condition (Tarakji et al. 2014). Generally, oral As discussed previously, the number of
malignant melanoma occurs at a slightly higher melanocytic nevi represents an independent risk
frequency in males and generally presents after factor for development of malignant melanoma,
50 years of age with the peak age of diagnosis with greater than 50 nevi increasing the risk
between 65 and 79 years (Alawi 2013; Femiano of malignant melanoma approximately four- to
et al. 2008). Unlike cutaneous malignant mela- fivefold (Lim et al. 2014). Sun protection at
noma, histopathologic parameters cannot be reli- an early age may lower the subsequent risk of
ably used to determine prognosis of oral malignant melanoma (Lim et al. 2014; MacLen-
malignant melanoma (Alawi 2013). Oral malignan et al. 2003).
nant melanoma is associated with a very poor The etiology of oral malignant melanoma is
prognosis; 5-year survival rates range between unknown, and unlike its cutaneous counterpart,
5% and 50% with a large cluster at 10–25% risk factors for development have not been clearly
(Femiano et al. 2008). Less than 10% of patients defined (Femiano et al. 2008).
with distant metastases survive greater than
5 years, and the 10-year survival rate has been Pathophysiology
reported to be 0% (Hashemi Pour 2008). Malignant melanomas may either develop de
novo or from a preexisting benign melanocytic
Etiology lesion (Chatzistefanou et al. 2016). Melanocytes
While the cause of malignant melanoma has not are neuroectodermal derivatives and normally
been clearly defined, multiple risk factors have migrate to the skin and other ectodermally derived
been associated with onset of the cancer (Lim mucosae (Femiano et al. 2008). Less frequently,
et al. 2014). melanocytes migrate to endodermally derived
Exposure to the sun is the most important mucosae, such as those found in the head and
environmental cause of cutaneous malignant mel- neck, and melanocytes have been observed in
anoma, with ultraviolet radiation, primarily ultra- the deep stroma of oral mucosa (Femiano et al.
violet A type, being most associated with 2008). Due to both extrinsic and intrinsic factors
tumorigenesis and development of the disease previously described, proliferation of malignant
(Lim et al. 2014). In light-skinned populations, melanocytes gives rise to a variety of melanoma
the main nonsolar source of exposure to ultravio- types.
let light are tanning beds, and several recent stud-
ies demonstrate that the risk of malignant Clinical-Pathologic Features
melanoma is increased by 20% for those who Malignant melanoma can have a variety of clini-
ever used indoor tanning (Lim et al. 2014). cal appearances, with early lesions typically
characterized by a macule or plaque with different represents 15% of cutaneous melanomas and is
hues (brown, black, blue, red, or white) or occa- more common in men (Lim et al. 2014). Typically,
sionally as an ulceration that does not heal (Lim they are found on the trunk, and, interestingly,
et al. 2014). The ABCDE acronym (asymmetry, one-third of lesions develop in the head and neck
border irregularity, color variegation, diameter (Lim et al. 2014). Clinically, nodular melanoma
greater than 6 mm, and evolution or surface ele- may be deeply pigmented (Fig. 16); however, due
vation) is commonly used to initially evaluate to the possibility of melanoma cells being so
pigmented cutaneous lesions, although not all poorly differentiated, these cells may stop produc-
malignant melanomas present with all of these ing melanin, resulting in a nonpigmented
features (Lim et al. 2014). The anatomic distribu- amelanotic macule. Lentigo maligna melanoma
tion of malignant melanoma differs by sex and accounts for 5–10% of melanomas and has a
age. In men, lesions are commonly located on the predilection for sun-exposed areas such as the
trunk (55%), especially the back (39%), while in nose, malar region, temple, forehead, neck, and
women, 42% of malignant melanoma lesions are forearms in older adults (Lim et al. 2014). It pre-
localized to the lower extremities, with 24% on sents as a slowly enlarging, asymmetric macule
the lower leg (Lim et al. 2014). with irregular borders that is variably pigmented
Four major clinical-pathologic subtypes of with tan, brown, black, and possibly white colors
non-oral malignant melanoma have been (Lim et al. 2014). Acral lentiginous melanoma,
described: superficial spreading melanoma, the least common subtype, accounts for less than
lentigo maligna melanoma, acral lentiginous mel- 5% of all melanomas but accounts for 70% of
anoma, and nodular melanoma (Lim et al. 2014). melanomas seen in African-Americans (Lim
Superficial spreading melanoma is the most com-
mon subtype, accounting for 70% of all mela-
noma diagnoses (Lim et al. 2014). Most lesions
of this type occur de novo, and, clinically, a super-
ficial spreading melanoma appears variegated
with a sharply marginated, irregular border and
is typically smaller than 3 cm (Lim et al. 2014).
Multiple hues and shades are often noted with
superficial spreading melanoma, such as tan,
brown, gray, black, blue, white, and pink (Lim
et al. 2014) (Figs. 14 and 15). Nodular melanoma
Fig. 14 Superficial spreading melanoma of the scalp Fig. 15 Superficial spreading melanoma of the cheek
(1.2 mm in depth) in an 86-year-old male (Image courtesy (0.7 mm in depth) in a 71-year-old male (Image courtesy
of Dr Simon Lee, The Skin Hospital, Darlinghurst NSW, of Dr Simon Lee, The Skin Hospital, Darlinghurst NSW,
Australia) Australia)
erythema and/or ulceration, which can poten-

tially cause pain (Mohan et al. 2013). Tooth
mobility or spontaneous exfoliation, root resorp-
tion, anesthesia/paresthesia, and bone loss may
be evident (Mohan et al. 2013). Diffuse, contig-
uous mucosal pigmentation should be viewed
suspiciously as possible malignant melanoma
compared to diffuse, noncontiguous pigmenta-
tion (Alawi 2013). While any mucosal site may
be affected, the palate is the most common
intraoral location of oral malignant melanoma
followed by the maxillary gingiva/alveolar crest
(Femiano et al. 2008) (Fig. 18a, b). There may be
Fig. 16 Nodular melanoma on the toe (5.7 mm in depth) radiographic evidence of “moth-eaten” or irreg-
in a 67-year-old male (Image courtesy of Dr Simon Lee,
The Skin Hospital, Darlinghurst NSW, Australia) ular bone destruction associated with these
lesions, and cervical lymph nodes may be palpa-
ble due to metastasis at initial presentation
(Hashemi Pour 2008).
Microscopically, superficial spreading mela-
noma, lentigo maligna melanoma, and acral
lentiginous melanoma demonstrate a lateral and
superficial spread of melanocytic tumor cells
along the basal layer of the surface epithelium
prior to invasion of the underlying connective
tissue, which is described as radial extension
(Lim et al. 2014). Pagetoid and nested epithelioid
melanocytes cells in the intraepidermal portion
with poor circumscription are characteristic of
superficial spreading melanoma (Lim et al.
2014). In contrast, nodular melanoma is charac-
Fig. 17 Malignant melanoma present on the lower labial
terized by vertical growth of malignant melano-
mucosa
cytes into the connective tissue, which typically
occurs early in the disease process. The tumor
et al. 2014). Clinically, it affects hairless areas like usually appears as pleomorphic, spindle-shaped,
subungual, palmar, and plantar regions and or epithelioid cells arranged in loosely aggregated
mucous membranes and presents as a variably sheets and cords.
colored macule, usually brown or black, which Oral malignant melanomas are usually charac-
develops irregular borders and increases in size terized by sheets or islands of malignant melano-
over time (Lim et al. 2014). cytes within the connective tissue with possible
Oral malignant melanoma, however, has no pagetoid spread (Alawi 2013; Chatzistefanou
such distinctive clinical appearance and is often et al. 2016) (Fig. 19). Poorly differentiated tumors
initially asymptomatic. The lesion typically may exhibit only minimal pigment or none at all
begins as a brown to black macule with irregular (Fig. 20). Like its cutaneous counterpart, oral
borders and may even lack pigment (Hashemi malignant melanomas exhibit an initial radial
Pour 2008) (Fig. 17). Lesions are relatively soft growth phase, typically followed by a vertical
to palpation and may be accompanied by pattern of growth with deeper tissue invasion
Fig. 18 Biopsy-proven gingival malignant melanoma in malignant cells and superficial underlying connective tis-
67-year-old male appearing as multiple black pigmented sue (b) (Images courtesy of Professor Camile Farah, UWA
lesions along the attached gingiva adjacent to upper ante- Dental School, University of Western Australia, Perth WA,
rior teeth (a). Hematoxylin- and eosin-stained histological Australia)
section of lesion demonstrating brown pigment in
(Chatzistefanou et al. 2016). The presence of (Alawi 2013). Surgical excision is the primary
malignant cells in the lamina propria and a high treatment modality for malignant melanoma,
tumor mitotic rate are characteristic of invading which is curative for most patients with early-
activity (Chatzistefanou et al. 2016). Immunohis- stage lesions (Chatzistefanou et al. 2016). Wide
tochemistry studies using antibodies directed excision is recommended, but the recommended
against HMB45, S100, MART1, and/or micro- surgical margin varies, depending on the depth of
phthalmia-associated transcription factor (MitF) the tumor (Lim et al. 2014). Lymph node dissec-
are necessary for definitive diagnosis of oral tion is typically performed on patients with clini-
malignant melanoma (Muller 2010) (Fig. 21). cally evident regional metastasis in the absence of
distant metastasis (Chatzistefanou et al. 2016).
Patient Management Adjuvant systemic therapies have limited success
Biopsy is mandatory for any persistent solitary in the treatment of advanced-stage malignant mel-
pigmented lesion, as they can be representative anoma, which include interferon-a, high-dose
of a variety of processes, from innocuous lesions interleukin 2, ipilimumab (a monoclonal antibody
to life-threatening malignant melanoma (Mohan that works to activate the immune system
et al. 2013). Once malignant melanoma is diag- by targeting CTLA-4, a protein receptor that
nosed, it is important, yet challenging, to deter- downregulates the immune system), and
mine if the lesion represents a primary malignancy bevacizumab (a recombinant humanized mono-
or a metastasis from a distant site, as this informa- clonal antibody that blocks angiogenesis by
tion will dictate tumor staging and direct therapy inhibiting vascular endothelial growth factor-A)
Fig. 21 Anti-HMB45 immunohistochemical analysis.

The malignant tumor cells (see Fig. 6) were strongly reac-
tive with the melanocytic marker HMB45
Multifocal/Diffuse Pigmentation
Physiologic Pigmentation
Fig. 19 Mucosal melanoma. Sheets and cords of malig- Epidemiology

nant melanocytes scattered throughout the lamina propria Physiologic (“racial”) pigmentation is the most
(Hematoxylin and eosin stain, 100)
common multifocal or diffuse oral mucosal pig-
mentation; however, it is not directly related
to skin color (Gaeta et al. 2002; Tarakji et al.
2014). It is typically observed in dark-skinned
individuals, most commonly in African, Asian,
or Mediterranean populations without gender pre-
dilection (Kauzman et al. 2004; Meleti et al.
2008). It is seen during the first two decades of
life but may not be observed and/or of individual
concern until later in life (Kauzman et al. 2004;
Tarakji et al. 2014).
Etiology
The etiology of physiologic pigmentation has not
been identified (Muller 2010).
Fig. 20 Amelanotic melanoma exhibiting only focal pig- Pathophysiology

mentation (arrow). The tumor cells are poorly differenti-
ated (Hematoxylin and eosin stain, 200)
The increased pigmentation associated with this
condition is attributed to increased melanocytic
activity rather than an increase in numbers
(Lim et al. 2014). The role of radiotherapy is of melanocytes. It has been reported that color
limited since malignant melanoma is radio resis- intensity of the lesions may be influenced by
tant compared with other cancers (Lim et al. hormones, smoking, and systemic medications
2014). (Muller 2010).
Clinical-Pathologic Features Patient Management

Physiologic pigmentation typically affects the Diagnosis of physiologic pigmentation is typi-
gingiva, where it presents as a bilateral, well- cally made based on clinical appearance, and
demarcated, ribbon-like band of brown pigment treatment is not indicated for this condition
that usually does not affect the marginal gingiva (Meleti et al. 2008). Biopsy may be indicated if
nor interfere with normal tissue architecture pigmentation is of recent onset in adulthood
(Kauzman et al. 2004; Tarakji et al. 2014) and/or the patient reports physical symptoms that
(Figs. 22 and 23). Other sites that may be affected may be related to a systemic disorder, such as
include the buccal mucosa, lips, palate, and Addison disease, that may cause development of
tongue (Kauzman et al. 2004). The color associ- oral pigmentation (Muller 2010). This condition
ated with this condition ranges from light brown may be of esthetic concern to patients, and
to black, and patients affected by physiologic although procedures such as gingivectomy, laser
pigmentation are asymptomatic (Muller 2010; therapy, and cryotherapy have been used to
Tarakji et al. 2014). Microscopically, this condi- remove affected tissues, these lesions may even-
tion is characterized by the presence of increased tually recur. The practice of gingival tattooing in
amounts of melanin deposition within the basal females is a custom that is practiced among sev-
cell layer (Gondak et al. 2012) (Fig. 24). eral African ethnic groups and may appear clini-
cally similar to physiologic pigmentation (Rawal
et al. 2007). Traditionally, products such as lan-
tern soot and botanical resins are applied to the
maxillary labial gingiva of preteen and teenaged
females via needles and thorns to the affected
Fig. 22 Physiologic pigmentation of the maxillary and

mandibular gingiva
Fig. 23 Physiological pigmentation in a patient of African

heritage appearing as widespread brown and black pig-
mentation along the attached gingiva (Image courtesy of Fig. 24 Physiologic pigmentation. Anti-MART1 anti-
Professor Camile Farah, Perth Oral Medicine & Dental body was used to highlight normal melanocytes (arrows)
Sleep Centre, Perth WA, Australia) residing in the basal epithelial layer
Fig. 25 Extensive gray/black coloration of the maxillary

labial attached gingiva as a result of intraoral cosmetic Fig. 26 Chemotherapy-induced pigmentation affecting
tattooing. Note the presence of diffuse brown pigmentation the tongue
involving the mandibular labial gingiva and the anterior
portions of the maxillary labial gingiva consistent with
physiological pigmentation (Image courtesy of Professor
Michael McCullough, Melbourne Dental School, Univer- Pathophysiology
sity of Melbourne, VIC, Australia)
In some cases, the coloration is true pigmentation
resulting from stimulation of melanin synthesis by
surfaces (Brooks and Reynolds 2007, Rawal et al. the drug and/or its metabolites; the mechanisms
2007.) This practice is primarily for cosmetic rea- may differ between different drugs. In other cases,
sons to make the teeth appear whiter, which is a drug precipitates deposit within the lamina propria
highly desirable beauty mark in some African or submucosa resulting in blue-brown-black
societies (Rawal et al. 2007) (Fig. 25). mucosal coloration (Alawi 2013; Yuan and Woo
2015).
Drug-Induced Melanosis
Epidemiology Drug-induced pigmentation can affect any
Mucosal coloration can be induced by an array of mucosal site. In general, the gingiva, tongue,
medications. It has been estimated that 10–20% of and hard palate are most commonly affected
all cases of acquired melanocytic pigmentation (Fig. 26). Some medications, such as
may be induced by drugs (Dereure 2001). hydroxychloroquine, produce characteristic pat-
terns of mucosal pigmentation; the palate is usu-
Etiology ally affected in patients taking this drug (Alawi
Several medications have been implicated in 2013). Minocycline can induce true melanocytic
drug-induced melanosis such as hormones and pigmentation and produce precipitates that
oral contraceptives; antipsychotics including deposit within soft and hard tissues, including
chlorpromazine; antimalarial drugs such as bone, and appear blue gray or even green in
hydroxychloroquine and quinacrine; chemothera- color (Hatch 2005; Kauzman et al. 2004;
peutic agents including bleomycin, busulfan, fluo- Bowen and McCalmont 2007; Tarakji et al.
rouracil, and imatinib; anti-retroviral agents 2014; Yuan and Woo 2015). Microscopically,
including zidovudine; anti-fungal drugs such as basilar hyperpigmentation and melanin inconti-
ketoconazole; and anti-microbial agents including nence without a concomitant increase in number
minocycline and tetracycline (Moraes et al. 2011; of melanocytes are characteristics of drug-
Alawi 2013; Yuan and Woo 2015). induced melanotic lesions.
Patient Management (Hassona et al. 2016; Muller 2010). Additionally,

Diagnosis of drug-induced melanosis can be the heat of the smoke is thought to be a stimulating
achieved if a temporal association is made factor for pigment development (Alawi 2013).
between the use of a medication and development Since smoker’s melanosis is more prevalent in
of pigmentation (Alawi 2013). Biopsy is women, it has been suggested that female sex
warranted if a diagnosis of drug-induced hormones (i.e., estrogen) may have a role in
melanosis cannot be appropriately rendered development of this condition (Kauzman et al.
(Alawi 2013). Drug-induced melanosis is clini- 2004; Muller 2010).
cally inconsequential beyond potential esthetic
concerns. Discontinuation of the medication Clinical-Pathologic Features
may eventually resolve the pigmentation, which Smoker’s melanosis typically presents as diffuse,
may take weeks to months to achieve (Alawi patchy melanosis affecting the anterior vestibular
2013). Malignant transformation of drug-induced maxillary and mandibular gingivae, buccal
melanotic lesions has not been reported (Tarakji mucosa, labial commissures, lateral tongue, pal-
et al. 2014). ate, and/or floor of the mouth (Muller 2010)
(Fig. 27). The color of the lesions is typically
brown to black (Alawi 2013). The areas of pig-
Smoker’s Melanosis mentation dramatically increase during the first
year of smoking and often correlate to the number
Epidemiology
Smoker’s melanosis is the term used to describe
oral mucosal pigmentation that develops second-
ary to heavy tobacco use. This condition has been
reported to affect nearly 22% of smokers and is
more common in females (Kauzman et al. 2004;
Muller 2010). This condition may cause oral pig-
mentation to develop in light-skinned individuals
and accentuate pigmentation in dark-skinned indi-
viduals (Tarakji et al. 2014).
Etiology
Polycyclic amines, such as nicotine and benzopy-
rene, are chemical compounds in tobacco
smoke that have demonstrated the ability to stim-
ulate melanocytes to produce melanin (Hassona
et al. 2016).
Pathophysiology
Melanin pigmentation in the skin is protective
against ultraviolet damage, and melanocytes in
non-sun-exposed areas produce melanin that
can bind to noxious substances (Meleti et al.
2008). It has been postulated that melanin produc-
Fig. 27 Smokers’ melanosis appearing as diffuse faint
tion stimulated by tobacco smoke may have a brown pigmentation on the buccal mucosa (Image courtesy
protective role against the harmful agents in the of Professor Camile Farah, Perth Oral Medicine & Dental
smoke, such as those described previously Sleep Centre, Perth WA, Australia)
of cigarettes smoked per day (Kauzman et al. Pathophysiology

2004). Histopathologically, this condition is char- Inflammatory conditions, such as lichen planus,
acterized by increased melanin pigmentation of cause perturbation of epithelial melanocytes,
the basal cell layer of the surface epithelium with resulting in increased melanin deposition in
collections of incontinent melanin pigmentation affected areas (Kauzman et al. 2004).
within the superficial connective tissue and in
scattered macrophages (Alawi 2013). Clinical-Pathologic Features
This condition is characterized by diffuse patches
of brown to black pigmentation of the involved
Patient Management
mucosa in the area of the underlying inflammatory
Diagnosis of smoker’s melanosis is usually
condition (Kauzman et al. 2004) (Figs. 28 and 29).
established by a positive history of tobacco use
Intraorally, these lesions are most often associated
correlated with characteristic physical findings on
with lichenoid inflammation, while skin lesions
clinical examination. If the lesion is present in an
attributed to post-inflammatory (inflammatory)
unexpected location and/or unusual changes are
hyperpigmentation commonly result from previ-
observed, such as surface elevation and/or
ous trauma (Alawi 2013). In rare cases, the pig-
increased melanin deposition, biopsy should be
mentation may be so dark that it clinically
considered (Kauzman et al. 2004). If only one
obscures the underlying lichenoid condition
mucosal site is affected, melanoma should be
(Alawi 2013). Histopathologic features of this
considered in the differential diagnosis as it can
condition include increased melanin pigment
also present as diffuse patchy pigmentation, and
within basal cells and melanin incontinence
tissue biopsy is warranted (Alawi 2013). Other
accompanied by typical lichenoid histologic fea-
causes of diffuse melanin pigmentation, such as
tures (Alawi 2013).
those described elsewhere in this chapter, should
be excluded. Cessation of smoking habits results
Patient Management
in gradual resolution of the lesions attributed to
Treatment is directed toward managing the under-
smoker’s melanosis, typically within a 3-year
lying inflammatory condition when symptomatic,
period (Kauzman et al. 2004; Tarakji et al.
typically with topical corticosteroids. Pigmenta-
2014). No additional treatment is recommended
tion may or may not resolve with resolution of the
as smoker’s melanosis is not considered a pre-
lichenoid inflammation, and if it does, it may take
neoplastic condition (Alawi 2013).
several months to fade (Alawi 2013).
Post-inflammatory (Inflammatory)
Hyperpigmentation
Epidemiology
Post-inflammatory (inflammatory) hyper-
pigmentation is a condition characterized by pig-
ment deposition in area(s) subjected to
inflammation or previous injury that is more com-
monly observed in dark-complexioned individ-
uals (Alawi 2013).
Etiology
The etiology of post-inflammatory (inflamma-
tory) hyperpigmentation has not been determined Fig. 28 Post-inflammatory (inflammatory) pigmentation
(Gondak et al. 2012; Tarakji et al. 2014). associated with lichenoid lesions on the buccal mucosa
2013; Fernandes et al. 2015; Nikitakis and

Koumaki 2013).
Pathophysiology
The precise pathophysiologic mechanism of
Laugier-Hunziker pigmentation is unclear, but it
is considered an acquired pigmentation disorder
that results from increased basal keratinocyte mel-
anin without an increase in melanocytes
(Nikitakis and Koumaki 2013).
Multifocal, macular hyperpigmentation of the oral
mucosa and lips is characteristic of Laugier-
Hunziker pigmentation (Alawi 2013; Nikitakis
and Koumaki 2013). Lesions may be solitary or
confluent, brown to black to gray in color, and
have been reported in all regions of the oral cavity,
including the lips, buccal mucosa, tongue, hard
palate, and gingiva (Nikitakis and Koumaki
2013). Melanotic longitudinal streaks in the nails
without associated nail dystrophy are frequently
associated with oral pigmentation (Alawi 2013;
Fig. 29 Post-inflammatory pigmentation on the left buc- Nikitakis and Koumaki 2013; Yago et al. 2008).
cal mucosa in a patient with mild oral lichen planus (Image Up to 60% of affected patients have nail involve-
courtesy of Professor Camile Farah, Perth Oral Medicine & ment with fingernails more commonly affected
than toenails (Fernandes et al. 2015). Similar
lesions may be observed on other cutaneous sur-
Laugier-Hunziker Pigmentation faces, such as the facial skin and abdomen, and
other mucosal surfaces, including the esophagus,
Epidemiology conjunctiva, and anogenital mucosa (Alawi 2013;
Laugier-Hunziker pigmentation (Laugier-Hunziker Nikitakis and Koumaki 2013). Typical histologic
syndrome, Laugier-Hunziker-Baran syndrome) is findings associated with Laugier-Hunziker pig-
characterized by acquired melanotic pigmentation mentation include increased basal keratinocyte
of the labial and buccal mucosa (Alawi 2013; Yago melanin without an increase in number of mela-
et al. 2008). This is considered a rare condition that nocytes, melanin incontinence, and epithelial
usually begins in the third to fifth decade of life acanthosis in the absence of rete ridges or inflam-
with an overall female-male ratio of 2:1 (Nikitakis mation (Nikitakis and Koumaki 2013).
and Koumaki 2013; Yago et al. 2008). This condi-
tion has been reported in individuals in North Patient Management
America, Europe, and Asia and has been more Treatment for this condition is typically not indi-
commonly observed in Caucasian or light-skinned cated unless there is an esthetic and/or psycholog-
individuals (Yago et al. 2008). ical concern (Nikitakis and Koumaki 2013). Laser
therapy and cryotherapy have been used to remove
Etiology pigmentation, but recurrence is possible (Nikitakis
While the etiology of Laugier-Hunziker pigmen- and Koumaki 2013). It is important to consider
tation is unknown, hormonal or genetic roles have systemic etiologies in the differential diagnosis of
not been associated with this condition (Alawi Laugier-Hunziker pigmentation, such as Addison
disease and Peutz-Jeghers syndrome, as these con- is also more common in females but is usually
ditions are also characterized by multiple oral diagnosed later in life. While the prevalence of
mucosal macules (Nikitakis and Koumaki 2013). oral mucosal hyperpigmentation (OMH) associ-
A thorough medical, social, and family history, in ated with adrenal insufficiency is not known,
addition to a complete review of systems, are OMH is observed only in primary disease states.
important in rendering an accurate diagnosis and
appropriate referral to medical specialists, if neces- Etiology
sary. Biopsy may be considered to confirm the The hypothalamus-pituitary-adrenal gland axis
clinical diagnosis and rule out other sources of is tightly coordinated to ensure glucocorticoid
oral pigmentation. Laugier-Hunziker pigmentation homeostasis (Charmandari et al. 2014). The
is a diagnosis of exclusion after all other potential hypothalamus produces corticotropin-releasing
sources for pigmentation have been eliminated as hormone (CRH) and vasopressin. These hor-
an etiology for the condition (Alawi 2013). mones act synergistically on the pituitary gland
Laugier-Hunziker pigmentation is not associated to activate pro-opiomelanocortin (POMC) gene
with malignant predisposition (Fernandes et al. expression (Anderson et al. 2016). The
2015; Rangwala et al. 2010; Yago et al. 2008). corresponding 241 amino acid POMC polypep-
tide then undergoes an array of posttranslational
modifications to yield several biologically distinct
Pigmentation Associated hormone peptides. These include adrenocortico-
with Systemic or Genetic Disorders tropic hormone (ACTH); α-, β-, and
γ-melanotropins (also known as melanocyte stim-
Adrenal Insufficiency (Addison ulating hormone), respectively, β- and
Disease) γ-lipotropins; β-endorphin; and metenkephalin
(Anderson et al. 2016). ACTH is secreted into
Epidemiology the circulation and binds to receptors in the adre-
Adrenal insufficiency is a potentially life- nal cortex to stimulate glucocorticoid production
threatening endocrinopathy that is characterized and release. Once serum cortisol levels are stabi-
by diminished production of glucocorticoids (cor- lized, ACTH and CRH synthesis are inhibited
tisol) with or without a concomitant deficiency in through an intricate negative feedback mecha-
mineralocorticoid and adrenal androgen levels nism. When reduced cortisol levels are sensed
(Naziat and Grossman 2000). Dysfunction in the by the hypothalamus, the CRH-POMC-ACTH-
hypothalamus-pituitary-adrenal gland axis gives cortisol signaling cascade is reactivated.
rise to adrenal insufficiency. Primary, secondary, OMH is observed only in primary adrenal
and tertiary forms of adrenal insufficiency are insufficiency (Charmandari et al. 2014). The con-
dependent upon the anatomic site of origin pre- stitutively low cortisol levels stimulate persistent
cipitating the dysfunction. POMC production to yield high levels of ACTH.
An estimated 4.4–6 new cases of primary adre- Since the defective adrenal glands are unable to
nal insufficiency develop per million people per sufficiently respond to ACTH, the signaling cas-
year (Charmandari et al. 2014). In contrast, sec- cade remains active. In conjunction with ACTH
ondary adrenal insufficiency is more common overproduction, α-MSH levels are also increased
than the primary disease with an estimated preva- in parallel. α-MSH is a short peptide encoded
lence of 150–280 per million people. Overall, the within the ACTH peptide and generated via post-
prevalence of Addison disease in Caucasians is translational cleavage (Anderson et al. 2016).
estimated to be between 1 in 8000–20,000 in the Since α-MSH is a potent stimulator of melano-
United States and Europe (Naziat and Grossman genesis, this triggers the mucocutaneous pigmen-
2000). Primary adrenal insufficiency manifests tation observed in primary adrenal insufficiency
more frequently in females than males and often (Anderson et al. 2016; Feller et al. 2014b). ACTH
between the ages of 30 and 50. Secondary disease and α-MSH levels are reduced in secondary and
tertiary adrenal insufficiency (Charmandari et al.

2014). Thus, the pigmentation does not occur in
these forms of the disease.
Pathophysiology
Primary adrenal insufficiency is caused by adre-
nocortical disease. While the most common cause
is autoimmune adrenalitis, other conditions such
as cancer, infection, and hemorrhagic infarction
can also directly damage the adrenal glands
(Charmandari et al. 2014). Several genetic disor-
ders may lead to congenital defects in adrenal
gland structure and function. Other genetic dis- Fig. 30 Oral mucosal pigmentation in a Caucasian patient
eases may affect sensitivity of the glands to with adrenal insufficiency. Melanin pigmentation is noted
ACTH, limit glucocorticoid synthesis, or acceler- in the basal epithelial layer. This patient was diagnosed
with Addison disease 2 months after he developed diffuse
ate cortisol metabolism. A number of medications
oral pigmentation and histopathologic evaluation of the
can also limit glucocorticoid biosynthesis or biopsy tissue (Hematoxylin and eosin stain, 200)
accelerate cortisol metabolism (Michels and
Michels 2014). Examples include phenobarbital
and phenytoin which activate cytochrome P450
signs and symptoms may become generalized.
enzymes thereby stimulating glucocorticoid
Complications may include weakness and
metabolism. The antimycotic fluconazole and
fatigue, gastrointestinal complaints, orthostatic
ketoconazole reduce cortisol synthesis by
hypotension, musculoskeletal pain, anorexia,
inhibiting mitochondrial cytochrome P450
salt craving, and behavioral changes
enzymes. In rare instances, the use of the tyrosine
(Charmandari et al. 2014). While the hyper-
kinase inhibitors imatinib, saracatinib, and
pigmentation is not clinically significant, its sud-
sunitinib has been associated with adrenal insuf-
den appearance may necessitate evaluation of the
ficiency and other endocrinopathies, including
patient for Addison disease.
hypothyroidism and alterations of glucose metab-
olism (Lodish 2013).
Patient Management
Secondary insufficiency is caused by surgical
Treatment of adrenal insufficiency should be
trauma and neoplastic (e.g., pituitary adenoma) or
implemented as soon as a deficiency state is rec-
genetic disorders (e.g., Prader-Willi syndrome)
ognized. Glucocorticoid replacement therapy via
affecting the anterior lobe of the pituitary gland
oral hydrocortisone supplementation (15–25 mg
resulting in reduced secretion of ACTH
daily divided in two or three doses) is usually the
(Charmandari et al. 2014). Tertiary adrenal insuf-
treatment of choice (Napier and Pearce 2014). The
ficiency is usually caused by chronic exposure to
exact daily dosage should be titrated based on the
exogenous glucocorticoids resulting in decreased
patient’s weight; higher dosing is typically
secretion of CRH and/or vasopressin from the
recommended for heavier patients. Low-dose
hypothalamus.
oral prednisone therapy (3–5 mg once daily) or
intramuscular dexamethasone (0.5 mg once daily)
Clinical-Pathologic Features can also be used. Dexamethasone injections are
The onset of primary adrenal insufficiency may recommended for patients who are unable to tol-
be insidious and nonspecific. The first sign of erate oral medications. Mineralocorticoid- and
disease may be diffuse bronzing of the skin androgen-replacement therapy is also frequently
with or without patchy OMH (Fig. 30). With necessary. Once serum cortisol levels normalize,
persistence of the cortisol deficiency, the clinical the pigmentation may eventually resolve.
Cushing Disease diabetes, dyslipidemia, obesity, and

neurocognitive and psychiatric disorders. Risk
Cushing syndrome is a potentially life- from death associated with cardiovascular com-
threatening disease caused by prolonged exposure plications also remains elevated.
to hypercortisolism that may arise from exoge- Cushing disease accounts for 65–80% of all
nous or endogenous causes (Sharma et al. 2015). ACTH-dependent forms of Cushing syndrome
Overadministration of glucocorticoids such as (Lacroix et al. 2015). It has an estimated preva-
dexamethasone and prednisone, or drugs that lence of 39.1 per million persons. Overall, females
reduce the clearance of synthetic glucocorticoids, are more commonly afflicted than males; ratios of
including itraconazole, are the major cause of 3–5:1 have been reported. Although Cushing dis-
Cushing syndrome. Endogenous Cushing syn- ease can present at any age, most cases are diag-
drome is classified into ACTH-dependent and nosed in the fourth decade, with females
ACTH-independent variants (Lacroix et al. frequently being diagnosed at an earlier age than
2015). males.
Cushing disease is the most common cause of
ACTH-dependent endogenous Cushing syn- Etiology
drome (Sharma et al. 2015). Cushing disease is Cushing disease is usually caused by a primary
primarily induced by an ACTH-secreting pitui- pituitary pathology – usually an ACTH-secreting
tary adenoma. Other ACTH-dependent forms of adenoma (Lonser et al. 2016). In rare instances,
Cushing syndrome may arise from ectopic tumors in other anatomic sites can also precipi-
ACTH- or, rarely, CRH-secreting tumors origi- tate ACTH-dependent ectopic Cushing syn-
nating in other anatomic sites. ACTH- drome. These include small cell neuroendocrine
independent Cushing syndrome develops sec- and carcinoid tumors of the lung and other
ondary to functional adrenal neoplasms (Lacroix organs, islet-cell tumors of the pancreas, medul-
et al. 2015). Oral melanocytic pigmentation only lary thyroid carcinoma, pheochromocytomas,
develops in ACTH-dependent Cushing syn- and thymomas. Hyperpigmentation may be
drome. The ensuing discussion will focus on observed in any ACTH-dependent form of Cush-
Cushing disease. ing syndrome.
Epidemiology Pathophysiology
The estimated incidence rate of endogenous Excessive and pathologically constitutive secre-
Cushing syndrome is 0.7–2.4 per million tion of ACTH results in persistent stimulation of
populations per year, with a standardized mortal- the adrenal glands to release cortisol (Lonser et al.
ity ratio of almost four (Sharma et al. 2015). It is 2016). Since the pituitary neoplasm is resistant to
possible that incidence rates of endogenous Cush- the negative feedback control mechanisms,
ing syndrome are underestimated. Studies of ACTH and cortisol levels remain high. The muco-
patients with uncontrolled diabetes, hypertension, cutaneous pigmentation develops via the same
or early-onset osteoporosis have revealed previ- mechanism as that described for primary adrenal
ously undiagnosed Cushing syndrome in a subset insufficiency, i.e., α-MSH levels increase in par-
of cases (De Leo et al. 2012). allel with ACTH.
Most patients die of disease within the first In rare instances, Cushing disease may also be
year after initial presentation. Even with appropri- a manifestation of genetic diseases, including
ate treatment, the risk for disease-related morbid- multiple endocrine neoplasia type 1 (MEN1) and
ity and mortality remains significantly higher than multiple endocrine neoplasia type 4 (MEN4)
that of the general population and may persist for (Schernthaner-Reiter et al. 2016). Germline muta-
several years after normalization of cortisol levels tions of the MEN1 and CDKN1B genes precipi-
(Lonser et al. 2016). In particular, treated patients tate MEN1 and MEN4 syndromes, respectively
may retain a high risk for future development of (Schernthaner-Reiter et al. 2016).
Germline mutations in the aryl-hydrocarbon suppression, male impotence, and female infertil-
receptor-interacting protein predispose to pitui- ity (Lacroix et al. 2015).
tary adenomas (pituitary adenoma predisposition
syndrome) (Lloyd and Grossman 2014). Cushing Patient Management
disease may also manifest in Carney complex There is no specific treatment for the pigmenta-
resulting from pituitary adenoma harboring a tion. Treatment of the underlying cause of Cush-
germline mutation in PRKAR1A (Schernthaner- ing disease – usually surgical removal of the
Reiter et al. 2016). Similarly, somatic mutations pituitary tumor – often times has an immediate
of GNAS (G-protein-coupled receptor alpha sub- inhibitory effect on cortisol secretion (Lau et al.
unit [Gsα], which activates adenylate cyclase) 2015). In cases where the tumor may be inopera-
also predispose to pituitary adenomas (Brown ble, radiation therapy may be employed, or the
et al. 2010). GNAS mutations are associated with hypercortisolism may be treated medicinally.
McCune-Albright syndrome. Patients with this Medical therapies can target the pituitary gland,
disorder also develop pigmented macular lesions the adrenal gland, or the peripheral tissues. Pitui-
of the skin known as café-au-lait spots. Caf- tary targeting is designed to inhibit ACTH syn-
é-au-lait pigmentation does not occur within the thesis and secretion. Cabergoline (dopamine
oral cavity. 2 receptor agonist) and pasireotide (somatostatin
5 receptor agonist) are two drugs that are currently
Clinical-Pathologic Features available for patients who are poor surgical can-
Oral mucosal and/or cutaneous hyper- didates or who failed surgical therapy (Lau et al.
pigmentation may be one of the earliest signs of 2015). Steroidogenic inhibitors including ketoco-
Cushing disease (Lacroix et al. 2015) (Fig. 31). nazole may be used to inhibit cortisol synthesis.
More significantly, prolonged exposure to hyper- Mifepristone is a progesterone receptor antagonist
cortisolism results in an array of variably severe that also inhibits glucocorticoid receptor activity.
and potentially life-threatening complications. Mifepristone reduces the hyperglycemia associ-
Most commonly these include but are not limited ated with Cushing disease. Resolution of the bio-
to obesity, diabetes mellitus, moon facies, hyper- chemical defect will result in normalization of
tension, amenorrhea, osteoporosis, hirsutism, ACTH and α-MSH levels. Over time, the pigmen-
abdominal striae, dorsocervical fat pads (“buffalo tation may eventually resolve.
hump”), cutaneous purpura, poor wound healing,
muscular weakness, psychological, psychiatric
and neurocognitive disturbances, immune Human Immunodeficiency Virus (HIV):
Associated Pigmentation
Epidemiology
OMH is a recognized occurrence in HIV-seropos-
itive and AIDS-afflicted individuals. If it
develops, the pigmentation usually becomes
apparent within the first 2 years after initial HIV
diagnosis and usually in patients with CD4+ T-cell
counts of 200 cells/mm3 or less (Feller et al.
2014a). A potential relationship between viral
load and OMH remains uncertain.
The overall prevalence of OMH is not known.
However, there are geographic and ethnic differ-
Fig. 31 Multifocal mucosal pigmentation on the hard ences that could reflect specific characteristics of
palate (arrows) in a patient who was eventually diagnosed the HIV infection, access to appropriate treatment,
with Cushing syndrome and/or administration of specific drug regimens.
In South Africa, Venezuela, and India, 18.5–38% gland or by medications used to treat the disease.
of HIV-seropositive patients were identified with Ritonavir (protease inhibitor) in combination with
OMH (Bravo et al. 2006; Chandran et al. 2016; exogenous steroids is known to induce adrenal
Feller et al. 2014a). In contrast, in Greece and Italy insufficiency which, in turn, may induce the pig-
OMH accounts for less than 2% and 7%, respec- mentation (Wood et al. 2015).
tively, of all examined patients. In general, muco-
sal pigmentation is usually more prominent in Pathophysiology
darker-skinned individuals and may be more The pathogenesis of HIV-associated pigmentation
prevalent in females than in males (Feller et al. varies depending on the etiologic agent. Similar to
2014a). In at least one study, HIV-associated other forms of OMH, the pigmentation is usually
OMH was also significantly associated with the result of increased melanogenesis without a
smoking (Chandran et al. 2016). change in melanocyte number. The pigment is
concentrated within the basal layer of the stratified
Etiology squamous epithelium and accompanied by mela-
The etiology of HIV/AIDS-associated pigmenta- nin incontinence within the papillary lamina pro-
tion is multifactorial. There is currently no evi- pria (Feller et al. 2014a). The pigment is often
dence HIV can directly infect or activate easily visualized in biopsy tissue with routine
melanocytes (Feller et al. 2014a). Instead, light microscopy. HIV-induced cytokine
HIV-induced cytokine dysregulation may induce dysregulation and AZT and other medications
OMH. Nonspecific, generalized oral mucosal may also induce pigmentation by stimulating
inflammation could also be contributory. melanocytic hyperplasia accompanied by an
Pro-inflammatory cytokines including interleukin increase in melanin synthesis.
(IL)-1, IL-6, and tumor necrosis factor (TNF)-α
are known to regulate melanocytes and Clinical-Pathologic Features
melanogenesis (Feller et al. 2014b). Constitutive The pigmentation may manifest as multiple dis-
upregulation of these and other pro-inflammatory crete light to dark brown macules or as patchy and
mediators may stimulate production of α-MSH diffuse. The coloration may appear anywhere
thereby leading to the pigmentation. within the oral cavity, but the gingiva tends to be
HIV-induced cytokine dysregulation typically the most commonly affected site. In darker-
parallels decreasing CD4+ T-cell counts (Feller skinned individuals, differentiating
et al. 2014a). HIV-associated pigment from physiologic pig-
More commonly, OMH may arise in response mentation may be difficult. The appearance,
to treatment with a number of different medica- extent, and intensity of OMH is also similar to
tions frequently used to treat HIV/AIDS and its that observed in other disorders known to induce
associated complications; zidovudine (azidothy- mucocutaneous pigmentation. The diagnosis of
midine [AZT]; nucleoside reverse transcriptase HIV-associated pigmentation is rendered if the
inhibitor) is just one example (Feller et al. pigment initially appears or becomes exacerbated
2014a). The pigment frequently appears within after the diagnosis of HIV infection or following
the first few weeks after initiation of the therapy. the initiation of therapy (Feller et al. 2014a).
When the drug is withdrawn, the pigment usually
diminishes. OMH is significantly more common Patient Management
in HIV-seropositive patients treated with antire- Apart from possible esthetic concerns, there does
troviral therapy (ART) than in ART-naïve not appear any clinical significance attributable to
individuals. HIV-associated OMH. However, new onset oral
Primary or secondary adrenocortical dysfunc- pigmentation in an individual deemed potentially
tion may occur in as many as 20% of HIV patients high risk for HIV infection, including intravenous
(Hruz 2014). This may be due to HIV-associated drug users, should prompt an evaluation for pos-
viral or mycobacterial infections of the adrenal sible infection.
Peutz-Jeghers Syndrome mucocutaneous pigmentation is observed in

essentially all patients with PJS (Ponti et al.
Peutz-Jeghers syndrome (PJS) is an autosomal 2016). Moreover, the hyperpigmentation can be
dominant disorder associated with oral and perioral observed in STK11-deficient murine models
melanocytic pigmentation, benign hamartomatous (Meserve and Nucci 2016). Nonetheless, the
polyps of the gastrointestinal tract, and increased mechanisms by which loss of STK11 function
risk for developing malignancies of the gastrointes- induces hyperpigmentation remain unclear.
tinal tract, breast, uterine cervix, ovary, pancreas,
and other anatomic sites (Riegert-Johnson et al. Clinical-Pathologic Features
2009). The risk is estimated to be 18-fold higher PJS is commonly associated with multiple mela-
than that of the general population. The hyper- notic macules of the lips accompanied by diffuse
pigmentation often manifests early in life and may freckling of the perioral skin (Ponti et al. 2016)
be the first sign of disease in some patients. (Fig. 32). The pigmented macules may coalesce to
produce broader areas of pigmentation. Less com-
Epidemiology monly, intraoral pigmentation may also be
Since PJS is a rare disorder, reliable estimates of observed; the tongue and buccal and/or labial
incidence and prevalence are lacking. Nonetheless, mucosae are typically affected. Pigmented spots
PJS has an estimated incidence of 1 in are also commonly observed on the fingertips.
8000–200,000 live births without gender or racial The pigmentation typically presents during
predilection (Riegert-Johnson et al. 2009). Mortal- infancy, childhood, or adolescence, and is often
ity associated with PJS is usually cancer related. the first sign of PJS. At least some of the pigmen-
tation may spontaneously resolve with age.
Etiology A biopsy of a pigmented lesion usually reveals
Approximately 75% of all PJS patients harbor a nonspecific histopathology (Ponti et al. 2016).
germline mutation in the SKT11 (LKB1) gene There is increased melanin pigmentation within
located on chromosome 19p13.3 (Meserve and the basal epithelial layer and melanin inconti-
Nucci 2016). The remaining patients do not have nence within the papillary lamina propria. There
known STK11 mutations; the genetic cause of these may also be evidence of melanocytic hyperplasia.
patients’ disease remains undetermined. Mutations Note that while highly characteristic, the pat-
in STK11-interacting proteins have not yet been tern of labial and perioral pigmentation is not
found in these latter patients. Thus, it has been pathognomonic for PJS. Laugier-Hunziker pig-
suggested that these patients may have large STK11 mentation is an acquired and idiopathic form of
gene rearrangements that cannot be identified by pigmentation that frequently mimics PJS and
routine molecular testing (Meserve and Nucci 2016).
Pathophysiology
STK11 is serine-threonine kinase that directs
energy sensing and nutrient metabolism through
activation of an array of downstream factors
(Shorning and Clarke 2016). Together, STK11
and its phosphorylated substrates help to regulate
cellular metabolism, proliferation, polarity, and
differentiation by maintaining and monitoring cel-
lular energy homeostasis. STK11 also contributes
to genomic stability by participating in DNA
double-strand break repair.
It is apparent that STK11 plays an important Fig. 32 Perioral melanosis associated with Peutz-Jeghers
role in melanocyte biology since the syndrome
should be considered in the differential diagnosis is primarily related to the occurrence of cancer
(Alawi 2013). However, Laugier-Hunziker pig- (Meserve and Nucci 2016). The pigmentation is
mentation typically manifests during adulthood not symptomatic and does not require treatment
and may be accompanied by pigmentation of the unless there is an esthetic concern.
nails. Patients with Laugier-Hunziker pigmenta-
tion do not exhibit STK11 mutations, and they do
not manifest with gastrointestinal polyps. Exogenous Causes of Clinical
Apart from the gastrointestinal polyps and can- Pigmentation
cer, other systemic complications may include
intussusception, rectal bleeding, iron deficiency Tattoos: Amalgam, Graphite,
anemia, and development of ovarian cysts and Ornamental
(Riegert-Johnson et al. 2009).
The most common nonphysiologic source of oral
Patient Management mucosal coloration is exogenous and not endoge-
The development of labial and perioral pigmenta- nous in origin (Alawi 2013). Amalgam tattoos are
tion early in life should prompt genetic testing for the most common cause of oral “pigmentation”
PJS (Meserve and Nucci 2016). In patients with a (Alawi 2013). They result from the iatrogenic
known family history or in newly diagnosed mucosal implantation of amalgam particles usu-
patients, surveillance strategies should be ally during the course of a dental procedure.
designed to ensure continuous and lifelong clini- Amalgam tattoos are macular, usually small and
cal monitoring. Surgical treatment may be needed frequently identified in close proximity to
to remove potentially obstructive gastrointestinal amalgam-restored teeth or in areas where such
polyps. Iron supplementation may be necessary teeth were previously present (Figs. 33a–c, 34,
for a subset of patients who are anemic. Prognosis 35, and 36). Amalgam tattoos may be identified
Fig. 33 Amalgam tattoo appearing clinically as a black (c) views confirming presence of amalgam particles
pigmented lesion on the labial gingiva of the tooth 16 (a). (Images courtesy of Professor Camile Farah, Perth Oral
Same lesion noted on multislice CT sagittal (b) and axial Medicine & Dental Sleep Centre, Perth WA, Australia)
Fig. 36 Amalgam tattoo appearing clinically as black

pigmented lesion in a 65-year-old female presenting on
the buccal mucosa adjacent to a heavily restored molar
(Image courtesy of Professor Camile Farah, Perth Oral
Fig. 34 Amalgam tattoo appearing clinically as black Medicine & Dental Sleep Centre, Perth WA, Australia)
pigmented lesion on the attached mucosa adjacent to
heavily restored molar (Image courtesy of Professor
Camile Farah, Perth Oral Medicine & Dental Sleep Centre,
Perth WA, Australia) in any oral location, but the gingiva and alveolar
mucosa are most commonly affected.
While an amalgam tattoo may be blue gray to
black in color, and thus the mucosa may appear
clinically pigmented, the mucosa is not actually
pigmented (Alawi 2013). The coloration is due
to the visualization of metallic particles embed-
ded within the lamina propria and/or submu-
cosa. Similarly, graphite tattoos may appear
clinically identical to amalgam tattoos
(Fig. 37). Graphite tattoos are caused by the
mucosal implantation of graphite particles typ-
ically originating from the tip of a pencil (Alawi
2013). These tattoos are usually the result of
accidental trauma.
Ornamental or intentional oral mucosal tattoos
have long been a custom in some parts of the
world, including within specific African tribal
Fig. 35 Biopsy-proven amalgam tattoo appearing clini- communities, which has been described previ-
cally as black pigmented lesion in a 30-year-old female at ously in this chapter (Gondak et al. 2012). The
the mucogingival junction adjacent to virgin canine and tattoo ink is usually plant based and may be com-
premolar teeth with braces. Lesion was remnant from
heavily restored primary dentition (Image courtesy of Pro-
bined with other carbon-based substances such as
fessor Camile Farah, Perth Oral Medicine & Dental Sleep burnt wood, plastic, India ink, or even pen ink.
Centre, Perth WA, Australia) Ornamental tattooing is a growing trend in other
where metallic amalgam particles may be evi-

dent on a radiograph, this may preclude the need
for biopsy diagnosis. After histopathologic
diagnosis, no additional intervention is needed.
While the esthetic concerns associated with
amalgam, graphite, and ornamental tattooing
may be significant for some individuals, treat-
ment is not indicated. However, if treatment is
requested, low-energy lasers can be used to
remove the tattoos (Yilmaz et al. 2010). Sub-
epithelial connective tissue grafts followed by
laser de-epithelialization or gingivoplasty have
also been used with success (Campbell and Deas
2009; Thumbigere-Math and Johnson 2014).
Alternatively, simple cold steel surgical exci-
sion of affected tissues is a straightforward
approach.
Fig. 37 Biopsy-proven graphite tattoo in a 63-year-old
female appearing clinically as a gray pigmented lesion on
the gingiva (Image courtesy of Professor Camile Farah,
Perth Oral Medicine & Dental Sleep Centre, Perth WA Metal-induced Discoloration
Australia)
Chronic exposure to various metals is known to
induce discoloration but not “true” pigmentation
of the oral mucosa (Alawi 2013; Hassona et al.
2016). Examples include lead, mercury, silver,
and bismuth, among others. Exposure to these
metals most commonly occurs through continual
ingestion of contaminated drinking water or
foods, such as fish and seafood, or through occu-
pational exposure. In most cases, the discoloration
appears as a black-blue line that follows the out-
lines of the marginal gingiva (Alawi 2013;
Hassona et al. 2016). This is known as a Burton
or Burtonian line in individuals with chronic lead
poisoning (Pearce 2007). Similar to an amalgam
Fig. 38 Ornamental ink tattooing involving the mandib- tattoo, a Burton line is not true pigmentation.
ular labial mucosa in a female patient which reads “In My
Stars” (Image courtesy of Dr Amanda Phoon Nguyen,
Instead, a chemical reaction occurs between sulfur
UWA Dental School, University of Western Australia, ions released by the regional oral flora and the
Perth WA, Australia) circulating lead. This results in the deposition of
lead sulfide within the marginal gingiva leading to
the discoloration. “Mercury lines” and “bismuth
parts of the world, including Eastern European lines” develop via similar types of chemical reac-
and Western countries (Fig. 38). tions with compounds released by oral bacteria.
For focal areas of discoloration, a biopsy Mucocutaneous argyria is due to the accumulation
diagnosis is first warranted since mucosal tat- of silver metal or silver sulfide within the lamina
toos may be difficult to reliably differentiate propria and submucosa and often manifests as
from benign and malignant melanocytic and/or generally diffuse bluish mucosal discoloration
vascular pathologies (Alawi 2013). In instances (Kim et al. 2009).
Identifying and eliminating the source of the ▶ Oral Lichen Planus

toxicity is critical to ensure there are no long- ▶ Oral Manifestations of Systemic Diseases and
lasting systemic and neurologic effects. Chela- their Treatments
tion therapy under professional supervision may ▶ Oral Mucosal Malignancies
be beneficial, but the extent of exposure and the ▶ Pediatric Oral Medicine
specific type of metal toxicity dictates which
chelating agent(s) will be used and the mode of
administration (Caito and Aschner 2015).
References
Succimer (2,3-dimercaptosuccinic acid
[DMSA]) is an orally administered chelating Alawi F. Pigmented lesions of the oral cavity: an update.
agent typically used for lead, mercury, or arsenic Dent Clin N Am. 2013;57(4):699–710.
poisoning. Intravenous dimercaprol can be used Anderson EJ, Cakir I, Carrington SJ, Cone RD, Ghamari-
in severe cases. Calcium-disodium ethylenedia- Langroudi M, Gillyard T, et al. 60 YEARS OF POMC:
regulation of feeding and energy homeostasis by alpha-
minetetraacetic acid (EDTA) is also MSH. J Mol Endocrinol. 2016;56(4):T157–74.
recommended for lead poisoning. A mono- Arava-Parastatidis M, Alawi F, Stoopler ET. Multifocal
isoamyl ester derivative of DMSA may be more pigmentation of the oral cavity. Oral melanoacanthoma
effective at chelating mercury than succimer. It J Am Dent Assoc. 2011;142(1):53–6.
Bastiaens M, ter Huurne J, Gruis N, Bergman W,
should be noted that while succimer has a limited Westendorp R, Vermeer BJ, et al. The melanocortin-1-
side-effect profile, intravenously administered receptor gene is the major freckle gene. Hum Mol
chelating agents can be associated with a wide Genet. 2001;10(16):1701–8.
array of serious adverse effects, including renal Berwick M, Buller DB, Cust A, Gallagher R, Lee TK,
Meyskens F, et al. Melanoma epidemiology and pre-
failure, seizures, coma, and even death (Caito vention. Cancer Treat Res. 2016;167:17–49.
and Aschner 2015). Bliss JM, Ford D, Swerdlow AJ, Armstrong BK,
Cristofolini M, Elwood JM, et al. Risk of cutaneous
melanoma associated with pigmentation characteristics
and freckling: systematic overview of 10 case-control
Conclusions and Future Directions studies. Int J Cancer. 1995;62(4):367–72.
Bowen AR, McCalmont TH. The histopathology of sub-
Melanin-associated pigmented lesions of the oral cutaneous minocycline pigmentation. J Am Acad
mucosa can range from innocuous findings to life- Dermatol. 2007;57(5):836–9.
Bravo IM, Correnti M, Escalona L, Perrone M, Brito A,
threatening conditions. It is important for oral Tovar V, et al. Prevalence of oral lesions in HIV patients
health-care providers to be familiar with the related to CD4 cell count and viral load in a Venezuelan
range of clinical phenomena associated with population. Med Oral Patol Oral Cir Bucal.
these types of pigmented lesions that affect both 2006;11(1):E33–9.
Brooks JK, Reynolds MA. Ethnobotanical tattooing of the
the oral cavity and cutaneous surfaces. As under- gingiva: literature review and report of a case. J Am
standing of genetics associated with melanogene- Dent Assoc. 2007;138(8):1097–101.
sis and human biology are further refined, targeted Brown RJ, Kelly MH, Collins MT. Cushing syndrome in
gene therapy and development of novel immuno- the McCune-Albright syndrome. J Clin Endocrinol
Metab. 2010;95(4):1508–15.
therapeutics will potentially improve detection, Caito S, Aschner M. Neurotoxicity of metals. Handb Clin
treatment, and prognosis of life-threatening mela- Neurol. 2015;131:169–89.
nin-associated pigmentation disorders, such as Campbell CM, Deas DE. Removal of an amalgam tattoo
melanoma. using a subepithelial connective tissue graft and laser
deepithelialization. J Periodontol. 2009;80(5):860–4.
Cantudo-Sanagustín E, Gutiérrez-Corrales A, Vigo-
Martínez M, Serrera-Figallo MÁ, Torres-Lagares D,
Cross-References Gutiérrez-Pérez JL. Pathogenesis and clinicohisto-
pathological characteristics of melanoacanthoma:
a systematic review. J Clin Exp Dent.
▶ Cutaneous Pathology of the Head and Neck 2016;8(3):e327–36.
▶ Gingival Pathology Chandran R, Feller L, Lemmer J, Khammissa RA. HIV-
▶ Head and Neck Tumors associated oral mucosal melanin hyperpigmentation: a
clinical study in a South African population sample. Kauzman A, Pavone M, Blanas N, Bradley G. Pigmented
AIDS Res Treat. 2016;2016:8389214. lesions of the oral cavity: review, differential diagnosis,
Charmandari E, Nicolaides NC, Chrousos GP. Adrenal and case presentations. J Can Dent Assoc.
insufficiency. Lancet. 2014;383(9935):2152–67. 2004;70(10):682–3.
Chatzistefanou I, Kolokythas A, Vahtsevanos K, Kim Y, Suh HS, Cha HJ, Kim SH, Jeong KS, Kim DH. A
Antoniades K. Primary mucosal melanoma of the case of generalized argyria after ingestion of colloidal
oral cavity: current therapy and future directions. silver solution. Am J Ind Med. 2009;52(3):246–50.
Oral Surg Oral Med Oral Pathol Oral Radiol. Lacroix A, Feelders RA, Stratakis CA, Nieman LK.
2016;122(1):17–27. Cushing’s syndrome. Lancet. 2015;386(9996):913–27.
De Leo M, Cozzolino A, Colao A, Pivonello R. Subclinical Lau D, Rutledge C, Aghi MK. Cushing’s disease: current
Cushing’s syndrome. Best Pract Res Clin Endocrinol medical therapies and molecular insights guiding future
Metab. 2012;26(4):497–505. therapies. Neurosurg Focus. 2015;38(2):E11.
Dereure O. Drug-induced skin pigmentation. Epidemiol- Lee CS, Thomas CM, Ng KE. An overview of the chang-
ogy, diagnosis and treatment. Am J Clin Dermatol. ing landscape of treatment for advanced melanoma.
2001;2(4):253–62. Pharmacotherapy. 2017;37(3):319–33.
Felix DH, Luker J, Scully C. Oral medicine: 7. Red and Lim GF, Cusack CA, Kist JM. Perioral lesions and derma-
pigmented lesions. Dent Update. 2013;40(3):231–4. toses. Dent Clin N Am. 2014;58(2):401–35.
236–8. Lloyd C, Grossman A. The AIP (aryl hydrocarbon
Feller L, Chandran R, Kramer B, Khammissa RA, receptor-interacting protein) gene and its relation to
Altini M, Lemmer J. Melanocyte biology and function the pathogenesis of pituitary adenomas. Endocrine.
with reference to oral melanin hyperpigmentation in 2014;46(3):387–96.
HIV-seropositive subjects. AIDS Res Hum Retrovir. Lodish MB. Clinical review: kinase inhibitors: adverse
2014a;30(9):837–43. effects related to the endocrine system. J Clin Endo-
Feller L, Masilana A, Khammissa RA, Altini M, Jadwat Y, crinol Metab. 2013;98(4):1333–42.
Lemmer J. Melanin: the biophysiology of oral melano- Lonser RR, Nieman L, Oldfield EH. Cushing’s disease:
cytes and physiological oral pigmentation. Head Face pathobiology, diagnosis, and management.
Med. 2014b;10:8. J Neurosurg. 2016:1–14.
Femiano F, Lanza A, Buonaiuto C, Gombos F, Di Spirito F, MacLennan R, Kelly JW, Rivers JK, Harrison SL. The
Cirillo N. Oral malignant melanoma: a review of the eastern Australian childhood nevus study: site differ-
literature. J Oral Pathol Med. 2008;37(7):383–8. ences in density and size of melanocytic nevi in relation
Fernandes D, Ferrisse TM, Navarro CM, Massucato EM, to latitude and phenotype. J Am Acad Dermatol.
Onofre MA, Bufalino A. Pigmented lesions on the 2003;48(3):367–75.
mucosa: a wide range of diagnoses. Oral Surg Oral Marangon Junior H, Souza PE, Soares RV, de Andrade BA,
Med Oral Pathol Oral Radiol. 2015;119(4):374–8. de Almeida OP, Horta MC. Oral congenital
Gaeta GM, Satriano RA, Baroni A. Oral pigmented melanocytic nevus: a rare case report and review of
lesions. Clin Dermatol. 2002;20(3):286–8. the literature. Head and Neck Pathol. 2015;9(4):481–7.
Gandhi SA, Kampp J. Skin cancer epidemiology, detec- Meleti M, Vescovi P, Mooi WJ, van der Waal I. Pigmented
tion, and management. Med Clin North lesions of the oral mucosa and perioral tissues: a flow-
Am. 2015;99(6):1323–35. chart for the diagnosis and some recommendations for
Gondak RO, da Silva-Jorge R, Jorge J, Lopes MA, the management. Oral Surg Oral Med Oral Pathol Oral
Vargas PA. Oral pigmented lesions: clinicopathologic Radiol Endod. 2008;105(5):606–16.
features and review of the literature. Med Oral Patol Meserve EE, Nucci MR. Peutz-Jeghers syndrome: patho-
Oral Cir Bucal. 2012;17(6):e919–24. biology, pathologic manifestations, and suggestions for
Hashemi Pour MS. Malignant melanoma of the oral cavity: recommending genetic testing in pathology reports.
a review of the literature. Indian J Dent Res. Surg Pathol Clin. 2016;9(2):243–68.
2008;19(1):47–51. Michels A, Michels N. Addison disease: early detection
Hassona Y, Sawair F, Al-Karadsheh O, Scully C. Preva- and treatment principles. Am Fam Physician.
lence and clinical features of pigmented oral lesions. Int 2014;89(7):563–8.
J Dermatol. 2016;55(9):1005–13. Mohan M, Sukhadia VY, Pai D, Bhat S. Oral malignant
Hatch CL. Pigmented lesions of the oral cavity. Dent Clin melanoma: systematic review of literature and report of
N Am. 2005;49(1):185–201. ix–x. two cases. Oral Surg Oral Med Oral Pathol Oral Radiol.
Hruz PW. HIV and endocrine disorders. Endocrinol Metab 2013;116(4):e247–54.
Clin N Am. 2014;43(3):xvii–xviii. Moraes PC, Noce CW, Thomaz LA, Cintra ML,
Jiang AJ, Rambhatla PV, Eide MJ. Socioeconomic and Correa ME. Pigmented lichenoid drug eruption second-
lifestyle factors and melanoma: a systematic review. ary to chloroquine therapy: an unusual presentation in
Br J Dermatol. 2015;172(4):885–915. lower lip. Minerva Stomatol. 2011;60(6):327–32.
Kaugars GE, Heise AP, Riley WT, Abbey LM, Svirsky JA. Muller S. Melanin-associated pigmented lesions of the oral
Oral melanotic macules: a review of 353 cases. Oral mucosa: presentation, differential diagnosis, and treat-
Surg Oral Med Oral Pathol. 1993;76(1):59–61. ment. Dermatol Ther. 2010;23(3):220–9.
Napier C, Pearce SH. Current and emerging therapies for Schernthaner-Reiter MH, Trivellin G, Stratakis CA.
Addison’s disease. Curr Opin Endocrinol Diabetes MEN1, MEN4, and carney complex: pathology and
Obes. 2014;21(3):147–53. molecular genetics. Neuroendocrinology.
Naziat A, Grossman A. Adrenal Insufficiency. In: De Groot 2016;103(1):18–31.
LJ, Chrousos G, Dungan K, et al., editors. Endotext. Sharma ST, Nieman LK, Feelders RA. Cushing’s syn-
South Dartmouth (MA): MDText.com, Inc.; 2000-. drome: epidemiology and developments in disease
Available from: http://www.ncbi.nlm.nih.gov/books/ management. Clin Epidemiol. 2015;7:281–93.
NBK279122/ Shen ZY, Liu W, Bao ZX, Zhou ZT, Wang LZ. Oral mel-
Nikitakis NG, Koumaki D. Laugier-Hunziker syndrome: anotic macule and primary oral malignant melanoma:
case report and review of the literature. Oral Surg Oral epidemiology, location involved, and clinical implica-
Med Oral Pathol Oral Radiol. 2013;116(1):e52–8. tions. Oral Surg Oral Med Oral Pathol Oral Radiol
Pasquali E, Garcia-Borron JC, Fargnoli MC, Gandini S, Endod. 2011;112(1):e21–5.
Maisonneuve P, Bagnardi V, et al. MC1R variants Shorning BY, Clarke AR. Energy sensing and cancer:
increased the risk of sporadic cutaneous melanoma in LKB1 function and lessons learnt from Peutz-Jeghers
darker-pigmented Caucasians: a pooled-analysis from syndrome. Semin Cell Dev Biol. 2016;52:21–9.
the M-SKIP project. Int J Cancer. 2015;136(3):618–31. Tarakji B, Umair A, Prasad D, Alsakran AM. Diagnosis of
Pearce JM. Burton’s line in lead poisoning. Eur Neurol. oral pigmentations and malignant transformations.
2007;57(2):118–9. Singap Dent J. 2014;35C:39–46.
Pinto A, Raghavendra S, Lee R, DeRossi S, Alawi F. Thumbigere-Math V, Johnson DK. Treatment of amalgam
Epithelioid blue nevus of the oral mucosa: a rare histo- tattoo with a subepithelial connective tissue graft and
logic variant. Oral Surg Oral Med Oral Pathol Oral acellular dermal matrix. J Int Acad Periodontol.
Radiol Endod. 2003;96(4):429–36. 2014;16(2):50–4.
Ponti G, Tomasi A, Manfredini M, Pellacani G. Oral muco- Wood BR, Lacy JM, Johnston C, Weigle DS,
sal stigmata in hereditary-cancer syndromes: from Dhanireddy S. Adrenal insufficiency as a result of
germline mutations to distinctive clinical phenotypes ritonavir and exogenous steroid exposure: report of
and tailored therapies. Gene. 2016;582(1):23–32. 6 cases and recommendation for management. J Int
Rangwala S, Doherty CB, Katta R. Laugier-Hunziker syn- Assoc Provid AIDS Care. 2015;14(4):300–5.
drome: a case report and review of the literature. Yago K, Tanaka Y, Asanami S. Laugier-Hunziker-Baran
Dermatol Online J. 2010;16(12):9. syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol
Rawal SY, Burrell R, Hamidi CS, Kalmar JR, Tatakis DN. Endod. 2008;106(2):e20–5.
Diffuse pigmentation of maxillary attached gingiva: Yilmaz HG, Bayindir H, Kusakci-Seker B, Tasar S,
four cases of the cultural practice of gingival tattoo. Kurtulmus-Yilmaz S. Treatment of amalgam tattoo
J Periodontol. 2007;78(1):170–6. with an Er, Cr:YSGG laser. J Investig Clin Dent.
Riegert-Johnson D, Gleeson FC, Westra W, Hefferon T, 2010;1(1):50–4.
Wong Kee Song LM, Spurck L, et al. Peutz-Jeghers Yuan A, Woo SB. Adverse drug events in the oral cavity.
syndrome. In: Riegert-Johnson DL, Boardman LA, Oral Surg Oral Med Oral Pathol Oral Radiol.
Hefferon T, Roberts M, editors. Cancer syndromes. 2015;119(1):35–47.
Bethesda: National Center for Biotechnology Informa-
tion (US); 2009.
White and Red Lesions of the Oral
Mucosa
Maryam Jessri, Hani Mawardi, Camile S. Farah, and

Sook-Bin Woo
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1209
Developmental Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1209
Fordyce Granules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1209
White Sponge Nevus (Cannon White Sponge Nevus, Familial White
Folded Dysplasia) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1210
M. Jessri
Australia, University of Western Australia, Perth,
WA, Australia
e-mail: maryam.jessri@gmail.com; mjessri@partners.org
H. Mawardi
Faculty of Dentistry, King Abdulaziz university, Jeddah,
Saudi Arabia
e-mail: hmawardi@kau.edu.sa
C. S. Farah (*)
S.-B. Woo
e-mail: swoo@rics.bwh.harvard.edu; swoo@partners.org

https://doi.org/10.1007/978-3-319-72303-7_16
1208 M. Jessri et al.
Hereditary Benign Intraepithelial Dyskeratosis

(Witkop Disease) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1210
Reactive Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1211
Chemical Desquamation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1211
Leukoedema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1212
Smokeless Tobacco Keratosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1212
Morsicatio Mucosae Oris (Chronic Bite
Keratosis) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1214
Benign Alveolar Ridge Keratosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1214
Contact Stomatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1216
Nicotinic Stomatitis (Stomatitis Nicotina) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1217
Hairy/Coated Tongue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1218
Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1220
Candidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1220
Oral Hairy Leukoplakia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1221
Immune-Mediated and Autoimmune
Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1222
Benign Migratory Glossitis (Geographic Tongue, Erythema Areata
Migrans, Migratory
Stomatitis) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1222
Desquamative Gingivitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1224
Plasma Cell Gingivostomatitis (Plasma Cell Orificial Mucositis) . . . . . . . . . . . . . . . . . . . . 1224
Lupus Erythematosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1228
Oral Graft Versus Host Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1229
Erythema Multiforme . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1232
Precancerous and Cancerous Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1233
Leukoplakia and Proliferative Verrucous
Leukoplakia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1233
Erythroplakia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1238
Oral Submucous Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1238
Actinic Cheilitis (Actinic Cheilosis, Solar Cheilosis, and Farmer’s Lip) . . . . . . . . . . . . . 1240
Oral Squamous Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1241
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1243
Abstract abnormal keratinization of the epithelium,

There are several conditions that can present as thickening of the epithelium, and epithelial
white or red macular, papular, and/or plaque- edema. Fibrosis and/or reduced vascularity of
like lesions of the oral mucosa. Based on etiol- the underlying mucosa may also lead to white-
ogy, red and white lesions of the oral cavity can ness which tends to appear deep without dis-
be divided into developmental, reactive, infec- cernible surface alterations. Some of the more
tious, immune-mediated/autoimmune, and common causes of redness (erythema) of the
potentially malignant and malignant condi- oral mucosa include reduced keratinization of
tions. Whiteness of the oral mucosa can be the oral epithelium, epithelial atrophy, erosion
caused by changes in the epithelium such as or inflammation, and vascular dilatation or pro-
keratinization of normally nonkeratinized liferation. Generally, the prevalence of red and
mucosa (such as the buccal mucosa), increased white oral lesions increases with age. Based on
keratinization of normally keratinized mucosa, diagnostic and inclusion criteria, and
White and Red Lesions of the Oral Mucosa 1209
characteristics of the population, prevalence of Developmental Conditions

oral mucosal lesions has been reported in 2–84%
of the population (Do et al. 2014). A large pro- Fordyce Granules
portion of red and white lesions are benign.
However, the most common premalignant con- Fordyce granules are benign sebaceous glands
dition in the oral cavity is a white plaque (leuko- commonly found in the oral cavity that have a
plakia), and this must be managed expeditiously high prevalence of up to 80%, and as such they
and appropriately. Many conditions can be accu- are generally considered to be a normal variation
rately diagnosed with careful history taking and of the oral mucosa. However, their density and
clinical examination. However, a biopsy is often prevalence are reportedly higher in individuals
necessary for a definitive diagnosis. This chapter with hyperlipidemia and Muir-Torre syndrome
discusses the clinical features of these white and (Ponti et al. 2015).
red lesions, how to distinguish between them,
and how to manage them.
Fordyce granules are a variation of the normal
Keywords oral phenotype. However, because of increased
White lesions · Red lesions · Premalignant prevalence around puberty, as well as with
lesions · Mucosal pathology · Benign mucosal increase in age, some authors suggest hormonal
pathology · Developmental conditions · influence in their etiopathogenesis although it
Reactive conditions · Potentially malignant is more likely that they become fully
lesions · Malignant lesions · Oral squamous expressed when patients reach adulthood
cell carcinoma (Choudhry et al. 1992).
Introduction Fordyce granules are seen in 80% of the general
adult population with no particular gender predi-
This chapter focuses on red and white macular, lection. They present as multiple asymptomatic,
papular, and plaque lesions of the oral mucosa. yellow or yellowish-white, 1–3 mm macules and
There are many conditions in this chapter papules, most commonly seen on the buccal
which overlap with entities discussed in other chap- mucosa, and vermilion of the upper lip. They
ters. For instance, oral lichen planus and lichenoid are generally bilateral and symmetrically distrib-
lesions will only be discussed briefly here as there uted (Fig. 1). Occasionally, some of the seba-
is a full-length chapter elsewhere in this textbook ceous glands may become hyperplastic and
dedicated specifically to this topic. Likewise, the papular (up to 3–5 mm in size) so that the patient
topic of oral candidosis is covered in great detail in or oral health care provider may become more
the chapter on ▶ “Oral and Maxillofacial Fungal aware of them.
Infections”, and malignant lesions are covered in
the chapter on ▶ “Oral Mucosal Malignancies”.
The conditions described in this chapter are divided Patient Management
by etiology as follows: Fordyce granules require no treatment other
than recognition of the condition and reassur-
• Developmental conditions ance of the patient. A biopsy is not usually
• Reactive conditions required because of their typical appearance
• Infections and distribution. Sebaceous hyperplasia is not
• Immune-mediated and autoimmune conditions uncommon, but sebaceous adenoma is rare
• Potentially malignant and malignant lesions (Izutsu et al. 2003).
Fig. 1 Fordyce granules.

Yellow papules on the left
buccal mucosa
White Sponge Nevus (Cannon White life. There is no effective treatment. Cases that
Sponge Nevus, Familial White Folded have reportedly responded to antibiotics or anti-
Dysplasia) bacterial mouth rinses are not likely to represent
this condition but instead a reactive keratosis.
White sponge nevus is a rare autosomal dominant
disorder with highly variable expressivity that
affects the oral and other mucosae, but not the skin. Hereditary Benign Intraepithelial
Dyskeratosis (Witkop Disease)
White sponge nevus is caused by mutation in genes Hereditary benign intraepithelial dyskeratosis
associated with keratin-4 (KRT4) or keratin-13 (HBID) is a rare autosomal dominant disorder
(KRT13), resulting in keratin instability and abnor- presenting with bulbar conjunctival and oral
mal aggregation of tonofilaments, which in turn plaques. It was first identified in 1960 and pre-
promotes abnormal proliferation and thickening dominantly affects descendants of Haliwa-Saponi
of the oral epithelium (Rugg et al. 1995; Shibuya Native Americans in North Carolina (Cummings
et al. 2003). et al. 2008).
Clinical-Pathologic Features Etiology and Pathophysiology

The lesions of white sponge nevus appear at birth, Recent haplotype analysis of families with HBID
early childhood, or adolescence and usually pre- showed a possible role of duplication of chromo-
sent in a bilateral, symmetric fashion as asymp- some 4q35, which may trigger uncontrolled cell
tomatic, thick, white, spongy plaques, usually on proliferation and premature keratinization of the
the buccal mucosa, ventral tongue, lip mucosa, epithelium (Allingham et al. 2001).
and soft palate (Songu et al. 2012). There may
also be esophageal, upper airway, and genital
lesions, but the skin is not affected. Clinical-Pathologic Features
Diagnosis is established through a biopsy HBID manifests at birth or early childhood
because other conditions such as chronic trau- with no gender predilection. Oral lesions are
matic keratoses may appear clinically similar. generally asymptomatic and present as
non-tender, spongy, white plaques on the buccal
Patient Management mucosa, lips, ventral surface of the tongue,
Patients should be reassured that this is a benign and floor of the mouth, usually in a bilateral
inherited condition that will persist throughout fashion. Ocular lesions present as white-gray
gelatinous plaques on the bulbar conjunctiva, substantial inflammation and should be differen-
and these may be asymptomatic, or patients tiated from superficial chemical desquamation.
may experience irritation, frequent lacrimation,
a feeling of a foreign body in the eye, and
photophobia. Corneal vascularization may lead
Chemical desquamation is induced by various irri-
to blindness in rare cases. One unusual feature of
tants including, but not limited to, mouthwashes
HBID is worsening of symptoms in spring and ®
with high-alcohol content (such as Listerine
summer. ®
(Johnson and Johnson, NJ, USA) and Pro-Health
A biopsy is usually required to confirm the
(Crest, Procter & Gamble Co., OH, USA) and
diagnosis and rule out other conditions such
strongly flavored toothpastes (Francalanci et al.
as white sponge nevus or even frictional keratosis.
2000). Such caustic dentifrices can lead to coagu-
lation and detachment of the most superficial 2–3
Patient Management layers of epithelial cells which slough off yet leave
Patients should be reassured that HBID is a benign behind intact thinner epithelium. In vitro studies
inherited condition that will persist throughout have shown desquamation of human oral mucosa
life. There is no effective treatment. within 24 hrs following exposure to dentifrice
resulting in an inflammatory response characterized
by upregulation of IL-1β, downregulation of IL-8,
and TNF-α secretion (Mostefaoui et al. 2002).
Reactive Lesions
Chemical Desquamation Clinical-Pathologic Features

Chemical desquamation is more common in
Superficial chemical desquamation of oral adults because they tend to use dental products
mucosa occurs in response to exposure to chem- that have stronger additives. It presents as
ical irritants present in mouth rinses and tooth- painless, wispy, gray-white threads, and
pastes, and it is also referred to as oral membranous material that can be easily
epitheliolysis. Harsher chemicals such as aspirin peeled off or spontaneously slough, leaving
or other chemicals used in dentistry such as behind normal mucosa (Fig. 2). Chronic expo-
methacrylate cause more coagulations, erosions, sure may be associated with leukoedema or
and ulcers (irritant contact stomatitis) because of cheilitis.
Fig. 2 Chemical
desquamation from a mouth
rinse: sloughing of the
superficial layers of
epithelium leaving behind
normal-looking mucosa
Fig. 3 Leukoedema of right buccal mucosa. (a) Diffuse, filmy, slightly reticulated area on the right buccal mucosa.
(b) Stretching the mucosa causes the lesion to disappear
Patient Management population with the highest prevalence in

Lesions resolve on ceasing or changing the African-American males (Madani and
offending toothpaste or mouth rinse to a version Kuperstein 2014; Pinto et al. 2014). Leukoedema
without the offending chemical. presents as asymptomatic, white-gray translu-
cent linear reticulations, most frequently seen
on the buccal mucosa and to a lesser extent, the
Leukoedema
lip mucosa and ventral tongue.
The complete disappearance of these pale
Leukoedema, in its primary form, is common
reticulations upon stretching the mucosa (the
enough to be considered a variation of normal,
so-called “stretch test”) is a diagnostic feature
with some studies reporting a prevalence of up to
(Fig. 3a, b). A biopsy is rarely necessary although
90% especially in dark-skinned patients because
the reticulations may be mistaken for those of
of the color contrast between the milky-white
lichen planus, prompting a biopsy.
leukoedema on darker mucosa.
Patient Management
Etiology and Pathophysiology Stretching the mucosa and the disappearance of
Leukoedema is the clinical term, while the patho- reticulations distinguish leukoedema from reticular
logic process is keratinocyte edema. It is the result of lichen planus which is a keratotic lesion. The patient
fluid accumulation within keratinocytes, a process should be reassured as to the benign nature of the
caused by mild local irritation, such as from ciga- condition. If there is an associated smoking habit, it
rette or marijuana smoking, the use of some tooth- is a good opportunity to discuss habit cessation.
pastes and mouth rinses, and from physical trauma
such as sucking (Heyl and Raubenheimer 1987). It
is often seen at the periphery of contact desquama- Smokeless Tobacco Keratosis
tions or even frictional or factitial keratosis.
Smokeless tobacco (ST) keratosis describes oral
Clinical-Pathologic Features changes caused by prolonged contact of the
Leukoedema is a condition of adults; however, it mucosa to ST products. This includes chewing
has been reported as early as 2 years of age in tobacco which takes several forms: loose leaf or
some patients, and transiently in the sucking pads shredded tobacco that may be sweetened and fla-
of infants (Madani and Kuperstein 2014). Its vored, tobacco plug that also may be sweetened
prevalence differs between gender and racial and sold as a compacted brick, or twist tobacco
groups ranging from 0.96% to 90% of the that is composed of tobacco leaves twisted into a
rope from which sections can be bitten or cut off. parakeratin formation. This is why many lesions
Another common product is snuff composed of resolve within days of habit cessation, especially
finely or coarsely ground, dry (that can be in earlier stages of the condition. However, when
inhaled), or moist powdered tobacco (that is leathery white plaques develop within these gray-
“dipped”) and sold loose or in prepackaged ish edematous plaques after years or decades of
sachets. Dissolvable tobacco tablets are also avail- use, the term leukoplakia could be applied despite
able. While the consumption rate of ST has its known etiology.
remained stable among American women (1 in
every 100), following a transient decrease Clinical-Pathologic Features
between 1986 and 2000, ST is regaining popular- The habit of using ST is particularly common
ity among American males (7 in every 100) (U.S among younger males (starting between 8 and
2014). In the 1980s, ST was thought to be strongly 14 years of age) in many populations worldwide
associated with the development of squamous cell including North America, Northern Europe, and
carcinoma (Winn et al. 1981); however more Asian countries. Early lesions appear as asymp-
recent studies have shown a low association tomatic, soft, gray-white, poorly demarcated,
(Rodu and Cole 2002). edematous changes of the mucosa with parallel
ridges, at the site of tobacco placement. Lesions
Etiology and Pathophysiology are not usually indurated or ulcerated (Fig. 4a, b).
ST keratosis in its early stage is a form of contact Common sites are the mandibular and maxillary
irritation that develops at the site where the vestibules. These lesions resolve within days to
tobacco product is placed. Cessation of the habit weeks of habit cessation. However, the use of ST
leads to complete restoration of mucosa to its at one site over years and decades may result in
normal appearance. However, prolonged expo- the development of well-demarcated, leathery,
sure for years may lead to the development of and often fissured white plaques of leukoplakia
contact irritation lesion which is generally not that generally will not resolve on discontinuation
reversible. Moist ST products with high alkalinity of the habit. Other oral changes associated with
are more strongly associated with the develop- ST use include gingival recession, periodontal
ment of contact irritation lesions. disease, caries, and occlusal wear (Kamath et al.
Although the term “keratosis” is convention- 2014).
ally used to describe this lesion, most ST lesions A biopsy is usually unnecessary but will show
show predominantly edema of superficial epithe- edema of superficial epithelial cells (similar to
lial cells often with only very focal or even no those seen in leukoedema) because of contact
Fig. 4 (a) Early smokeless tobacco lesion after 6 days of (b) Smokeless tobacco lesion showing poorly demarcated
use: fissured, poorly demarcated slightly gray-white lesion of parallel pale gray-white ridges and folds in the vestibule
the lower lip and vestibule; there is no significant keratosis. (Images courtesy of Dr Jeffrey Stone, Lowell, MA, USA)
injury, while the mid- and lower epithelial cells life with a higher predilection for females (Woo
are normal. However, once a leukoplakia has been and Lin 2009). The most common sites are the
established, the lesions should be biopsied to eval- buccal mucosae (often appearing as an extension
uate for dysplasia. or accentuation of linea alba), the lateral/ventral
tongue, and the lower lip mucosa. Most MMO
Patient Management lesions are bilateral, and more than half of
Most ST lesions are readily diagnosed based on the patients do not report a history of such habits,
history and clinical examination. The early gray- or the habits may be nocturnal. The majority of
white and ridged lesions resolve with habit cessa- cases present as asymptomatic, poorly demar-
tion within days to a few weeks. The dense white cated, thickened, shaggy, white, ragged, papules
lesions of leukoplakia that develop after years of and plaques that may be associated with focal
use generally do not resolve on habit cessation and areas of erythema or ulceration (Fig. 5a–c).
have the potential for dysplasia and carcinoma Often times, patients report being able to remove
similar to other leukoplakias. Pooled analysis of desquamated wisps of tissue from the surface of
previous studies showed ST lesions have a weak the lesion.
association with oral cancer (OR = 1.81, 95% CI: A biopsy will exhibit histopathologic findings
1.04, 3.17) compared with conventional cigarette of reactive keratosis.
smoking (Wyss et al. 2016).
Patient Management
MMO is a benign lesion, and patients should be
Morsicatio Mucosae Oris (Chronic Bite reassured that these are reactive lesions usually
Keratosis) caused by a parafunctional habit, whether con-
scious, unconscious, or nocturnal, with no malig-
Morsicatio mucosae oris (MMO) or chronic bite/ nant potential. However, all patients should have
frictional keratosis is a benign, trauma-induced an examination of the muscles of mastication.
lesion of the oral mucosa. MMO must be differ- Muscle tenderness suggests a clenching or
entiated from leukoplakia which has malignant bruxing habit with the potential for developing
potential. myofascial pain, and fabricating a night guard
may be appropriate. However, using a habit-
Etiology and Pathophysiology breaking device purely for managing MMO has
As opposed to acute bite trauma which usually not generally been successful in eradicating these
presents as an ulcer, MMO is caused by chronic lesions. Such devices themselves may cause the
trauma to the nonkeratinized mucosa, usually same frictional keratosis if the patient continues
associated with parafunctional habits, whether the habit and macerates the mucosa against the
conscious or unconscious. This leads to para- device.
keratosis and benign epithelial hyperplasia. This
includes nibbling or sucking on the mucosa, as
well as rubbing of the mucosa against dental pros- Benign Alveolar Ridge Keratosis
theses or other hardware such as orthodontic
braces and piercings. Similar lesions have been Benign alveolar ridge keratosis (BARK) is a
reported in the oral mucosa of the glassblowers benign frictional/traumatic hyperkeratosis on
(Schiodt et al. 1980). Its counterpart on the keratinized alveolar ridge mucosa or the palatal
keratinized mucosa is benign alveolar ridge kera- mucosa (Natarajan and Woo 2008). Historically,
tosis (see later). BARK may have been classified under oral leu-
koplakia which implies potential for malignant
Clinical-Pathologic Features transformation (Waldron and Shafer 1975;
MMO is usually seen in individuals over the age Napier et al. 2003). However, BARK is a distinct
of 35 and peaks in the fifth and sixth decades of histopathologic and clinical entity that should be
Fig. 5 Morsicatio mucosa oris (all images are from a white plaque along the linea alba region, with fading mar-
single patient). (a) Poorly demarcated linear plaque along gins. (c) Poorly demarcated white papules and plaques of
the bite line of the tongue. (b) Poorly demarcated red and the right lower lip mucosa and contiguous buccal mucosa
differentiated from other white keratinized Clinical-Pathologic Features

lesions of the oral cavity, and most importantly BARK is noted during the fifth to seventh decades
distinguished from leukoplakia because it has no of life, and males are more commonly affected
malignant potential (Woo et al. 2014). It should (Natarajan and Woo 2008). It presents as an
also be differentiated from “alveolar ridge kera- asymptomatic poorly demarcated white plaque,
tosis” which is not a specific histopathologic most commonly seen on the mandibular
entity, but rather any keratotic lesion on the retromolar pad (often bilaterally), but also on the
ridge, frictional, dysplastic, or cancerous (Chi edentulous maxillary or mandibular alveolar ridge
et al. 2007). mucosa (Fig. 6a, b). The surface of a BARK lesion
is often rough and slightly verrucous, which raises
the possibility of verrucous leukoplakia.
Etiology and Pathophysiology A biopsy may be performed on suspicious
BARK is a benign, reactive lesion which results lesions to establish the diagnosis, and the histo-
from mechanical trauma, likely from food pathologic features are specific.
crushed against the edentulous alveolar ridge
mucosa. The oral mucosa responds with deposi-
tion of keratin and benign epithelial hyperplasia. Patient Management
It is the oral counterpart of the skin lesion, BARK is a benign lesion without potential for
lichen simplex chronicus, a frictional/factitial malignant transformation, and no treatment is
keratosis, that shares similar histopathologic required. Due to similarity in clinical presentation,
features. BARK should be differentiated from leukoplakia
Fig. 6 Benign alveolar ridge keratosis: poorly demarcated white plaque of the (a) right retromolar pad and (b) left
retromolar pad
which is a clinical entity that has malignant clinical findings. Long-standing contact with an
potential. irritant results in coagulation of the surface epi-
thelial cells such as seen in smokeless tobacco
lesions. More caustic agents such as aspirin, or
Contact Stomatitis dental materials such as methacrylate, lead to
inflammation, erosion, and ulceration.
Lesions of contact stomatitis are red and/or white Allergic contact stomatitis or contact hypersen-
that are located where a known contactant has sitivity reaction develops as a result of a type IV
been placed. It can be divided into two main types: hypersensitivity reaction to a contactant such as
cinnamic aldehyde or peppermint in dentifrices
(a) Irritant contact stomatitis resulting from and candies or mercury in amalgam restorations
direct injury to the mucosa from an irritating (Isaac-Renton et al. 2015).
substance placed against the mucosa, but with
more damage than simple chemical Clinical-Pathologic Features
desquamation Irritant contact stomatitis is generally seen in
(b) Allergic contact stomatitis or contact hyper- adults because the pediatric population is unlikely
sensitivity reaction resulting from hypersensi- to use strongly flavored dentifrices or smokeless
tivity to a component of the contactant tobacco or be involved in complex dental proce-
dures. Mild irritant contact stomatitis may only
A systemic hypersensitivity reaction to other result in patients sensing or observing a change in
agents such as foods or flavoring agents (such as the color or texture of the mucosa, and patients may
phenolic compounds) is a different entity that may not seek care for this condition. An example is the
result in the swelling of the lip such as is seen in asymptomatic, wrinkled, white lesions seen in
orofacial granulomatosis, which is discussed smokeless tobacco use or reactive keratosis caused
elsewhere. by mouthwash (Fig. 7a, b). For more caustic sub-
stances such as aspirin or methacrylate, changes
Etiology and Pathophysiology develop within minutes to hours of contact. Ery-
Irritant contact stomatitis develops due to expo- thema develops at the site of placement followed by
sure of oral mucosa to a local chemical irritant variable gray-white changes from edema and coag-
that, depending on causticity, may lead to variable ulation of the epithelium and, depending on the
Fig. 7 Contact stomatitis: (a) Diffuse, white translucent showing complete resolution of the lesion, 40 days after
change of the ventral tongue in a female patient with discontinuation of rinsing with 10% carbamide peroxide
10–15-year history of rinsing with 10% carbamide perox- mouthwash
ide mouthwash. (b) Ventral tongue of the same patient,
length of exposure and strength of the contactant, resolve completely upon discontinuation of use of
painful ulceration (Spencer et al. 2016). This is those products. If this is acute and caused by
usually easily diagnosed by taking a good history placement of aspirin or exposure to more caustic
and correlating this with the clinical presentation; dental materials, topical steroid therapy (such as
therefore a biopsy is not usually necessary. fluocinonide 0.05% gel or betamethasone
Allergic contact stomatitis or contact hypersen- dipropionate 0.05% ointment) may help to pro-
sitivity reaction occurs in areas where there is direct mote healing.
contact with the offending agent, such as mucosal Allergic contact stomatitis or contact hyper-
contact with amalgam, candies, or chewing gum. sensitivity reaction: Once the biopsy has
The area has a red and/or white macule or reticu- confirmed/established the nature of this lesion,
lated area that is poorly demarcated and that is removal of the contactant (such as amalgam) or
usually sensitive or painful; ulcers may be present. cessation of the habit (such as eating candies
One form of contact hypersensitivity reaction pre- or chewing gum) is a definitive therapy
sents as desquamative gingivitis where the gingiva (Woo 2012). Topical steroids help resolve
is diffusely bright red. A biopsy shows sheets of lesions more quickly, and topical anesthetics
polyclonal plasma cells, and as such this condition such as benzocaine help to ease pain. If the
is known as plasma cell gingivitis. biopsy shows plasma cell stomatitis, patch test-
In most cases, the diagnosis is readily arrived at ing may be helpful to identify the specific
because of the location and appearance of the allergen.
lesion together with the history of contact with
an offending agent. Removal of the offending
contactant (such as replacing an amalgam with a Nicotinic Stomatitis (Stomatitis
composite restoration) may lead to resolution of Nicotina)
the lesion. If in doubt, a biopsy should be
performed to rule out other conditions such as Nicotinic stomatitis (NS) is an inflammatory con-
erythroleukoplakia. Contact hypersensitivity dition of the hard palatal mucosa presenting as
reactions may be lichenoid on histopathology. thickened and hyperkeratotic alteration of the pal-
atal mucosa, commonly seen with pipe, cigar, or
Patient Management reverse smokers (Ramulu et al. 1973). Reverse
Irritant contact stomatitis: For chronic exposure to smoking lesions which are the most severe form
other mildly caustic substances, the lesions will of nicotinic stomatitis have been classified by the
Fig. 8 Nicotinic stomatitis:

diffuse whiteness of the
palatal mucosa with
cobblestone appearance and
red puncta (Image courtesy
of Dr Ivan Stojanov, Case
Western Reserve
University, Cleveland,
Ohio, USA)
WHO as an oral potentially malignant condition lesions should be followed up regularly to monitor
(Warnakulasuriya et al. 2007). for malignant transformation, particularly reverse
smokers (Saunders 1958; Alvarez Gomez et al.
Etiology and Pathophysiology 2008; van der Eb et al. 1993).
NS is a misnomer because the lesions develop in
response to the intense heat associated with
smoking habits and not from nicotine. It is partic- Hairy/Coated Tongue
ularly prominent in reverse smokers because the
heat from placing the lit end of the cigarette in the Hairy tongue (HT) is an acquired benign oral
mouth is intense; this is a practice that is not condition characterized by marked elongation of
infrequent in India and some Southeast Asian filiform papillae resulting in a hairlike appearance
communities. It has also been reported in patients or a matted/coated appearance of the tongue
who habitually consume extremely hot beverages. dorsum.
As a result of chronic exposure to heat, the palatal
mucosa becomes hyperkeratotic and thickened, Etiology and Pathophysiology
and the orifices of excretory salivary ducts HT is caused by retention or accumulation of
become inflamed. keratin on the filiform papillae and/reduced nor-
mal desquamation; the first is usually caused by
Clinical-Pathologic Features dehydration, and the second by poor diet (Manabe
NS is more common in males in the fifth decade et al. 1999). In the first circumstance, patients
and older, and is usually asymptomatic. The pal- have dry mouths where their salivary glands are
atal mucosa is diffusely whitened, and established producing less watery and more sticky, mucus-
lesions are fissured, with a cobblestone or “dried containing viscid saliva, so that keratin is retained.
mud” appearance. The surface often contains This is most frequently seen in patients who have
scattered 1–3 mm, red punctuate papules that rep- salivary gland hyposalivation from taking anti-
resent the inflamed orifices of minor salivary cholinergic medications, not drinking sufficient
gland ducts (Fig. 8). Because these lesions are water, with chronic anxiety or as a result of
fairly uniform appearing and symmetric, any smoking tobacco. Less frequent causes of hypo-
localized area that appears raised, warty, or fleshy salivation include head and neck radiation for
must be viewed with suspicion and biopsied. cancer and Sjogren’s syndrome. In the second
circumstance, there is reduced mechanical des-
Patient Management quamation of the keratin on the filiform papillae
Early NS lesions may regress on cessation of pipe in individuals who consume mostly soft, pro-
smoking; however, patients with persistent cessed foods and insufficient coarse foods such
Fig. 9 Hairy tongue. (a) Elongated yellow brown filiform papillae of the mid- and posterior dorsal tongue.
(b) Two-month follow-up of the same patient after improving hydration and chewing fresh pineapple
as fresh fruits and vegetables. This includes hos- should be evaluated for oral candidosis which
pitalized patients, patients who are very ill, and may look similar, but will usually involve sites
those with poor diet. These lesions may be mis- other than the tongue and does not usually have a
diagnosed as candidosis because of the whiteness diffuse, symmetric appearance on the tongue dor-
of the tongue and because cultures may be posi- sum alone. This is particularly important in
tive for candida although that may merely repre- patients who are on antibiotics, where it is impor-
sent normal oral carriage. tant to distinguish between dehydration and/or
poor oral intake from illness and the presentation
Clinical-Pathologic Features associated with oral candidosis.
HT is generally seen in adults because it is
strongly associated with hyposalivation and Patient Management
chronic illness, and there may be a male predilec- HT is self-limiting with no serious sequelae, and
tion. It is usually asymptomatic and generally patients should be reassured that they do not have
affects the anterior two-third of the tongue dor- an infection. Improved hydration, eating a diet
sum, sparing the lateral borders and the tip containing fresh fruits and vegetables, and reduc-
(Fig. 9a, b). These matted papillae may be stained ing habits that cause dehydration of the mucosa
by the natural color of foods, food dyes, tobacco, (such as smoking and using alcoholic mouth
or pigment produced by pigment-producing rinses) will improve this condition. Brushing the
(chromogenic) bacteriae on the tongue. Common tongue gently with a soft toothbrush or gentle use
colors are brown, yellow, or black (hence, the term of a tongue scraper helps to remove the retained
black HT). Prolonged contact with bismuth sub- keratin and promote desquamation, but should be
salicylate, an antacid, may also discolor the used sparingly so as not to cause further irritation
tongue dorsum (Gurvits and Tan 2014). to the dorsal tongue epithelium. Anecdotal evi-
Some patients report halitosis, dysgeusia, dence suggests that eating acidic and fibrous foods
and/or a stale or metallic taste, symptoms that such as pineapple may also reduce keratin reten-
are often associated with a dry mouth (Gurvits tion, while brushing the tongue with diluted
and Tan 2014). The matted, hairy texture may sodium hypochlorite solution can also be
cause gagging. If burning is present, the patient effective.
Infections candidosis often occurs after antibiotic therapy or

high-dose steroid therapy in susceptible individ-
Candidosis uals and is common in those with HIV/AIDS
(Reichart et al. 2000). When lesions are present
Candidosis is the most common fungal infection diffusely on the tongue dorsum, they auto-
in the mouth. inoculate the palatal mucosa, and these are
referred to as “kissing lesions.”
Etiology and Pathophysiology Erythematous candidosis: As the name
Oral candidosis is most commonly caused by implies, it presents as erythematous,
Candida albicans. This organism can be isolated raw-appearing lesions of the oral mucosa and
from the oral cavity of 30–50% of the asymptom- has been further subclassified based on the clinical
atic dentate population; this prevalence likely presentation, anatomical site, or etiology as
increases with age. This merely indicates carriage, follows:
and hence a positive carriage culture in the
absence of clinical manifestations should not be • Denture stomatitis or chronic atrophic
interpreted as representative of an active infection candidosis characterized by sensitive or pain-
(Tejani et al. 2016). Predisposing factors ful, well-delineated erythema limited to the
for candidosis include (a) alterations in the local denture-bearing areas, more commonly seen
environment, such as hyposalivation and use of on the palatal mucosa (Fig. 10b).
topical steroids; (b) alterations in the systemic • Median rhomboid glossitis or central
environment, such as use of systemic antibiotics papillary atrophy of the midline of the dorsum
and immunosuppressive agents; diabetes mellitus; of the tongue characterized by an often
hematinic deficiencies; intrinsic immunodefi- ovoid area of depapillation and
ciency syndromes or acquired immunodeficiency erythema just anterior to the foramen cecum
such as HIV/AIDS; and c) positive candidal (Fig. 10c).
carriage. Other members of the Candida genus • Angular cheilitis characterized by painful ery-
that can affect the oral cavity include thema and fissuring of the corners of the
C. guilliermondii, C. tropicalis, C. dubliniensis, mouth (Fig. 10d). Reduced vertical dimen-
C. krusei, and C. parapsilosis; however, they sion leads to dampness and maceration pre-
are less common in the general population and disposing to candidal growth in this particular
are more frequently seen in patients with form of candidosis. This is often exacerbated
HIV/AIDS. by preexisting iron or vitamin B12 deficiency.
This form of candidosis is often associated
with concomitant infection with Staphylococ-
Clinical-Pathologic Features cus aureus (Ohman et al. 1986; Smith
Candidosis occurs across a broad age range et al. 2003).
depending on clinical circumstances as outlined
above. Patients may be asymptomatic but more Hyperplastic candidosis: It presents as asymp-
often present with sensitivity and a burning sen- tomatic white plaques that cannot be scraped off.
sation, or even pain, and sometimes dysgeusia It is more common in the anterior buccal mucosa
(Sharon and Fazel 2010). Several clinical mani- and lateral tongue. Hyperplastic candidosis may
festations exist as follows: be associated with endocrinopathies and hairy
Pseudomembranous candidosis or thrush: leukoplakia.
This presents as white, curdy papules and plaques The diagnosis is usually established by the clin-
composed of tangled hyphae, yeast, and desqua- ical appearance of the lesion or by identifying
mated epithelial cells (Fig. 10a). These adherent hyphae through a scrape and potassium hydroxide
papules and plaques may or may not be scraped preparation or by cytologic examination. A biopsy
off the mucosal surface leaving behind erythema- is not usually necessary, but if performed, hyphae
tous, often bleeding mucosa. Pseudomembranous are readily identified.
Fig. 10 (a) Pseudomembranous candidosis: white glossitis and angular cheilitis in an edentulous after antibi-
plaques and papules and erythema involving the hard and otic therapy. (d) Angular cheilitis: erythematous, macer-
soft palate. (b) Erythematous candidosis: erythema of the ated areas at the commissures
palatal mucosa beneath a denture. (c) Median rhomboid
Patient Management recurrent infection episodes, prophylaxis regi-

Topical and systemic antifungal medications are mens should be considered. Drug resistance to
discussed elsewhere, including management of fluconazole may develop in patients on long-
prostheses which act as fomites. In brief, topical term antifungal therapy, and other agents include
therapy includes nystatin rinses and pastilles, voriconazole, itraconazole, posaconazole, and
clotrimazole and miconazole troches, and, in echinocandins.
some countries, topical amphotericin. Combina-
tions of antifungal agents and a topical steroid
(such as nystatin and triamcinolone or Oral Hairy Leukoplakia
clotrimazole and betamethasone) are useful for
atrophic candidiasis related to dentures and Oral hairy leukoplakia (OHL) is a benign condi-
for angular cheilitis. Treatment of concomitant tion of the tongue caused by Epstein-Barr virus
Staphylococcus infections is with topical (EBV) and is most frequently seen in immuno-
erythromycin. Systemic therapy includes compromised patients such as those with
fluconazole. HIV/AIDS as well as in patients on immunosup-
Patients with recalcitrant disease should be pressive therapy such as organ transplant recipi-
evaluated for systemic disease such as diabetes ents (Bhayat et al. 2010). However, OHL has also
mellitus or even HIV/AIDS. In patients been reported in immunocompetent individuals
treated with long-term systemic steroids or with (Greenspan et al. 2016).
Fig. 11 Hairy leukoplakia:

white, adherent plaque with
linear folds running parallel
to the long axis of the left
lateral tongue
Etiology and Pathophysiology Patient Management

OHL is caused by EBV infection within the muco- OHL is a benign lesion and may be the first sign
sal epithelium, and biopsies show the presence of of HIV infection. As such, all patients carrying
EBV-encoded RNA within the nuclei of epithelial this diagnosis who are not known to be immu-
cells. The current theory or etiopathogenesis sug- nocompromised should have an HIV test and be
gests initial infection of basal epithelial cells with evaluated for latent immunocompromise.
EBV followed by replication of EBV in the epi- Lesions resolve with antiretroviral therapy.
thelial cells and B cells (Slots et al. 2006). Circu- Treatment with systemic valaciclovir and topical
lating cytotoxic T cells function to maintain a treatments such as 25% podophyllin resin, 1%
latent state of the virus during this process. In penciclovir, or 5% acyclovir have shown some
immunocompromised and immunosenescent benefits (Walling et al. 2003; Moura et al. 2010).
patients, there is a natural decrease in the numbers In patients with iatrogenic immunosuppression,
of cytotoxic T cells leading to active replication OHL may resolve on reduction of immunosup-
and circulation of EBV-infected B cells (Slots pression. Candidosis should be treated with anti-
et al. 2006). fungal agents.
OHL in HIV/AIDS is generally seen in the fourth Immune-Mediated and Autoimmune
decade of life, and males are affected more fre- Conditions
quently (male-to-female ratio 4:1) (Dongo et al.
2013; Stojanov and Woo 2015). Men who have Benign Migratory Glossitis (Geographic
sex with men with HIV seropositivity have the Tongue, Erythema Areata Migrans,
highest prevalence of OHL. OHL presents most Migratory Stomatitis)
frequently on the lateral borders of the tongue as
an asymptomatic, white, adherent plaque with Benign migratory glossitis (BMG) is a chronic,
linear folds that run parallel to the long axis of benign inflammatory condition of the tongue
the lateral tongue (Fig. 11). Other sites include the characterized by relapsing-recurring loss of fili-
buccal mucosa, and lesions are generally bilateral. form papillae; it affects 1–2% of the population
OHL is diagnosed by biopsy and confirmation (Jainkittivong and Langlais 2005). Patients may
of the presence of EBV by in situ hybridization seek professional advice because of the unusual
studies. Oftentimes, there is secondary candidosis appearance of the tongue or increased sensitiv-
noted on the biopsy. ity of their mucosa to spicy or acidic food.
Etiology and Pathophysiology 40, others deem it to be more frequent in children

The exact pathophysiology of BMG is with a decreasing prevalence with increasing age
unknown. However, it often occurs in atopic (Banoczy et al. 1975; Assimakopoulos et al.
patients, namely, those with or have a history 2002). BMG has a female predilection (1.5:1),
of asthma, eczema, hay fever, food sensitivities, and patients may be asymptomatic or experience
and other allergies (Goregen et al. 2010). In the burning, soreness, and/or sensitivity especially
absence of atopy in the patient, a positive his- upon eating acidic and spicy foods. It most fre-
tory of such conditions may be elicited in first- quently presents on the dorsal or ventral tongue.
degree relatives. It is also associated with pso- BMG typically begins as one or more depapillated
riasis (especially the generalized pustular form) areas on the dorsal tongue which enlarge to form
and Reiter disease. BMG lesions tend to flare slightly depressed, red patches with a white sur-
when patients are under stress or are ill (Miloglu rounding rim giving rise to an annular or
et al. 2009). circinate appearance. This results in a map-like
pattern, hence the name “geographic tongue”
Clinical-Pathologic Features (Fig. 12a, b). It is self-limiting and heals within a
BMG affects a wide age range; while some report few days with a variable period of quiescence
it to occur mostly in individuals over the age of before it recurs. When sites other than the tongue
Fig. 12 (a) Benign migratory glossitis characterized by of the dorsum with only faint white rim. (c) Migratory
macular erythema with atrophy of filiform papillae and stomatitis: white circular and linear lesions of the lower
slightly elevated white, circinate borders. (b) Benign lip mucosa
migratory glossitis characterized by patchy depapillation
such as the lip mucosa, floor of the mouth, or soft brushing (Lo Russo et al. 2009). Lichen planus,
palate are affected, it is referred to as migratory lichenoid lesions, and mucous membrane
stomatitis or stomatitis areata migrans (Fig. 12c). pemphigoid tend to occur in middle-aged females.
A biopsy is usually unnecessary if the history is Because of pain on brushing, there may be abun-
typical but may be performed to confirm the dant materia alba on the teeth leading to even
diagnosis. more inflammation and erythema.
Desquamative gingivitis presents as brightly
Patient Management erythematous macular and/or diffuse areas of mar-
If BMG is asymptomatic, no treatment is indicated, ginal and attached gingiva, usually on the buccal
and patients should be provided information and aspect, although the palatal and lingual gingivae
reassurance. Symptomatic BMG lesions may be may also be affected (Fig. 13a–c). Ulcers and
managed with 2% viscous lidocaine and/or liquid heaped-up remnants of ruptured bullae may be
diphenhydramine in equal volumes for symptom present at the edges of erythema.
control. Other agents may include topical steroids In most cases, patients are referred for biopsy
and antifungal medications. More severe cases may or management because good plaque control has
be treated with topical steroid rinses such as dexa- not resulted in resolution of lesions. A biopsy
methasone oral rinse or steroid gels and creams. should be obtained from peri-lesional tissue;
half should be sent in formalin for routine histo-
pathologic examination, and the other half
Desquamative Gingivitis should be submitted either fresh if in a medical
center or in Michel medium if the tissue
Desquamative gingivitis is a descriptive term that is mailed, for direct immunofluorescence studies
refers to gingival erythema that is usually diffuse, (Suresh and Neiders 2012). The histopathologic
sometimes with noticeable peeling of gingival tis- features vary depending on the diagnosis. In gen-
sues. It is a clinical finding that has been associated eral, if the patient already has had a skin
with several disorders, some of which may repre- biopsy and a known diagnosis of a blistering
sent true desquamation and loss of epithelium. disorder, it is usually unnecessary to perform an
oral biopsy.
Desquamative gingivitis is a clinical finding Patient Management
resulting from three main classes of disorders Management is directed toward treating the
including: underlying condition. Patients should avoid the
offending contactant if the diagnosis is contact
1. Lichen planus or lichenoid mucositis hypersensitivity reaction. Management of lichen
2. Autoimmune vesiculobullous disorders and ,in planus and autoimmune disorders is generally
particular, mucous membrane pemphigoid and with topical steroids. This may be applied directly
less often pemphigus vulgaris (Scully and onto the mucosa or within custom trays.
Porter 1997; Lo Russo et al. 2008) Intralesional steroid injections are helpful for
3. Contact hypersensitivity reaction (such as large ulcers, and systemic therapy may be appro-
plasma cell gingivostomatitis which is often priate for more severe disease; this is discussed in
associated with exposure to contactants such the relevant chapters.
as flavoring agents in candies, chewing gum, or
dentifrices)
Plasma Cell Gingivostomatitis (Plasma
Clinical-Pathologic Features Cell Orificial Mucositis)
Of the three entities, lichen planus is the most
common, and most patients experience mild to Plasma cell gingivostomatitis (PCG) is a rare,
moderate oral sensitivity, pain, and bleeding on yet distinctive, benign inflammatory condition
Fig. 13 Desquamative gingivitis: (a) diffuse erythema of (c) localized erythema of the buccal attached interproximal
the buccal attached gingiva without striations in a patient gingiva of the upper left central and lateral incisor teeth in a
with lichen planus. (b) Diffuse erythema of the buccal patient with pemphigus vulgaris
attached gingiva in mucous membrane pemphigoid and
characterized by extensive infiltration of plasma stippling similar to the findings in desquamative

cells within the connective tissue of the oral mucosa. gingivitis. Gingival bleeding is common because
the epithelium is eroded and inflamed (Fig. 14).
Etiology and Pathophysiology Although the gingiva is the most common site of
The first cluster of cases was caused by hypersen- involvement, other oral mucosal sites such as the
sitivity to a component of chewing gum (Kerr buccal and palatal mucosa as well as extraoral
et al. 1971). Since then, flavoring agents such as sites such as the pharyngeal mucosa may also be
cinnamaldehyde in chewing gum and toothpastes, affected.
mint candy, and herbs and spices have also been Conditions such as erythematous/erosive gin-
recognized as causative factors (Anil 2007). gival lichen planus and mucous membrane
pemphigoid, or even leukemia, may have the
Clinical-Pathologic Features same clinical presentation. As such, a biopsy is
This is a condition of adults with no gender pre- always required to establish the diagnosis, and
dilection. Patients report soreness and sensitivity this shows sheets of polyclonal plasma cells.
especially on eating acidic and spicy foods and
sometimes on brushing their teeth. The marginal Patient Management
and attached gingiva presents with diffuse, bright Similar to other hypersensitivity conditions, iden-
erythema with swelling, edema, and loss of tifying the causative agent is of prime importance,
Fig. 14 Plasma cell

gingivostomatitis
manifesting as generalized
moderate facial gingival
erythema with mild edema
in a 32-year-old female
and patch testing may be useful. Patients should identified. Oral LP may be idiopathic, but
keep a diary of possible exposures, especially to lichenoid mucosal reactions indistinguishable
flavoring agents, and whether avoidance resolves from idiopathic LP may be seen in other con-
lesions. Treatment modalities include topical and ditions including:
systemic steroids (Solomon et al. 2008). How-
ever, lesions will persist as long as the patient is 1. Drug-induced hypersensitivity reactions to
exposed to the antigen. In cases of gross gingival medications such as antihypertensive agents,
enlargement (plasma cell granuloma), surgical including β-blockers, angiotensin-convert-
excision is indicated for plaque control, followed ing enzyme inhibitors, and diuretics (in
by topical steroids. particular hydrochlorothiazide) and nonste-
roidal anti-inflammatory drugs (Yuan and
Woo 2015)
Oral Lichen Planus 2. Hepatitis C especially in patients with
HLA-DR6 living around the Mediterranean
Lichen planus (LP) is a common chronic muco- Sea (Carrozzo et al. 2005)
cutaneous condition that may affect the oral 3. Contact hypersensitivity to amalgam
mucosa in more than half of the affected individ- restorations
uals (Altman and Perry 1961; Cheng et al. 2016). 4. Chronic graft versus host disease
While concomitant presentation of cutaneous and 5. Thyroid disease (or medications to treat
oral LP is common, only 10–15% of patients with thyroid disease) (Garcia-Pola et al. 2016)
oral LP develop cutaneous lesions (Cheng et al.
2016). Vulvovaginal-gingival and peno-gingival Because oral LP may be associated with a
LP is a subgroup of LP collectively referred to as variety of other conditions, some authorities
gingival-genital syndrome that is associated with suggest that oral LP is not a single specific
HLA-DQB1*0201. This condition presents with disease but rather a mucosal reaction with a
desquamative gingivitis and often runs a more characteristic clinical and histopathologic
severe course sometimes with buccal mucosa phenotype.
fibrosis (Setterfield et al. 2006).
Etiology and Pathophysiology Oral LP is more commonly seen in women (male/
LP is an immune-mediated condition in which female 1:2–3) in the sixth decade (De Rossi and
basal cells are destroyed by cytotoxic CD8+ Ciarrocca 2014). The WHO diagnostic criteria for
T cells (Lavanya et al. 2011). Although some lichen planus was modified in 2003 and again in
consider oral LP to be an autoimmune 2016 (van der Meij and van der Waal 2003; Cheng
disease, the target antigen has yet to be et al. 2016). Typical oral LP is almost always
Fig. 15 Reticular lichen planus of (a) right buccal mucosa, (b) left buccal mucosa, and (c) dorsum of the tongue
presenting primarily as poorly demarcated keratotic papules
bilateral and symmetric and affects the buccal Atrophic oral LP is best seen on the tongue
mucosa, tongue, and attached gingiva. Lesions dorsum where there is loss of the filiform and
may be classified into the following, often over- fungiform papillae and there is diffuse keratosis
lapping categories: or white papules.
Reticular/keratotic (classic) oral LP is charac- Bullous oral LP is extremely rare, and most
terized by mostly asymptomatic white bullae break down to form erythematous/erosive
intersecting loops and lines forming Wickham oral LP.
striae or papules on a variably erythematous back- Oral LP that presents with bilateral, symmetric
ground (Cheng et al. 2016). Lesions are generally striations occurring at the typical oral sites may
bilateral and involve the buccal mucosa, tongue not require biopsy. Cases that are asymmetric with
dorsum and ventrum, lip mucosa, and gingiva; questionable striations should be biopsied, and
this may be associated with erythema erythematous/erosive lesions presenting as
(Fig. 15a–c). desquamative gingivitis should also have a por-
Erythematous/erosive oral LP frequently tion of the biopsy submitted for direct immuno-
involves the gingiva and presents as red, erythem- fluorescence studies to rule out mucous
atous areas of mostly buccal (and less commonly membrane pemphigoid and other autoimmune
palatal and lingual) gingiva which is commonly vesiculobullous disorders. “Plaque-type oral LP”
referred to as desquamative gingivitis (Fig. 13a). occurring as a solitary white plaque or a plaque
Ulcerative oral LP presents as ulcerated oral within more typical oral LP should be viewed with
mucosa with a yellow fibrin membrane usually suspicion, and biopsy is always indicated. It
with a surrounding erythematous rim and subtle should be noted that many oral dysplasias present
peripheral reticulations (Fig. 16a–d). with a histopathologic features of “lichenoid
Fig. 16 Ulcerative lichen planus (all images are from a single patient): reticulated, erythematous, and ulcerated (yellow
fibrin membrane) of the bilateral hard palate (a and b) and buccal mucosa (c and d)
inflammatory infiltrate,” but this should not be cutaneous lupus erythematosus (SCLE) are sub-
automatically construed as dysplasia arising in sets of lupus erythematosus (LE) which is a
oral LP. chronic multisystemic autoimmune disorder that
often presents with oral lesions (Nico et al. 2011;
Patient Management Tsokos 2011; Ranginwala et al. 2012).
Symptomatic cases are managed with topical ste-
roid gels, creams, and rinses. More severe cases Etiology and Pathophysiology
may require systemic steroid therapy in conjunc- LE is an autoimmune disease, and a combination
tion with hydroxychloroquine, mycophenolate of genetic, hormonal, and environmental
mofetil, or tumor necrosis factor inhibitors. In factors (e.g., smoking and exposure to ultraviolet
cases of oral contact lichenoid hypersensitivity light) may contribute to its development or
reactions, removal of the causative agent such as progression (Tsokos 2011). Genetic predisposi-
an amalgam restoration may resolve the lesions tion plays a pivotal role in pathogenesis of
(Yuan and Woo 2015). Malignant transformation LE, and this includes single-gene deficiencies
has been reported in 0.1–1.0% of oral LP although that affect the immune system (Rullo and
some of such cases had a history of smoking. Tsao 2013). Antibodies produced in this
condition target double-stranded DNA, histones,
and ribonucleoproteins and are deposited in
Lupus Erythematosus several organs including the kidney, liver, joints,
skin, and mucous membrane resulting in
Systemic lupus erythematosus (SLE), discoid protean clinical presentations (Ippolito et al.
lupus erythematosus (DLE), and subacute 2011).
Clinical-Pathologic Features taken from lesional tissue in DLE, is diagnostic

LE generally affects women of childbearing age (lupus band test). Serology is often positive for
(female:male 8–10:1) (Tsokos 2011). The oral antinuclear antibody, anti-dsDNA, anti-Smith,
mucosa can be affected in the absence of skin anti-ribonucleoproteins, and anti-SSA.
lesions in up to 20% of patients with DLE and
45% of patients with SLE (Lourenco et al. 2007; Patient Management
Nico et al. 2008). Involvement of oral mucosa is Oral lesions can generally be managed with topi-
not a common finding in SCLE, and this has been cal steroids such as clobetasol or fluocinonide if
attributed to the important role of UV light in lesions are localized, by steroid rinses such as
pathogenesis of SCLE (Sontheimer 2005). dexamethasone, or by intralesional steroid injec-
Extraoral presentations of SLE in the head and tions. Systemic therapy is generally initiated and
neck area include a photodistributed or “butterfly” maintained by the patient’s dermatologist or
rash on the malar region, corresponding to the rheumatologist.
area of the face that is mostly exposed to the UV
light. Cutaneous lesions of DLE present as atro-
phic plaques with follicular plugging and evi- Oral Graft Versus Host Disease
dence of post-inflammatory hyperpigmentation.
SCLE is the most photosensitive subtype of LE, Graft versus host disease (GVHD) is an immune-
and lesions mostly involve the sun-exposed area mediated, multi-organ complication that occurs
of the skin in the V-area of the neck, upper trunk, after allogenic hematopoietic cell transplantation
dorsum of the hands, and the shoulders (allo-HCT) used for the treatment of hematologi-
(Sontheimer 2005). cal malignancies and diseases resulting in bone
Oral lesions of LE cause pain and sensitivity marrow failure (such as aplastic anemia). Histor-
and present as aphthous-like ulcers or poorly ically GVHD was classified into acute and chronic
demarcated, red and white, reticulated lesions of categories based on time from transplantation,
the buccal, lip, and palatal mucosa (Lourenco with acute GVHD occurring within the first
et al. 2007) (Fig. 17a, b). 100 days posttransplantation and chronic GVHD
An incisional biopsy and direct immunofluo- as an extension of acute GVHD or developing de
rescence studies are required to confirm the diag- novo after 100 days. Current thinking, however,
nosis. Granular deposition of IgG, IgM, and/or suggests that acute and chronic GVHD have dis-
IgA at the basement membrane zone in biopsies tinct etiologies and clinical manifestations
taken from clinically normal skin for SLE, and (Pavletic and Fowler 2012).
Fig. 17 Oral presentation of lupus erythematous (both palatal and (b) white reticulations and erythema of the left
images are from a single patient). (a) Erythema with slight buccal mucosa
surrounding faint white reticulated lesion of the right hard
Etiology and Pathophysiology accompanied by ulcers and resembles chemother-

Disparity in human leukocyte antigens (HLAs) apy and neutropenic ulcers except that (1) the
between the donor and recipient is the most keratinized tissues of the hard palatal mucosa and
important risk factor for developing GVHD tongue dorsum are often affected and (2) patients are
because of an alloimmune response by the donor’s engrafted and no longer neutropenic.
immune cells against the surface antigens of the A skin biopsy establishes the diagnosis,
recipient’s cells which are mismatched although hypersensitivity to medications is an
(Vogelsang et al. 2003). The current guidelines important differential diagnosis.
recommend 8/8 match between donor and recipi- Chronic oral GVHD: Lichenoid and
ent HLA-A, HLA-B, HLA-C, and HLA-DRB loci sclerodermatous skin involvement, keratoconjunc-
(Lee et al. 2007b). Other factors such as sex, tivitis sicca, liver disease, obstructive lung
recipient’s advanced age, source of progenitor disease, gastrointestinal disease, and genital disease
cells, and intensity of conditioning regimen may with fibrosis are frequently encountered. Unlike
also affect the severity of GVHD. acute GVHD, the oral mucosa is affected in
Tissue damage from chemotherapy and radia- 50–70% of patients with chronic GVHD (Mays
tion therapy during pretransplantation condition- et al. 2013). Patients may present with sensitivity,
ing, infection, and immunosuppressive therapy pain, and burning of the mucosa. There is both
results in the activation of antigen-presenting xerostomia and hyposalivation caused by destruc-
cells. Presentation of mismatched cell surface tion of salivary gland parenchyma. The National
host antigens leads to activation and clonal expan- Institutes of Health (NIH) has devised clinical and
sion of donor lymphocytes which culminates in histopathological criteria for scoring chronic
tissue destruction through pro-inflammatory cyto- GVHD for standardization of diagnosis (Treister
kine production, resulting in acute GVHD which et al. 2010).
is an exaggerated inflammatory response (Ferrara The diagnosis is usually made on clinical evalu-
et al. 2009). ation alone, and a biopsy is not usually necessary.
The pathophysiology of chronic GVHD is Oral chronic GVHD has three common findings:
poorly understood. One theory proposes
chronic GVHD to be an end-stage presentation (a) Mucosal lesions that are lichen planus-like
of alloreactivity in which donor T cells have with lacey, white reticulations, erythema, and
differentiated into Th2 cells causing activation ulcerations. The most common sites are the
of B cells and production of autoantibodies. buccal mucosa, lip mucosa, and tongue
Alternatively, it has been postulated that mucosa although any mucosa may be
poor/dysfunctional immunologic recovery involved (Fig. 18a–c).
results in altered self-tolerance (Kataoka et al. (b) Superficial mucoceles of the palatal and buc-
2001). cal mucosa which are occasionally symptom-
atic (Fig. 19).
Clinical-Pathologic Features (c) Dry mucosa with little to no floor-of-mouth
Acute oral GVHD: This tends to occur within days pooling.
to weeks of engraftment with erythroderma and
sometimes skin blistering. The liver is often Less frequent findings include:
affected leading to jaundice, and involvement of
the gastrointestinal tract leads to abdominal pain (a) Scarring and fibrosis leading to trismus and
and diarrhea (Ion et al. 2014). The oral mucosa is loss of the vestibule, especially in long-
affected in less than 10% of patients with a median standing disease
age of 49 years and a 2:1 male-to-female ratio (Ion (b) Rampant caries from hyposalivation
et al. 2014). Patients report pain, sensitivity, or a (c) Development of oral dysplasia and squamous
burning sensation. It is characterized by marked oral cell carcinoma likely due to chronic
mucosal erythema and/or desquamation often immunosuppression
Fig. 18 Oral chronic graft versus host disease (all images (c) Erythematous and diffuse keratotic changes of the hard
are from a single patient). (a) Diffuse erythema involving palate with multiple superficial mucoceles (Images cour-
more than 75% of the right buccal mucosa. (b) Diffuse tesy of Dr Nathaniel Treister, Harvard School of Dental
erythema and linear ulceration of the left buccal mucosa. Medicine, Boston, MA, USA)
of developing secondary cancer is greater in

patients surviving 10 or more years after allo-
HCT transplant (Demarosi et al. 2005).
Patient Management and Future

Directions
Acute GVHD is managed with calcineurin inhib-
itors (cyclosporine or tacrolimus), high-dose ste-
roids, sirolimus, and mycophenolate mofetil.
Chronic GVHD of the oral mucosa is usu-
ally successfully managed with a combination
of topical steroids, topical tacrolimus,
intralesional steroid injections, and/or sys-
temic steroids and immunosuppressive ther-
Fig. 19 Superficial mucocele (arrow) on the hard palatal apy, depending on the severity of oral
mucosa of a patient with oral chronic graft versus host disease and the extent of involvement of the
disease skin and other organ systems. Ulcers should
be cultured to rule out herpes simplex virus
As with other similar lesions in the mouth, infection. Hyposalivation is managed with fre-
these take the form of leukoplakia and its variants, quent sips of water, and cholinergic agents,
erythroplakia, ulcers, and mass lesions. The risk such as pilocarpine and cevimeline, and
topical fluoride applications are helpful for the EM is categorized into minor and major types and
prevention of caries. Scarring and trismus can chronic recurrent oral erythema multiforme. In
be managed with stretching exercises with/ minor EM, there is little-to-no mucous membrane
without stretching devices, intralesional ste- and minimal (10%) skin involvement; the major
roid injections, and surgery to release fibrotic type however is characterized with more exten-
bands. Regular follow-up is essential for early sive mucous membrane and skin involvement.
detection of dysplasia and squamous cell Chronic recurrent oral EM is nearly always asso-
carcinoma. ciated with HSV infection, and patients may expe-
There is ongoing research into managing rience several episodes a year (Farthing et al.
GVHD by using targeted therapies to reduce cyto- 2005).
kine production, modulate the activity of antigen- Erythematous pruritic papules appear on the
presenting cells, and control T-cell numbers and skin of the extremities, some of which develop
activity. typical “target,” “bull’s eye,” or “iris” lesions.
Such lesions are generally less than 3 cm in diam-
eter and are composed of a central necrotic and
Erythema Multiforme erythematous disc surrounded by a pale edematous
ring and an outer circle of dusky erythema
Erythema multiforme (EM) is an acute hypersensi- (Auquier-Dunant et al. 2002). Cutaneous lesions
tivity reaction with mucocutaneous manifestations. progress centripetally to involve the trunk. The oral
It is considered distinct from Stevens-Johnson syn- mucosa is affected in 20–70% of patients, and these
drome and toxic epidermal necrolysis which are present as painful ovoid or irregular ulcers on any
necrolytic syndromes with the latter being the mucosal surface with a background of moderate to
more severe form (Bastuji-Garin et al. 1993). severe erythema. Hemorrhagic crusts of the lip
vermilion are a common but are not an invariable
Etiology and Pathophysiology finding (Fig. 20a–d) (Farthing et al. 2005).
EM is a hypersensitivity reaction primarily to an While cultures for HSV are usually negative in
infectious agent with more than 70% of cases EM patients, elevated serum IgM and IgG (at least
associated with herpes simplex virus (HSV) infec- four times over baseline) to HSV is supportive of
tion, as well as with M. pneumonia infection usu- the diagnosis. Lesional tissue may also be positive
ally in children (Sun et al. 2003; Schalock et al. by polymerase chain reaction for HSV. For the
2006). Hypersensitivity to medications such as diagnosis of M. pneumonia, detection of IgM for
antibiotics (e.g., penicillins and sulfonamides), plasma membrane antigens protein 1 and protein
anticonvulsants (phenytoin), or analgesics 116 by enzyme immunoassay is the most sensitive
(NSAIDs) forms a minority of cases (Sanchis (Lee et al. 2017).
et al. 2010; Langley et al. 2016). Asymptomatic
(subclinical) reactivation of HSV may also cause Patient Management
this condition. In addition, some have considered A careful history taking and bloodwork as men-
a role for genetic predisposition to EM with HLA tioned above are essential for establishing whether
DQ3, HLA-B35, HLA-A33, HLA-DR53, and the trigger is infectious or medication-induced.
HLA-DQB1*030 being associated with recurrent EM is self-limiting and, management is directed
EM (Schofield et al. 1994). toward pain control with topical anesthetics
and analgesics, supportive care such as hydration,
Clinical-Pathologic Features and promotion of healing of mucocutaneous
Adults between the age of 20 and 40 are most lesions with topical and/or systemic steroids.
commonly affected, with 20% of the cases occur- Daily antiviral therapy has been shown to prevent
ring in children with a slight predilection for recurrent EM in patients with viral trigger, and this
females. As discussed above, a large proportion in itself may be a useful diagnostic tool (Tatnall
of patients have a recent history of HSV infection. et al. 1995).
Fig. 20 Recurrent erythema multiforme secondary to labial mucosa. (b) Ulceration of the right hard palate with
reaction to fluconazole (all images are from a single diffuse erythema. (c) Erythema and ulceration of the
patient): (a) crusting of the upper lip with ulceration of tongue dorsum. (d) Ulceration of the right ventral tongue
the wet-dry border of the upper lip, extending to upper
discussed earlier in this chapter are white but

Precancerous and Cancerous Lesions
not leukoplakias.
Approximately 40% of true leukoplakias show
Leukoplakia and Proliferative
histologic evidence of dysplasia, carcinoma in
Verrucous Leukoplakia
situ, or invasive squamous cell carcinoma
(SCC). The other 60% will show hyperkeratosis
Leukoplakia is a clinical diagnosis defined by
or parakeratosis, acanthosis, or atrophy, with or
WHO as a white plaque of questionable risk
without inflammation; these have been given the
having excluded (other) known diseases or dis-
name keratosis of unknown significance (KUS).
orders that carry no increased risk for oral cancer
(Warnakulasuriya et al. 2007). It is the most
common premalignant (potentially malignant) Etiology and Pathophysiology
condition of the oral cavity. Because all other Risk factors for the development of intraoral leu-
known disorders that carry no increased risk for koplakia are similar to those for oral SCC and as
oral cancer must be ruled out, the diagnosis of such include cigarette smoking, excessive alcohol
leukoplakia is, by definition, one of exclusion. consumption, areca nut use, personal or familial
While some lesions may be ruled out on clinical history of cancer or cancer therapy, chronic immu-
features alone, others will require a biopsy for nosuppression, age, and some syndromes (such as
definitive diagnosis. Many conditions already dyskeratosis congenita). Other risk factors include
ultraviolet light damage for lesions of the vermil- 2. Nonhomogenous leukoplakia. This takes sev-
ion and human papillomavirus in a small number eral forms.
of cases (Bagan et al. 2010; Woo et al. 2013). a. Verrucous leukoplakia which has, at least
Regardless of histologic grade, oral leukopla- focally, a rough surface and may be leathery
kia has a heterogeneous molecular profile and in appearance; this also tends to have a well-
exhibits loss of heterozygosity at 3p and/or 9p, demarcated border and often occurs on the
which is associated with an increased risk of gingiva (Fig. 21b).
malignant transformation (Rosin et al. 2000; b. Nodular leukoplakia which has, at least
Lingen et al. 2011; Gomes et al. 2015). Aneu- focally, a nodular surface and is also well
ploidy and hypermethylation have been reported demarcated, although this may be difficult
in oral dysplastic lesions, and aneuploidy has to distinguish from, or coexist with,
been positively associated with higher histopath- verrucous leukoplakia, and it may be useful
ologic grade of dysplasia (Lingen et al. 2011). to combine verrucous and nodular leuko-
Mutation and loss of heterozygosity of TP53 and plakia into a single category.
loss or overexpression of p53 is a frequent c. Erythroleukoplakia. This has areas of ery-
molecular finding in dysplastic leukoplakias thema within the leukoplakia that may be
(Rosin et al. 2000; Lingen et al. 2011). Although patchy or speckled (speckled leukoplakia);
inactivating mutations in TP53 are generally the erythematous component is generally
considered “driver mutations” in carcinogenesis, not well demarcated (Fig. 21c).
overexpression of p53 is due to stabilizing muta-
tions in the gene that prolongs the half-life of the
protein (Lingen et al. 2011). Overexpression of The rate of progression to oral cancer has been
matrix metalloproteinase 1 and 9 mRNA has also reported to be 1–7% for homogenous leukoplakia,
been associated with the progressive phenotype 4–15% for verrucous leukoplakia, and 18–47% for
of dysplastic lesions (Jordan et al. 2004). erythroleukoplakia (Hsue et al. 2007; Liu et al.
2012; Anderson and Ishak 2015). However,
Clinical-Pathologic Features morsicatio mucosae oris and benign alveolar ridge
Leukoplakia most often presents as a solitary keratosis which have no malignant potential may
localized white plaque and less commonly as be historically included in the category of leuko-
multifocal or extensive lesions that affect contig- plakia resulting in dilution and underrepresentation
uous sites. of the true prevalence of dysplasia and progression
Oral localized leukoplakia (OLL): OLL con- to cancer (Woo et al. 2014; van der Waal 2015).
stitutes 85% of all oral potentially malignant dis- In general, true leukoplakias do not regress but
orders with a global prevalence of 2–4%. It show progression and enlargement over time
usually affects individuals in the sixth decade of either noticeably or at a barely perceptible rate.
life or older, with increasing prevalence with The appearance of the lesion may also change
increasing age. The male/female is approximately from being homogenous to nonhomogenous and
2–3:1, and 38–62% of lesions occur in smokers from being soft to being firm and indurated.
(Woo et al. 2014; Maia et al. 2016; Naveen- Proliferative verrucous leukoplakia (PVL):
Kumar et al. 2016). It is generally asymptomatic, Although the WHO considers PVL to be a subset
and the tongue, gingiva, buccal mucosa, and pal- of conventional localized leukoplakia, there are
atal mucosa are the most commonly affected sites many differences between the two which may war-
(Liu et al. 2012). rant classifying it separately (Table 1). PVL is
Leukoplakia is classified as follows: characterized by relentlessly progressive involve-
ment of the oral mucosa by white plaques, often
1. Homogenous leukoplakia. This presents as a verrucous and fissured, at multiple, noncontiguous
well-demarcated, uniform white plaque that is sites, or it may present as a single large lesion with
often fissured (Fig. 21a). or without involvement of contiguous sites; a size
Fig. 21 (a) Homogenous localized leukoplakia: sharply Boston, MA, USA). (b) Erythroleukoplakia of the right
demarcated white plaque of the right buccal mucosa that dorsal and ventrolateral tongue that on excision revealed a
showed moderate dysplasia (Images courtesy of Dr squamous cell carcinoma. (c) Verrucous leukoplakia of the
Nathaniel Treister, Harvard School of Dental Medicine, right ventrolateral tongue
of 3 cm2 is often used as a criterion for this diag- All patients with leukoplakia must be biopsied
nosis in a single large lesion (Fig. 22a–d). Although to establish a definitive diagnosis. Lesions that
the average age at diagnosis of PVL is in the may have been clinically diagnosed as leukopla-
seventh decade, most patients will report that kia may in fact be histopathologically frictional
lesions have been present for years prior (Bagan keratosis, candidosis, or some other white lesion.
et al. 2010, 2011). A homogenous form of PVL In one study, this constituted approximately 75%
may exist but would be rare. As its name suggests, of all “clinical leukoplakias” (Woo et al. 2014).
the most common form is the verrucous/nodular Between 39% and 53% of localized leukoplakias
form. However, proliferative erythroleukoplakia is show evidence of epithelial dysplasia or neoplasia
a variant that is often mistaken for oral lichen at the time of diagnosis, and almost one third of
planus because of its widespread, often bilateral dysplastic lesions progress to form invasive can-
nature, with red and white areas, and sometimes cer (Brouns et al. 2014; Woo et al. 2014).
trabecular keratosis that may be mistaken for retic- In lesions that are large, multiple biopsies
ulations. As such, the less specific term “prolifera- should be performed such as from a white area,
tive leukoplakia” may be a more appropriate name from a red area, and from an indurated area (Para-
for this condition. shar 2014; Gomes et al. 2015). In one study of
Table 1 Comparison between localized leukoplakia and proliferative leukoplakia

Feature Leukoplakia Proliferative leukoplakia
Demographics Older males Older females
Association High association with smoking Low association with smoking (up to 42%) (Cerero-
with smoking (38–62%) (Maia et al. 2016; Naveen- Lapiedra et al. 2010)
Kumar et al. 2016)
Distribution Single site Multifocal or extensive contiguous sites
Common sites Tongue, gingiva, and buccal mucosa Gingiva, alveolar mucosa, and palatal mucosa
Histopathology ~ 40% dysplastic or SCC <10% dysplastic or SCC
at first biopsy Mostly verrucous hyperplasia or KUS
Risk of Overall: 1–15% Overall: 60–100%
malignant Annual: 1–3% Annual: 10%
transformation
Architecture Could be homogenous or Mostly nonhomogenous, usually verrucous/nodular
nonhomogenous or erythroleukoplakic
Management Excision or ablation Difficult to manage because of the extent of the lesion;
follow-up and excision of invasive cancers as they
develop
SCC squamous cell carcinoma, KUS keratosis of unknown significance
Fig. 22 Proliferative verrucous leukoplakia. (a) Partially mucosa with a poorly demarcated, fissured, fairly homog-
demarcated, white plaque on maxillary buccal gingiva. (b) enous white plaque. (d) Partially demarcated plaque of the
Well-demarcated verrucous white plaque on the palatal mandibular buccal gingivae and vestibule
mucosa. (c) Involvement of ~50% of the right buccal
incisional biopsies and subsequent excision of 2011). As such, they are not likely to regress
oral leukoplakias, 29% of the patients with and more likely to progress, although the time
single-site biopsy and 12% of the patients with to development of SCC varies greatly from
multiple-site biopsies were deemed patient to patient (Dost et al. 2014). OLL with
underdiagnosed. In addition, 12% of patients moderate-to-severe dysplasia should be excised
with single-site biopsy and only 2% of patients with clear margins if clinically appropriate (such
with multiple-site biopsies had unexpected carci- as young patients with small lesions), and all
noma which were diagnosed in later resection of patients should be followed up indefinitely for
the lesions (Lee et al. 2007a). recurrence or the development of new
A recent systematic review of the literature leukoplakias at a noncontiguous site. Recurrence
showed patients with PVL to have undergone at has been reported in approximately 7–38% of
least nine biopsies during their follow-up period lesions based on the definition of leukoplakia,
(mean: 7 years; range: 0.5–15 years) (Abadie et al. site, and treatment (such as laser ablation
2015). Sequential biopsies are essential for monitor- vs. resection) (Lodi and Porter 2008;
ing lesions of PVL because most lesions begin as Kuribayashi et al. 2012). Patients with leukopla-
KUS and progress to dysplasia and invasive cancer kia exhibiting carcinoma in situ and invasive
over decades (Parashar 2014; Abadie et al. 2015). SCC should be referred to a cancer center for
management.
Patient Management and Future Proliferative verrucous leukoplakia: Periodic
Directions multisite biopsy especially of verrucous, ery-
Localized leukoplakia exhibiting keratosis of thematous, indurated, and bulky areas is
unknown significance: KUS lesions should be recommended. Areas that show moderate-to-
reevaluated by the clinician to determine whether severe dysplasia should be monitored closely or
they may represent reactive/frictional keratoses. excised if possible, although in most cases, it is
Criteria for reactive lesions include poor demar- not possible to obtain margins free of dysplasia,
cation, lack of fissuring, location at a site that can and dysplastic cells repopulate the surgical site.
easily be traumatized, waxing and waning nature Areas that show carcinoma in situ or invasive
with even complete resolution, and then recur- carcinoma require complete excision with the
rence. Discussion with the pathologist is very understanding that the margins should be free
helpful. If the clinical lesion is one of a true of carcinoma, but will likely not be free of dys-
leukoplakia, narrow excision or ablation should plasia or KUS.
be considered if the lesion is small, so that surgery Within 4–12 years of follow-up, 74% of PVL
is minimally morbid, and if the patient is young. progress to cancer (Cabay et al. 2007). Because
Research on the molecular changes in KUS many initial biopsies show KUS, this is evidence
would help clarify whether they exhibit similar that KUS lesions are precancerous although
genomic alterations as dysplasia or even SCC. without the histopathologic phenotype of
Localized leukoplakia with dysplasia: Some dysplasia.
believe that mild dysplasias may regress, and as Adjunctive aids such as the use of toluidine
such, watchful waiting is appropriate (Lodi and blue or autofluorescence techniques may be useful
Porter 2008). It is more likely that mild reactive in such targeted cases and especially for follow-
epithelial atypia that may be seen in frictional ups. However, findings must be interpreted with
keratoses and in other benign inflammatory con- caution because of low specificity of such tools
ditions has been diagnosed as mild dysplasia (Bhatia et al. 2013; Bhatia et al. 2014). More
and, as such, regressed with treatment or sponta- detail about these devices is found in the chapter
neously. Some believe that even moderate-to- on Oral Mucosal Malignancies.
severe dysplasias do not require treatment. How- Research on the molecular changes in PVL,
ever, molecular studies have shown that these especially the earlier lesions that show only
carry similar mutations as SCC (Lingen et al. KUS, would help clarify whether they exhibit
Fig. 23 Erythroplakia of
the right maxillary
edentulous alveolar ridge
with ulceration
similar genomic alterations as dysplasia or even Clinical-Pathologic Features

SCC. If so, targeted therapy may be useful for the Oral erythroplakia is most commonly seen in the
management of this condition. middle aged and the elderly with a substantially
higher predilection for males (Reichart and
Philipsen 2005). Lesions are usually asymptom-
Erythroplakia atic, and the most commonly involved sites
include the floor of the mouth, tongue, soft palate,
Erythroplakia is a premalignant lesion character- and buccal mucosa. Erythroplakic lesions appear
ized by a red plaque and is strongly associated as smooth or granular, velvety plaques with gen-
with dysplasia and squamous cell carcinoma erally well-demarcated margins (Fig. 23).
(Warnakulasuriya et al. 2007). According to All require biopsy, and over 70–90% of lesions
WHO definition, erythroplakia is “a fiery red exhibit carcinoma in situ and invasive squamous
patch that cannot be characterized clinically or cell carcinoma (Shafer and Waldron 1975;
pathologically as any other definable disease” Mashberg and Feldman 1988).
(Axell et al. 1984; Warnakulasuriya et al. 2007).
Therefore, similar to leukoplakia, the diagnosis Patient Management
of erythroplakia is based on exclusion of Lesions that exhibit dysplasia or squamous cell
other red lesions of the oral cavity (Shafer and carcinoma require excision or resection. Malig-
Waldron 1975). nant transformation occurs in 14–50% of cases
(Reichart and Philipsen 2005). As such, close
Etiology and Pathophysiology follow-up of the patient for life is recommended.
This is a premalignant condition. Similar to oral
squamous cell carcinoma, smoking, excessive
alcohol consumption, personal or familial history Oral Submucous Fibrosis
of cancer, male gender, advanced age, history
of cancer therapy, and prolonged immuno- Oral submucous fibrosis (OSF) is an insidious,
suppression are the major risk factors for potentially malignant lesion caused by chewing
developing erythroplakia (Shafer and Waldron areca nut, with 7–13% of cases exhibiting trans-
1975). Erythroplakia is uncommon, and as such formation to squamous cell carcinoma (Pindborg
there is limited data on its molecular characteris- et al. 1984; Murti et al. 1985). It is characterized
tics although mutations in TP53 have been by progressive mucosal fibrosis that can affect
reported (Reichart and Philipsen 2005; van der most of the oral cavity including the lips and
Waal 2009). buccal mucosa resulting in trismus. In advanced
cases, fibrosis of the upper third of esophageal implicated in carcinogenic process (Nair et al.
mucosa may result in dysphagia. 2004). If left unrepaired, DNA damage is a threat
Areca, which is the endosperm of Areca cate- to genomic integrity, and their misrepair can
chu palm tree, is commercially available in South potentially lead to activation of the apoptosis
Asia as the main component of betel quid and pathway, inducing chromosomal rearrangements,
gutkha which are used for their stimulant or psy- DNA deletions, and other deleterious mutations
choactive properties (Arakeri and Brennan 2013). implicated in carcinogenic process.
Betel quid (“paan”) is composed of the Piper betel
leaf wrapped around the chopped areca nut, Clinical-Pathologic Features
chopped tobacco leaves, and other components Although there is a dose-dependent relationship
such as slaked lime and spices. Gutkha is increas- between chewing areca nut and the development
ingly replacing betel quid in popularity. It is usu- of OSF, currently OSF is not only more common
ally sold in prepackaged sachets and is composed in younger individuals (in the second or third
of areca nut, powdered tobacco, slaked lime, cat- decade), but in addition younger patients (under
echu (acacia extract), and flavorings. 40 years of age) have been reported to develop
OSF in response to shorter periods of exposure to
Etiology and Pathophysiology areca nut compared to older individuals (Jacob
Areca nut contains alkaloids (the most potent of et al. 2004; Ranganathan et al. 2004). OSF is
which is arecoline), flavonoids, and copper, all of more common in males. Often times, patients
which interfere with collagen metabolism report pain, burning, and sensitivity in the
(Tilakaratne et al. 2006). Chronic exposure to mouth. The buccal mucosa, tongue, and soft pal-
alkaloids induces synthesis of interleukin ate are among the most commonly affected sites
6, tumor necrosis factor, and transforming growth although in late stages, the disease might affect the
factor beta (TGF-β) which modulate differentia- entire oral mucosa and include the oropharynx.
tion of fibroblasts resulting in accumulation of Clinical presentation of OSF depends on staging
collagen (Rajalalitha and Vali 2005). Flavonoids which is based on the degree of fibrosis and mouth
such as tannins and catechins stabilize collagen opening (More et al. 2012). Early clinical lesions
molecules and inhibit collagenase through (stage 1) are characterized by stomatitis, including
increasing the local concentration of cytokines vesicle formation, petechiae, post-inflammatory
and TGF-β (Arakeri and Brennan 2013). The hypermelanosis, and ulceration. In moderately
high content of copper in areca nut upregulates advanced lesions (stage 2), the mucosa has a
lysyl oxidase which is essential to collagen cross- marble-like pallor and fibrous bands that can be
linkage (Arakeri and Brennan 2013). palpated in the buccal mucosa, and there is trismus
The carcinogenic properties of betel quid and (Fig. 24a–c). Such fibrosis may be extensive in
gutkha are due to isolated or synergistic action of stage 3 disease (More et al. 2012).
tobacco and areca nut (Nair et al. 2004; Arakeri A biopsy should be performed when leukopla-
and Brennan 2013). Carcinogenic effects of areca kia, erythroplakia, persistent ulceration, or a mass
nut are attributed to polyphenols, alkaloids (most lesion is noted, suspicious for transformation to
importantly, arecoline), metabolites of alkaloids dysplasia and/or carcinoma.
(e.g., arecoline N-oxide), and areca nut-specific
nitrosamines such as N-nitrosoguvacoline, Patient Management
N-nitrosoguvacine, 3-propionaldehyde, and Currently, there is no cure of OSF, and it does not
3-propionitrile (Angadi and Rao 2011; Kuo et al. regress with cessation of the habit. Early stages of
2015). In chronic exposure to such molecules, OSF can be treated with intralesional steroid
there is reduced cellular antioxidant glutathione injections (Arakeri and Brennan 2013). Patient
resulting in increased oxidative stress and subse- with trismus may benefit from stretching the jaw
quent DNA damage which, when unrepaired, may using stacked tongue depressors or employing jaw
lead to gene rearrangements and deletions rehabilitation devices to increase and maintain
Fig. 24 Submucous fibrosis: (a) reduced mouth opening palpable fibrotic bands. (c) Diffuse whiteness of right
at 31 mm. (b) Diffuse whiteness with marbled-like pallor ventrolateral tongue
and macular erythema of right buccal mucosa with
range of motion. Advanced cases may require Etiology and Pathophysiology

surgical release of the fibrotic bands (Arakeri Similar to actinic keratosis, which is a solitary
and Brennan 2013; Warnakulasuriya and Kerr keratotic and dysplastic lesion, AC develops
2016). OSF is a potentially malignant disorder due to chronic exposure of the lip vermilion to
that often displays evidence of dysplasia in the ultraviolet (UV) light, in particular UVB.
overlying epithelium with 7–13% of the patients UVB can cause mutations in tumor suppressor
developing oral squamous cell carcinoma. As gene TP53 and other mutational events increas-
such, close, long-term follow-up is recommended ing the risk for developing squamous cell
(Yoithapprabhunath et al. 2013). carcinoma.
Actinic Cheilitis (Actinic Cheilosis, Solar AC is normally seen in the middle-aged popula-
Cheilosis, and Farmer’s Lip) tion with a strong predilection for Caucasian
men (male/female of 10:1), and patients may
Actinic cheilitis (AC) is a disorder that commonly report pain and/or sensitivity. Most patients
affects the vermilion border of the lower lip as a relate a history of long-term sun exposure
result of sun damage. It is considered a potentially whether from work (such as farming or outdoor
malignant condition. occupations) or from recreational activities
Fig. 25 Actinic cheilitis

characterized by blurring of
the vermilion-skin border
and moderate erythema and
vascular ectasia with
scattered faint white
changes; this is particularly
noticeable on the lower lip
(such as boating or golfing). Fair-skinned individ- Oral Squamous Cell Carcinoma

uals (skin phototypes I and II) or those with a
history of sunburns during childhood are at Oral squamous cell carcinoma (OSCC) is the
high risk for developing AC. The most frequent eighth most common cancer worldwide (Scully
clinical findings include blurring of the vermilion- and Bagan 2009). OSCC may be preceded by or
skin interface, dryness, fissuring, atrophy, scaly arise in a setting of leukoplakia, erythroplakia, or
changes of the lower lip, and less commonly OSF. Considering the complexity and importance
swelling and erythema (Fig. 25). Early lesions of a timely diagnosis and correct management in
appear as pale, blotchy, smooth areas and/or the prognosis of patients, OSCC has been
dry fissures on the lower lip that slowly discussed in greater detail in a separate chapter
progress to form rough, scaly areas or firm on Oral Mucosal Malignancies.
keratotic papules and ulcers which may represent
actinic keratosis or even squamous
cell carcinoma. Lesions may also appear as
Risk factors for developing OSCC are similar to
leukoplakia or erythroleukoplakia (Camara
that of oral epithelial dysplasia and include history
et al. 2016).
of tobacco use, excessive alcohol consumption,
A biopsy to rule out dysplasia is indicated in
areca nut use, history of cancer and cancer treat-
cases with localized, scaly, or firm papules because
ment, chronic immunosuppression and autoim-
this may represent actinic keratosis, which is
mune disease, genetic and dietary factors,
by definition at least dysplastic if not outright
advanced age, male gender (likely related to
squamous cell carcinoma (Camara et al. 2016).
habits), and human papillomavirus (HPV) infec-
tion (Warnakulasuriya et al. 2005; Scully and
Patient Management Bagan 2009). While tobacco use is perceived to
AC is an irreversible condition and has the poten- be the major contributing factor in etiology of
tial for slow progression to squamous cell carci- OSCC in low- and middle-income countries,
noma. Patients should have regular follow-ups, HPV infection has been associated with pharyn-
limit sun exposure, and apply sunscreen routinely geal and base-of-tongue cancer in younger
(Goldman 2015). Lesions exhibiting dysplasia populations with lower or no tobacco exposure
may be treated with either topical therapies such (Sturgis and Cinciripini 2007).
5-fluorouracil, imiquimod and cryotherapy, Environmental carcinogens such as
vermilionectomy, or laser ablation (Shah et al. benzopyrenes and nitrosamines from cigarette
2010). Squamous cell carcinoma is treated with smoke and arecoline from areca nut cause OSCC
surgical excision. and induce somatic mutations. Mutations in TP53,
Fig. 26 Oral squamous cell carcinoma. (a) Erythroplakia moderately differentiated invasive squamous cell carci-
of the floor of the mouth in a male patient with 40-year noma. (b) Erythroleukoplakia of the left tongue with
history of cigarette smoking (60 pack-years). Patient pre- thick exophytic plaques in a female patient with
viously treated with T3N0 HPV-negative oropharyngeal non-Hodgkin lymphoma status post-allogenic stem cell
squamous cell carcinoma, with recent diagnosis of lung transplant (10 years prior). An incisional biopsy of the
carcinoma. Incisional biopsy of the erythroplakia revealed lesion revealed invasive squamous cell carcinoma
CDKN2A, PIK3CA, NOTCH, EGFR, and Wnt resonance imaging (MRI) are used to determine
pathways have been reported in head and neck clinical staging of the tumor. Stage I and II tumors
squamous cell carcinoma (Agrawal et al. 2011; generally have favorable prognosis and are typi-
Stransky et al. 2011; CancerGenomeAtlasNetwork cally treated with en bloc resection with or without
2015). Patients with familiar cancer syndromes lymph node dissection (Haddad et al. 2008). Many
such as dyskeratosis congenita, Fanconi anemia, patients are diagnosed in late stages (stages III and
and Bloom syndrome are at higher risk for devel- IV) and are treated via a multidisciplinary approach
oping oral squamous cell carcinoma because of including surgery and adjuvant or primary radia-
inherited mutations (Savage 1993; van Monsjou tion and chemotherapy (Haddad et al. 2008).
et al. 2013; Sarode et al. 2016). EGFR is overexpressed in most OSCC tumors,
and consequently, cetuximab, a monoclonal anti-
Clinical-Pathologic Features body against EGFR, shows promise in the treat-
Traditionally, OSCC affects older males (male-to- ment of OSCC (Laimer et al. 2007; Dai et al. 2014;
female ratio 2:1) and often presents as leukopla- Martinez-Useros and Garcia-Foncillas 2015).
kia, erythroplakia, PVL, nonhealing ulcers, or Early diagnosis strongly impacts survival, and the
mass lesions (Fig. 26a, b). Lesions tend to be 5-year survival rate is over 80% for stage I tumors
indurated and most often affect ventrolateral and <30% for stage IV tumors. Patients should be
tongue and floor of the mouth. Early lesions are followed up indefinitely because they are at high
generally painless or have minimal symptoms, risk for developing a second malignancy.
while advanced lesions may present with pain,
paresthesia, or tooth mobility.
Patient Management
Treatment of OSCC is highly dependent upon clin- Red and white lesions of the oral cavity include a
ical staging. Once a tissue diagnosis is established, wide variety of conditions; these range from reac-
intraoral and extraoral imaging such as panoramic tive reversible conditions such as frictional kerato-
radiographs, computed tomography (CT), positron ses to potentially malignant and malignant lesions
emission tomography (PET) scan, and magnetic such as oral leukoplakia. Lesions can be small and
isolated or involve the entire mucosa. Similarly, Zhang N, El-Naggar AK, Jasser SA, Weinstein JN,
lesions may be entirely asymptomatic or may result Treviño L, Drummond JA, Muzny DM, Wu Y,
Wood LD, Hruban RH, Westra WH, Koch WM,
in mucosal sensitivity, burning, and in some cases Califano JA, Gibbs RA, Sidransky D, Vogelstein B,
severe pain. Management of oral lesions is based Velculescu VE, Papadopoulos N, Wheeler DA,
on their etiology and prognosis. Advances in basic Kinzler KW, Myers JN. Exome sequencing of
science and, in particular, next-generation sequenc- head and neck squamous cell carcinoma reveals
inactivating mutations in NOTCH1. Science.
ing are improving our understanding of the etiol- 2011;333(6046):1154–7.
ogy, development, and progression of malignant Allingham RR, Seo B, Rampersaud E, Bembe M, Challa P,
and potentially malignant lesions (Jessri and Liu N, Parrish T, Karolak L, Gilbert J, Pericak-Vance
Farah 2014). As this is translated into clinical prac- MA, Klintworth GK, Vance JM. A duplication in chro-
mosome 4q35 is associated with hereditary benign
tice, it will lead to earlier and more accurate diag- intraepithelial dyskeratosis. Am J Hum Genet.
nosis, resulting in better management and targeted 2001;68(2):491–4.
therapy in appropriate cases. Altman J, Perry HO. The variations and course of lichen
planus. Arch Dermatol. 1961;84:179–91.
Alvarez Gomez GJ, Alvarez Martinez E, Jimenez
Gomez R, Mosquera Silva Y, Gaviria Nunez AM,
Garces Agudelo A, Alonso Duque A, Zabala
Cross-References Castano A, Echeverri Gonzalez E, Isaac Millan M,
Ramirez Ossa D. Reverse smokers’s and changes in
▶ Clinical Evaluation of Oral Diseases oral mucosa. Department of Sucre, Colombia. Med
▶ Cutaneous Pathology of the Head and Neck Oral Patol Oral Cir Bucal. 2008;13(1):E1–8.
Anderson A, Ishak N. Marked variation in malignant trans-
▶ Gingival Pathology
formation rates of oral leukoplakia. Evid Based Dent.
▶ Head and Neck Tumors 2015;16(4):102–3.
▶ Interface Between Oral and Systemic Disease Angadi PV, Rao SS. Areca nut in pathogenesis of oral
▶ Laboratory Medicine and Diagnostic Pathology submucous fibrosis: revisited. Oral Maxillofac Surg.
2011;15(1):1–9.
▶ Normal Variation in the Anatomy, Biology, and
Anil S. Plasma cell gingivitis among herbal toothpaste
Histology of the Maxillofacial Region users: a report of three cases. J Contemp Dent Pract.
▶ Oral and Maxillofacial Fungal Infections 2007;8(4):60–6.
▶ Oral Lichen Planus Arakeri G, Brennan PA. Oral submucous fibrosis: an over-
view of the aetiology, pathogenesis, classification, and
▶ Oral Manifestations of Systemic Diseases and
principles of management. Br J Oral Maxillofac Surg.
Their Treatments 2013;51(7):587–93.
▶ Oral Mucosal Malignancies Assimakopoulos D, Patrikakos G, Fotika C, Elisaf M.
▶ Oral Ulcerative Lesions Benign migratory glossitis or geographic
tongue: an enigmatic oral lesion. Am J Med.
▶ Oral Vesicular and Bullous Lesions
2002;113(9):751–5.
▶ Orofacial Pain in Patients with Cancer and Auquier-Dunant A, Mockenhaupt M, Naldi L, Correia O,
Mucosal Diseases Schroder W, Roujeau JC. Correlations between clinical
▶ Pharmacotherapeutic Approaches in Oral patterns and causes of erythema multiforme majus,
Stevens-Johnson syndrome, and toxic epidermal
Medicine
necrolysis: results of an international prospective
▶ Soft and Hard Tissue Operative Investigations study. Arch Dermatol. 2002;138(8):1019–24.
in the Diagnosis and Treatment of Oral Disease Axell T, Holmstrup P, Kramer RH, Pindborg JJ, Shear M.
International seminar on oral leukoplakia and associ-
ated lesions related to tobacco habits. Community Dent
Oral Epidemiol. 1984;12(3):145–54.
References Bagan J, Scully C, Jimenez Y, Martorell M. Proliferative
verrucous leukoplakia: a concise update. Oral Dis.
Abadie WM, Partington EJ, Fowler CB, Schmalbach 2010;16(4):328–32.
CE. Optimal management of proliferative verrucous Bagan JV, Jimenez-Soriano Y, Diaz-Fernandez JM, Murillo-
leukoplakia: a systematic review of the literature. Cortes J, Sanchis-Bielsa JM, Poveda-Roda R, Bagan L.
Otolaryngol Head Neck Surg. 2015;153(4):504–11. Malignant transformation of proliferative verrucous leu-
Agrawal N, Frederick MJ, Pickering CR, Bettegowda C, koplakia to oral squamous cell carcinoma: a series of
Chang K, Li RJ, Fakhry C, Xie TX, Zhang J, Wang J, 55 cases. Oral Oncol. 2011;47(8):732–5.
Banoczy J, Szabo L, Csiba A. Migratory glossitis. A Cummings TJ, Dodd LG, Eedes CR, Klintworth
clinical-histologic review of seventy cases. Oral Surg GK. Hereditary benign intraepithelial dyskeratosis: an
Oral Med Oral Pathol. 1975;39(1):113–21. evaluation of diagnostic cytology. Arch Pathol Lab
Bastuji-Garin S, Rzany B, Stern RS, Shear NH, Naldi L, Med. 2008;132(8):1325–8.
Roujeau JC. Clinical classification of cases of toxic epi- Dai W, Li Y, Zhou Q, Xu Z, Sun C, Tan X, Lu L.
dermal necrolysis, Stevens-Johnson syndrome, and ery- Cetuximab inhibits oral squamous cell carcinoma inva-
thema multiforme. Arch Dermatol. 1993;129(1):92–6. sion and metastasis via degradation of epidermal
Bhatia N, Lalla Y, Vu AN, Farah CS. Advances in optical growth factor receptor. J Oral Pathol Med. 2014;43
adjunctive AIDS for visualisation and detection of oral (4):250–7.
malignant and potentially malignant lesions. Int J Dent. De Rossi SS, Ciarrocca K. Oral lichen planus and lichenoid
2013;2013:194029. mucositis. Dent Clin N Am. 2014;58(2):299–313.
Bhatia N, Matias MA, Farah CS. Assessment of a decision Demarosi F, Lodi G, Carrassi A, Soligo D, Sardella
making protocol to improve the efficacy of VELscope A. Oral malignancies following HSCT: graft versus
in general dental practice: a prospective evaluation. host disease and other risk factors. Oral Oncol.
Oral Oncol. 2014;50(10):1012–9. 2005;41(9):865–77.
Bhayat A, Yengopal V, Rudolph M. Predictive value of Do LG, Spencer AJ, Dost F, Farah CS. Oral mucosal
group I oral lesions for HIV infection. Oral Surg Oral lesions: findings from the Australian national survey
Med Oral Pathol Oral Radiol Endod. 2010;109 of adult oral health. Aust Dent J. 2014;59(1):114–20.
(5):720–3. Dongo M, Goncalves LS, Ferreira SM, Noce CW, Dias EP,
Brouns E, Baart J, Karagozoglu K, Aartman I, Junior AS. Gender differences in oral manifestations
Bloemena E, van der Waal I. Malignant transformation among HIV-infected Brazilian adults. Int Dent
of oral leukoplakia in a well-defined cohort of J. 2013;63(4):189–95.
144 patients. Oral Dis. 2014;20(3):e19–24. Dost F, Le Cao K, Ford PJ, Ades C, Farah CS. Malignant
Cabay RJ, Morton Jr TH, Epstein JB. Proliferative transformation of oral epithelial dysplasia: a real-
verrucous leukoplakia and its progression to oral carci- world evaluation of histopathologic grading. Oral
noma: a review of the literature. J Oral Pathol Med. Surg Oral Med Oral Pathol Oral Radiol.
2007;36(5):255–61. 2014;117(3):343–52.
Camara PR, Dutra SN, Takahama Junior A, Fontes KB, Farthing P, Bagan JV, Scully C. Mucosal disease series.
Azevedo RS. A comparative study using WHO and Number IV. Erythema multiforme. Oral Dis.
binary oral epithelial dysplasia grading systems in 2005;11(5):261–7.
actinic cheilitis. Oral Dis. 2016 Sep;22(6):523–9. Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host
CancerGenomeAtlasNetwork. Comprehensive genomic disease. Lancet. 2009;373(9674):1550–61.
characterization of head and neck squamous cell carci- Francalanci S, Sertoli A, Giorgini S, Pigatto P, Santucci B,
nomas. Nature. 2015;517(7536):576–82. Valsecchi R. Multicentre study of allergic contact
Carrozzo M, Brancatello F, Dametto E, Arduino P, cheilitis from toothpastes. Contact Dermatitis.
Pentenero M, Rendine S, Porter SR, Lodi G, Scully C, 2000;43(4):216–22.
Gandolfo S. Hepatitis C virus-associated oral lichen Garcia-Pola MJ, Llorente-Pendas S, Seoane-Romero JM,
planus: is the geographical heterogeneity related to Berasaluce MJ, Garcia-Martin JM. Thyroid disease
HLA-DR6? J Oral Pathol Med. 2005;34(4):204–8. and oral lichen Planus as comorbidity: a pros-
Cerero-Lapiedra R, Balade-Martinez D, Moreno-Lopez pective case-control study. Dermatology. 2016;232
LA, Esparza-Gomez G, Bagan JV. Proliferative (2):214–9.
verrucous leukoplakia: a proposal for diagnostic Goldman GD. Treatment of actinic cheilitis. Dermatol
criteria. Med Oral Patol Oral Cir Bucal. 2010;15(6): Surg. 2015;41(10):1193–4.
e839–45. Gomes CC, Fonseca-Silva T, Galvao CF, Friedman E, De
Cheng YL, Gould A, Kurago Z, Fantasia J, Muller S. Marco L, Gomez RS. Inter- and intra-lesional molecu-
Diagnosis of oral lichen planus: a position paper of lar heterogeneity of oral leukoplakia. Oral Oncol.
the American Academy of oral and maxillofacial 2015;51(2):178–81.
pathology. Oral Surg Oral Med Oral Pathol Oral Goregen M, Melikoglu M, Miloglu O, Erdem
Radiol. 2016;122:332–54. T. Predisposition of allergy in patients with benign
Chi AC, Lambert 3rd PR, Pan Y, Li R, Vo DT, Edwards E, migratory glossitis. Oral Surg Oral Med Oral Pathol
Gangarosa P, Neville BW. Is alveolar ridge keratosis a Oral Radiol Endod. 2010;110(4):470–4.
true leukoplakia?: a clinicopathologic comparison of Greenspan JS, Greenspan D, Webster-Cyriaque J. Hairy
2,153 lesions. J Am Dent Assoc. 2007;138(5):641–51. leukoplakia; lessons learned: 30-plus years. Oral Dis.
Choudhry R, Hodgins MB, Van der Kwast TH, Brinkmann 2016;22(Suppl 1):120–7.
AO, Boersma WJ. Localization of androgen Gurvits GE, Tan A. Black hairy tongue syndrome. World J
receptors in human skin by immunohistochemistry: Gastroenterol. 2014;20(31):10845–50.
implications for the hormonal regulation of hair Haddad R, Annino D, Tishler RB. Multidisciplinary
growth, sebaceous glands and sweat glands. J Endo- approach to cancer treatment: focus on head and neck
crinol. 1992;133(3):467–75. cancer. Dent Clin N Am. 2008;52(1):1–17, vii.
Heyl T, Raubenheimer EJ. Sucking pads (sucking calluses) Kuo TM, Luo SY, Chiang SL, Yeh KT, Hsu HT, Wu CT, Lu
of the lips in neonates: a manifestation of transient CY, Tsai MH, Chang JG, Ko YC. Fibrotic effects of
leukoedema. Pediatr Dermatol. 1987;4(2):123–8. arecoline N-oxide in oral potentially malignant disor-
Hsue SS, Wang WC, Chen CH, Lin CC, Chen YK, Lin ders. J Agric Food Chem. 2015;63(24):5787–94.
LM. Malignant transformation in 1458 patients with Kuribayashi Y, Tsushima F, Sato M, Morita K, Omura
potentially malignant oral mucosal disorders: a follow- K. Recurrence patterns of oral leukoplakia after cura-
up study based in a Taiwanese hospital. J Oral Pathol tive surgical resection: important factors that predict the
Med. 2007;36(1):25–9. risk of recurrence and malignancy. J Oral Pathol Med.
Ion D, Stevenson K, Woo SB, Ho VT, Soiffer R, Antin JH, 2012;41(9):682–8.
Treister NS. Characterization of oral involvement in Laimer K, Spizzo G, Gastl G, Obrist P, Brunhuber T,
acute graft-versus-host disease. Biol Blood Marrow Fong D, Barbieri V, Jank S, Doppler W, Rasse M,
Transplant. 2014;20(11):1717–21. Norer B. High EGFR expression predicts poor progno-
Ippolito A, Wallace DJ, Gladman D, Fortin PR, sis in patients with squamous cell carcinoma of the oral
Urowitz M, Werth V, Costner M, Gordon C, Alarcon cavity and oropharynx: a TMA-based immunohisto-
GS, Ramsey-Goldman R, Maddison P, Clarke A, chemical analysis. Oral Oncol. 2007;43(2):193–8.
Bernatsky S, Manzi S, Bae SC, Merrill JT, Ginzler E, Langley A, Anooshiravani N, Kwan S, Zeller J, Pope E.
Hanly JG, Nived O, Sturfelt G, Sanchez-Guerrero J, Erythema multiforme in children and Mycoplasma
Bruce I, Aranow C, Isenberg D, Zoma A, Magder LS, pneumoniae aetiology. J Cutan Med Surg. 2016;20
Buyon J, Kalunian K, Dooley MA, Steinsson K, van (5):453–7.
Vollenhoven RF, Stoll T, Weisman M, Petri Lavanya N, Jayanthi P, Rao UK, Ranganathan K. Oral
M. Autoantibodies in systemic lupus erythematosus: lichen planus: an update on pathogenesis and treatment.
comparison of historical and current assessment of J Oral Maxillofac Pathol. 2011;15(2):127–32.
seropositivity. Lupus. 2011;20(3):250–5. Lee JJ, Hung HC, Cheng SJ, Chiang CP, Liu BY, Yu CH,
Isaac-Renton M, Li MK, Parsons LM. Cinnamon spice and Jeng JH, Chang HH, Kok SH. Factors associated with
everything not nice: many features of intraoral underdiagnosis from incisional biopsy of oral leuko-
allergy to cinnamic aldehyde. Dermatitis. 2015;26 plakic lesions. Oral Surg Oral Med Oral Pathol Oral
(3):116–21. Radiol Endod. 2007a;104(2):217–25.
Izutsu T, Kumamoto H, Kimizuka S, Ooya K. Sebaceous Lee SJ, Klein J, Haagenson M, Baxter-Lowe LA, Confer
adenoma in the retromolar region: report of a case with DL, Eapen M, Fernandez-Vina M, Flomenberg N,
a review of the English literature. Int J Oral Maxillofac Horowitz M, Hurley CK, Noreen H, Oudshoorn M,
Surg. 2003;32(4):423–6. Petersdorf E, Setterholm M, Spellman S, Weisdorf D,
Jacob BJ, Straif K, Thomas G, Ramadas K, Mathew B, Williams TM, Anasetti C. High-resolution donor-recip-
Zhang ZF, Sankaranarayanan R, Hashibe M. Betel quid ient HLA matching contributes to the success of
without tobacco as a risk factor for oral precancers. Oral unrelated donor marrow transplantation. Blood.
Oncol. 2004;40(7):697–704. 2007b;110(13):4576–83.
Jainkittivong A, Langlais RP. Geographic tongue: clinical Lee WJ, Huang EY, Tsai CM, Kuo KC, Huang YC, Hsieh
characteristics of 188 cases. J Contemp Dent Pract. KS, Niu CK, Yu HR. The role of serum Mycoplasma
2005;6(1):123–35. pneumoniae IgA, IgM, and IgG for the diagnosis of
Jessri M, Farah CS. Harnessing massively parallel Mycoplasma pneumonia-related pneumonia in school-
sequencing in personalized head and neck oncology. age children and adolescents. Clin Vaccine Immunol.
J Dent Res. 2014;93(5):437–44. 2017 Jan 5;24(1). pii: e00471-16.
Jordan RC, Macabeo-Ong M, Shiboski CH, Dekker N, Lingen MW, Pinto A, Mendes RA, Franchini R,
Ginzinger DG, Wong DT, Schmidt BL. Overexpression Czerninski R, Tilakaratne WM, Partridge M, Peterson
of matrix metalloproteinase-1 and -9 mRNA is associ- DE, Woo SB. Genetics/epigenetics of oral pre-
ated with progression of oral dysplasia to cancer. Clin malignancy: current status and future research. Oral
Cancer Res. 2004;10(19):6460–5. Dis. 2011;17(Suppl 1):7–22.
Kamath KP, Mishra S, Anand PS. Smokeless tobacco use Liu W, Shi LJ, Wu L, Feng JQ, Yang X, Li J, Zhou ZT,
as a risk factor for periodontal disease. Front Public Zhang CP. Oral cancer development in patients with
Health. 2014;2:195. leukoplakia – clinicopathological factors affecting out-
Kataoka Y, Iwasaki T, Kuroiwa T, Seto Y, Iwata N, come. PLoS One. 2012;7(4):e34773.
Hashimoto N, Ogata A, Hamano T, Kakishita E. The Lo Russo L, Fedele S, Guiglia R, Ciavarella D, Lo Muzio L,
role of donor T cells for target organ injuries in acute Gallo P, Di Liberto C, Campisi G. Diagnostic pathways
and chronic graft-versus-host disease. Immunology. and clinical significance of desquamative gingivitis.
2001;103(3):310–8. J Periodontol. 2008;79(1):4–24.
Kerr DA, McClatchey KD, Regezi JA. Idiopathic Lo Russo L, Fierro G, Guiglia R, Compilato D, Testa NF,
gingivostomatitis. Cheilitis, glossitis, gingivitis syn- Lo Muzio L, Campisi G. Epidemiology of
drome; atypical gingivostomatitis, plasma-cell gingivi- desquamative gingivitis: evaluation of 125 patients
tis, plasmacytosis of gingiva. Oral Surg Oral Med Oral and review of the literature. Int J Dermatol. 2009;48
Pathol. 1971;32(3):402–23. (10):1049–52.
Lodi G, Porter S. Management of potentially malignant Northern Ireland: size (extent) matters. Oral Dis.
disorders: evidence and critique. J Oral Pathol Med. 2003;9(3):129–37.
2008;37(2):63–9. Natarajan E, Woo SB. Benign alveolar ridge keratosis (oral
Lourenco SV, de Carvalho FR, Boggio P, Sotto MN, Vilela lichen simplex chronicus): a distinct clinicopathologic
MA, Rivitti EA, Nico MM. Lupus erythematosus: clin- entity. J Am Acad Dermatol. 2008;58(1):151–7.
ical and histopathological study of oral manifestations Naveen-Kumar B, Tatapudi R, Sudhakara-Reddy R,
and immunohistochemical profile of the inflammatory Alapati S, Pavani K, Sai-Praveen KN. Various forms
infiltrate. J Cutan Pathol. 2007;34(7):558–64. of tobacco usage and its associated oral mucosal
Madani FM, Kuperstein AS. Normal variations of oral lesions. J Clin Exp Dent. 2016;8(2):e172–7.
anatomy and common oral soft tissue lesions: evalua- Nico MM, Vilela MA, Rivitti EA, Lourenco SV. Oral
tion and management. Med Clin North Am. 2014;98 lesions in lupus erythematosus: correlation with cuta-
(6):1281–98. neous lesions. Eur J Dermatol. 2008;18(4):376–81.
Maia HC, Pinto NA, Pereira Jdos S, de Medeiros AM, da Nico MM, Romiti R, Lourenco SV. Oral lesions in four
Silveira EJ, Miguel MC. Potentially malignant oral cases of subacute cutaneous lupus erythematosus. Acta
lesions: clinicopathological correlations. Einstein (Sao Derm Venereol. 2011;91(4):436–9.
Paulo). 2016;14(1):35–40. Ohman SC, Dahlen G, Moller A, Ohman A. Angular
Manabe M, Lim HW, Winzer M, Loomis CA. Architec- cheilitis: a clinical and microbial study. J Oral Pathol.
tural organization of filiform papillae in normal and 1986;15(4):213–7.
black hairy tongue epithelium: dissection of differenti- Parashar P. Proliferative verrucous leukoplakia: an elusive
ation pathways in a complex human epithelium disorder. J Evid Based Dent Pract. 2014;14
according to their patterns of keratin expression. Arch (Suppl):147–153.e141.
Dermatol. 1999;135(2):177–81. Pavletic SZ, Fowler DH. Are we making progress in
Martinez-Useros J, Garcia-Foncillas J. The challenge of GVHD prophylaxis and treatment? Hematology Am
blocking a wider family members of EGFR against Soc Hematol Educ Program. 2012;2012:251–64.
head and neck squamous cell carcinomas. Oral Oncol. Pindborg JJ, Murti PR, Bhonsle RB, Gupta PC, Daftary
2015;51(5):423–30. DK, Mehta FS. Oral submucous fibrosis as a precan-
Mashberg A, Feldman LJ. Clinical criteria for identifying cerous condition. Scand J Dent Res. 1984;92(3):224–9.
early oral and oropharyngeal carcinoma: erythroplasia Pinto A, Haberland CM, Baker S. Pediatric soft tissue oral
revisited. Am J Surg. 1988;156(4):273–5. lesions. Dent Clin N Am. 2014;58(2):437–53.
Mays JW, Fassil H, Edwards DA, Pavletic SZ, Bassim CW. Ponti G, Meschieri A, Pollio A, Ruini C, Manfredini M,
Oral chronic graft-versus-host disease: current Longo C, Mandel VD, Ciardo S, Tomasi A,
pathogenesis, therapy, and research. Oral Dis. Giannetti L, Pellacani G. Fordyce granules and hyper-
2013;19(4):327–46. plastic mucosal sebaceous glands as distinctive stig-
Miloglu O, Goregen M, Akgul HM, Acemoglu H. The mata in Muir-Torre syndrome patients:
prevalence and risk factors associated with benign characterization with reflectance confocal microscopy.
migratory glossitis lesions in 7619 Turkish dental out- J Oral Pathol Med. 2015;44(7):552–7.
patients. Oral Surg Oral Med Oral Pathol Oral Radiol Rajalalitha P, Vali S. Molecular pathogenesis of oral sub-
Endod. 2009;107(2):e29–33. mucous fibrosis – a collagen metabolic disorder. J Oral
More CB, Das S, Patel H, Adalja C, Kamatchi V, Pathol Med. 2005;34(6):321–8.
Venkatesh R. Proposed clinical classification for oral Ramulu C, Raju MV, Venkatarathnam G, Reddy
submucous fibrosis. Oral Oncol. 2012;48(3):200–2. CR. Nicotine stomatitis and its relation to carcinoma
Mostefaoui Y, Claveau I, Ross G, Rouabhia M. Tissue of the hard palate in reverse smokers of chuttas. J Dent
structure, and IL-1beta, IL-8, and TNF-alpha secretions Res. 1973;52(4):711–8.
after contact by engineered human oral mucosa with Ranganathan K, Devi MU, Joshua E, Kirankumar K,
dentifrices. J Clin Periodontol. 2002;29(11):1035–41. Saraswathi TR. Oral submucous fibrosis: a case-control
Moura MD, Haddad JP, Senna MI, Ferreira e Ferreira E, study in Chennai, South India. J Oral Pathol Med.
Mesquita RA. A new topical treatment protocol for oral 2004;33(5):274–7.
hairy leukoplakia. Oral Surg Oral Med Oral Pathol Oral Ranginwala AM, Chalishazar MM, Panja P, Buddhdev KP,
Radiol Endod. 2010;110(5):611–7. Kale HM. Oral discoid lupus erythematosus: a study of
Murti PR, Bhonsle RB, Pindborg JJ, Daftary DK, Gupta twenty-one cases. J Oral Maxillofac Pathol.
PC, Mehta FS. Malignant transformation rate in oral 2012;16(3):368–73.
submucous fibrosis over a 17-year period. Community Reichart PA, Philipsen HP. Oral erythroplakia – a review.
Dent Oral Epidemiol. 1985;13(6):340–1. Oral Oncol. 2005;41(6):551–61.
Nair U, Bartsch H, Nair J. Alert for an epidemic of oral Reichart PA, Samaranayake LP, Philipsen HP. Pathology
cancer due to use of the betel quid substitutes gutkha and clinical correlates in oral candidiasis and its vari-
and pan masala: a review of agents and causative ants: a review. Oral Dis. 2000;6(2):85–91.
mechanisms. Mutagenesis. 2004;19(4):251–62. Rodu B, Cole P. Smokeless tobacco use and cancer of the
Napier SS, Cowan CG, Gregg TA, Stevenson M, Lamey upper respiratory tract. Oral Surg Oral Med Oral Pathol
PJ, Toner PG. Potentially malignant oral lesions in Oral Radiol Endod. 2002;93(5):511–5.
Rosin MP, Cheng X, Poh C, Lam WL, Huang Y, Lovas J, Slots J, Saygun I, Sabeti M, Kubar A. Epstein-Barr virus in
Berean K, Epstein JB, Priddy R, Le ND, Zhang L. Use of oral diseases. J Periodontal Res. 2006;41(4):235–44.
allelic loss to predict malignant risk for low-grade oral Smith AJ, Robertson D, Tang MK, Jackson MS,
epithelial dysplasia. Clin Cancer Res. 2000;6(2):357–62. MacKenzie D, Bagg J. Staphylococcus aureus in the
Rugg EL, McLean WH, Allison WE, Lunny DP, Macleod oral cavity: a three-year retrospective analysis of clin-
RI, Felix DH, Lane EB, Munro CS. A mutation in the ical laboratory data. Br Dent J. 2003;195(12):701–3;
mucosal keratin K4 is associated with oral white discussion 694.
sponge nevus. Nat Genet. 1995;11(4):450–2. Solomon LW, Wein RO, Rosenwald I, Laver N. Plasma cell
Rullo OJ, Tsao BP. Recent insights into the genetic basis of mucositis of the oral cavity: report of a case and review
systemic lupus erythematosus. Ann Rheum Dis. of the literature. Oral Surg Oral Med Oral Pathol Oral
2013;72(Suppl 2):ii56–61. Radiol Endod. 2008;106(6):853–60.
Sanchis JM, Bagan JV, Gavalda C, Murillo J, Diaz Songu M, Adibelli H, Diniz G. White sponge nevus: clin-
JM. Erythema multiforme: diagnosis, clinical manifes- ical suspicion and diagnosis. Pediatr Dermatol.
tations and treatment in a retrospective study of 2012;29(4):495–7.
22 patients. J Oral Pathol Med. 2010;39(10):747–52. Sontheimer RD. Subacute cutaneous lupus erythematosus:
Sarode GS, Batra A, Sarode SC, Yerawadekar S, Patil S. 25-year evolution of a prototypic subset (sub-
Oral cancer-related inherited cancer syndromes: a phenotype) of lupus erythematosus defined by
comprehensive review. J Contemp Dent Pract. characteristic cutaneous, pathological, immunological,
2016;17(6):504–10. and genetic findings. Autoimmun Rev. 2005;4(5):
Saunders WH. Nicotine stomatitis of the palate. Ann Otol 253–63.
Rhinol Laryngol. 1958;67(3):618–27. Spencer A, Gazzani P, Thompson DA. Acrylate and meth-
Savage SA. Dyskeratosis Congenita. In: Pagon RA, Adam acrylate contact allergy and allergic contact disease: a
MP, Ardinger HH, et al., editors. GeneReviews(R). 13-year review. Contact Dermatitis. 2016;75(3):157–64.
Seattle: University of Washington; 1993. GeneReviews Stojanov IJ, Woo SB. Human papillomavirus and Epstein-
is a registered trademark of the University of Barr virus associated conditions of the oral mucosa.
Washington, Seattle. All rights reserved. Semin Diagn Pathol. 2015;32(1):3–11.
Schalock PC, Dinulos JG, Pace N, Schwarzenberger K, Stransky N, Egloff AM, Tward AD, Kostic AD,
Wenger JK. Erythema multiforme due to Mycoplasma Cibulskis K, Sivachenko A, Kryukov GV, Lawrence
pneumoniae infection in two children. Pediatr MS, Sougnez C, McKenna A, Shefler E, Ramos AH,
Dermatol. 2006;23(6):546–55. Stojanov P, Carter SL, Voet D, Cortés ML, Auclair D,
Schiodt M, Larsen V, Bessermann M. Oral findings in Berger MF, Saksena G, Guiducci C, Onofrio RC,
glassblowers. Community Dent Oral Epidemiol. Parkin M, Romkes M, Weissfeld JL, Seethala RR,
1980;8(4):195–200. Wang L, Rangel-Escareño C, Fernandez-Lopez JC,
Schofield JK, Tatnall FM, Brown J, McCloskey D, Hidalgo-Miranda A, Melendez-Zajgla J,
Navarrete C, Leigh IM. Recurrent erythema multi- Winckler W, Ardlie K, Gabriel SB, Meyerson M,
forme: tissue typing in a large series of patients. Br J Lander ES, Getz G, Golub TR, Garraway LA, Grandis
Dermatol. 1994;131(4):532–5. JR. The mutational landscape of head and neck
Scully C, Bagan JV. Oral squamous cell carcinoma: over- squamous cell carcinoma. Science. 2011;333
view of current understanding of aetiopathogenesis and (6046):1157–60.
clinical implications. Oral Dis. 2009;15(6):388–99. Sturgis EM, Cinciripini PM. Trends in head and neck
Scully C, Porter SR. The clinical spectrum of cancer incidence in relation to smoking prevalence: an
desquamative gingivitis. Semin Cutan Med Surg. emerging epidemic of human papillomavirus-
1997;16(4):308–13. associated cancers? Cancer. 2007;110(7):1429–35.
Setterfield JF, Neill S, Shirlaw PJ, Theron J, Vaughan R, Sun Y, Chan RK, Tan SH, Ng PP. Detection and
Escudier M, Challacombe SJ, Black MM. The genotyping of human herpes simplex viruses in cuta-
vulvovaginal gingival syndrome: a severe subgroup of neous lesions of erythema multiforme by nested PCR.
lichen planus with characteristic clinical features and a J Med Virol. 2003;71(3):423–8.
novel association with the class II HLA DQB1*0201 Suresh L, Neiders ME. Definitive and differential diagnosis
allele. J Am Acad Dermatol. 2006;55(1):98–113. of desquamative gingivitis through direct immunofluo-
Shafer WG, Waldron CA. Erythroplakia of the oral cavity. rescence studies. J Periodontol. 2012;83(10):1270–8.
Cancer. 1975;36(3):1021–8. Tatnall FM, Schofield JK, Leigh IM. A double-blind, pla-
Shah AY, Doherty SD, Rosen T. Actinic cheilitis: a treat- cebo-controlled trial of continuous acyclovir therapy in
ment review. Int J Dermatol. 2010;49(11):1225–34. recurrent erythema multiforme. Br J Dermatol.
Sharon V, Fazel N. Oral candidiasis and angular cheilitis. 1995;132(2):267–70.
Dermatol Ther. 2010;23(3):230–42. Tejani S, Sultan A, Stojanov I, Woo SB. Candidal carriage
Shibuya Y, Zhang J, Yokoo S, Umeda M, Komori predicts candidiasis during topical immunosuppressive
T. Constitutional mutation of keratin 13 gene in familial therapy: a preliminary retrospective cohort study.
white sponge nevus. Oral Surg Oral Med Oral Pathol Oral Surg Oral Med Oral Pathol Oral Radiol.
Tilakaratne WM, Klinikowski MF, Saku T, Peters TJ, persistence, and resistance to treatment with
Warnakulasuriya S. Oral submucous fibrosis: review valacyclovir. J Infect Dis. 2003;188(6):883–90.
on aetiology and pathogenesis. Oral Oncol. Warnakulasuriya S, Kerr AR. Oral submucous fibrosis: a
2006;42(6):561–8. review of the current management and possible direc-
Treister NS, Stevenson K, Kim H, Woo SB, Soiffer R, tions for novel therapies. Oral Surg Oral Med Oral
Cutler C. Oral chronic graft-versus-host disease scoring Pathol Oral Radiol. 2016;122(2):232–41.
using the NIH consensus criteria. Biol Blood Marrow Warnakulasuriya S, Sutherland G, Scully C. Tobacco, oral
Transplant. 2010;16(1):108–14. cancer, and treatment of dependence. Oral Oncol.
Tsokos GC. Systemic lupus erythematosus. N Engl J Med. 2005;41(3):244–60.
2011;365(22):2110–21. Warnakulasuriya S, Johnson NW, Van Der Waal
U.S. Department of Health and Human Services. The I. Nomenclature and classification of potentially malig-
health consequences of smoking – 50 years of progress: nant disorders of the oral mucosa. J Oral Pathol Med.
a report of the surgeon general. Atlanta: U.S. Depart- 2007;36(10):575–80.
ment of Health and Human Services, National Center Winn DM, Blot WJ, Shy CM, Pickle LW, Toledo A,
for Chronic Disease Prevention and Health Promotion, Fraumeni Jr JF. Snuff dipping and oral cancer among
Office on Smoking and Health; 2014. women in the southern United States. N Engl J Med.
Vogelsang GB, Lee L, Bensen-Kennedy DM. Pathogenesis 1981;304(13):745–9.
and treatment of graft-versus-host disease after Woo S-B. Oral pathology a Comprehensive atlas and text
bone marrow transplant. Annu Rev Med. with EXPERT CONSULT – online and print. London:
2003;54:29–52. Elsevier Health Sciences; 2012.
van der Eb MM, Leyten EM, Gavarasana S, Woo SB, Lin D. Morsicatio mucosae oris – a chronic oral
Vandenbroucke JP, Kahn PM, Cleton FJ. Reverse frictional keratosis, not a leukoplakia. J Oral Maxillofac
smoking as a risk factor for palatal cancer: a cross- Surg. 2009;67(1):140–6.
sectional study in rural Andhra Pradesh, India. Int J Woo SB, Cashman EC, Lerman MA. Human
Cancer. 1993;54(5):754–8. papillomavirus-associated oral intraepithelial neopla-
van der Meij EH, van der Waal I. Lack of clinicopathologic sia. Mod Pathol. 2013;26(10):1288–97.
correlation in the diagnosis of oral lichen planus based Woo SB, Grammer RL, Lerman MA. Keratosis of
on the presently available diagnostic criteria and sug- unknown significance and leukoplakia: a preliminary
gestions for modifications. J Oral Pathol Med. study. Oral Surg Oral Med Oral Pathol Oral Radiol.
2003;32(9):507–12. 2014;118(6):713–24.
van Monsjou HS, Wreesmann VB, van den Brekel MW, Wyss AB, Hashibe M, Lee YA, Chuang SC, Muscat J,
Balm AJ. Head and neck squamous cell carcinoma in Chen C, Schwartz SM, Smith E, Zhang ZF,
young patients. Oral Oncol. 2013;49(12):1097–102. Morgenstern H, Wei Q, Li G, Kelsey KT,
van der Waal I. Potentially malignant disorders of the oral McClean M, Winn DM, Schantz S, Yu GP, Gillison
and oropharyngeal mucosa; terminology, classification ML, Zevallos JP, Boffetta P, Olshan AF. Smokeless
and present concepts of management. Oral Oncol. tobacco use and the risk of head and neck cancer:
2009;45(4–5):317–23. pooled analysis of US studies in the INHANCE con-
van der Waal I. Oral leukoplakia, the ongoing discussion sortium. Am J Epidemiol. 2016; 184(10):703–716.
on definition and terminology. Med Oral Patol Oral Cir Yoithapprabhunath TR, Maheswaran T, Dineshshankar J,
Bucal. 2015;20(6):e685–92. Anusushanth A, Sindhuja P, Sitra G. Pathogenesis and
Waldron CA, Shafer WG. Leukoplakia revisited. A clini- therapeutic intervention of oral submucous fibrosis.
copathologic study 3256 oral leukoplakias. Cancer. J Pharm Bioallied Sci. 2013;5(Suppl 1):S85–8.
1975;36(4):1386–92. Yuan A, Woo SB. Adverse drug events in the oral cavity.
Walling DM, Flaitz CM, Nichols CM. Epstein-Barr virus Oral Surg Oral Med Oral Pathol Oral Radiol.
replication in oral hairy leukoplakia: response, 2015;119(1):35–47.
Oral Mucosal Malignancies
Camile S. Farah, Omar Kujan, Stephen Prime, and

Rosnah Binti Zain
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1251
Oral Potentially Malignant Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1255
Leukoplakia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1256
Erythroplakia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1265
Oral Submucous Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1273
Actinic Cheilitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1275
Chronic Hyperplastic Candidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1277
Assessment of Oral Potentially Malignant Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1279
Adjunctive Tools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1282
Vital Staining . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1284
C. S. Farah (*)
O. Kujan
e-mail: omar.kujan@uwa.edu.au
S. Prime
School of Oral and Dental Sciences, University of Bristol,
Bristol, UK
e-mail: stephensprime@gmail.com
R. B. Zain
Department of Oral Pathology, MAHSA University, Kuala
Lumpur, Malaysia
Oral Cancer Research and Coordinating Centre, University
of Malaya, Kuala Lumpur, Malaysia
e-mail: rosnahmz@um.edu.my; profrosnah@mahsa.edu.my

https://doi.org/10.1007/978-3-319-72303-7_21
1250 C. S. Farah et al.
Reflectance Visualization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1284

Optical Fluorescence Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1288
Oral Cytology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1299
Salivary Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1302
Biomarkers of Malignant Transformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1305
DNA Ploidy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1306
Loss of Heterozygosity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1306
DNA Methylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1306
MicroRNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1307
Cellular Senescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1307
Gene Expression Profiling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1308
Management of Oral Potentially Malignant Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1308
Oral Squamous Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1311
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1313
Etiology/Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1318
Clinical-Pathologic Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1336
Molecular Basis of Oral Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1353
Genomic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1354
Human Papillomavirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1356
Genetic Predisposition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1356
Tumor Stroma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1357
Functional Heterogeneity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1357
Metabolomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1357
MicroRNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1358
Circulating Cells and DNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1358
Exosomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1358
Predictive Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1359
Prognostic Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1359
Therapeutic Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1360
Primary Prevention and Early Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1360
Early Stage Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1361
Diagnostic Delay . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1361
Oral Mucosal Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1363
Screening Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1364
Opportunistic Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1366
Mouth Self-Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1369
Use of Mobile Apps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1370
Management of Oral Squamous Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1370
Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1370
Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1375
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1375
Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1378
Reconstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1386
Neck Dissection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1388
Rehabilitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1394
Radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1394
Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1400
Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1401
Prognosis, Complications, and Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1403
Role of General Dental Practitioners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1407
Other Mucosal Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1408
Oropharyngeal Squamous Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1408
Oral Mucosal Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1410
Kaposi Sarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1410
Malignant Salivary Gland Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1412
Oral Mucosal Malignancies 1251

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1413
Abstract Molecular biomarkers · Carcinogenesis ·

Oral mucosal malignancies are a heterogeneous Management Guidelines · Surgery · Radiation
group of conditions commonly encountered in therapy · Reconstruction
oral medicine practice, for which oral medicine
specialists play a central role in both diagnosis
and management. Although various descrip-
tions are used to define the entities included Introduction
under this broad category of diseases, the most
common of these is oral squamous cell carci- Tumors of the oral cavity and mobile lip encompass
noma (OSCC). OSCC accounts for up to 90% benign, dysplastic, and neoplastic processes rang-
of oral mucosal malignancies and is a devastating from papillomas to squamous cell carcinoma
ing disease. Despite momentous gains in detec- (Table 1). Oral mucosal malignancies are a hetero-
tion, diagnosis, treatment, as well as community geneous group of conditions covering epithelial,
and health practitioner awareness of this dis- soft tissue, salivary, and hematolymphoid tumors.
ease, there remains a significant amount of Oral cancer refers to all aggressive neoplasms
work to be done to limit its alarming effects on that affect the external lip, oral cavity, and oro-
patients and their families. Many OSCCs arise pharynx; however, the predominant type is oral
de novo, while others are preceded by more squamous cell carcinoma (OSCC) and can affect
common conditions known collectively as oral all tissues of epithelial origin (Barnes et al. 2005;
potentially malignant disorders (OPMD). Oral Rethman et al. 2010). The terms oral cancer and
medicine specialists exert a significant amount oral cavity cancer describe an abnormal malignant
of time and skill dealing with the diagnosis and growth in the oral cavity arising from oral epithe-
treatment of OPMD and are best placed to play a lium. The boundaries of “oral cancer” are
leading role in their therapy. With the ever- ill-defined with various reports that include differ-
increasing understanding of the molecular ent sites as defined by the International Classifi-
pathogenesis of OPMD and OSCC, clinicians cation of Disease (ICD-DA) (World Health
must be prepared to adopt new concepts Organization 2016) where malignancies of the
of diagnosis and management and be able to lip, oral cavity, and pharynx (C01–C14) are
articulate these to their patients in a personal- grouped together (Table 2). Furthermore, the use
ized manner. With these concepts in mind, of the term “oral cancer” differs with different
this chapter details the etiology, pathogenesis, reports in the literature; thus comparison of inci-
clinical presentation, pathological features, dence or prevalence of oral cancer is difficult
and management approaches of OPMD across studies. Many reports of oral cancer
and OSCC. include only the oral cavity (C01–C06) and oro-
pharynx (C10), while others include malignancies
of the salivary glands (C07, C08) and malignan-
Keywords cies of the tonsils, nasopharynx, pyriform sinus,
Oral mucosal malignancies · Oral cancer · hypopharynx, and other ill-defined sites of the lip,
Oral squamous cell carcinoma · Head and oral cavity, and pharynx (C09–C14).
neck cancer · Oral potentially malignant Differing definitions have been used when
disorders · Oral leukoplakia · Malignant referring to malignancies of the oral cavity.
transformation · Early detection · Optical In view of the differences in etiology and tumor
imaging · Adjunctive aids · Brush cytology · behavior, it is best to use standardized sites for
Table 1 WHO classification of tumors of the oral cavity Table 2 Definitions for malignant neoplasms of the lip,
and mobile tongue (Adapted from WHO Classification oral cavity, and pharynx (ICD-10; 2016)
of Head and Neck Tumors) (El-Naggar et al. 2017)
ICD-O-3
ICD-O Site code
Tumor codes 1. Lip C00
Epithelial tumors and lesions 2. Oral cavity
Squamous cell carcinoma 8070/3 Other and unspecified parts of the C02
Oral epithelial dysplasia tongue
Low grade 8077/0 Gum C03
High grade 8077/2 Floor of mouth C04
Proliferative verrucous leukoplakia Palate C05
Papillomas Other and unspecified parts of mouth C06
Squamous cell papilloma 8052/0 (e.g., cheek)
Condyloma acuminatum 3. Salivary gland
Verruca vulgaris Parotid gland C07
Multifocal epithelial hyperplasia Other and unspecified parts of the major C08
Tumors of uncertain histogenesis salivary glands
Congenital granular cell epulis 3. Pharynx
Ectomesenchymal chondromyxoid tumor 8982/0 (i) Oropharynx
Soft tissue and neural tumors Base of tongue C01
Granular cell tumor 9580/0 Oropharynx C10
Rhabdomyoma 8900/0 (ii) Nasopharynx C11
Lymphangioma 9170/0 (iii) Pyriform sinus C12
Hemangioma 9120/0 (iv) Hypopharynx C13
Schwannoma 9560/0 4. Other and ill-defined sites in the lip, C14
oral cavity, and pharynx
Neurofibroma 9540/0
E.g., Waldeyer’s ring (C14.2)
Kaposi’s sarcoma 9140/3
Myofibroblastic sarcoma 8825/3
Oral mucosal sarcoma 8720/3
Salivary-type tumors prognosis than cancers of the oral cavity
Mucoepidermoid carcinoma 8430/3 (C02–C06). Most cancers of the oral cavity are
Pleomorphic adenoma 8940/0 HPV-negative with an etiology mainly related to
Hematolymphoid tumors established lifestyle habits, namely, tobacco,
CD30-positive T cell lymphoproliferative 9718/3 alcohol, and betel quid use, with a poorer prog-
disorder nosis (Canto and Devesa 2002; Carvalho et al.
Plasmablastic lymphoma 9735/3 2005). Cancers of the external lip (C00) repre-
Langerhans cell histiocytosis 9751/3 sent yet another cancer of differing etiology,
Extramedullary myeloid sarcoma 9930/3 incidence, and prognosis and should be carefully
The morphology codes are from the International delineated from those of the oral cavity proper
Classification of Diseases for Oncology (ICD-O). Behav-
ior is coded/0 for benign tumors; /1 for unspecified, bor-
(C02–C06). Other definitions of oral cancer also
derline, or uncertain behavior; /2 for a carcinoma in situ include salivary gland tumors, but these malig-
and grade III intraepithelial neoplasia; and /3 for malignancies (C07–08) of the major salivary glands
nant tumors (parotid; C07, and submandibular and sublin-
gual; C08) do not share etiological, pathological,
global comparison of cancer of the oral cavity, or prognostic features with cancers of the oral
namely, C02–C06, where C01 is used for malig- mucosa.
nancies of the base of the tongue and is excluded Worldwide, oral cancer has one of the highest
from oral cavity cancers. Base of tongue malig- mortality rates among all malignancies (Jemal et al.
nancies is etiologically more similar to that 2011). It is recognized as the eleventh most com-
of oropharynx with a majority being positive mon cancer with over 300,000 new cases expected
for human papillomavirus (HPV) with better each year (Ferlay et al. 2013). There is significant
disparity in geographical incidence across the populations and has not changed significantly for
world, suggesting geographical differences in risk the past three decades outside Western countries
factors, most of which have been identified in (Warnakulasuriya 2009b; Shield et al. 2017).
epidemiological studies (Johnson et al. 1996, The poor prognosis for oral malignancies can
2001, 2012). In South Asia and the Indian subcon- largely be attributed to the late stage of diagnosis
tinent, oral cancer accounts for almost one third of of these cancers. Patients with a delayed diagnosis
all malignancies, in contrast to the Western world of oral or oropharyngeal carcinoma are 30% more
where it is comparatively uncommon and accounts likely to present with an advanced stage tumor
for only 2–5% of all malignancies (Johnson 2001; compared to those without a delayed diagnosis
Jemal et al. 2008). India, Sri Lanka, and Pakistan (Lo et al. 2003; Pitchers and Martin 2006; Gomez
have the highest levels of the disease where it is the et al. 2009). The TNM classification system is
most common cancer for men in these countries widely used to delineate the extent and spread of a
and accounts for up to 30% of all new cases of cancerous lesion, and there is a significant decrease
cancer, in comparison with just 3% in the UK and in prognosis with more advanced TNM stage at
6% in France (Cancer Research UK 2015). initial presentation. The 5-year survival rates for
The prevalence of oral cancers is high in countries stage I and II tumors are 85% and 66%, respectively,
of South Asia and the Indian subcontinent, while this decreases for stage III and IV tumors to
where distinct cultural practices, such as betel nut 41% and 9% (Sciubba 2001). Almost half of all oral
chewing, and varying patterns of tobacco and alco- cancers are diagnosed at stage III/IV despite the fact
hol use are important risk factors that predispose that these lesions are in an area easily visualized by
individuals to cancer of the oral cavity (Krishna medical and dental practitioners (Gomez et al.
Rao et al. 2013). 2009). As such, an emphasis should be placed on
Ninety percent of oral cancers are OSCCs the earlier diagnosis of these cancers.
(Lingen et al. 2008; Warnakulasuriya 2009b). OSCC is often preceded by lesions such as
Traditional risk factors for OSCC are the con- leukoplakia or erythroplakia that have the poten-
sumption of alcohol, tobacco, and betel quid tial to progress to malignancy. Lesions that have
(McDowell 2006; Boyle and Levin 2008; Petti the potential to progress to malignancy are
2009; Warnakulasuriya 2009a). Recently, HPV referred to as oral potentially malignant disorders
has been attributed as a causative factor in cancers (OPMDs). The prevalence of OPMD worldwide
of the base of the tongue, tonsils, and oropharynx has recently been reported to be 4.47% (95%
in patients that lack these traditional risk factors CI = 2.43–7.08) (Mello et al. 2018). The
(Warnakulasuriya 2009a; Rethman et al. 2010). most prevalent OPMD is oral submucous fibrosis
Alcohol and tobacco have a synergistic effect (4.96%; 95%CI = 2.28–8.62) and oral leukopla-
with heavy drinkers and smokers having kia (4.11%; 95%CI = 1.98–6.97). OPMDs are
38 times the risk of developing oral cancer com- identified more commonly in males (59.99%;
pared to those who refrain from both. Epidemiol- 95%CI = 41.27–77.30). Asian and South Amer-
ogy figures are updated with GLOBOCAN 2012 ican/Caribbean populations have the highest prev-
data in later section. Current trends show an alence rates of 10.54% (95%CI = 4.60–18.55)
increase in the incidence of oral cancer among and 3.93% (95%CI = 2.43–5.77), respectively.
several populations despite an increase in knowl- The key to improved patient prognosis is
edge about etiological and risk factors for OSCC believed to be through early detection of these
(Warnakulasuriya 2009b). The global incidence lesions (Mignogna et al. 2002a; Neville and Day
of lip, oral cavity, and pharyngeal cancers is 2002). Detecting dysplastic changes at an early
529,500, corresponding to 3.8% of all cancer stage allows for active intervention before
cases, and is predicted to rise by 62% to 856,000 they progress to malignancy. Other conditions,
cases by 2035 because of changes in demographics such as oral lichen planus (OLP), are also consid-
(Shield et al. 2017). Despite significant advances in ered to be potentially malignant disorders
cancer therapies, the 5-year survival rate for oral (Warnakulasuriya et al. 2007; Napier and Speight
cancer globally remains at 50% for most 2008; Scully and Bagan 2009a; van der Waal
2010). There is also evidence that chronic hyper- meta-analysis has indicated that a COE, while
plastic candidosis may also induce dysplastic having a relatively high sensitivity at 93%, has
changes in oral epithelium (McCullough et al. a poor specificity at 31% and cannot reliably
2002; Sitheeque and Samaranayake 2003). differentiate between benign and dysplastic
OPMDs however do not always precede OSCC, lesions (Epstein et al. 2012). Analysis states
and there is still much that is unknown about the that a number of benign conditions mimic oral
pathogenesis of oral malignancy. malignancy, and dysplasia may be found in
Current practice for the detection of malignant clinically normal mucosa (Epstein et al. 2012).
or potentially malignant lesions involves a con- The review suggests that further research
ventional oral examination (COE) with visual should be undertaken into adjunctive technolo-
and tactile examination by the clinician, with gies to improve the reliability of clinicians in
leukoplakia or erythroplakic lesions considered screening for malignant and potentially malig-
suspicious for oral epithelial dysplasia (OED) nant disorders (Epstein et al. 2012). These
or OSCC (Farah and McCullough 2008; van der devices use the principles of vital staining, reflec-
Waal 2009; Dost et al. 2013). Induration and tance, or tissue autofluorescence and aim to
fixation are tactile signs that may suggest oral enhance visual detection of lesions and to differ-
malignancy. To confirm the diagnosis, these are entiate between benign and malignant lesions
usually referred to a specialist center for biopsy (Rethman et al. 2010). This concept is utilized
of the lesion for a definitive diagnosis and man- in commercially available devices such as tolui-
agement of the condition. A biopsy is considered dine blue, ViziLite Plus™, Microlux/DL™,
the gold standard for the diagnosis of OED and Orascoptic DK™, VELscope1, Identafi1, DOE
OSCC as it allows for a thorough evaluation of SE Kit™, and Sapphire Plus™ (Farah and
the epithelial architecture of the lesion (Natarajan McCullough 2007; McIntosh et al. 2009). The
and Eisenberg 2011). For OPMDs such as OLP, aims of these products are twofold: firstly to aid
current practice is to recall patients regularly and the clinician in the detection of potentially malig-
observe any changes, such as loss of homogeneity, nant lesions and secondly to highlight areas of
which may indicate carcinogenesis, and to biopsy clinically visible lesions that are most likely to
the lesion as indicated (Mignogna et al. 2001; have undergone dysplastic changes. This could
Gonzalez-Moles et al. 2008). However, observa- assist in determining the ideal site of biopsy and
tion of any such change is highly clinician- also the margins of the lesion to determine the
dependent, and even with meticulous follow-up, extent of excision required.
early malignant changes may be overlooked This chapter focuses on oral mucosal malig-
(Mignogna et al. 2006). In addition, histological nancies with special reference to oral squamous
changes indicative of dysplasia can be found even cell carcinoma and its precursor lesions. Salivary
in clinically normal mucosa (Thomson 2002; gland tumors are covered in ▶ “Salivary Gland
Epstein et al. 2012). Disorders and Diseases”, while base of tongue
While screening programs to identify malig- tumors and oropharyngeal carcinoma are covered
nant lesions have been trialed, their cost- in the chapter ▶ “Head and Neck Tumors”. Lip
effectiveness in the general population is uncer- cancers are covered in this chapter but are also
tain, and the onus has fallen on primary care covered in detail in the chapter ▶ “Cutaneous
providers to screen patients for such lesions Pathology of the Head and Neck”. Likewise oral
(Downer et al. 1995; Lim et al. 2003; mucosal melanoma is described here for com-
Sankaranarayanan et al. 2005; Brocklehurst pleteness, but is covered in detail in ▶ “Pigmented
et al. 2010). Currently the US Preventive Ser- Lesions of the Oral Mucosa”. Although OPMDs
vices Task Force states that there is insufficient are covered in this chapter, these lesions are also
evidence to assess the balance of benefits or harm explored in the chapter ▶ “White and Red Lesions
of routine screening for oral cancer (U.S. Preven- of the Oral Mucosa”, while specific entities are
tive Services Task Force 2013). Of concern, a covered in more detail in other chapters such as
▶ “Oral Lichen Planus” and ▶ “Oral and Maxil- described under this term may transform to can-
lofacial Fungal Infections.” cer, rather that there is a family of morphological
alterations among which some may have an
increased potential for malignant transformation
Oral Potentially Malignant Disorders (Warnakulasuriya et al. 2007). Potentially malig-
nant disorders of the oral mucosa are not only site-
Advances in the understanding of oral carcinogen- specific predictors but also indicators of risk
esis have led to the adoption of new terminologies of likely future malignancies elsewhere in oral
for labeling groups of lesions and conditions mucosa, even clinically normal appearing oral
that precede oral cancer and display an increased mucosa (Warnakulasuriya et al. 2007).
risk of malignant transformation. These are defined The most common OPMDs are leukoplakia
as oral potentially malignant disorders (OPMD) (Fig. 1), erythroplakia (Fig. 2), oral submucous
(Warnakulasuriya et al. 2007; van der Waal 2009). fibrosis (OSMF) (Fig. 3), actinic cheilitis (Fig. 4),
These same lesions have previously been defined as and oral lichen planus (Fig. 5). Other conditions
“epithelial precursor lesions” (Barnes et al. 2005), such as discoid lupus erythematosus (Fig. 6) and
“precancerous” lesions and conditions (World hereditary conditions such as dyskeratosis
Health Organization 1973; Kramer et al. 1978), congenita and epidermolysis bullosa are also clas-
and “morphologically altered tissue in which cancer sified as OMPDs (Warnakulasuriya et al. 2007;
is more likely to occur than in its apparently normal van der Waal and Scully 2011). Special emphasis
counterpart” (Kramer et al. 1978; Axell et al. 1996). has been placed on the premalignant nature of
The term “oral potentially malignant disor- OLP and the underlying mechanism of OSMF
ders” conveys that not all lesions and conditions (Napier and Speight 2008). Chronic hyperplastic
Fig. 1 Leukoplakia affecting multiple sites including the right (a) and left (b) buccal mucosa, floor of the mouth (c) and
lateral tongue (d)
Oral leukoplakia (OL) is a keratotic lesion that

cannot be scraped off and appears on the mucosal
surfaces of the mouth. It harbors the risk of a
patient developing OSCC. The World Health
Organization (WHO) defines leukoplakia as “a
white plaque of questionable risk having excluded
(other) known diseases or disorders that carry no
increased risk for cancer” (Barnes et al. 2005;
Warnakulasuriya et al. 2007). It is a clinical term
only and histopathologically may show atrophy
or hyperplasia and may or may not demonstrate
dysplasia. It has a variable behavioral pattern
Fig. 2 Erythroplakia at the junction of the hard and soft
palate but with an assessable tendency for malignant
transformation (Warnakulasuriya et al. 2007).
candidosis (Fig. 7) has also been classified as an OL is the second most common OPMD after
OPMD, although this is not widely accepted. OSMF, but the most common when OSCC is
Identification of the malignant potential determi- concerned. Using a pooled analysis, the estimated
nants of this group of disorders has attracted the global prevalence of leukoplakia is approximately
interest of clinicians and researchers all over the 2%, although this figure is likely to be an over-
world, but much work remains in this respect. estimation (Petti 2003; van der Waal 2009).
Leukoplakia is six times more prevalent in
smokers, and alcohol use is also a risk factor in
Leukoplakia its development (van der Waal 2009).
Leukoplakias share the same etiological fac-
Leukoplakia is a clinical term that simply tors as OSCC, for which tobacco, alcohol use, and
means “white patch.” It was first used in 1877 specific viral infections are considered major risk
by Erno Schwimmer, a Hungarian dermatologist factors (Warnakulasuriya et al. 2007; van der Waal
who described an oral white lesion probably and Scully 2011). It is asymptomatic and thus
representing a syphilitic glossitis (Schwimmer often detected during routine oral examination.
1877; Tanaka and Ishigamori 2011). The term Leukoplakic lesions are seen more frequently in
is thought to have been originally coined in 1861 men and in patients aged 40–70 years.
by Karl Freiherr von Rokitansky to describe OL is also one of the presenting features
white lesions of the urinary tract (Widran et al. of dyskeratosis congenita (Zinsser-Engman-Cole
1974; Reece and Koontz 1975; Petrou et al. syndrome), a rare, progressive bone marrow fail-
2003). It is very important that “leukoplakic ure syndrome characterized by a heterogeneous
reactive keratotic lesions” which are caused by triad of reticulated skin hyperpigmentation, nail
chronic irritation, local trauma, and other etiolo- dystrophy, and oral leukoplakia (Handley et al.
gies, be distinguished from “idiopathic leukopla- 2006). The condition was first described in 1906,
kia.” Many use the term leukoplakia to refer and recent evidence points to telomerase dysfunc-
to any white patch in the oral cavity, while some tion, ribosome deficiency, and protein synthesis
restrict the term to denoting only those lesions dysfunction (Jyonouchi et al. 2011; Ballew and
with histological epithelial dysplasia. Table 3 Savage 2013). Up to 80% of patients with the
provides a list of the most common white or condition present with OL with a heightened
predominantly white benign oral mucosal lesions risk of oral malignancy (Handley et al. 2006).
and conditions (van der Waal 2009). This present The reported rate of malignant transformation
chapter uses the term “leukoplakia” to refer to of OL in a pooled analysis ranges from 0.13% to
“idiopathic leukoplakia” (Farah et al. 2014b). 34.0%, with a mean of 14.9% (Warnakulasuriya
Fig. 3 Oral submucous fibrosis involving the buccal mucosa (a) and causing limited opening (b). (Images courtesy of
Professor WM Tilakaratne, Faculty of Dental Sciences, University of Peradeniya, Sri Lanka)
Fig. 4 Actinic cheilitis with non-homogeneous leukopla- Fig. 6 Discoid lupus erythematosus with mild dysplasia
kia and orthokeratosis involving the palate
and Ariyawardana 2016). However, the rate

of annual transformation ranges from 0.3%
to 6.9%, with a mean of 3.8% per year and a
follow-up time of 2.4–11 years (Warnakulasuriya
and Ariyawardana 2016).
The morphological characteristics and color
of the lesion’s surface have allowed the
clinical identification of two major variants: the
homogeneous and the non-homogeneous types.
The homogeneous type is defined as a predomi-
nantly white uniform flat lesion with a smooth,
wrinkled, or corrugated surface and a constant
Fig. 5 Reticular and erosive oral lichen planus on the texture throughout (Figs. 8, 9, 10, 11, 12, 13,
buccal mucosa and 14) (Axell et al. 1996). Non-homogeneous
Table 3 The most common white or predominantly white

benign diseases of the oral mucosa and their main diagnos-
tic criteria (Adapted from Warnakulasuriya et al. 2007 and
van der Waal 2009)
Lesion Main diagnostic criteria
Aspirin burn History of local application of
aspirin tablets
Candidosis, Clinical presentation
pseudomembranous (pseudomembrane, often
symmetrical pattern)
Candidosis, There is no consensus in the
hyperplastic literature as to whether to
recognize a hyperplastic
subtype of oral candidosis:
some refer to these lesions as
Candida-associated
leukoplakia
Frictional lesion Presence of mechanical
irritation (e.g., habit of
vigorous toothbrushing)
Hairy leukoplakia Clinical aspect (incl. bilateral
localization on the tongue);
histopathology (including
Fig. 7 Chronic hyperplastic candidosis involving the buc- EBV)
cal commissure Leukoedema Clinical presentation
(including symmetrical
pattern)
leukoplakia is defined as a predominantly white or
Linea alba Clinical presentation
white-and-red lesion that may have an irregular (including location at the line
flat, nodular, or exophytic pattern (Figs. 15, 16, of occlusion on the cheek
17, 18, 19, 20, 21, 22, 23, 24, 25, and 26). In this mucosa)
spectrum, verrucous, papillary, or exophytic Lupus erythematosus Clinical presentation
(including bilateral pattern);
lesions with homogeneous color or texture are history of skin lesions;
classified as non-homogeneous leukoplakias histopathology
(Figs. 27, 28, and 29). Put differently, homoge- Morsicatio Clinical presentation; history of
neous lesions are those that are consistent in habitual chewing or biting of
appearance and texture across the entire surface the cheeks, tongue, or lips
of the lesion, while non-homogeneous lesions are Papilloma Clinical presentation;
histopathology
those that are uneven in color, composition,
Syphilis, secondary Clinical presentation;
and/or texture from one area to another. This (“mucous patches”) demonstration of T. pallidum;
implies that the full extent of the lesion is discern- serology
ible, and where the lesion commences and termi- Tobacco-induced Palatal lesions in reverse
nates is well characterized. lesions smokers are considered oral
potentially malignant disorders
A rare special type of non-homogeneous
Smoker’s palate Clinical presentation; history of
leukoplakia characterized by a verrucous (nicotinic stomatitis) smoking
surface is proliferative verrucous leukoplakia Snuff-induced lesion Clinical presentation; site
(PVL) (Fig. 30). It represents a unique entity where snuff is placed
with the highest risk of malignant progression White sponge nevus Clinical presentation (often
(Gillenwater et al. 2014). This type of lesion symmetrical pattern); family
history
has special clinical characteristics: its female
Fig. 8 Homogeneous leukoplakia on right lateral tongue. Fig. 11 Faint homogeneous leukoplakia involving the
Histopathology showed parakeratosis with no epithelial soft palate in a 57-year-old male past smoker. Lesion was
dysplasia excised. Histopathology confirmed ortho- and para-
keratosis with moderate epithelial dysplasia
Fig. 9 Homogeneous leukoplakia on the floor of the Fig. 12 Homogeneous leukoplakia on the gingival tissues
mouth in a 56-year-old female smoker. Histopathology between the lower right lateral incisor (42) and canine (43).
showed mild epithelial dysplasia Histopathology showed keratosis with no dysplasia
to male ratio is 4:1, it is most common among

elderly patients (>60 years), it features a lack of
risk factors, and it frequently occurs at the buccal
mucosa and oral tongue surfaces (Gillenwater
et al. 2014). It is important to differentiate PVL
from oral hairy leukoplakia, which appears as a
verruciform white lesion of the oral mucosa usu-
ally on the lateral margin of the tongue in patients
with acquired immunodeficiency syndrome and
related to reactivation of the Epstein-Barr virus
(Gillenwater et al. 2014).
Fig. 10 Wrinkled, flat homogeneous leukoplakia involv- PVL is essentially a clinical diagnosis, as the
ing the lingual attached mucosa extending onto the floor of
the mouth. Histopathology showed orthokeratosis with no
histopathologic features of any lesion along the
epithelial dysplasia spectrum of the disease are indistinguishable from
Fig. 15 Non-homogeneous leukoplakia on the right lat-

eral tongue. Histopathology confirmed mild epithelial
dysplasia
Fig. 13 Homogeneous leukoplakia involving the attached

gingiva histopathologically diagnosed as carcinoma in situ
Fig. 16 Patient with non-homogeneous leukoplakia on

left lateral border of tongue, confirmed histopathologically
as keratosis with mild oral epithelial dysplasia
Fig. 14 Homogeneous leukoplakia involving the gingival

tissues
non-PV- associated lesions of the same type. PVL

is considered to be a progressive type of oral
leukoplakia that is impossible to recognize in its
developmental stages and is a diagnosis typically
always made in retrospect. The lesion typically
begins as non-dysplastic keratotic lesions that
over time become confluent, widespread, and
Fig. 17 Non-homogeneous leukoplakia on right lateral
multifocal in appearance and are exquisitely diffi- and dorsal tongue suggestive of oral lichen planus. Histo-
cult to successfully treat without recurrence or pathology showed epithelial hyperplasia with no epithelial
persistence (Hansen et al. 1985). dysplasia but with concomitant Candida
Fig. 18 Non-homogeneous leukoplakia on right ventral

tongue. Histopathology showed moderate epithelial
dysplasia
Fig. 21 Non-homogeneous leukoplakia on lower labial
mucosa. Histopathology showed orthokeratosis and epi-
thelial hyperplasia with mild epithelial dysplasia
Fig. 19 Non-homogeneous leukoplakia involving the

attached gingiva, confirmed histopathologically as moder-
ate epithelial dysplasia Fig. 22 Patient with non-homogeneous leukoplakia on
floor of the mouth, confirmed histopathologically as kera-
tosis with severe oral epithelial dysplasia
Fig. 20 Non-homogeneous leukoplakia on labial gingival Fig. 23 Non-homogeneous leukoplakia on the right lat-
tissues and attached mucosa. Histopathology showed eral tongue with verrucous hyperplasia noted on histopath-
orthokeratosis with no epithelial dysplasia ological examination
Fig. 24 Nodular leukoplakia involving upper anterior and Fig. 27 Verrucous leukoplakia involving the attached
posterior gingiva gingiva diagnosed histopathologically as orthokeratosis
and epithelial hyperplasia and no evidence of dysplasia
Fig. 25 Non-homogeneous leukoplakia on right posterior

lateral tongue with nodular appearance and areas of ulcer-
Fig. 28 Verrucous leukoplakia involving attached mucosa
ation, confirmed histopathologically as severe epithelial
diagnosed histopathologically as oral lichen planus
dysplasia
Fig. 26 Non-homogeneous nodular leukoplakia on left

lateral and dorsal tongue confirmed histopathologically as Fig. 29 Verrucous leukoplakia involving the attached
well-differentiated squamous cell carcinoma mucosa and gingiva
Fig. 30 Proliferative verrucous leukoplakia in an 84-year- onto the lower left alveolus (d). Histopathology of multiple
old female smoker involving the hard and soft palate (a) biopsy sites confirmed the presence of ortho- and para-
and left buccal mucosa (b). Note that there is no loss of keratosis with no epithelial dysplasia. In the clinical con-
autofluorescence of the buccal lesion consistent with ker- text this is consistent with proliferative verrucous
atotic changes only without underlying dysplasia proven leukoplakia
by biopsy (c). There is extension of the thick leukoplakia
The buccal mucosa is most often the site of

initial involvement, followed by the hard and soft
palate, alveolar mucosa, tongue, floor of the
mouth, gingiva, and lip (Arduino et al. 2013).
In its early form, especially with isolated lesions,
the clinical findings of PVL cannot be distin-
guished from conventional idiopathic leukoplakia
(Fig. 31). PVL lesions can mimic oral lichenoid
lesions (OLL) or oral lichen planus (OLP) lesions
initially (Lopes et al. 2015), and hence broad
consideration of early diagnosis and careful
monitoring with subsequent biopsy of lesions Fig. 31 Early presentation of proliferative verrucous
over time is required. leucoplakia involving the gingival tissues
Smokeless tobacco keratosis is an indepen- than a high school education (3.9%), and those
dent entity that needs to be distinguished from living in the South (3.9%) (Mazurek et al. 2014).
oral leukoplakia. The lesion appears at the It is most commonly used by individuals in con-
corresponding site of tobacco placement, most fre- struction (10.8%) and mining industries (18.8%).
quently in the mandibular vestibule. It is best Overall, it is estimated that 15% of chewing
described clinically as a patch of corrugated tobacco users and 60% of snuff users will develop
grayish-white raised surface with vague borders. clinical lesions (Neville and Day 2002). The malig-
Prevalence of smokeless tobacco use in the nant potential of this type of lesion is lower than
USA has increased slightly from 2.7% in 2005 to that of oral leukoplakia (Gupta and Johnson 2014).
3.0% in 2010 (Mazurek et al. 2014). In 2010, Unlike homogeneous leukoplakia, non-homo-
smokeless tobacco use was highest among adults geneous leukoplakia is often associated with mild
aged 25–44 years (3.9%), males (5.6%), complaints of localized pain or discomfort and a
non-Hispanic whites (4.0%), those with no more greater risk of malignant transformation (Axell
et al. 1996). Both types may histopathologically
exhibit various degrees of orthokeratosis or para-
keratosis, mild inflammation with or without epi-
thelial dysplasia of several grades, and/or
carcinoma in situ (Figs. 32, 33, 34, 35, 36, 37,
and 38). A high grade (i.e., moderate or severe) of
oral epithelial dysplasia (OED) has traditionally
been associated with an increased malignant poten-
tial (Warnakulasuriya and Ariyawardana 2016).
Notably, the histological diagnosis of OED is 4.2
times greater for lesions that display
non-homogeneous features (Fig. 39) (Dost et al.
Fig. 32 Hyperparakeratosis (black arrows) and basal cell 2013). OED has been used as a predictor of malig-
hyperplasia (white arrows) showing no features of cellular nant transformation, but its efficacy is still ques-
atypia in a 55-year-old female presenting with a leukoplakia
involving the left buccal mucosa (100; Hematoxylin and
tionable as a considerable percentage of
eosin stain). Note parakeratin is markedly thickened and leukoplakia may transform into malignancy with-
epithelium has broad blunt-ended rete ridges out having OED at the time of initial biopsy (Dost
Fig. 33 Keratosis with mild epithelial dysplasia epithelium (a; 100). Mitotic figures (yellow arrows),
(low-grade dysplasia) in a 61-year-old male presenting anisocytosis, and hyperchromatasia are limited to the
with a leukoplakia on the right ventral tongue. Note the lower third of epithelium (b; 200) (Hematoxylin and
architectural and cytological changes of suprabasal mitoses eosin stain)
and hyperchromatasia are limited to the lower third of
Certain clinical features have been associated

with an increased risk of malignant transformation
(Table 5, Fig. 40), knowledge of which can help
clinicians in making management decisions.
Although many patient and lesion characteristics
feed into a predictive risk profile of oral leukopla-
kia malignant transformation, homogeneity is
considered the best clinical predictor available.
Therefore, any changes to surface morphology
and color should be taken very seriously, and a
biopsy from the site of change should be arranged
(Dost et al. 2013).
Fig. 34 Hyperkeratosis with moderate epithelial dyspla- While numerous patient and lesion attributes
sia (low-grade dysplasia) (100; Hematoxylin and eosin have been associated with increased risk of malig-
stain). There is increased thickness of orthokeratosis (black nant transformation of OPMD, it is still not possi-
arrow). Architectural and cytological changes including
loss of polarity of basal cells, drop-shaped rete ridges ble to predict, on an individual basis, which lesions
(yellow arrows), and increased mitoses (red arrows) are will progress to malignancy. A 2016 systematic
limited to the lower two thirds of the epithelium review of observational studies aiming to ascertain
important risk factors for malignant transformation
of OL identified the grade of dysplasia, advanced
age, female gender, lesion size greater than
200 mm2, and non-homogeneous type as the
most important determinants of the malignant
potential of this disorder (Warnakulasuriya and
Ariyawardana 2016).
Erythroplakia
Erythroplakia is a clinical term that describes a red

lesion. However, for the purpose of this chapter,
Fig. 35 Floor of the mouth keratotic lesion diagnosed as “erythroplakia” is intended to denote lesions with
hyperkeratosis with moderate epithelial dysplasia (high- an increased risk of malignancy (Figs. 41 and 42).
grade dysplasia) (200; Hematoxylin and eosin stain). Erythroplakia, also known as erythroplasia, is defined
Note several atypical mitoses (red arrows), irregular epi-
thelial stratification, loss polarity of basal cells,
as “a fiery red patch that cannot be characterized
anisocytosis, anisonucleosis, and drop-shaped rete ridges clinically or pathologically as any other definable
(yellow arrows) disease” (Barnes et al. 2005; Warnakulasuriya et al.
2007; van der Waal 2009). The term erythroplasia
was originally used in 1911 by Queyrat to describe a
et al. 2014). A binary grading system that stratifies red, precancerous lesion of the penis (Queyrat 1911;
OED lesions into “high risk” and “low risk” has Tanaka and Ishigamori 2011).
been shown to be more useful than traditional Generally, the lesion is a solitary one that helps
grading methods (Kujan et al. 2006c) and has distinguish the condition from other systemic con-
recently been entered into the latest edition of the ditions (van der Waal 2009). Erythroplakia has the
WHO Classification of Head and Neck Tumours clinical appearance of a flat or slightly depressed
but is yet to be widely adopted (El-Naggar et al. red patch with a smooth or coarse surface. It is
2017). Architectural and cytological features of most commonly found on the floor of the mouth,
OED are detailed in Table 4. ventral surface of the tongue, soft palate, and
Fig. 36 Hyperkeratosis and severe epithelial dysplasia drop-shaped rete ridges, increased numbers of mitotic fig-
(high-grade dysplasia) that extends to the upper third of ures, superficial mitoses (red arrows in a), and irregular
epithelium in a 67-year-old male with non-homogeneous epithelial stratification. Superficial bizarre mitoses (yellow
leukoplakia of the floor of the mouth (a; 100). Architec- arrows in b) are noted (b; 200) (Hematoxylin and eosin
tural and cytological features of dysplasia are present stain)
including nuclear hyperchromatism and pleomorphism,
0.2% (Villa et al. 2011). While the condition is

not as prevalent as leukoplakia, on biopsy it fre-
quently demonstrates epithelial dysplasia. In one
study assessing 65 biopsies of erythroplakia, 51%
displayed invasive squamous cell carcinoma,
while a further 40% were carcinoma in situ,
highlighting the seriousness of the condition
(Shafer and Waldron 1975). Of those that display
epithelial dysplasia, a large proportion of these
undergo malignant transformation (van der Waal
2009).
Fig. 37 Hyperkeratosis and severe epithelial dysplasia
(high-grade dysplasia) that involves nearly the full thick-
ness of epithelium in an elderly male presenting with a Oral Lichen Planus
non-homogeneous leukoplakia of floor of the mouth
(100; Hematoxylin and eosin stain). An area of possible
microinvasive squamous cell carcinoma is noted (yellow Oral lichen planus (OLP) is a chronic inflamma-
arrows) tory condition characterized by a subepithelial
T-cell lymphocytic infiltrate that degenerates the
basal cell layer and can present in various clinical
tonsillar fauces (Villa et al. 2011). If the lesion has forms including reticular, erosive, ulcerative,
mixed color, it is termed erythroleukoplakia or, plaque-like, and bullous (Figs. 48, 49, and 50).
more commonly, speckled leukoplakia (Figs. 43, Despite evidence indicating that patients with
44, 45, 46, and 47). The size varies, and the border OLP carry an increased risk of developing oral
of the lesion can vary from well circumscribed to carcinoma, its malignant potential is still debated
fading into the surrounding structures. The etiol- (van der Waal 2009). Some authors believe that
ogy is similar to that described for OL. Men and OLP is entirely benign and propose that the exam-
women are affected with no predilection. The age ples of malignant transformation of OLP are pre-
of incidence peaks in the sixth and seventh sentations of “lichenoid dysplasia” (Lovas et al.
decades. Its prevalence varies from 0.02% to 1989).
unknown if OLP itself has a propensity to develop

into OSCC in a stepwise progression or if there is
indeed a separate condition that precedes malig-
nancy. A condition, labeled “lichenoid dysplasia,”
was proposed as a distinct histopathological entity
by Krutchkoff and Eisenberg, further complicating
the diagnosis and management of patients with OLP
in relation to potential malignancy (Krutchkoff and
Eisenberg 1985). Krutchkoff and Eisenberg claimed
that cases of malignant transformation of OLP were
initially cases of dysplasia with lichenoid inflamma-
tion, which were misdiagnosed on initial histologi-
cal analysis due to their similarities (Eisenberg and
Krutchkoff 1992) (Fig. 51). This was based on a
review of reported cases of malignant transforma-
tion of OLP with many, on retrospective analysis,
displaying dysplasia on the initial biopsy. No con-
sensus on this topic has yet been reached. It remains
unknown if the dysplastic change evident in
lichenoid dysplasia (LD) is due to chronic inflam-
mation, and subsequent cancer development
representing true malignant transformation, or if
dysplasia was always present and diagnosis compli-
cated by presence of subepithelial lymphocytic
infiltrate.
In 2003, the WHO diagnostic criteria for OLP
were modified according to a proposal by van der
Meij and van der Waal to include histopathologi-
cal absence of epithelial dysplasia (van der Meij
et al. 2003). Histological diagnosis of OLP can be
difficult, as presence of overriding characteristics
of lichen planus present on a specimen may cause
dysplasia to be easily overlooked and dysplastic
changes disregarded as reactive changes to
Fig. 38 Epithelial hyperplasia and hyperkeratosis with inflammation. Furthermore, OLP itself displays
mild epithelial dysplasia and lichenoid features suggestive
of lichenoid epithelial dysplasia in a 65-year-old female
many features characteristic of epithelial dyspla-
with non-homogeneous leukoplakia on the left lateral sia even when dysplasia is not present (De Jong
tongue (a; 25). Note the band-like lymphocytic infiltrate et al. 1984; Sousa et al. 2009). Due to these
(yellow arrows). Epithelium in boxed area (shown in b) similarities, there is a high level of interobserver
shows dysplastic changes (white arrows) and lichenoid
changes (yellow arrows) (b; 100). Note basal cell degen-
variability in the histological diagnosis of OLP
eration and squamoid change (red arrows in c) at the (van der Meij et al. 1999).
epithelial-lamina propria interface associated with a band- Molecular analysis of OLP lesions has been
like lymphocytic infiltrate (c 100). (Hematoxylin and performed to determine if there was a loss of
eosin stain)
heterozygosity (LOH) that may indicate malig-
nant changes in these lesions (Zhang et al.
OLP is considered an OPMD, but with the avail- 1997). It was found that LOH in lesions diagnosed
able evidence, its true malignant potential remains as OLP was similar to that of reactive lesions
unclear and warrants further investigation. It is rather than dysplasia, indicating that OLP itself
All OPMDs
Lesion Extension* Single Multiple
Lesion color** White Mixed white and red
Lesion Texture Uniform Irregular/Ulcerated
Homogeneous Non-homogeneous
Clinical descriptor*** These lesions are 4.2 times more likely to
show OED compared to homogeneous
lesions which present with no dysplasia
Location**** Tongue and/or floor of mouth Other sites
OR = 2.6 (CI 1.0-6.9) OR = 4.4 (CI 2.2-9.0) OR = 5.4 (CI 2.2-12.8)

Odds ratio (OR) for OED/malignancy compared to other for OED/malignancy compared to all for OLP presenting in multiple site
tissue sites, in homogeneous lesions other clinical diagnoses lesions compared to single site
Fig. 39 Schematic representation of selected oral poten- from Dost et al. 2013). *( p = 0.001), **( p = 1.2106),
tially malignant disorder characteristics that may predict ***( p = 3.01019), ****( p = 0.005)
dysplasia on histopathology. (Adapted with permission
Table 4 Architectural and cytological changes in the Table 5 Clinical parameters associated with an increased
diagnosis of epithelial dysplasia (El-Naggar et al. 2017) risk of malignant transformation of oral leukoplakia
Cytological changes Architectural changes Gender (women have a higher risk)
Abnormal variation in Irregular epithelial Duration of the leukoplakia
nuclear size stratification Leukoplakia of unknown etiology (non-smokers,
Abnormal variation in Loss of polarity of basal nondrinkers)
nuclear shape cells Location on the floor of the mouth and/or on the lateral
Abnormal variation in cell Drop-shaped rete pegs surfaces of the tongue
size Non-homogeneous leukoplakia (speckled and verrucous
Abnormal variation in cell Increased numbers of leukoplakias have higher risk for malignant
shape mitotic figures transformation)
Increased nuclear to Abnormally superficial Size >200 mm2
cytoplasmic ratio mitotic figures History of previous oral carcinoma
Atypical mitotic figures Premature individual cell
keratinization
Increased number and Keratin pearls within rete RNA sequencing of OLP, LD, and OED tissues
size of nucleoli ridges by Farah and colleagues suggests a close molecu-
Hyperchromasia Loss of epithelial cell
lar and biological relationship exists between LD
cohesion
and OLP (Fig. 52) and indicates that there is
significant biological distinction between LD
and OED, as is between OLP and OED. Biologi-
does not have a malignant risk (Zhang et al. 1997; cal pathway and gene ontology analysis of the
Accurso et al. 2011). A similar analysis in lesions three datasets indicates that inflammatory signal-
diagnosed as LD found similarities in LOH to ing predominates in OLP and LD. The two most
OED, giving further weight to the argument that enriched pathways by gene set analysis were com-
it is LD, not OLP itself, that has a malignant mon to OLP and LD and were the type II inter-
potential (Zhang et al. 2000). feron signaling and T-cell receptor signaling
Predictive risk factors for malignant transformation of oral leukoplakia
Patient characteristics Lesion characteristics
INCREASED RISK
Presence of
Male Sex Female Yes No
dysplasia
Younger <5 years Lesion duration >5 years

Age Advanced age (>60y)
age since diagnosis
Lateral tongue, floor of mouth, Other

Site intraoral sites
Yes Smoker No retromolar trigone / soft palate
>200 mm2 Size <200 mm2

Alcohol
No Yes
use
Yes Multifocality No
Chronic alcohol
No mouthwash Yes
No Homogeneity Yes
use
Infection with
History of head Yes No
Candida albicans
No and neck Yes
cancer DNA
Yes No
aneuploidy
Fig. 40 Predictive risk factors for malignant transformation of oral leukoplakia
Fig. 41 Erythroplakia on the palate. Histopathology con-

firmed carcinoma in situ (Image courtesy of Dr Agnieszka
Frydrych, WA Oral Medicine, Perth WA, Australia)
pathways. Given the close apparent relationship

between OLP and LD, the data is consistent with a
model where OLP and LD are analogous lesions Fig. 42 Erythroplakia involving both the upper and lower
gingivae. Histopathology confirmed moderate to severe
and where OLP progresses to malignancy through dysplasia (Image courtesy of Professor Peter Brennan,
LD; however, this requires further investigation. Portsmouth Hospitals, NHS Trust, Portsmouth, UK)
Fig. 43 Erythroleukoplakia (speckled leukoplakia) involving the left floor of the mouth (a) and right soft palate
extending onto the buccal mucosa (b) in the same patient. Both were biopsy-proven carcinoma in situ
Fig. 46 Erythroleukoplakia involving the labial gingiva

Fig. 44 Speckled leukoplakia with ulceration involving associated with the lower left premolars (teeth 34 and 35)
the right hard and soft palate. Histopathology confirmed in a 74-year-old male non-smoker. Histopathology con-
squamous cell carcinoma firmed squamous cell carcinoma in situ
Fig. 47 Erythroleukoplakia with erosion and epithelial

Fig. 45 Erythroleukoplakia with epithelial sloughing sloughing involving the right lateral tongue with verrucous
involving the left soft palate. Histopathology confirmed changes. Histopathology confirmed squamous cell
squamous cell carcinoma carcinoma
Fig. 48 Reticular oral lichen planus in the same patient involving the right (a) and left (b) lateral tongue and right (c) and
left (d) buccal mucosa
Furthermore, this suggests very strongly that OLP patients (419 patients). A significant increase of
does not carry significant malignant transforma- malignant transformation risk was noted among
tion potential in its own right. smokers (OR = 2, 95% CI [1.25–3.22]), alco-
Irrespective of the above observations, OLP holics (OR = 3.52, 95% CI [1.54, 8.03]), and
has been reported to be associated with a low hepatitis C virus-infected patients (OR = 5, 95%
malignant transformation rate, varying from CI [1.56–16.07]), compared to patients without
0.5% to 2.5%, with the most commonly quoted these risk factors.
figure at approximately 1% (Fig. 53) (Casparis In a separate meta-analysis and systematic
et al. 2015). Indeed in a meta-analysis, oral review, the overall malignant transformation rate
lichenoid lesions (OLL) (Fig. 54) were found to of OLL was 2.43% compared to 1.37% for OLP
have a higher risk of malignant transformation (Giuliani et al. 2018). Among 7429 records
than OLP (2.5% vs. 1.1% pooled proportion screened, only 21 were included in this review.
(PP), respectively) (Aghbari et al. 2017). Pooling Ninety-two out of 6559 patients developed
data for OLP malignant transformation from OSCC, with an overall malignant transformation
57 studies (19,676 patients) resulted in an overall rate of 1.40% (1.37% for OLP and 2.43% for
PP of 1.1% [95% CI 0.9%, 1.4%], while pooling OLL), with an annual malignant transformation
data from 14 recent studies that used the World rate of 0.20%. Female gender, erosive erythema-
Health Organization 2003 diagnostic criteria tous clinical forms, and tongue site appear to
resulted in an overall PP of 0.9% [95% CI slightly increase transformation risk (Giuliani
0.5–1.3]. The risk of malignant transformation et al. 2018). OLL are similar to OLP, but do not
was higher (PP = 2.5%, 95% CI [1–4]) in OLL demonstrate the entire typical clinicopathological
Fig. 49 Examples of ulcerative and erosive oral lichen planus involving the right (a, b) and left (c) buccal mucosa, right
lateral tongue (d), and hard palate mucosa and palatal gingivae (e)
Ramirez et al. 2009). It is now clearer that they

carry greater risk of transformation to OSCC and
perhaps should be considered OPMD in their own
right.
A higher incidence of malignant transforma-
tion has been demonstrated among smokers, alco-
holics, and hepatitis C virus-infected patients;
however these associations require further inves-
tigation. The effectiveness of the current protocol
for periodically recalling OLP patients for the
early detection of oral cancer is questionable
(Mattsson et al. 2002), as there are no definitive
Fig. 50 Plaque-type lichenoid lesion involving the left
hard palate. Histopathologically confirmed as oral lichen criteria that can be used to aid in the detection of
planus with no epithelial dysplasia malignant change in OLP. Using visible changes,
such as the loss of homogeneity, to direct the
requirements of OLP (van der Meij and van der selection of the biopsy site has failed to aid
Waal 2003). OLL can be reactive lesions to amal- the identification of true areas of malignant
gam restorations, drugs, and graft-versus-host dis- change (Mignogna et al. 2002b), but currently is
ease (GvHD) or can be idiopathic (Cortes- the best clinical approach available. In this regard,
Fig. 51 Oral lichen planus (a, d), lichenoid dysplasia (b, e), and oral epithelial dysplasia (c, f). The clinical (a–c) and
histopathological (d–f) similarities of these lesions pose some difficulties for the diagnosing clinician
assessment of OLP in terms of tissue changes is million individuals, primarily in India (Cox and
best undertaken as outlined in Fig. 39 as it relates Walker 1996; Tilakaratne et al. 2006). The muco-
to OPMD (Dost et al. 2013). A non-homogeneous sal surfaces of the oral cavity, oropharynx and,
clinical appearance was strongly associated with frequently, the upper third of the esophagus are
underlying dysplasia in both univariate and mul- common sites for OSMF. Histopathologically,
tivariate analysis (P < 0.001; OR = 4.4, CI OSMF is characterized by fibrosis and
[2.2–9]). Currently the safest approach is to con- hyalinization in the lamina propria, caused by an
tinue to review patients with OLP 6-monthly in an unknown process, covered by atrophic overlying
effort to detect malignant changes early. epithelium that predisposes it to the develop-
ment of squamous cell carcinoma (Fig. 57)
(Warnakulasuriya et al. 2007). Between 7% and
Oral Submucous Fibrosis 25% of cases present with OED on histopatholog-
ical examination, approximately 7.6% of OSMF
Oral submucous fibrosis (OSMF) is a chronic, cases develop an oral malignancy (Cox and
debilitating oral mucosal disease that involves a Walker 1996). In a long-term follow-up study of
high risk of malignant transformation (Tilakaratne 66 patients with OSMF spanning 17 years
et al. 2006). OSMF presents clinically with (median observation 10 years) in Kerala, India,
burning sensations, blanching, marked stiffness, 7.6% of patients developed OSCC. The malignant
and an eventual inability to open the mouth transformation rate over the 15-year observation
(Fig. 55) (Tilakaratne et al. 2006; Jayasooriya period (median 8 years) was 4.5%, with an annual
et al. 2011). Etiologically, OSMF has a strong malignant transformation rate of approximately
link with the habitual social chewing of areca 0.5% (Murti et al. 1985). Although OSMF is charac-
nut/betel quid (Fig. 56). Thus, it is very common terized by fibrosis of the subepithelial connective
in patients from the South Asia region and the tissue, the overlying epithelial changes contribute
Indian subcontinent. The estimated number of to malignant transformation. It has been shown
patients diagnosed with OSMF exceeds 2.5 however that there is a significant increase in the
Fig. 52 Bioinformatic analysis of OPMD transcriptomes. showing log fold change between margins relative to nor-
Venn analysis of global gene expression showing common malized mean expression level. Red dots are significant
and uniquely expressed genes in each group (a). Hierar- differentially expressed genes, as determined by DESeq
chical clustering of all samples shows that generally OLP analysis (FDR <0.05) (c). Again OLP and OED (bottom
and LD cases tend to cluster away from OED cases. Sam- right plot) appear to display the greatest amount of genetic
ples are annotated according to diagnosis, and relative diversity, while LD and OLP (top right plot) display the
expression of selected genes is shown by truncated least amount of genetic difference. OLP Oral lichen planus,
heatmap (b). Molecular diversity is lowest between OLP LD Lichenoid dysplasia, OED Oral epithelial dysplasia
and LD. MA plots of differential expression analysis
incidence of epithelial dysplasia as the thickness (mean standard deviation) and ranged from
of fibrosis increases (P = 0.004) (Jayasooriya 0.25 to 1.9 mm; however the mean thickness of
et al. 2011). The mean thickness of fibrosis of fibrosis of dysplastic lesions was 1.17 0.52 mm
non-dysplastic lesions was 0.91 0.41 mm and ranged from 0.48 to 3 mm.
Fig. 53 Malignant
transformation of oral
lichen planus lesion to oral
squamous cell carcinoma.
Changes to appearance of
lesion occurring on the left
buccal mucosa over a
15-month period, from
7 December 2016 (a),
8 March 2017 (b), and
9 August 2017 (c) to
14 March 2018 (d)
Actinic Cheilitis (Figs. 58, 59, 60, 61, 62, 63, 64, and 65). Histo-
pathology shows varied features of hyperkerato-
Actinic cheilitis (actinic keratosis/solar keratosis) sis, OED, and early squamous cell carcinoma,
is a clinical term describing ulcerative, sometimes with prominent solar elastosis sometimes noted
crusted lesions that form in response to sun expo- (van der Waal 2009). Elderly men are at higher
sure. It predominantly occurs on the vermilion of risk for this condition than other groups, espe-
the lower lip with blurring of the vermilion border. cially with occupational solar exposure (Pukkala
The most frequent clinical features of actinic et al. 2009). The prevalence of actinic cheilitis in
cheilitis are white, red and white, or red plaques, studies that do not define occupational exposure is
followed by ulcerated or pigmented lesions reported at 0.23% (Kaugars et al. 1999), while in
studies that are limited to outdoor workers this is with OSCC in a cohort of 125 subjects with
as high as 15.5–39.2% (Junqueira et al. 2011; de actinic cheilitis (Pinera-Marques et al. 2010),
Souza Lucena et al. 2012). There are no incidence whereas in a Chilean retrospective study of
figures available from the literature. A provisional 232 lip lesions, 72 (31%) were diagnosed with
diagnosis may be made on clinical grounds, OSCC (Ochsenius et al. 2003).
but a definitive diagnosis requires a biopsy Despite lesions being easily accessible and
(Warnakulasuriya et al. 2007). No accurate data readily visualized, several factors are attributed
is available on the malignant transformation to the late clinical diagnosis of actinic cheilitis
rates of actinic cheilitis, although in one Greek including lack of knowledge of the importance
retrospective study of 65 patients with actinic of the lesion, lack of associated pain, and an initial
cheilitis, 11 cases (16.9%) presented with OSCC, clinical appearance which is often dismissed as
suggesting its malignant transformation rate benign or inflammatory pathology by many prac-
(Markopoulos et al. 2004). In another study, titioners (Vieira et al. 2012).
3.2% of Brazilian fishermen were diagnosed There are varied treatment options for manag-
ing actinic cheilitis including vermilionectomy,
topical application of 5-fluorouracil (5-FU),
chemical peel with trichloroacetic acid, cryother-
apy, electrocauterization, CO2 laser ablation,
imiquimod, photodynamic therapy, YAG laser
therapy, and follow-up with intense local photo-
protection (Vieira et al. 2012). Vermilionectomy is
still the treatment of choice, since it allows for
histopathological review of all removed tissue and
provides satisfactory surgical and cosmetic out-
comes. Any treatment however should be
complemented with preventative sun protection
as well as adherence to regular review for effec-
Fig. 54 Isolated oral lichenoid lesion on the buccal
mucosa without widespread bilateral features of oral lichen tive clinical control of the disease (Vieira et al.
planus 2012).
Fig. 55 Oral submucous fibrosis in a betel nut user. Note (c) buccal mucosa is evident with keratotic tissue also
the limited maximum opening and the orange/brown stain noted on the right side
on his teeth and tongue (a). Fibrosis of the right (b) and left
Fig. 56 Areca nut tree (a), fruit (b), and nut (c). (Images courtesy of Professor WM Tilakaratne, Faculty of Dental
Sciences, University of Peradeniya, Sri Lanka)
Chronic Hyperplastic Candidosis
Chronic hyperplastic candidosis (CHC) (also

incorrectly known as candidal leukoplakia) is a
type of oral mucosal lesion associated with
chronic infection of Candida albicans that pre-
sents clinically as an adherent chronic white patch
typically on the commissures of the oral mucosa
(McCullough et al. 2002), although it can be
located elsewhere in the oral cavity, such as the
dorsal or lateral border of the tongue (Fig. 66).
Candida-associated leukoplakia appears mostly
as erosive, ulcerated, or non-homogeneous
lesions. It is still unclear how Candida infection
mitigates malignant transformation, although Fig. 57 Histopathology of oral submucous fibrosis char-
acterized by fibrosis and hyalinization in the lamina pro-
associations have been found between oral yeast
pria. (Image courtesy of Professor WM Tilakaratne,
load and OED (Barrett et al. 1998; McCullough Faculty of Dental Sciences, University of Peradeniya, Sri
et al. 2002; Sitheeque and Samaranayake 2003) Lanka)
Fig. 58 Homogeneous leukoplakia on lower lip of a Fig. 61 Actinic cheilitis presenting as a thin white plaque
female, diagnosed histopathologically with mild oral epi- with moderate epithelial dysplasia
thelial dysplasia. Note blurring of the vermilion border
consistent with actinic cheilitis
Fig. 62 Actinic cheilitis in a female showing ulceration,

erythema, and blurring of the vermilion border diagnosed
Fig. 59 Actinic cheilitis presenting with a thin white histopathologically as moderate epithelial dysplasia
plaque with mild epithelial dysplasia
Fig. 63 Chronic ulceration and erosion of the lower lip of

Fig. 60 Actinic cheilitis presenting as non-homogeneous a female with evidence of background actinic cheilitis.
leukoplakia with mild epithelial dysplasia Histopathology confirmed squamous cell carcinoma
and that the degree of dysplasia correlates posi- candidosis is estimated to occur in 9–40% of all
tively with the amount of yeast in the oral cases (Meurman 2010).
cavity (McCullough et al. 2002). Nevertheless, The reason for malignant transformation of
progression to malignancy of chronic hyperplastic the oral mucosa has not yet been determined. It
is possible that Candida itself may produce car-

cinogens that lead to point mutations in the
epithelium (Mohd Bakri et al. 2010). Certain
strains of C. albicans have been shown to be
able to convert ethanol into acetaldehyde,
an established carcinogen (Tillonen et al.
1999). Localized increases in concentration of
acetaldehyde may initiate malignant changes in
the oral epithelium. It is also possible that
C. albicans does not initiate or exacerbate the
malignant process but simply that dysplastic
epithelium provides a favorable environment
Fig. 64 Generalized changes to the lower lip in a Cauca-
sian male with white and pigmented spots consistent with for the species to grow in. While the link
actinic cheilitis. Histopathology showed orthokeratosis between chronic hyperplastic candidosis and
with no dysplasia oral malignancy has not been established, an
association between the two seems likely and
further research is required.
Assessment of Oral Potentially

Malignant Disorders
Early detection has shown efficacy in improving

the clinical outcomes of OSCC (Lingen et al.
2008). Opportunistic screening for oral cancer
and OPMDs is recommended as part of the
patient’s routine dental visit. Despite their limita-
tions in the early detection of oral cancer, the
Fig. 65 Actinic cheilitis involving lower lip with a crusted
lesion on left aspect biopsy-proven oral squamous cell standard of care for the diagnosis and identifica-
carcinoma tion of lesions with suspicious oral malignancies
Fig. 66 Examples of chronic hyperplastic candidosis involving the commissure (a), buccal mucosa (b), hard palate
mucosa (c), and lateral tongue (d)
is currently still based on the use of conventional Accurate diagnosis of OPMD relies on a com-
oral examination and histopathological evaluation prehensive intraoral and extraoral examination to
of a tissue sample by surgical biopsy. Over recent assess lesion location, color, size, texture, and
years however, there has been an enhanced under- border distinctness. This is however only part of
standing that better assessment and more accurate the approach required to assess such lesions. A
diagnosis of oral mucosal lesions, and OPMD in comprehensive diagnostic process should include
particular, is facilitated by the use of white light risk assessment of the patient and lesions under-
visualization of the oral mucosa supplemented taken by gathering patient information through an
with optical magnification in a combination of initial questionnaire followed by patient consulta-
loupes and headlights commonly used in dentistry tion (Fig. 68). Lesion examination and discovery
and otolaryngology. Assessment with white LED should follow with white light examination under
(light emitting diode) light (Fig. 67) in compari- magnification, followed by fluorescence or spec-
son to halogen or incandescent provides better troscopy assessment with a diagnostic adjunctive
color contrast and truer color distinction, thus to permit collection of additional information that
facilitating the assessment of homogeneous and may help in discrimination between one OPMD
non-homogeneous lesions and allowing better and another or between OPMD and benign
discrimination between them. This clearly has pathology (Fig. 69). Once adequate clinical infor-
implications for management strategies, as mation is gathered about the OPMD, then deter-
non-homogeneous lesions require closer atten- mination of the need for further tests and
tion. Addition of optical, or even digital magnifi- investigations inclusive of biopsy and pathology
cation, allows better assessment of surface is undertaken. Given the definition of leukoplakia,
textural changes and once again leads to enhanced and erythroplakia in particular, histopathological
appraisal of suspicious lesions that may be assessment would appear to be paramount, in
discounted had such subtle changes not been deciding on a management plan for these lesions.
detected or appreciated. The combination of Accurate diagnosis of OLP, OSMF, CHC, or
white light illumination and magnification is a actinic cheilitis also allows appropriate determi-
powerful combination that should be used for nation of suitable management plans whether
the assessment of all OPMD and OSCC. these include pharmacotherapeutic or surgical
Fig. 67 White LED

headlight and 2.5 loupes
enhance clinical assessment
of mucosal lesions and are
also useful for surgical
management of OPMD
and OSCC
PREDICTIVE RISK ASSESSMENT OF HEAD AND NECK CANCER
About you, your history, your habits and your symptoms Lower Risk Higher Risk
20s 30s-40s 50s-60s 70s-80s
FEMALE MALE
I smoke cigarettes or other forms of tobacco such as bidis, cigars, cigarillos, little cigars,
NO Former Smoker YES
kreteks, pipes, or hookas
I use areca nut or betel quid on a regular basis NO Former User YES
I chew tobacco, use spit tobacco (dip or oral dissolvable tobacco products), sniff or
NO Former Tobacco User YES
inhale snuff
I drink alcohol frequently and consume large amounts NO Former Drinker YES
I have not had HPV vaccination (age above 26) NO YES

I started my HPV vaccines, but did not get all 3 shots (ages 9-26) NO YES
I have not completed my HPV vaccine series of 3 shots within a 6-month period (ages
NO YES
9-26)
I have oral sex with several partners NO YES

My partner(s) engages in sex with several others NO YES
I have a family history of head or neck cancer including mouth, lips, nose, or throat NO YES
I have a personal history of cervical cancer (females only) NO YES
I have a personal history of prostate or breast cancer NO YES
I have Fanconi anaemia, Ataxia-telangiectasia, Xeroderma pigmentosum, Bloom’s
NO YES
syndrome, Dyskeratosis congenita, or Li-Fraumeni syndrome
I suffer from an immunosuppressive disorder or condition NO YES
I do not eat a diet rich in vegetables and fruits NO YES

I eat salt preserved foods regularly (examples: salted fish, salted meat) NO YES
I work with wood, sawdust, asbestos, toxic fumes NO YES
I do not protect my lips from the sun’s ultraviolet (UV) rays with balm that has sun
NO YES
protective factor
I have very poor oral hygiene NO YES
I use high-alcohol containing mouthwashes on a regular basis NO YES
I have a white or red patch or ulcer on the gums, tongue or lining of my mouth NO YES
I have pain or difficult swallowing; a feeling of something caught in my throat NO YES
I have a mass or lump in the neck; pain or swelling in the face, chin or neck NO YES
I have a sore throat or a cough that doesn’t go away NO YES
I have trouble breathing or speaking; hoarseness or a change in my voice NO YES
I have swollen/enlarged glands or lymph nodes in my neck NO YES
Fig. 68 Head and neck squamous cell carcinoma predic- American Dental Association, the Oral Cancer Founda-
tive risk assessment algorithm. This list of head and neck tion, the Georgia Cancer Center at Augusta University,
cancer risk factors and symptoms is derived from informa- Cancer Australia, and published literature. Some of the
tion published by the National Cancer Institute (NCI), the symptoms may also relate to other illnesses or conditions
RISK ASSESSMENT LESION DISCOVERY LESION INVESTIGATION
Leukoplakia
Lichen Planus
OSCC
Intra and Extra
Patient Oral Head &
Fluorescence or
Information Patient Neck Exam Differential Biopsy &
and Risk Consultation with White Spectroscopy
Diagnosis Pathology
Assessment Light and Examination
Loupes
CLINICAL JUDGEMENT
Diagnosis
Treatment Plan
Management
Fig. 69 The diagnostic process for oral mucosal lesions incorporating examination with white light and magnification,
followed by fluorescence
approaches. Appropriate incorporation of adjunc- The camera settings should be fixed including
tive optical technologies into the diagnostic pro- single point autofocus, shutter speed and ISO,
cess for OPMDs should be undertaken by experts spot metering, drive mode, white balance, pic-
trained in oral mucosal pathology and with skill in ture control, and image quality. Aperture (f/stop)
interpreting optical findings from these devices; can be altered between intraoral photos (f/20 or
otherwise the amount of nonspecific diagnostic higher) and extraoral shots (f/6 to f/10). Manual
noise can compromise their use (Macey et al. exposure is preferred to automatic exposure for
2015). Adherence to a decision-making protocol better control of images.
for fluorescence imaging has been shown to
increase sensitivity and specificity in the diagnos-
tic process (Fig. 70) (Bhatia et al. 2014). Adjunctive Tools
Changes occur over time with the clinical
presentation of OPMD, and as such there is a A tremendous amount of research has been car-
need for accurate identification and documenta- ried out to assess the efficacy of adjunctive tools,
tion. Therefore, it is always advisable to digitally devices, and techniques in improving the preven-
photograph all lesions and document these in the tion and early detection of oral cancer and ulti-
patient’s record. Immediate and intermediate mately improving patient prognosis. However,
benefits can be gained by taking photographs. due to either poor study design or complicated
These serve to assist with treatment planning, techniques, none of these methods have been
risk management, compliance, and education. recommended as a replacement for the current
Keeping the same settings is important so true gold standard of a surgical biopsy and histopath-
changes observed over time are easily observed. ological examination (Macey et al. 2015).
No lesions present – no
further follow-up
No review/
referral required Lesion healed No
on review referral
Background Conventional Oral Fluorescence Combined Lesion Review by
information Examination Examination Exam present dentist
Refer to
Lesion present
Oral
Refer to Oral on review
Medicine
Medicine
Age, gender, Homogeneous leukoplakia Based on VELscope Lesions with LAF Lesions which on combined If at the review the
smoking, suggestive of keratosis, alone, LAF with are reviewed findings are considered lesion has healed or
alcohol, and lichenoid lesions or partial or no under COE to benign or where LAF can be can be discounted as
mouthwash “Other” not suspicious for blanching are assess if there is accounted for on clinical benign on clinical
consumption dysplasia are marked as considered suspicious any clinical grounds, are marked by the grounds then the
are recorded. requiring no further for dysplasia and explanation for dentist as no follow-up lesion is marked as no
follow-up. marked for referral. LAF (eg. required. follow-up required by
Head and neck pigmentation, the dentist.
cancer risk Homogeneous leukoplakia Lesions with LAF with vascularity, Lesions which based on
assessment with no suggestive complete blanching traumatic COE findings are suspicious Lesions which have
completed as etiology, or “Other” are considered inflammation). for dysplasia are referred to not healed on review,
indicated. lesions which could not be benign and marked Oral Medicine. and where LAF cannot
discounted as benign are for review. be accounted for on
marked for review or Lesions where LAF cannot clinical grounds
referral by the dentist. Lesions with no LAF be accounted for on clinical referred to Oral
are marked as not grounds and are not Medicine.
Non-homogeneous lesions requiring any follow- suspicious for dysplasia
are considered suspicious up. with COE are marked for
for dysplasia until proven review to assess for healing
otherwise and marked for and possible traumatic
referral based on COE. causes.
Fig. 70 Decision-making protocol for incorporation of ▶ https://doi.org/10.1016/j.oraloncology.2014.07.002).

autofluorescence examination to aid the detection of LAF Loss of autofluoresecence, COE Conventional oral
OSCC and OPMD. (Adapted from Bhatia et al. 2014 – examination
To date, most adjunctive tools have been adjunctive technologies like toluidine blue,
assessed in terms of secondary or tertiary referral brush biopsy or fluorescence imaging as a screen-
centers by experienced specialists with significant ing tool to reduce oral cancer mortality”
expertise in assessing OPMD and OSCC (Farah (Brocklehurst et al. 2013). They go on to state
and McCullough 2007; McIntosh et al. 2009; that “Further RCTs are recommended to assess
Farah et al. 2012; Vu and Farah 2014; Lalla the efficacy and cost-effectiveness of a visual
et al. 2016; Awan et al. 2011a). Some however examination as part of a population-based screen-
have extended this to use by general dental prac- ing programme in low, middle and high-income
titioners with more than satisfactory results countries” (Brocklehurst et al. 2013). Although on
(Bhatia et al. 2014). The literature appears to balance these statements are true and well
draw significant distinction for their use by gen- founded, adjuncts can provide the specialist oral
eral practitioners compared to specialists. The medicine clinician with additional clinical infor-
most recent recommendation by the American mation that can be used in individual patient sce-
Dental Association Council on Scientific Affairs narios to make decisions about treatment planning
and the Center for Evidence-Based Dentistry con- and management. These adjunctive devices can
cludes that “For patients seeking care for suspi- enhance lesion discovery, visualization, surveil-
cious lesions, immediate performance of a biopsy lance, and removal, but must be used as comple-
or referral to a specialist remains the single most mentary tools rather than a replacement for a
important recommendation for clinical practice” thorough clinical assessment. It should be remem-
(Lingen et al. 2017), while one Cochrane Review bered that they are not stand-alone diagnostic
states that “None of the adjunctive tests can be devices, but accessory devices designed to facili-
recommended as a replacement for the currently tate and not provide a diagnosis. Their true suc-
used standard of a scalpel biopsy and histological cessful implementation in clinical practice is
assessment” (Macey et al. 2015), and another underpinned by a thorough understanding of
“There was no evidence to support the use of mucosal pathology, a working knowledge of
optics, and a healthy appreciation of the interrela- acetic acid to reduce the background level of
tionship between the two. Ultimately, optical staining. Only positive areas will retain a stain
adjunctive imaging should be seen through the after this decolorization process (Fig. 72). The
prism of other imaging modalities used in den- data indicate that there is limited value in using
tistry and medicine, specifically centered on the toluidine blue staining as an adjunctive method
oral mucosa. For the purposes of this chapter, a for the detection of oral cancer and precancer.
brief description of the most commonly verified However, toluidine blue staining may be helpful
devices and techniques is provided. for clinicians in choosing incisional biopsy sites
within suspicious lesions (Warnakulasuriya and
Johnson 1996; Martin et al. 1998).
Vital Staining
Tolonium chloride, more commonly known as Reflectance Visualization

toluidine blue (Fig. 71), is a metachromatic dye
of the thiazine group that has been used effec- There are several commercially available devices
tively in vitro as a nuclear stain because of its that utilize reflectance in conjunction with an acetic
affinity for the perinuclear cisternae of DNA and acid mouthwash to improve detection of OPMDs:
RNA (Martin et al. 1998). The evaluation of this ViziLiteTM (Zila Inc., AZ, USA), Microlux/DLTM
method as an adjunctive tool for the early detec- (AdDent Inc., CT, USA), and Orascoptic DK™
tion of oral cancer started as early as the 1960s. (Sybron Dental Specialities, CA, USA). This tech-
The staining technique involves rinsing the muco- nique aims to visualize the abnormal mucosa that is
sal surfaces with 1% acetic acid in the preopera- invisible under ordinary incandescent light. The
tive phase and then applying a 1% aqueous normal mucosa appears blue as it absorbs the
toluidine blue dye to the suspicious lesion for light, whereas the abnormal epithelium reflects
approximately 30 s, followed by a tap water the light and appears white (so-called aceto-
rinse. The lesion is then lightly blotted with 1% white) with sharp and defined borders.
Fig. 71 Toluidine blue (TB) oral examination. The tech- staining pattern is considered a strong predictor of severe
nique involves application of acetic acid to the lesion for disease, although any staining pattern or equivocal result
10–20 s (either rinsed or applied using a cotton applicator), warrants further investigation or follow-up for restaining.
followed by rinsing with water for 10–20 s, followed by A 1% TB solution may be prepared from laboratory-grade
application of TB (with a cotton applicator) for 10–20 s, TB or purchased as a pharmaceutical-grade TB in single-
then reapplication of acetic acid for 10–20 s, followed by a use swab kits. (Image courtesy of Clinical Professor
second rinse with water. A positive result is equated with A. Ross Kerr, New York University College of Dentistry,
the residual binding of the blue dye. An intense dark-blue NY, USA)
Fig. 72 Non-homogeneous leukoplakia with biopsy- (TBlue). (Images courtesy of Clinical Professor A. Ross
proven severe epithelial dysplasia on right lateral tongue Kerr, New York University College of Dentistry, NY,
before (a) and after (b) staining with toluidine blue USA)
ViziLiteTM and ViziLite PlusTM documented inherent problems with toluidine

ViziLiteTM and ViziLite PlusTM (Zila Inc., AZ, blue staining as a diagnostic adjunct in the detec-
USA) are commercially available kits using tion of epithelial dysplasia and its high false-
chemiluminescent light with or without toluidine negative rate for carcinoma and mild to moderate
blue to enhance the visibility and detection of dysplasia (Farah and McCullough 2007).
OPMDs. To use, the ViziLiteTM light stick is Another study investigated the efficacy of the
bent, breaking the glass inside and resulting in individual components of the ViziLiteTM system
chemiluminescence. A bluish-white light is emit- in providing improved visualization of early oral
ted with a wavelength ranging from 430 to mucosal lesions (Oh and Laskin 2007). No addi-
530 nm. The manufacturer advises that the patient tional lesions were found using chemiluminescent
rinse their mouth with acetic acid wash for better light. Most the lesions were found during the
visualization, although there is no evidence this is initial examination under incandescent light, and
necessary or beneficial. no additional lesions were found with ViziLiteTM
One study evaluated the efficacy of ViziLiteTM illumination. Further, they stated that ViziLiteTM
in enhancing visualization of oral mucosal lesions illumination made visualization more difficult due
and in highlighting OPMD and malignant lesions to distracting highlights on the oral mucosa
(Farah and McCullough 2007). Although chemi- (Oh and Laskin 2007). A separate study was car-
luminescence subjectively enhanced visualization ried to further assess lesions identified during a
of white lesions, there was no significant differ- conventional oral soft tissue examination with
ence in lesion size, ease of visibility, or border ViziLiteTM and application of toluidine blue to
distinctness for oral lesions examined with or evaluate its adjunctive value (Epstein et al.
without ViziLiteTM. In addition, ViziLiteTM 2008). The ViziLiteTM exam improved the bright-
could not distinguish between epithelial hyperpla- ness and/or sharpness of margins in 61.8% of
sia, dysplasia, carcinoma, and inflammatory identified lesions. There were no lesions that had
mucosal conditions, all of which appeared aceto- not previously been identified by oral exam and
white under chemiluminescent light and were that were subsequently identified by the adjunc-
considered ViziLiteTM-positive. The examination tive use of ViziLiteTM. It was concluded that fur-
with ViziLiteTM did not change the provisional ther research was needed in other populations
diagnosis or alter the biopsy site (Farah and using different study designs before clinicians
McCullough 2007). ViziLiteTM Plus, which can be confident that specificity is improved sig-
includes a staining solution similar to toluidine nificantly over conventional visual examination
blue, is unlikely to make a significant change to while the negative predictive value remains near
the usefulness of the product, given the 100% (Epstein et al. 2008).
In a case series evaluating the utility of visibility of 34 lesions, but it did not help detect
ViziLiteTM for the examination of OPMD, any clinically undetected lesions, change the pro-
patients underwent ViziLiteTM examination visional diagnosis, or alter the biopsy site. Micro-
followed by surgical biopsy (Awan et al. 2011b). lux™/DL demonstrated a sensitivity of 77.8% and
75.4% of lesions showed aceto-whitening. a specificity of 70.7% and a positive predictive
Although aceto-whitening was seen in the major- value of 36.8%. Microlux™/DL appears useful at
ity of dysplastic lesions, the device failed to dis- enhancing visibility of lesions, but it is a poor
tinguish between dysplastic and non-dysplastic discriminator of inflammatory, traumatic, and
lesions. The sensitivity and specificity of chemi- malignant lesions (McIntosh et al. 2009). None-
luminescence for detecting a dysplastic lesion theless, the study did show for the first time that
were 77.3% and 27.8%, respectively. The authors white light is far more beneficial than routine
concluded that although ViziLiteTM has the ability incandescent operatory lights for the detection of
to visualize OPMD, it does not accurately delin- oral cancer and OPMDs.
eate dysplastic lesions (Awan et al. 2011b). Over- One study evaluated the effectiveness of
all, the utility of ViziLiteTM is poor, and the Microlux™/DL with and without toluidine blue
evidence does not support its use in routine clin- (TB) in screening patients with OPMD and OSCC
ical practice nor in the hands of oral medicine (Ibrahim et al. 2014). A total of 53 suspicious
specialists. lesions were detected by examination compared
to 52 and 51 by Microlux™/DL and Microlux™/
Microlux™/DL DL plus TB, respectively. Compared to oral
Microlux™/DL consists of a battery-powered examination the sensitivity of Microlux™/DL
LED transilluminator that produces diffuse light was 94.3%, the specificity was 99.6%, and the
(Fig. 73) and shares the same principle as positive predictive value was 96.2%. Compared
ViziLiteTM. Similarly, the manufacturer recom- to biopsy, the sensitivity of Microlux™/DL was
mends the use of 1% acetic acid rinse prior to 100%, the specificity was 32.4%, and the positive
the Microlux™/DL use. A case series to assess predictive value was 17.9%. Although Micro-
the efficacy of acetic acid mouthwash and dif- lux™/DL uncovered new lesions not seen on rou-
fused light illumination (Microlux™/DL) as a tine examination, it did not alter the provisional
diagnostic aid in visualizing oral mucosal lesions clinical diagnosis or alter the biopsy site. Tolui-
and to assess its ability to highlight malignant and dine blue did not improve the effectiveness of
potentially malignant lesions was carried out the outcomes of Microlux™/DL (Ibrahim et al.
(McIntosh et al. 2009). Microlux™/DL enhanced 2014).
Current evidence suggests that LED-based
reflectance visualization would help in discover-
ing new mucosal pathologies that are not visible
under incandescent light (McIntosh et al. 2009)
and that white light-based examination may help
in improving diagnostic performance in high-risk
populations (Farah and McCullough 2007; Oh
and Laskin 2007).
Narrow Band Imaging

Narrow band imaging (NBI) (Olympus Medical
Systems, Tokyo, Japan) is a reflectance spectros-
copy technology that provides real-time noninva-
sive optical image enhancement of mucosa
Fig. 73 Microlux™/DL device illuminating an ulcerated (Fig. 74) (Bhatia et al. 2013; Vu and Farah 2014,
lichenoid lesion on the left lateral tongue 2016; Vu et al. 2015). It uses a short wavelength
et al. 2012; Bhatia et al. 2013; Nguyen et al.

2013; Vu and Farah 2014). A prospective series
of patients presenting with either white, red, or
red-white oral mucosal lesions were assessed with
NBI for the detection of OPMD (Vu et al. 2015).
A total of 272 lesions from 95 patients were
observed. The sensitivity, specificity, positive pre-
dictive value, negative predictive value, and accu-
racy for the detection of OPMD or worse by NBI
were 100%, 74.63%, 92.38%, 100%, and 93.77%
respectively, when compared with conventional
oral examination. NBI aided the detection of
24 lesions undetected by conventional oral
examination and 13 lesions undetected by white
light endoscopy. Although the microvascular
intrapapillary capillary loop (IPCL) pattern of
OPMD may not distinctly correlate with patho-
logical diagnoses of OPMD, NBI demonstrates
great utility as a visualization adjunct for detecting
and visualizing OPMD as it has high diagnostic
accuracy and can aid the detection of lesions that
may not be identified by COE or WL examination
alone (Figs. 75, 76, 77, and 78) (Vu et al. 2015).
In a systematic review assessing the efficacy
of NBI for detection and surveillance of poten-
tially malignant and malignant lesions in the oral
cavity and oropharynx, the sensitivity, specific-
ity, positive predictive value, negative predictive
value, and accuracy for white light ranged
between 56%–96%, 60–100%, 33–100%,
Fig. 74 Narrow band imaging endoscopic stack and
87–99% and 66–89% respectively, whereas it
image of lesion displayed by high-definition monitor
screen during intraoral assessment of oral lesion in oral was 87–96%, 94–98%, 73–96%, 97–98%, and
medicine outpatient clinic 92–97%, respectively, for NBI (Vu and Farah
2014). They stated that while more research
blue light of 415 nm that penetrates into the was required to determine the full value of NBI,
mucosa, highlighting superficial capillaries as it had great potential in accurately aiding the
brown, and another parallel wavelength of green detection and assessment of neoplastic lesions
light at 540 nm that identifies prominent vessels in and influencing how these lesions were managed
the submucosal layer as cyan (Tan et al. 2012). (Vu and Farah 2014). Furthermore, NBI demon-
The reflected light is captured by a charged, strates better specificity than autofluorescence in
coupled device located at the tip of the endoscope, assessing head and neck lesions (Nguyen et al.
and a colored composite image is then created by 2013).
the image processor, which is displayed on a high- The current data supports NBI as a visualiza-
definition monitor screen (Piazza et al. 2008). tion adjunct for the detection of OPMDs
NBI has shown promising results for use as an undetected by COE or white light examination
adjunct to COE, with higher sensitivity and alone (Vu et al. 2015). It has also been found
greater positive and negative predictive values however to be more beneficial in identifying
and accuracy than COE and white light (Yang OSCC (Nguyen et al. 2013) and in defining
Fig. 75 Verrucous
leukoplakia on right lateral
tongue viewed with white
light and endoscopic
magnification (a). Same
area viewed in NBI mode
(b) demonstrating dark
brown, dilated type III IPCL
(yellow dashed ovals).
Histopathology confirmed
verrucous carcinoma with
adjacent verrucous
hyperplasia and mild
epithelial dysplasia
surgical resection margins of OSCC (Farah et al. that can be employed in both in vivo and in vitro
2016, 2018b; Farah 2018). modes. There are several oncological applications
for in vivo fluorescence spectroscopy (Wagnieres
et al. 1998).
Optical Fluorescence Imaging Assessment of oral mucosal AF properties
involves illumination of the tissue using the visi-
Optical fluorescence imaging or tissue auto- ble light spectrum. This causes the absorption of a
fluorescence is a phenomenon best described as portion of the photons by molecules within the
the ability of photons to travel through tissue and tissue called fluorophores (Roblyer et al. 2009),
interact with tissue components. The disruption of which are located in the epithelial layer (e.g.,
the tissue’s morphology and structure in either nicotinamide adenine dinucleotide [NADH]
dysplastic or cancerous lesions influences tissue and flavin adenine dinucleotide [FAD]) or the
fluorescence and results in color alterations that stroma (e.g., elastin and collagen cross-links)
can be interpreted visually. (Richards-Kortum and Sevick-Muraca 1996).
Fluorescence spectroscopy, a major form of The fluorophores then emit lower energy photons,
optical imaging, is a noninvasive diagnostic which can be detected from the mucosal surface as
adjunct that evaluates the biochemical composi- fluorescence (Roblyer et al. 2009). The presence
tion and structure of tissue autofluorescence (AF) of disease can alter the absorption properties of
Fig. 76 Erythroleukoplakia
involving the right soft
palate viewed with white
light and endoscopic
brown, dilated type IV
IPCL (yellow dashed
ovals), with a generalized
area of type III IPCL (red
dashed ovals).
Histopathology confirmed
squamous cell carcinoma
tissue due to changes in blood concentration, The VELscope ® (Fig. 79) and Identafi ®
nuclear size distribution, or disruption to collagen (Fig. 80) are commercially available devices
cross-links. Changes in epithelial thickness, such that use the principles of AF and tissue reflec-
as epithelial hyperplasia, may limit the fluores- tance to discriminate between normal and abnor-
cence signal produced by the strongly fluorescent mal tissue. In addition, new handheld devices
collagen layer, and these lesions may display loss such as Bio/Screen ® (AdDent Inc., CT, USA)
of autofluorescence (LAF) (De Veld et al. 2005). (Fig. 81) and ViziLite Pro (DenMat, CA, USA)
Malignant lesions display reduced fluorescence using similar technology are now commercially
due to a reduction in the number of collagen and available; however studies are yet to examine
elastin cross-links present as well as altered con- their efficacy, although this would not be
centrations of FAD or imbalance between fluores- expected to differ from that for VELscope ®
cent NADH and non-fluorescent NAD+. This given the similarity of the system and incident
affects the distribution and concentration of wavelength of blue light and filter system. These
fluorophores within the epithelium and stroma tools are described below in order to illustrate
and influences the ability of the epithelium to LAF and diascopic fluorescence (Fig. 82) as
emit fluorescence after stimulation with an exci- indicators of tissue change that provide the clini-
tation light (De Veld et al. 2005; Pavlova et al. cian with additional information and aid in
2008; Roblyer et al. 2009; Shin et al. 2010). diagnosis.
Fig. 77 Superficial
ulceration and erosion
involving the right lateral
tongue with some
associated keratosis viewed
with white light and
endoscopic magnification
(a). Same area viewed in
NBI mode (b)
demonstrating dark brown,
dilated, and haphazard type
IV IPCL in several locations
(yellow and red dashed
ovals). Black dashed oval in
(b) shows additional type
IV IPCL. Histopathology
confirmed squamous cell
carcinoma
VELscope ® and VELscope ® Vx presence, vessel dilatation, and inflammatory

The Visually Enhanced Lesion Scope reactions. VELscope ® has received special atten-
(VELscope ®; LED Medical Diagnostics Inc., tion and has been evaluated as a diagnostic aid
Barnaby, Canada) and the third-generation cord- for the detection of oral cancer and OPMDs
less version VELscope ® Vx use direct tissue AF (Awan et al. 2011a; Farah et al. 2012; Bhatia
to enhance oral mucosal abnormalities (Bhatia et al. 2013, 2014). VELscope ® has shown high
et al. 2013). VELscope ® is a simple and nonin- sensitivity for the detection of severe dysplasia,
vasive handheld device that utilizes a blue light carcinoma in situ, and OSCC; however, false-
of 400–460 nm wavelength to view intraoral negative diagnoses can result from overlooking
areas (Fig. 83). The blue light causes normal early dysplastic lesions (Mehrotra et al. 2010;
tissues to fluoresce bright green, whereas abnor- Awan et al. 2011a; Farah et al. 2012). Benign
mal tissue appears dark. Normal oral mucosa lesions, such as inflammation, are also associated
emits a pale green AF, while abnormal tissue with the loss of stromal AF. This may limit the
shows decreased levels of AF and appears dark diagnostic specificity, especially in low-risk
in comparison to healthy tissue (Figs. 84, 85, 86, populations. In assessing studies on the efficacy
87, 88, 89, 90, 91, and 92) (Awan et al. 2011a; of VELscope ®, it should be noted that most
Farah et al. 2012; Bhatia et al. 2013, 2014). studies do not specifically state which device
The darker appearance of abnormal tissue is (VELscope ® or VELscope ® Vx) they have
mainly due to stromal remodeling, hemoglobin used. This is an important determining factor as
Fig. 78 Ulcerated
erythroleukoplakia
involving the right floor of
the mouth viewed with
white light and endoscopic
brown type IV IPCL pattern
extending onto the floor of
the mouth and ventral
tongue. Histopathology
confirmed moderately
differentiated squamous
cell carcinoma
the first-generation VELscope ® devices had poor examination alone demonstrated a sensitivity of
blue light output and required that the operatory 30% and a specificity of 63%. The accuracy of
was completely darkened for adequate visualiza- dysplasia identification was 55%. VELscope ®
tion. Additionally, most studies reported in the examination could not provide a definitive diag-
literature use either the first or second version of nosis regarding the presence of epithelial dyspla-
the VELscope ®. The second-generation device sia. Loss of autofluorescence was noted not to be
had significantly better blue light output, and this useful in diagnosing epithelial dysplasia without
has been maintained in the third-generation cord- relevant clinical interpretation (Farah et al. 2012).
less device (VELscope ® Vx). In a randomized controlled trial, the use of
A case-series study to assess the efficacy of VELscope ® for oral cancer detection in patients
direct tissue autofluorescence imaging using with premalignant lesions was evaluated (Rana
VELscope ® in detection of oral mucosal lesions et al. 2012). The use of VELscope® led to higher
was conducted (Farah et al. 2012). Patients were sensitivity compared to white light alone (100%
examined under routine incandescent light, vs. 17%) but lower specificity (74% vs. 97%). A
followed by examination with VELscope ®. loss of fluorescence was detected in all dysplastic
Incisional biopsies were performed for definitive lesions, but 37.84% of cases of leukoplakia/
histopathological diagnosis. VELscope ® enhan- erythroplakia and 81.08% of cases of oral lichen
ced the visibility of 41 lesions and helped detect planus also showed loss of tissue fluorescence. Of
5 clinically undetected lesions. VELscope ® all examined lesions, 64.23% showed loss of
Fig. 81 BioScreen ® device
evaluated in one study (McNamara et al. 2012).

A conventional oral examination (COE) was
performed under regular dental incandescent
(white) light, followed by VELscope ® examina-
tion. The authors noted that, as has been seen in
other studies, common inflammatory conditions,
such as traumatic ulceration, benign migratory
glossitis, inflammatory papillary hyperplasia,
and chronic mucositis, consistently demon-
strated visual fluorescence loss, as did areas
Fig. 79 VELscope1 Vx handheld device rich in lymphoid tissue or melanin pigmentation.
As a result of these and other factors that result in
reduced fluorescence, the significance of a given
LAF area would appear to ultimately rest on
conventional oral exam and the knowledge or
experience of the clinician. The authors stated
that a comprehensive oral examination is more
valid than fluorescence examination in discrimi-
nation of benign mucosal alterations from pre-
malignancy and did not support use of this
technology as an adjunct to oral cancer screening
(McNamara et al. 2012).
Using VELscope® alone to screen patients in
routine general dental practice overestimates the
burden of significant oral mucosal abnormalities
Fig. 80 Identafi ® device displaying the violet light, with and may lead to over-referral. For this purpose, a
the operator filters to be worn during examination decision-making protocol (see Fig. 70) with par-
ticular emphasis on careful clinical interpretation
fluorescence, while only 4.88% of the lesions and reviewing lesions where appropriate was
could be identified as dysplasia (Rana et al. 2012). established (Bhatia et al. 2014). This resulted in
The benefit of using VELscope ® in screening a decrease in the number of unnecessary referrals
for OPMDs presenting to a dental clinic for ini- that may occur if LAF alone is relied upon (Bhatia
tial oral evaluation and routine dental care was et al. 2014). By using the decision-making
Fig. 82 Diascopic fluorescence. There is diffuse loss of blanching (diascopic fluorescence) of the anterior aspect
fluorescence of the right lateral tongue with ill-defined of the lesion (b), which becomes more evident as the mirror
borders suggestive of an inflammatory condition (a). is pushed backward in a constant movement (c–f)
Application of pressure with a dental mirror causes
protocol with VELscope ® Vx, 146 patients with a In an attempt to better understand the molecu-
total of 222 oral mucosal lesion lesions were lar pathways associated with fluorescence proper-
screened. COE detected 161 oral mucosal lesions, ties of OPMD visualized with VELscope ®,
but an additional 61 lesions were detected with various OPMD mucosal biopsies were assessed
VELscope ® Vx. COE alone showed a sensitivity by RNA-seq transcriptomic analysis and corre-
of 44.0% and specificity of 99.0%, while lated with their clinical fluorescence characteris-
VELscope ® Vx alone showed a sensitivity of tics (Kordbacheh et al. 2016). Although each
64.0% and specificity of 54.3%. Using the lesion type had a specific set of histology-related
decision-making protocol, the sensitivity and differentially expressed genes (DEGs), all tested
specificity were 73.9% and 97.9%, respectively. samples also shared a number of DEGs. Gene
Using the decision-making protocol allows for the ontology enrichment revealed LAF in oral
meaningful detection of oral mucosal lesions epithelial hyperplasia (OEH) was mostly due to
requiring specialist referral by incorporating changes in inflammation, cell cycle regulation,
VELscope ® Vx into routine general dental prac- and apoptosis, while in oral epithelial dysplasia
tice, without compromising patient care (Bhatia (OED) was due to inflammation, angiogenesis,
et al. 2014). and extracellular matrix remodeling.
Inflammatory reactions were associated with

diascopic fluorescence (DF) for both OEH and
OED (Kordbacheh et al. 2016). The authors con-
cluded that by following a clinical protocol that
includes assessment of clinical features and
review of lesions and taking into account biolog-
ical considerations of LAF and blanching of
lesions, a reduction in the number of unnecessary
referrals and false-positive findings compared
with using LAF alone can be achieved
(Kordbacheh et al. 2016).
In addition to its role in detection and visuali-
zation of OPMD and OSCC, VELscope ® may aid
in surgical removal of OPMD by more clearly
delineating the true extent of a lesion and thereby
facilitating more complete clearance of the lesion
(Farah et al. 2018a) (refer to section “Manage-
ment of Oral Potentially Malignant Disorders”).
It has been shown that the molecular profile of
OPMD changes with divergence away from the
center of the lesion and that autofluorescence-
determined margins are superior to white light
Fig. 83 Clinician with cordless VELscope ® Vx handheld
device positioned for oral mucosal examination
margins in achieving a clear molecular margin
when excising an OPMD (Farah et al. 2018a).
Fig. 84 Plaque-type oral lichen planus (a) as viewed with fluorescence (b) showing central area of loss of
autofluorescence
Fig. 85 Chronic hyperplastic candidosis visualized with white light (a) and with fluorescence (b) showing loss of
autofluorescence
Fig. 86 Leukoplakia on soft palate (a) showing loss of autofluorescence (b) in a male smoker. Note the area of LAF
extends well beyond the leukoplakic lesion noted in (a). Histopathology confirmed mild epithelial dysplasia
Fig. 87 Leukoplakia on the left lateral tongue in a 65-year-old male non-smoker (a) viewed under fluorescence (b)
showing LAF. Histopathology confirmed mild epithelial dysplasia
Fig. 88 Ulcerated lesion with raised margins and indura- fluorescence (b) showing LAF. There was no diascopic
tion on the posterior right lateral border of the tongue in a fluorescence noted. Histopathology confirmed poorly dif-
59-year-old male non-smoker (a) and viewed with ferentiated oral squamous cell carcinoma
Fig. 89 Oral lichenoid lesion on left lateral tongue (a) with diffuse loss of fluorescence (b)
Differential expression analysis showed that inde- autofluorescence margin compared to the lesion
pendent of histology, there was greater molecular center and white light margin. Furthermore, the
dysregulation between the lesion center and autofluorescence and white light margins were

Contemporary Oral Medicine

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Contemporary Oral Medicine

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Camile S.

With 1623 Figures and 299 Tables

ISBN 978-3-319-72301-3 ISBN 978-3-319-72303-7 (eBook)

# Springer Nature Switzerland AG 2019

The dominant pattern of education of oral health professionals and provision

The text starts with scholarly discussions of principles of diagnosis and

Philadelphia, USA Martin S. Greenberg

January 2019 Camile S. Farah

This book is a culmination of 4 years’ work. Our dream was to realize a

Normal Variation in the Anatomy, Biology, and Histology of

Head and Neck Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627

Odontogenic Bacterial Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . 819

Pediatric Oral Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1641

Neurophysiology of Orofacial Pain . . . . . . . . . . . . . . . . . . . . . . . . . 1749

Orofacial Pain in Patients with Cancer and Mucosal Diseases . . . . 2187

Camile S. Farah BDSc, MDSc (OralMed, OralPath), PhD, GCEd (HE),

and orofacial pain. He is Convenor of the postgraduate training program in

Clinical Associate Professor, UWA Dental School, University of Western

Ramesh graduated with a BDSc from the University of Western Australia in

Michael J. McCullough BDSc, MDSc (OralMed, OralPath), PhD, FRACDS

Michael is Professor of Oral Medicine at the Melbourne Dental School, the

graduate courses in Oral Medicine, has published 128 articles in peer-reviewed

S. Abramowicz Oral and Maxillofacial Surgery and Pediatrics, Emory

Kazunori Adachi Division of Pharmacology, Meikai University School of

Ivan Alajbeg University of Zagreb School of Dental Medicine, Zagreb,

Faizan Alawi Department of Pathology, University of Pennsylvania School

Fernanda Almeida Department of Oral Health Sciences, Faculty of

Galit Almoznino Department of Oral Medicine, Sedation and Maxillofacial

Ali Alnuaimi Oral Anatomy, Medicine, and Surgery Section, Melbourne,

Mohammad S. Alrashdan Faculty of Dentistry, Department of Oral

Ramesh Balasubramaniam UWA Dental School and Oral Health Centre of

Andrea Bargellini Gnathology Unit, Department of Surgical Sciences,

Rafael Benoliel Department of Diagnostic Sciences, Rutgers School of

Rudolf Boeddinghaus Perth Radiological Clinic, Subiaco, WA, Australia

Sonja Boy Department of Oral Pathology, Sefako Makgatho Health Sciences

Marieke T. Brands Department of Oral and Maxillofacial Surgery, Queen

Peter A. Brennan Department of Oral and Maxillofacial Surgery, Queen

Angus Cameron The University of Sydney, Sydney, NSW, Australia

Barbara Carey Eastman Dental Hospital, London, UK

Maria Clotilde Carra Department of Periodontology, Service of Odontology,

Marco Carrozzo Center for Oral Health Research, Department of Oral

Tommaso Castroﬂorio Gnathology Unit, Department of Surgical Sciences,

Swagnik Chakrabarti Head and Neck Oncology Services, Tata Memorial

Stephen J. Challacombe Department of Oral Medicine, King’s College

Sok Ching Cheong Cancer Research Malaysia, CARIF Oral Cancer

Katharine Ciarrocca Dental College of Georgia, Augusta University,

David Hillman Department of Pulmonary Physiology and Sleep Medicine,

Luiz P. Kowalski Head and Neck Surgery and Otorhinolaryngology

Kiyoshi Koyano Faculty of Dental Science, Kyushu University, Fukuoka,

Omar Kujan UWA Dental School, University of Western Australia, Perth,

Moni A. Kuriakose Department of Head and Neck Surgery/Plastic and

Gilles J. Lavigne Faculty of Dental Medicine, Univeristé de Montréal,

Jair C. Leão Oral Medicine Unit, Departamento de Clínica e Odontologia

Stefania Leuci Oral Medicine Complex Unit, Department of Neuroscience,

Giovanni Lodi Dipartimento di Scienze Biomediche, Chirurgiche e

Annabelle Mahar Department of Tissue Pathology and Diagnostic, Royal

Maddalena Manfredi Dipartimento di Medicina e Chirurgia, Centro

Daniele Manfredini School of Dentistry, University of Padova, Padova, Italy

Marie Marklund Department of Orthodontics, Umeå University, Umeå,

Marie Anne Teresa J. Matias Perth Radiological Clinic, Subiaco, WA,

Hani Mawardi Faculty of Dentistry, King Abdulaziz university, Jeddah,

Michael J. McCullough Oral Anatomy, Medicine, and Surgery Section,

L. G. Mercuri Department of Orthopedic Surgery, Rush University Medical

Alan Mighell Department of Oral Medicine, School of Dentistry, University