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WHO Classification of Tumours of the Digestive System is the third volume of the 4th Edition of the WHO series on
histological and genetic typing of human tumours. This authoritative, concise reference book provides an inter-
national standard for oncologists and pathologists and will serve as an indispensable guide for use in the design
WHO Classification of Tumours of
of studies monitoring response to therapy and clinical outcome. This book also provides user-friendly algorithmic
approaches to the diagnosis of the major tumours of the digestive tract.
the Digestive System
Diagnostic criteria, pathological features, and associated genetic alterations are described in a strictly disease-
oriented manner. Sections on all recognized neoplasms and their variants include new ICD-O codes, incidence, age
and sex distribution, location, clinical signs and symptoms, pathology, genetics, and predictive factors.
WHO Classification Tumours of the Digestive System

The book, prepared by more than 100 authors from 22 countries, contains some 700 colour photographs, numer- Edited by Fred T. Bosman, Fátima Carneiro, Ralph H. Hruban, Neil D. Theise
ous tables and figures and more than 3700 references.
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4th Edition
WHO Classification of Tumours of

the Digestive System
Edited by
Fred T. Bosman
Fátima Carneiro
Ralph H. Hruban
Neil D. Theise
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Lyon, 2010
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WHO Classification of Tumours of the Digestive System
Editors Fred T. Bosman, M.D., Ph.D.

Fátima Carneiro, M.D., Ph.D.
Ralph H. Hruban, M.D.
Neil D. Theise, M.D.
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The WHO Classification of Tumours of the Digestive System

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Bosman F.T., Carneiro F., Hruban R.H., Theise N.D. (Eds.):
WHO Classification of Tumours of the Digestive System.
IARC: Lyon 2010
IARC Library Cataloguing in Publication Data
WHO classification of tumours of the digestive system - 4th edition / edited by Fred T. Bosman ... [et al.]
(World Health Organization classification of tumours)
1. Digestive System Neoplasms − classification 2. Digestive System Neoplasms − genetics

3. Digestive System Neoplasms − pathology
I. Bosman, F.T. II. Series
ISBN 978-92-832-2432-7 (NLM Classification: WI 15)

Contents http://publications.iarc.fr/Book-And-Report-Series/Who-Iarc-Classification-Of-Tumours
1 Diagnostic terms revisited 9 9 Tumours of the anal canal 183

Premalignant lesions of the digestive system 10 WHO and TNM classifications 184
Nomenclature and classification of neuroendocrine Tumours of the anal canal 185
neoplasms of the digestive system 13
10 Tumours of the liver and intrahepatic bile ducts 195
2 Tumours of the oesophagus 15 WHO and TNM classifications 196
WHO and TNM classifications 16 Focal nodular hyperplasia and hepatocellular adenoma 198
Squamous cell carcinoma 18 Hepatocellular carcinoma 205
Adenocarcinoma 25 Intrahepatic cholangiocarcinoma 217
Neuroendocrine neoplasms 32 Combined hepatocellular-cholangiocarcinoma 225
Lymphoma 34 Hepatoblastoma 228
Mesenchymal tumours 35 Mucinous cystic neoplasms 236
Secondary tumours and melanoma 37 Lymphoma 239
Mesenchymal tumours 241
3 Tumours of the oesophagogastric junction 39 Secondary tumours 251
Adenocarcinoma 40 Diagnostic algorithms 254
4 Tumours of the stomach 45 11 Tumours of the gallbladder and extrahepatic bile ducts 263
WHO and TNM classifications 46 WHO and TNM classifications 264
Gastric carcinoma 48 Carcinoma 266
Hereditary diffuse gastric cancer 59 Neuroendocrine neoplasms 274
Neuroendocrine neoplasms 64 Mesenchymal tumours 277
Lymphoma 69 Lymphoma 278
Mesenchymal tumours 74 Secondary tumours and melanoma 278
Secondary tumours 79
12 Tumours of the pancreas 279
5 Tumours of the ampullary region 81 WHO and TNM classifications 280
WHO and TNM classifications 82 Ductal adenocarcinoma 281
Adenomas and other premalignant neoplastic lesions 83 Ductal adenocarcinoma variants and mixed
Invasive adenocarcinoma 87 neoplasms 292
Neuroendocrine neoplasms 92 Serous neoplasms 296
Mucinous cystic neoplasms 300
6 Tumours of the small intestine 95 Intraductal neoplasms 304
WHO and TNM classifications 96 Acinar cell neoplasms 314
Carcinoma 98 Pancreatoblastoma 319
Neuroendocrine neoplasms 102 Neuroendocrine neoplasms 322
B-cell lymphoma 108 Solid-pseudopapillary neoplasm 327
T-cell lymphoma 112 Mesenchymal tumours 331
Mesenchymal tumours 115 Lymphoma 332
Secondary tumours 117 Secondary tumours 333
Diagnostic algorithms 334
7 Tumours of the appendix 119
WHO and TNM classifications 120 Contributors 338
Adenocarcinoma 122 Sources of charts and photographs 345
Neuroendocrine neoplasms 126 References 348
Miscellaneous tumours 129
Subject index 403
8 Tumours of the colon and rectum 131
WHO and TNM classifications 132
Carcinoma 134
Familial adenomatous polyposis 147
Lynch syndrome 152
MUTYH-associated polyposis 156
Serrated polyps and serrated polyposis 160
Juvenile polyposis 166
Peutz-Jeghers syndrome 168
Cowden syndrome 171
Neuroendocrine neoplasms 174
B-cell lymphoma 178
CHAPTER 1
Diagnostic terms revisited
Premalignant lesions of the digestive system
Nomenclature and classification

of neuroendocrine neoplasms
of the digestive system
Premalignant lesions R.D. Odze

R.H. Riddell
J.H. van Krieken
G.Y. Lauwers
of the digestive system F.T. Bosman
F. Carneiro
G.J.A. Offerhaus
M. Rugge
J.-F. Fléjou M. Shimizu
K. Geboes T. Shimoda
R.M. Genta N.D. Theise
T. Hattori M. Vieth
R.H.Hruban
Introduction and historical perspective Controversies regarding terminology and thus, there will always be a certain
Pathologists are often confronted with In the previous (3rd) edition of the WHO lack of consistency when this is artificially
biopsies of the digestive system that Classification of Tumours of the Digestive translated into discrete categories. One
show architectural and/or cytological fea- Tract (2000) an attempt was made to repercussion of the Vienna grading system
tures of precursors of invasive neoplasia, clarify some of these issues by introducing is that it recommended a change in termi-
either squamous or columnar. Historically, the term “intraepithelial neoplasia” as a nology from “dysplasia” to “intraepithelial
noninvasive neoplasia of the digestive synonym for lesions classified morpholog- neoplasia.” However, pathologists from the
system has been termed “dysplasia” by ically as dysplasia. USA and some European countries con-
pathologists when obvious, unambiguous, Furthermore, in 2000, a group of gastro- tinue to use the term “dysplasia,” whereas
architectural and/or cytological alterations intestinal pathologists convened in Vienna,
of epithelium normally associated with Austria, for the purpose of developing a Table 1.01 Precursor lesions of invasive neoplasia
neoplastic growth are present, without new system for the classification of dys- (intraepithelial neoplasia) of the tubal gut.
evidence of infiltration into the lamina plasia that would help to address the limi- Oesophagus
propria {2674}. tations discussed above {2842, 3090}. The Barrett-associated dysplasia
In 1982, Riddell et al. proposed a classi- goal of the “Vienna system”, as it was Adenomatous
fication system for dysplasia in the tubal termed, was to minimize the widely recog- Non-adenomatous
gut, which provided a meaningful method nized discrepancies in morphological in- Foveolar
Serrated
of estimating the risk of progression to terpretation of precursor lesions of invasive
Squamous dysplasia
cancer in patients with inflammatory neoplasia among pathologists in North
bowel disease (IBD) {2674}. This “IBD America and Europe and those in Japan, Stomach
dysplasia-grading system” was accepted and to reach consensus on the nomencla- Gastritis-associated dysplasia
quite readily, at least in the USA and in ture. Ultimately, the Vienna grading system Adenomatous (type 1)
most European countries, as the “stan- is very similar to the one proposed by Foveolar (type 2)
Adenoma
dard” method of assessing cancer risk in Riddell et al., except that the former uses Intestinal type
patients with IBD. The system was the term “noninvasive neoplasia”, which is Pyloric-gland type
adopted by clinicians and was subse- a synonym of intraepithelial neoplasia, Foveolar type
quently adapted for other, noninvasive instead of “dysplasia” and also uses the Fundic gland polyp-associated dysplasia
neoplastic conditions of the gastrointesti- term “suspicious for invasive carcinoma”
nal tract, such as those that occur in for lesions that show equivocal cytological Small intestine
Crohn disease-associated dysplasia
Barrett oesophagus, chronic gastritis and and/or architectural features of tissue inva-
Adenoma
colorectal adenomas {2654, 2752, 962}. sion. Differences in use of the term “carci- Intestinal type
In addition, it was used to classify squamous noma” are due to the fact that pathologists Brunner gland
neoplastic lesions of the oesophagus in North America and Europe typically de- Hamartoma-associated dysplasia
{2742A}. fine this lesion as one that has histological
Colon
As use of this grading system spread to evidence of invasive growth, whereas most
Inflammatory bowel disease-associated dysplasia
other regions of the world, such as Japan, Japanese pathologists diagnose carci- Adenomatous
a number of limitations became evident noma solely on the basis of the architec- Serrated
{2841}. Such limitations stem from increas- tural and cytological changes observed, Villous hypermucinous
ing recognition of the morphological and without requiring morphological evidence Adenoma
clinical heterogeneity of precursor lesions of invasive growth. Conventional
of invasive neoplasia of the digestive Not surprisingly, modification of the Traditional serrated
Sessile serrated adenoma/polyp
system, lack of reproducibility in the grad- nomenclature has not resolved the high
Without dysplasia
ing of dysplasia among pathologists level of intra- and interobserver variability With dysplasia
worldwide, lack of universally accepted with regard to the pathological classifica- Hamartoma-associated dysplasia
diagnostic criteria for each distinct grade tion of neoplastic precursor lesions, and
of dysplasia, and lack of universal agree- particularly for epithelial lesions that reveal Anus
Squamous dysplasia (anal intraepithelial neoplasia)
ment on the definition of invasive carci- borderline features between regeneration
HPV/condyloma-associated dysplasia
noma, in particular, between pathologists and neoplasia {2841, 2135, 3090}. This is Bowen disease (perianal squamous intraepithelial
in North America and Europe and those not surprising since precursor lesions of in- neoplasia)
in Japan {2841}. vasive neoplasia develop on a continuum,
10 Diagnostic terms revisited

most Japanese pathologists use the term dysplasia in Barrett oesophagus and IBD Table 1.02 Precursor lesions of invasive neoplasia
“intraepithelial neoplasia”. This has led to {3539A, 1838A, 936A, 3274, 1277}, and (intraepithelial neoplasia) of the gallbladder, biliary tract,
pancreas and liver.
much confusion among pathologists and, sessile serrated adenomas/polyps (SSA/P)
particularly, clinicians with regard to the in the colon which contain few, if any, dys- Gallbladder/biliary tree
meaning of the terms “dysplasia” and plastic features, but are now recognized BilIN 1–3
“intraepithelial neoplasia.” Furthermore, as a contributor to colon cancer {3274, Intraductal (bile ducts) or intracystic (gallbladder)
papillary neoplasms with intraepithelial neoplasia
since the publication of the Vienna grading 1277, 1400, 2993}.
Mucinous cystic neoplasm with intraepithelial
system, precursor lesions of invasive neo- Tables 1.01 and 1.02 highlight some of the neoplasia
plasia have been identified and character- major types of precursor lesions of invasive Adenoma
ized in other gastrointestinal organs, such neoplasia of the gastrointestinal tract, liver,
as the pancreas and anus, in which the biliary tract and pancreas. The following Pancreas/ampulla
term “intraepithelial neoplasia” has been definitions and guidelines are offered: PanIN 1–3
Intraductal papillary mucinous neoplasms with
used instead of “dysplasia” e.g. pancreatic dysplasia
intraepithelial neoplasia (PanIN), anal canal Neoplasia Mucinous cystic neoplasm with dysplasia
intraepithelial neoplasia (ACIN) {1083, One classical definition of neoplasia is the Ampullary adenoma
2979, 2851A}. following: “A neoplasm is an abnormal Noninvasive pancreaticobiliary papillary neoplasm
Thus, at the current time, two different terms mass of tissue, the growth of which Flat intraepithelial neoplasia (dysplasia)
are used among pathologists to describe exceeds and is uncoordinated with that of Liver
precursor lesions of invasive neoplasia of normal tissue, and persists in the same Large and small cell change
the gastrointestinal tract. In some organs, excessive manner after cessation of any Dysplastic nodules
such as the oesophagus, stomach and stimulus that may have evoked the change” Liver cell adenoma (rare)
colon, the term “dysplasia” is used by some {2163A, 2052A, 736A, 2867A}. However,
and “intraepithelial neoplasia” by others. not all neoplastic conditions lead to a mass. Carcinoma in situ
Such differences may be institutional or Furthermore, as indicated above, difficulties The term “carcinoma in situ” has been used
geographical. On the other hand, in some arise when morphological features that to refer to cytologically malignant lesions in
organs there is better agreement on usage. define a specific type of neoplasia are not squamous or columnar epithelium that do
For instance, although the term “intraep- present. not show invasive growth. Although valid
ithelial neoplasia” is exclusively used for from a biological point of view, use of the
anal lesions, in the pancreas, the term Intraepithelial neoplasia term “carcinoma in situ” in pathology re-
“intraepithelial neoplasia” is used for some Intraepithelial neoplasia is a term used to ports is strongly discouraged, particularly
lesions (PanINs), but “dysplasia” is used for describe lesions that generally display for columnar precursor lesions of invasive
others (mucinous cystic neoplasms and cytological or architectural alterations neoplasia. Lesions with these features are
intraductal papillary mucinous neoplasms). perceived to reflect underlying molecular encompassed within the terms “high-grade
abnormalities that may lead to invasive dysplasia” (or “high-grade intraepithelial
Current WHO classification and definitions carcinoma. However, molecular alterations neoplasia”) since neither type of lesions
The consensus meeting that preceded the are not invariably reflected in the pres- show invasive growth, and the clinical
publication of the 4th edition of the WHO ence of such cytological/architectural implications and treatment regimens are
classification did not lead to an agreement atypia. Thus, “intraepithelial neoplasia” similar. However, one exception is in the
on one term for noninvasive neoplasia for includes morphologically recognizable setting of hereditary diffuse gastric carci-
several reasons. First, specific cytological lesions with such atypia (for example, IBD- noma (HDGC) where the term “in situ signet
and/or architectural abnormalities of pre- associated dysplasia) or without (for ex- ring cell carcinoma” has become standard.
cursor lesions of invasive neoplasia differ ample sessile serrated andenoma/polyp).
considerably according to anatomical The types of intraepithelial neoplasia, and Intramucosal adenocarcinoma
location/organ, and the histology of the the morphological characteristics associ- The definition of intramucosal carcinoma
native epithelium and their biological char- ated with these presursor lesions of inva- varies in different parts of the world {2841,
acteristics, and malignant potential, vary sive neoplasia differ per organ (Tables 2842}. In the USA and in most European
substantially among different organ sites. 1.01 and 1.02). Key elements of the defi- countries, the term is applied to lesions
Second, recent advancements in our un- nition of intraepithelial neoplasia are that that show histological evidence of inva-
derstanding of the timing, type, and se- all lesions are morphologically identifiable, sion into the lamina propria or muscularis
quence of molecular events that lead to have the potential to become malignant mucosa, but not into the submucosa. Histo-
neoplastic transformation, have made clear and are noninvasive. logical evidence of invasion includes, but
that clonal, molecular abnormalities that is not limited to, infiltration of the stroma
lead to dysregulation of cell proliferation Dysplasia by single cells, or small clusters of cells,
and differentiation, and an increasing risk Traditionally, dysplasia is defined as histo- atypical or complex glandular arrange-
for subsequent neoplastic progression, logically unequivocal neoplastic epithelium ments that are beyond that present in
may occur without typical morphological without evidence of tissue invasion. The normal mucosa, presence of a stromal
characteristics of noninvasive neoplasia. term is distinct from intrepithelial neoplasia response such as desmoplasia, and
Examples are aneuploidy and mutations in since it refers to the presence of morpho- evidence of lymphovascular invasion. In
TP53 and CDKN2A, that precede the logical features of neoplasia. some circumstances, such as in Barrett
development of morphological features of oesophagus-associated dysplasia and
Premalignant lesions of the digestive system 11

chronic gastritis-associated dysplasia, it find it ambiguous, and as such, its use is all precursor lesions of invasive neoplasia,
is difficult to determine with certainty to be avoided in digestive-tract, liver, bil- regardless of the presence or absence of
whether a high-grade lesion has invaded iary tract and pancreas pathology. In the traditional morphological features of neo-
the lamina propria and, therefore, there is tubal gut, the term “indefinite for dysplasia plasia. The term “dysplasia” is used in
significant interobserver variability with (intraepithelial neoplasia)” is used instead pathology reports for some forms of pre-
regard to separating high-grade dyspla- of “atypia” to describe lesions that raise invasive neoplasia, such as those that
sia from intramucosal adenocarcinoma concerns for, but are not diagnostic of, arise in chronic inflammatory conditions
{2353}. As a result, in some parts of the neoplasia. of the oesophagus, stomach, and colon.
world, such as Japan, the term “noninva- However, the term “intraepithelial neopla-
sive carcinoma” is used to reflect lesions Summary sia” is also acceptable in these settings.
that show cytological and/or architectural With improvements in our understanding For the anus, only the term “intraepithelial
features of “carcinoma” regardless of of the molecular alterations involved in neoplasia” is used. For preinvasive neo-
whether invasion into the lamina propria carcinogenesis, particularly related to plastic lesions in the pancreas and biliary
can be documented histologically. conditions in which chronic inflammation tract, both terms are used but depending
is the main stimulus for oncogenesis, and on the specific type of lesion.
Epithelial atypia with the advent of studies that intend to In the subsequent chapters of the current
In diagnostic pathology, the term “atypia” establish correlation between genotype edition of the WHO classification of tumours
has been loosely used both as a descrip- and phenotype, pathologists now recog- of the digestive system, the specific
tive term, to capture cytological and/or nize a broad spectrum of precursor terminology, classifications, and histo-
architectural features of potentially neo- lesions of invasive carcinoma, including logical features of these lesions are
plastic epithelium, but also as a diagnostic lesions that do not necessarily show described in detail.
term to define epithelial lesions that differ morphological abnormalities typical of
from normal, but do not quite reach the neoplasia.
histological threshold of true neoplasia. As Therefore, in the current (4th) edition of
a diagnostic term, it lacks general consensus the WHO classification, the term intra-
among pathologists worldwide, clinicians epithelial neoplasia is used to encompass

Nomenclature and classification G. Rindi

R. Arnold
D.S. Klimstra
G. Klöppel
of neuroendocrine neoplasms F.T. Bosman
C. Capella
P. Komminoth
E. Solcia
of the digestive system
Introduction Such concepts stem from evidence that and the assessment of proliferation fraction
One of the major problems in the man- biological characteristics and stage at according to the ENETS scheme {2684,
agement of patients with gastrointestinal diagnosis largely determine the clinical 2685}. Evidence that the proliferation
(neuro)endocrine tumours (NETs) is the behaviour of NETS. As it does for other fraction has prognostic significance is
lack of universally accepted standards, epithelial neoplasms, the ENETS grading available for NETs of foregut origin, includ-
both for nomenclature (i.e. the clinical sig- and staging system formally recognizes ing stomach and pancreas {250, 850,
nificance of current definitions) and for the malignant potential of NETs and 1705, 2514, 2676, 2682, 2686}. The pro-
staging of disease {2114}. Based on a organizes their classification according to posed grading based on proliferation has
wealth of evidence, the most recent WHO grade and stage. three tiers (G1, G2, G3) with the following
classification of 2000 {3013} provided a definitions of mitotic count and Ki67 index:
rational approach to the nomenclature WHO 2010 classification – G1: mitotic count, < 2 per 10 high power
and classification of NETs of the digestive In the present volume of the WHO classifi- fields (HPF) and/or ≤ 2% Ki67 index;
system, developing a coherent terminol- cation of tumours, we attempt to bridge the – G2: mitotic count 2–20 per 10 HPF
ogy and allowing the prognostic stratification above-mentioned classification gap by and/or 3–20% Ki67 index;
of these neoplasms. This WHO classification introducing a grading scheme and apply- – G3: mitotic count > 20 per 10 HPF
has served as a basis for establishing ing the terms NET and NEC as widely and/or > 20% Ki67 index.
criteria for practical management, as re- accepted and used by clinicians in both the The grading requires mitotic count in at
flected in the guidelines of many scientific EU and USA. The term “neuroendocrine” is least 50 HPFs (1 HPF = 2 mm2) and Ki67
societies {2343–2345, 2567, 2621}. How- adopted here to indicate the expression of index using the MIB antibody as a
ever, while most institutions in the Euro- neural markers in neoplastic cells with percentage of 500–2000 cells counted in
pean Union (EU) adhere to the WHO 2000 otherwise exquisitely endocrine properties areas of strongest nuclear labelling (“hot
classification scheme, the scheme has not and phenotype. The term “neuroendocrine spots”). If grade differs for mitotic count
achieved widespread acceptance in neoplasm” can be used synonymously with compared with Ki67 index, it is suggested
diagnostic practice in the United States of “neuroendocrine tumour”. that the higher grade be assumed. Evi-
America (USA). The reasons for this dence to support this grading scheme is
include: (1) the embedding of stage- Grading classification available for the stomach, duodenum and
related information within a grading Grading is performed on the basis of mor- pancreas NETs {772, 868, 1705, 2449},
system; (2) the complicated clinical– phological criteria (see individual chapters) but is still lacking for NETs of the intestine.
pathological classification schemes; and
(3) the category “uncertain behaviour,”
which has met with resistance from both Table 1.03 Transition scheme for the new classification (WHO 2010) including previous definitions for neuroendocrine
neoplasms of the digestive system (WHO 1980 and 2000).
clinicians and pathologists {850}. In addi-
tion, the continued widespread use of the WHO 1980 WHO 2000 WHO 2010
term “carcinoid,” with its largely incorrect
I Carcinoid 1. Well-differentiated endocrine tumour 1. NET G1 (carcinoid)b
benign connotation, hampered universal
(WDET)a
acceptance of this classification system. 2. Well-differentiated endocrine 2. NET G2b
Taking into account the considerations carcinoma (WDEC)a
stated above, the European Neuroen- 3. Poorly differentiated endocrine 3. NEC (large cell or small cell type)b,c
docrine Tumor Society (ENETS) has carcinoma/small cell carcinoma (PDEC)
recently proposed two complementary
classification tools – a grading classification II Mucocarcinoid 4. Mixed exocrine-endocrine 4. Mixed adenoneuroendocrine
and a site-specific staging system {2684, III Mixed forms carcinoid- carcinoma (MEEC) carcinoma (MANEC)
2685}. The intention was to improve the adenocarcinoma
WHO 2000 classification by strengthening IV Pseudotumour lesions 5. Tumour-like lesions (TLL) 5. Hyperplastic and preneoplastic
its appreciation of the following concepts: lesions
(1) tumour heterogeneity, i.e. tumours
differ according to the site of origin; (2) {1106, 3013, 3516}
G, grade (for definition, see text); NEC, neuroendocrine carcinoma; NET, neuroendocrine tumour.
tumour differentiation i.e. tumours differ a
The difference between WDET and WDEC was defined according to staging features in the WHO 2000
according to tumour cell differentiation
classification. G2 NET does not necessarily translate into WDEC of the WHO 2000 classification.
status; and (3) malignancy, i.e. long-term b
Definition in parentheses for the International Classification of Diseases for Oncology (ICD-O) coding.
follow-up indicates that NETs as a cate- c
“NET G3” has been used for this category but is not advised, since NETs are by definition well-differentiated.
gory are malignant.
Site-specific staging system number of mitoses (< 20 per 10 HPF); Reporting of NETs
Grading is combined with a site-specific grade G1 and G2 are defined according Minimum requirements for the reporting of
staging system to improve prognostic to proliferation fraction and histology. This NETs are the exact site and size and the
strength. Since the grading and staging definition encompasses neoplasms termed distance from the resection margins (for
schemes are still evolving, it is expected “carcinoid tumour” in the WHO 2000 clas- resection specimens; see specific chap-
that the grade definitions as well as site- sification {3013, 3516} (Table 1.03). ters for site-specific requirements) {1599,
specific definitions of TNM (tumour, node, 1608}.
metastasis) stage {2996} may need ad- Definition of neuroendocrine carcinoma Microscopically, the number of mitoses
justment in the future, following accumu- (NEC) counted per 10 HPF, the number of HPF
lation of additional follow-up or molecular A NEC is a poorly differentiated, high- assessed and the Ki67 index are essential.
data. We feel that the introduction of an grade malignant neoplasm composed of Assessment of endocrine function should
approach that combines the classification small cells or large to intermediate cells, be provided upon specific clinical request.
of grade and stage provides a framework sometimes with organoid features resem- The diagnosis should contain: (1) the
that can be applied to NETs in all body bling NET, diffusely expressing the general classification of the lesion (NET or NEC);
organs. Furthermore, distinction of grading markers of neuroendocrine differentiation (2) the grade (G1, G2 or G3); (3) the rele-
and staging allows prognostically relevant (diffuse expression of synaptophysin; faint vant TNM stage (for resection specimens;
grading information to be applied to NETs or focal staining for chromogranin A), with see specific chapters); and (4), upon spe-
in metastatic sites whereas, previously, all marked nuclear atypia, multifocal necrosis cific request the cell type and functional
such NETs were grouped together in the and a high number of mitoses (> 20 per activity. One may add in parentheses the
classification system. The TNM staging 10 HPF); high grade (G3) defined accord- WHO 2000 definitions according to stag-
classifications are presented in each rel- ing to the proliferation fraction and histol- ing (well-differentiated endocrine tumour
evant chapter, together with other histo- ogy. This definition refers to neoplasms [WDET], well-differentiated endocrine car-
pathological variables with recognized previously classified as small cell carcinoma, cinoma [WDEC] or poorly differentiated
prognostic value. In addition, the WHO 2010 large cell (neuro)endocrine carcinoma, endocrine carcinoma [PDEC]).
classification system reports in brackets or poorly differentiated (neuro)endocrine Finally, the suffix “oma” following the
the WHO 2000 definitions linked to the carcinoma {1106, 3013} (Table 1.03). name of a hormone (e.g. somatostatinoma,
codes for the International Classification gastrinoma) is only appropriate when
of Disease Oncology (ICD-O) {904A} Definition of mixed adenoneuroendocrine there is a clinical syndrome related to
(Table 1.03). carcinoma (MANEC) excess production of that hormone. In
MANECs have a phenotype that is mor- case of immunohistochemical evidence
Definition of neuroendocrine neoplasms phologically recognizable as both gland- only, terms such as somatostatin-producing
Definition of neuroendocrine tumour (NET) forming epithelial and neuroendocrine, NET or gastrin-producing NET are not
A NET is defined as a well-differentiated, and are defined as carcinomas since both encouraged; rather, the staining result
neuroendocrine neoplasm composed of components are malignant and should be may be apended to the broad NET diag-
cells with features similar to those of the graded. A component of squamous cell nostic category (e.g. NET with immuno-
normal gut endocrine cell, expressing carcinoma is rare. Arbitrarily, at least 30% histochemically demonstrated gastrin
general markers of neuroendocrine differ- of either component should be identified production).
entiation (usually diffuse and intense to qualify for this definition. The identifica-
chromogranin A and synaptophysin) and tion in adenocarcinoma of scattered
hormones (usually intense but not neces- neuroendocrine cells by immunohisto-
sarily diffuse) according to site, with mild- chemistry does not qualify for this definition.
to-moderate nuclear atypia and a low

CHAPTER 2
Tumours of the oesophagus
Squamous cell carcinoma
Adenocarcinoma
Neuroendocrine neoplasms
Lymphoma
Mesenchymal tumours
Secondary tumours and melanoma

WHO classificationa of tumours of the oesophagus

Epithelial tumours Mesenchymal tumours
Premalignant lesions Granular cell tumour 9580/0
Squamous Haemangioma 9120/0
Intraepithelial neoplasia (dysplasia), low grade 8077/0* Leiomyoma 8890/0
Intraepithelial neoplasia (dysplasia), high grade 8077/2 Lipoma 8850/0
Glandular Gastrointestinal stromal tumour 8936/3
Dysplasia (intraepithelial neoplasia), low grade 8148/0* Kaposi sarcoma 9140/3
Dysplasia (intraepithelial neoplasia), high grade 8148/2 Leiomyosarcoma 8890/3
Melanoma 8720/3
Carcinoma Rhabdomyosarcoma 8900/3
Squamous cell carcinoma 8070/3 Synovial sarcoma 9040/3
Adenocarcinoma 8140/3
Adenoid cystic carcinoma 8200/3 Lymphomas
Adenosquamous carcinoma 8560/3
Basaloid squamous cell carcinoma 8083/3 Secondary tumours
Mucoepidermoid carcinoma 8430/3
Spindle cell (squamous) carcinoma 8074/3
Verrucous (squamous) carcinoma 8051/3
Undifferentiated carcinoma 8020/3
Neuroendocrine neoplasmsb
Neuroendocrine tumour (NET)
NET G1 (carcinoid) 8240/3
NET G2 8249/3
Neuroendocrine carcinoma (NEC) 8246/3
Large cell NEC 8013/3
Small cell NEC 8041/3
Mixed adenoneuroendocrine carcinoma 8244/3
___________________________________________________________
a
The morphology codes are from the International Classification of Diseases for Oncology (ICD-O) {904A}. Behaviour is coded /0 for benign tumours, /1 for
unspecified, borderline or uncertain behaviour, /2 for carcinoma in situ and grade III intraepithelial neoplasia, and /3 for malignant tumours.
b
The classification is modified from the previous (third) edition of the WHO histological classification of tumours {691} taking into account changes in our understanding
of these lesions. In the case of neuroendocrine neoplasms, the classification has been simplified to be of more practical utility in morphological classification.
* These new codes were approved by the IARC/WHO Committee for ICD-O at its meeting in March 2010.
16 Tumours of the oesophagus

TNM classificationa of carcinoma of the oesophagus

T - Primary tumour Prognostic grouping
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour Squamous cell carcinomac
Tis Carcinoma in situ/high-grade dysplasia
T1 Tumour invades lamina propria, muscularis mucosae, or Group T N M Gradec Locationc
submucosa Group 0 Tis 0 0 1 Any
T1a Tumour invades lamina propria or muscularis mucosae Group IA 1 0 0 1, X Any
T1b Tumour invades submucosa Group IB 1 0 0 2, 3 Any
T2 Tumour invades muscularis propria 2, 3 0 0 1, X Lower, X
T3 Tumour invades adventitia Group IIA 2, 3 0 0 1, X Upper, middle
T4 Tumour invades adjacent structures 2, 3 0 0 2, 3 Lower, X
T4a Tumour invades pleura, pericardium, or diaphragm Group IIB 2, 3 0 0 2, 3 Upper, middle
T4b Tumour invades other adjacent structures such as aorta, 1, 2 1 0 Any Any
vertebral body, or trachea Group IIIA 1, 2 2 0 Any Any
3 1 0 Any Any
N - Regional lymph nodes 4a 0 0 Any Any
NX Regional lymph nodes cannot be assessed Group IIIB 3 2 0 Any Any
N0 No regional lymph-node metastasis Group IIIC 4a 1, 2 0 Any Any
N1 Metastasis in 1 to 2 regional lymph nodes 4b Any 0 Any Any
N2 Metastasis in 3 to 6 regional lymph nodes Any 3 0 Any Any
N3 Metastasis in 7 or more regional lymph nodes Group IV Any Any 1 Any Any
M - Distant metastasis
M0 No distant metastasis Adenocarcinoma
M1 Distant metastasis
Group T N M Graded
Group 0 Tis 0 0 1
Anatomic stage grouping – All carcinomasb Group IA 1 0 0 1, 2, X
Group IB 1 0 0 3
Stage T N M 2 0 0 1, 2, X
Stage 0 Tis N0 M0 Group IIA 2 0 0 3
Stage IA T1 N0 M0 Group IIB 3 0 0 Any
Stage IB T2 N0 M0 1, 2 1 0 Any
Stage IIA T3 N0 M0 Group IIIA 1, 2 2 0 Any
Stage IIB T1, T2 N1 M0 3 1 0 Any
Stage IIIA T4a N0 M0 4a 0 0 Any
T3 N1 M0 Group IIIB 3 2 0 Any
T1, T2 N2 M0 Group IIIC 4a 1, 2 0 Any
Stage IIIB T3 N2 M0 4b Any 0 Any
Stage IIIC T4a N1, N2 M0 Any 3 0 Any
T4b Any N M0 Group IV Any Any 1 Any
Any T N3 M0
Stage IV Any T Any N M1
_____________
a
{762, 2996}
b
The TNM classification and stage grouping for oesophageal GISTs can be found on page 47.
c
Other carcinomas, apart from adenocarcinomas, can be grouped by the scheme for squamous cell carcinoma.
d
X, value unknown.
A help desk for specific questions about the TNM classification is available at http://www.uicc.org.
Classification 17
Squamous cell carcinoma E. Montgomery

J.K. Field
of the oesophagus P. Boffetta
Y. Daigo
M. Shimizu
T. Shimoda
Definition most of China (with the exception of approaches that of never-smokers within
Squamous cell carcinoma (SCC) of the southern provinces such as Hunan, 10–20 years. Smoking black tobacco,
oesophagus is a malignant epithelial Guangxi, Guizhou and Yunnan), regions of high-tar and hand-rolled cigarettes and
tumour with squamous-cell differentiation, central Asia, northern India, and southern pipes might exert a stronger effect than
microscopically characterized by keratino- Europe {634}. In areas with a high risk of smoking other products. Chewing tobacco-
cyte-like cells with intercellular bridges developing cancer of the oesophagus, containing products is an important risk
and/or keratinization. SCC is the predominant histological type. factor in India and southern Africa, but is
It has been suggested that ethnic factors of unconfirmed relevance in central Asia.
ICD-O codes are involved in susceptibility to this cancer; In the latter region, use of opium (smoking
Intraepithelial neoplasia (dysplasia) populations at higher risk in central Asia and eating) might have (or at least might
Low grade 8077/0 are of Turkish or Mongolian (not Cau- have in the past) contributed to the high
High grade 8077/2 casian) origin, and rates in African-Amer- incidence of this cancer.
Squamous cell carcinoma 8070/3 icans are two- to threefold those in Alcohol. Alcohol consumption is another
Basaloid squamous cell carcinoma Caucasian Americans, regardless of sex. important risk factor for oesophageal SCC
8083/3 Incidence rates are 2–10 times higher in {293}. It is unclear whether there are differ-
Spindle cell (squamous) carcinoma men than in women. In many high-risk ences in the carcinogenic potency of
8074/3 areas, a decrease in the incidence of oeso- various alcoholic beverages. It has been
Undifferentiated carcinoma 8020/3 phageal SCC has occurred during recent suggested that there is a reduction in the
Verrucous (squamous) carcinoma decades, in tandem with a sharp increase excess risk of oesophageal SCC after
8051/3 in oesophageal adenocarcinomas in low- cessation of alcohol drinking, but only after
risk populations (northern Europeans and 15–20 years. The effect of alcohol is inde-
Epidemiology Caucasians in the USA). pendent from that of tobacco, but the
The geographical distribution of oeso- interaction between the two exposures is
phageal cancer is characterized by wide Etiology synergistic. Together, tobacco-smoking
variations within relatively small areas. Tobacco. Tobacco-smoking is a major risk and alcohol consumption account for
High rates (> 50 per 100 000 population) factor for oesophageal SCC {285}. The in- > 90% of cases of oesophageal SCC in
are recorded in men and women in the creased risk in heavy smokers, relative to western Europe and North America; how-
north of the Islamic Republic of Iran and nonsmokers, is of the order of four- to ever, this proportion is lower in developing
various provinces of eastern China, eightfold. A strong dose–risk relationship countries, particularly in selected areas of
(Henan, Jiangsu, Shanxi), in certain areas has been shown for smoking duration and Asia and South America where risk is very
of Kazakhstan and among men from Zim- average consumption. Quitting smoking high.
babwe. Intermediate rates in men (10–50 substantially reduces the risk of oeso- Hot beverages. Intake of hot maté, an
per 100 000 population) occur in eastern phageal cancer: the relative risk declines herbal beverage, is an important risk
Africa, southern Brazil, the Caribbean, within 5 years after cessation and factor for this neoplasm in northern
A B
Fig. 2.01 A Age-standardized incidence (per 100 000) of oesophageal cancer in men. Numbers on the map indicate regional average values {842A}. B Selected highest age-standardized
incidence (per 100 000) of oesophageal cancer in men (1998–2002) {842}.

Fig. 2.02 Macroscopic classification of squamous cell carcinoma of the oesophagus. From: Japanese Esophageal Cancer Society, Japanese Classification of Esophageal Cancer,
10th edition, 2009 {1388}.
Argentina, southern Brazil and Uruguay. Other factors. Oesophageal cancer is Endoscopy and chromoendoscopy
The effect appears to relate to the high related to ionizing radiation, particularly in Superficial oesophageal cancer is com-
temperature of this beverage: studies women who have undergone radiother- monly observed as a slight elevation or
from other areas suggest that intake of hot apy for breast cancer. shallow depression on the mucosal
beverages (e.g. hot tea in the Islamic Other environmental agents that are surface, a minor morphological change
Republic of Iran, Japan and Singapore; hot suspected but not proven to cause oeso- compared with advanced cancer.
coffee in Puerto Rico; and hot drinks or phageal cancer are infection by human Macroscopically, three types can be
soups in China, Hong Kong Special papilloma virus (HPV) and combustion distinguished: polypoid, flat, and ulcerated.
Administrative Region) increases the risk fumes. Chromoendoscopy using toluidine blue or
of oesophagitis and oesophageal SCC, Patients with Plummer-Vinson syndrome, Lugol iodine spray may be of value.
although the evidence is less consistent a sideropenic dysphagia caused by Toluidine blue, a metachromatic stain from
than for maté. deficiency of iron, riboflavin and other the thiazine group, has affinity for RNA and
Dietary factors. Dietary factors probably vitamins, show an increased incidence of DNA, and stains areas that are richer in
play a role in the etiology of oesophageal oesophageal and hypopharyngeal can- nuclei than the normal mucosa. Lugol
SCC {3548}. Low intake of fresh fruits and cers. The risk of oesophageal cancer is solution reacts with glycogen in normal
vegetables, fresh or frozen meat or fish, also increased among patients with squamous epithelium, whereas precancer-
and dairy products and high intake of coeliac disease. Patients with achalasia ous and cancerous lesions (but also
barbecued meat may all increase the risk; are also at increased risk for carcinoma inflamed areas and gastric heterotopia) are
however, the available data do not allow {1371, 1794, 3677}. not stained. However, superficially invasive
establishment of a preventive role of carcinomas cannot be clearly recognized
specific micronutrients, and prevention Localization by simple endoscopy. A newer technique
trials with retinol, riboflavin, selenium, Oesophageal SCC is located most com- called endocytoscopy is based on the tech-
vitamin E and zinc have failed to show a monly in the middle third followed by the nology of light-contact microscopy and can
benefit. lower and upper third, respectively, of the be used together with vital staining, allowing
In several areas of China, intake of pickled oesophagus {1832, 2938}. real-time assessment of nuclei, reducing the
vegetables has been associated with an number of biopsies required for diagnosis
increased risk of oesophageal SCC. The Clinical features {1676}. Confocal endomicroscopy, in which
active carcinogens might be mycotoxins The most common symptoms of advanced a confocal microscope is affixed to an
or N-nitroso compounds. Mycotoxins, oesophageal cancer are dysphagia, weight endoscope, also can be used to improve
including fumonisin B1, have been loss, retrosternal or epigastric pain, and targeting of biopsy sites {688, 2508}. Narrow-
detected in mouldy corn from high-risk regurgitation caused by strictures {798}. band imaging has also been used to facili-
areas in China and southern Africa. In Superficial SCC usually has no specific tate the detection of early lesions {1684}.
Japan, eating bracken fern has been symptoms, but is sometimes associated Endoscopic ultrasonography is used to
associated with an elevated risk of oeso- with a tingling sensation and, therefore, is evaluate the depth of tumour infiltration and
phageal cancer. sometimes detected during endoscopy of para-oesophageal lymph-node involvement
the upper gastrointestinal tract {791, 3152}. {2046, 2535}. Oesophageal carcinoma often
Squamous cell carcinoma 19

the ulcerative type described in the Ming

classification. Type 4, which is the least
common, is characterized by wide intra-
mural infiltration of tumour cells with only
a small mucosal defect or ulceration and
thickness and stiffness of the oeso-
phageal wall. Type 5 is an unclassified
type showing mixed patterns.
Tumour spread and staging

Oesophageal SCC invades both horizon-
tally and vertically. When invasion is
restricted to the mucosa or the submucosa,
irrespective of the presence of regional
lymph-node metastases, the lesion is
referred to as “superficial oesophageal
carcinoma” {294, 3170}. The term “early
oesophageal carcinoma” is also used in
China and Japan, and is defined as intra-
mucosal carcinoma regardless of the
A B presence of lymph-node metastases
Fig. 2.03 Squamous cell carcinoma of the oesophagus, superficial type (subtype 0-IIc according to the guidelines of the {1038, 3170}. In several studies from
Japanese Esophageal Society). A Fresh specimen: slight mucosal depression with irregular margin. B With Lugol iodine Japan, superficial carcinomas accounted
solution, the carcinoma remains unstained. for 10–20% of all resected carcinomas,
whereas in North America and European
presents on endosonography as a circum- type (which is early stage) and advanced countries, superficial carcinomas are
scribed or diffuse wall-thickening with a type. Superficial type (0 type) indicates that much less frequently reported {905}.
predominantly echo-poor or echo-inhomo- tumour invasion limited to the mucosa or The term “advanced oesophageal carci-
geneous pattern. As a result of tumour submucosa, and advanced type (types 1–5) noma” is used for a tumour that invades
penetration through the wall and into sur- extends into and beyond the muscularis beyond the muscularis propria.
rounding structures, the endosonographic propria {1388}. The superficial type is sub- The TNM (tumour, node, metastasis)
wall layers are destroyed. classified as follows: 0-I (protruding type) system used by the American Joint
is polypoid or plaque-like; 0-II (superficial
Computed tomography and magnetic and flat type) is either slightly elevated
resonance imaging (subtype 0-IIa), completely flat (subtype
In advanced carcinomas, computed tomo- 0-IIb), or slightly depressed (subtype 0-IIc).
graphy (CT) and magnetic resonance Type 0-III is described as a superficial and
imaging (MRI) give information on local and excavated type. Type 0-II is often an
systemic spread. Tumour growth is charac- obscure or occult lesion {294} that shows
terized as swelling of the oesophageal wall, unstained areas using Lugol iodine solution.
with or without direct invasion to surrounding Type 0-I and 0-II lesions can be managed
A
organs {2549}. Lymph-node enlargement by endoscopic mucosal resection or endo-
can be assessed. Three-dimensional CT or scopic submucosal dissection {1697}.
MRI images may effectively demonstrate For the classification of advanced oeso-
lesions of stage T2, T3 and T4, but not T1. phageal SCC, Ming has proposed three
The combination of the metabolic information major types: fungating, ulcerative and
from 18-fluoro-2-deoxyglucose-positron infiltrating {2084}. On the other hand, the
emission tomography (FDG-PET) with the Japanese guidelines for clinical and B
anatomical information from CT in inte- pathological studies of carcinoma of the
grated PET/CT scanners can be valuable oesophagus propose the following types:
for staging oesophageal carcinoma by type 1: protruding; type 2: ulcerative
combining metabolic and anatomical localized; type 3: ulcerative infiltrating;
information in a single imaging study {872, type 4: diffuse infiltrating; and type 5:
2104, 2710}. unclassified. Type 1 has a predominantly C
exophytic growth pattern, while type 2 is
Fig. 2.04 Macroscopic appearance of squamous cell
Macroscopy well-demarcated and shows an intramural
carcinoma of the oesophagus (cut surfaces). A Type 0-I
The gross appearance of oesophageal growth pattern and central surface ulcera- (superficial, protruding). B Type 2 (advanced), ulcerative
SCC varies according to the depth of in- tion. Type 3 has as an ill-defined tumour localized. C Type 4 (advanced), diffuse infliltrating.
vasion, and is classified by the Japanese margin with intramural extension and deep Classified according to the guidelines of the Japanese
Esophageal Society into major superficial ulceration. Types 2 and 3 correspond to Esophageal Society.

A B
Fig. 2.05 Squamous cell carcinoma of the oesophagus with intramural invasion. A Low-power view: intramural invasion is evident. B Medium-power view: displaying a well- to
moderately differentiated carcinoma.
Committee on Cancer (AJCC) and the or upper mediastinal lymph nodes, while invasion {2806}. SCC invades the muscularis
International Union against Cancer carcinomas of the middle and the lower propria and extends into the adventitia,
(UICC) is the most widely accepted staging third metastasize to the lower mediastinal from where it may spread to adjacent
system {762, 2996}. The 2009 seventh or perigastric lymph nodes {56, 112}. Skip- tissues or organs, such as the trachea,
edition AJCC (but not the UICC) has node metastasis can be encountered. bronchi, aorta, lung, and pericardium; it
incorporated prognostic groupings in The most common sites for haematogenous may cause mediastinitis, pleural fistulas,
addition to purely anatomical ones for metastases include the liver, lungs, adren- and tracheo-oesophageal fistulas {3022}.
staging oesophageal SCC. These include als and kidneys, and occasionally the Advanced oesophageal SCC spreads
the addition of grade (G1–G4; well- central nervous system (CNS) {1971, 3022}. either with an expansive or infiltrative
differentiated, moderately differentiated, Treatment groups. Following clinical growth pattern. The former pattern com-
poorly differentiated, and undifferentiated, staging, two treatment groups are con- prises a solid mass with a smooth, broad
respectively) and location in the oesophagus sidered. One is for potentially curative edge, while the latter contains isolated
(upper, middle or lower third) as well as treatment (e.g. surgery, radiotherapy, multi- tumour cells or small nests with an irregular
depth of invasion, based on data that show modal therapy) for locoregional disease, invasion front. Occasionally, a desmoplastic
that squamous carcinomas in the upper and the other is palliative treatment; e.g. stromal reaction or prominent lymphocytic
and middle oesophagus and those that radio- and/or chemotherapy; for advanced infiltration can be observed {527}.
are not well-differentiated are more SCC {1031}. Oesophageal early-stage Additionally, invasive SCC can spread
aggressive than those in the lower oeso- SCC and high-grade intraepithelial into adjoining non-neoplastic squamous
phagus or are well-differentiated. The num- neoplasia (dysplasia) can be treated by surface epithelium, ducts, or even gastric
ber of positive nodes determines the N endoscopic mucosal resection or endo- mucosa in a pattern that appears similar
stage rather than the location of involved scopic submucosal dissection {2404, 2946}. to that of intraepithelial neoplasia. This
nodes. “Tis” is defined as “high-grade dys- pattern has been termed “intraepithelial
plasia” by the AJCC, which is considered Histopathology spread” {3167, 3172}. In some instances,
equivalent to carcinoma in situ and non- Oesophageal SCC is defined as a squa- the intraepithelial spread involves only the
invasive carcinoma. In both the UICC and mous neoplasm that penetrates the epithe- basal half of the replaced non-neoplastic
AJCC systems, T1 and T4 have been sub- lial basement membrane into the lamina squamous epithelium {3167}.
divided as of 2009 to provide additional propria or deeper tissue layers. Depending
information. on tumour grade, variable amounts of
Metastases are usually to regional lymph keratinization are seen, manifested by cells
nodes, found in about 60% of patients at showing brightly eosinophilic opaque cyto-
the time of diagnosis. The frequency of plasm. Invasion into the lamina propria is
lymph-node metastasis correlates with initiated by the proliferation of rete-like
depth of invasion (about 5% for intra- projections of neoplastic squamous epi-
mucosal carcinoma and about 40% for thelium with pushing borders. Both hori-
submucosal carcinoma) {112, 1823}. zontal and vertical spread is observed.
Intramural metastasis (also called intra- Tumours commonly penetrate vertically
mural lymphatic spread) is common, through the oesophageal wall and invade
being seen in up to 16% of cases {1497, intramural lymphatic channels and veins.
1696}. It is associated with advanced Invasion of mucosal and submucosal lym-
stage and shortened survival. phatic channels is also common, and the Fig. 2.06 Verrucous (squamous) carcinoma of the
Tumours of the upper third of the oeso- frequency of lymphatic and blood-vessel oesophagus: highly differentiated keratinized cells with
phagus commonly spread to the cervical invasion increases with increasing depth of minimal cytological atypia and a pushing pattern of invasion.

osseous, cartilaginous and skeletal-muscle

differentiation {1115}. In immunohisto-
chemical and ultrastuctural studies, most
cases display various degrees of epithelial
differentiation and a transition between
epithelial and sarcomatous differentiation.
However, there remains a possibility of two
independent malignant cell clones {1763}.
Basaloid squamous cell carcinoma

A B Basaloid SCC is a distinct, unusual variant
that occurs more commonly in the upper
Fig. 2.07 Spindle cell carcinoma of the oesophagus. A The large polypoid mass of the lesion is surrounded by extensive
intraepithelial neoplasia (arrows). B The transition from an area of conventional cells to an area of spindle cells. aerodigestive tract {187, 3298}. It is more
common in older men, who present with
dysphagia. Microscopically, it consists of
basaloid cells with oval to round nuclei,
open pale chromatin, and scant baso-
philic cytoplasm. It is arranged in solid or
cribriform lobules with comedonecrosis
{1621A}. Areas of squamous intraepithelial
neoplasia or conventional SCC are com-
monly observed {3429}. Adenoid cystic
carcinoma and basaloid squamous cell
carcinoma should be distinguished: ade-
noid cystic carcinoma is less aggressive
{1838}.
Precursor lesions
The development of oesophageal SCC is
A thought to be a multistep process, progress-
ing from normal squamous epithelium,
intraepithelial neoplasia (dysplasia), to
invasive carcinoma {616, 661, 2608}.
Most data regarding squamous precursor
lesions originate from the Far East, where the
term “intraepithelial neoplasia” is favoured
over “dysplasia”. The term “intraepithelial
neoplasia” is thus used herewith.
Intraepithelial neoplasia is classified as low-
grade (LGIEN) or high-grade (HGIEN).
B C Epidemiologically, LGIEN is associated with
Fig. 2.08 Basaloid squamous cell carcinoma of the oesophagus showing a solid growth pattern. A Solid growth pattern. a low risk of invasive carcinoma, whereas
B Comedo-like necrosis. C Small gland-like structures. HGIEN is associated with a high risk {661,
2946}. Morphologically, intraepithelial neo-
Verrucous (squamous) carcinoma Spindle cell (squamous) carcinoma plasia shows both architectural and
Verrucous carcinoma is an extremely rare, Spindle cell carcinoma is an SCC with a cytological abnormalities. Architectural
distinct, highly differentiated variant of variable spindle-cell component. Synonyms abnormalities include cellular disorganiza-
SCC. It is usually associated with chronic include carcinosarcoma, sarcomatoid tion/loss of polarity and downward growth
oesophagitis, achalasia, diverticular carcinoma, pseudosarcomatous SCC, of the epithelium {2945, 3168}. Cytological
disease, or gastro-oesophageal reflux polypoid carcinoma, metaplastic carci- abnormalities include hyperchromasia,
disease {1502}. Grossly, it is an exophytic, noma, SCC with a spindle-cell component, increased nucleus : cytoplasm ratio and
papillary, or warty mass. Microscopically, and carcinoma with mesenchymal stroma mitotic activity. In LGIEN, the abnormalities
it consists of highly differentiated keratin- {1763}. Grossly, it is polypoid, usually are confined to the lower half of the epithe-
ized cells with minimal cytological atypia. involving the middle and lower third of the lium. In HGIEN, the abnormalities involve the
Papillary projections are prominent. The oesophagus. Microscopically, it is biphasic upper half, and cytological alterations are
tumour shows a pushing rather than an with epithelial and spindle cells. The greater than those in LGIEN. In the Far East,
infiltrating margin {2413}, growing slowly epithelial element is typically well- to mod- the terms “squamous cell carcinoma in situ”
and invading locally. Metastases are erately-differentiated SCC or exclusively and “noninvasive carcinoma” are used for
uncommon. carcinoma in situ. The spindle-cell compo- HGIEN in which the full thickness of the ep-
nent is usually high-grade. It may show ithelium is involved. {2839, 2842, 2946, 3170}.

Basal cell hyperplasia Undifferentiated carcinoma. This lacks

Basal cell hyperplasia has been defined definite microscopic features of squamous
histologically as involvement of > 15% of differentiation. The tumour cells form nests
the thickness of the squamous epithelium and sheet-like arrangements. Immunohisto-
{2198}. The upper limit of the basal cell chemically, tumours express squamous
layer can be defined as the level above epithelial markers. Such neoplasms must be
which the nuclei are separated by a dis- distinguished from neuroendocrine/small
tance greater than the nuclear diameter cell NEC. Immunohistochemically, undif-
{863}. Basal cell hyperplasia is a reactive ferentiated carcinoma is negative for neuro-
change in response to inflammation. endocrine markers. A
Endoscopically, this lesion does not retain
Lugol iodine applied to the mucosa at Genetic susceptibility
endoscopy {2198, 2232}. The presence of Familial predisposition to oesophageal
multiple unstained areas in the mucosa is cancer has been studied predominantly in
a risk factor for multicentric SCCs of the association with focal non-epidermolytic
head and neck {3643}. In the oesophagus, palmoplantar keratoderma (NEPPK or
several studies have shown that some tylosis) {1262, 2156, 2157}. This autosomal
patients who have multiple unstained dominantly inherited disorder of the palmar
mucosal areas also have genetic poly- and plantar skin surfaces segregates with
morphisms {3643}. However, the role of oesophageal cancer in three pedigrees,
basal cell hyperplasia in the development two of which are extensive {784, 1169, B
of SCC is controversial. 3077}. The causative locus is known as the Fig. 2.09 Intraepithelial neoplasia of the oesophagus.
tylosis oesophageal cancer (TOC) gene A Low-grade (LGIEN): an increased number of basal cells
Grading and maps to 17q25 between the anony- and mild cytological atypia are displayed. B High-grade
Grading oesophageal SCCs is traditionally mous microsatellite markers D17S1839 (HGIEN): architectural disarray, loss of polarity and
based on mitotic activity, nuclear atypia and D17S785 {1516, 2690, 2691}. cellular atypia (much greater than in A) are evident.
and degree of squamous differentiation. The genetic defect is thought to be in a
However, although incorporated into the molecule involved in the physical structure however, some authors suggest that, as the
2009 AJCC prognostic groupings {762}, of stratified squamous epithelia, whereby TOC pathology occurs in epithelia, it is
grading is controversial as a means of loss of gene function may alter oesophageal likely that an epithelial–mesenchymal inter-
determining prognosis {2804}. integrity, thereby increasing susceptibility to action is involved in this disease.
Well-differentiated carcinoma. There is environmental mutagens. Several candi- The genomic region containing the TOC
prominent keratinization and a minor date genes, including envoplakin (EVPL), gene also associates with sporadic oeso-
component of nonkeratinizing basal-like integrin b4 (ITGB4) and plakoglobin, have phageal SCCs {1372, 2895, 3411}, adeno-
cells. The keratinized component shows been excluded as the TOC gene following carcinoma of the oesophagus {751} and
squamous pearl formation akin to the integration of the genetic and physical primary breast cancers {918} in studies of
appearance of non-neoplastic squamous maps of this region {2692}. loss of heterozygosity (LOH). The CYGB
epithelium (normal oesophageal squamous Linkage and haplotype analysis have gene also plays a role in lung and head
epithelium does not keratinize). Tumour mapped the TOC locus to a 42.5 kb region and neck cancer {2157, 2912, 3569}.
cells are arranged in sheets and mitotic that contains the promoter of one gene In Asians, polymorphisms in ALDH1B1 and
counts are typically low compared with (FLJ22341), the entire cytoglobin gene ALDH2, the genes encoding aldehyde
those for moderately and poorly differen- (CYGB) and the 5’ end of an uncharacter- dehydrogenase, are associated with oeso-
tiated tumours. ized gene that completely overlaps CYGB phageal SCC {340, 629}. The effects of
Moderately differentiated SCC. This is the in the opposite orientation {1739}. Sequenc- these polymorphisms are synergistic with
most common histological type, demon- ing of genomic DNA from affected and alcohol use and smoking. Additionally, some
strating variable histological features unaffected TOC family members has polymorphisms in ALDH1, result in accu-
ranging from parakeratotic to poorly kera- identified two putative disease-specific mulation in acetaldehyde, which causes
tinized lesions. Generally, pearl formation alterations, but they are located in regions flushing upon ingestion of alcohol (“Asian
is absent. However, definite histological of no known function. However, it has been flush”) {340} in about one third of east Asians
criteria for moderately differentiated SCC shown that the expression of CYGB in (Chinese, Japanese and Koreans).
are not established and grading is thus oesophageal biopsies from tylotic patients
affected by inter-observer variability. is reduced by 70% compared with normal Molecular pathology
Poorly differentiated SCC. This consists oesophagus. As this is an autosomal Mutation in the TP53 gene (17p13) is an
predominantly of basal-like cells forming disease, it has been argued that these re- early event, sometimes detectable in
large and small nests with frequent central sults exclude haploinsufficency as a mech- intraepithelial neoplasia. The frequency
necrosis. The nests consist of sheets or anism for the disease and suggests a novel and type of mutation varies by geographic
pavement-like arrangements of tumour trans-allele interaction. The mechanism by region, suggesting that some TP53 muta-
cells, and are occasionally punctuated by which the downregulation of CYGB may tions may occur as the result of exposure
small numbers of parakeratotic or keratin- cause the TOC phenotype is unclear, as to exogenous risk factors. However, even
ized cells. the function of CYGB is unknown {2030}; in SCCs from western Europe, TP53 does

not show the same tobacco-associated surgical resection [R0] or radiological and DNA ploidy. Aneuploidy of cancer cells,
mutations as in lung cancers {2134}. endoscopic response to chemoradiation as determined by flow cytometry or image
Amplification of cyclin D1 (11q13) occurs therapy), and morphological and molecular analysis, has been identified in 55–95% of
in 20–40% of SCCs and is frequently features of the tumour {278, 1858}. oesophageal SCCs {1591}. Patients with
detected in cancers that retain expression Morphological factors. The extent to which diploid tumours usually survive longer
of the Rb protein, supporting the notion the carcinoma has spread is the most than those with aneuploid tumours; how-
that these two factors cooperate within the important prognostic factor; the TNM ever, a prognostic impact independent of
same pathway {1428}. Inactivation of classification is the most widely-used tumour stage (TNM) has not been
CDKN2A, either by homozygous deletion staging system. confirmed in the majority of studies {729,
or de novo methylation, appears to be Staging. All studies indicate that the 2010, 1591, 1823}.
associated with advanced cancer. Other depth of invasion and the presence of Extent of resection. The frequency of
potentially important genetic alterations nodal or distant metastases are inde- locoregional recurrence is negatively
include transcriptional inactivation of the pendent predictors of survival {1305, correlated with the distance of the primary
FHIT gene (fragile histidine triad, a pre- 1496, 1905}. In particular, any lymph-node tumour from the proximal resection margin
sumptive tumour suppressor on 3p14) by involvement, regardless of the extent of {1766, 3176}.
methylation of 5’ CpG islands, and deletion the primary tumour, indicates poor prog- Molecular factors. The TP53 gene is
of the TOC gene on 17q25 {2132, 3411}. nosis {1542, 3128, 3152}. Other histopatho- mutated in 35–80% of oesophageal SCCs
Furthermore, analysis of clones on 3p21.3 logical features associated with a poor {2134}. Some studies have indicated a
and 9q32, where frequent LOH occurs in prognosis include vascular and/or lym- negative prognostic influence for nuclear
oesophageal cancer {2152}, led to the phatic invasion {1305, 2806} and an infil- accumulation of p53 {485, 2937}, but this
identification of the novel genes DLEC1 trative growth pattern of the primary has not been observed consistently {575,
(deleted in lung and esophageal cancer-1) tumour {2804}. 1313}. Other potential prognostic factors
and DEC1 (deleted in esophageal cancer-1) Differentiation. Although most (but not all include growth factors and their receptors
{645, 1809, 2306, 3616}. Although the {1196, 1305}) studies have not shown a {1578}, proto-oncogenes (e.g. ERBB2,
function of these genes remains to be significant influence of tumour grade on FGF3/INT2) {1312}, cell-cycle regulators
clarified, reverse-transcriptase-polymerase survival {764, 2699, 2804, 3121}, tumour- (e.g. cyclin D1 {2185, 2951}), tumour-
chain reaction (RT-PCR) experiments grade has nonetheless been incorporated suppressor genes {3166}, redox defence-
indicate that 33–53% of primary oeso- into the 2009 AJCC TNM classification as system components (e.g. metallothionein
phageal cancers lack functional tran- a factor affecting prognostic grouping {762}. and heat-shock proteins {1508}), E-cadherin
scripts, and introduction of DLEC1 or Assessment of early-stage carcinoma for {123}, VEGF {2934} and matrix protein-
DEC1 cDNA into cancer cell lines endoscopic treatment. In many cases, ases {2194, 3278, 3590}. Molecular clas-
suppresses cell growth. Recent evidence early-stage oesophageal SCCs are mod- sification using these single biomarkers
suggests frequent silencing of LRP1B (low erately and poorly differentiated. Well- plus novel markers identified through
density lipoprotein receptor-related protein differentiated early SCC is rare {1388}. genomic and proteomic approaches were
1B) and CRABP1 (cellular retinoic acid Since early-stage carcinomas can often shown to be independent prognostic
binding protein 1) expression by genetic be managed by endoscopic resection or parameters {1201, 1358, 3182, 3334,
and/or epigenetic mechanisms in primary endoscopic submucosal dissection {1388}, 3577}; however, none of the factors tested
oesophageal cancers {3020, 3184}. Am- additional factors can be assessed to so far is indicated for use in clinical practice.
plification of several proto-oncogenes has better stratify risk and identify patients
also been reported: FGF4 (HST1), FGF6 who do not require additional post-
(HST2), EGFR, MYC {2134}. Analyses of endoscopy treatment (surgery or chemo-
genome-wide gene expression profiles radiation) {769, 1387, 2945, 2946}. Lesions
and proteomic approaches have identified that can be managed endoscopically
candidate tumour suppressor genes, include those with: (1) invasion confined to
oncogenes, and cancer-related micro- the mucosa with downward growth from
RNAs {644, 1086, 2602, 3576}. The mech- the epithelium or submucosal invasion to a
anisms by which these various genetic depth of 200 μm or less from the muscu-
events correlate with phenotypical changes laris mucosae {1387}; (2) expansive growth
and cooperate in the sequence of events of neoplastic cells without small nests or
leading to SCC remain unknown. scattered cells infiltrating into stroma; and
(3) no lymphovascular invasion {3155}.
Prognosis and predictive factors Lymphocytic infiltration. Intense lympho-
Overall, the prognosis for oesophageal cytic response to the tumour has been as-
SCC is poor; 5-year survival rates are sociated with a better prognosis {764, 2804}.
about 10%. A cure can only be anticipated Cell proliferation. The cancer-cell prolifer-
in patients with superficial cancer. The ation index, determined immunohisto-
probability of survival depends upon the chemically by antibodies to proliferating
patient’s general health (performance sta- cell nuclear antigen (PCNA) or Ki67 is not
tus, weight loss, haemoglobin level), TNM an independent prognostic factor {1313,
stage at diagnosis, treatment (radicality of 1730, 2803, 3661}.

Adenocarcinoma of the oesophagus J.-F. Fléjou

R.D. Odze
E. Montgomery
P. Chandrasoma
H. Höfler
P. Boffetta
S.J. Spechler
Definition In addition to increases in incidence, Barrett oesophagus and

A malignant epithelial tumour of the oeso- adenocarcinoma of the oesophagus and gastro-oesophageal reflux
phagus with glandular differentiation. of the oesophagogastric junction share The epidemiological features of adeno-
These tumours arise predominantly from some epidemiological characteristics that carcinoma of the oesophagus and OGJ
columnar (“Barrett”) mucosa in the lower clearly distinguish these neoplasms from match those of patients with known intes-
third of the oesophagus. Rarely, adenosquamous cell oesophageal carcinoma tinal metaplasia in the distal oesophagus,
carcinoma originates from heterotopic and adenocarcinoma of the distal stom- i.e. Barrett oesophagus {3507}, which has
gastric mucosa in the upper oesophagus, ach. These include a high male : female been identified as the single most
or from mucosal and submucosal glands. ratio (between 4 : 1 and 7 : 1) and a important precursor lesion and risk factor
higher incidence among whites and for oesophageal adenocarcinoma, irre-
ICD-O codes groups with higher socioeconomic status spective of the length of the segment with
Dysplasia (intraepithelial neoplasia) {285}. intestinal metaplasia. Intestinal metaplasia
Low grade 8148/0 of the oesophagus develops when the
High grade 8148/2 Etiology squamous oesophageal epithelium is
Adenocarcinoma 8140/3 Hereditary factors replaced by columnar epithelium during
Adenoid cystic carcinoma 8200/3 Although familial association has been the process of healing after repetitive
Adenosquamous carcinoma 8560/3 reported, population-based studies have injury, and is typically associated with
Mucoepidermoid carcinoma 8430/3 shown that the influence of genetic gastro-oesophageal reflux disease (GORD)
factors is limited, consistent with the rapid {3036}. Intestinal metaplasia can be de-
Epidemiology changes in incidence rates observed in tected in most patients with oesophageal
In high-resource countries, the incidence many populations over a very short adenocarcinoma {1557}.
and prevalence of oesophageal adeno- period {1720}. The relative risk of oesophageal adeno-
carcinoma has risen during the last carcinoma in patients with Barrett oeso-
decades of the 20th century {1720}. Pop- phagus is in the order of 30–60 {1720},
ulation-based studies in the United States
of America (USA) and several European
countries indicate that the incidence of
oesophageal adenocarcinoma doubled
between the early 1970s and late 1980s
and continues to increase at a rate of
about 5% per year {285, 1720}. This is
paralleled by rising rates of adenocarci-
noma of the oesophagogastric junction
(OGJ) and of the proximal stomach,
reducing the likelihood that this increase
is attributable to changes in the classifi- A B
cation of anatomically close lesions. In the
early 2000s, the incidence of oeso-
phageal adenocarcinoma was estimated
at 1–5 per 100 000 population per year in
Europe and North America, exceeding
that of squamous cell oesophageal
cancer. The countries with the highest
incidence were the United Kingdom UK),
Australia, the Netherlands and the USA.
Relatively lower rates of incidence are
reported from eastern Europe and Scan- C D
dinavia. In Latin America, Asia and Africa, Fig. 2.10 Endoscopy (A, B) and confocal laser endomicroscopy (C, D) of Barrett oesophagus. A On endoscopy, the
oesophageal adenocarcinoma is uncom- pink metaplastic columnar mucosa extends both circumferentially and with “tongues.” B On narrow band imaging, the
distinction between columnar mucosa and squamous mucosa is enhanced. C Squamous mucosa (the confocal laser
mon, but increases have also been endomicroscope is placed en face on the mucosa). The capillaries are accentuated by fluorescein, administered
reported. intravenously to the patient. D Barrett mucosa without dysplasia. Note the regular cell borders and empty areas within
individual cells (corresponding to goblet cells).
Adenocarcinoma 25
A B
Fig. 2.11 Barrett oesophagus. A Intestinal metaplasia adjacent to squamous epithelium (low power). B Typical metaplastic mucosa with a villiform pattern, and with goblet cells and
columnar cells (high power).
with approximately 5% of patients having in patients with GORD include a markedly individuals of normal weight {1111, 1669}.
a previous diagnosis of Barrett oesophagus increased duration of oesophageal expo- The pathogenetic basis of the association
{747}. A meta-analysis of studies in sure to refluxed gastric and duodenal con- with obesity is not fully elucidated, but
patients with Barrett oesophagus has tents owing to a defective barrier function one of the mechanisms may be through
shown an incidence of oesophageal of the lower oesophageal sphincter and central obesity, which may increase intra-
adenocarcinoma of the order of 6.1 per ineffective clearance function of the tubular abdominal pressure, promoting GORD
1000 person-years, which reduced to 3.9 oesophagus {3067}. Experimental and and Barrett oesophagus {780}.
per 1000 person-years when only high- clinical data indicate that combined
quality studies were considered {3660}. oesophageal exposure to gastric acid and Alcohol
This translates into a life-time risk of about duodenal contents (bile acids and In contrast to squamous-cell oesophageal
10% in these patients. pancreatic enzymes) appears to be more carcinoma, there is no association
The biological significance of so-called detrimental than isolated exposure to between alcohol consumption and oeso-
“ultra-short” Barrett oesophagus or intes- gastric juice or duodenal contents alone phageal adenocarcinoma {285}.
tinal metaplasia just beneath a normal Z {3068}. Combined reflux is thought to
line has yet to be clarified {2251}. Whether increase cancer risk by promoting cellular Diet
adenocarcinoma of the OGJ or proximal proliferation, and by exposing the oeso- The evidence linking specific dietary
stomach is also related to foci of intestinal phageal epithelium to potentially genotoxic factors (including foods that may cause
metaplasia at or immediately below the gastric and intestinal contents, e.g. nitros- the lower oesophageal sphincter to relax
OGJ {1207, 2907, 3033} is discussed in amines {3068}. {3223}) to risk of oesophageal adeno-
Chapter 3. There is need for an evaluation carcinoma is inconsistent {285}.
of the impact of periodic endoscopic Tobacco-smoking
screening of Barrett oesophagus patients Smoking has been identified as another Helicobacter pylori
on mortality from oesophageal adeno- major risk factor for oesophageal adeno- Case–control studies have reported a
carcinoma. carcinoma, the relative risk for ever-smokers reduced risk of oesophageal adenocarci-
Chronic GORD is the usual underlying vs never-smokers being in the order of 2 noma among individuals infected with
cause of the repetitive mucosal injury and {1333}. Tobacco-smoking may account Helicobacter pylori, in particular of CagA
also provides an abnormal environment for as many as 40% of cases. The risk of type {285}. A similar protective association
during the healing process that predis- oesophageal adenocarcinoma remains has been observed for GORD {1048}. The
poses to intestinal metaplasia {3036}. The elevated up to 30 years after smoking mechanism may involve reduction of the
relative risk of oesophageal adenocarci- cessation {3556}, suggesting that tobacco- amount of gastric acid that is refluxed into
noma in persons with recurrent reflux smoking acts through an early-stage the oesophagus.
symptoms, compared with persons with- carcinogenic effect.
out such symptoms, is in the order of 5–10 Medications
{164, 823, 1721, 3555, 3629}. The more Overweight and obesity Several studies have observed an increased
frequent, more severe, and longer-lasting An association between risk of oeso- risk of oesophageal adenocarcinoma
the symptoms of reflux, the greater the phageal adenocarcinoma and overweight following use of medications that lower
risk. In a Swedish study, the risk of oeso- and obesity has been observed in many stomach acidity and relax the gastro-
phageal adenocarcinoma was increased populations and it is considered to be oesophageal sphincter, e.g. H2-receptor
by 40-fold in persons with long-standing causal {3548}. In meta-analyses, the risk antagonists, proton-pump inhibitors, tricyclic
and severe symptoms {1721}. Factors was increased 1.5–1.9-fold among antidepressants, calcium-channel blockers
predisposing for the development of overweight individuals and 2.4–2.8-fold and anti-asthma agents {285}. However,
Barrett oesophagus and adenocarcinoma among obese individuals, compared with the available evidence points towards a

role of the underlying medical conditions. It criteria, a new system for categorizing dysplasia, but instead categorizes epithe-
has been suggested that the use of non- Barrett oesophagus, identify both the lial alterations as negative, indefinite, non-
steroidal anti-inflammatory drugs (NSAIDs) circumferential extent (C) and the maximum invasive low- or high-grade intraepithelial
is protective {1090}, but confounding by extent (M) of Barrett metaplasia {2904}. neoplasia, and invasive neoplasia {2654,
indication may also be responsible for the The risk of developing adenocarcinoma is 2674, 2842}. In the Vienna system, the non-
observed effect in this case. reported to be lower in patients with short- invasive high-grade epithelial neoplasia
segment Barrett oesophagus, than in those category is separated into “high-grade ade-
Localization with long-segment Barrett oesophagus noma/dysplasia”, “noninvasive carcinoma
Adenocarcinoma may occur anywhere in {2905}. (carcinoma in situ)” and lesions considered
a segment of columnar-lined oesophagus. “suspicious for invasive carcinoma”. The
It develops most often (but not always) in Histopathology invasive neoplasia category is separated
areas of mucosa with intestinal metaplasia In North America and parts of Europe, the into intramucosal and submucosal adeno-
(goblet cells) most commonly in the distal diagnosis of Barrett oesophagus is carcinoma {2842}.
region of the columnar-lined segment restricted to columnar epithelium with
{3232}. Adenocarcinoma in a short goblet cells {2354, 3447}. However, some Macroscopy
segment of Barrett oesophagus is easily authorities accept columnar epithelium Grossly, dysplasia may be undetectable
mistaken for adenocarcinoma of the OGJ. without goblet cells as part of the definition or appear as flat, irregular, plaque-like,
Since adenocarcinomas originating from {478, 2675, 2906, 3169}. nodular, polypoid, eroded, or ulcerated
the distal oesophagus may infiltrate the Barrett epithelium shows a variety of cell mucosa {147, 387, 1195, 2136, 2653,
OGJ and carcinoma of the proximal types such as goblet cells (“specialized”), 2654, 3245}. The risk of malignancy is de-
stomach may grow into the distal oeso- mucinous columnar cells, enterocytes, pendent on the macroscopic appearance
phagus, these entities are frequently diffi- Paneth cells, neuroendocrine cells, and of the lesion. For instance, patients with at
cult to distinguish. However, it is now epithelium with mixed features (multi- least one macroscopically detectable
considered that adenocarcinomas that layered epithelium with squamous and lesion are more likely to develop high-
cross the OGJ should be called adeno- columnar features) {997}. The underlying grade dysplasia or cancer {1195}. The
carcinomas of the OGJ, regardless of glands may be mucous, oxyntic or both. presence of mucosal nodules or ulcers
where the bulk of the tumour lies {2963}; it Duplication of the muscularis mucosae is has been associated with a higher risk of
is therefore very likely that a significant a common feature {1827}. high-grade dysplasia or adenocarcinoma
proportion of those OGJ cancers are {387, 2136}. Dysplastic epithelium may
indeed Barrett adenocarcinomas origi- Intraepithelial neoplasia in Barrett appear as a well-defined adenoma-like
nating from a metaplastic oesophageal oesophagus polyp, but these lesions show a high
mucosa (see Chapter 3). General comments association with high-grade dysplasia
Exceptionally, adenocarcinoma also oc- Adenocarcinoma in Barrett oesophagus and adenocarcinoma within adjacent flat
curs in the middle or proximal third of the develops through a progressive sequence mucosa {147, 3245}. Thus, the preferred
oesophagus, in the latter usually from a of morphologically identifiable premalig- term is “polypoid dysplasia arising in Barrett
congenital islet of heterotopic columnar nant lesions termed “dysplasia”. Worldwide, oesophagus” rather than “adenoma” {3245}.
mucosa, present in up to 10% of the there are two classification systems used
population. for dysplasia in Barrett oesophagus: the Histopathology
system proposed by the Inflammatory Dysplasia is diagnosed by the presence
Barrett oesophagus Bowel Disease (IBD) Dysplasia Morphology and degree of cytological and architectural
Symptoms and signs Study Group, which classifies dysplasia atypia {2135, 2353, 2654, 2842}.
Barrett oesophagus as the precursor of as negative, indefinite, or positive (low- or Negative for dysplasia. This term is
most adenocarcinomas is clinically silent high-grade) and the Vienna classification applied to cases that show metaplastic
in up to 90% of cases. The symptomatology system, which does not use the term columnar epithelium, either with or without
of Barrett oesophagus, when present, is
that of GORD {1733, 2896, 3034}.
Endoscopy
The endoscopic analysis of the squamo-
columnar junction aims at the detection of
columnar metaplasia in the distal oesoph-
agus according to anatomical landmarks.
If the length of the columnar lining in this
distal oesophagus is > 3 cm, it is termed
“long-segment” Barrett oesophagus. When
the length is < 3 cm, it is termed “short- A B
segment” Barrett oesophagus. Single or
Fig. 2.12 Dysplasia in Barrett oesophagus. A Low-grade dyplasia. The nuclei are elongated and crowded with mild
multiple finger-like (1–3 cm) protrusions of pleomorphism, while the crypt architecture is relatively preserved. B High-grade dyplasia. The nuclei in the glands are
columnar mucosa are classified as short- enlarged and hyperchromatic and the changes extend to the surface. In the glands and on the surface, the nuclei have
segment type. The Prague C and M lost their polarity.
Adenocarcinoma 27
is modest at best {740}. Previously pub-

lished criteria of intramucosal adenocar-
cinoma include: (1) single cells or small
clusters of compact back-to-back glands
within the lamina propria; (2) a cribriform
or solid pattern of growth with expansion
and distortion of the adjacent crypts; and
(3) a highly distorted/irregular glandular
proliferation not explained by the pres-
ence of preexisting glands. The presence
of necrosis and/or desmoplasia also
favours adenocarcinoma, although these
features are rarely present in carcinomas
limited to the mucosa and, in fact, may not
be present in submucosal invasive
carcinomas either {2409}. Intraluminal
necrosis was shown to be predictive of
carcinoma at the time of resection in one
study {3717}.
Other cases. Some cases of dysplasia
show cuboidal-shaped cells, with round- to
oval-shaped nuclei and high nucleo-
A B cytoplasmic ratio, but without nuclear
Fig. 2.13 Adenocarcinoma in Barrett oesophagus. A Large ulcerated tumour in the lower part of a long-segment Barrett stratification, which has been termed “non-
oesophagus. B Short-segment Barrett oesophagus with an occult intramucosal adenocarcinoma (arrows and inset). adenomatous” dysplasia {2747}. Foveolar
dysplasia, indicating the presence of
neoplastic epithelial cells rich in mucin, is
goblet cells, with regenerative changes. of the cell cytoplasm. The nuclei are rare in Barrett oesophagus. In the early
Regenerating Barrett oesophagus may elongated, enlarged, crowded, hyper- stages of development, dysplasia may be
show a slight degree of crypt budding and chromatic, show an irregular contour, a limited to the crypt bases, without surface
branching, atrophy, and even cystic dense chromatin pattern either with or involvement {1889, 3702}. These cases
change, particularly adjacent to or under- without multiple inconspicuous nucleoli, are often associated with traditional full-
neath ulcers. The nuclei may be slightly en- mild pleomorphism and mild loss of length crypt dysplasia in biopsies else-
larged, hyperchromatic, show prominence polarity, mucin depletion and increased where in the oesophagus.
of nucleoli and mild nuclear stratification, mitoses. The diagnostic reproducibility of dysplasia
particularly at the bases of the crypts. High-grade dysplasia. This is diagnosed is highly dependent on the level of
Indefinite for dysplasia. The “indefinite” by the presence of marked cytological expertise of the observer, and is less
category is used most often where tech- abnormalities and/or significant architec- pronounced at the two extremes of the
nical issues render the interpretation of tural complexity of the glands. Cytological spectrum (negative and high-grade) than
atypia difficult, where atypia approaches abnormalities of high-grade dysplasia it is for lesions in the middle (indefinite
but does not quite attain dysplasia, par- include marked nuclear pleomorphism and low-grade) {2135, 2654}. The American
ticularly when it is related to inflammation and loss of polarity, irregularity of nuclear College of Gastroenterology strongly
and ulceration, and atypical (dysplasia- contour, increased nucleocytoplasmic recommends that all diagnoses of dys-
like) changes present in the bases of the ratio, increased number of atypical mitoses plasia be confirmed by an expert
crypts, but without surface involvement particularly in the upper levels of the gastrointestinal pathologist before patient
{1889, 2353}. However, recent evidence crypts, and full-thickness nuclear stratifi- management {3447}.
suggests that this represents true “early” cation in the crypts and the surface
dysplasia {1889}. In general, the presence epithelium. Architectural abnormalities of Adenocarcinoma
of an abrupt transition from non-atypical high-grade changes include crypt bud- Symptoms and signs
to atypical epithelium is suggestive of true ding, branching, marked crowding, or Symptoms of advanced adenocarcinoma
neoplasia. For inflammation-associated villiform contour of the epithelium and, are similar to those of squamous cell
atypia, increased anti-GORD therapy is rarely, intraluminal papillae, bridges or a carcinoma {798}. Superficial adenocarci-
recommended, followed by repeat biopsies cribriform growth pattern. noma has no specific symptoms. It can
after 3–6 months in order to re-evaluate Intramucosal adenocarcinoma. High-grade be discovered in patients presenting with
the atypical area. dysplasia can be difficult to distinguish symptoms of GORD, or during the
Low-grade dysplasia. This is characterized from intramucosal adenocarcinoma, the surveillance of patients with Barrett
by crypts with relatively preserved latter being defined by the presence of oesophagus {2896}.
architecture, or only minimal distortion, invasion of the lamina propria. Observer
containing cells with atypical pencil- agreement in separating high-grade
shaped nuclei limited to the basal portion dysplasia from intramucosal adenocarcinoma

Endoscopy
Areas with high-grade dysplasia are often
multicentric and occult. Therefore system-
atic tissue sampling has been recom-
mended when no abnormality is evident
macroscopically {817}. The endoscopic
aspect has poor reliability in the prediction
of invasive or noninvasive neoplasia {124}.
The addition of indigo carmine chromo-
endoscopy, acetic acid chromoendoscopy,
narrow-band imaging, and confocal laser
endomicroscopy has been proposed to
improve detection of early neoplasia in
Barrett oesophagus {636, 749, 1538,
3538}. The endoscopic pattern of the early
stages of the tumour may be that of a
small polypoid adenomatous-like lesion,
but is more often flat, depressed, elevated
or occult {1732, 1733}. The usual pattern
of advanced adenocarcinoma as seen by
endoscopy is that of an axial, and often Fig. 2.14 Adenocarcinoma of the oesophagus, well- to moderately differentiated (“low-grade”).
tight, stenosis in the distal third of the
oesophagus; with a polypoid tumour;
bleeding occurs on contact. one third having a polypoid or fungating Tumour spread and staging
appearance. Occasionally, multifocal tu- Adenocarcinomas spread first locally and
Radiology mours may be present {1823, 2991}. The deeply within the oesophageal wall. Distal
Today, barium studies are helpful mostly rare adenocarcinomas arising independ- spread to the stomach may occur. Like
for the analysis of stenotic segments; they ently of Barrett oesophagus from ectopic squamous cell carcinoma, tumours
are less efficient than endoscopy for the gastric glands and oesophageal glands limited to the mucosa or submucosa are
detection of flat abnormalities. Computed display predominantly ulceration and called superficial adenocarcinomas. A
tomography (CT) will detect distant polypoid gross features, respectively. specific issue for adenocarcinomas is the
thoracic and abdominal metastases. These tumours are also found in the upper almost constant presence of a double
and middle third of the oesophagus, but muscularis mucosae in Barrett oesophagus.
Endoscopic ultrasonography are infrequent {494, 1479}. Cancers infiltrating between the inner and
At high frequency, some specificities in outer muscularis mucosae are still
the echoic pattern of the mucosa and Histopathology considered to be intramucosal cancer,
submucosa of the columnar-lined oeso- Oesophageal adenocarcinomas are typi- but they have a higher frequency of angio-
phagus are displayed. However, the pro- cally papillary and/or tubular. A large lymphatic invasion and lymph-node
cedure is only suitable for the staging of majority of cases belong to the intestinal metastases compared with those that are
tumours previously detected at endo- type according to the Laurén classification limited to the original lamina propria {9,
scopy; the tumour is hypoechoic. Lymph {2802}. A few tumours are of the diffuse 1969}. Extension through the oeso-
nodes adjacent to the oesophageal wall type and show rare glandular formations, phageal wall into adventitial tissue, and
can also be visualized by this technique and sometimes signet-ring cells {2460, then into adjacent organs or tissues is
{2507, 2726}. 2991}. Differentiation may result in neuro- similar to squamous cell carcinoma.
endocrine cells, Paneth cells and squa- Common sites of local spread comprise
Macroscopy mous cells. Mucinous adenocarcinomas, the mediastinum, tracheobronchial tree,
The cancer may arise anywhere within i.e. tumours with > 50% of the lesion lung, aorta, pericardium, heart and spine
Barrett oesophagus, although early can- consisting of mucin, also occur. {1823, 3022}. Barrett adenocarcinoma
cers are often contiguous with the squa- metastasizes to para-oesophageal and
mous epithelium. Adjacent to the tumour, Grading paracardial lymph nodes, and those of
the typical salmon-pink mucosa of Barrett Most adenocarcinomas are well or the lesser curvature of the stomach and
oesophagus may be evident, especially moderately differentiated {2460, 2802}. In the coeliac nodes. Distant metastases
in early carcinomas. At early stages, the biopsy specimens of well-differentiated occur late. The TNM classification used
gross findings of Barrett adenocarcinoma tumours, the infiltrating component may for squamous cell carcinoma is applicable
may be subtle, with irregular mucosal be difficult to recognize as invasive to Barrett adenocarcinoma and provides
bumps or small plaques. At the time of {1823}. Glandular structures are only prognostically significant data {762, 2996,
diagnosis, most tumours are advanced, slightly formed in poorly differentiated 3277}.
with deep infiltration of the oesophageal adenocarcinomas and absent in undiffer-
wall. The advanced carcinomas are entiated tumours.
predominantly flat and ulcerated with only
Adenocarcinoma 29
A B
Fig. 2.15 Adenosquamous carcinoma of the oesophagus. A The lesion displays glands and islands with intercellular bridges typical of squamous differentiation. B On Alcian blue
staining (pH 2.5), droplets of acid mucin are apparent in some of the cells in the glandular component, but not in the squamous component.
Other carcinomas inheritance pattern {796, 809, 814, 958, Other polymorphisms alter risk, but none
Adenosquamous carcinoma 1433, 2592, 2720, 3295}. However, typical are suitable for routine clinical testing.
This carcinoma has mixed elements of risk factors, such as obesity, may Examples of these include increased risk
adenocarcinoma and squamous cell potentiate risk in susceptible family in persons with poly A tracts involving the
carcinoma, which remain clearly distin- members {466}. xeroderma pigmentosum group C (XPC)
guishable within the tumour. Linkage analysis in families has not been gene, the cyclin D1 polymorphism
reported. However, increased susceptibility (G870A) {451}, and polymorphisms of the
Mucoepidermoid carcinoma to oesophageal adenocarcinoma in cyclooxygenase 2 (PTGS2/COX2) gene
This rare carcinoma shows an intimate persons with polymorphisms in genes in {841, 2139}, epidermal growth factor
mixture of squamous cells, mucus- various pathways that govern inflammatory (EGF) gene {1742} and matrix metallo-
secreting cells and cells of an intermediate response and nucleic acid repair is known. protein genes {320}, and an apparent
type {3180}. The first reported was an association be- protective effect with Lys751Gln homozy-
tween a variant of the GSTP1 (glutathione gous variant of xeroderma pigmentosum
Adenoid cystic carcinoma S-transferase P1) gene and Barrett oeso- group D (ERCC2/XPD), XRCC1 (X-ray
This neoplasm is also infrequent and phagus and adenocarcinoma {3367}. repair cross-complementing 1) Arg399Gly
believed to arise, like the mucoepidermoid Other variants of the GST gene (GSTM1 homozygous variant {452}, and NAD(P)H:-
variant, from oesophageal glands {1479}. and GSTT1) may augment the smoking- quinine oxireductase 1 (NQO1 TT) C609T
Both lesions tend to be of salivary gland associated risk for adenocarcinoma {453}. polymorphism {715}.
type with a generally favourable prognosis.
Basaloid squamous cell carcinoma has a
similar appearance to adenoid cystic
carcinoma but is more aggressive {1838}.
The presence of associated squamous
carcinoma in situ is a strong argument for
the diagnosis of basaloid carcinoma. Oeso-
phageal adenocarcinoma can also arise
from ectopic gastric glands, or oeso-
phageal glands {494, 811}.
Genetic susceptibility
Several lines of evidence suggest genetic
susceptibility to oesophageal adenocarci-
noma arising from Barrett oesophagus.
The striking predominance in white males
and the early age of onset of Barrett
oesophagus in some families support the
involvement of genetic factors {467, 1425}.
Several reports describe familial clustering
of Barrett oesophagus, adenocarcinoma
and reflux symptoms in up to three genera- Fig. 2.16 Adenoid cystic carcinoma of the oesophagus showing a typical cribriform pattern and thus resembling its
tions, a subset with an autosomal dominant counterpart in the salivary gland.

Molecular pathology Table 2.01. Frequency of the most common genetic alterations found in oesophageal adenocarcinomas and their
Multiple genetic alterations are involved in precursor lesions.
the development and progression of Gene Alteration Frequency and timing References
Barrett oesophagus to oesophageal
CDKN2A (p16) Promoter 80%, early occurrence {2144, 2502}
adenocarcinoma. Genetic alterations in methylation, LOH
tumour suppressor genes, oncogenes,
growth factor receptors or enzymes that TP53 Mutation, LOH 40–80%, increases from LGD {996, 1415, 1525, 1740,
play important roles in diverse cellular to HGD and cancer 2195, 3610, 3655}
functions such as cell-cycle control, CCND1 Overexpression 30% in metaplasia {138, 186, 1740, 2931}
apoptosis, cell signalling, cell adhesion 90% in cancer
and genetic stability, signal transduction
ERBB2 Overexpression, 0–70%, late occurrence {138, 1718, 1740,
or DNA repair have been identified. amplification 2638, 3431}
Loss and gains of several chromosomal loci
have been identified. The majority of studies EGFR Overexpression, 30–60% {1700, 1718, 1740}
demonstrate gains in the region of 8q (MYC mutation (rare)
region) and 20q, and losses at 3p (FHIT), KRAS Mutation 21% {3016A}
4q, 5q (APC) and 18q (SMAD4, DCC), with
PTGS2 (COX2) Upregulation 79%, correlated with expression {383, 3415}
an increasing number of chromosomal of VEGFA, VEFGC
alterations in the metaplasia–intraepithelial
neoplasia–carcinoma sequence {1651}. AMACR Overexpression 72–96%, progressive increase {736, 2836}
The frequency and type of the main from low-grade dysplasia
genetic alterations described in oeso- IMP3 (insulin-like — Sensitive and specific for HGD {1904}
phageal adenocarcinoma are presented growth factor II mRNA and adenocarcinoma
in Table 2.01. Of these, only TP53 gene binding protein)
mutation and ensuing p53 protein over-
HGD, high-grade dysplasia; LGD, low-grade dysplasia; LOH, loss of heterozygosity.
expression, and AMACR expression,
have been suggested as potentially useful
to strengthen a diagnosis of dysplasia. Stage grouping has been divided into: (1) regression {235A, 3145A, 1739B} and
There is evidence for an increasing role of purely anatomical stages applicable to all absence of lymph-node involvement and
epigenetic alterations in the carcinogene- types of carcinomas; and (2) prognostic metastatic disease {4569} are recognized
sis of oesophageal adenocarcinomas and groups that separate squamous from to be the strongest prognostic factors.
gene silencing by promoter methylation adenocarcinoma {762, 2996}.
has been demonstrated frequently for the On a molecular level, considerable nega- Factors for prediction of response to
E-cadherin, APC, CDKN2A/p16, MGMT, tive prognostic impact has been demon- chemotherapy on pretreatment biopsies
and TMEFF2/HPP1 genes {2819}. strated for ERBB2/Her2-neu amplification The identification of biomarkers (e.g. en-
or overexpression, TP53 mutations, zymes related to 5-fluorouracil metabolism
Prognosis and predictive factors expression of COX2, PRAP1/UPA, and or multidrug resistance) for prediction of
Prognostic factors after surgery MMP1 and DNA ploidy (4N) {1718}. NFκB response to preoperative treatment in
Prognosis is dependent on the depth of expression is also associated with clinical practice is a subject of ongoing
mural invasion and the presence of negative clinical outcome {1375}. intense research, as is profiling of differential
lymph-node or distant metastases, as expression of genes involved in apoptosis,
summarized in the current TNM (tumour, Prognostic factors after preoperative calcium homeostasis, stress response
node, metastasis) and American Joint (radio)chemotherapy and surgery and the epidermal differentiation complex
Committee on Cancer/International Union Surgery plays a central role in the treat- in responders and nonresponders to pre-
Against Cancer (AJCC/UICC) staging ment of oesophageal adenocarcinoma. operative therapy {1917B, 1917A, 1739A}.
system. The staging of carcinoma of the Advanced-stage tumours are also treated However, data generated from these
oesophagus has undergone important with preoperative radiochemotherapy and studies should at present be regarded as
modifications between the sixth and chemotherapy {630A, 955A}. Assessment preliminary.
seventh editions of TNM: T1 was subdivided of histopathological tumour regression
in order to distinguish mucosal (T1a) and grade (TRG) after preoperative treatment
submucosal (T1b) depth of invasion, and provides highly valuable prognostic infor-
T4 was divided according to the adjacent mation. A three-tiered classification system
structures that were invaded between T4a (complete tumour regression: 0% residual
(pleura, pericardium, or diaphragm) and tumour; subtotal or partial tumour regres-
T4b (other adjacent structures such as sion: 1–50% residual tumour; minor or no
aorta, vertebral body, or trachea); re- tumour regression: > 50% residual tumour)
gional lymph nodes are subdivided by has been shown to be the best reflection
number involved rather than by location; of tumour response to preoperative
distant metastases has been simplified to treatment {1971A, 528A, 3561A, 1739B,
M1 rather than subdivided by location. 3145A, 2714A, 480A}. Complete tumour
Adenocarcinoma 31
Neuroendocrine neoplasms R. Arnold

C. Capella
of the oesophagus D.S. Klimstra
G. Klöppel
P. Komminoth
E. Solcia
G. Rindi
Definition reported in the oesophagus {2115}. Most

Neoplasms with neuroendocrine differen- NECs arise in males, the male-to-female
tiation including well-differentiated (low- to ratio being 6 : 1 or higher. Age at presen-
intermediate-grade) neuroendocrine tu- tation is widely variable, ranging from 30
mours (NETs) and poorly differentiated to 82 years, but reported cases occur
(high-grade) neuroendocrine carcinomas most frequently in the sixth and seventh
(NECs) arising in the oesophagus. Mixed decades of life {1993, 2116}. The reported
adenoneuroendocrine carcinomas (MANECs) frequency of these neoplasms as a
have an exocrine and an endocrine com- proportion of all oesophageal cancers
ponent, with one component exceeding ranges between 0.05% and 7.6% {335,
30%. 728, 1288, 1765, 1993}. MANECs are
observed in males in their sixth or seventh
ICD-O codes decades of life {448, 537, 1993}.
NET G1 (carcinoid) 8240/3 Etiology
NET G2 8249/3 Patients with oesophageal NECs often
Neuroendocrine carcinoma (NEC) 8246/3 have a history of heavy smoking. An indi-
Large cell NEC 8013/3 vidual case was associated with long
Small cell NEC 8041/3 standing achalasia {158, 2594}. Co-existing
Mixed adenoneuroendocrine Barrett oesophagus is frequently reported,
carcinoma (MANEC) 8244/3 both in pure NETs or NECs and in
MANECs {335, 1616, 1993, 2777, 2829}.
Synonyms
Synonyms for oesphageal NETs include: Localization
carcinoid, well-differentiated endocrine Most neuroendocrine neoplasms of the
tumour/carcinoma {3013}. Synonyms for oesophagus are typically located in the Fig. 2.17 Neuroendocrine carcinoma (NEC) of the
lower third of the oesophagus, paralleling oesophagus.
NECs include: poorly differentiated
endocrine carcinomas, high-grade neuro- the increase in endocrine cell number in
endocrine carcinoma, small cell and large the distal oesophagus {448, 2116, 2259, syndrome and hypercalcemia have been
cell endocrine carcinomas. 2642, 2962}. Most of the rare true NETs reported {728}. In addition, in the older
(carcinoids) are found in the lower literature, a case of watery diarrhoea,
Classification oesophagus in association with Barrett hypokalaemia-achlorhydria (WDHA) syn-
NETs and NECs of the oesophagus are oesophagus and adenocarcinoma. Oeso- drome, attributable to ectopic production
classified on the basis of criteria common phageal NETs may also occur as rare inci- of vasoactive intestinal peptide (VIP) by a
to all gastrointestinal and pancreatic neuro- dental findings associated with heterotopic MANEC (small cell/squamous cell carci-
endocrine neoplasms (see Chapter 1). oxyntic mucosa {1616}. Of the more noma) and a case of carcinoid syndrome
Most oesophageal neuroendocrine neo- frequent NECs and MANECs, almost all have been described {338, 3469}. Oeso-
plasms are NECs or MANECs, with either occur in the distal half of the oesophagus phago-gastroscopy with multiple biopsies
an adenocarcinoma or a squamous cell {335, 728, 1993}. In a recent retrospective is the initial diagnostic procedure to evalu-
carcinoma component, usually of large series of 40 cases, only one was reported ate the background of dysphagia as the
size and located in the lower part of the in the proximal oesophagus, and five in the leading tumour symptoms. Staging in-
oesophagus. middle oesophagus {1993}. cludes endoscopic ultrasound, multipha-
sic computed tomography (CT) and/or
Epidemiology Clinical features magnetic resonance imaging (MRI) of the
Oesophageal neuroendocrine neoplasms NETs are often incidental findings. In NECs chest and evaluation of distant metastases.
are exceedingly rare. About 100 cases and MANECs, dysphagia, gastro-oeso- Whether radiolabelled somatostatin ana-
have been reported, the majority being phageal reflux disease (GORD), severe logue scintigraphy [Octreoscan(R)] or 68-
NECs (poorly differentiated neuroendo- weight loss and sometimes chest pain and Gallium PET may be relevant staging
crine carcinomas) {1221, 1320, 2116, blood in stool/haematemesis are the main procedures for these mostly poorly differ-
2150, 3171}. In an earlier analysis of 8305 symptoms. Patients with NECs or MANECs entiated, high-grade malignant neoplasms
NETs (“carcinoid tumours”) at different often present at an advanced stage {1288, remains to be established.
anatomical sites, only 3 (0.04%) were 1765}. Inappropriate antidiuretic hormone

Macroscopy fitting the present G3 class (see Chapter 1). diagnostic marker {1993, 2909, 3664}.
NETs are small, polypoid and rarely ulcer- Similar to their counterparts in the lung Positive staining for thyroid transcription
ated. They are often associated with Barrett {3288}, the cells of these neoplasms are factor 1 (TTF1) has also been observed in
oesophagus and adenocarcinoma {1616}. large to intermediate in size, with a low 2 out of 6 and 15 out of 21 cases, respec-
Most oesophageal NECs and MANECs nucleus-to-cytoplasm ratio, nuclei with tively, investigated in two different studies
are large (4–10 cm in diameter), present evident nucleoli and vesicular chromatin, {3594, 3664}. Some cases were reported
as fungating or ulcerated masses and and often abundant eosinophilic cytoplasm. to be positive for calcitonin and adreno-
deeply infiltrate the oesophageal wall Large cell NECs are positive for chromo- corticotropic hormone (ACTH), although in
{1616, 2259, 2642, 2962}. granin A, synaptophysin, Grimelius silver the absence of any hyperfunctional syn-
impregnation, and neuron-specific enolase drome {2150}. Staining for periodic-acid
Histopathology and may display characteristic membrane- Schiff and keratin 5/6 or p63 may help to
NET bound neurosecretory granules at ultra- distinguish areas of adeno- or squamous
G1 NETs are very rare in the oesophagus structural examination {2962}. differentiation {1993}.
(for appropriate grading, see Chapter 1). Small cell NECs. Small cell NEC of the
Most of these neoplasms are polypoid oesophagus is indistinguishable from its MANEC
and are small lesions found as incidental counterpart in the lung on the basis of Oesophageal MANECs with a NET
findings in association with Barrett histological and immunohistochemical component are exceedingly rare and re-
oesophagus and adenocarcinomas. features or clinical behaviour {3288}. The ported in association with Barrett oeso-
Histologically, oesophageal NETs are cells may be small with dark nuclei of phagus and adenocarcinoma {448}.
characterized by uniform bland, tumour round or oval shape and scanty cyto- Oesophageal MANECs usually combine
cells with an insular growth pattern and plasm, or larger with more cytoplasm a NEC component with a gastrointestinal-
solid to cribriform structures. Besides (intermediate cells) forming solid sheets type adenocarcinoma or, more rarely, a
positive staining for chromogranin A and and nests. Foci of squamous cell or squamous cell carcinoma component
synaptophysin, strong immunoreactivity adenocarcinoma and/or mucoepidermoid {448, 537}. In oesophageal MANECs, the
for vesicular monoamine transporter 2 carcinoma may also be observed, a find- adenocarcinoma component seems to be
(VMAT2) was reported in two oeso- ing that raises the possibility of an origin more frequently observed. In a recent
phageal NETs associated with heterotopic from pluripotent cells present in the series of 40 oesophageal NECs and
oxyntic mucosa, indicating an entero- squamous epithelium or ducts of the sub- MANECs, adenocarcinoma was reported
chromaffin-like cell (ECL-cell) phenotype mucosal glands {3171}. Argyrophylic granin 15 out of 16 MANECs {1993}. A squa-
{448, 1616}. ules can be demonstrated by Grimelius mous cell carcinoma component appears
G2 NETs are probably more frequent. stain, and small dense-core granules are to be more present in oesophageal
Indeed most oesophageal “carcinoids” always detected by electron microscopy MANECs from Chinese and Japanese
reported in the older literature are malig- {1320}. Immunohistochemistry for chromo- series {2150, 3594, 3664}. The NEC com-
nant, large, ulcerated lesions, deeply granin A, synaptophysin, NCAM1/CD56, ponent displays the morphology and the
invasive, often with synchronous metas- B3GAT1/Leu7 and neuron-specific eno- immunophenotype described for pure
tases {2642}, and display a solid-nest, lase is usually positive, synaptophysin NECs.
acinar or trabecular structure, with evident being reported to be the most sensitive
mitoses, reported as “abundant” or “con-
siderable”, and with focal necrosis {2259,
2642, 2962}.
NEC
Oesophageal NECs (poorly differentiated
neuroendocrine carcinomas) are aggres-
sive, deeply infiltrative neoplasms, with
synchronous metastases {1616, 1993,
2642}. In the older literature, these
neoplasms may still have been called
“carcinoids” {2259, 2642, 2962}.
Microscopically, they display either large-
cell or small-cell features. Large cell
NECs are more frequent, being reported
in 27 out of 40 cases recently investi-
gated, and often associate with Barrett
oesophagus {1993}.
Large cell NECs. Also defined as “atypical
carcinoid” in the older literature {2642},
these neoplasms may show an organoid
pattern, with solid nests or acinar struc-
tures, focal necrosis and high mitotic rate, Fig. 2.18 Large cell neuroendocrine carcinoma (NEC) of the oesophagus.
Prognosis and predictive factors and disease-free at 1–23 years after No difference in survival was observed
In contrast to other gastrointestinal sites surgical excision {554, 1616}. Two out of between small cell and large cell NECs.
{2684, 2685}, there is no proposal for a three oesophageal NETs from the analysis Interestingly, however, large cell pure
TNM/staging classification for neuroendo- of 8305 cases of “carcinoid tumours” NECs are associated with Barrett oeso-
crine neoplasms of the oesophagus. The {2115} were associated with distant phagus.
relative rarity of oesophageal NETs and metastases. Established treatment recommendations
NECs may account for this. For practical In contrast, the overall survival of patients cannot be expected for this rare entity. As
purposes the staging of oesophageal with NECs is short and reported in the for neuroendocrine neoplasms elsewhere,
NECs may be performed according to the older literature as < 6 months {1765}. surgery is the treatment of choice. Most
TNM/staging classification for oeso- Prognosis largely depends on stage and reports indicate that the preferred surgi-
phageal carcinomas {762, 2996}. tumour type. In a recent retrospective cal intervention is oesophagectomy, or
Despite the limited statistics on survival series of 40 oesophageal NECs and subtotal variants with gastro-oesophageal
available for oesophageal NETs and NECs, MANECs, better survival was reported for anastomosis, associated with preopera-
prognosis correlates reasonably with the patients with locoregional disease vs pa- tive neoadjuvant therapy as described for
grade and stage of the disease {2116}. tients with distant metastases {1993}. Sur- adenocarcinoma or squamous cell carci-
Oesophageal NETs are rarely associated vival was better for patients with MANEC noma in patients with MANECs. Small
with lymph-node metastases and have an than for patients with pure NEC, most likely lesions (< 1.5 cm in size) may by treated
excellent prognosis. Eleven patients with because of the higher stage observed in curatively by endoscopic resection.
primary oesophageal NETs were all alive pure NECs compared with MANECs.
Lymphoma of the oesophagus H.K. Müller-Hermelink

J. Delabie
Y.H. Ko
E.S. Jaffe
S. Nakamura
Definition ICD-O codes Clinical features

Primary lymphoma of the oesophagus is Diffuse large B-cell lymphoma 9680/3 Tumours predominantly occur in the inter-
defined as an extranodal lymphoma Marginal zone lymphoma of mediate and lower portion of the oesoph-
arising in the oesophagus, with the bulk mucosa-associated lymphoid agus and may cause dysphagia {1089}.
of disease localized to this site {1341}. tissue (MALT lymphoma) 9699/3
Contiguous lymph-node involvement may Macroscopy
be seen, but peripheral and mediastinal Epidemiology The macroscopic appearance is nonspe-
lymph nodes, spleen or liver should not The oesophagus is a very uncommon cific, ranging from small polypoid masses
be affected and chest radioimaging and primary site, accounting for < 1% of that can be removed by mucosectomy
leukocyte count should be normal. Thus, patients with lymphoma {2364}. Oeso- {1246} to larger nodular or tumorous
by exclusion of any other site, the primary phageal involvement is more common as lesions, ulcerated tumours or more exten-
clinical presentation is in the oesophagus a secondary either from mediastinum, sive sometimes multifocal involvement.
and therapy is directed at this site. from nodal disease or from a primary
Most frequently, primary oesophageal lym- gastric location. Less than 30 cases of Histopathology
phomas are diffuse large B-cell lymphoma bona fide primary oesophageal lymphoma The morphological and cytological fea-
(DLBCL) {2769} or extranodal marginal- have been described as single case tures of reported cases are typical of the
zone lymphoma of mucosa-associated reports or as small series of two cases. respective lymphoma subtypes found
lymphoid tissue (MALT lymphoma) {1246, Patients are frequently male and usually elsewhere in the gastrointestinal tract.
1582, 2106}. Presentation of classical aged > 50 years. MALT lymphomas of the Secondary involvement of the oesophagus
Hodgkin lymphoma has also been reported oesophagus are mostly reported from may occur in the dissemination of any
in the oesophagus, but is considered an Asian countries. type of lymphoma but is rare.
extension of nodal disease {596, 1441}. Immunodeficiency associated with infection Data on molecular pathology are not
Primary oesophageal T-cell lymphoma with HIV {3480} and chronic immunosup- available owing to the rarity of these
has been described, but is exceedingly pression {1023} appear to be risk factors. tumours.
rare {914}. Involvement of the oesophagus
in widespread primary intestinal T-cell
lymphoma has also been reported {46}.

Mesenchymal tumours M. Miettinen

C.D.M. Fletcher
of the oesophagus L.-G. Kindblom
W.M.S. Tsui
Definition referred to as “leiomyomatosis”. This syn-

A group of nonepithelial tumours with drome is caused by germline deletions in
variable histogenesis, including smooth the collagen IV subunit genes, among them
muscle, stromal/Cajal cell, fibroblastic/- COL4A5 and COL4A6, found at chromo-
myofibroblastic, endothelial, and Schwann- some Xq22 {1151}. For forms of leiomy-
ian origin, although the latter are, in a strict omatosis that involve these genes,
sense, of neuroectodermal and not inheritance is X-linked, causing a more
mesenchymal origin. severe syndromic phenotype in men.
Somatic deletions in the same genes have
ICD-O codes been identified in sporadic leiomyomas,
Granular cell tumour 9580/0 suggesting a common pathogenesis {1150}.
Fig. 2.19 Oesophageal leiomyoma. Grossly, this tumour
Haemangioma 9120/0
often forms a demarcated mass with a grey, trabeculated
Leiomyoma 8890/0 Leiomyosarcoma or whorled cut surface.
Lipoma 8850/0 Malignant smooth-muscle tumours are
Gastrointestinal stromal tumour 8936/3 very rare in the oesophagus. They are
Kaposi sarcoma 9140/3 recognized by a histological resemblance
Leiomyosarcoma 8890/3 to smooth muscle, nuclear atypia, mitotic
Rhabdomyosarcoma 8900/3 activity, and immunohistochemical pres-
Synovial sarcoma 9040/3 ence of SMA and desmin. Many reported
examples have presented as polypoid
Leiomyoma intraluminal masses, and prognosis has
Leiomyoma, the most common mesenchy- been poor {2073}.
mal tumour of the oesophagus, occurs over
a wide range of ages from childhood Gastrointestinal stromal tumour (GIST) A
onwards and is twice as frequent in males For definition, terminology, incidence,
as in females. Leiomyomas are typically clinical and pathological features, we refer
located in the distal to middle oesophagus to the sections on gastric and small-
and often manifest as dysphagia. The intestinal GISTs (Chapters 4 and 6). GISTs
tumour varies from a minimal intramural are very rare in the oesophagus and com-
nodule to a larger mural nodule to an prise 10–20% of the combined group of
externally extending mediastinal mass, but smooth-muscle and stromal tumours. Most
most are 1–3 cm in size {1135, 2073, 2879}. are clinically detected as intraluminal distal
Grossly, oesophageal leiomyomas form oesophageal masses causing dysphagia,
firm to hard greyish-white masses. Histo- but externally extending oesophageal
logically they are composed of irregularly GISTs can manifest as mediastinal tumours. B
oriented bundles of well-differentiated Occasional examples have been inciden- Fig. 2.20 Oesophageal leiomyoma, arising as a demarcated
smooth-muscle cells. Cytoplasmic eosino- tally detected during radiological screening intramural nodule. Histologically, this tumour is composed
philic inclusions are often present, and or surveillance studies, and such tumours of relatively paucicellular, well-differentiated smooth-muscle
calcification and infiltration by eosinophilic can have a good prognosis, an exception cells. Note the eosinophilic cytoplasmic inclusions, especially
granulocytes are not uncommon. Mitotic among this group of tumours, among in the centre.
activity is scant, if present. Immunohisto- which sarcomas predominate.
chemical positivity for smooth muscle actin Most of these GISTs are spindle-cell Granular cell tumour
(SMA) and desmin is typical; desmin labels tumours with sarcomatoid features Granular cell tumours are usually incidental
cytoplasmic inclusions. In contrast to including significant mitotic activity, but endoscopic findings in the distal oesopha-
gastrointestinal stromal tumours (GIST), occasional epithelioid examples have gus and measure < 1 cm. Rare larger
leiomyomas are negative for KIT and also been reported {287, 2073}. Oeso- examples can cause dysphagia. Incidence
DOG1/ANO1. phageal GISTs are KIT-positive, and KIT is higher in African Americans, and
Childhood (and adult) cases include mutations reported are similar to those tumour multiplicity is common, as has
patients with familial Alport syndrome who, identified in gastric GISTs. The patholog- been previously observed for granular
in addition to renal glomerular disease, ical and genetic features of these tumours cell tumours in soft tissue.
may have longitudinally extending complex are described in more detail in Chapter 4. Most cases lack nuclear atypia and
intramural oesophageal leiomyomas, often mitotic activity, and immunohistochemical
myogenic regulatory proteins (MyoD1 or

myogenin) is required for diagnosis.
Synovial sarcoma
Isolated cases of biphasic synovial
sarcomas have been reported in the
upper oesophagus. These have mostly
occurred in children and young adults.
Grossly, they formed polypoid intraluminal
A A masses, and were histologically similar to
synovial sarcomas in soft tissue with
glandular elements that were positive for
keratin and epithelial membrane antigen
(EMA) {259, 281}.
Other mesenchymal tumours

Glomus tumours, lipomas, and schwan-
nomas similar to those more commonly
seen in the stomach and intestines are
very rare in the oesophagus. Kaposi
B B sarcoma occurs with some frequency in
Fig. 2.21 Oesophageal gastrointestinal stromal tumour Fig. 2.22 Granular cell tumour of the oesophagus. patients with HIV/AIDS and post-transplant
(GIST). A The tumour involves the wall beneath the A Pseudoepitheliomatous hyperplasia is often elicited in patients. For description of these entities,
squamous epithelium. B Moderately cellular spindle cell the overlying squamous epithelium. B In the muscularis we refer to the section on mesenchymal
GIST with dilated capillaries. propria, it intermingles with the smooth-muscle elements. tumours of the stomach and colon
(Chapters 4 and 8).
detection of S100 protein is a consistent Lymphangioma

finding. Pseudoepitheliomatous hyperpla- Lymphangiomas vary from small mucosal
sia of the squamous epithelia may be lesions to pedunculated polyps and large
present in mucosally extending lesions. masses that may involve surrounding
Presence of nuclear atypia and mitotic structures extending into the medi-
activity raise the concern of biological astinum. Most have occurred in older
potential necessitating documented adults, arising in the middle and lower
complete excision and follow-up in such third underneath an intact mucosa, and
cases {1013}. many have been characterized as
cavernous lymphangiomas. Some cystic
Haemangioma lymphangiomas of the neck in infants have
Most reported oesophageal haemangiomas involved the upper oesophagus {2833}.
have been polypoid intraluminal lesions
measuring 1–3 cm that have occurred in Rhabdomyosarcoma
older adults, with an apparent predomi- Only a small number of well-documented
nance in males. Histologically they have rhabdomyosarcomas (of embryonal type)
been variably characterized as capillary have been reported in the oesophagus.
(the majority of cases) or cavernous. These tumours have occurred in the distal
Endoscopic polypectomy has been the oesophagus in older adults {3381}.
usual treatment {3003}. Immunohistochemical demonstration of
desmin and nuclear expression of

Secondary tumours and melanoma C. Iacobuzio-Donahue

G.M. Groisman
of the oesophagus
Definition of new-onset dysphagia in a patient with a

Tumours of the oesophagus that originate known malignancy may suggest an
from an extra-oesophageal neoplasm or oesophageal metastasis. Although all
that are discontinuous with a primary modes of imaging have value when
tumour elsewhere in the oesophagus. evaluating oesophageal metastases,
endoscopic ultrasound is used most often
Epidemiology to define the extent of oesophageal
In a series of 4198 cases of malignant involvement. Minimally invasive thoraco-
oesophageal disease, 114 (2.7%) were scopy may facilitate the diagnosis of
metastases from non-oesophageal primary carcinosis of the oesophagus caused by Fig. 2.23 Primary melanoma of the oesophagus.
The oesophagogastric junction is on the left (arrows).
neoplasms {2625}. A higher frequency breast cancer {2625, 2971, 2995}.
(6.1% of autopsy cases) was reported in
Japan {2108}. Malignant melanoma (ICD- Melanoma
O code, 8720/3) of the oesophagus is an Cases of melanoma of the oesophagus
extremely rare neoplasm with < 300 cases typically arise in the middle or distal
reported {2792, 3373}. oesophagus of older adults {1829, 2792}.
The most common clinical complaint is
Origin of metastases dysphagia. At endoscopy, the neoplasms
After exclusion of pharyngeal carcinomas, are polypoid and melanin pigmentation is
gastric carcinomas and malignant medi- seen in almost all cases {889, 2792}.
astinal neoplasms involving the oeso-
phagus by direct extension, metastatic Histopathology
neoplasms may reach the oesophagus by The histopathology of oesophageal meta-
haematogenous or lymphatic dissemina- stases will be most similar to the primary Fig. 2.24 Primary malignant melanoma of the distal
tion. Any primary neoplasm is a potential neoplasm of origin. A pertinent clinical oesophagus. The diagnosis is supported by the fact that
source of haematogenous spread to the history, the submucosal distribution of the the zone of atypical junctional proliferation of melanocytes
oesophagus, whereas lymphatic spread is lesion, the absence of epithelial surface is located adjacent to the invasive tumour.
mainly seen in association with breast and involvement and the presence of adeno-
lung tumours. The most common origins of carcinoma in the wall of the squamous
oesophageal metastases are breast and lined oesophagus is generally sufficient to Prognosis and predictive factors
lung carcinomas, followed by melanoma distinguish metastatic from primary Oesophageal metastasis is a sign of
{1844, 2108, 3461}. Metastasis from carci- oesophageal carcinoma. Difficulty may advanced disease, but the outcome is
nomas of the thyroid, cervix, ovary, arise when a metastatic squamous cell better when the growth rate of the primary
prostate and kidney have also been carcinoma involves the oesophageal tumour is slow {2382} or when systemic
reported {594, 1777, 2108, 2227, 3291}. mucosa or a metastatic adenocarcinoma therapy is employed, as for metastatic
infiltrates the lower oesophageal mucosa. breast cancer {167, 2625}.
Localization In those instances, clinical history and
The most common site of haematogenous immunohistochemical stains including Melanoma
metastases is the middle third of the “organ-specific” markers may help in The preferred therapy is total or near-total
oesophagus. reaching the diagnosis. oesophagectomy followed by radiother-
apy and/or chemotherapy {139, 1829,
Clinical features Melanoma 3410}. The prognosis is poor. Median
Metastatic lesions typically form sympto- Histologically, the tumours are composed survival is between 8 and 24 months
matic or asymptomatic submucosal of spindle and/or epithelioid cells, similar {1829, 2792}.
nodules, but may also produce large to their cutaneous counterparts. An in situ
symptomatic, obstructive tumours {2971}. component, which helps to establish the
The most common symptom is dyspha- diagnosis of primary melanoma, is seen
gia; achalasia, haematemesis, weight in the majority of cases {2792}. Immuno-
loss and anaemia are less commonly histochemistry (S100 protein, Melan A,
seen {167, 2625, 2995}. The development HMB45) helps to confirm the diagnosis.
Secondary tumours and melanoma 37

CHAPTER 3
Tumours of the oesophagogastric junction
Adenocarcinoma of the oesophagogastric junction

Adenocarcinoma R.D. Odze

J.-F. Fléjou
of the oesophagogastric junction P. Boffetta
H. Höfler
E. Montgomery
S.J. Spechler
Definition important clinical issue. For investigators

Adenocarcinomas that straddle the junction intent on determining the origin of those
of the oesophagus and stomach are tumours, however, such precision can be
designated as tumours of the oesophago- critical.
gastric junction (OGJ). This definition Endoscopists in North America and
includes many tumours formerly called Europe generally identify the OGJ as the
cancers of the gastric “cardia”. Squamous most proximal extent of the gastric folds
cell carcinomas that occur at the OGJ are {2018}. In vivo, the location of the proximal
considered to be carcinomas of the distal extent of the gastric folds is affected by
oesophagus, even if they cross the OGJ. respiration, gut motor activity and the
degree of distention of the oesophagus
ICD-O code 8140/3 and stomach, all of which can vary from
moment to moment. In resected specimens
Definition of the oesophagogastric junction that include the OGJ, the level of the prox-
Fig. 3.01 Topography of the oesophagogastric junction
Conceptually, the OGJ is defined as the imal extent of the gastric folds is affected
and proximal stomach {3033}.
point at which the oesophagus ends and by traction on the oesophagus, which is
the stomach begins. Practically, there are often a function of how the specimen is
no universally accepted and clearly mounted. Bulky tumours at the OGJ also glands or a mixture of mucous glands and
reproducible landmarks that identify the may completely obliterate the tops of the oxyntic glands. Regardless, this represents
OGJ with precision. Different criteria are gastric folds. Endoscopists in Asia often use an extremely short segment of mucosa
used by anatomists, radiologists, physiol- the distal extent of the palisade vessels and is probably of little consequence in
ogists, surgeons and endoscopists {3036}. (fine longitudinal veins in the lamina propria terms of cancer risk {479, 480, 2352}.
For instance, in the normal patient, the of the distal oesophagus) as their land-
OGJ can be defined by many criteria: the mark for the OGJ because of difficulty in Diagnostic criteria
end of the tubular oesophagus, the identifying gastric folds in a population Various diagnostic criteria have been
squamo-columnar junction, the peritoneal with a high prevalence of chronic atrophic used to classify tumours in the region of
reflection, the angle of His, the proximal gastritis {535, 2233, 3402}. Furthermore, the OGJ as either oesophageal or gastric
limit of gastric rugal folds, the distal limit the level at which the palisade vessels {567, 1079, 1152, 1292, 1462, 2093, 2149}.
of squamous epithelium, the proximal limit terminate can be irregular and difficult to In most of these classification systems,
of gastric oxyntic mucosa, the distal limit localize with precision, and this is not a the anatomical location of the epicentre,
of the lower oesophageal sphincter, and practical landmark for routine use in or predominant mass of the tumour, is
the distal limit of palisading vessels. When surgical specimens. used to determine whether the neoplasm
the oesophagus is damaged by gastro- The choice of the “best” landmark for the is oesophageal or gastric in origin. The use
oesophageal reflux disease (GORD), most OGJ is necessarily arbitrary. Adeno- of endoscopic criteria, as in North America
of these landmarks are destroyed. Few carcinomas that straddle the OGJ, wher- and Europe, suggests that many gastric
studies have addressed this issue specifi- ever that is, are likely to have originated “cardia” cancers actually represent distal
cally and, in the absence of a validated either from Barrett oesophagus or from the oesophageal cancers secondary to Barrett
landmark, the accuracy of any criterion proximal stomach. Since the majority of oesophagus. This correlates well with
cannot be assessed meaningfully. published studies on Barrett oesophagus epidemiological data that show a similar
Systems proposed for the classification of conducted over the past 20 years have incidence rate, over the last four decades,
these tumours, such as the Siewert classi- used the proximal extent of the gastric with oesophageal adenocarcinoma, and
fication, used in some parts of the world folds as the landmark for the OGJ and, in an etiological association with GORD in
as a surgical guide {1462, 2963}, have the absence of compelling data for the use some studies. Owing to the use of divergent
generally been based on the location of of alternative markers, it seems reasonable classification systems, the patient popu-
the epicentre of the tumour in relation to the to use that landmark despite its consider- lations used in studies on cancers of the
OGJ, but the authors of these systems able shortcomings. proximal stomach are heterogeneous.
often do not provide specific criteria for The proximal stomach is often referred to Some include patients with gastric tumours
identifying the OGJ. as the “cardia”, but the histology of this and others with tumours of oesophageal
For the treatment of patients with tumours region is controversial. Some authorities origin. The following guidelines are based
that cross the border between the oeso- suggest that the “cardia” is composed of on the definition of the OGJ described
phagus and the stomach, great precision pure oxyntic glands, while others propose above: (1) adenocarcinomas that cross the
in identification of the OGJ is not usually an that it is composed of pure mucous OGJ are considered adenocarcinomas of
40 Tumours of the oesophagogastric junction

the OGJ, regardless of where the bulk of than for oesophageal adenocarcinoma
the tumour lies; (2) adenocarcinomas {3556}. The role of alcohol, dietary factors
located entirely above the OGJ, as defined and medication has not been fully estab-
above, are considered to represent oeso- lished {1512}. Some case–control studies
phageal carcinomas; and (3) adenocarci- have reported a reduced risk of Barrett
nomas located entirely below the OGJ are oesophagus and oesophageal adenocar-
considered to be gastric in origin. For the cinoma among individuals who are positive
latter group, use of the ambiguous and for Helicobacter pylori, particularly those
often misleading term “carcinoma of the gas- infected with the cag A type {285}. A sim-
tric cardia” is discouraged in favour of the ilar protective association has been
term “carcinoma of the proximal stomach”. observed for GORD {1048}. However,
there are no data on the effect of infection
Epidemiology with H. pylori on OGJ cancers. Fig. 3.02 Adenocarcinoma (CA) with deep infiltration at
The epidemiology of adenocarcinoma of the oesophagogastric junction and several lymph nodes
the OGJ shares many characteristics with Clinical features with metastases (arrows), as visualized by endoscopic
that of adenocarcinoma of the distal oeso- Patients with adenocarcinomas that strad- ultrasonography.
phagus in particular, and also with those dle the OGJ comprise a heterogeneous
of the proximal stomach. Reliable popu- population of those with Barrett cancer,
lation-based data on the incidence of which is associated with GORD, and
adenocarcinoma of the OGJ are not avail- those with gastric cancer, which is asso-
able because cancer registries typically ciated with H. pylori infection {3035}.
distinguish adenocarcinomas of the distal Thus, some patients with OGJ tumours
oesophagus only from those of the proxi- describe a prior history of GORD symp-
mal stomach. toms, whereas others may describe a
Incidence rates of OGJ adenocarcinomas history of peptic ulcer disease. Both in the
are higher among Caucasians, in men oesophagus and stomach, intestinal meta-
compared with women, and in the middle- plasia caused by chronic inflammation
aged and elderly {1512}. The incidence of appears to predispose to the development
OGJ adenocarcinoma has increased of adenocarcinoma. However, metaplastic
markedly in the second half of the 20th epithelium per se does not cause symptoms.
century {3706}. In 1985–1989, incidence Patients with adenocarcinomas of the
rates in Connecticut were 3.0 per 100 000 OGJ generally present with symptoms of
in men and 0.6 per 100 000 in women dysphagia, weight loss, and abdominal
{3706}. The incidence of adenocarcinoma pain. Early OGJ cancers infrequently
of the OGJ appears to be rising in parallel cause symptoms, and the presence of
with that of adenocarcinoma of the lower dysphagia, weight loss or abdominal pain
oesophagus {347, 2521}. usually indicates that the tumour is bulky Fig. 3.03 Adenocarcinoma of the oesophagogastric
and incurable. Uncommonly, cancers of junction.
Etiology the OGJ are discovered at an early,
The risk factors for development of adeno- curable stage during endoscopic surveil-
carcinoma of the OGJ mainly parallel those lance of patients known to have Barrett that the cancer arose from Barrett oeso-
of adenocarcinoma of the lower oeso- oesophagus {2896}. phagus. If possible, the proximal stomach
phagus {1512}. GORD and intestinal should be examined by retroflexion of the
metaplasia have been strongly and Endoscopy and imaging endoscope in order to assess the extent
consistently associated with an increased OGJ adenocarcinomas are typically diag- of gastric involvement. Computed tomo-
risk of adenocarcinoma of the OGJ {402, nosed by endoscopic examination and graphy (CT) is used to detect distant
547, 1721}. Although difficult to determine biopsy sampling. The OGJ is identified metastases (M staging) in the chest and
because of variation in the definitions used endoscopically as the most proximal abdomen. For assessment of tumour
in previous studies, the risk of adeno- extent of the gastric folds. Large circum- depth (T staging) and local/regional
carcinoma may be lower in patients with ferential tumours may obliterate this lymph node involvement (N staging), endo-
intestinal metaplasia of the proximal anatomical landmark, obliging the endoscopic ultrasonography is the diagnostic
stomach than in patients with intestinal scopist to estimate the location of the modality of choice {275}. Occasionally, it
metaplasia of the distal oesophagus (Barrett OGJ. The endoscopist should attempt to can be difficult to distinguish reactive
oesophagus) {402, 567}. identify whether there is columnar-lined (inflammatory) changes from metastases
Increasing body weight and obesity play (Barrett) oesophagus (see Adenocarcinoma in lymph nodes by ultrasonographic
a role in adenocarcinoma of the OGJ of the oesophagus), and obtain biopsy criteria, especially for ulcerated tumours.
independent from GORD {546, 1722}. specimens of the oesophageal columnar In these cases, endoscopic ultrasonography
Tobacco-smoking has been associated lining. The finding of dysplastic columnar can be used to guide fine needle aspiration
with an increased risk of adenocarcinoma epithelium in the oesophagus of a patient of the suspicious lymph node.
of the OGJ, although the data are weaker with an OGJ tumour is strong evidence
Adenocarcinoma 41
the proximal oesophageal resection margin frequent finding in tumours at this site.
is recommended for these cases. Proximal Adenosquamous carcinoma should be
spread can also involve lower mediastinal distinguished from mucoepidermoid
nodes. Lymphatic spread from proximal carcinoma of the oesophagus, which is
gastric cancers frequently extend distally believed to develop from mucus glands
to lymph nodes in the oesophagogastric and is similar to such tumours that
angles, and also to those surrounding the develop from the salivary glands {3180}.
left gastric artery, and also may involve Although the term “mucoepidermoid” was
para-coeliac and para-aortic lymph used in the past synonymously with
nodes {47, 1624}. adenosquamous carcinomas {2495}, the
latter are distinguished by the presence of
Fig. 3.04 Adenocarcinoma of the proximal stomach
Histopathology marked nuclear pleomorphism, occasional
(“pylorocardiac type”).
Adenocarcinoma keratin pearls, and the anatomical sepa-
Most cancers that arise at the OGJ are ration of the two components within the
Tumour spread and staging adenocarcinomas {3023}. Histologically, tumour. It is generally accepted that this
Currently, staging of carcinomas of the several types are recognized: papillary, malignancy results from divergent differ-
OGJ is based on the following TNM tubular, mucinous, signet ring cell and entiation of malignant cells rather than a
(tumour; node; metastasis) criteria: a other poorly cohesive non-signet ring cell collision of two tumour types.
tumour whose centre is located within carcinomas, and mixed carcinomas (see
5 cm of the OGJ and which also extends Chapter 4). The relative proportion of well- Small cell carcinoma
into the oesophagus is staged according differentiated, gland-forming carcinomas Small cell carcinoma can also occur at
to the scheme for oesophageal carcinoma. is significantly lower for tumours that arise this site. The prognosis is poor, although
Tumours with an epicentre in the stomach in the OGJ compared with pure oeso- after radiochemotherapy some cases
> 5 cm from the OGJ, or those within 5 cm phageal carcinomas {2802}. Signet ring show favourable behaviour {255, 1667}
of the OGJ without extension in the oeso- carcinomas are far less common in the (see Neuroendocrine tumours of the oeso-
phagus, are staged according to the proximal than in the distal stomach, and phagus).
scheme for gastric carcinoma {762, 2996}. are not usually accompanied by atrophic
The main clinical differences between gastritis {3444}. Well-differentiated “tubular” Grading
staging for the oesophagus versus the adenocarcinomas may present consider- Adenocarcinomas of the OGJ are graded
stomach is that: (1) oesophageal cancer able difficulty for diagnosis since the neo- as well-, moderately, or poorly differentiated.
incorporates tumour grade as a significant plastic tubules may reveal a deceptively Unfortunately, interobserver agreement
prognostic variable; and (2) metastasis in bland and regular appearance, and are on tumour grading is poor. Nevertheless,
7 or more regional lymph nodes (N3) is thus easily mistaken for benign hyperplasia tumour grading is now incorporated into
divided into N3a (7 to 15 nodes) and N3b or dysplasia {2315}. separate prognostic categories that are
(16 or more nodes) for gastric carcinomas. used for TNM staging of oesophageal
In addition, for lesions classified as oeso- Pylorocardiac carcinoma cancers (tumours in which the epicentre
phageal cancer, T1 and T4 are further Mulligan et al. {3101} termed neoplastic is located within 5 cm of the OGJ and with
subdivided in order to provide greater lesions that resemble normal pyloric involvement of oesophagus) {1362,
information for imaging and management, glands “pylorocardiac carcinomas”. Such 2672}. Blomjous et al. {282} reported that
regional lymph nodes (N) are subdivided lesions are typically located in the proximal 3.6% of gastric “cardiac” cancers were
by the number involved rather than by stomach, contain tall epithelial cells with well-differentiated, 31% were moderately
their location, and distant metastasis (M) clear or pale cytoplasm and basal or cen- differentiated, and 43% were poorly
is indicated as M1 and is not subdivided trally located nuclei. However, this pattern differentiated, but other investigators have
by location. Stages are now divided into: of growth is difficult to distinguish reliably revealed a greater proportion of well-
(1) purely anatomical stages that are from other types of gland-forming adeno- differentiated cancers, particularly when
applicable to both oesophageal and carcinomas, so the significance of this “early” carcinomas are included in the
gastric carcinomas; and (2) are also subtype is unclear {3101}. For instance, analysis {2149, 2302, 3206}.
divided into separate prognostic groups “clear cell” adenocarcinoma of the proximal
based on tumour grade, as mentioned stomach probably represents a similar Precursor lesions
above. For oesophageal adenocarcinomas, histological subtype {972}. Regardless of the precise anatomical site
distinction between well- and moderately- of origin (oesophagus vs proximal stom-
differentiated (G1 and G2) and poorly- Adenosquamous carcinoma ach), many, but not all, adenocarcinomas
differentiated (G3) cancers is important Adenosquamous carcinoma has mixed of the OGJ develop via a precursor stage
for stage groupings IA, IB and IIA {762, elements of adenocarcinoma and squa- of intestinal metaplasia. Tumours may
2996}. mous cell carcinoma. The diagnosis rests arise in endoscopically visible segments
Adenocarcinomas located at the OGJ on the finding of a mixture of neoplastic of Barrett oesophagus or in short or ultra-
have a proclivity for proximal spread glandular and squamous elements, and short segments of oesophageal columnar
mainly via lymphatics in the submucosa not merely the presence of benign meta- metaplasia that are difficult, if not impos-
of the oesophagus. For this reason, intra- plastic squamoid foci in an otherwise sible, to identify endoscopically. The
operative frozen-section examination of typical adenocarcinoma. The latter is a prevalence of intestinal metaplasia in a

biopsy obtained from this region is variable. gastritis in distal biopsies. However, intes- specific genetic alterations of OGJ
In patients with a visible segment of tinal metaplasia may also occur in gastric tumours is difficult owing to the use of
columnar epithelium in the distal oeso- oxyntic mucosa as part of chronic atrophic disparate and inconsistent clinical and
phagus measuring > 3 cm, the prevalence pan-gastritis. This usually results either pathological criteria for these tumours in
of intestinal metaplasia is 90%. For patients from infection with H. pylori or from the literature. Nevertheless, both loss and
with < 3 cm length of columnar epithelium, autoimmune gastritis and is easily recog- gain of chromosomal loci have been iden-
the prevalence of intestinal metaplasia is nized by the fact that chronic inflammation, tified in “gastric cardia” adenocarcinomas
close to 30%. The incidence of intestinal atrophy and intestinal metaplasia are and in adenocarcinomas of the distal
metaplasia in endoscopically normal present in both the proximal and distal oesophagus. The most prevalent gains
patients varies by 5–15% in different stomach. This scenario is common in (> 40% of tumours), with inclusion of
studies {3036A}. There are limited data on populations in which the prevalence of assigned candidate genes, were found at
cancer progression of intestinal metaplasia infection with H. pylori is high. Finally, 1q, 7p (EGFR), 7q, 8q (MYC), 17q
when it is found in a biopsy from the OGJ intestinal metaplasia may develop in pure (ERBB2), 19q, 20pq. Losses are most
region, but it is believed that the risk is mucus or mixed mucus/oxyntic glands in frequently observed at 3p, 4q, 5q (APC,
higher when it occurs in the distal oeso- the OGJ region, in association with chronic MCC at 5q21, α-catenin at 5q31), 9p, and
phagus than in the proximal stomach atrophic pan-gastritis. In this case, it is 18q (SMAD4, DCC) and on the Y chro-
{2907}. difficult to determine whether the intestinal mosome in males {3352, 3353}. A detailed
Careful examination of the type of epithe- metaplasia developed in metaplastic analysis of the amplicon at chromosome
lium in which intestinal metaplasia occurs, oesophageal columnar mucosa or meta- 7q21 identified the gene encoding the
and its pathological associations, suggests plastic gastric oxyntic mucosa with atrophy cell-cycle regulator Cdk6 as the target of
the following: when intestinal metaplasia and pseudopyloric metaplasia. The risk of recurrent high-level amplifications at 7q21
is found in a biopsy from visible columnar- cancer associated with these different {3354}.
lined oesophagus and the length is < 3 scenarios has not been established, partly Mutations in TP53 are the most frequent
cm, this is considered “short-segment” owing to paucity of data as a result of alterations in OGJ tumours. TP53 ab-
Barrett oesophagus. The risk of cancer management guidelines that discourage normalities have been reported in 31–63%
associated with short-segment Barrett biopsies in endoscopically normal patients. of “gastric cardia” tumours and 50–79%
oesophagus is believed to be similar to, or However, dysplasia and adenocarcinomas of oesophageal tumours {996, 3195}. The
only slightly less, than that associated of the OGJ region are not frequently asso- prevalence of TP53 mutations is
with “long-segment” Barrett oesophagus ciated with chronic atrophic gastritis, which considerable higher in “gastric cardia”
{615, 953}. When intestinal metaplasia is suggests strongly that most of these adenocarcinomas than in antral adeno-
detected in a biopsy from the OGJ in a tumours arise in metaplastic oesophageal carcinomas (42% vs 25%) {874}. In one
patient with an endoscopically normal mucosa (i.e. ultra-short segment Barrett study, the prevalence of TP53 mutations
oesophagus, there are several possibilities. oesophagus). was similar in adenocarcinomas of the
One is that intestinal metaplasia is occur- oesophagus (53%) and “cardia” adeno-
ring in an area of “ultra-short” (microscopic) Molecular pathology carcinomas (58%), but not “non-cardia”
Barrett oesophagus (< 1 cm), which is the Adenocarcinomas of the OGJ share many gastric adenocarcinomas (17%) {1339}.
most common scenario for intestinal similarities at the molecular level with Loss of heterozygosity (LOH) of TP53 at
metaplasia in this region. These patients adenocarcinomas of the oesophagus and chromosome 17p13 was found in 83% of
have no evidence of chronic atrophic distal stomach. Unfortunately, delineating “cardia” carcinomas {996} and in 63% of
A B
Fig. 3.05 Regression of adenocarcinoma of the oesophagogastric junction after radiochemotherapy. A The photo of the gross specimen shows ulceration, but no mass lesion.
B Histologically, there is ulceration and underlying neoplastic mucin lakes, but no viable epithelium.
Adenocarcinoma 43
“non-cardia” gastric tumours, compared Prognosis and predictive factors response defined by 18-fluoro-2-deoxy-
with 46% in oesophageal adenocarcinomas The completeness of resection, lymph- glucose-PET (FDG-PET) has been shown
in other studies {3610}. node status and the presence of post- to be predictive of both survival and
Other abnormalities detected in “cardia” surgical complications are the most histopathological response {1898}. Factors
cancers include overexpression of important prognostic factors for patients predictive of response to neoadjuvant
ERBB2 (about 20%) and increased with adenocarcinoma of the OGJ {2417, therapy have been studied in oeso-
expression of CDX2 (about 41%) {382, 2964}. TP53 mutations were associated phageal or gastric adenocarcinomas, but
3028}. In one study, proteome analysis of with more advanced disease and poor not specifically in OGJ tumours {820, 1223}.
a small number of “gastric cardia” adeno- prognosis in one study, which included Decreased expression of thymidylate
carcinomas revealed 23 differentially adenocarcinomas of the oesophagus and synthase, a key enzyme in the metabolism
expressed proteins {518}. of the proximal stomach {1339}. Correlation of 5-fluorouracil (5FU) has been shown to
Promoter methylation of the RAS- between elevated expression of COX2 be associated with a positive response in
association domain family 1A (RASSF1A) (PTGS2) and reduced survival has been a study that included OGJ tumours {87}.
gene was detected in 59% of “gastric found for adenocarcinomas of the oeso- However, no molecular markers are
cardia” adenocarcinomas in one study phagus, but not the proximal stomach {382}. currently used in clinical practice to guide
{3353}. There are considerable differences The yTNM staging system is recom- the treatment of patients with carcinomas
between oesophageal, “cardia” and “non- mended for patients treated with neoadju- of the OGJ.
cardia” gastric adenocarcinomas in pro- vant chemotherapy {762, 2996}.
moter methylation of the APC and Histopathological response categorized
CDKN2A (p16) genes (APC: 78% vs 32% by the three-tiered system proposed for
vs 84%, respectively; and CDKN2A: 54% gastric and oesophageal cancers has
vs 36% vs 10%, respectively) {2805}. limitations {219}. An early metabolic

CHAPTER 4
Tumours of the stomach
Gastric carcinoma
Hereditary diffuse gastric cancer
Lymphoma
Mesenchymal tumours
Secondary tumours
WHO classificationa of tumours of the stomach

Epithelial tumours Neuroendocrine carcinoma (NEC) 8246/3
Premalignant lesions Large cell NEC 8013/3
Adenoma 8140/0 Small cell NEC 8041/3
Intraepithelial neoplasia (dysplasia), low grade 8148/0* Mixed adenoneuroendocrine carcinoma 8244/3
Intraepithelial neoplasia (dysplasia), high grade 8148/2* EC cell, serotonin-producing NET 8241/3
Gastrin-producing NET (gastrinoma) 8153/3
Carcinoma
Adenocarcinoma 8140/3 Mesenchymal tumours
Papillary adenocarcinoma 8260/3 Glomus tumour 8711/0
Tubular adenocarcinoma 8211/3 Granular cell tumour 9580/0
Mucinous adenocarcinoma 8480/3 Leiomyoma 8890/0
Poorly cohesive carcinoma (including signet Plexiform fibromyxoma 8811/0*
ring cell carcinoma and other variants) 8490/3*
Schwannoma 9560/0
Mixed adenocarcinoma 8255/3
Inflammatory myofibroblastic tumour 8825/1
Carcinoma with lymphoid stroma Gastrointestinal stromal tumour 8936/3
(medullary carcinoma) 8512/3 Kaposi sarcoma 9140/3
Hepatoid adenocarcinoma 8576/3 Leiomyosarcoma 8890/3
Squamous cell carcinoma 8070/3 Synovial sarcoma 9040/3
Neuroendocrine neoplasmsb Lymphomas

Secondary tumours
NET G2 8249/3
___________________________________________________________
a
The morphology codes are from the International Classification of Diseases for Oncology (ICD-O) {904A}. Behaviour is coded /0 for benign tumours, /1 for un-
specified, borderline or uncertain behaviour, /2 for carcinoma in situ and grade III intraepithelial neoplasia, and /3 for malignant tumours; b The classification is
modified from the previous WHO histological classification of tumours {691} taking into account changes in our understanding of these lesions. In the case of neu-
roendocrine neoplasms, the classification has been simplified to be of more practical utility in morphological classification; * These new codes were approved by
the IARC/WHO Committee for ICD-O at its meeting in March 2010.
TNM classificationa of tumours of the stomach

Carcinoma of the stomach
T – Primary tumour N – Regional lymph nodes
TX Primary tumour cannot be assessed NX Regional lymph nodes cannot be assessed
T0 No evidence of primary tumour N0 No regional lymph-node metastasis
Tis Carcinoma in situ: intraepithelial tumour without invasion of N1 Metastasis in 1 to 2 regional lymph nodes
the lamina propria, high-grade dysplasia N2 Metastasis in 3 to 6 regional lymph nodes
T1 Tumour invades lamina propria, muscularis mucosae, or N3 Metastasis in 7 or more regional lymph nodes
submucosa N3a Metastasis in 7 to 15 regional lymph nodes
T1a Tumour invades lamina propria or muscularis mucosae N3b Metastasis in 16 or more regional lymph nodes
T1b Tumour invades submucosa
T2 Tumour invades muscularis propria M – Distant metastasis
T3 Tumour invades subserosa M0 No distant metastasis
T4 Tumour perforates serosa or invades adjacent structures M1 Distant metastasis
T4a Tumour perforates serosa (visceral peritoneum)
T4b Tumour invades adjacent structuresb,c,d
46 Tumours of the stomach

Stage grouping
Stage T N M Stage T N M
Stage 0 Tis N0 M0 Stage IIIA T4a N1 M0
Stage IA T1 N0 M0 T3 N2 M0
Stage IB T2 N0 M0 T2 N3 M0
T1 N1 M0 Stage IIIB T4b N0, N1 M0
Stage IIA T3 N0 M0 T4a N2 M0
T2 N1 M0 T3 N3 M0
T1 N2 M0 Stage IIIC T4a N3 M0
Stage IIB T4a N0 M0 T4b N2, N3 M0
T3 N1 M0 Stage IV Any T Any N M1
T2 N2 M0
T1 N3 M0
Carcinoid of the stomache

T – Primary tumourf M – Distant metastasis
TX Primary tumour cannot be assessed M0 No distant metastasis
T0 No evidence of primary tumour M1 Distant metastasis
Tis Carcinoid in situ/dysplasia (tumour less than 0.5 mm, confined
to mucosa) Stage grouping
T1 Tumour confined to mucosa and 0.5 mm or more but no Stage T N M
greater than 1 cm in size; or invades submucosa and is no
greater than 1 cm in size Stage 0 Tis N0 M0
T2 Tumour invades muscularis propria or is more than 1 cm in size Stage I T1 N0 M0
T3 Tumour invades subserosa Stage IIA T2 N0 M0
T4 Tumour perforates visceral peritoneum (serosa) or other organs Stage IIB T3 N0 M0
or adjacent structures Stage IIIA T4 N0 M0
N – Regional lymph nodes Stage IIIB Any T N1 M0
NX Regional lymph nodes cannot be assessed Stage IV Any T Any N M1
N0 No regional lymph-node metastasis
N1 Regional lymph-node metastasis
Gastrointestinal stromal tumour (GIST)

T – Primary tumour Stage grouping for gastric GISTi
TX Primary tumour cannot be assessed Stage T N M Mitotic rate
T0 No evidence for primary tumour Group IA T1, T2 N0 M0 Low
T1 Tumour 2 cm or less in greatest dimension Group IB T3 N0 M0 Low
T2 Tumour more than 2 cm but not more than 5 cm Group II T1, T2 N0 M0 High
T3 Tumour more than 5 cm but not more than 10 cm T4 N0 M0 Low
T4 Tumour more than 10 cm in greatest dimension Group IIIA T3 N0 M0 High
N – Regional lymph nodes Group IIIB T4 N0 M0 High
NX Regional lymph nodes cannot be assessedg Group IV Any T N1 M0 Any rate
N0 No regional lymph-node metastasis Any T Any N M1 Any rate
N1 Regional lymph-node metastasis Stage grouping for small-intestinal GISTi
M – Distant metastasis Stage T N M Mitotic rate
M0 No distant metastasis Group I T1, T2 N0 M0 Low
M1 Distant metastasis Group II T3 N0 M0 Low
G – Histopathological grading Group IIIA T1 N0 M0 High
Grading for GIST is dependent on mitotic rateh T4 N0 M0 Low
Low mitotic rate: 5 or fewer per 50 hpf Group IIIB T2, T3, T4 N0 M0 High
High mitotic rate: more than 5 per 50 hpf Group IV Any T N1 M0 Any rate
Any T Any N M1 Any rate
____________________
a
{762, 2996}; b The adjacent structures of the stomach are the spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small
intestine, and retroperitoneum; c Intramural extension to the duodenum or oesophagus is classified by the depth of greatest invasion in any of these sites, including
stomach; d Tumour that extends into gastrocolic or gastrohepatic ligaments or into greater or lesser omentum, without perforation of visceral peritoneum, is T3;
e
Neuroendocrine tumour (NET) or well-differentiated neuroendocrine tumour/carcinoma; f For any T, add (m) for multiple tumours; g NX: Regional lymph-node
involvement is rare for GISTs, so that cases in which the nodal status is not assessed clinically or pathologically could be considered N0 instead of NX or pNX;
h
The mitotic rate of GIST is best expressed as the number of mitoses per 50 high power fields (hpf) using the 40 × objective (total area, 5 mm2 in 50 fields);
i
Staging criteria for gastric tumours can be applied in primary, solitary omental GISTs. Staging criteria for intestinal tumours can be applied to GISTs in the oesophagus,
colon, rectum, and mesentery.
Classification 47
Gastric carcinoma G.Y. Lauwers

F. Carneiro
S. Franceschi
E. Montgomery
D.Y. Graham M. Tatematsu
M.-P. Curado T. Hattori
Definition high at > 60 per 100 000 males include

Gastric carcinomas are malignant epithelial eastern Asia (Republic of Korea and
neoplasms. They represent a biologically Japan), eastern Europe and central and
and genetically heterogeneous group of Latin America. Low-incidence areas
tumours with multifactorial etiologies, both (< 15 per 100 000 population) include
environmental and genetic. They are North America, northern Europe, and most
characterized by broad morphological countries in Africa and south-eastern Asia
heterogeneity with respect to patterns of {634}. The “intestinal” type of adenocarci-
architecture and growth, cell differentiation noma (ICD-O code 8144/3) is relatively
and histogenesis. predominant in high-incidence regions of
the world, whereas the “diffuse” type
ICD-O codes (ICD-O code 8145/3) is relatively more
Adenoma 8140/0 common in low-incidence areas. Cancers
Intraepithelial neoplasia (dysplasia) of the antrum and pylorus are most
Low grade 8148/0 common in high-incidence geographical
High grade 8148/2 areas, whereas cancers of the proximal
Fig. 4.01 Growth patterns of early gastric carcinoma.
Adenocarcinoma 8140/3 stomach (“cardia”) occur most commonly
Papillary adenocarcinoma 8260/3 where incidence is low {2483}.
Tubular adenocarcinoma 8211/3 Countries with a high incidence of gastric rise, presumably due to the advancing age
Mucinous adenocarcinoma 8480/3 cancer and where asymptomatic patients of the global population {2489}. More specif-
Poorly cohesive carcinoma are screened have a high proportion ically, there has been a shift in the propor-
(including signet ring cell carcinoma (30–50%) of early gastric cancer (e.g. tion of some subtypes. For instance, the
and other variants) 8490/3 Japan) {1210, 2377}, an invasive carcinoma incidence of “tubular” adenocarcinoma has
Mixed adenocarcinoma 8255/3 that is limited to the mucosa, or the decreased mainly in young patients {1471}.
Adenosquamous carcinoma 8560/3 mucosa and submucosa. In contrast, the Paradoxically, despite the overall decreas-
Carcinoma with lymphoid stroma proportion of early gastric cancer is much ing rates of gastric cancer, the incidence of
(medullary carcinoma) 8512/3 lower (16–24%) in North America and “diffuse” carcinoma localized to the proximal
Hepatoid adenocarcinoma 8576/3 European countries {445, 1057, 1067}. stomach has been increasing {2101}.
Squamous cell carcinoma 8070/3
Undifferentiated carcinoma 8020/3 Time trends Age and sex distribution
There has been a steady decline in both the Gastric carcinoma is rare in persons aged
Epidemiology incidence and mortality of gastric carcinoma < 30 years. In general, incidence increases
Gastric cancer accounts for 7.8% of cancers worldwide over the last 15 years. However, progressively with age in males and
worldwide {842A}. Areas where incidence is the absolute incidence rate continues to females {634}. In young people, tumours
A B
Fig. 4.02 Age-standardized incidence (per 100 000) of stomach cancer in males {842A}. A Worldwide incidence. Numbers on the map indicate regional average values.
B The incidence of stomach cancer is decreasing worldwide, including in countries with a high disease burden.

are more likely to be hereditary, a greater acids) is not well understood, and H. pylori baseline {3541}. When considering pre-
proportion are of the “diffuse” type and is not an important risk factor for stump cancerous lesions as end-points, eradica-
females are more frequently affected than cancer, its growth being impaired by tion of H. pylori is found to have a
males {1471, 2101}. gastroduodenal reflux {1644, 2978}. significant beneficial effect {1810, 1828,
2051, 3654}. Finally, a randomized con-
Etiology Infection with H. pylori trolled trial study of 544 H. pylori-positive
Smoking H. pylori infection, which is commonly Japanese patients with early gastric
An association between smoking and acquired during early childhood and cancer has shown a significant reduction
gastric cancer that is not explained by persists throughout adult life unless eradi- in the recurrence of cancer (from 4% to
bias or confounding factors has been cated, is the most important cause of distal 1.4%) in the group receiving eradication
shown {1025, 1333}. Futhermore, smoking gastric carcinoma {316}. In a subset of therapy after endoscopic resection {917}.
also potentiates the carcinogenic effect of patients, persistent infection with H. pylori Factors associated with colonization and
infection with cagA-positive Helicobacter for several decades induces a series of pathogenicity of H. pylori comprise outer
pylori {330, 2970, 3680}. phenotypical changes (i.e. chronic gastritis, membrane proteins, including BabA,
mucosal atrophy, focal intestinal metapla- SabA, OipA, AlpA/B, homB {1452, 1953,
Diet sia and dysplasia) that occur before the 2350} as well as the virulence factors
Certain dietary habits are associated with development of “intestinal” type adeno- cagA in the cag pathogenicity island
an increased risk of gastric cancer, espe- carcinoma {602, 612, 782, 2749, 3467}. (cagPAI) and the vacuolating cytotoxin
cially of “intestinal” type. These include Nested case–control studies and prospec- vacA {156, 210, 462}. Polymorphic deter-
high intakes of salt-preserved and/or tive cohort studies have underscored the minants influencing the expression of
smoked foods {1788, 2935} and low increased relative risk associated with vacA cytotoxin include the signal region
intakes of fresh fruit and vegetables, H. pylori infection; in a meta-analysis eval- (s1 and s2), mid-region (m1 and m2),
particularly in combination with H. pylori uating prospective studies in subjects intermediary region (i1 and i2) and d
infection {773, 799, 1332, 2543, 2935}. tested at least 10 years before diagnosis, region (d1 and d2) {2312, 2363, 2668}.
High intakes of all meat, red meat, and the odds ratio was 5.9 (95% confidence Strains producing the cagA protein that
processed meat have been associated interval, 3.4–10.3) {882, 1157, 2316, 2491}. induce a greater degree of inflammation
with an increased risk of “non-cardia” The relative risk increases when the most are associated with gastric precancerous
cancer {1024}. The true impact of dietary sensitive testing procedures, e.g. immuno- lesions and a greater risk of developing
factors is difficult to assess in observa- blot, are used {2096, 2969}. The preventive “non-cardia” cancer {2440, 2568, 2609}.
tional studies owing to insufficient accu- role of antibiotic therapy has been noted in Although the risk of gastric cancer in
racy in the assessment of exposure and patients free of atrophy or metaplasia at some countries of Europe and North
in controls for confounding factors {1332}.
Trials of antioxidant supplements

Despite claims for a protective effect
associated with high intake of fresh fruit
and vegetables {1332}, a recent meta-
analysis of randomized trials comparing
antioxidant supplements (i.e. β-carotene
and vitamins A, C, E and selenium, alone
or in combination) with placebo or no
intervention did not show a significant
protective effect on the incidence of
gastric cancer {271}. The results seem, A B
however, to be influenced by whether the Fig. 4.03 Early gastric carcinoma in the antrum, endoscopic view. A Conventional endoscopy. B Chromoendoscopy
trials are performed in well-nourished pop- markedly improves the visibility of the lesion.
ulations or in those likely to have nutritional
deficiencies (in which antioxidants may
have a beneficial effect) {2604}. In the
latter case, a significant reduction (11%) in
mortality is noted in individuals receiving
β-carotene, vitamin E and selenium, no-
tably in individuals aged < 55 years {2604}.
Bile reflux
The risk of gastric carcinoma increases
5–10 years after gastric surgery, especially
after a Bilroth II operation (which increases
bile reflux) has been performed. However, A B
the mechanism (including the role of bile Fig. 4.04 Advanced gastric carcinoma, endoscopic view. A Type 2 (fungating). B Type 3 (ulcerated).
Gastric carcinoma 49
cause DNA damage (usually generating individual (or familial) susceptibility to car-
point mutations, the commonest being cinogenesis associated with H. pylori {777}.
G:C->A:T.) and provoking either DNA repair It has been suggested that in individuals
or apoptosis {604}. In vivo, an increase in with alleles that predispose to inflammation,
the formation of micronuclei in peripheral infection with H. pylori may cause increased
blood lymphocytes {3110}, DNA damage production of gastric interleukin 1 β, leading
{1716}, and DNA-adduct formation have to severe and sustained inflammation that
been noted in individuals infected with would increase the risk of developing
H. pylori. Infection has also been associ- gastric cancer {104, 776, 778, 855}.
ated with modified expression of specific
oncogenes or tumour-suppressor genes, Localization
e.g. CTNNB1 (β-catenin), CCND1 (cyclin The most frequent site of “non-cardia”
D1), TP73 (p73) and CDKN1B (p27) {767, gastric cancer is the antro-pyloric region.
888, 3481}. Carcinomas of the “cardia” have been
Fig. 4.05 Growth patterns of advanced gastric cancer
Corpus-predominant gastritis with multifocal most commonly reported in North American
according to the Borrmann classification.
gastric atrophy, and hypo- or achlorhydria and European populations {632}, but this
is seen in approximately 1% of subjects is likely to change subsequent to revision
America has been related to vacA geno- infected with H. pylori. As a direct conse- of the classification of adenocarcinomas
type {856, 1293}, such relationships have quence of elevation in gastric pH, there is a of the oesophagogastric junction and the
not been observed in east Asian countries; change in gastric flora, with colonization by TNM (tumour, node, metastasis) classifi-
the consequences of variation in vacuo- anaerobic bacteria responsible for the for- cation of 2009 {762, 2996}. According to
lating activity are apparently dependent mation of carcinogenic nitrosamines {2795}. the TNM classification, if the epicentre of
on geographical region {2363}. Finally, the role of bone marrow-derived a tumour is within 5 cm of the oesophago-
Ammonia, which stimulates cell replication, cells that may contribute to repopulation of gastric junction and extends into the
is abundantly liberated by the potent ure- the mucosa, in the setting of mucosal distal oesophagus, the tumour should be
ase activity of H. pylori bacteria. H. pylori damage, may lead to the development of staged as an oesophageal carcinoma.
also causes increased expression of the metaplasia and neoplasia {603, 1250}. Consequently, the gastric antrum is likely
inducible isoform of nitric oxide synthetase, The severity and extent of gastritis caused to become the most common site of
with continuous production of oxidants and by H. pylori are modulated by cytokines. gastric carcinoma in North American and
reactive nitrogen intermediates, including Polymorphisms of the interleukin 1 β (IL1B) European series, in conformity with the
nitric oxide {1973}. Nitrosated compounds gene (initiation and amplification of inflam- rest of the world. Carcinomas in the body
are recognized gastric carcinogens in the matory response) and the interleukin 1 of the stomach are typically located along
experimental setting. Free radicals, oxi- receptor antagonist gene (IL1RN) (modula- the greater or lesser curvature.
dants and reactive nitrogen species all tion of inflammation) are associated with
Clinical features
Endoscopy is a sensitive and specific
diagnostic test for gastric cancer. Modern
video-endoscopy allows the recognition
of subtle changes in colour, relief, and
architecture of the mucosal surface.
Although detection of lesions associated
with early gastric cancer can be improved
using chromoendoscopy and narrow-band
imaging, a substantial number of such
lesions still escape detection {1247}.
B Gastric cancers are classified endoscop-
ically according to growth pattern {1390,
2186}. Early gastric cancers are divided
into three types: protruded (type 0-I);
superficial (type 0-II); and excavated
(type 0-III) {1389}. The superficial type
accounts for 80% of early gastric cancers
and is further subdivided into 0-IIa (elevated
type), 0-IIb (flat type), and 0-IIc (depressed
type), the latter being the most common
{3572}. Histologically, most early gastric
cancers have a tubular or papillary archi-
A C tecture.
Fig. 4.06 Early gastric cancer, macroscopic features. A Type 0-IIc (superficial depressed). B Type 0-I (protruded). The risk of deep and multifocal penetra-
C Type 0-IIa (superficial elevated). tion of the submucosa and of lymphatic

invasion vary according to type, being Positron emission tomography (PET) in types are common. Diffuse (infiltrative)
greater for type 0-IIc. Infiltration of the combination with CT imaging may be tumours (type 4) spread superficially,
gastric wall (linitis plastica or “leather superior to either alone for preoperative producing flat, plaque-like lesions, with or
bottle”) may be suspected if there is staging {505, 1854, 2728}. Laparoscopic without shallow ulcerations. With exten-
limited flexibility of the gastric wall. Since staging may be the only way to exclude sive infiltration, linitis plastica may
the invasive cells percolate beneath a peritoneal seeding in the absence of ascites. develop. Mucinous adenocarcinomas
usually normal mucosa, the diagnosis appear gelatinous with a glistening cut
may require multiple, “jumbo” biopsies. Macroscopy surface.
The depth of invasion of the tumour is Noninvasive neoplasia – intraepithelial
staged by endoscopic ultrasound. neoplasia or dysplasia – may present as a Tumour spread and staging
Radiology with barium meal is still used in flat process that is difficult to detect by Gastric carcinomas can spread either by
mass-screening protocols in Japan, conventional endoscopy but may be direct extension to adjacent organs,
followed by endoscopy if an abnormality apparent after dye-staining, or as a metastasis or peritoneal dissemination.
is detected. Recently, testing for serum polypoid growth (sometimes reported as Carcinomas of the “intestinal” type pref-
pepsinogen has been used as a screen- adenoma), or with an intermediate erentially metastasize haematogenously
ing tool to identify high-risk patients and appearance as a depressed or reddish or to the liver, whereas carcinomas composed
detect early cancers {2080}. discoloured mucosa. The macroscopic of poorly cohesive cells (“diffuse” type)
Tumour staging before treatment decision type of early gastric carcinoma is classi- preferentially metastasize to peritoneal
involves endoscopic ultrasound for char- fied using criteria similar to those used in surfaces {432, 2151}. Mixed carcinomas
acterization of the primary tumour, but is endoscopy {1390, 2186}. The gross exhibit the metastatic patterns of both
less useful for nodal (N) staging, whereas appearance of advanced carcinoma is types {2151}.
computed tomography (CT) is used to described according to the Borrmann clas- “Diffuse” cancers of the antro-pyloric region
detect lymph-node and liver metastases. sification {308}. Fungating and ulcerated have a high frequency of serosal and
A B
Fig. 4.07 A Mucinous carcinoma of the stomach. Irregular cords and clusters of mucus-secreting epithelial elements are readily identified floating in the abundant mucinous
material. B Mixed carcinoma. The lesion shows both papillary (intestinal) and poorly cohesive (diffuse) components.
A B
Fig. 4.08 A Tubular adenocarcinoma of the stomach. Note the tall columnar and mucin-rich cellular elements reminiscent of normal foveolar epithelium. B Papillary adenocarcinoma
composed of exophytic projections lined by cuboidal neoplastic cells.
classification proposed by the International thus contributing to harmonization of the

Union Against Cancer and the American histological typing of carcinomas of the
Joint Committee on Cancer (UICC/AJCC): gut. The main categories are tubular, pap-
(1) T1 was subdivided to delineate mu- illary, mucinous, poorly cohesive (including
cosal and submucosal depth of invasion; signet-ring cell type) and mixed carcino-
(2) T2a and T2b were separated into T2 mas. The WHO classification, however,
(muscularis propria) and T3 (subserosa); does not take into account histogenesis,
(3) T3 and T4 were changed to T4a differentiation or epidemiological data.
(penetrates serosa) and T4b (invades
adjacent structures), respectively; (4) The Tubular adenocarcinoma
T, N, and M categories are now almost This type is composed of dilated or slit-like
Fig. 4.09 Undifferentiated gastric carcinoma. identical to those for the oesophagus (and and branching tubules of varying diame-
oesophago-gastric junction) except that ter. Acinar structures may also be present.
lympho-vascular invasion and lymph-node N3 (metastasis in 7 or more regional lymph Individual neoplastic cells can be colum-
metastases. These tumours also commonly nodes) is divided into N3a (7–15 nodes) nar, cuboidal, or flattened by prominent
invade the duodenum via submucosal or and N3b (≥ 16 nodes) for gastric but not intraluminal mucin. A clear cell variant has
subserosal routes or via the submucosal oesophageal carcinomas {762, 2996}. been recognized. The degree of nuclear
lymphatics. Duodenal invasion occurs atypia varies from low- to high-grade
more frequently than expected on the basis Histopathology {792, 2301}. There is a poorly differentiated
of gross examination and, in practical The heterogeneity of gastric carcinomas variant, sometimes called solid carcinoma.
terms, resection margins should be moni- is reflected in part by the diversity of the Tumours with prominent lymphoid stroma
tored by intraoperative consultation. When various histopathological classification are sometimes called carcinoma with lym-
the carcinoma penetrates the serosa, peri- schemes on record. Although the most phoid stroma {3463}, medullary carcinoma
toneal implants generally flourish. Bilateral commonly used are those of WHO and {2083}, or lymphoepithelioma-like carci-
massive involvement of the ovaries Laurén {1758}, several other schemes noma {3445}. The degree of desmoplasia
(Krukenberg tumour) can result from have been proposed, including those of varies and may be conspicuous.
transperitoneal or haematogenous spread. Ming {2085}, Nakamura {2214}, Mulligan
The principal value of nodal dissection is {2182}, Goseki {1039} and Carneiro {426}. Papillary adenocarcinoma
the detection and removal of metastatic This is a well-differentiated exophytic
disease and appropriate staging. The WHO classification carcinoma with elongated finger-like
accuracy of pathological staging is This is a strictly descriptive scheme that processes lined by cylindrical or cuboidal
proportional to the number of regional recognizes five main types of gastric cells supported by fibrovascular connec-
lymph nodes examined and their anatom- adenocarcinoma and rare entities. The tive tissue cores. The cells tend to maintain
ical location in relation to the neoplasm. If major advantage of the WHO classification their polarity. Some tumours show tubular
only nodes that are close to the tumour are is the recognition of morphological patterns (papillotubular) differentiation. Rarely,
assessed, many cancers can be classified that are also exhibited by neoplasms in micropapillary architecture is present. The
incorrectly. Staging for gastric carcinoma other segments of the gastrointestinal degree of cellular atypia and mitotic index
was substantially modified in the 2009 tract, such as the small and large bowel, vary; there may be severe nuclear atypia.
The invading edge of the tumour is
usually sharply demarcated; the tumour
may be infiltrated by acute and chronic
inflammatory cells.
Mucinous adenocarcinoma
This tumour is composed of malignant
epithelium and extracellular mucinous
pools. By convention, the tumour shows
more than 50% extracellular mucin. Muci-
nous carcinomas may contain scattered
signet-ring cells.
Poorly cohesive carcinomas, including

signet ring cell carcinoma and other
variants
Poorly cohesive carcinomas are composed
of neoplastic cells that are isolated or
arranged in small aggregates. These
encompass:
Fig. 4.10 Poorly cohesive carcinoma. This example displays a combined cellular infiltrate, with classic signet ring cells, Signet-ring cell type is defined as a tumour
bizarre/pleomorphic cells and smaller eosinophilic cells. composed predominantly or exclusively of

A B
Fig. 4.11 Hepatoid adenocarcinoma of the stomach. A The tumour is composed of hepatocyte-like neoplastic cells Fig. 4.12 Adenosquamous carcinoma of the stomach:
growing in a sheet-like pattern. B Immunohistochemical staining for α-fetoprotein confirms the presence of hepatocytic the neoplasm combines adenocarcinoma and squamous
differentiation. cell carcinoma, with a transition between both elements.
signet-ring cells, characterized by a central mixed and indeterminate types {1758}. lymphoid stroma {2008, 2192, 2222, 3445,
optically clear, globoid droplet of cyto- Diffuse carcinomas consist of poorly 3463, 3512, 3600}, choriocarcinoma {1321},
plasmic mucin with an eccentrically cohesive cells with little or no gland for- carcinosarcoma {1311, 1463, 2247, 2825},
placed nucleus. Malignant signet-ring cells mation. Intestinal carcinomas form glands parietal cell carcinoma {411, 3613}, ma-
may form a lace-like gland or delicate with various degrees of differentiation. lignant rhabdoid tumour {2694, 3337},
microtrabecular pattern in the mucosa or Tumours containing approximately equal mucoepidermoid carcinoma {1140}, Paneth
be accompanied by marked desmoplasia quantities of intestinal and diffuse cell carcinoma {2405}, undifferentiated
in deeper levels of the stomach wall. In some components are termed “mixed”. carcinoma, mixed adeno-neuroendocrine
cases, signet-ring cells may be restricted Undifferentiated tumours are classified as carcinomas, endodermal sinus tumour,
to the mucosa in combination with other indeterminate. The Ming classification embryonal carcinoma, pure gastric yolk-
variants of poorly cohesive cells within the {2085} is based on patterns of growth and sac tumour and oncocytic adenocarci-
deeper levels of the gastric wall. invasion at the advancing edge and noma {1760}.
Other cellular variants of poorly cohesive divides tumours into expanding and
carcinoma include tumours composed of infiltrative types. Nakamura categorizes Hepatoid adenocarcinoma
neoplastic cells resembling histiocytes or all tumours as either differentiated or Hepatoid adenocarcinoma is composed of
lymphocytes; others have deeply eosino- undifferentiated {2214}. The Mulligan large polygonal eosinophilic hepatocyte-
philic cytoplasm; some poorly cohesive system divides tumours into mucus, like neoplastic cells. α-Fetoprotein (AFP)
cells may show irregular, bizarre nuclei. intestinal, and pyloro-cardiac gland types can be detected in situ, but also in the
A mixture of the different cell types can be {2182}. Goseki recognizes four types on serum. Bile and periodic acid-Schiff (PAS)-
present, including few signet-ring cells. the basis of tubular differentiation and positive and diastase-resistant intracyto-
intracellular production of mucin {1039}. plasmic eosinophilic globules can be
Mixed carcinoma Finally, the Carneiro system recognizes observed. Other rare AFP-producing carci-
These carcinomas display a mixture of four categories (glandular, isolated cell, nomas include well-differentiated papillary
discrete morphologically identifiable solid and mixed) on the basis of morphol- or tubular-type adenocarcinoma with clear
glandular (tubular/papillary) and signet- ogy and immunophenotype; thus tumours cytoplasm and yolk-sac tumour-like carci-
ring/poorly-cohesive cellular histological designated as “intestinal” by the Laurén noma {1326, 1361, 2169, 2203}.
components. Any discrete histological classification are subclassified into tumours
component should be reported; although with intestinal, gastric or mixed differenti- Gastric carcinoma with lymphoid stroma
the prognostic relevance of the proportion ation {426, 431, 865}. Lines of differentiation This tumour, also reported as lympho-
of each component has not been estab- can be established using gastric markers epithelioma-like carcinoma or medullary
lished, preliminary data suggest that any (mucins MUC5AC, MUC6, and trefoil carcinoma, is characterized by poorly
signet-ring/poorly cohesive cellular histo- peptide TFF1), intestinal markers (MUC2, developed tubular structures associated
logical component is associated with a transcription factor CDX2 and CD10), and with a prominent lymphoid infiltration of
poor prognosis. others (pepsinogen-1) {426, 1692, 1694, the stroma. These tumours frequently
Mixed carcinomas are clonal {447A, 3705} 1938, 1939, 2956, 3312}. Some studies have affect the proximal stomach or gastric
and phenotypic divergence has been shown that phenotypic characterization has stump and are more common in males
attributed to somatic mutation in the prognostic value {1113, 1786, 3430}. while > 80% are associated with infection
E-cadherin gene (CDH1), which is with Epstein-Barr virus (EBV) {2192}.
restricted to the signet-ring/poorly-cohesive Rare histological variants The role of EBV in carcinogenesis is
component {1941}. Uncommon histological variants represent debated, but occurs at an early stage since
about 5% of gastric cancers. These in- EBV can be found in adjacent dysplasia.
Other classification schemes clude adenosquamous carcinoma {2148, The prognosis for patients with these
In the Laurén classification, tumours are 2249, 3648}, squamous cell carcinoma tumours is reportedly better than that for
separated into diffuse (ICD-O code {1994, 3539}, hepatoid adenocarcinoma patients with typical gastric cancers {2008,
8145/3), intestinal (ICD-O code 8144/3), {1326, 1361, 2169, 2203}, carcinoma with 2192, 2222, 3445, 3463, 3512, 3600}.
Gastritis
Classification schemes, such as the
Sydney system, have attempted to com-
bine topographic, morphological, and eti-
ological information into a reporting system
designed to include both grading and
staging of gastritis {726, 2589, 2750, 2751}.
Autoimmune gastritis develops secondary
to the development of autoantibodies to
A B parietal and chief cells and thus affects
the body fundic mucosa. It is associated
with the formation of intestinal metaplasia
and an increased risk of developing
gastric carcinoma, mostly of intestinal
type {3014}. A cross-reactive mechanism
between H. pylori and gastric epithelial
antigens that may be responsible for, or
at least participate in, the pathogenesis of
autoimmune gastritis has been proposed
{642}.
C D
Fig. 4.13 Examples of gastric adenocarcinomas exhibiting different phenotypes. A Gastric foveolar cell mucin, Intestinal metaplasia
MUC5AC(+). B Pyloric-gland cell mucin, MUC6(+). C Intestinal goblet-cell mucin, MUC2(+). D Small-intestinal brush The two main types of intestinal metapla-
border differentiation, CD10(+). sia are: “complete” (also designated as
“small intestinal type” or type I), and “in-
Gastric choriocarcinoma predictive of regional lymph-node metas- complete” (types IIA/II and IIB/III) {857,
Gastric choriocarcinomas usually display tasis with improved outcome {1098, 1781, 859}. Using newly developed antibodies,
syncytiotrophoblast and cytotrophoblast 2109}. Scirrhous stromal reaction has an immunohistochemical classification of
elements admixed with adenocarcinoma. been noted as a predictor of aggressive intestinal metaplasia is possible. Com-
Yolk-sac and hepatoid components can behaviour and peritoneal seeding {1278}. plete-type metaplasia shows decreased
also be seen. Human chorionic gonado- expression of “gastric” mucins (MUC1,
tropin can be detected in situ and in the Grading MUC5AC and MUC6) and expression of
serum. These tumours are frequently asso- The grading system applies primarily to MUC2, an intestinal mucin. In contrast, in
ciated with haematogenous dissemination tubular and papillary carcinomas (not incomplete intestinal metaplasia, gastric
and nodal metastases {1321}. other types). Well-differentiated adeno- mucins are co-expressed with MUC2.
carcinomas are composed of well-formed These expression patterns show that in-
Early gastric cancer glands, sometimes resembling metaplastic complete intestinal metaplasia has a
This is an invasive carcinoma that is limited to intestinal epithelium. Moderately differen- mixed gastric and intestinal phenotype
the mucosa, or the mucosa and submucosa, tiated adenocarcinomas are composed of reflecting an aberrant differentiation pro-
regardless of nodal status. Most such can- neoplams that are intermediate between gramme {2656}. Some studies (but not all)
cers measure 2–5 cm and are located on the well- and poorly differentiated. Poorly indicate a positive correlation between
lesser curvature and around the angulus differentiated adenocarcinomas comprise the degree of incomplete intestinal
{1822, 2086}. If untreated, most progress highly irregular glands that are recognized metaplasia and the extent of intestinal
over a few months to several years {3313}. with difficulty. They may also be graded metaplasia and risk of progression to
Tubular and papillary variants represent as low-grade (well- and moderately carcinoma {679, 782, 858, 1473, 2716,
50% and 30%, respectively, of cases. differentiated) or high-grade (poorly 2743, 2988}. Some authors also claim that
Signet ring cell carcinoma and “poorly differentiated). intestinal metaplasia is a paracancerous
differentiated” carcinoma represent 25% not a precancerous lesion {1460}.
and 15% of cases, respectively, and are Precursor lesions In another pattern of metaplasia termed
usually depressed or ulcerated {808, Gastritis and intestinal metaplasia spasmolytic polypeptide-expressing meta-
1822, 3572}. Particularly in high-incidence areas, some plasia (SPEM), the expression of TFF2
patients with H. pylori-associated chronic spasmolytic polypeptide is associated
Stromal reactions gastritis develop atrophy followed by with oxyntic atrophy. SPEM, which char-
The four common stromal responses to intestinal metaplasia over time. This is the acteristically develops in the gastric body
invasive gastric carcinoma are marked beginning of a sequence of events that and fundus, appears to share some char-
desmoplasia, lymphocytic infiltration, stro- may culminate in neoplasia, especially acteristics with pseudopyloric metaplasia,
mal eosinophilia and a granulomatous adenocarcinoma of “intestinal” type {601, has a strong association with chronic
response. The density of tumour-infiltrating 602, 1319}. infection with H. pylori and with gastric
lymphocytes, particularly peritumoral adenocarcinoma, and may represent
regulatory T cells, has been shown to be another pathway to gastric neoplasia {1094}.

A B
Fig. 4.14 Intraepithelial neoplasia (dysplasia). A Low grade: the lesion shows mild cytological atypia with basally Fig. 4.15 Intraepithelial neoplasia (dysplasia) of gastric
located, polarized and pencillate hyperchromatic nuclei. B High grade: the neoplastic tubules display enlarged rounded phenotype (type II). The cells have a characteristic clear
markedly atypical nuclei with stratification and loss of polarization. to pale eosinophilic cytoplasm.
Premalignant lesions associate with prominent mitoses usually neoplasia {1764, 2840}. For instance,
In Chapter 1, a historical perspective and located near the proliferative zone in the lesions interpreted by the latter as high-
an overview of terminology used for pre- mucus-neck region. In intestinal metaplasia, grade intraepithelial neoplasia (dysplasia)
malignant lesions in the present edition areas indefinite for intraepithelial neoplasia have been frequently classified by Japan-
are presented, including the definition of may exhibit a hyperproliferative meta- ese pathologists as “noninvasive intramu-
intraepithelial neoplasia/dysplasia. Major plastic epithelium. The glands may appear cosal carcinoma.” In an attempt to resolve
interpretative problems associated with closely packed and lined by cells with this issue, several proposals have been
diagnosing gastric intraepithelial neoplasia large, hyperchromatic basally located made regarding terminology of the morpho-
(dysplasia) include distinguishing such nuclei. The cytoarchitectural alterations logical spectrum of lesions ranging from
conditions from reactive or regenerative tend to decrease from the base of the non-neoplastic changes to early invasive
changes associated with active inflam- glands to their superficial portion. cancer, including the Padova and Vienna
mation, and the distinction between intra- classifications {2753, 2842, 3090}.
mucosal and invasive carcinoma {1764, (3) Intraepithelial neoplasia (dysplasia) Intraepithelial neoplasia (gastric epithelial
2840}. Recognizing that the terminology This category comprises unequivocally dysplasia) can have polypoid, flat, or
of dysplasia is entrenched in the European epithelial neoplastic proliferations char- slightly depressed growth patterns; the
and particularly North-American literature, acterized by variable cellular and archi- flat or slightly depressed patterns may
as well as in clinical practice, “intraepithelial tectural atypia, but without convincing show an irregular appearance on chromo-
neoplasia” and “dysplasia” are acceptable evidence of invasive growth. endoscopy or microvasculature anomalies
terms. The following three categories There are well-known differences between on narrow-band imaging, which are not
should thus be considered: Japanese and European/North American apparent with conventional white-light
pathologists in categorizing intraepithelial endoscopy. In European countries and
(1) Negative for intraepithelial neoplasia
(dysplasia)
This category includes benign mucosal
processes that are inflammatory, meta-
plastic, or reactive in nature.
(2) Indefinite for intraepithelial neoplasia

(dysplasia)
The use of this term represents a prag-
matic solution to an ambiguous morpho-
logical pattern, but is not a final diagnosis.
This category is favoured where there is
doubt as to whether a lesion is neoplastic
or non-neoplastic (i.e. reactive or regen-
erative), particularly in small biopsies
exhibiting inflammation. In such cases,
the dilemma is usually solved by cutting
deeper levels, by obtaining additional
biopsies, or after correcting for possible
etiologies. Foveolar hyperproliferation
may be seen, showing irregular and
tortuous tubular structures with epithelial
mucus depletion, a high nucleus to cyto- Fig. 4.16 Intramucosal invasive neoplasia/intramucosal carcinoma. In addition to invasion of the muscularis mucosae,
plasm ratio, and loss of cellular polarity. this lesion is distinguished from high-grade intraepithelial neoplasia (dysplasia) by architectural glandular anomalies,
Large, oval/round, hyperchromatic nuclei i.e. crowding, excessive branching and budding.
Low-grade intraepithelial neoplasia Gastric polyps

(dysplasia). Shows minimal architectural Neoplastic polyps
disarray and only mild-to-moderate cyto- Neoplastic polypoid lesions in the stom-
logical atypia. The nuclei are elongated, ach encompass carcinoma (primary or
polarized, and basally located, and mitotic secondary), neuroendocrine tumours
activity is mild-to-moderate. For polypoid (addressed in separate chapters of this
lesions, the term “low-grade adenoma” has volume), adenomatous polyps (intestinal
been used {2842}. type), gastric-type adenomas (pyloric-
High-grade intraepithelial neoplasia gland adenomas and foveolar-type
A (dysplasia). Comprises neoplastic cells adenomas), and fundic gland polyps.
that are usually cuboidal, rather than
columnar, with a high nucleus to cyto- Adenomatous polyps
plasm ratio, prominent amphophilic nucleoli, Adenomatous polyps usually show
more pronounced architectural disarray, evidence of intestinal-type differentiation
and numerous mitoses, which can be (absorptive cells, goblet cells, endocrine
atypical. Importantly, the nuclei frequently cells, or even Paneth cells), express
extend into the luminal aspect of the cell, intestinal markers (MUC2 and CD10), and
and nuclear polarity is usually lost. For are negative for gastric mucins (MUC5AC
polypoid lesions, the term “high-grade and MUC6) {1694, 2467}. The risk of
adenoma” has been used {2842}. malignant transformation is related to size
B (> 2 cm) and presence of high-grade
Fig. 4.17 Pyloric-gland adenoma. A The lesion is Intramucosal invasive dysplasia {2470}. However, the importance
characterized by closely packed pyloric gland-type neoplasia/intramucosal carcinoma of the phenotype (intestinal-type versus
tubules lined with cuboidal to low columnar epithelial cells This term defines carcinomas that invade gastric) is debated {13, 2468}.
containing round nuclei and pale to eosinophilic the lamina propria and are distinguished Gastric-type adenomas. These encom-
cytoplasm. B Immunoexpression of MUC6 (marker of from intraepithelial neoplasia (dysplasia) pass pyloric-gland adenoma and foveolar-
pyloric-gland mucin) is characteristic.
not only by desmoplastic changes that can type adenomas. Pyloric-gland adenoma
be minimal or absent, but also by distinct is a rare neoplasm with gastric epithelial
North America, the term “adenoma” has structural anomalies, such as marked differentiation characterized by closely
been applied when the neoplastic prolif- glandular crowding, excessive branching, packed pyloric gland-type tubules with a
eration produces a discrete, protruding and budding. Intraluminal necrotic debris monolayer of cuboidal to low columnar
lesion. In Japan, however, “adenomas” is common. Single infiltrating cells can also epithelial cells containing round nuclei
include all gross types (i.e. flat, elevated, be seen within the lamina propria in the and pale to eosinophilic cytoplasm {515,
and depressed). In the stomach, most absence of desmoplasia. The neoplastic 1694, 2467}. Foveolar-type adenomas are
cases of intraepithelial neoplasia (dyspla- cells in intramucosal invasive neoplasia are rare in general but more common in
sia) have an intestinal phenotype (adeno- usually cuboidal with a high nucleus to patients with familial adenomatous poly-
matous; type I) resembling colonic cytoplasm ratio. Round nuclei with promi- posis (FAP) {13, 1694}, and predominantly
adenomas with crowded, tubular glands nent nucleoli and marked loss of polarity express MUC5AC without MUC6 {515}.
lined by atypical columnar cells with over- are common. Mitoses are usually numerous Whether they are low-risk lesions or not is
lapping, pencillate, hyperchromatic and/or and atypical mitoses can be identified. debated {13, 2468}
pleomorphic nuclei, with pseudostratifi- The diagnosis of intramucosal carcinoma
cation and inconspicuous nucleoli, mucin indicates that there is an increased risk of Fundic-gland polyps
depletion, and lack of surface maturation lymphatic invasion and lymph-node metas- Fundic-gland polyps may occur sporadi-
{1396}. Other variants include a gastric tasis. In some circumstances, novel endo- cally, in patients with FAP {2467}, or as a
phenotype (foveolar or pyloric phenotype; scopic techniques can allow treatment of familial condition confined to the stomach
type II) in which the cells are cuboidal or the patient without open surgery, particu- without polyposis coli {3306} and also
low-columnar, with clear or eosinophilic larly for lesions of < 2 cm in size and for affect patients receiving long-term treat-
cytoplasm, and show round to oval nuclei those that are well-differentiated {2211}. ment with proton-pump inhibitors {96, 883}.
{1396}. The two types may be distin- Sporadic fundic-gland polyps have very
guished by expression of mucin, CD10, Invasive neoplasia weak malignant potential, and the fre-
and CDX2 (intestinal/adenomatous: This terminology defines carcinomas that quency of dysplasia is very low {1381,
MUC2, CD10, and CDX2; gastric/foveolar: show invasion beyond the lamina propria. 3092}. Patients with FAP may develop
MUC5AC, absence of CD10 and low In the stomach, the diagnosis of invasive dysplasia (in up to 48% of cases) in
expression of CDX2) {2311, 2468, 2471}, neoplasia is associated with a varying risk fundic-gland polyps, but carcinomas are
as well as by background changes in the of nodal and distant metastasis and extremely rare {16, 159}.
gastric mucosa {13}. Cases with hybrid overall prognosis. Surgical resection, The frequent finding of genetic alteration
differentiation may also occur {2468}. sometimes with neoadjuvant therapy, is involving the APC/β-catenin pathway,
Intraepithelial neoplasia (dysplasia) is recommended. either sporadic or arising in the setting of
stratified into two grades, low or high. FAP, suggests that fundic-gland polyps
may be neoplastic {14, 15, 3272}.

Non-neoplastic polyps Table 4.01 Frequency of the most common genetic alterations found in gastric carcinomas of “intestinal” and “diffuse” types.
Non-neoplastic polyps of the stomach Frequencya
encompass hyperplastic polyps, hamarto- Gene Alteration References
“Intestinal” “Diffuse”
matous polyps (Peutz-Jeghers polyp,
carcinoma carcinoma
juvenile polyp, Cronkhite-Canada syndrome-
associated polyp), and miscellaneous APC LOH, mutation 30–40% < 2% {1784, 2245A, 3178}
lesions with polypoid growth pattern {425, BCL2 Overexpression — 10–30% {168, 1782}
2467}).
CDH1 Mutation, hypermethylation, — > 50% {151, 220, 470, 1082,
LOH 1408, 1937, 1940, 2014}
Hyperplastic polyps
Hyperplastic polyps are the second most CDKN1B Reduced expression 40–50%b {1543, 3566, 3627}
common gastric polyps and typically CTNNB1 Mutation 17–27% {3450}
arise in previously damaged gastric
Cyclin E Overexpression 15–20% b
{50}
mucosa {17, 425, 2467}, arising in a back-
ground of H. pylori gastritis or autoimmune DCC LOH 60% < 1% { 2307, 3329}
gastritis. Malignant transformation, although ERBB2 Amplification 10–15% < 1% {204, 2348, 3378}
rare, is well-documented {427, 433, 3089,
FGFR2 Amplification — 35% c
{1136, 2990}
3685}.
KRAS Mutation 1–28% d
< 1% {331, 1552, 2393, 3559}
Polyposis syndromes MET Amplification 20–40%b {1678}
Peutz-Jeghers polyps, juvenile polyps,
MYC Overexpression 40–45% b
{395, 1661}
and Cowden polyps generally do not
occur sporadically, but rather as part of PTEN LOH, mutation 20–30% e
{1839}
hereditary polyposis syndromes. Some RB1 Reduced expression — 30%b {828}
cases of juvenile polyposis may affect the
stomach only {750}. Gastric Peutz-Jeghers TP53 Mutation, LOH 25–40%f 0–21%f {1314, 1459, 3644}
polyps are characterized histologically by LOH, loss of heterozygosity
a
branching bands of smooth muscle The frequencies are presented according to the two major histotypes of the Lauren classification, i.e., “intestinal”
derived from muscularis mucosae, and and “diffuse” (roughly corresponding to the “well-differentiated” and “poorly differentiated” carcinomas of the
hyperplasia, elongation and cystic Japanese classification), as reported in the relevant cited literature.
b
Correlates with prognosis and/or more advanced disease.
change of foveolar epithelium; the deeper c
Present only in advanced cases.
glandular components tend to show d
Mostly occuring in carcinomas with microsatellite instability.
atrophy. However, syndromic gastric e
Associated with invasion and metastasis.
polyps can be difficult to distinguish from f
Frequent in aneuploid (60–70%) but rare in diploid carcinoma.
hyperplastic polyps.
Finally, susceptibility to carcinogens and hypermethylation is seen in 12–30% of
Genetic susceptibility their precursors varies among individuals. gastric carcinomas. Reduced expression
Familial diffuse gastric cancer with auto- A role for polymorphisms of genes of CDKN2A correlates with depth of
somal dominant inheritance, caused by encoding for glutathione S-transferase invasion and metastasis in some studies
germline mutation of the E-cadherin gene enzymes (known to metabolize tobacco- {221}. Hypermethylation with reduced
was reported in 1998 {1081}. This new related carcinogens) and N-acetyltrans- expression of the retinoic acid receptor
syndrome, hereditary diffuse gastric ferase 1 {2767, 3500} has been suggested. β(RARB) gene is observed in 60–65% of
cancer, is described in the next chapter “intestinal” carcinomas, but not in
of this volume. Molecular pathology “diffuse” carcinomas {1141}. Hyperme-
The risk of gastric cancer is also Gastric cancers are characterized by ge- thylation of RUNX3 (a member of the
increased in dominantly inherited cancer- netic and epigenetic changes that affect RUNX family that plays a role in TGF-β
predisposition syndromes such as FAP oncogenes, tumour suppressor genes, signalling) is observed in 45–65% of
and Lynch syndrome {415, 1930}, and and DNA mismatch repair (MMR). Conse- gastric cancers, sometimes accompa-
also in Li-Fraumeni syndrome with quently, deregulation of cellular proliferation, nied by reduced expression of RUNX3 in
germline mutation of TP53 {3379}. It was adhesion, differentiation, signal transduc- adjoining non-neoplastic gastric mucosa
reported recently that among patients tion, telomerase activity, and DNA repair {2241}. Biallelic inactivation of RUNX3 can
with Peutz-Jeghers, those with frameshift has been reported. Different genetic path- also be caused by homozygous deletion
mutations in the STK11 gene develop ways have been described for various and, rarely, by mutation {1835}.
aggressive gastric cancers {2950}. Carriers histological types of gastric cancer. Aberrant acetylation is frequently detected
of mutations in MSH2 also have an in H3 and H4 histone genes, in both the
increased risk of gastric cancer {3387}. Promoter methylation, acetylation and promoter and coding regions, and is
Furthermore, a novel germline mutation of demethylation associated with reduced expression of
the LKB1 gene has been reported in a Aberrant CpG island promotor methyla- CDKN1A in gastric carcinoma {2094}.
patient with sporadic Peutz-Jeghers with tion of several genes has been described Demethylation of some genes, such as
early-onset gastric cancer {3159}. in gastric cancer. CDKN2A (p16) gene melanoma antigen family (MAGE) and
synuclein-γ (SNCG) has been described For patients meeting these criteria, endo- only 23% versus > 50% for those under-
in gastric cancer. Demethylation of the scopic resection is likely to be an going more aggressive lymphadenec-
MAGEA1 and MAGEA3 promoters is ineffective therapeutic modality and tomy (D2) {1476}.
more frequently observed in advanced surgery should be considered {1041,
adenocarcinoma and is associated with a 2384, 2766}. However, some authors Histological typing
worse prognosis {1233}. SNCG methylation claim that small intramucosal gastric The value of histological typing of the
is more frequent in cancers with lymph- cancers of undifferentiated histology, tumour in predicting tumour prognosis is
node metastasis {3609}. measuring < 20 mm in size and without controversial. Whether the prognosis for
lymphovascular invasion have a negligible “diffuse” carcinoma (Laurén classification)
Microsatellite instability (MSI) risk of lymph-node metastasis and could is or is not worse than that for “intestinal”
The MSI or mutator phenotype is caused also be considered for endoscopic carcinoma is debated {1989, 3019}. Re-
by defects in the MMR system responsible resection {1200}. cently, it has been suggested that
for the correction of mismatches that “diffuse” carcinomas encompass lesions
occur during DNA replication. In gastric Staging of advanced gastric cancer with different prognosis, i.e. a low-grade
cancer, MSI is mainly caused by epige- The stage of gastric cancer with special desmoplastic subtype (with no or scarce
netic silencing (promoter methylation) of reference to extension to the serosa and angio-lympho-neuroinvasion) and a high-
the MLH1 gene {429}. Somatic mutations lymph nodes (summed up in the TNM grade subtype (with anaplastic cells)
of MMR genes are very rare in sporadic staging system) remains the strongest {525}. The prognosis for patients with
gastric cancer {2553}. MSI is observed in prognostic indicator. Five-year survival is poorly cohesive carcinoma is particularly
5–10% of “diffuse” carcinomas and in 60–80% for patients with tumours that bad for children and young adults, for
15–40% of “intestinal” carcinomas. Gastric invade the muscularis propria, but 50% whom diagnosis is often delayed {2613,
carcinomas with a high level of MSI (MSI- for those with tumours invading the 3343} and who are likely to fit into the
high) are characterized by antral location, subserosa {1354, 3651}. Unfortunately, at category of hereditary diffuse gastric
“intestinal” phenotype and expanding the time of diagnosis most patients with cancer. Some investigators have found
growth pattern. MSI-high tumours show a advanced carcinoma already have that only the Goseki classification {1989}
better prognosis than do MSI-low {223, lymph-node metastases for which only added additional prognostic information
536, 737, 1783, 3558}. Several reports palliative surgery can be envisaged to the TNM stage {1989, 3019} with 5-year
have shown a relation between MSI and {853}. Often seen in advanced cases, survival of patients with mucus-rich
tumour multiplicity {536, 1783}. lymphatic and vascular invasion specifi- (Goseki II and IV) T3 tumours being
cally carry a poor prognosis. Reported significantly worse than that for patients
Prognosis and predictive factors data support the value of a number- with mucus-poor (Goseki I and III) T3
Early gastric cancer based classification scheme for reporting tumours (18% versus 53%; p < 0.003)
Early gastric cancers have a low inci- nodal involvement in gastric cancer {1989}. The scheme proposed by
dence of vessel invasion and lymph-node {2702}. In patients with involvement of 1–6 Carneiro et al. is also believed to have
metastasis and a good prognosis (about lymph nodes, the 5-year survival rate is prognostic value {431}. Some patients
90% of patients survive 10 years). Various 46% compared with 30% in patients with with medullary carcinoma have a better
multivariate analyses have identified 7–15 lymph nodes involved. The extent of prognosis than those with other histological
submucosal invasion; tumour diameter regional lymphadenectomy performed types {737}, some being in Lynch-syndrome
> 3.0–3.5 cm; the presence of vascular and quality of lymph-node evaluation kindreds with MSI-high, a feature associ-
invasion; the presence of lymphatic per- have also been stressed significantly. ated with better survival. Not all studies
meation; depressed or ulcerated lesions Patients undergoing a “curative” gastrec- agree that stromal inflammatory response
and undifferentiated histology as inde- tomy but limited lymph-node dissection and pushing margins predict a better
pendent risk factors for nodal metastasis. (D1/D0) have an overall 5-year survival of prognosis {1989, 3019}.

Hereditary diffuse gastric cancer F. Carneiro

A. Charlton
D.G. Huntsman
Definition (1) Two or more documented cases of was much lower (12.5%) {2395}. CDH1
Hereditary diffuse gastric cancer (HDGC) diffuse gastric cancer in first- or second- mutations have not been found in families
is an autosomal-dominant cancer-suscep- degree relatives, with at least one being with weaker histories of gastric cancer;
tibility syndrome that is characterized by diagnosed before the age of 50 years; or however, mutation rates of up to 10% have
signet ring cell (diffuse) gastric cancer (2) Three or more cases of documented been described in individuals with no fam-
and lobular breast cancer. The genetic diffuse gastric cancer in first- or second- ily history but DGC diagnosed at less than
basis for this syndrome was discovered in degree relatives, independent of age of age 35 years, from populations with a low
1998 by Guilford et al. {1081}, who identi- diagnosis {397}. Women in these families incidence of gastric cancer {1501, 3136}.
fied germline mutations of the E-cadherin also have an elevated risk of lobular There are striking population-specific
(CDH1) gene (MIM No. 192090) by linkage breast cancer {341, 1501, 1513, 2855, 3136}. differences regarding the fraction of
analysis and mutation screening in three IGCLC criteria for genetic testing, updated families with aggregation of gastric cancer
Maori kindreds with multigenerational, in 2009 {871} are shown in Table 4.02. An and frequency of CDH1 germline mutations.
diffuse gastric cancer in New Zealand. alternative genetically-based nomenclature, In countries with a low incidence of gas-
proposed by the New Zealand group, in tric cancer, the frequency of germline
MIM No. 137215 which the term “HDGC” is restricted to alterations in the CDH1 gene is > 40%,
families with germline mutations in the while in countries with a moderate or high
Diagnostic criteria CDH1 gene {1081, 1082}. incidence of gastric cancer, the frequency
In families with an aggregation of gastric The IGCLC definition for HDGC will be used of alterations in CDH1 is about 20% {2396}.
cancer, the histopathology of the tumours for the remainder of this section {871}. These observations in moderate- or high-
is often unknown; these cases are desig- incidence countries are probably related
nated as familial gastric cancer (FGC). Epidemiology to clustering of gastric cancer attributable
When the histopathological type of one or The vast majority of gastric cancers are to environmental risk factors (lifestyle,
more gastric cancers is known, discrete sporadic, but approximately 1–3% result diet) and/or variation in genes conferring
syndromes/diseases can be diagnosed; from an inherited predisposition {870, a weak susceptibility {2396}.
these include HDGC, familial diffuse 2396, 2439}.
gastric cancer (FDGC) and familial intes- The prevalence of HDGC is uncertain, Localization
tinal gastric cancer (FIGC) {397}. partly due to the recent identification of Most index cases with HDGC present with
On the basis of clinical criteria, the this syndrome. In a review of 439 families cancers that are indistinguishable from
International Gastric Cancer Linkage with aggregation of gastric cancer {2395}, sporadic diffuse gastric cancer, often with
Consortium (IGCLC) in 1999 defined CDH1 mutations were preferentially linitis plastica, which can involve all
families with the HDGC syndrome as observed in families fulfilling the clinical topographic regions within the stomach.
those fulfilling one of the following criteria for HDGC (36.4%). In FDGC, the Systematic complete mapping of total
features: frequency of germline mutations in CDH1 gastrectomies from asymptomatic carriers
A B
Fig. 4.18 Mapping of gastric mucosal zones (semi-opaque colours) and location of foci of stage T1a signet ring cell (diffuse) carcinoma (black circles) on photos of two stomachs.
Adapted from Charlton et al. {493}. A Asymptomatic CDH1-mutation carrier, aged 15 years; the map indicates the location of 318 foci and mucosal zones. B Asymptomatic CDH1-
mutation carrier, aged 19 years, from the same family; the map indicates the location of 115 foci and mucosal zones.
Hereditary diffuse gastric cancer 59

Table 4.02 Criteria for testing for CDH1 mutation: updated strategies, patients presented with clini- histopathological examination of the re-
recommendations from the International Gastric Cancer cally detected gastric cancer, usually at sected stomach {195}. Chromoendo-
Linkage Consortium (IGCLC).a
an advanced stage. The age at onset of scopy was shown to increase the
1. Two or more documented cases of gastric cancer clinically significant diffuse gastric cancer likelihood of detecting T1a foci of > 4 mm
in first-degree relatives, with at least one may be extremely variable (range, 14–85 when compared with white-light endo-
documented case of diffuse gastric cancer years), even within families. In one large scopy {2910}, but this technique has
diagnosed before the age of 50 years Maori kindred (Family A), the youngest been discontinued owing to concerns
2. Three or more cases of documented diffuse individual to die from gastric cancer was over the toxicity of Congo red {566}. The
gastric cancer in first- or second-degree relatives, aged 14 years, but the oldest known likelihood of obtaining positive biopsies is
independent of age of onset asymptomatic mutation-carrier was aged improved by increasing the number of
3. Diffuse gastric cancer before the age of 40 years 75 years {276, 1501, 2541}. biopsies to 24 or more {195}, and by the
without a family history cumulative experience of the same endo-
4. Families with diagnoses of both diffuse gastric Genetic testing scopist regularly performing HDGC en-
cancer and lobular breast cancer, with one case Probands from populations with a low or doscopy {566, 2910}. Experience with
before the age of 50 years moderate incidence of gastric cancer, chromoendoscopy has led to an appreci-
_____________ who fulfil the criteria listed in Table 4.02, ation that pale areas are visible with stan-
a
In addition, in cases where expert pathologists are offered genetic testing. The age at dard endoscopy, but they are subtle and
detect carcinoma in situ adjacent to diffuse-type
which to offer testing to at-risk relatives would be easily overlooked by most
gastric cancer, genetic testing should be considered
since this is rarely, if ever, seen in sporadic cases. should take into consideration the earliest endoscopists {566}.
age of onset of cancer in that family. Endoscopic surveillance is recommended
Testing from late adolescence or in the for individuals aged < 20 years, individuals
of CDH1 mutations show microscopic, early 20s occurs in families with early aged > 20 years who elect to delay
usually multiple, foci of intramucosal signet onset gastric cancer {566, 1501}. surgery, or for whom prophylactic gastrec-
ring cell (diffuse) carcinoma in almost all The guidelines of the IGCLC recommend tomy (biopsy-negative) is unacceptable,
cases {195, 276, 428, 493, 1148, 1290, that asymptomatic carriers of CDH1 mu- but gastrectomy with curative intent
2322, 2712}. These foci of carcinoma can tations be offered prophylactic gastrec- (biopsy-positive) is acceptable, and those
involve any topographic region of the tomy or annual endoscopic surveillance with mutations of undetermined signifi-
stomach and are limited to the gastric (in selected groups) as risk-reduction cance (e.g. missense) {1501, 2910}.
mucosa. As all regions of the gastric strategies.
mucosa can be affected, pathological Prophylactic/curative total gastrectomy
examination of the resected specimen Endoscopic surveillance Total gastrectomy is recommended in at-risk
should include confirmation of the pres- Since the foci of T1a carcinoma are small family members aged > 20 years, who
ence of a complete cuff of proximal squa- (many < 1 mm), and are located beneath a have a CDH1 mutation {276}. In biopsy-
mous oesophageal mucosa and distal normal surface epithelium, without distor- positive individuals, a curative total gas-
duodenal mucosa. tion of the pit or gland architecture, it is not trectomy is advised, regardless of age.
surprising that endoscopic detection is Recent data show that pregnancy can be
Clinical features difficult in asymptomatic CDH1-mutation carried to full term following a prophylactic
Age at clinical manifestation carriers. In most cases, multiple endo- gastrectomy {1500}. Prophylactic gas-
Before the advent of genetic identification scopic biopsies carried out before gastrectomy has an estimated mortality rate
of carriers of CDH1 mutations, and the sub- trectomy fail to detect the multiple foci of of up to 2% {1931}.
sequent implementation of risk-reduction stage T1a carcinoma identified by
Breast cancer
Breast cancer occurs with an increased
frequency in HDGC families; most cases
are lobular. Loss of E-cadherin expression
and poorly cohesive morphology is common
to both diffuse gastric carcinoma and
lobular breast carcinoma. Current esti-
mates of lifetime cumulative risk for
female lobular breast cancer are 60% by
age 80 years {871}. Gastric cancer, how-
ever, is the main cause of mortality in
individuals with CDH1 mutations. Enhanced
screening to detect lobular breast carci-
noma should be considered {871, 1664}.
A B Macroscopy
Fig. 4.19 Endoscopic views of intramucosal diffuse carcinoma, confirmed by biopsy, in two different asymptomatic Stomachs from asymptomatic CDH1-
CDH1-mutation carriers from the same family. A Chromoendoscopic pale area with well defined margins. mutation carriers nearly always appear
Adapted from {2910}. B A subtle pale area is visible on standard white-light endoscopy. normal to the naked eye, are normal to

palpation, and slicing shows normal In a large Maori family in New Zealand, the
mucosal thickness. Unlike most sporadic greatest density and largest foci of T1a car-
gastric cancers, there is no mass lesion cinomas were located in the distal stomach
{428, 493, 2712}. In some apparently and the body–antral transitional zone in
normal stomachs, close inspection may many, but not all stomachs {276, 493}.
show white patches after formalin fixation Individual foci of intramucosal (T1a) signet
that correspond to intramucosal signet ring cell (diffuse) carcinoma are small,
ring cell carcinoma. ranging from 0.1 mm to 10 mm, with most
being < 1 mm in diameter {1287, 2712}.
Tumour spread and staging The signet ring cell (diffuse) carcinomas
The pathology in asymptomatic CDH1- observed in asymptomatic CDH1-mutation
Fig. 4.20 Formalin-fixed stomach showing barely
mutation carriers represents a new carriers show absent or reduced staining discernible pale patches on the body–antrum transitional
paradigm in cancer. There is multifocal for E-cadherin {428, 558, 1290}, in keep- zone in the same 15-year-old asymptomatic CDH1-
invasive cancer, without a mass lesion, and ing with a clonal origin of the cancer foci, mutation carrier as shown in Fig. 4.18A. These
without symptoms. Systematic complete indicating that the second CDH1 allele has correspond to foci of T1a signet ring cell carcinoma.
pathological mapping of stomachs removed been down-regulated or lost. Down-
from asymptomatic CDH1-mutation carriers regulation of the second allele in large Precursor lesions
show that almost all (96%) {2396} contain numbers of widely separated lesions The following precursors to T1a signet
multiple foci of intramucosal signet ring cell strongly suggests that this “second hit” ring cell carcinoma are recognized:
(diffuse) carcinoma of TNM stage T1a. has occurred as a transcriptional field (1) signet ring cell carcinoma in situ (Tis),
These T1a tumours are invasive cancers by effect, and not as an independent mutation corresponding to the presence of signet
definition yet may remain indolent for a long event in each lesion {276}. ring cells within the basal membrane,
time and carry a very low risk for metastasis. Background changes in the gastric mucosa substituting normal epithelial cells, gener-
Less commonly, larger foci of intramucosal of prophylactic gastrectomy specimens can ally with hyperchromatic and depolarized
carcinoma can involve superficial and deep encompass mild chronic gastritis, some- nuclei; (2) a pagetoid spread pattern (not
mucosa. times displaying the features of lymphocytic necessarily associated with an invasive
gastritis. Occasionally, an inflammatory carcinoma) of signet ring cells below the
Histopathology granulomatous reaction is observed at the preserved epithelium of glands and
Early-stage HDGC in CDH1-mutation periphery of some collapsing glands. foveolae, but within the basal membrane
carriers is characterized by multiple foci of Foveolar hyperplasia and tufting of surface {428}. In these lesions, E-cadherin immuno-
invasive (T1a) signet ring cell (diffuse) car- epithelium, focally with globoid change is expression is reduced or absent {428,
cinoma in the superficial gastric mucosa, also a frequent finding and, in some areas, 2396}. Strictly following criteria for the
with no nodal metastases {276, 493, 558, vacuolization of surface epithelium is strik- identification of these precursors will
1290}. At the neck-zone level, neoplastic ing {428, 430, 2395}. Additionally, erosions diminish the risk of over-diagnosing non-
cells are small, and usually enlarge towards and cysts can be observed in non-neo- specific changes and distinguish precur-
the surface of the gastric mucosa, with plastic mucosa. Intestinal metaplasia and sors from mimics of signet ring cells in
transitional forms between. The foci of intra- infection with H. pylori are typically absent. situ, including telescoped normal glands
mucosal carcinoma are composed of The IGCLC has prepared a proforma for {3238, 3671}. Confirmation of carcinoma
mitotically inactive neoplastic cells. {276, reporting the pathology of gastrectomy in situ (Tis) by an independent histo-
1286}. Pathological mapping of the entire specimens from patients with HDGC {871}. pathologist with experience in this area is
gastric mucosa has been performed in
many stomachs from kindred with different
CDH1 mutations {195, 276, 428, 493, 1148,
1290, 2322, 2712}. There is wide variation
in the number of T1a foci observed in these
stomachs, both within and between
kindreds, ranging from one focus {428} to
hundreds of tiny foci {276, 493}. Histological
examination of the entire gastric mucosa is
required (one section per block) before the
absence of neoplasia can be claimed.
The cause of this variation in number of foci
is presently unknown, although both back-
ground genetics and environmental factors
are probable contributing factors {276}.
Early invasive carcinoma is not restricted to
any topographic region in the stomach: foci Fig. 4.21 Typical invasive focus of T1a intramucosal Fig. 4.22 T1a signet ring cell (diffuse) carcinoma with
have been identified from the “cardia” to signet ring cell (diffuse) carcinoma. The signet ring cells immunostaining for E-cadherin. Signet ring cells show
the pre-pyloric region, without evidence of are usually smaller at the neck zone, and larger nearer absent or reduced expression of E-cadherin (arrows).
antral clustering {195, 428, 1290, 2712}. the surface of the gastric mucosa.

Genetic susceptibility
Mutations in the CDH1 gene have been
identified in families with HDGC from
different geographic regions and ethnicities
{276, 397, 955, 1082, 1290, 2673}. In clin-
ically defined HDGC, CDH1 mutations are
detected in 30–40% of cases {870, 1501,
2394, 2396}.
The CDH1 gene is located on the long arm
of chromosome 16 (16q22.1), comprises
16 exons transcribed into a 4.5 kb mRNA
and encodes E-cadherin {249}. E-cadherin
is a transmembrane protein that is pre-
dominantly expressed at the basolateral
Fig. 4.23 Signet ring cell carcinoma in situ (Tis). membrane of epithelial cells, where it
exerts cell–cell adhesion and invasion-
suppression functions {1076, 2206}. The
strongly recommended. Noteworthy is the extracellular domain of E-cadherin plays
discrepancy between the numerous a key role in the correct folding and homo-
invasive carcinoma (T1a) foci and the low and heterodimerization of the proteins, as Fig. 4.24 Pagetoid spread of signet-ring cells (arrow
heads) representing Tis, and invasion of the lamina
number or absence of carcinoma in situ well as in the adhesion mechanism itself.
propria by a signet-ring cell (empty star), indicating T1a
(Tis) lesions, indicating that invasion of The cytoplasmic domain of the protein invasive intramucosal signet-ring cell carcinoma.
the lamina propria by signet ring cells interacts with the catenins (α, β, γ, p120ctn)
usually occurs without morphologically indirectly influencing the organization of
detectable carcinoma in situ {428}. Unlike the actin cytoskeleton {280}. In addition to point mutations, large
the usual neoplastic progression sequence germline deletions akin to those described
from dysplasia to carcinoma, the preinva- Type of CDH1 mutation in the Lynch-syndrome genes have been
sive neoplastic precursor, Tis, is absent, Of the identified germline mutations in found in 6.5% of HDGC families who
or is present in far fewer numbers than CDH1, 75–80% are truncating (including tested negative for point mutations
T1a invasive carcinoma, and moreover, nonsense, splice-site and frameshift {2394}. It is likely that these deletions
can be geographically distant from foci of mutations, predicted to produce premature occur through mechanisms involving
T1a invasive carcinoma. termination codons) and the remaining mainly nonallelic homologous recombina-
On the basis of these precursors, a model 20–25% are missense mutations {276, 430}. tion in Alu repeat sequences {2394}. Such
for the development of diffuse gastric The latter may have functional effects deletions can be detected by multiplex
cancer in carriers of deleterious germline through alteration of residues critical to ligation-dependent probe amplification
CDH1 mutations has been proposed protein structure or through alternative (MLPA). Unlike the somatic mutations in
{428, 430}. splicing {1501, 3134, 3135}. Although a CDH1 that occur in sporadic gastric
range of different techniques have been cancers and cluster around exons 7 and
used for detecting mutations, direct 8, the germline mutations in CDH1 in
sequencing is the method of choice. HDGC families span the whole length of
the gene and no hot spots have been
identified. This means it is necessary to
screen all 16 exons of the gene in families
that potentially have HDGC, except those
from Newfoundland who may carry
discrete founder mutations {1501}.
Molecular pathology
Second-hit inactivation mechanism for
E-cadherin
As is the case for sporadic diffuse gastric
cancers, diffuse gastric cancer developing
in germline CDH1-mutation carriers gen-
erally display abnormal or absent expres-
sion of E-cadherin {428, 1286, 1290}, in
accordance with the two-hit model of
A B tumour-suppressor gene inactivation. In
Fig. 4.25 Model for the development of hereditary diffuse gastric carcinoma. A Signet ring cell carcinoma in situ, this regard, sporadic and hereditary
noninvasive. Single signet-ring cells are shown on the left, pagetoid-spread pattern on the right. B Early diffuse gastric cases of DGC are identical and although
cancer. The diagram shows invasion into the lamina propria. the use of immunohistochemistry for the

diagnosis of DGC can be useful, it does

not allow identification of the subset of
cases with germline mutations. In cases
of HDGC, the CDH1 gene can be inacti-
vated by a number of mechanisms. Most
frequently, this occurs via promoter
methylation (epigenetic modification) and
less frequently by loss of heterozygosity
(LOH) and CDH1 mutations {194, 1047,
2397}. An intragenic deletion in the wild-
type allele has also been reported {2391}.
The second hit in CDH1 may differ in pri-
mary tumours and metastases, epigenetic
A B
Fig. 4.26 Absence of E-cadherin expression as shown by immunohistochemistry. A Signet ring cell carcinoma in situ
changes (promoter methylation) being
(ellipse). B Pagetoid spread of signet ring cells (arrow heads).
more frequent in HDGC primary tumours
and LOH in metastases {2397}.
mucosal carcinomas remain indolent for Prognosis and predictive factors
Alterations in other tumour suppressor undefined periods of time, while a few Presumably, complete silencing of the
genes and oncogenes progress to higher-stage gastric cancer. CDH1 gene is necessary for disease
Humar et al. {1286} have suggested that penetrance or, in other words, for invasive
the initiation of diffuse gastric cancer Alternative genes in HDGC families that cancer to occur. Based on data from eleven
seems to occur at the proliferative zone of do not show mutations in CDH1 families, Pharoah et al. {2541} estimated
the gastric epithelium and correlates with In more than two thirds of cases of HDGC, the cumulative risk of developing clinically
absent or reduced expression of junc- no CDH1 germline mutations are identified significant gastric cancer by age 80 years
tional proteins, activation of the SRC and the disease remains genetically to be 67% for men and 83% for women.
(c-src) system, and epithelial–mesenchymal unexplained. Searching for mutations in Females were found to have a 39% risk of
transition. It remains to be seen whether genes encoding E-cadherin-binding breast cancer {2541}. Updated analysis
inactivation of c-src kinase marks the de- partners within the adhesion complex, in 2008 (unpublished) indicate an esti-
velopment of early diffuse gastric cancer. namely the catenins (α, β, γ, p120ctn) has mated risk of more than 80% for the
Identification of the molecular mecha- not disclosed any germline mutations, development of gastric cancer and 60%
nisms underlying disease progression will suggesting that catenins are not major for lobular breast cancer in carriers of
help to explain why most early intra- susceptibility genes for HDGC {1929}. germline mutations in CDH1 {871}.
Germline mutations in TP53 were detected If foci of carcinoma are limited to the
in two studies of families with gastric cancer gastric mucosa, prognosis is likely to be
and no mutation in CDH1 {1514, 2392}. excellent after total gastrectomy, although
Searching for mutations in other candi- long-term survival with HDGC after gas-
date genes for HDGC has so far provided trectomy remains unknown. It is possible
no clues for alternative causal genes for that curative gastrectomies for gastric
this hereditary syndrome {1514, 2392}. disease will unmask an additional risk for
As most HDGC families that show no carcinoma at other sites in HDGC patients.
mutation in CDH1 have been too small or The diagnosis of HDGC offers the
otherwise not suitable for linkage analysis, opportunity for pre-symptomatic genetic
whole-genome sequencing using high- screening for at-risk family members and
throughput methods may ultimately life-saving cancer risk-reduction surgery
identify the genetic basis of their suscep- for carriers of CDH1 mutations. In addi-
tibility to cancer. This is now practical tion to its importance for affected families,
through the development of massively HDGC, through the study of prophylactic
Fig. 4.27 Sequencing of the CDH1 gene in a patient with parallel single-molecule sequencing techno- gastrectomy specimens, has provided a
hereditary diffuse gastric cancer reveals a frameshift logies {126, 2273}. unique window to study the earliest stage
mutation in exon 8. of diffuse gastric cancer.

Neuroendocrine neoplasms E. Solcia

R. Arnold
of the stomach C. Capella
D.S. Klimstra
G. Klöppel
P. Komminoth
G. Rindi
Definition gastrin cell, ghrelin cell or adrenocorti- ratio, 2.8 : 1) at a mean age of 55 years
Neoplasms with neuroendocrine differen- cotrophic hormone (ACTH) cell NETs are (range, 21–38 years) {2683}. NETs
tiation including neuroendocrine tumours very rare and may arise in both the composed of EC, gastrin or ghrelin cells
(NET) and neuroendocrine carcinomas corpus–fundus and antrum. represent less than 1% of all gastric neuro-
(NEC) arising in the stomach. Mixed adeno- NECs (poorly differentiated endocrine endocrine neoplasms.
neuroendocrine carcinomas (MANEC) carcinomas) and MANECs are also rare
have an exocrine and an endocrine com- and may arise in any part of the stomach. NEC and MANEC. NECs (poorly differenti-
ponent, with one component exceeding ated neuroendocrine carcinomas) account
30%. Epidemiology for 6–16% of gastric neuroendocrine neo-
Incidence and time trends plasms, are more common in men (male-to-
ICD-O codes In the past, gastric NETs were reported to female ratio, 2 : 1) and present at a mean
Neuroendocrine tumour (NET) occur with an incidence of 0.002–0.1 per age of 63 years (range, 41–61 years) {2682,
NET G1 (carcinoid) 8240/3 100 000 population per year and to 2683}. No specific epidemiological data are
NET G2 8249/3 account for 2–3% of all gastrointestinal available for MANECs.
Neuroendocrine carcinoma (NEC) 8246/3 NETs {1002} and 0.3% of gastric neoplasms
{1935}. However, more recent studies Etiology
based on endoscopic techniques and ECL cell NETs
Small cell NEC 8041/3
increased awareness of such lesions have Gastrin has a trophic effect on ECL cells in
Mixed adenoneuroendocrine suggested that the incidence of these humans and in experimental animals {305,
carcinoma (MANEC) 8244/3 tumours might be much higher, reaching 1101}. Long-standing hypergastrinaemia,
EC cell, serotonin-producing NET 8241/3 11–41% of all gastrointestinal NETs resulting either from unregulated hormone
Gastrin-producing NET (gastrinoma) {2982}. The incidence of gastric NETs is release by a gastrinoma or from a second-
8153/3 higher in Japan where these neoplasms ary response of antral gastrin cells to
represent 30% of all gastrointestinal NETs; achlorhydria, is consistently associated
Synonyms this may be atributable to the high inci- with ECL-cell hyperplasia {305}. Other
Synonyms for gastric NET include: carci- dence of chronic atrophic gastritis in this factors may also be involved in ECL-cell
noid and well-differentiated endocrine country, as well as to intensive screening oncogenesis, including mutation or dele-
tumour/carcinoma {3013}. Synonyms for by endoscopy {2155}. Recent population- tion of the multiple endocrine neoplasia I
NEC include: poorly differentiated endo- based studies of gastric NETs showed (MEN1) gene at 11q13 in MEN1-ZES
crine carcinomas, high-grade neuro- that the annual incidence was 0.18–0.24 patients {683}, and inflammation coupled
endocrine carcinoma, small cell and large per 100 000 among Caucasians and 60% with severely altered mucosal structure
cell endocrine carcinomas. higher among African Americans {1137}. and function in A-CAG patients, with a
As for NETs at other sites of the gastro- possible role for several growth factors,
Classification intestinal tract, the incidence of gastric including transforming growth factor α
Gastric NETs and NECs are classified on NETs shows an incremental trend in the (TGFα) and basic growth factor (bFGF)
the basis of criteria that are common to all last three decades {3624}. {304, 3343}. The most severe A-type, corpus-
gastrointestinal and pancreatic neuro- predominant, chronic atrophic gastritis,
endocrine neoplasms (see Chapter 1). Age and sex distribution with total loss of parietal cells, achlorydria,
Most neuroendocrine neoplasms of the ECL cell NET. Type-I gastric ECL cell gastrin-cell hypertrophy and hyperplasia
stomach are NETs – well-differentiated, NETs have been reported to represent and secondary hypergastrinaemia, is usu-
nonfunctioning enterochromaffin-like (ECL) 74% of all gastric neuroendocrine neo- ally caused by a T-cell- and antibody-
cell carcinoids (ECL cell NETs) – and plasms and to occur most often in females mediated antiparietal cell autoimmune
arise predominantly in the corpus-fundus (male-to-female ratio, 1 : 2.5), with a mean process. Sometimes this process super-
region {3013}. Three distinct types are age at biopsy of 63 years (range, 15–88 venes over a long-standing chronic gastritis
recognized: (1) type I, associated with years). Type-II ECL cell NETs represent 6% caused by Helicobacter pylori {1308}. In a
autoimmune chronic atrophic gastritis of all gastric neuroendocrine neoplasms minority (about 20%) of cases, corpus-
(A-CAG); (2) type II, associated with and show no sex predilection (male-to- prevalent subtotal atrophy with a few
multiple endocrine neoplasia type 1 (MEN1) female ratio, 1 : 1) at a mean age of 50 surviving H. pylori and extensive multifocal
and Zollinger-Ellison syndrome (ZES); and years (range, 28–67 years). Type-III ECL intestinal metaplasia were found in associa-
(3) type III, sporadic (i.e. not associated cell NETs account for 13% of all gastric tion with gastrin-cell hyperplasia, hypergas-
with A-CAG or MEN1-ZES). Serotonin- neuroendocrine neoplasms and are trinaemia as well as ECL-cell hyperplasia,
producing enterochromaffin (EC) cell, observed mainly in males (male-to-female dysplasia and neoplasm(s) {3014}.

Clinical features ACTH-producing NET

ECL cell, histamine-producing NET This rare neoplasm is associated with
Of the three types of ECL cell NETs, two, Cushing syndrome owing to ectopic
(types I and II), associate with hypersecretion of ACTH {1203, 3026}.
gastrinaemia. Type-I ECL cell NETs arise in
a background of A-CAG, and predomi- NEC and MANEC
nantly involve the corpus–fundus mucosa. These neoplasms usually present with
Clinical signs include achlorhydria and, clinically nonspecific symptoms similar to
less frequently, pernicious anaemia. those of conventional gastric cancer,
Hypergastrinaemia or antral gastrin cell often at an advanced stage, with distant
hyperplasia are observed in all cases of metastases.
A-CAG associated with ECL cell tumour
Fig. 4.28 Type III (sporadic) ECL cell NET (carcinoid) of
disease {2686}. Type-I NETs are typically Macroscopy
the gastric body. The surrounding mucosa is normal.
small (usually < 1 cm), multiple and multi- ECL cell, histamine-producing NET
centric. Hypertrophic-hypersecretory gas- Type-I ECL cell NETs are multiple in ap-
ZES results from hypergastrinaemia caused tropathy and high levels of circulating proximately 60% of cases {2683}, usually
by gastrin-producing neoplasms (gastrino- gastrin are critical diagnostic findings for appearing as small, tan-coloured nodules
mas) that are preferentially located in the type-II ECL cell NETs {3010}. ECL-cell or polyps that reside in the mucosa or,
duodenum and pancreas; associated ECL- hyperplasia and/or dysplasia are invariably less often, the submucosa. Most neoplasms
cell proliferation is usually limited to hyper- present in the fundic peritumoral mucosa (77%) are < 1 cm in diameter and 97% of
plastic lesions of the simple linear type {2683}. Type-II NETs are usually multiple neoplasms are < 1.5 cm. The muscularis
{241, 1798, 3009}. MEN1, an inherited and < 1.5 cm in size {2683}. propria is involved in only a minority of
neoplasia syndrome, causes a variety of Type-III (sporadic) ECL cell NETs do not cases (7%). Patients with type-II NETs
neuroendocrine neoplasms, including gas- associate with hypergastrinaemia, A-CAG have an enlarged stomach with thickened
trinomas. In patients with MEN1-associated or MEN1-ZES. They are generally solitary gastric wall (0.6–4.5 cm), due to severe
ZES (MEN1-ZES), ECL-cell lesions are growths, arise in a gastric mucosa void of hypertrophic-hypersecretory gastropathy,
often dysplastic or overtly neoplastic in significant pathological lesions except for multiple mucosal-submucosal neoplasms,
nature {3010}. Thus long-standing, severe gastritis and in the absence of ECL-cell often larger in size than the average type-I
hypergastrinaemia usually causes only hyperplasia/dysplasia. Multiple neoplasms tumour, and < 1.5 cm in 75% of cases
moderate ECL-cell hyperplasia in ZES have been observed rarely. Type-III NETs {2683}. Type-III ECL cell NETs are usually
patients lacking the MEN1 syndrome, may present either: (1) with symptoms single and in 33% of cases are > 2 cm in
whereas in MEN1-ZES patients, ECL-cell similar to those of an adenocarcinoma, size. Infiltration of the muscularis propria
hyperplasia progresses to dysplasia in including dyspepsia, gastric haemorrhage, and of the serosa is found in 76% and
53% of cases and to formation of neoplasms mass obstruction, weight loss and metas- 53% of cases, respectively {2683}.
in 23% of cases {241}. tasis; or (2) with endocrine symptoms of an
“atypical carcinoid syndrome” character- NEC and MANEC
NEC and MANEC ized by red cutaneous flushing in the NECs (poorly differentiated neuroendo-
It is likely that NECs and MANECs share the absence of diarrhoea. The atypical carci- crine carcinomas) may form a large fun-
complex pathogenetic setting of the com- noid syndrome occurs in cases with gating mass deeply infiltrating the gastric
mon gastric adenocarcinoma. The gastrin- extensive liver metastases that cause the wall and often metastatic to lymph nodes
promoting role for ECL cell NETs is retained release of substantial amounts of histamine and liver {500}. MANECs usually present
in the exceedingly rare cases of MANECs and 5-hydroxytryptophan {2341, 2696}. as conventional gastric cancer.
with an ECL cell NET component that
develop in a background of A-CAG {447}. EC cell, serotonin-producing NET Histopathology
This rare neoplasm is occasionally found NET
Localization in association with a carcinoid syndrome NETs of the stomach are intensely im-
NET {549}. munoreactive for chromogranin A and
ECL cell NETs of types I, II, and III are all synaptophysin. Most gastric NETs are
located in the mucosa of the body–fundus Gastrin producing NET (gastrinoma) predominantly composed of ECL cells,
or body–antrum border of the stomach. NETs that produce gastrin may present in stain for the marker vesicular monoamine
The rare gastrin cell NETs are located in association with ZES due to overproduction transporter 2 (VMAT2) and show vesicular
the antro-pyloric region, while EC cell of gastrin and may thus be defined as secretory granules with characteristic ultra-
tumours may occur in any part of the gastrinoma (more frequently occurring in structure {412, 2686, 2687}. They specifi-
stomach {2683}. The single functioning the duodenum). It should be noted that cally produce histamine and histidine
ghrelin cell tumour so far described was immunohistochemical demonstration of decarboxylase, which are, however, difficult
reported in the corpus {3302}. gastrin in the absence of a syndromic to demonstrate by immunohistochemical
condition does not merit use of the term methods in routinely processed specimens
NEC and MANEC gastrinoma (see Chapter 6). {3132}. In the literature, they have been
NECs and MANECs may arise at any site commonly labelled as “ECL carcinoids”,
in the stomach {447, 1555, 2683}. although minor cell subpopulations
expressing serotonin, ghrelin, gastrin, so-

matostatin, pancreatic polypeptide (PP), or
α-human chorionic gonadotrophin (α-hCG)
have been detected {2453, 2686, 2688}.
ECL cell, histamine-producing NET. The
majority of type-I and type-II and a minority
of type-III ECL cell NETs are characterized
by small, microlobular–trabecular aggre-
gates formed by regularly distributed, often
aligned cells (mosaic-like pattern), with
regular, monomorphic nuclei, usually inap-
parent nucleoli, and rather abundant, fairly
A B
Fig. 4.29 Type-III (sporadic) ECL cell carcinoid (NET). A The tumour extends from the mucosa into the submucosa,
eosinophilic cytoplasm. Mitoses are almost
with a well-delineated inferior border. B The carcinoid (left) has round, regular, isomorphic nuclei.
absent, and angioinvasion is infrequent
{2682}. Neoplasms with these features fit
the current G1 class (for grading, see of type I or II, and are often deeply invasive The cells are uniform with scanty cytoplasm
Chapter 1) and are usually limited to the and associated with local and/or distant and show predominant immunoreactivity
mucosa or submucosa. metastases {2682}. for gastrin.
Type-III sporadic ECL cell NETs often EC cell, serotonin-producing NET. This is
display more aggressive features than do a very rare neoplasm in the stomach {549, NEC
types I and II. These neoplasms may show 2686}. Its histopathology is similar to that These highly malignant neoplasms are
a prevalence of solid, cellular aggregates of the ileal NETs. The tumour cells are composed of large, poorly formed tra-
and large trabeculae, crowding and irreg- argentaffin, intensely argyrophilic and beculae, nests or sheets of anaplastic
ular distribution of round to spindle and immunoreactive for chromogranin A, round, polyhedral to spindle cells, small
polyhedral tumour cells, either with fairly synaptophysin and anti-serotonin antibodies. to fairly large in size, and immunoreactive
large vesicular nuclei and prominent The presence of EC cells is confirmed via for general neuroendocrine markers,
eosinophilic nucleoli, or with smaller, hyper- electron microscopic detection of charac- including chromogranin A, synaptophysin,
chromatic nuclei, irregular chromatin teristic pleomorphic, intensely osmiophilic neural cell adhesion molecule (NCAM1/-
clumps and small nucleoli. Scarce necrosis granules similar to those of normal gastric CD56), protein gene product 9.5 (PGP9.5)
but considerable mitotic activity, sometimes EC cells. and/or neuron-specific enolase {1427,
with atypical mitotic images, may be Gastrinoma (gastrin-producing NET). True 2682, 2686, 2932}. Gastric NECs often
present. Neoplasms with these histological gastric gastrinomas are very rare {1607}. show multifocal, abundant necrosis and a
features display a relatively high mitotic rate Well-differentiated gastrin-producing NETs high mitotic rate (> 20 mitoses per 10
(mean, 9 per 10 high power fields [HPF]) are small, mucosal-submucosal nodules, HPF), thus fitting the current G3 class (for
and a high Ki67-labelling index (mean, found incidentally at endoscopy or in a grading, see Chapter 1). Based mainly on
about 1000 per 10 HPF) {2682}, fitting the gastrectomy specimen, more frequently in nuclear structure and cell size, two
current G2 class (for grading, see Chapter proximity of the pylorus, either on its gastric subtypes can be identified, small cell and
1). Type-III NETs more frequently express or, especially, its duodenal slope. They may large cell, similar to the corresponding
TP53 (60% of cases) and display lymphatic show a characteristic thin, trabecular– lung cancers. Large cell NECs often show
and vascular invasion than most neoplasms gyriform pattern or a solid nest pattern. more vesicular nuclei, with more prominent
A B
Fig. 4.30 A Type-I ECL cell NET (carcinoid) in a patient with pernicious anaemia. B Type-II ECL cell NET (carcinoid) in a patient with multiple endocrine neoplasia type 1 (MEN1)
and Zollinger-Ellison syndrome (ZES).

nucleoli as well as a more organoid struc- by the synchronous or metachronous de-

ture, suggestive of moderate neuroendo- velopment of multiple endocrine neo-
crine differentiation, as confirmed by more plasms in different endocrine organs by
diffuse reactivity for neuroendocrine mark- the third decade of life. The parathyroid
ers. Mixed neuroendocrine (especially of glands are involved in 90–97%, endocrine
large-cell type) and non-neuroendocrine pancreas in 30–82%, duodenal gastrino-
cancer may also be found {2932}. This mas occur in 25%, pituitary adenomas in
finding parallels the frequent occurrence > 60%, and foregut NETs (stomach, lung,
of foci of ordinary cancer in the intra- thymus) in 5–9% of cases {683}. Other,
mucosal component of otherwise pure so-called “non-classical” MEN1 neoplasms,
NECs {2686}. Evidence for progression such as cutaneous and visceral lipomas,
from NET (G1 and G2) to high-grade (G3) thyroid and adrenal adenomas, and skin
NEC has only rarely been obtained. All angiofibromas, may occur {683, 2431}.
the evidence indicates that gastric G3
NEC is a distinct, highly malignant cancer Molecular pathology
that should be clearly distinguished from NET
G1 and G2 NET. The MEN1 tumour-suppressor gene has
been mapped to chromosome 11q13
MANEC {181, 477, 683, 1746}. It encodes a 610-
Gastric MANECs are mixed carcinomas amino acid nuclear protein, called multiple
with a NET-cell component consisting of at endocrine neoplasia I or “menin”, whose
least 30% of the whole neoplasm (for suppressor function involves direct bind- Fig. 4.31 Gastrin-producing NET (gastrinoma) of the
definition, see Chapter 1). MANECs are ing to JunD and inhibition of JunD-acti- pylorus, displaying a trabecular growth pattern.
relatively rare in the stomach, despite the vated transcription {42, 477}. High rates
frequent occurrence of a minor (< 30%) of loss of heterozygosity (LOH) at the
component of cells with neuroendocrine MEN1 gene locus have been reported in The association of gastric ECL cell NETs
differentiation in gastric adenocarcinoma, MEN1 syndrome-associated neoplasms, and primary hyperparathyroidism has been
a phenomenon that should not prevent its such as endocrine pancreatic, pituitary recently proposed as a familial syndrome
classification as adenocarcinoma. The and parathyroid neoplasms {2612, 3226}. that is independent from MEN1 and still
neuroendocrine component of the gastric LOH at 11q13 of type-II gastric NETs was requiring genetic confirmation {550}.
MANEC usually comprises a NEC, often of found in 9 out of 10 patients with MEN1
large-cell type {1427}, and rarely a NET investigated {222, 306, 390, 683}. These NEC and MANEC
{447, 1555}. The exocrine component is findings support the concept that gastric The available data on the genetics of
usually an adenocarcinoma with variable NETs are integral components of the NECs and MANECs are scant; however,
grade of differentiation {447, 924, 1427, MEN1 phenotype, sharing with parathy- gastric NECs, like NECs at other sites of
1555, 2640}. Gastric MANEC displays a roid and islet cell neoplasms the highest the gastrointestinal tract, display multiple
distinct immunophenotype with expression frequency of LOH at 11q13. In multiple chromosomal abnormalities involving key
of neuroendocrine markers consistent NETs from the same stomach, the deletion cell-cycle regulatory genes, including
with that observed in pure neuroendo- size in the wild-type allele differed from TP53 (the most frequent), FHIT (fragile
crine neoplasms restricted to the neuro- one neoplasm to another, suggesting a histidine triad gene) (3p), DCC (deleted
endocrine component only, possibly also multiclonal origin {683}. in colorectal carcinoma) and SMAD4/-
with expression of carcinoembryonic anti- The role of MEN1 in non-MEN1- DPC4 (deleted in pancreatic cancer locus
gen (CEA) in a fraction of cases {447, associated gastric NETs is more contro- 4) (18q) and MEN1, with a higher fre-
924, 1427, 1555, 2640}. versial. LOH at 11q13 and 11q14 regions quency of allelic imbalances than NETs
has been reported in less than half of {925, 2560}. Data on gastric MANEC indi-
Genetic susceptibility cases {640, 683, 925, 2560}. Mutation of cate a relatively higher frequency of chro-
NET MEN1 is rarely observed in sporadic mosomal abnormalities in the NEC vs the
Information on genetic susceptibility is gastric neuroendocrine neoplasms {909, adenocarcinoma component; however,
scant; however, similar to other NETs of the 1036, 3253}. shared LOH at chromosome 5q, 11q, 17p
gastrointestinal tract, gastric ECL cell NETs Of the other genetic abnormalities inves- and 18q suggested a close genetic
display a relatively small number of genetic tigated, mutations of the REG1A gene relationship and a possible multistep
abnormalities, the most relevant and involved in ECL cell cycle control have progression from a common precursor
frequent being associated with the MEN1 been described in type-I NETs {1191}. lesion {924, 1555}.
gene {1798, 3010}. In patients with familial X-chromosomal marker loss, with com-
MEN1-ZES, type II gastric carcinoids arise mon minimal deletion region restricted to Precursor lesions
in 13–30% of cases, vs exceptional cases Xq25 and Xq26, has often been demon- ECL cell NETs arising in hypergastrinaemic
in patients with sporadic ZES, despite strated in gastric NETs and NECs, similar conditions (types I and II) develop through
equally elevated, long-lasting serum levels to other neuroendocrine neoplasms of the a sequence of hyperplasia–dysplasia–
of gastrin {1418, 1798}. MEN1 is a rare foregut, but not those of midgut or hindgut neoplasia that is well-documented {3009}.
dominantly inherited disorder characterized origin {171, 639, 2562}. The successive stages of hyperplasia are
termed simple, linear, micronodular, and type III, while distant (liver) metastases with sharp regression and disappearance
adenomatoid. Dysplasia is characterized (M1) are found in 2.5%, 10% and 69% of of hyperplastic and neoplastic ECL cell
by moderately atypical cells with features cases of type III, respectively {2449, growth {2761}. For ECL cell NETs of
of enlarging or fusing micronodules, 2682, 2683}. Thus, most ECL cell NETs of < 1 cm, endoscopic surveillance with
microinvasion or newly formed stroma. type I and II are stage I, i.e. T1 N0 M0, biopsies has been suggested. Recently,
When the nodules increase in size to and only a few would be stage IIa or T2 similar results were obtained with long-
> 0.5 mm or invade the submucosa, the N0 M0. Most ECL cell NETs of type III and acting somatostatin analogues {403,
lesion is classified as microcarcinoid NECs (poorly differentiated endocrine 1074}, which also controlled hypergastri-
(< 0.5 cm) or plain carcinoid (≥ 0.5 cm). carcinomas) fit stages IIa, IIb (T3 N0 M0), naemia and ECL cell growth {638}. In ECL
The entire spectrum of ECL cell growth, IIIa (T4 N0 M0), IIIb (any T N1 M0) or even cell NETs of type 2, surgical removal of
from hyperplasia to dysplasia and neo- IV (any T, Any N, M0) {2684}. the gastrinoma is carried out first {2323}
plasia has been observed in MEN1-ZES The prognosis for patients with gastric since lifelong treatment with proton-pump
and A-CAG. A similar sequence of lesions NETs is highly variable. A striking differ- inhibitors is very effective in preventing
has been shown in experimental models ence exists between ECL cell NETs, which hypersecretion of gastric acid and pep-
of the disease, mostly based on hyper- are mostly indolent or low-grade malignant, tic-ulcer disease, but does not suppress
gastrinaemia secondary to pharmacolog- and NECs, which are invariably high-grade hypergastrinaemia, resulting in the
ical inhibition of acid secretion in rodents malignant. In ECL cell NETs, favourable neoplasm becoming aggressive and
{3192}. Linear hyperplasia or more prognosis associates with growth within necessitating surgery {2323}. Therapy
advanced changes have been shown to mucosa–submucosa, absence of angio- with long-acting somatostatin analogues
represent a risk factor for the develop- invasion, size < 1 cm, absence of an endo- has also proved effective {3257}. ECL cell
ment of gastric ECL cell tumours in crine syndrome, CAG or MEN1-ZES clinical NETs of type III and of > 1 cm, deeply in-
patients with MEN1-ZES {241}, while the background. Most type-I, A-CAG associ- vasive, G2 and/or associated with the
presence of dysplastic lesions has been ated, NETs have an excellent prognosis, “atypical” carcinoid syndrome, as well as
proven to markedly increase the risk of as do the majority of type-II MEN1-ZES for gastric NETs causing gastrinoma or
developing ECL cell tumours {121}. NETs {2683, 2686}. Aggressive behaviour Cushing syndrome {2761} are generally
of ECL cell NETs associates with invasion treated by surgery.
Prognosis and predictive factors of the muscularis propria or beyond, size The prognosis for gastric NECs is invari-
The issue of TNM/staging classification of > 1 cm, angioinvasion, presence of endo- ably poor {2004, 2682}, most patients
neuroendocrine neoplasms is as yet crine syndrome, high mitotic activity (G2 presenting with deeply invasive, ad-
unsettled. The classification recently pro- grading) and sporadic occurrence {2323, vanced-stage disease and short survival.
posed by the American Joint Committee on 2682, 2683, 2686}. Only exceptional Aggressive surgery and chemotherapy
Cancer (AJCC) and the International Union tumour-related deaths were observed in should be considered for any NECs, G3
Against Cancer (UICC) and embraced by patients with NETs of type I, while only 1 either small cell or large cell with more
WHO is for “carcinoid”, i.e. well-differentiated out of 10 patients died from NETs of type II. organoid, poorly differentiated histology
lesions only. By converse, the classification Of patients with type-III NETs, mortality was {303, 2004}.
proposed by the European Neuroendo- 27%, with a mean survival of 28 months
crine Tumor Society (ENETS) is also meant {303, 2683}.
for high-grade neoplasms {2684}. In the In type-1 ECL cell NETs, antrectomy to
stomach, both classifications are substan- remove the main source of gastrin, and
tially in agreement. Lymph-node metas- removal of as much as possible of the
tases (N1) are detected in about 5% of neoplasm (especially if > 1 cm in size),
cases of type I, 30% of type II and 71% of proved to cure about 80% of patients,

Lymphoma of the stomach S. Nakamura

H.K. Müller-Hermelink
J. Delabie
Y.H. Ko
J.H. van Krieken
E.S. Jaffe
Definition Age and sex distribution H. pylori has been shown to be present in
Primary gastric lymphomas are defined Incidence rates are similar in men and 90% of cases limited to the mucosa and
as lymphomas originating in the stomach. women. The age range is wide, but most submucosa, falling to 76% when deep sub-
Lymphomas at this site are considered patients are aged > 50 years at presentation. mucosa is involved, and is present in only
primary if the main bulk of disease is 48% of cases with extension beyond the
located in the stomach. Any histological Etiology submucosa {2223}. Sequential serological
subtype can present in the stomach, but Infection with H. pylori studies {2492} and retrospective studies of
the main two histological subtypes Epidemiological and experimental studies archival gastric biopsy material {2217,
(> 90% of cases) are extranodal marginal- have demonstrated an association between 3726} have shown that infection by H. pylori
zone lymphoma of mucosa-associated H. pylori infection and development of precedes the development of lymphoma.
lymphoid tissue (MALT lymphoma) and gastric lymphoma {727, 2492, 3551}.
diffuse large B-cell lymphoma (DLBCL). DLBCL
DLBCLs represent about half of gastric MALT lymphoma H. pylori infection is seen less frequently in
lymphomas. Hussel et al. have shown that continued DLBCLs with or without a MALT lymphoma
proliferation of gastric MALT lymphoma component (52–71% and 25–38%, re-
ICD-O codes cells from patients infected with H. pylori spectively) {317, 847, 993, 1481}. This
Diffuse large B-cell lymphoma 9680/3 depends on the presence of T-cells specif- suggests that some DLBCLs may arise
Mantle cell lymphoma 9673/3 ically activated by H. pylori antigens from long-standing H. pylori-associated
Marginal zone lymphoma of {1294}. The importance of this stimulation MALT lymphomas. In contrast to early
mucosa-associated lymphoid tissue in vivo has been clearly demonstrated by reports, two recent studies showed that
(MALT lymphoma) 9699/3 the induction of patient remissions in MALT eradication of H. pylori results in durable
lymphomas confined to the stomach and histological complete remission in 50–60%
Epidemiology treated with antibiotics to eradicate H. py- of patients with gastric DLBCL with areas
Incidence lori, and confirmed in many studies {3551, of concomitant MALT lymphoma {506,
Some 25–50% of all non-Hodgkin lym- 3550, 3563, 3565}. 2147}. These findings suggest that a
phomas arise at extranodal sites {2418}, Initial studies of low-grade gastric MALT antigenic drive may remain present in a
with the gastrointestinal tract being the lymphoma suggested that the tumour was subset of aggressive gastric lymphomas.
commonest extranodal site, accounting associated with H. pylori infection in > 90%
for about 4–20% of all non-Hodgkin of cases {770, 3551}; subsequent studies Immunosuppression
lymphomas in Asian countries, North have shown a lower incidence (62–77%) In general, lymphomas associated with
America and Europe, and up to 25% of {317, 993, 1481, 2223, 3571}, but also that immunodeficiency show a predilection
cases in the Middle East. Within the the density and detectability of H. pylori for extranodal sites, particularly the gas-
gastrointestinal tract, the stomach is the infection decreases as the lymphoma trointestinal tract, irrespective of the
most commonly involved site (50–75% of evolves from chronic gastritis {2223}. cause of the immunodeficiency {1817}.
cases), followed by the small intestine
(10–30% of cases) and the large intestine
(5–10% of cases) {1622, 2219}.
Lymphoma constitutes 5–10% of all
gastric malignancies and incidence is
apparently increasing worldwide, al-
though this may be partly due to
improvements in diagnostic procedures
{530, 1073}. About 30–60% of primary
gastric lymphomas are MALT lymphomas
{1620, 1622, 2219}, the remainder being
primary gastric diffuse large B-cell lym-
phoma (PG-DLBCL). There is remarkable
variation in the incidence of gastric MALT
lymphoma, which is only partially related A B
to the incidence of Helicobacter pylori Fig. 4.32 Gastric MALT lymphoma with H. pylori infection but not t(11;18)/BIRC3-MALT1; the tumour regressed after
infection. eradication of H. pylori. A Endoscopically, a vague superficially depressed lesion with bleeding is visible. B The spraying
of indigo carmine highlights the depressed lesion and erosions.
Lymphoma 69
epithelium, forming lymphoepithelial le-

sions.
Macroscopy
Grossly, the lesions appear as erosions,
ulcers, early cancer-like superficially
depressed erosions, discoloured areas,
cobblestone lesions (superficial-spreading
type), protrusions (mass-forming type),
and giant folds (diffuse-infiltrating type)
{2216, 2230}.
A B Histopathology
Fig. 4.33 Gastric MALT lymphoma with t(11;18)/BIRC3-MALT1 but not H. pylori infection. A Endoscopically, a superficial The lymphoma cells infiltrate around
lesion with small nodules mimicking cobblestones is visible. B The spraying of indigo carmine highlights the cobblestone reactive lymphoid follicles, external to a
lesion. preserved follicle mantle, in a marginal
zone pattern. As the lesion progresses,
the neoplastic cells erode, colonize and
The incidence, clinical features and histo- Low-grade lymphoma tends to be super- eventually overrun some or most of the
logy of the lesions is indistinguishable ficial. High-grade lymphoma is usually as- follicles (follicular colonization) {1346}.
from those that develop outside the stom- sociated with more florid lesions, often The characteristic marginal zone B-cells
ach. Up to 23% of gastrointestinal non- presents with diffusely infiltrative nodular are of intermediate size with pale cyto-
Hodgkin lymphomas arising in patients masses, and may mimic advanced gastric plasm and a slightly irregular nucleus,
infected with human immunodeficiency carcinoma. It is often difficult to distinguish resembling those of centrocytes, the term
virus (HIV) occur in the stomach and the lymphoma from carcinoma endoscopi- “centrocyte-like” cells being applied to the
vast majority of these are diffuse large cally. neoplastic component of MALT lym-
B-cell or Burkitt lymphomas {218}, although phomas. The accumulation of more
occasional MALT lymphomas have been Other imaging abundant pale-staining cytoplasm may
described {3549}. Aggressive B-cell lym- Staging work-up for gastric lymphoma lead to a monocytoid appearance. Alter-
phomas in this setting are almost always includes computed tomography (CT) and natively, the marginal zone B cells may
associated with Epstein-Barr virus (EBV). endoscopy of the upper gastrointestinal more closely resemble small lymphocytes.
Cases of EBV-associated DLBCL without tract. Endoscopic ultrasound is carried out Plasmacytic differentiation is present in
known immunodeficiency are rare and to assess the extent of lymphoma infiltration approximately one third of cases and may
occur predominantly in the elderly, being through the gastric wall and the involvement be very prominent with Dutcher bodies.
related to the senescent immune system. of perigastric lymph nodes {2504, 3116}. Large cells resembling centroblasts or
This lymphoma shows a more aggressive Positron emission tomography (PET) scan immunoblasts are usually present, but are
clinical course than does EBV-negative using 18-fluoro-2-deoxyglucose (FDG) in the minority.
DLBCL {576, 1789, 2421, 3652}. bears a documented diagnostic value The lymphoma cells infiltrate and destroy
only for DLBCLs, but is controversial for adjacent gastric glands to form lympho-
Clinical features MALT lymphomas, which are frequently epithelial lesions; those that are typical of
Symptoms and signs reported as FDG-PET-negative owing to MALT lymphoma are aggregates of three
Patients with low-grade lymphomas often their lower metabolism, reflecting indolent or more marginal-zone cells with distortion
present with a long history of nonspecific clinical behaviour, and small volume of or destruction of the glandular epithelium,
symptoms, including dyspepsia, nausea disease {91, 787}. often together with eosinophilic degener-
and vomiting. High-grade lesions may ation of epithelial cells. Transformed
appear as a palpable mass in the MALT lymphoma centroblast- or immunoblast-like cells may
epigastrium and can cause severe symp- Definition be present in variable numbers in MALT
toms, including weight loss. Bone-marrow Gastric MALT lymphoma is an extranodal lymphoma, but when solid or sheet-like
involvement, elevated lactate dehydroge- lymphoma composed of morphologically proliferations of transformed cells are
nase and B symptoms (fever, weight loss, heterogeneous small B cells, including present, the tumour should be diagnosed
night sweats), are less common in gastric marginal zone (centrocyte-like) cells, cells as DLBCL and the presence of accompa-
than nodal DLBCL. resembling monocytoid cells, small lym- nying MALT lymphoma noted. The term
phocytes, and scattered immunoblasts “high-grade MALT lymphoma” should not
Endoscopic appearance and centroblast-like cells. There is be used, and the term “MALT lymphoma”
At the time of diagnosis, lymphomas can plasma-cell differentiation in a proportion should not be applied to a large B-cell
vary greatly in size and appearance. The of the cases. The lymphoma often grows lymphoma, even if it has arisen in a MALT
tumours can present as superficial- in the marginal zone surrounding reactive site or is associated with lymphoepithelial
spreading, mass-forming, diffuse-infiltrat- B-cell follicles and extends further into the lesions.
ing, and unclassified types, which are interfollicular region. The neoplastic cells
generally related to histological grade {2216}. typically infiltrate the gastric glandular

H. pylori, is significantly associated with

H. pylori-negativity and nuclear expression
of BCL10, and can identify cases that will
not respond to eradication of H. pylori
{1325, 1872, 2226, 2228–2230, 3125}. This
translocation is also associated with a low
risk of an onset of additional genetic dam-
age and also histological transformation
into a large cell aggressive lymphoma
{3061}. The translocations t(1;14)/BCL10-
Fig. 4.34 Gastric MALT lymphoma with perifollicular IGH {3096, 3628}, t(14;18)/IGH-MALT1
distribution around reactive follicles (lower) and {2657, 3096} and t(3;14)/FOXP1-IGH
lymphoepithelial lesions (upper). {999, 2224, 2774} are infrequently detected.
Extra copies of MALT1 and FOXP1, often
Immunohistochemistry suggestive of partial and complete
The immunophenotype of the cells of trisomies 18 and 3, are detected in 25%
gastric MALT lymphoma is similar to that and 17% of cases. The presence of extra
of the marginal zone B cells. They are copies of MALT1 is significantly associ-
CD20+, CD79a+, BCL2+, CD5–, CD10–, ated with progression or relapse of lym-
CD23–, CD43+/–, CD11c+/– (weak) and phoma, and is an independent adverse
typically express IgM, less often IgA or prognostic factor for event-free survival
IgG and rarely IgD. Immunoglobulin light- {2224}. Studies of the immunoglobulin Fig. 4.35 Gastric MALT lymphoma showing a diffuse
chain restriction is most evident in cells genes of MALT lymphoma cells has shown infiltrate extending into the submucosa.
showing plasmacytoid differentiation. the sequential accumulation of somatic
There is no specific marker for MALT mutations, consistent with ongoing, antigen- MALT lymphoma, although molecular
lymphoma at present. Cyclin D1 and CD10 driven selection and proliferation {486, studies may also demonstrate clonal
are useful for distinguishing mantle cell 742, 2607}. Study of the third comple- B cells in some non-neoplastic MALT pro-
lymphoma from follicular lymphoma, mentary determining region of the im- liferations or persistent clonal populations
respectively. Immunostaining with anti-ker- munoglobulin heavy-chain gene shows a in gastric MALT lymphomas even after
atin antibodies aids the identification of pattern of changes associated with the histological complete remissions {2128,
lymphoepithelial lesions. Highlighting generation of antibody diversity and 3564}. Distinction between MALT lym-
follicular dendritic cells with antibodies to increased antigen-binding affinity {246}. phoma and other small B-cell lymphomas
CD21, CD23 or CD35 helps to demonstrate is based on a combination of the charac-
underlying follicular dendritic-cell networks Differential diagnosis teristic morphological and immunopheno-
in cases in which the lymphoid follicles The differential diagnosis of MALT lym- typical features.
have been completely overrun by the lymphoma and gastritis caused by H. pylori
phoma. EBV is rarely associated with MALT on the basis of small biopsy specimens Mantle cell lymphoma
lymphomas {1789, 1873, 2416, 3570}. may sometimes be difficult. Distinction Definition
from reactive processes is based mainly Mantle cell lymphoma typically involves
Molecular pathology on the presence of destructive infiltrates both spleen and intestines and may pres-
Four translocations – t(11;18)(q21;q21), of extrafollicular B cells, typically with the ent as an isolated mass or as multiple
t(1;14)(p22;q32) and t(14;18)(q32;q21) morphology of marginal zone B cells polyps throughout the gastrointestinal
and t(3;14)(p14.1;q32) – are specifically {3550}. In borderline cases, immuno- tract where it is referred to as multiple lym-
associated with MALT lymphomas, and phenotyping or molecular genetic analysis phomatous polyposis {599}. While gastric
result in the production of a chimeric to assess B-cell clonality is necessary to involvement is commonly encountered in
protein (BIRC3-MALT1) or in translocational help establish or exclude a diagnosis of patients with disseminated nodal mantle
deregulation (BCL10, MALT1, FOXP1) {49,
161, 2226, 2415, 3096, 3097, 3520}.
Trisomy of chromosomes 3, 18 or, less
commonly, others is a nonspecific but
frequent finding in MALT lymphoma. The
chromosomal translocations all converge
on the activation of the same oncogenic
pathway associated with nuclear factor
κ-light-chain-enhancer of activated of
activated B cells (NF-κB) {821}. The
t(11;18)(q21;q21) translocation, which
occurs most frequently in gastric MALT A B
lymphomas (15–30% of cases) {161, 2224, Fig. 4.36 Gastric MALT lymphoma. A Lymphoepithelial lesions adjacent to centrocyte-like cells infiltrating grandular
2229}, is not seen in gastritis caused by epithelium. B Immunostaining for keratin highlights lymphoepithelial lesions.
Lymphoma 71
cell lymphoma or multiple lymphomatous

polyposis {2330}, primary gastric mantle-
cell lymphoma is extremely rare {539,
2611}. Morphologically and immuno-
phenotypically, the lymphoma is indistin-
guishable from mantle cell lymphoma of
lymph nodes, with a diffuse and monoto-
nous infiltrate of cells with scanty
cytoplasm and irregular nuclei that
express B-cell markers and cyclin D1 A B
owing to the t(11;14)(q13;q32) juxtaposi-
tioning the cyclin D1 gene and the
immunoglobulin heavy-chain gene. Rare
cases of mantle cell lymphoma that are
negative for cyclin D1 may be identified
by overexpression of SOX11 {2175}.
Diffuse large B-cell lymphoma (DLBCL)

Definition
DLBCL is a neoplasm of large B-lymphoid
cells with nuclear size equivalent to or C D
exceeding that of normal macrophage Fig. 4.37 Gastric MALT lymphoma: variation in appearance of centrocyte-like cells. A Predominantly monocytoid
nuclei or more than twice the size that of appearance. B Clear cell variant. C Lymphoplasmacytoid appearance (arrows). D Prominent plasma-cell differentiation
a normal lymphocyte. The term “primary (arrows) and Dutcher bodies (arrowhead).
gastric DLBCL” (PG-DLBCL) is used for
tumours that are localized to the stomach larger than normal lymphocytes, often CD10, BCL6 and IRF4/MUM1 varies {512,
at presentation. PG-DLBCL may arise de infiltrating and destroying the gastric 2225, 2576, 3164}. Expression of CD10 is
novo or more rarely from transformation of glandular architecture. Lymphoepithelial found in 20–40%, BCL6 in 40–60%, and
a prior MALT lymphoma. The term “high- lesions by large cells with vesicular nuclei IRF/MUM1 in 50–60% of PG-DLBCL
grade MALT lymphoma” should be are infrequent. cases, implying that both activated B-cell
avoided. About 30–50% of PG-DLBCLs have and germinal-centre types exist {1118}.
components of MALT lymphoma {1622, The neoplastic cells express CD5 in < 5%
Macroscopy 2219, 2448}, but the extent of this low- of cases. These CD5+ DLBCL cases
At the time of diagnosis, the tumours vary grade component varies from only small usually represent de novo DLBCL distinct
greatly in size, and often show an ulcer- residual foci to dominant MALT lymphoma from Richter syndrome of CLL/SLL and
ated mass, mimicking advanced gastric with only a small proportion of solid or blastoid variant of mantle cell lymphoma
carcinomas (mass-forming type) {2216}. sheet-like transformed blasts. Tumours {3589}. EBV-positive DLBCL, as revealed
The cut section is yellow-to cream- with the former characteristics are often by in situ hybridization for EBV-encoded
coloured with a “fish-flesh” consistency. indistinguishable from de novo PG- mRNA (EBER), occur in 5–10% of cases
DLBCL and should be diagnosed as mainly among the elderly and have a
Histopathology DLBCL, noting the presence of accom- worse clinical course than EBV-negative
DLBCLs of the stomach are morphologi- panying MALT lymphoma. The term DLBCL unless treated mildly with ritux-
cally similar to DLBCLs at other sites. “high-grade MALT lymphoma” should not imab {576, 1789, 2421, 2473, 3652}.
Tumours consist of diffuse sheets of large, be used for tumours with the latter char-
blastic lymphoid cells, two to four times acteristics. The differentiation between Molecular pathology
transformed MALT lymphoma and de Chromosomal translocations involving the
novo PG-DLBCL is not clinically important immunoglobulin heavy-chain gene locus
since the two entities behave similarly. (IGH@) are frequent in DLBCL, and include
The activated B-cell and the germinal- t(3;14)(q27;q32), t(14;18)(q32;q21) and
centre types of DLBCL can both present t(8;14)(q24;q32), resulting in transcriptional
as a primary gastric lymphoma. dysregulation of BCL6, BCL2, and MYC,
respectively {2225}. In PG-DLBC, trans-
Immunohistochemistry locations involving IGH@ are detected in
The neoplastic cells are of B-cell pheno- 32% of cases. The most frequent partner
type, expressing pan B-cell antigens gene is BCL6 (20–36% of cases), followed
(CD19, CD20, CD22, CD79a), but may by MYC and FOXP1, but rarely BCL2. The
lack one or more of these. Monotypic t(11;18)/BIRC3-MALT1 translocation, spe-
Fig. 4.38 Gastric MALT lymphoma with t(11;18)/BIRC3-
MALT1 shows a relatively monotonous proliferation of surface and/or cytoplasmic expression of cific for MALT lymphoma, is infrequently
centrocyte-like cells with a small number of scattered immunoglobulin light chains can be detected in DLBCL with or without MALT
large cells. detected. The reported incidence of lymphoma {242, 3269}. Extra copies of

MALT1/BCL2, FOXP1/BCL6, and MYC,

often suggestive of partial or complete
trisomies 18, 3, and 8, are identified in
24%, 21%, and 10% of cases, respectively.
Genetic aberrations such as deletion of
6q, loss of TP53, amplification of chromo-
some region 3q27 and the myeloid/lym-
phoid or mixed-lineage leukaemia gene
(MLL) regions have also been reported
for PG-DLBCL {3060}.
Burkitt lymphoma
Classical Burkitt lymphomas may be A B
encountered in the stomach {113, 2477}. Fig. 4.39 Gastric DLBCL. A Tumour mass with central ulceration. B Endoscopic ultrasound shows a diffuse infiltrate
The morphology is identical to that of of lymphoma extending into the submucosa.
Burkitt lymphoma encountered elsewhere,
with diffuse sheets of medium-sized cells
with scanty cytoplasm and round/oval lymphomas have a cytotoxic T-cell pheno- system {2759} of 2003 is a modification of
nuclei containing small nucleoli. Within type, similar to that seen in enteropathy- the TNM staging system. The latter takes
the sheets there are numerous macro- associated T-cell lymphomas {1789, 3665, into account: (1) the depth of tumour
phages, giving a “starry sky” appear- 3696}. The neoplastic cells may display infiltration; (2) the extent of nodal involve-
ance. Mitoses are frequent and apoptotic features of intraepithelial T-lymphocyte ment; and (3) the extent of local tissue
debris is abundant. The cells express differentiation (e.g. expression of the infiltration by lymphoma.
CD10, CD20 and BCL6, but not BCL2. human mucosal lymphocyte 1 antigen, MALT lymphomas have an indolent natural
Nearly 100% of nuclei are immuno- CD103). These lymphomas may occur course and eradication of H. pylori results
reactive for Ki67. The cases carry t(8;14). sporadically outside the setting of coeliac in a high rate of complete remission in
The proportion that are EBV positive disease. Extranodal natural killer/T-cell 60–100% of patients {851, 2552, 2597,
varies, being relatively low (15–20%) in (NK/T-cell) lymphoma of nasal type 3235, 3550}. The time taken to achieve
sporadic Burkitt lymphoma, and higher in (EBV+) is also seen in east Asian coun- remission in these patients varies from 4–6
cases associated with immunodeficiency tries {555, 2942}. Nasal-type NK/T-cell weeks to 18 months. Cases with
(25–40%). lymphomas and enteropathy-associated t(11;18)/BIRC3-MALT1 are associated with
T-cell lymphomas have in common the resistance to H. pylori-eradication therapy.
T-cell lymphoma expression of CD56 (NCAM1) and cyto- Surgery, radiotherapy, and chemotherapy
Primary gastric T-cell lymphomas are toxic molecules such as granzyme B, have been used for PG-DLBCLs alone or
rare and heterogeneous. Adult T-cell TIA1, and perforin in addition to pan-T-cell in various combinations. Irrespective of
leukaemia/lymphoma is common in areas markers. Therefore, the presence or treatment modality, patient 5-year survival
of endemic infection with human T-cell absence of EBV is mandatory for their dis- varies from 60% to 90% {851, 2597}.
leukaemia virus 1 (HTLV-1) infection, rep- tinction. Some of the remainder are similar Younger age, limited clinical stage, and the
resenting up to 7% of gastric lymphomas to peripheral T-cell lymphomas encoun- presence of IGH@/oncogene transloca-
{2219, 2942}. The lymphoma cells are typ- tered in lymph nodes, including anaplastic tions are indicators for increased overall
ically CD4+, CD25+, and CCR4+ in addition large cell lymphoma that expresses survival and event-free survival, whereas
to carrying pan T-cell markers. No cytotoxic anaplastic lymphoma kinase (ALK+). deep invasion is an adverse prognostic
granule-associated proteins are detected factor, but only for event-free survival
{1134}. In areas where HTLV-1 infection is Hodgkin disease {2225}.
not endemic, most primary gastric T-cell Classical Hodgkin lymphoma may involve
the gastrointestinal tract, but this is usu-
ally secondary to nodal disease. Primary
gastric classical Hodgkin lymphoma is
extremely rare {3722}, and should be
differentiated from EBV-positive DLBCL of
the elderly {150, 576, 2421, 2473, 3652}.
Prognosis and predictive factors

The Ann Arbor staging system {421} is not
easily applied to gastrointestinal lym-
phomas, therefore alternative staging
systems have been proposed. The
Fig. 4.40 Gastric DLBCL. The neoplastic cells infiltrate “Lugano” system {2715} of 1994 is an
the glandular epithelium to form structures reminiscent of adaptation of the Ann Arbor staging
lymphoepithelial lesions. classification whereas the “Paris” staging
Lymphoma 73
Mesenchymal tumours of the stomach M. Miettinen

C.D.M. Fletcher
L.-G. Kindblom
W.M.S. Tsui
Definition Gastrointestinal stromal tumour (GIST) study of specimens from resection of car-
A group of nonepithelial tumours of vari- Definition and terminology cinoma of the oesophagogastric junction
able mesenchymal cell histogenesis. It is GIST is the most common primary mes- {10}. We estimate that approximately 25%
customary to include neuroectodermal enchymal tumour of the gastrointestinal of gastric GISTs (not counting minimal
tumours, such as Schwann cell tumours, tract and spans a clinical spectrum from incidental tumours) are clinically malig-
in this category. benign to malignant. It is generally immuno- nant. Surveillance Epidemiology and End
histochemically positive for KIT (CD117), Results (SEER) data indicate that GISTs
ICD-O codes phenotypically paralleling Cajal-cell dif- (interpolated from data on leiomyosarco-
Glomus tumour 8711/0 ferentiation, and most examples contain mas) account for 2.2% of all malignant
Granular cell tumour 9580/0 KIT- or PDGFRA-activating mutations. gastric tumours {3237}.
Leiomyoma 8890/0 Most gastric smooth-muscle tumours GISTs typically occur in older adults
Plexiform fibromyxoma 8811/0 defined before the current concept of (median age in most series, about 60–65
Schwannoma 9560/0 GIST are actually GISTs, as are leiomyo- years) without a distinct difference in inci-
Inflammatory myofibroblastic blastomas and tumours formerly desig- dence between men and women. Rarely,
tumour 8825/1 nated as gastrointestinal autonomic nerve gastric GISTs occur in children, some of
Gastrointestinal stromal tumour 8936/1 tumours (GANTs). whom have Carney triad or Carney-
Benign Stratakis syndrome.
(prognostic groups 1, 2, 3a) 8936/0 Epidemiology
Uncertain malignant potential The results of population-based studies in Clinical features
(group 4) 8936/1 Iceland and Sweden have suggested an The most common presentations include
Malignant annual incidence of GIST of 11–14.5 per vague abdominal complaints, symptoms
(groups 3b, 5, 6a, 6b) 8936/3 100 000; approximately 60% of these related to tumour ulcer, acute and chronic
Kaposi sarcoma 9140/3 tumours arise in the stomach {2291}. bleeding with or without anaemia, and
Leiomyosarcoma 8890/3 However, minimal GISTs that are detected abdominal mass; gastric-outlet obstruction
Synovial sarcoma 9040/3 incidentally are probably more common: is rare. These symptoms are also common
a frequency of 10% was reported in a to other gastric mesenchymal tumours.
A A B
B C D
Fig. 4.41 Gross appearance of gastric GISTs. A Small Fig. 4.42 Spindle cell GIST. A Sclerosing spindle cell GIST is paucicellular with abundant collagenous matrix.
tumour with central umbilicated ulcer. B Large tumour with B Palisaded-vacuolated GIST contains abundant perinuclear vacuoles and shows nuclear palisading. C The hypercellular
a central cystic cavity. variant shows dense cellularity with little mitotic activity. D Sarcomatous spindle cell GIST with diffuse nuclear
enlargement and hyperchromasia, and conspicuous mitotic activity.

Many smaller GISTs are detected inci-

dentally during endoscopy, surgery, or
computed tomography (CT) scans.
Malignant gastric GISTs spread into the
omentum and elsewhere in the abdominal
cavity, and metastasize to the liver.
While some malignant GISTs were fatal
within 1–2 years before the advent of ther-
apies based on tyrosine-kinase inhibitors,
other GISTS may metastasize after a long A B
delay and, in some cases, even patients
with liver metastases can survive for a
long period. Most GISTs are sporadic, but
gastric GISTs can occur rarely in connec-
tion with syndromes such as Carney triad
(GIST, pulmonary chondroma, paragan-
glioma) or Carney-Stratakis syndrome
(GIST plus paraganglioma). These GISTs
occur in younger age groups (including
children) and more commonly in women.
Carney triad-associated GISTs often have C D
an epithelioid morphology and occur in Fig. 4.43 Epithelioid GIST. A Sclerosing epithelioid GIST is paucicellular with epithelioid cells in abundant collagenous
gastric antrum. Patients with familial GIST matrix. B Epithelioid GIST with discohesive pattern and nuclear atypia. C Cellular epithelioid GIST with a pseudopapillary
syndrome and germline KIT mutations pattern. D Sarcomatoid epithelioid GIST with marked pleomorphism and mitotic activity.
can have multiple GISTs throughout the
gastrointestinal tract. Approximately 20
such families have been reported. Rarely, whereas some examples show diffuse membrane-associated, or sometimes as
gastric GISTs are associated with neuro- hypercellular pattern, and others show sar- perinuclear dots. However, a small minority
fibromatosis type 1 (NF1), a syndrome comatoid features with significant nuclear (< 5%), especially GISTs with mutant
conveying increased risk of GIST. atypia and mitotic activity. Epithelioid GISTs PDGFRA, may have very limited, if any,
may show sclerosing, discohesive, hyper- positivity {2032}. Anoctamin-1 (ANO1), a
Macroscopy cellular, sometimes with pseudopapillary chloride-channel protein detected by
Gastric GISTs can occur in any part of the pattern, or sarcomatous morphology with DOG1 antibody, is emerging as an equally
stomach. They vary from minimal mural significant atypia and mitotic activity. sensitive and specific marker {805, 2079}.
nodules to large complex masses with vari- Myxoid matrix may be present {2077}. KIT and DOG1 are also expressed in inter-
ably intraluminal and external components. Most gastric GISTs show strong positivity for stitial cells of Cajal, whose stem cell-like
Some GISTs are attached to the gastric wall KIT (CD117), which appears as cytoplasmic, subcohort is believed to be the histogenetic
with a narrow pedicle forming an appar-
Table 4.03. Prognosis for patients with gastrointestinal stromal tumours (GIST), based on long-term follow-up.
ently external mass, sometimes considered
“omental” GIST. Gastric GISTs may extend Tumour parameters Progressive disease during follow-up
into capsules of liver and spleen, trans- (% of patients)a
verse mesocolon, and into the pancreas. Prognostic Size Mitotic rate Gastric Small-intestinal
On sectioning, GISTs vary in colour from group per 50 HPFs GISTs GISTs
pale to pink tan, and haemorrhage and
cystic degeneration are common, espe- 1 ≤2 ≤5 0 0
cially in larger tumours {2077, 3543}. 2 >2≤5 ≤5 1.9 4.3
3a > 5 ≤ 10 ≤5 3.6 24
Histopathology
Gastric GISTs have a broad morphological 3b > 10 ≤5 12 52
spectrum. Most are spindle cell tumours,
4 ≤2 >5 0b 50b
while epithelioid histology is seen in 20–25%
of cases, with a number of cases showing 5 >2≤5 >5 16 73
mixed histology. Nuclear pleomorphism is 6a > 5 ≤ 10 >5 55 85
relatively uncommon, and occurs more
often in epithelioid tumours. Distinctive 6b > 10 >5 86 90
histological patterns among spindle cell HPF, high power field
GISTs include sclerosing type, seen espe- a
cially in small tumours that often contain Based on observation of 1784 patients in studies carried out by the Armed Force Institute of Pathology (AFIP).
Intestinal GISTs generally follow the behaviour of small-intestinal GISTs.
calcifications. The palisaded-vacuolated b
Denotes tumour categories with very small numbers of cases. Data based on reference {2066}.
subtype is one of the most common,
A B C
D E F
Fig. 4.44 Patterns of KIT immunostaining seen in GISTs. A Diffuse strong staining. B Strong staining with perinuclear dot pattern. C Strong perinuclear dot pattern and weak
cytoplasmic staining. D Membrane pattern. E Focal and delicate positivity in an epithelioid GIST. F KIT-negative GIST; only mast cells are positive. This tumour carried a mutation
in PDGFRA exon 14.
origin for GIST {1206, 1570}. Most spindle In order of decreasing frequency, the chromosomes 14 and 22 {779, 1153}. GISTs
cell GISTs are positive for CD34, whereas mutation types include in-frame deletions, in Carney-Stratakis syndrome (GIST plus
epithelioid examples are less consistently single-nucleotide substitutions, duplications, paraganglioma) are associated with
positive. A minority of gastric GISTs and insertions. Complex mutations com- germline mutations of succinate dehydroge-
expresses smooth muscle actin (SMA), and bining the above types can occur in some nase subunits B, C, and D. However, the
rare examples show positivity for desmin, cases. Deletions most commonly involve genetic basis for the Carney triad (GIST,
keratins (usually limited to keratin 18), or codons 557 and 558. The most common paraganglioma, pulmonary chondroma) is
S100 protein {2066}. single-nucleotide substitutions lead to unknown {435, 3093}.
V559D, V559A, V560D, W557R, and L576P.
Prognostic factors, grade and stage Gastric GISTs with exon 11 deletions have a Glomus tumour
The most useful and best studied prog- worse prognosis than those with single-nu- This rare tumour occurs in adults, especially
nostic factors are tumour size and mitotic cleotide substitution mutations. Duplications women. It usually presents as a 2–5 cm
activity (typically expressed as number of (1–18 codons) typically involve the 3’ intramural mass with symptoms similar to
mitotic figures per 50 high power fields, portion of exon 11 and are usually associ- those of gastric GISTs. Histological and
[HPF]), with a total area of 5 mm2. In the ated with a more favourable prognosis. KIT immunohistochemical features are similar
TNM classification, grading is based on exons 13 and 17 are rarely involved. Such to those of peripheral glomus tumours.
mitotic rate (< 5 mitoses per 50 HPFs is mutations include K642E and N822K, Features that are specific to gastric glomus
considered to be a low mitotic rate, while among others. A subset of gastric GISTs, tumours include plexiform growth within
> 5 mitoses per 50 HPFs is considered to especially tumours with epithelioid morpho- the muscular propria and vascular
be a high mitotic rate). The stage combines logy, has mutations in PDGFRA, which is involvement. The latter has no adverse
tumour size and mitotic activity. Estimates closely homologous to KIT. Most common prognostic significance. Immunohisto-
of metastatic rate for prognostic groups of these is exon 18 substitution D842V, and chemically, there is strong expression of
defined by tumour size and mitotic rate these mutant tumours are notably resistant SMA and pericellular laminin/collagen IV,
are shown in Table 4.03. It should be to imatinib. PDGFRA exon 12 deletions and but no KIT, DOG1/ANO1, CD34, or desmin.
noted that staging criteria are different for exon 14 substitutions are rare mutations. Focal synaptophysin positivity is not
gastric and small intestinal GISTs to re- Most KIT mutations are heterozygous, but uncommon and should not lead to
flect the more aggressive course of small- homozygous mutations can occur (via mistaken diagnosis of a neuroendocrine
intestinal GISTs with similar parameters. hemizygosity), and these tumours are often tumour. Most glomus tumours are benign,
more aggressive than corresponding but metastasis has been reported in a
Molecular pathology heterozygous mutants {1750}. tumour of > 5 cm in size with mitotic activity
KIT-activating mutations, leading to consti- GISTs in children or associated with NF1 {133, 2070}.
tutional activation of the KIT signalling path- do not contain KIT or PDGFRA mutations
way, are usually seen in exon 11, and most {2067, 2585}. Other recurrent genetic
of these tumours are sensitive to imatinib. changes include deletions/monosomy of

Inflammatory myofibroblastic tumour

This tumour is found more commonly in
children and young adults. The patient
develops gastric or intestinal mural
masses that can clinically and grossly
simulate a GIST. Some patients have
multiple tumours, including extragastro-
intestinal ones involving the omentum or
mesenteries. The tumours vary in size
from a few centimetres to > 10 cm. Most
are clinically benign, but rare malignant
examples have occurred.
Histologically, they typically have a hetero-
geneous composition with a variably promi-
nent lymphoplasmacytic infiltration and
fibrosis. Enmeshed in this background is
the neoplastic component: spindled to
epithelioid myofibroblast with often abun-
dant amphophilic cytoplasm, with vague
resemblance to rhabdomyoblast. While
mitotic activity is usually low, high cellularity
and mitotic activity occur in malignant
examples, although data are insufficient to
delineate histological criteria for malig-
nancy. Immunohistochemically, the tumour
cells are often positive for anaplastic lym-
phoma kinase (ALK), and variably for SMA,
but negative for KIT and DOG1/ANO1. ALK
gene rearrangements can often be shown
by fluorescent in situ hybridization (FISH)
or polymerase chain reaction (PCR)-based
studies examining ALK fusion transcripts;
fusion partner genes include 5-amino-
imidazole-4-carboxamide ribonucleotide
formyltransferase (ATIC), clathrin heavy-
chain 1 (CLTC), Ran-binding protein
(RANBP2), and tropomyosins 3 and 4 Fig. 4.45 Schematic distribution of KIT mutations involving different regions of the KIT receptor tyrosine kinase
molecule, and selected downstream effectors in the KIT signalling pathway.
(TPM3, TPM4) {574, 994, 1485}.
Leiomyoma and leiomyosarcoma

Intramural leiomyoma is rare and, in our ambiguous criteria of malignancy should a microtrabecular pattern in a collage-
experience, is approximately 50 times be designated as having uncertain ma- nous background. Focal nuclear atypia is
less common than GIST. These tumours lignant potential, and complete excision common, but mitotic activity only excep-
usually occur in older adults and clinically and follow-up is necessary. tionally exceeds 5 per 50 HPFs. Immuno-
present similarly to GISTs. The tumours histochemically, gastric schwannomas
vary from minimal mural nodules to Schwannoma are positive for S100 protein and usually
masses of > 5 cm in size. However, mini- Schwannoma is rare in the stomach, oc- glial fibrillary acidic protein (GFAP), but
mal leiomyomas have been commonly curring with a frequency similar to that of they can be distinguished from GISTs
found in oesophagogastric resections for leiomyoma. These tumours often occur in since they are negative for KIT and
carcinoma {10}. Histologically, these older adults, and form intramural masses DOG1, and usually also for CD34 {646}.
tumours are composed of well-differenti- of 2–10 cm that can ulcerate and present
ated smooth-muscle cells with no or little in a manner similar to GIST, gross features Plexiform fibromyxoma
atypia and mitotic activity, or isolated included. The behaviour of these tumours This very rare, recently described mes-
mitosis. Immunohistochemically, leiomy- is benign and recurrence is exceptional. enchymal tumour that is apparently spe-
omas are positive for SMA and desmin, Histologically typical is a relatively cir- cific to stomach, occurs in the antrum and
and are negative for KIT, DOG1/ANO1, cumscribed mass, often partly sur- pyloric region, often extending into the
and CD34. Smooth-muscle tumours with rounded by patches of lymphoid duodenal bulb. It occurs over a wide
atypia and mitotic activity are designated infiltration, sometimes with germinal cen- range of ages, from childhood to old age,
leiomyosarcomas, and such tumours are tres. The tumour is composed of variably equally in men and women. Clinically, the
distinctly rare in the stomach. Cases with organized tumour cells, often arranged in tumour manifests similar to GIST, but
A B
Fig. 4.47 Inflammatory myofibroblastic tumour. A The tumour contains an admixture of elongated tumour cells and
lymphoplasmacytic infiltration. B The cells can also have a more epithelioid, ganglion cell-like morphology.
A B
Fig. 4.46 Glomus tumour is composed of uniform cells Fig. 4.48 Schwannoma typically shows a peritumoral lymphoid cuff. Higher magnification typically reveals a
with round nuclei and clear to eosinophilic cytoplasm, often microtrabecular pattern of tumour cells.
giving a “fried egg” appearance. The eosinophilic material
in the centre is pre-existing gastric smooth muscle.
gastric outlet obstruction is more common. Synovial sarcoma Kaposi sarcoma

Prognosis is good, and there is no ten- Only a small number of primary synovial sar- According to screening studies con-
dency for recurrence. Histologically, the comas in the stomach have been reported. ducted in the 1990s, gastrointestinal
tumour is characterized by a multinodular, These tumours have occurred in young or Kaposi sarcoma occurred in 38% and
plexiform involvement of gastric muscular middle-aged adults. They have varied small 51% of patients in patients with HIV/-
propria. An extra-gastric non-plexiform (2–3 cm) mucosal or submucosal plaque or AIDS in Italy and Uganda and was most
component may also be present. The tu- cup-like lesions to large transmural masses commonly detected in the stomach,
mour nodules are relatively paucicellular of > 10 cm. Histologically, most have been being usually multifocal. Many patients
with a prominent capillary pattern, and monophasic spindle cell tumours, and only showed simultaneous involvement of the
contain abundant acid mucopolysaccha- isolated biphasic examples have been colon. Most lesions are incidental small
ride-rich myxoid matrix. The tumour cells reported. Detection of keratins and epithelial submucosal nodules in asymptomatic
are bland spindle cells, and mitotic activity membrane antigen (EMA) helps to identify patients, but some form larger mural
is low, generally not exceeding 5 per 50 monophasic tumours that are negative for masses and may present with gastroin-
HPFs. Immunohistochemically, the tumour KIT and DOG1/ANO1. Prognosis varies, but testinal bleeding and simulate a GIST.
cells are positive for SMA and CD10 and is good for small tumours, especially in the These tumours may also occur in immuno-
negative for KIT and DOG1. Desmin-posi- absence of poorly differentiated, mitotically suppressed post-transplant patients
tivity has been reported {2069, 3160}. active histology {259, 1959}. {2462, 2639}.
A B
Fig. 4.49 Gastric plexiform fibromyxoma. A The tumour involves the gastric wall in a plexiform manner. B The tumour Fig. 4.50 Monophasic synovial sarcoma may involve
shows high vascularity, and the spindled cells are scattered in a myxoid matrix. mucosa. Note uniform spindle cells and high cellularity.

Histologically, this tumour typically appears

as a haemorrhagic, vascular spindle-cell
proliferation. It may contain focal cytoplasmic
eosinophilic hyaline globules. Immunohisto-
chemical demonstration of human herpes-
virus-8 (HHV-8) in tumour-cell nuclei is
diagnostically helpful. Other typical features
include positivity for CD31, CD34, and
podoplanin (PDPN/D2-40) {1455}.

Haemangiomas rarely occur in the stom-
ach. They may be associated syndromes
such as blue rubber bleb naevus, and
mucosal teleangiectasias occur in Osler-
Rendu-Weber disease. We have seen
isolated examples of haemangioma vari-
ants, such as epithelioid haemangioma
involving an artery. Lipomas are more
common in the colon and are discussed
in Chapter 8. In some cases, calcifying Fig. 4.51 Kaposi sarcoma contains a cellular, haemorrhagic spindle-cell proliferation with little pleomorphism.
fibrous (pseudo)tumour involves the
gastric wall, and can also occur in the Gastric or intestinal involvement of involve stomach but is more common in
intestines. Inflammatory fibroid polyps abdominal dedifferentiated liposarcoma small intestine (see Chapter 6). Desmoid
may occur more often in the stomach, but should be distinguished from primary fibromatosis can also involve gastric and
are discussed with tumours of the small mesenchymal tumours because, by their intestinal walls in some cases simulating
intestine, where resection of symptomatic morphological spectrum, these liposarco- gastric tumours such as GIST. Some of
examples seems to be more common mas can simulate a wide variety of other these desmoids occur in patients with
(see Chapter 6). mesenchymal tumours, especially GISTs. familial adenomatous polyposis.
Gastrointestinal clear cell sarcoma can
Secondary tumours of the stomach C. Iacobuzio-Donahue

G.M. Groisman
Definition common clinical presentations include

Tumours of the stomach that originate anaemia and gastrointestinal bleeding,
from an extra-gastric neoplasm or that are abdominal pain or dyspepsia {404, 674,
discontinuous with a primary tumour 1056, 3560}. The time interval between the
elsewhere in the stomach. diagnosis of a primary neoplasm and its
metastasis to the stomach varies accord-
Epidemiology ing to the tumour type. For example, in
Metastatic disease involving the stomach most patients with lung or oesophageal
is unusual. In a series of 771 patients with carcinomas that had metastasized to the
gastric neoplasms found at endoscopy, stomach, the metastases were diagnosed
only 2.6% were secondary tumours {404}. within 2 years of diagnosis of the primary Fig. 4.52 Multiple gastric metastases from rhabdomyo-
The incidence of gastric metastasis found malignancy. In contrast, half of melanoma sarcoma of the spermatic cord in a boy aged 15 years.
in autopsy cases is 0.2–1.4%, whereas or breast carcinoma metastases to the
that seen in autopsies performed specifi- stomach are diagnosed > 2 years after
cally in cancer patients is 1.7–5.4% {658, diagnosis of the primary tumour {674}. In endoscopic evaluation may be normal.
725, 1056, 2048, 3211}. some patients, the development of gastric The most common endoscopic appear-
metastasis leads to the initial diagnosis of ance of a gastric metastasis is of a nodule
Clinical features their cancer. As metastases to the stomach resembling a submucosal tumour, seen as
Gastric metastases are symptomatic in are frequently limited to the submucosa a mass with a smooth surface, normal-
half of the patients affected. The most and seromuscular layers, the results of coloured mucosa and a central depression
Histopathology
The features of metastases to the stomach
are similar to those observed in other
organs. In most cases the metastasis is
located within the submucosal or muscu-
laris propria layers, with little or no
involvement of the mucosa. The lack of an
in situ component within the mucosa may
also serve as a clue that the neoplasm is
a metastasis. In cases with mucosal
involvement, the distinction from a primary
adenocarcinoma may be difficult. Immuno-
histochemistry may help to differentiate
A B between a primary gastric cancer (fre-
Fig. 4.53 A Metastasis of lobular breast carcinoma to gastric oxyntic mucosa. Differentiation from a primary gastric quently positive for keratin 7, MUC5AC,
cancer may be difficult without additional ancillary studies. B Immunostaining for gross cystic disease fluid protein MUC2, and CDX2), and metastases from
(GCDFP) demonstrates strong positive labelling, consistent with origin from a breast primary. a variety of extra-gastric primary sites,
such as metastatic melanoma (positive
or ulceration (“volcano-like” lesion). In common primary neoplasms of origin are for Melan A and S100 protein), metas-
some patients, the presence of metastatic also malignant melanomas or carcinomas tases from ovary and breast (positive for
lobular breast cancer may resemble an of the breast, as well as carcinomas of the keratin 7, gross cystic disease fluid protein
advanced gastric cancer with features of oesophagus, lung, and pancreas {674, and estrogen/progesterone receptors),
linitis plastica {674, 1056, 3150}. Imaging 2346, 3461}. Metastases from primary lung (positive for keratin 7 and thyroid
is particularly useful in cases of submu- neoplasms of the kidney, testis, uterus, transcription factor-1 [TTF1] and those
cosal tumours for which mucosal biopsies ovary and colon have also been described from liver, kidney and prostate (negative
give negative results. Radiography – com- {404, 1056}. Two thirds of breast-cancer for keratins 7 and 20 and positive for
puted tomography (CT) scan and/or dou- metastases to the stomach are lobular hepatocyte-paraffin-1 antibody [HepPar1],
ble-contrast barium meal – or endoscopic carcinomas {2028, 3150}. paired box gene 8 [PAX8] and prostate-
ultrasonography may show pathological specific antigen [PSA] {551, 2335, 2380,
thickening of the gastric wall {2894}. Macroscopy 2475, 3267}.
Solitary metastases to the stomach are
Origin more common than multiple metastases. Prognosis and predictive factors
Cancers can metastasize to the stomach However, whether single or multiple, most Gastric metastases usually represent a
by lymphohaematogenous spread (i.e. gastric metastases are located in the late, disseminated stage of the patient’s
melanoma, breast cancer or lung cancer), upper two thirds of the stomach. Metas- disease in which other haematogenous
by direct extension (pancreatic or oeso- tases are typically seen as a raised nodule metastases may also be found. The prog-
phageal cancer) or by intraperitoneal covered by normal mucosa that may have nosis is poor but varies depending on the
dissemination (i.e. ovarian cancer) {830}. a central ulceration. In some instances the source of the metastasis. In one series,
Although virtually all primary neoplasms metastasis forms a polypoid mass or a overall survival after the diagnosis of
can metastasize to the stomach, large necrotic ulcer reminiscent of a primary gastric metastasis from a variety of primary
series of autopsy studies indicate that gastric carcinoma. Metastatic lobular car- origins ranged from 0 to 14 months, with a
gastric metastases most often originate cinoma of the breast may diffusely infiltrate median of 4.75 months {404}. In patients
from malignant melanomas or carcinomas the wall of the stomach, simulating linitis with breast carcinoma, the median survival
of the breast, oesophagus and lung plastica. Pigmented metastatic melanoma after development of gastric metastasis
{1056}. In patients who present with gastric may be seen as small black mucosal spots was 10 months, with 23% of patients
metastasis in the clinical setting, the most {404, 674, 1056, 2894}. surviving > 24 months {3150}.

CHAPTER 5
Tumours of the ampullary region
Adenomas and other premalignant lesions
Invasive adenocarcinoma
WHO classificationa of tumours of the ampullary region

Epithelial tumours Mucinous adenocarcinoma 8480/3
Signet ring cell carcinoma 8490/3
Premalignant lesions Squamous cell carcinoma 8070/3
Intestinal-type adenoma 8144/0 Undifferentiated carcinoma 8020/3
Tubular adenoma 8211/0 Undifferentiated carcinoma with osteoclast-like
Tubulovillous adenoma 8263/0 giant cells 8035/3
Villous adenoma 8261/0
Noninvasive pancreatobiliary papillary neoplasm Neuroendocrine neoplasmsb
with low-grade dysplasia Neuroendocrine tumour (NET)
(low-grade intraepithelial neoplasia) 8163/0* NET G1 (carcinoid) 8240/3
Noninvasive pancreatobiliary papillary neoplasm NET G2 8249/3
with high-grade dysplasia
(high-grade intraepithelial neoplasia) 8163/2* Neuroendocrine carcinoma (NEC) 8246/3
Flat intraepithelial neoplasia (dyplasia), Large cell NEC 8013/3
high grade 8148/2 Small cell NEC 8041/3
Carcinoma EC cell, serotonin-producing NET 8241/3
Adenocarcinoma 8140/3 Gangliocytic paraganglioma 8683/0
Invasive intestinal type 8144/3 Somatostatin-producing NET 8156/3
Pancreatobiliary type 8163/3*
Adenosquamous carcinoma 8560/3 Mesenchymal tumours
Clear cell carcinoma 8310/3
Hepatoid adenocarcinoma 8576/3 Secondary tumours
Invasive papillary adenocarcinoma 8260/3
___________________________________________________________
EC, enterochromaffin.
a
Morphology code of the International Classification of Diseases for Oncology (ICD-O) {904A}. Behaviour is coded /0 for benign tumours, /1 for unspecified,
borderline or uncertain behaviour, /2 for carcinoma in situ and grade III intraepithelial neoplasia, and /3 for malignant tumours.
b
The classification is modified from the previous (third) edition of the WHO histological classification of tumours {691} taking into account changes in our
understanding of these lesions. In the case of neuroendocrine neoplasms, the classification has been simplified to be of more practical utility in morphological
classification.
TNM classificationa of carcinoma of the ampullary region

T - Primary tumour Stage grouping
T0 No evidence of primary tumour Stage T N M
Tis Carcinoma in situ Stage 0 Tis N0 M0
T1 Tumour limited to ampulla of Vater or sphincter of Oddi Stage IA T1 N0 M0
T2 Tumour invades duodenal wall Stage IB T2 N0 M0
T3 Tumour invades pancreas Stage IIA T3 N0 M0
T4 Tumour invades peripancreatic soft tissues, or other adjacent organs or Stage IIB T1, T2, T3 N1 M0
structures Stage III T4 Any N M0
N – Regional lymph nodes Stage IV Any T Any N M1
NX Regional lymph nodes cannot be assessed
M – Distant metastasis
M0 No distant metastasis
____________________
a
{762, 2996}
82 Tumours of the ampullary region

Adenomas and other premalignant D.S. Klimstra

J. Albores-Saavedra
neoplastic lesions R.H. Hruban
G. Zamboni
Definition
Preinvasive neoplastic lesions of the
ampulla of Vater include intestinal-type
adenomas (which are the most common),
noninvasive papillary neoplasms of pan-
creatobiliary type, and flat intraepithelial
neoplasia (dysplasia) of the ampullary
epithelium. Intestinal-type adenomas are
benign epithelial neoplasms exhibiting
tubular, villous, or mixed patterns that
resemble adenomas of the small and large
intestines. Noninvasive papillary neoplasms
are exophytic neoplasms with cytological
features resembling those of papillary
neoplasms of the biliary tree, including
architectural complexity and, usually,
marked cytological atypia. Flat intraepithe-
lial neoplasia (dysplasia) is a grossly
subtle, non-exophytic preinvasive lesion
composed of cytologically atypical cells
arranged along the native ampullary Fig. 5.01 Gross appearance of ampullary adenoma Fig. 5.02 Whole mount of an ampullary adenoma (right)
epithelium. Flat intraepithelial neoplasia (right). Cut section demonstrates relationship to bile duct showing relationship to bile duct (arrow) and pancreatic
(dysplasia) is rarely encountered in the (arrow) and pancreatic duct (arrowhead). ducts (arrowhead).
absence of invasive carcinoma.
means that it is now more common to predominantly noninvasive neoplasms
ICD-O codes detect adenomas before the development are noninvasive papillary neoplasms.
Intestinal-type adenoma 8144/0 of invasive carcinoma. These neoplasms have not been de-
Tubular adenoma 8211/0 Ampullary adenomas may occur sporad- scribed in patients with FAP.
Tubulovillous adenoma 8263/0 ically or in the setting of familial adeno-
Villous adenoma 8261/0 matous polyposis (FAP) (and its variant, Clinical features
Noninvasive pancreatobiliary papillary Gardner syndrome) {88, 1690, 2916}. The Patients with ampullary adenomas gener-
neoplasm with low-grade dysplasia prevalence of ampullary adenomas in ally present with signs and symptoms of
(low-grade intraepithelial neoplasia) patients with FAP is 50–95% {88, 2309, biliary obstruction, including jaundice,
8163/0 2351}, and the lifetime risk is nearly 100% abdominal pain, weight loss, and occa-
Noninvasive pancreatobiliary papillary {272, 374}. Most patients with sporadic sionally pancreatitis {1825, 2187, 2371,
neoplasm with high-grade dysplasia ampullary intestinal-type adenomas are 2575, 2729, 2765, 3498, 3583} accompa-
(high-grade intraepithelial neoplasia) between 33 and 81 years of age (mean, 61 nied by elevation of serum bilirubin, serum
8163/2 years); females outnumber males by 2.6 : 1 glutamic oxaloacetic transaminase, serum
Flat intraepithelial neoplasia (dysplasia), {457, 2365, 2533, 2729, 2997}. Patients glutamic pyruvic transaminase, and alka-
high grade 8148/2 with FAP with ampullary adenomas have a line phosphatase. Some patients also have
mean age of 41 years and men and women cholelithiasis or choledocholithiasis {2729,
Epidemiology are equally affected {88, 2351, 2916}. 2997}. Other patients are asymptomatic,
Adenomas of the small intestine are Noninvasive papillary neoplasms are and the ampullary adenomas are detected
uncommon, but 80% of them occur in the uncommon compared with intestinal-type during endoscopic screening. Endoscopic
duodenum near the ampulla {157, 363, adenomas, and they are rarely encoun- ultrasound is helpful to determine the size
2533, 2765, 3536}. Ampullary adenomas tered in the absence of an associated in- of the polyp and to evaluate lesions for an
are found at autopsy in 0.04–0.12% of vasive carcinoma. Only 12% of ampullary invasive carcinoma {2049}.
individuals {176, 2901, 2997}. Until recently, carcinomas associated with a noninva- In patients with FAP, asymptomatic polyps
most ampullary adenomas were reported sive precursor lesion have components of are frequently found by endoscopic
to be associated with an invasive adeno- noninvasive papillary neoplasms; most of screening after prophylactic colectomy to
carcinoma at diagnosis {2365, 2729, 3059}, the remainder are associated with intestinal- prevent colorectal adenocarcinoma {2916};
but the increased use of endoscopy type adenomas {70}. Even fewer (6%) ampullary adenomas in such patients do
Adenomas and other premalignant neoplastic lesions 83

A B
Fig. 5.03 Intestinal-type adenoma of the ampulla. A Intestinal-type adenoma extending into peri-ampullary glands. B Intestinal-type adenoma with pseudostratified, elongate nuclei.
not usually become symptomatic until 10–15 Histopathology severe nuclear atypia and marked archi-
years after removal of the colon {2351}. Intestinal-type adenoma tectural complexity (such as cribriforming)
Noninvasive papillary neoplasms are rare, Intestinal-type adenomas may arise any- are not found in low-grade dysplasia.
and their distinctive clinical features are not where within the ampullary region, including Mitotic figures can be frequent and are
well-defined, patients usually presenting in from the duodenal-type mucosa of the predominantly basally located.
a similar fashion as those with intestinal- surface of the papilla, the transitional In high-grade dysplasia, the glandular
type adenomas {70}. Since flat intra- mucosa within the ampulla itself, and the architecture is more complex, and cribri-
epithelial neoplasia does not produce a terminal portions of the pancreatic and formed glands are often present. The
mass lesion, it is presumably asympto- biliary ducts {3330}. Commonly, adeno- nuclei are moderately to markedly atypical
matic until invasive carcinoma develops, matous epithelium involves more than one and are not basally polarized. Mitoses are
which explains why few cases of pure flat of these microanatomic regions {3059}. At present at all levels of the epithelium, and
intraepithelial neoplasia have been de- the periphery of the polypoid lesion, flat some may be atypical. The individual cells
tected. adenomatous changes (flat intraepithelial may have features indistinguishable from
neoplasia/dysplasia) may extend into the those of invasive carcinoma, although they
Macroscopy pancreatic and common bile ducts or into are still confined within the basement mem-
Sporadic ampullary intestinal-type adeno- the periampullary ductules within the brane of the mucosa, and there is no stro-
mas generally measure 1–3 cm {3583}; sphincter of Oddi. mal reaction and no infiltrative or expansile
tubular adenomas are smaller than villous Tubular adenomas are usually smaller than growth. High-grade dysplasia includes the
adenomas. Intestinal-type adenomas usu- villous or tubulovillous adenomas and have conceptual category of “carcinoma in situ.”
ally arise from the intestinal epithelium cov- a polypoid growth pattern {2533}. They Most of the columnar cells making up
ering the papilla, so they often project into consist of tubular glands resembling the adenomas contain modest amounts of
the duodenal lumen as a pale soft polyp or basal portions of the intestinal crypts. mucin within the apical cytoplasm. True
plaque {274}. Less commonly the adenoma Villous adenomas are usually more sessile. goblet cells are also found, usually in
is confined within the ampulla (“intra-am- The neoplastic cells in villous adenomas areas of low-grade dysplasia.
pullary”), resulting in a prominent bulging line variably long simple or branching Paneth cells and neuroendocrine cells are
papilla covered by intact duodenal mucosa papillae that are more exuberant than the particularly numerous in intestinal-type
{3583}. Villous adenomas have a feathery normal villi of the duodenal mucosa. Villous adenomas {846, 1637, 2351}.
appearance whereas tubular adenomas adenomas are more likely to have high As in large-bowel adenomas, ampullary
are bosselated. Patients with FAP who un- grade dysplasia or an associated invasive adenomas may contain foci in which mucin
dergo endoscopic screening may have a carcinoma than tubular adenomas. By has “spilled” into the stroma from the
minimally granular or even normal-appear- arbitrary definition, tubulovillous adenomas glands at the base of the polyp, simulating
ing ampulla that nonetheless exhibits ade- contain more than 25% of both tubular and an invasive mucinous adenocarcinoma.
nomatous changes on biopsy {88, 1309}. villous patterns. This “pseudoinvasion” is often characterized
Noninvasive papillary neoplasms presum- In all intestinal-type adenomas, the nuclei by an inflammatory reaction to the mucin
ably arise from the epithelium of the common are oval, hyperchromatic, and pseudo- accompanied by recent or past haemor-
channel or distal pancreatic and biliary ducts, stratified. In adenomas with low-grade rhage. No neoplastic cells are found within
so they are often grossly intra-ampullary. dysplasia, the nuclei are located predomi- the mucin.
Flat intraepithelial neoplasia does not nantly at the basal aspect of the cells, and
produce a mass lesion but may appear the apical cytoplasm is amphophilic. Full- Noninvasive papillary neoplasm,
grossly as subtle mucosal granularity, thickness pseudostratification of the nuclei, pancreatobiliary type
usually adjacent to a frank invasive adeno- moderate nuclear atypia, and mild glandu- Although most noninvasive ampullary
carcinoma. lar architectural complexity may occur, but neoplasms are intestinal-type adenomas,

some more closely resemble a subset of goblet cells are inconspicuous, contrasting Intraductal papillary neoplasms of the bile
the intraductal papillary neoplasms of the with the normal duodenal mucosa. The ducts and pancreatic ducts (intraductal
bile ducts and pancreas {929, 1493, 1593, presence of significant nuclear atypia or an papillary mucinous neoplasms [IPMN])
2252} and are designated noninvasive increased ratio of nucleus to cytoplasm may grow along the ducts to involve the
papillary neoplasms, pancreatobiliary type, raises the possibility of high-grade ampullary epithelium secondarily. These
of the ampulla {70}. The papillae of pan- dysplasia or invasive carcinoma {685}, but neoplasms may have an intestinal morpho-
creatobiliary-type noninvasive papillary making a distinction between high-grade logy {1493, 2252}, and when they involve
neoplasms are complex and arborizing dysplasia and invasive carcinoma on the the ampulla they are almost indistinguish-
and are usually lined by moderately to basis of cytology may be very difficult {196}. able from primary ampullary adenomas
markedly atypical cells. The marked on the basis of a biopsy. Radiographic and
architectural complexity may result in Immunohistochemistry endoscopic correlation is helpful.
intraepithelial lumen formation and cribri- Intestinal-type adenomas label with anti-
forming. The degree of dysplasia (based bodies to keratins 7 and 20. They express Invasive pancreatic and common bile duct
on the highest grade present) should be markers of intestinal differentiation, adenocarcinomas
specified. Almost all pancreatobiliary-type including MUC2 and CDX2, but not These carcinomas can also simulate
noninvasive papillary neoplasms have at MUC1 {553, 2574}. Immunohistochem- ampullary adenomas when they invade the
least focal high-grade dysplasia, and istry for carcinoembryonic antigen (CEA) ampulla as they have a striking propensity to
many cases also have an associated and CA19-9 produces predominantly sur- colonize basement membranes {2574},
invasive carcinoma {70, 929, 1493, 1593, face-membrane labelling in adenomas including the mucosa of the ampulla or
2252}. The epithelial lining consists of with low-grade dysplasia, but intense cyto- duodenum. Paradoxically, the malignant
cuboidal cells with round nuclei predom- plasmic labelling may be found in areas cells may appear to be better differentiated
inantly arranged in a single layer. Paneth of high-grade dysplasia {3583}. Stains for and morphologically more intestinal than the
cells are not found, although an endo- chromogranin or synaptophysin will high- underlying invasive carcinoma within the
crine cell component may be detectable light scattered neuroendocrine cells. stroma, and they can closely simulate an
by immunohistochemical labelling. The Pancreatobiliary-type noninvasive papil- intestinal-type adenoma. Immunolabelling
invasive carcinomas arising in association lary neoplasms express keratin 7 and can facilitate the diagnosis, as most pancre-
with pancreatobiliary-type noninvasive MUC1, but not MUC2, except in scattered atic ductal adenocarcinomas colonizing the
papillary neoplasms usually have a tubular goblet cells that may be present. Labelling ampullary mucosa express keratin 7 and
pattern of growth and are usually also for keratin 20 and CDX2 is also largely MUC1 and are negative for the intestinal
classified as pancreatobiliary-type adeno- negative in pancreatobiliary-type papil- markers keratin 20, MUC2, and CDX2, which
carcinomas, although some may also be lary noninvasive neoplasms {2574}. are expressed by ampullary adenomas
of intestinal type. {2574}.
Differential diagnosis
Flat intraepithelial neoplasia (dysplasia) The differential diagnosis of ampullary
Although most invasive ampullary carci- adenomas is particularly problematic
nomas arise from adenomas or pancreato- when dealing with endoscopic biopsies.
biliary-type noninvasive papillary neoplasms,
some appear to arise from nonpolypoid Reactive atypia
precursor lesions and this is known as flat The most common lesion to mimic an
intraepithelial neoplasia (dysplasia). Flat adenoma is reactive atypia; any condition
intraepithelial neoplasia (dysplasia) may causing ampullary inflammation (such as
be found in the ampulla, usually in the lithiasis, ampullary stricture, or prior
intra-ampullary or bile duct epithelia, and instrumentation) may induce dramatic
almost always adjacent to invasive reactive epithelial atypia. Reactive atypia
carcinomas {1568}. Microscopically, the is characterized by large nuclei with an A
dysplastic epithelium can be truly flat or it open chromatin pattern, thick nuclear
may have micropapillary projections lack- membranes, and prominent nucleoli. Full-
ing fibrovascular cores. The minimally thickness nuclear pseudostratification is
pseudostratified cells are cuboidal to usually not present in reactive atypia. The
columnar and show round to oval nuclei cytoplasm is often abundant and mucin-
with marked nuclear atypia, mitoses, and rich, in contrast to the more limited, mucin-
loss of nuclear polarity. depleted cytoplasm that often characterizes
adenomas. Ampullary adenomas have
Cytopathology more elongated nuclei with significant
Cytologically, adenomas contain small pseudostratification and hyperchromasia. B
cluster and sheets of columnar cells. The Outside the setting of FAP, it is uncommon Fig. 5.04 Intestinal-type villous adenoma with high-grade
basally located nuclei are elongated and to diagnose an ampullary adenoma in the dysplasia arising in the ampulla of Vater. A Low-power
uniform, with inconspicuous nucleoli and a absence of an endoscopically identifiable view showing striking papillary architecture.
fine chromatin pattern {3399, 3533}. polypoid lesion, so correlation with endo- B High magnification: note the complex papillary
Although cytoplasmic mucin may be present, scopic findings may also be helpful. architecture and considerable cytological atypia.
Adenomas and other premalignant neoplastic lesions 85

A B
Fig. 5.05 Noninvasive pancreatobiliary-type papillary neoplasm with high-grade dysplasia (high-grade intraepithelial neoplasia). A The low-power architecture is markedly complex
with numerous micropapillae. B The neoplastic cells have abundant mucinous cytoplasm and show focal loss of nuclear polarity.
An ampullary adenoma may be misdiag- changes that parallel the increasing grades ampullary adenoma is greater than the
nosed as invasive carcinoma when of dysplasia. Although mutations in the likelihood of finding invasive carcinoma in
adenomatous epithelium extends into peri- APC gene contribute to the development of a colonic adenoma or in an extra-
ampullary ductules within the smooth mus- ampullary adenomas, only 17% of sporadic ampullary duodenal adenoma of similar
cle of the sphincter of Oddi. This ampullary adenomas have APC mutations size {2533, 2869}. About 30–50% of
phenomenon is especially troublesome {23}. Nuclear accumulation of β-catenin is ampullary masses showing only adenoma
when the adenoma exhibits high-grade more common in adenomas without APC on a biopsy specimen prove to contain
dysplasia, or when deep endoscopic mutations {3428}. Mutations in codon 12 invasive carcinoma upon resection
biopsies are poorly oriented. The lack of a (or, less commonly, codon 13) of the KRAS {2050, 2765, 2869}. Surgical excision via
stromal response around the atypical oncogene occur in about 40% of ampullary pancreatoduodenectomy or transduodenal
glands and identification of continuity with adenomas {70, 559, 1257, 3428}, with ampullectomy may be indicated if the
benign ductular epithelium help to estab- equal frequency in low-grade and high- lesion is too large to be removed endo-
lish the noninvasive nature of these foci. grade dysplasia {1257}. FAP-associated scopically {3536}.
adenomas appear to have a lower fre- We do not know how long it takes for an
Genetic susceptibility quency of KRAS mutations {3428}. Abnor- ampullary adenoma to evolve into inva-
Patients with FAP/Gardner syndrome, an malities in the BRAF gene are uncommon sive carcinoma. The natural history of
autosomal dominant condition caused by in ampullary adenomas {3428}. TP53 gene ampullary adenomas in patients with FAP
germline mutations in the adenomatous mutations, and nuclear accumulation of may differ from that of sporadic adeno-
polyposis coli (APC) gene on chromo- p53 protein, may occur in adenomas, mas. When detected at an early stage,
some 5 (5q21–22) {378}, also have a high generally those with high-grade dysplasia ampullary and periampullary adenomas
risk of developing adenomas of the {2832, 3161}. Ampullary adenomas only in patients with FAP are often small
ampulla and periampullary duodenum, rarely (9%) have abnormalities in DNA mis- (< 0.5 cm) and show no high-grade
and adenomas in patients with FAP are match repair proteins or show microsatellite dysplasia on biopsy. Although complete
usually multiple {88, 1690, 2916}. Nearly instability {2748, 3428}. endoscopic removal may not be possible,
100% of these patients will develop these patients can be followed very
ampullary adenomas during their lifetime, Prognosis and predictive factors closely, and most show minimal progres-
and progression to ampullary adeno- Ampullary intestinal-type adenomas and sion in the size or degree of dysplasia
carcinoma is a consequence if the pancreatobiliary-type noninvasive papil- over at least 3 years {61, 375, 2005}. In
adenomas are not detected and treated lary neoplasms are preinvasive neoplasms the familial setting, detection of high-
in a timely manner. associated with a risk of progression to grade dysplasia in a biopsy of an am-
invasive adenocarcinoma {232, 457, 1663, pullary adenoma suggests that complete
Molecular pathology 2365, 3327, 3536}. Villous adenomas have surgical removal (including the possibility
The development of invasive ampullary a greater risk of malignant transformation of pancreatoduodenectomy) should be
carcinoma within an adenoma occurs than tubular adenomas {2533}. The likeli- performed.
through a sequence of molecular genetic hood of finding invasive carcinoma in an

Invasive adenocarcinoma J. Albores-Saavedra

R.H. Hruban
of the ampullary region D.S. Klimstra
G. Zamboni
Definition
A gland-forming malignant epithelial neo-
plasm, usually with an intestinal or pancre-
atobiliary phenotype, which originates in
the ampulla of Vater. The ampulla may be
affected by carcinomas arising from the
duodenal mucosa, the distal common bile
duct, or the head of the pancreas, but
only those carcinomas either centred on
the ampulla, circumferentially surrounding
it, or demonstrating complete replace-
ment of the ampulla are regarded as
“ampullary carcinoma” for the purposes
of classification {70, 762}.
ICD-O codes
Invasive intestinal type 8144/3 Fig. 5.06 Adenocarcinoma of the ampulla of Vater, Fig. 5.07 Polypoid mucinous adenocarcinoma of the
Pancreatobiliary type 8163/3 luminal view. ampulla of Vater extending along the duodenal mucosa.
Clear cell carcinoma 8310/3 of the pancreas and carcinomas of the preoperative staging information {406,
Hepatoid adenocarcinoma 8576/3 gallbladder and extrahepatic bile ducts, 1670}. While endoscopic biopsy yields a
Invasive papillary adenocarcinoma probably because the relatively small area correct histological diagnosis in most
8260/3 of mucosa in the ampulla {1172, 1173}. patients {3535, 3584}, in cases of adeno-
Mucinous adenocarcinoma 8480/3 Ampullary carcinomas are more common carcinoma arising in an adenoma, a
Signet ring cell carcinoma 8490/3 in men than in women, and are usually superficial biopsy may miss invasive foci
Squamous cell carcinoma 8070/3 diagnosed in patients between the ages of and show only the adenoma {3091,
Undifferentiated carcinoma 8020/3 60 and 80 years (range, 29–85 years). 3583}.
Undifferentiated carcinoma with Patients with ampullary adenocarcinomas
osteoclast-like giant cells 8035/3 associated with familial adenomatous poly- Macroscopy
posis (FAP) or its variant, Gardner syn- Ampullary carcinomas are classified
Epidemiology drome, or neurofibromatosis tend to be macroscopically as intra-ampullary, peri-
Carcinoma of the ampulla of Vater is an younger than those with sporadic tumours ampullary duodenal, mixed exophytic
uncommon and heterogeneous neoplasm. {272, 578, 608, 1378, 2359, 2501, 3293}. and mixed ulcerated on the basis of gross
When compared with all other cancer sites appearance and extent of involvement of
in terms of frequency in the USA, this neo- Clinical features the ampulla and periampullary duodenum
plasm ranks as 85th in men and 101st in The clinical presentation of ampullary {70}. Microscopic whole-mount sections
women. Between 1985 and 2005, the inci- carcinoma includes persistent jaundice, that include the ampulla, common bile
dence of ampullary carcinoma was 0.7 abdominal pain, pancreatitis and weight duct, pancreatic duct, and duodenal
cases per 100 000 males and 0.4 cases loss {78}. Anaemia due to occult gastro- mucosa are helpful to demonstrate the
per 100 000 females {1240}. According to intestinal bleeding occurs in some patients. relationship of the carcinoma to each of
the Survey Epidemiology and End Results The classical Courvoisier sign (a distended these structures. Large (> 4 cm) ampullary
(SEER) programme of the National Cancer and palpable gallbladder) is not common. carcinomas are difficult to classify grossly
Institute, the incidence of ampullary carci- The laboratory data reflect biliary ob- because they involve multiple structures.
noma has been increasing annually for the struction, with elevated serum levels of Likewise, large carcinomas of the head of
past 32 years in the USA, but this is likely to bilirubin, glutamic-oxaloacetic transami- the pancreas, duodenum, or distal com-
be related to increased surveillance, espe- nase, glutamic pyruvic transaminase and mon bile duct may extend into the
cially screening for second cancers after alkaline phosphatase in > 60% of patients. ampulla and closely resemble a primary
an initial primary colon cancer {78, 654}. Endoscopic ultrasound, computed tomo- ampullary carcinoma. When a carcinoma
Ampullary carcinomas represent 0.5% of graphy (CT), and endoscopic retrograde is clearly centred in an adjacent structure
all gastrointestinal malignancies {78}. They cholangiopancreatography (ERCP) are and only extends peripherally to involve
are less common than ductal carcinomas useful diagnostic tools and may provide the ampulla, it is best classified as a
Invasive adenocarcinoma 87
The glands are lined predominantly by size and contour with prominent nucleoli.
columnar cells with pseudostratified oval It should be recognized, however, that
or elongated nuclei showing varying adenomas with high-grade dysplasia are
degrees of atypia and a variable number impossible to distinguish from invasive
of mitotic figures. In some carcinomas, adenocarcinomas by brush cytology
goblet cells are interspersed with the alone.
columnar cells. Rarely, Paneth cells and
endocrine cells are also present. Dirty-type Immunohistochemistry
necrosis as seen in adenocarcinomas of Most intestinal-type adenocarcinomas are
the colon is not as common in ampullary positive for keratin 20 and only about half
intestinal-type adenocarcinomas. Most of are positive for keratin 7, whereas most
these tumours are associated with an pancreatobiliary-type adenocarcinomas
adenoma. Adenocarcinomas arising in are keratin 7-positive and keratin 20-
adenomas are usually smaller and have a negative {754, 1020}. The markers of
A better prognosis than adenocarcinomas intestinal phenotype, CDX2 and MUC2,
unrelated to adenomas. label intestinal-type adenocarcinomas,
but are negative in those with a pancreato-
Pancreatobiliary-type adenocarcinoma biliary phenotype, which are MUC1-positive
This tubular invasive adenocarcinoma {553, 867, 3493, 3650}. Because mucinous
displays a cell phenotype similar to that and signet ring cell carcinomas express
of pancreatic ductal or extrahepatic bile CDX2 and MUC2, they are sometimes
duct carcinomas. It is composed of simple considered to be variants of intestinal-type
or branching glands associated with an adenocarcinomas. Most adenocarcinomas
abundant desmoplastic stroma. The of the ampulla express carcinoembryonic
epithelium consists of a single layer of antigen (CEA) and CA19-9, but these
B cuboidal or columnar cells, usually without markers do not distinguish intestinal-type
Fig. 5.08 Intestinal-type adenocarcinoma. A Low-power nuclear pseudostratification {70, 3650}. from pancreatobiliary-type adenocarcino-
view. B The neoplastic glands are composed of columnar The nuclei are rounder than in intestinal mas {2011, 3584}. In one study, 34% of
cells with intestinal phenotype. type adenocarcinomas. In general, ampullary carcinomas showed no ex-
greater cytological atypia and more pression of SMAD4 (DPC4) {2016}.
mitotic figures are seen in the pancreato-
primary of the adjacent organ. The term biliary-type adenocarcinoma than the Ultrastructure
“periampullary carcinoma” has been intestinal-type adenocarcinoma. Small Two types of ampullary carcinomas
used for neoplasms for which the site of solid clusters of neoplastic cells are seen display distinctive ultrastructural features:
origin is unclear, but this nonspecific term in the less differentiated tumours. A focal the intestinal-type adenocarcinoma and
should be avoided. micropapillary pattern occurs in < 5% of the high-grade neuroendocrine carcino-
pancreatobiliary-type adenocarcinomas mas. The former is similar to colonic
Histopathology {1532}. This micropapillary pattern is a adenocarcinoma and to intestinal-type
The vast majority of invasive carcinomas marker of clinical aggressiveness in other adenocarcinoma of the gallbladder,
of the ampulla show a tubular (85–95%) organs such as the breast and urinary extrahepatic bile ducts and pancreas and
growth pattern. These tumours should be bladder, but its significance in ampullary is composed of columnar cells with abun-
classified according to the predominant neoplasms is unknown. Occasionally dant organelles and mucin vacuoles,
component. The remaining carcinomas pancreatobiliary-type adenocarcinomas arranged around glandular lumina. The
are morphological variants of adenocar- arise in association with intestinal-type most characteristic ultrastructural feature
cinomas, or undifferentiated carcinomas. adenomas or noninvasive papillary is the presence of tall microvilli with
High-grade neuroendocrine carcinomas neoplasms. A small number of invasive
(large cell neuroendocrine carcinomas carcinomas of the ampulla show a mixed
and small cell carcinomas) have also intestinal and pancreatobiliary phenotype.
been described {1586, 2254, 3119, 3709}.
Cytologically, most adenocarcinomas Cytopathology
have an intestinal phenotype (50–80%) or Information about the diagnosis of
a pancreatobiliary phenotype (15–20%) ampullary carcinomas by brush cytology
{70, 867, 1566}. is very limited. In one study of 32 am-
pullary neoplasms {196}, comparison of
Intestinal-type adenocarcinoma cytological and histological diagnoses
This type of invasive adenocarcinoma is revealed a sensitivity and specificity of
the most common malignant epithelial 100%. Carcinomas are characterized by
tumour of the ampulla and consists of sim- cell clusters, small tubules or isolated
ple or cribriformed tubular glands similar to cells with a marked degree of atypia. Fig. 5.09 Pancreatobiliary-type adenocarcinoma of the
those of adenocarcinomas of the colon. There is considerable variation in nuclear ampulla of Vater, with stromal desmoplasia.

filamentous core rootlets and glycocalyceal

bodies {70}. The core microfilaments are
continous with the terminal web of the api-
cal cytoplasm. High-grade neuroendocrine
carcinomas contain neurosecretory-type
granules. Isolated or small clusters of round
neurosecretory granules can be identified
at the periphery of the cytoplasm of at least
some cells. The scant cytoplasm also
contains arrays of paranuclear intermediate
filaments. A B
Fig. 5.10 Adenosquamous carcinoma of the ampulla of Vater. A Both glandular and squamous differentiation are
Histological variants present. B Collections of clear cells are seen in the glands and squamous nests.
Adenosquamous carcinoma
This unusual neoplasm represents 1% of
all ampullary carcinomas and is charac-
terized by a variable combination of two
malignant components, one glandular
and the other squamous {3017A}. Although
the proportion of each component varies,
the adenocarcinoma usually predominates,
is well- to moderately differentiated, and of
pancreatobiliary phenotype. The squamous-
carcinoma component is focally keratinizing
and by convention should represent at A B
least 25% of the tumour. In contrast, any
Fig. 5.11 Comparison of: A Primary clear cell carcinoma of the ampulla with mucin production; and B Metastatic clear
amount of glandular differentiation suffices
cell carcinoma of the kidney.
to designate a predominantly squamous
neoplasm as adenosquamous carcinoma.
In some cases, clear cells line the glands resembling hepatocytes that grow in cystically dilated glands. The strips and
and are mixed with the squamous sheets or cords. The latter cells are polyg- glands are lined by columnar cells with an
elements. A micropapillary pattern can be onal with abundant eosinophilic cytoplasm intestinal phenotype, whereas the cells
seen rarely {1532}. Some adenosquamous are immunoreactive for α-fetoprotein, arranged in small groups or clusters may
carcinomas arise from preexisting ade- HepPar1 antibody and polyclonal CEA in have a signet-ring cell morphology. Some
nomas. a canalicular pattern. Bile pigment has mucinous adenocarcinomas are associ-
occasionally been identified. ated with a component of intestinal
Clear cell carcinoma adenocarcinoma, a noninvasive papillary
This exceedingly rare form of ampullary High-grade neuroendocrine carcinoma neoplasm or an intestinal-type adenoma.
carcinoma has a striking resemblance to and mixed carcinomas Extensive sampling may be needed to
metastatic renal cell carcinoma {78, Both small cell neuroendocrine carci- demonstrate the neoplastic cells in the
3391}. Clear cell carcinoma is composed noma and large cell neuroendocrine car- mucin pools of some mucinous adeno-
predominantly or exclusively of polygonal cinoma can arise in the ampulla {1586, carcinomas. Some intestinal-type adeno-
cells with abundant clear cytoplasm, well- 2254, 3119, 3709} and are regarded as carcinomas contain a focal mucinous
defined cytoplasmic membranes and subtypes of neuroendocrine carcinoma, component, which is insufficient to clas-
centrally placed hyperchromatic nuclei. grade 3 (G3). Both can arise in associa- sify the tumour as a mucinous adenocar-
The cells are arranged in nests, cords or tion with intestinal-type adenomas {2254}. cinoma. Since the vast majority of
solid sheets and at least some contain The histological features resemble those mucinous adenocarcinomas of the am-
cytoplasmic mucin, a useful feature that of their pulmonary counterparts, and the pulla express the intestinal markers CDX2
can distinguish it from renal cell carci- mitotic rate is > 20 per 10 high power and MUC2, these tumours are regarded
noma. Because of its rarity, the biological fields, by definition. as variants of intestinal-type adenocarci-
behaviour of clear cell carcinoma of the nomas.
ampulla is unknown. Mucinous adenocarcinoma
Approximately 5% of the ampullary Invasive papillary adenocarcinoma
Hepatoid adenocarcinoma carcinomas in the SEER database are Exophytic neoplasms with a papillary ar-
Fewer than five cases of hepatoid adeno- mucinous adenocarcinomas {78}. The chitecture can occur in the ampulla, sim-
carcinoma of the ampulla have been diagnosis of mucinous adenocarcinoma ilar to those arising in the gallbladder and
reported to date {946, 2826}. As its name requires that > 50% of the tumour should extrahepatic bile ducts. In the past, these
implies, this neoplasm consists of an ade- be composed of stromal mucin that neoplasms have been classified as non-
nocarcinoma, usually with an intestinal contains small groups of malignant invasive and invasive papillary carcino-
phenotype, as well as cells closely epithelial cells, epithelial strips or ruptured mas {74, 84, 1215}. Noninvasive lesions
Squamous cell carcinoma Differential diagnosis

This exceedingly rare ampullary carci- The strategic location of the ampulla of
noma is composed entirely of cells with Vater at the intersection of the pancreas,
squamous differentiation. Keratinizing duodenum and common bile duct, where
and nonkeratinizing types exist {70}. malignant neoplasms with similar pheno-
Most ampullary carcinomas with predom- types arise, makes establishing the organ
inant squamous features prove to be of origin of these carcinomas difficult.
adenosquamous carcinomas when ex- Carcinomas of the ampulla, pancreas,
tensively sampled and stained for mucin. gallbladder and extrahepatic bile ducts
share cell phenotypes, molecular abnor-
Undifferentiated carcinoma malities and a field effect for carcino-
Fig. 5.12 Mucinous adenocarcinoma of the ampulla of
There are two types of undifferentiated genesis {81, 1172, 1173}, and multiple
Vater. A strip of neoplastic intestinal-type epithelium is
surrounded by abundant extracellular mucin. carcinoma of the ampulla. The first is synchronous or metachronous primaries
composed of small (non-neuroendocrine) may involve these sites in an individual
are now designated “noninvasive papillary cells while in the second type spindle patient {43, 826, 1205, 2299, 2319}.
neoplasms.” When an invasive carcinoma cells predominate and resemble a When relatively small pancreatic carcino-
arises in association with a noninvasive sarcoma (sarcomatoid carcinoma). mas extend into the ampulla and the bulk
papillary neoplasm, the invasive component The first type is highly cellular with mini- of the mass is in the pancreas, the neo-
should be diagnosed, graded, and mal stroma and is composed of relatively plasm is recognizable as a pancreatic
staged separately from the noninvasive small cells with scant cytoplasm, vesicular primary. However, large ductal carcinomas
component. In the ampulla, most such in- nuclei and prominent nucleoli arranged in of the pancreas often extend into the
vasive carcinomas are of pancreatobiliary solid sheets or nests {70, 2124}. There are ampulla, obliterating this structure and
or intestinal type. Only rarely does an no glands or signet-ring cells. Numerous mimicking a primary ampullary carcinoma.
invasive carcinoma maintain a papillary mitotic figures and necrosis of variable Moreover, the histological and immuno-
growth pattern in the invasive elements, extent are common. Immunohistochemical histochemical features of pancreatic
and although a descriptive term of “inva- stains for neuroendocrine markers are ductal carcinomas can be identical to
sive papillary carcinoma” could be used negative. those of pancreatobiliary-type ampullary
for these neoplasms, most can be more The second type of undifferentiated carci- carcinomas {81}. A very useful micro-
accurately classified on the basis of noma consists predominantly of fascicles scopic feature is the presence of a resid-
cellular differentiation and morphology as of spindle cells, some of which are keratin- ual ampullary adenoma or noninvasive
one of the other histological variants of positive, supporting their epithelial pheno- papillary neoplasm associated with or
ampullary carcinoma. type. When extensively sampled, these adjacent to the invasive carcinoma.
tumours often contain glandular structures Colonization of the ampullary epithelium by
Signet ring cell carcinoma or nests of frank epithelial cells. Consider- invasive pancreatic ductal adenocarcinoma
Signet ring cell carcinoma is a highly able cytological atypia including the can simulate a primary ampullary adenoma,
malignant neoplasm that represents 2% presence of pleomorphic and anaplastic but the lesion retains the immunophenotype
of all carcinomas of the ampulla {78}. It giant cells may be present in the spindle- of pancreatic carcinoma (including MUC1
consists predominantly of epithelial cells cell component. When heterologous expression), whereas ampullary adenomas
with cytoplasmic mucin that pushes the elements such as cartilage, bone and have an intestinal phenotype (positive for
nuclei towards the periphery of the cells skeletal muscle are present, the term keratin 20, MUC2, and CDX2). Carcinomas
{51, 284, 802}). Some neoplastic cells, “carcinosarcoma” is justified {1539}. of the duodenum and common bile duct
however, contain little or no cytoplasmic may also extend into the ampulla and
mucin and appear undifferentiated. A Undifferentiated carcinoma with create similar diagnostic problems. Again,
minor component of tubular adenocarci- osteoclast-like giant cells the epicentre of the neoplasm is used to
noma and clusters of neuroendocrine A very rare form of undifferentiated define the site of origin.
cells have been identified in a few signet carcinoma that contains numerous multi- Metastatic renal cell carcinoma may
ring cell carcinomas. Although signet ring nucleated osteoclast-like giant cells has mimic clear cell carcinoma of the ampulla
cells can be found in mucinous adeno- been documented in the ampulla {70}. {3391}. The presence of mucin, immuno-
carcinomas, the diagnosis of signet ring This carcinoma is similar to undifferenti- reactivity for CEA and lack of reactivity for
cell carcinoma is reserved for those cases ated carcinomas with osteoclast-like giant CD10 and the renal cell carcinoma (RCC)
with the characteristic diffuse pattern of cells reported in the gallbladder, extra- antigen favour a diagnosis of clear cell
infiltration, usually without significant extrahepatic bile ducts and pancreas {69, carcinoma of the ampulla. Signet ring cell
cellular mucin accumulation. Tumours with 2124, 3493}. The giant cells in these carcinomas should be distinguished from
mild atypia, few mitotic figures and tumours are histiocytic and non-neoplastic goblet cell carcinoids, which have a
endocrine cells can be confused with and label positively for CD68. In contrast, prominent organoid or nesting pattern;
goblet cell carcinoid tumours. The infil- the neoplastic mononuclear cells may be the goblet cells are less atypical and
trating growth pattern, lack of a nesting keratin-positive and are often p53-positive. mitotic figures are not seen. In addition,
pattern, and the mildly atypical neoplastic the possibility of secondary involvement
signet-ring cells favour a diagnosis of from a gastric primary needs to be
signet ring cell carcinoma. excluded.

Immunohistochemical lymphoid markers

are useful to separate malignant lym-
phomas from undifferentiated carcinomas.
Metastatic malignant melanoma can
simulate a primary ampullary carcinoma
{3351}; however, the former is immuno-
reactive for HMB45, Melan A and other
melanocytic markers.
Precursor lesions A B
Ampullary carcinomas may arise in asso-
Fig. 5.13 A Undifferentiated carcinoma of the ampulla of Vater, sarcomatoid type. B The neoplastic epithelial nests
ciation with intestinal-type adenomas, express keratin AE1/AE3. A small number of spindle cells are also positive for keratin.
noninvasive papillary neoplasms, or flat
intraepithelial neoplasia (dysplasia).
lower frequency than in colorectal carci- carcinomas confined to the ampulla,
Genetic susceptibility nomas. High-level microsatellite instability reported in the SEER data, suggests that
Patients with FAP have a 100- to 200-fold has been identified in 0–10% of ampullary many of these tumours had in fact
increased risk of developing ampullary carcinomas {2748, 2885}. Overexpression extended to the duodenal submucosa
adenocarcinoma {272, 2359, 2501} with an of epidermal growth factor (EGF) is found (AJCC stage pT2).
estimated lifetime incidence of up to 12%. in 50–65% of invasive ampullary carcino- Patients with well-differentiated carcino-
However, a multicentre analysis of 1262 mas {366, 897, 2660}, and ERBB2 and mas do better than those with poorly
patients with FAP found that ampullary ERBB3 are also overexpressed in differentiated carciomas {78}. Carcinomas
carcinomas occur in only 4% of patients ampullary carcinomas {3293}. that arise from adenomas have a more
with FAP {3046}. FAP-associated ampullary favourable prognosis than adenocarcino-
carcinomas arise in a background of Tumour spread and staging mas not associated with adenomas,
multiple adenomas involving the ampulla Carcinomas spread directly from the probably because the former are detected
and periampullary duodenum. Patients ampullary mucosa through the sphincter earlier {78}. The intestinal-type ampullary
with colorectal carcinoma have an excess of Oddi to the duodenal submucosa and adenocarcinoma has a more favourable
risk of developing ampullary cancer, which muscularis propria to reach the underlying prognosis than the pancreatobiliary type,
appears to be part of the spectrum of pancreas or periduodenal soft tissues. probably because the former usually
Lynch syndrome {654}. An excess risk of The vast majority of carcinomas confined arises from a pre-existing adenoma {179,
ampullary adenocarcinomas has also to the ampullary mucosa or sphincter of 2714, 3535}. The prognosis for patients
been reported in patients with type 1 multiple Oddi do not metastasize, but those that with ampullary mucinous carcinomas is
neurofibromatosis (von Recklinghausen extend to the submucosa do (42% of not better than for those with intestinal- or
disease) {578, 608, 1586}. cases). Nodal metastases occur most pancreatobiliary-type adenocarcinomas
commonly in the peripancreatic lymph {78}, in contrast to mucinous carcinomas
Molecular pathology nodes followed by metastases in the liver, of the breast and pancreas, and their
Wide variations in the frequency of genetic peritoneum, lungs and pleura. corresponding ductal carcinomas.
abnormalities have been reported in The current American Joint Committee on Other negative prognostic factors include
ampullary carcinomas, but little is known Cancer and the International Union a high level of microsatellite instability
about their clinical implications. Moreover, against Cancer (AJCC/UICC) TNM staging {2748}, size of the tumour, and vascular
the genetic abnormalities of ampullary system for ampullary carcinoma {762, and perineural invasion {179, 3113}.
carcinomas have not been correlated with 1060, 2996} is widely used.
intestinal or pancreatobiliary type. Muta-
tions in exons 5, 6 and 7 of the TP53 gene Prognosis and predictive factors
have been detected in 59–94% of am- The prognosis of patients with ampullary
pullary carcinomas {559, 1586, 2633, carcinoma is determined by tumour stage,
2637, 2831, 3583} and appear to be a late histological type, histological grade and
event in carcinogenesis. Mutations in presence of pre-existing adenoma {78}.
codon 12 (and rarely codon 13) of the The best predictor of prognosis is stage
KRAS oncogene have been recorded in of disease {78, 179, 1291, 2336, 2603,
13–75% of ampullary carcinomas {2633, 2885, 3217}. Based on the SEER data,
2637, 2831}. KRAS mutations do not carcinomas localized to the ampulla
correlate with histological type, grade, have a significantly better 5-year survival
stage of disease or prognosis. Loss of rate (45%) than those with regional (31%)
expression of the SMAD4 tumour suppres- extension beyond the ampulla directly
sor gene has been detected in 34% of into surrounding tissues, or distant
ampullary carcinomas {2016}. Mutations in disease (4%) (metastasis in distant lymph
the APC and β-catenin (CTNNB1) genes nodes or in visceral organs). The high
occur in ampullary carcinomas, but at a mortality rates for patients with ampullary
Neuroendocrine neoplasms G. Klöppel

R. Arnold
J. Albores-Saavedra
E. Solcia
of the ampullary region C. Capella
D.S. Klimstra
G. Rindi
P. Komminoth
Definition Epidemiology
Neoplasms arising in the ampulla of Vater Ampullary NETs account for approximately
and periampullary region that have pre- 20% of all neuroendocrine neoplasms of
dominantly neuroendocrine differentiation. the duodenum and for 70% of those of the
These include well-differentiated (low- to ampullary-periampullary region {943}. The
intermediate-grade) neuroendocrine tu- mean age of diagnosis is 54 years (range,
mours (NETs) and poorly differentiated 28–74 years) and the sex ratio is almost
(high-grade) neuroendocrine carcinomas one. Approximately 15–25% (in one study
(NECs). NECs include large cell NEC and up to 50%) of NETs are associated with
small cell NEC. Mixed adenoneuro- neurofibromatosis type 1 (NF1), i.e. von
endocrine carcinoma (MANEC) has ex- Recklinghausen disease {666, 943, 1127}.
Fig. 5.14 Neuroendocrine tumour (NET) of the ampulla of
ocrine and neuroendocrine components, Gangliocytic paragangliomas account for
Vater. A probe is inserted in the bile duct.
with each component exceeding 30%. 20–25% of ampullary-periampullary neuro-
endocrine neoplasms, presenting at an Macroscopy
ICD-O codes average age of 54 years and showing an NETs (carcinoid tumours) are mostly
Neuroendocrine tumour (NET) equal sex distribution {372, 943}. NECs 1–2 cm in diameter (mean, 1.8 cm; range,
NET G1 (carcinoid) 8240/3 account for almost 5% of ampullary-peri- 1.3–5.0 cm). They cause a widening of the
NET G2 8249/3 ampullary neoplasms, present at a mean papilla of Vater with obstruction of the
Neuroendocrine carcinoma (NEC) 8246/3 age of 70 years (range, 50–89 years) and ampulla by submucosal infiltration {307,
Large cell NEC 8013/3 affect males more frequently than females 943, 1960}. The overlying mucosa of the
Small cell NEC 8041/3 {943, 2254, 3670} (see Chapter 6). ampulla is usually intact and rarely ulcer-
Mixed adenoneuroendocrine ated. A few neoplasms are infiltrative,
carcinoma (MANEC) 8244/3 Clinical features intramural nodules of rather large size (up
EC cell, serotonin-producing NET 8241/3 Neuroendocrine neoplasms of the am- to 5 cm in diameter). Periampullary neo-
Gangliocytic paraganglioma 8683/0 pulla commonly lead to obstructive jaun- plasms in general do not obstruct the am-
Somatostatin-producing NET 8156/3 dice, rarely to acute pancreatitis, or pulla, but may involve the papilla of Vater.
haemorrhage. In addition, they may arise Gangliocytic paragangliomas are mainly
Synonyms in patients with NF1. Hormonal syndromes found in the periampullary region where
Synonyms for ampullary NETs include such as carcinoid syndrome and they produce polypoid lesions protruding
carcinoid and well-differentiated endo- Zollinger-Ellison (gastrinoma) syndrome into the duodenal lumen. These neoplasms
crine tumour/carcinoma {3013}. Synonyms are usually absent. The somatostatinoma have a mean diameter of 1.7 cm {413}.
for NEC include poorly differentiated syndrome (diabetes mellitus, diarrhoea, NECs form polypoid and often ulcerated
endocrine carcinomas, high-grade neuro- steatorrhoea, hypohydria or achlorhydria, masses in the ampulla and papilla of
endocrine carcinoma, small cell and large anaemia and gallstones) is almost never Vater, with a mean size of 2.5 cm (range,
cell endocrine carcinomas. observed {943, 1055}. Some neoplasms, 0.8–4 cm).
especially those located in the peri-
ampullary region, are asymptomatic and Histopathology
often discovered incidentally. NETs
Most NETs of the ampulla have a nested,
trabecular or cribriform growth pattern.
The uniform neoplastic cells have moder-
ate amounts of cytoplasm and round
nuclei with “salt and pepper” chromatin.
Mitoses are usually rare (< 2 per 10 high
power fields [HPF]). The grading of these
neoplasms is detailed in Chapter 1. NETs
express chromogranin A, synaptophysin
and CD56 (NCAM1).
Somatostatin-producing NET. NETs that
A B produce somatostatin are predominantly
Fig. 5.15 Somatostatin-producing neuroendocrine tumour (NET G1, somatostatinoma) of the ampulla. A Tubuloglandular composed of tubuloglandular structures
differentiation and psammoma bodies are evident. B Immunolabelling for somatostatin. admixed with a variable proportion of

insular and trabecular structures (“glandu- expression of S100 protein. The ganglion
lar carcinoids”). In about one third of cases, cells may be scattered as single elements
the glands contain psammoma bodies, or aggregated in clusters and label with
leading to the alternative descriptor “psam- antibodies to synaptophysin. In some
momatous somatostatinoma.” They express gangliocytic paragangliomas, the three
synaptophysin; chromogranin A is only components intermingle with the normal
positive in about 50% of cases. In addition to smooth muscle and small ductules of the
the somatostatin-producing cells, the neo- ampulla, resulting in a very complex lesion.
plasms may have minor cell populations The complex composition of the ganglio-
that are positive for gastrin, secretin, cytic paragangliomas suggests that they
calcitonin, pancreatic polypeptide and may be a hamartoma of pancreatic anlage
Fig. 5.16 Gangliocytic paraganglioma. Low-power view
adrenocorticotropic hormone (ACTH) {413, {1105, 2531}. Ultrastructurally, the epithelial showing polypoid submucosal tumour.
666, 943, 1960}. Ultrastructural examination cells have abundant cytoplasm packed
shows large, moderately electron-dense with dense-core secretory granules, while
secretory granules, similar to those found in the ganglion cells are larger and contain a Deep mural invasion, angioinvasion, and
normal somatostatin-producing D cells of small number of neuroendocrine granules neuroinvasion are common {2254, 3670}.
the intestinal mucosa {413}. of small size and more numerous second- All NECS are immunoreactive for keratins,
Gangliocytic paraganglioma. These neo- ary lysosomes. The spindle cells are especially 7, 8 and 18, and synaptophysin
plasms are characterized by their tripha- packed with intermediate filaments and {943, 2254, 3670}. They may also express
sic cellular differentiation, consisting of resemble either sustentacular cells or chromogranin A and CD56, and occasion-
neuroendocrine cells, spindle-shaped cells Schwann cells {2531}. ally p53 and CDKN1B/p27/Kip1. TTF1 is
with Schwannian differentiation, and gan- usually not expressed, in contrast to many
glion cells, which vary in terms of relative NECs similar neoplasms in the lung. Some neo-
abundance and distribution within each Histologically, there are two types of NEC: plasms are associated with adenomas in
neoplasm. The neuroendocrine cells have one with rather small cells, comparable to the adjacent mucosa of the papilla {2254}.
an eosinophilic or amphophilic cytoplasm small cell NEC of the lung; the other with
and uniform ovoid nuclei, with low or no quite large cells, resembling large cell NEC MANEC
mitotic activity. They are arranged in of the lung. Both types display a diffuse, MANECs contain a significant (> 30%)
ribbons, solid nests, or pseudoglandular solid and/or trabecular growth pattern with component of mucin-producing adeno-
structures that rarely may contain psam- areas of necrosis. NECs composed of carcinoma or rarely squamous cell carci-
moma bodies {943}. small cells have nuclei with abundant chro- noma {2254}. The two components may
The neuroendocrine cells are immuno- matin, but inconspicuous nucleoli; NECs be adjacent or intermingled.
reactive for pankeratin, synaptophysin with large cells have vesicular nuclei with a
and chromogranin A and often express distinct nucleolus. The mitotic rate is high Differential diagnosis
pancreatic polypeptide, followed in fre- (> 20 per 10 HPF), the proliferative rate The differential diagnosis for most
quency by somatostatin and vasoactive ranges from 30% to 80%; NECs are thus ampullary NETs (carcinoid tumours) is
intestinal peptide (VIP) {413, 943, 3055}. histological grade 3 (G3; Chapter 1). A minor similar to that for other NETs in the tubular
The sometimes numerous spindle cells component (< 30% of the neoplastic cells) gastrointestinal tract. The glandular
form small fascicles or envelope nerve of conventional adenocarcinoma or squa- pattern and psammoma bodies of so-
cells and axons and show intense mous cell carcinoma may be associated. matostatin-producing NETs may cause
A B
Fig. 5.17 Gangliocytic paraganglioma. A Gangliocytic cells, neuroendocrine cells and Schwann cells can be seen. B Immunolabelling for S100 protein highlights Schwann cells.
but occur less often in the ampullary

region {3055} (see Chapter 6).
Staging, prognosis and predictive factors

The new grading (see Chapter 1) and
TNM/staging classifications recently
proposed for foregut neuroendocrine
tumours (see Chapter 6) should be
applied to neuroendocrine neoplasms of
the ampulla, as both grade and stage are
prognostically important {2449}.
Somatostatin-producing NETs without other
Fig. 5.18 Small cell neuroendocrine carcinoma (NEC) Fig. 5.19 Small cell neuroendocrine carcinoma (NEC) with hormone expression carry a significant risk
displaying typical cytological features. a solid growth pattern and rosette-like structures (right). of metastasis (> 50%) if they involve the
the muscularis propria, are > 2 cm, and
have an increased proliferation rate {307,
confusion with well-differentiated adeno- Genetic susceptibility 666, 943, 1295, 1960}. However, even
carcinoma. Unlike adenocarcinomas, NF1 neoplasms with a diameter of 1–2 cm or
however, the somatostatin-producing Patients with von Recklinghausen disease even smaller can metastasize to paraduo-
NETs are composed of uniform cells with have a significant risk of developing denal lymph nodes {943, 2003, 2874}.
bland nuclei, few mitotic figures and a somatostatin-producing ampullary-peri- Liver metastases are rare. Complete
distinct finely granular eosinophilic cyto- ampullary NETs {372, 413, 1127}. In surgical removal is effective and ensures
plasm. When the cytoplasm is abundant, addition, these patients may develop other survival in many patients {943}. In case of
these neoplasms can be confused with neoplasms, such as GIST {251, 608, 3347}. recurrence, the liver is the most common
normal Brunner glands in endoscopic Some patients with NF1 and ampullary site of metastasis {1295}.
biopsy specimens. Gangliocytic para- somatostatin-producing NETs also have a Gangliocytic paragangliomas usually fol-
gangliomas can be confused with NETs phaeochromocytoma involving one or both low a benign course; however, occasional
(carcinoid tumours) when the neuro- adrenal glands, a clinical situation that can large neoplasms (size, > 2 cm) may
endocrine component predominates or in considerably complicate patient manage- spread to local lymph nodes, mainly man-
the case of primary mesenchymal neo- ment. Both gangliocytic paraganglioma ifesting as to the neuroendocrine compo-
plasms such as gastrointestinal stromal and somatostatin-producing NETs have nent of the lesion {358, 1327}.
tumours (GISTs) in which the spindle-cell been associated with NF1 {1533, 3076}. NECs usually present at advanced stages,
component is predominant. i.e. with lymph-node, liver and other re-
MEN1 mote metastases {2254, 3670}. The mean
MEN1-associated neuroendocrine tumours survival time for patients with metastases
are frequent in the first part of the duodenum is 14.5 months {2254, 3670}.

CHAPTER 6
Tumours of the small intestine
Carcinoma
B-cell lymphoma
T-cell lymphoma
Mesenchymal tumours
Secondary tumours
WHO classificationa of tumours of the small intestine

Tubular 8211/0 Mixed adenoneuroendocrine carcinoma 8244/3
Villous 8261/0 EC cell, serotonin-producing NET 8241/3
Tubulovillous 8263/0 Gangliocytic paraganglioma 8683/0
Dysplasia (intraepithelial neoplasia), low grade 8148/0* Gastrinoma 8153/3
Dysplasia (intraepithelial neoplasia), high grade 8148/2 L cell, Glucagon-like peptide-producing
and PP/PYY-producing NETs 8152/1*
Hamartomas Somatostatin-producing NET 8156/3
Juvenile polyp
Peutz-Jeghers polyp Mesenchymal tumours
Leiomyoma 8890/0
Carcinoma Lipoma 8850/0
Adenocarcinoma 8140/3 Angiosarcoma 9120/3
Mucinous adenocarcinoma 8480/3 Gastrointestinal stromal tumour 8936/3
Signet ring cell carcinoma 8490/3 Kaposi sarcoma 9140/3
Adenosquamous carcinoma 8560/3 Leiomyosarcoma 8890/3
Medullary carcinoma 8510/3
Squamous cell carcinoma 8070/3 Lymphomas
Secondary tumours
b
NET G2 8249/3
___________________________________________________________
a
b
The classification is modified from the previous (third) edition of the WHO histological classification of tumours {691} taking into account changes in our
understanding of these lesions. In the case of neuroendocrine neoplasms, the classification has been simplified to be of more practical utility in morphological
classification.
96 Tumours of the small intestine

TNM classificationa of tumours of the small intestineb

Carcinoma of the small intestine
T – Primary tumour
TX Primary tumour cannot be assessed Stage grouping
T0 No evidence of primary tumour
Tis Carcinoma in situ Stage T N M
T1 Tumour invades lamina propria, muscularis mucosae or Stage 0 Tis N0 M0
submucosa Stage I T1, T2 N0 M0
T1a Tumour invades lamina propria or muscularis mucosae Stage IIA T3 N0 M0
T1b Tumour invades submucosa Stage IIB T4 N0 M0
T2 Tumour invades muscularis propria Stage IIIA Any T N1 M0
T3 Tumour invades subserosa or nonperitonealized perimuscular Stage IIIB Any T N2 M0
tissue (mesentery or retroperitoneumc) with extension 2 cm Stage IV Any T Any N M1
or less
T4 Tumour perforates visceral peritoneum or directly invades
other organs or structures (includes other loops of small
intestine, mesentery, or retroperitoneum more than 2 cm and
abdominal wall by way of serosa;for duodenum only, invasion
of pancreas)
N – Regional lymph nodes

N1 Metastasis in 1 to 3 regional lymph nodes
N2 Metastasis in 4 or more regional lymph nodes
Carcinoid of the small intestined
T – Primary tumoure
TX Primary tumour cannot be assessed Stage grouping
T0 No evidence of primary tumour
T1 Tumour invades lamina propria or submucosa and is no Stage T N M
greater than 1 cm in sizef Stage I T1 N0 M0
T2 Tumour invades muscularis propria or is greater than 1 cm in Stage IIA T2 N0 M0
size Stage IIB T3 N0 M0
T3 Jejunal or ileal tumour invades subserosa. Stage IIIA T4 N0 M0
Ampullary or duodenal tumour invades pancreas or Stage IIIB Any T N1 M0
retroperitoneum Stage IV Any T Any N M1
T4 Tumour perforates visceral peritoneum (serosa) or invades
other organs or adjacent structures

_____________
a
{762, 2996}
b
The TNM classification and stage grouping for small-intestinal GISTs can be found on page 47.
c
The nonperitonealized perimuscular tissue is, for jejunum and ileum, part of the mesentery and, for duodenum in areas where serosa is lacking, part of the
retroperitoneum.
d
Neuroendocrine tumour (NET, well-differentiated neuroendocrine tumour/carcinoma).
e
For any T, add (m) for multiple tumours.
f
Tumour limited to ampulla of Vater for ampullary gangliocytic paraganglioma.
Classification 97
Carcinoma of the small intestine N.A. Shepherd

N.J. Carr
J.R. Howe
A.E. Noffsinger
B.F. Warren
Definition are risk factors {990, 2061, 2288, 2626,

A malignant epithelial tumour of the small 2669, 3553}. One study showed that indi-
intestine. Neoplasms of the periampullary viduals with Crohn disease have an
region include those of the duodenal increased risk of adenocarcinoma of the
mucosa, ampulla of Vater, common bile small intestine of 86-fold {1063}. There is
duct and pancreatic ducts. also epidemiological evidence that
cigarette use and alcohol consumption
ICD-O codes are risk factors {2269}.
Adenocarcinoma 8140/3 Carcinoma can develop in ileostomies in
Mucinous adenocarcinoma 8480/3 patients with ulcerative colitis or familial
Signet ring cell carcinoma 8490/3 adenomatous polyposis (FAP) subsequent
to colonic metaplasia and intraepithelial
Epidemiology neoplasia in the ileostomy mucosa {932,
Relative to the length and surface area of 2697}. Carcinoma can also arise in ileal Fig. 6.01 Adenocarcinoma of the small intestine.
the small intestine, adenocarcinomas at conduits {3305} and in ileal reservoirs,
this site are remarkably rare {2854}. Data both continent abdominal (Kock) {610}
from the United States Surveillance, Epi- and pelvic {2921, 3403}.
demiology and End Results (SEER) pro-
gramme for 1973–2005 show an average Localization
annual age-adjusted incidence rate for The duodenum is the main site of occur-
adenocarcinoma of the small intestine of rence, with more adenocarcinomas aris-
6.8 per million; men are affected slightly ing in the duodenum than in the jejunum
more often than women, and the inci- and ileum combined {545, 2854, 3237}.
dence in African Americans is about twice In the duodenum, carcinomas are most
that in Whites {2854}. The median age at common around the ampulla of Vater
manifestation is approximately 67 years {2797}, possibly owing to biliary or pan- Fig. 6.02 Metastatic colonic carcinoma affecting the
{3237}. creatic effluents. Occasionally, an adeno- small bowel. Mimicry of a primary tumour may be
carcinoma arises in a Meckel diverticulum profound, both macroscopically and histologically.
Etiology {1695}.
The model of the adenoma–carcinoma
sequence is believed to apply to the small Clinical features Imaging
intestine as well as the large intestine Symptoms and signs The radiological methods that have the
{2854}. Small-bowel adenocarcinomas are gen- highest diagnostic accuracy are spiral
There is evidence from SEER data that the erally asymptomatic in their early stages, computed tomography (CT) scan with
incidence of adenocarcinoma of the duo- but occult gastrointestinal bleeding may contrast medium and enteroclysis; the
denum is increasing at roughly the same occur, leading to anaemia. As they grow two methods can be complementary. With
rate as colon carcinoma, whereas the larger, they may cause symptoms of enteroclysis, a filling defect, an irregular
incidence of adenocarcinoma of the bowel obstruction, with cramp-like abdo- and circumscribed thickening of the folds
jejunum and ileum has remained stable minal pain, bloating, and emesis. In a with wall rigidity, slowed motility, eccentric
{545}. This observation raises the possi- review of 172 small-bowel tumours from a passage of the contrast medium, or a
bility that the risk factors for duodenal and single institution, 63% of patients had clear stenosis may be observed {359}.
colon carcinomas are similar. Further- abdominal pain, 48% had vomiting, 44% Small-bowel adenocarcinoma may ap-
more, patients with carcinoma of the small had weight loss, 37% had occult blood in pear on CT scan as an annular lesion, a
intestine have a significantly increased the stool, 28% had a palpable mass, and discrete nodular mass, or an ulcerative
risk of developing cancers at other sites, 23% had gastrointestinal bleeding {3173}. lesion, often with corresponding narrow-
particularly cancer of the colorectum, Duodenal and ampullary tumours may ing of the lumen. CT scan, with global
pancreas, gallbladder and bile ducts, and obstruct the bile duct and cause jaun- vision of the abdomen, can contribute to
sarcoma of the soft tissues {2834}. dice. Locally advanced small-bowel staging of the tumour {1034, 1952}
Chronic inflammation can be associated tumours may perforate, leading to peri- Endoscopic methods have the added ad-
with the development of small-intestinal tonitis, or be associated with carcino- vantage of being able to obtain a tissue
adenocarcinoma. In particular, long-stand- matosis, leading to bowel obstruction and diagnosis at the time of the procedure,
ing Crohn disease and coeliac disease ascites. but visualization of jejunal and ileal lesions

can be challenging owing to the length of

the small bowel. Duodenal tumours can
be viewed by upper endoscopy, and
ampullary tumours are best seen with a
side-viewing endoscope. Distal ileal lesions
may be seen on colonoscopy, and the
proximal small-bowel mucosa may be
visualized by push enteroscopy, but this
will generally only reach 50–100 cm from
the ligament of Treitz; double-balloon endo-
scopy is another method that allows view-
ing of the more distal small bowel {2012}.
Capsule endoscopy has become a useful
means of visualizing the entire length of
the small bowel, and has proven an
effective noninvasive method of diagnos-
ing these tumours {2520}.
Macroscopy
The macroscopic pathology of small-bowel
carcinomas is determined by a number of
factors, of which stage and site are the Fig. 6.03 Ileal adenocarcinoma, moderately differentiated, diffusely infiltrating the muscularis propria of the ileum.
most significant. Many carcinomas of the
jejunum and ileum are detected at an
advanced stage {334, 663, 3315}. Another reached a large size; they are usually differentiating primary small-bowel carci-
determinant is the presence or absence of circumscribed nodules measuring not more noma from transcoelomic metastatic
predisposing factors, namely, an associ- than 2–3 cm in diameter. They may be spread to the small bowel from a primary
ated adenoma, coeliac disease, Crohn within the wall of the duodenum or project carcinoma of the colon. Small-intestinal
disease, radiotherapy, previous surgery into the lumen as a polypoid nodule. carcinomas show a different keratin
(notably pouch surgery and ileostomy), Unusual macroscopic features, such as a 7/keratin 20 profile, with 50% being positive
polyposis syndromes, Meckel diverticulum lack of ulceration, the predominance of an for keratin 7 and about 40% being positive
and intestinal duplication. extramural component and the presence for keratin 20 {516, 1785}. AMACR/P504S
Most small-intestinal carcinomas are of multicentricity, should alert the pathol- immunostaining may also be helpful as this
annular constricting tumours, but they ogist to the possibility that the tumour is a is commonly expressed in colorectal
may be protuberant and polypoid on metastasis. cancer but not in small-intestinal carcinoma
occasion {663}. Jejunal and ileal carcinomas {514}. Accurate diagnosis is important
are usually relatively large, annular, con- Histopathology because the small-intestinal mucosa has a
stricting tumours with circumferential Histologically, small-bowel carcinomas particular tendency to mimicry of a pre-
involvement of the wall of the intestine resemble their commoner counterparts in existing adenoma, adjacent to invasive
{334}. Most have already penetrated the the colon and rectum. However, there are a adenocarcinoma, when metastatic adeno-
muscularis propria at the time of presen- higher proportion of poorly differentiated carcinoma (especially from the colorectum)
tation and there is often involvement of the tumours {1731} and there is now good involves the small intestine. This phenom-
serosal surface {663}. Adenocarcinoma of evidence that, despite morphological enon can give rise to the erroneous diag-
the ileum may mimic Crohn disease clini- similarities, small-intestinal carcinomas show nosis of primary carcinoma of the small
cally, radiologically, endoscopically and differing immunophenotypes. This is espe- intestine {2924}.
at macroscopic pathological assessment cially important in view of the difficulties in
{1245}. Conversely, adenocarcinoma is a
recognized complication of small-intestinal
Crohn disease, but it may be very difficult
to identify the tumour in an area of severe
intestinal Crohn disease {664}.
Duodenal carcinomas are usually more
circumscribed, with a macroscopically
demonstrable adenomatous component
in 80% of cases {1663}. Thus, they are
often protuberant or polypoid and the
central carcinomatous component may
show ulceration {663, 2137}. Carcinomas A B
arising at the ampulla of Vater may cause Fig. 6.04 A Tubulovillous adenoma of the duodenum and the ampulla of Vater, which is greatly distended. B Villous
obstructive jaundice before they have adenoma of the duodenum adjacent to normal mucosa.
Carcinoma 99
A B
Fig. 6.05 Adenocarcinoma. A Well-differentiated, invasive. B Poorly differentiated, infiltrating fat.
Tumours arising at the ampulla of Vater Tumour spread and staging Grading
display, not surprisingly, either intestinal The spread of small-bowel carcinomas is The system by which small-intestinal
or pancreaticobiliary phenotypes, both similar to that of the large bowel. Direct carcinomas are graded is identical to that
morphologically and immunohistochemi- spread may cause adherence to adjacent used for the large bowel, namely, well-,
cally {553, 1091, 2714, 2885}. Immuno- structures in the peritoneal cavity, usually moderately and poorly differentiated, or
histochemical markers such as MUC a loop of small intestine, although the high- and low-grade.
proteins, trefoil peptides and keratin stomach, colon or greater omentum may
subtypes, especially keratins 7 and 20, also be involved. Lymphatic spread to Precursor lesions
can be used to help differentiate the two regional lymph nodes is common. Adenomas
phenotypes. This is important for treatment Haematogenous and transcoelomic spread There is good evidence for an adenoma–
and because the intestinal type has the also occur. Diffuse involvement of the adenocarcinoma sequence in the small
better prognosis {2714}. ovaries, Krukenberg tumour, has been intestine as for the colon {1457, 2871,
Even rarer types of carcinoma of the small reported {1887}. Staging of carcinomas of 3161}. Residual adenomatous tissue at
intestine include adenosquamous carci- the small intestine is by the TNM (tumour, the margins is seen in 42–65% of duodenal
nomas {1064, 2272, 2564}, carcinomas node, metastasis) classification {875, adenocarcinomas {1457, 3161}. Studies
with a prominent neuroendocrine-cell 3534}. A separate TNM classification performed before the advent of advanced
component {1367} and those with tripartite scheme is used for tumours of the am- endoscopic techniques showed a high
differentiation, namely with glandular, pulla of Vater because of the complicated incidence of invasive adenocarcinoma
squamous and endocrine components anatomy of this site. Alternative staging among patients with small-bowel adeno-
{199, 368}. Primary small cell carcinomas systems have been proposed {3174}. mas. For example, one study performed
(poorly differentiated endocrine carcino- in 1982 reported invasive adenocarcinoma
mas) are especially rare {3670}.
A B
Fig. 6.06 Mucinous adenocarcinoma of the ileum arising in a patient with Crohn disease. A Large mucin-filled lakes. B More mucin than neoplastic epithelium.

in 65% of patients with small-intestinal Intraepithelial neoplasia (dysplasia) Between 10% and 25% of small-bowel
adenomas {2534}. More recent studies, The incidence of small-intestinal adenocarcinomas show a high level of micro-
however, demonstrate a lower incidence, carcinoma is increased in patients with satellite instability (MSI-H) and patients
which is most likely related to the now chronic inflammatory conditions affecting with these tumours have a better prognosis
commonplace practice of performing the small bowel, such as Crohn disease than do those with microsatellite-stable
upper endoscopy in patients with non- and coeliac disease {1058, 1422, 2038, tumours {22, 351, 724, 1184, 2563, 2582,
specific symptoms. In a recent study by 2061, 2626}. In patients with Crohn disease, 2635, 3494}. Hypermethylation or loss of
Catalano et al., invasive adenocarcinoma invasive adenocarcinoma is preceded by MLH1 and APC has also been demon-
was found in only 6 out of 103 patients intraepithelial neoplasia or dysplasia, strated {350, 3142}.
(5.8%) with duodenal adenomas {456}. which may appear either flat or polypoid
As a result of the widespread use of endo- endoscopically. In one study, dysplasia Prognosis and predictive factors
scopy, the earliest stages of neoplastic was identified adjacent to 75% of Crohn In a review of 4995 patients with small-
change have been identified and charac- disease-associated small-intestinal adeno- bowel adenocarcinoma reported to the
terized in adenomas of the duodenum carcinomas {2966}. Histologically, the National Cancer Database (USA) between
and peri-ampullary region. In patients with dysplasia seen in the small bowel appears 1985 and 1995, the overall 5-year survival
FAP, random biopsy specimens of ileal similar to inflammatory bowel disease- was 30.5% and median survival was 19.7
mucosa show foci of abnormal, dysplastic associated colonic dysplasia. months. For stage I lesions, 5-year
crypts resembling dysplastic aberrant survival was 65% (median, > 60 months);
crypt foci of the colon in some patients, Genetic susceptibility stage II, 48% (median, 54.5 months);
supporting the concept that, at least in Patients with FAP, MUTYH polyposis, stage III, 35% (median, 29.8 months) and
patients with FAP, oligocryptal adenomas Lynch syndrome, Peutz-Jeghers syndrome stage IV 4% (median, 9 months). Inde-
are a step in the development of epithelial and juvenile polyposis all have an in- pendent risk factors that significantly
neoplasms of the small intestine {247}. creased risk of developing small-intestinal correlated with improved survival based
Similarly, biopsy of the proximal small- carcinoma. upon multivariate analysis were age
intestine in a group of FAP patients < 75 years, jejunal or ileal site (versus
showed frequent microadenomas similar Molecular pathology duodenal), well- or moderately differenti-
to those observed in APC-knockout (Min) The relative rarity of small-intestinal ated tumours (relative to poorly differenti-
mice {2588}. In patients with FAP and in adenocarcinoma means that the molecular ated), whether cancer-directed surgery
patients with sporadic adenomas, in- pathology is poorly understood and the was performed, and tumour stage (local
creasing grades of dysplasia are identifi- genetic abnormalities only partly charac- vs regional, regional vs metastatic) {1256}.
able adjacent to foci of early invasive terized. There is uncertainty as to the A study from the Swedish Cancer
adenocarcinoma {1457}. similarities with large-intestinal carcinoma Registry of 926 patients with small-bowel
Although adenomas can occur through- and the importance of the adenoma– adenocarcinoma between 1960 and 1988
out the small intestine, the commonest carcinoma sequence, and the molecular found an overall 5-year survival of 24% for
site is the ampullary and peri-ampullary abnormalities that underpin that sequence, those with duodenal tumours and 28% for
region {2854}. Adenomas can be multiple, in small-bowel carcinoma {277, 2871}. patients with jejunal and ileal tumours.
a finding that should prompt evaluation of APC mutations are infrequent in small- Multivariate analysis revealed that female
the patient for a polyposis syndrome. bowel carcinoma {134, 3494} but over- sex and treatment in the later years of the
Histologically, adenomas in the small expression of p53 is common {3494} and study (1985–1988) were significantly
intestine are similar to those in the colon, there is good evidence for the involve- correlated with improved survival {3678}.
but with a propensity to be more villous or ment of the Wnt signalling pathway {277}. In the SEER database for 1988–2001, in
tubulovillous in architecture {2271, 3536}. Typical of adenocarcinomas in the gut, 1852 patients diagnosed with small-bowel
The adenomatous cells resemble those of there is loss of E-cadherin expression, adenocarcinoma, the median survival
colonic adenomas, with varying degrees β-catenin gene (CTNNB1) mutation and was 13.9 months and overall 5-year sur-
of dysplasia. Goblet cells are prevalent in β-catenin nuclear localization {2190, vival was 27%. For those with localized
most adenomas, and some lesions contain 3494}. Mutations of SMAD4 and KRAS and tumours, the 5-year survival rate was 57%
Paneth and endocrine cells {846, 2087}. activation of the RAS–RAF–MAPK pathway (median, 50 months), regional disease
have all been described {134, 277}. was 34% (median, 22 months), and
metastatic disease was 3% (median,
5 months) {1529}.
Carcinoma 101
Neuroendocrine neoplasms C. Capella

R. Arnold
of the small intestine D.S. Klimstra
G. Klöppel
P. Komminoth
E. Solcia
G. Rindi
Definition neoplasms (see Chapter 1). Neuroendo- patients the gastrinomas are found in the
Neoplasms with neuroendocrine differen- crine neoplasms of the small intestine pancreas {1616}. In multiple endocrine
tiation including neuroendocrine tumours exhibit site-related differences, depending neoplasia type 1 (MEN1)-associated ZES,
(NET) and neuroendocrine carcinomas on their location in the duodenum and the gastrinomas of most, if not all patients,
(NEC) arising in the small intestine. Mixed proximal jejunum when compared with dis- are in the duodenum {119, 735, 2554}.
adenoneuroendocrine carcinomas (MANEC) tal jejunum, ileum and Meckel diverticulum.
have an exocrine and an endocrine For this reason, this chapter is divided into Age and sex distribution
component, one of which exceeds 30%. three parts. For details on tumours of the Males are more frequently affected (male-
ampullary region, see Chapter 5. to-female ratio, 1.5 : 1), with a mean age at
ICD-O codes presentation of 59 years {370}. Gastrin-
Neuroendocrine tumours (NET) producing NETs associated with ZES
NET G1 (carcinoid) 8240/3 Neuroendocrine neoplasms of (gastrinomas) arise earlier in life than non-
NET G2 8249/3 the duodenum and proximal functioning NETs (mean age at diagnosis,
Neuroendocrine carcinoma (NEC) 8246/3 39 vs 66 years) {3011}. Somatostatin-
jejunum producing NETs and gangliocytic para-
Small cell NEC 8041/3 Neuroendocrine neoplasms of the duo- gangliomas are both almost equally
Mixed adenoneuroendocrine denum comprise NETs, including mainly distributed between the sexes and are
carcinoma (MANEC) 8244/3 somatostatin-producing and rare serotonin- usually diagnosed in the fourth or fifth
Enterochromaffin cell (EC cell), producing (EC cell) NETs, rare NECs and decade of life {943, 3011}. Poorly differ-
serotonin-producing NET 8241/3 MANECs, and the functional (“syndromic”) entiated neuroendocrine carcinomas
Gangliocytic paraganglioma 8683/0 gastrinoma. (NECs) of the ampullary region (Chapter
Gastrinoma 8153/3 5) are more common in men than women
L cell, Glucagon-like peptide-producing Epidemiology and present at a mean age of 70 years.
and PP/PYY-producing NETs 8152/1 Incidence and time trends The few non-ampullary NECs recorded in
Somatostatin-producing NET 8156/3 Neuroendocrine neoplasms of the duode- the literature occurred in males aged
num are rare, accounting for 5.7–7.9% of 57–69 years {2099, 2817}.
Synonyms neuroendocrine neoplasms of the digestive
Synonyms for intestinal NET include: system {1002, 3407}. The number of duo- Etiology
carcinoid, well-differentiated endocrine denal endocrine neoplasms showed a For nonfamilial cases, little is known about
tumour/carcinoma {3013}. Synonyms for gradual and steady increase (57%) be- possible etiological factors. A history of
NEC include: poorly differentiated endo- tween 1986 and 2000 {2998}, which may gastritis caused by Helicobacter pylori
crine carcinomas, high-grade neuro- partly reflect increased diagnosis of inci- and long-term treatment with proton
endocrine carcinoma, small cell and large dentally identified lesions as a result of the pump-inhibitors is significantly associated
cell endocrine carcinomas. increased availability of advanced endo- with an increased risk of sporadic duode-
scopic and radiological imaging. Jejunal nal gastrin-producing NETs (G cell NETs)
Classification neoplasms account for about 1% of all gut and an increased density of G cells
Intestinal NETs and NECs are classified on neuroendocrine neoplasms {1002, 3407}. {2052}.
the basis of criteria common to all gastro- Of NETs, gastrinomas represent the largest
intestinal and pancreatic neuroendocrine group (62%) in reported series of neuro- Localization
endocrine neoplasms arising in the upper Most duodenal neuroendocrine neoplasms
small intestine, followed by somatostatin- {370}, are located in the first and the second
producing NETs (18–21%), gangliocytic part, they are rare in the third and fourth part
paragangliomas (9%), undefined neoplasms of the duodenum. Nonfunctioning gastrin-
(5.6%) and pancreatic polypeptide (PP)- producing NETs are located in the duode-
producing NETs (1.8%) {3011}. Approxi- nal bulb, while the site of gastrinomas
mately 50% of sporadic (non-inherited) associated with ZES is in the first, second or
gastrin-producing NETs (G cell NETs) are third part of the duodenum or in the upper
functioning (gastrinomas) and are associ- jejunum {3011}. The preferential location of
ated with Zollinger-Ellison syndrome (ZES). somatostatin-producing NETs, gangliocytic
Of all patients with a sporadic gastrinoma, paragangliomas and NECs is at, or very
Fig. 6.07 Gastrinoma (gastrin-producing NET) displaying about 60–75% of neoplasms are located in close to, the ampulla of Vater (Chapter 5)
immunoreactivity to gastrin. the duodenum, while in the remaining {369, 372, 413, 1960, 3011, 3143, 3670}.

Very few cases of extra-ampullary somato- Macroscopy can also arise in the duodenum of patients
statin-producing NETs, gangliocytic para- NETs with MEN1 {119}. Electron microscopy
gangliomas or poorly differentiated NEC in NETs of the duodenum and upper reveals typical G cells with vesicular
the duodenum have been reported {413, jejunum usually form small (< 2 cm in granules {413}.
943, 2099, 2817}. diameter), grey, polypoid lesions within Somatostatin-producing NETs. These
the submucosa with an intact or focally neoplasms usually exhibit a predominant
Clinical features ulcerated overlying mucosa. However, tubulo-glandular component admixed
Most neoplasms, especially those located some examples appear as infiltrative with a variable proportion of insular and
in the duodenal bulb, are asymptomatic intramural nodules of rather large size (up trabecular areas {943}.
and are discovered incidentally, e.g. by to 5 cm in diameter). The neoplasms are EC cell, serotonin-producing NETs. The
imaging, endoscopy or pathological ex- multiple in about 13% of cases {370}. classic “midgut EC cell carcinoid” is very
amination of gastrectomy and duodeno- Gastrin-producing NETs tend to be rare both in the duodenum and upper
pancreatectomy specimens removed for smaller (0.8 cm) {413}, 1.8 cm for somato- jejunum {413}.
gastric and pancreatic cancers. Neuro- statin-producing NETs {943, 3011, 3055} Gangliocytic paragangliomas. These neo-
endocrine neoplasms of the duodenum and 1.7 cm for gangliocytic paragan- plasms appear as an infiltrative lesion
produce symptoms either by virtue of gliomas {413}. The gastrinomas in MEN1 composed of an admixture of three cell
local infiltration causing haemorrhage, are multiple and tiny (sometimes < 1 mm types: spindle cells, epithelial cells, and
intestinal obstruction and obstructive in size) in contrast to sporadic gastrino- ganglion cells (see Chapter 5).
jaundice (nonfunctioning neoplasms) or, mas {118}.
less frequently, by secreted peptide NECs
hormones (functioning neoplasms). The NECs These aggressive neoplasms may
localization of somatostatin-producing NECs measure 2–4 cm and present as assume the features of either small cell
NETs, gangliocytic paragangliomas, and focally ulcerated, or protuberant lesions carcinoma or large cell carcinoma.
poorly differentiated neuroendocrine car- {3143, 3670} (Chapter 5).
cinomas in the ampullary region explains MANECs
their frequent association with obstructive Histopathology MANECs are most frequently observed
biliary disease. NETs in the ampullary–periampullary region
ZES with hypergastrinaemia, gastric hyper- Gastrin-producing NETs (G cell NETs). (Chapter 5).
secretion, and refractory peptic-ulcer These neoplasms are formed by uniform
disease, is the only syndrome of neuro- cells with scant, lightly eosinophilic Genetic susceptibility
endocrine hyperfunction consistently cytoplasm, arranged in broad gyriform MEN1
observed in association with neuroendo- trabeculae and vascular pseudorosettes. This inherited tumour syndrome is signifi-
crine neoplasms of the duodenum and Tumour cells have uniform round nuclei cantly associated with functioning gastrino-
upper jejunum {370, 735, 1225, 3011, containing stippled chromatin and incon- mas, but not with other types of NET of the
3477}. spicuous nucleoli. Necrosis is virtually duodenum and upper jejunum. Approxi-
The association with ZES is found in about never seen. Their proliferative index (Ki67) mately 25–33% of patients with gastrinomas
40–50% of duodenal gastrin-producing is usually between 2% and 10% {119} and develop these neoplasms in the setting of
NETs {1616, 3011}. Neoplasms associ- thus G2 (Chapter 1). Angioinvasion is MEN1 {413}. The vast majority of these
ated with overt ZES (gastrinomas) differ found in some cases. Immunohistochem- gastrinomas are located in the duodenum
from their apparently nonfunctioning ically, chromogranin A and gastrin are {2555}. Loss of heterozygosity (LOH) at the
counterparts in arising earlier in life and widely expressed. Other peptides detected MEN1 gene locus has been found in 4 out
having a higher incidence of metastatic in tumour-cell subpopulations are chole- of 19 (21%) duodenal MEN1 gastrinomas
and non-bulbar cases {3011}. cystokinin, PP, neurotensin, somatostatin, {1908}, while a slightly higher rate of LOH
Well-differentiated serotonin-producing insulin, and the α chain of human chorionic on 11q13 for MEN1 gastrinomas (41%; 14
tumours (carcinoids) are unusual in the gonadotropin {413}. Caudal-related home- out of 34 neoplasms) was reported in an
upper small intestine. It follows that duo- obox 2 (CDX2) is positive in three quarters extended study of MEN1 and sporadic
denal carcinoids only exceptionally give of cases {1706}. G cell NETs also express gastrinomas {684}. A low incidence of LOH
rise to the classical carcinoid syndrome, somatostatin receptors {2450}. Interest- on 11q13 in MEN1-associated gastrinomas
associated with liver metastases of the ingly, somatostatin, which is known to suggests that these neoplasms could arise
neoplasm {413, 3055}. In none of the inhibit the release of gastrin from gastrino- due to inactivation of the wild-type allele via
cases of somatostatin-producing NETs so mas, is detected more frequently in non- point mutations or small deletions rather
far reported did the patients develop functioning G cell NETs than in tumours than via loss of a large segment of chromo-
“somatostatinoma” syndrome (diabetes associated with ZES {413}. MEN1-associ- some 11 {1908}. Molecular analyses now
mellitus, diarrhoea, steatorrhoea, hypo- or ated gastrinomas display a multifocal enable a distinction to be made between
achlorhydria, anaemia and gallstones) G-cell and somatostatin-cell hyperplasia hyperplastic G cell lesions and neoplastic
that has been described in association in the adjacent mucosa and/or Brunner lesions in the duodenum of patients with
with some pancreatic somatostatin- glands, while sporadic G cell NETs lack ZES–MEN1. LOH at the MEN1 locus has
producing NETs {943, 3011}. such lesions {119}. Recently, it has been been detected in about 50% of MEN1-
shown that, in addition to gastrinomas, associated gastrinomas {120}. Allelic loss
multiple tiny somatostatin-producing NETs was found in tiny (300 μm diameter)

lower intestine. Overall for the small intes-

tine both classifications are substancially
in agreement.
Recent studies have demonstrated the
prognostic relevance of the newly pro-
posed TNM classification system for
foregut neuroendocrine neoplasms with
statistical significance for stage and
grade {2449}.
NETs
A B Gastrin-producing NETs (G cell NETs).
Fig. 6.08 Lymph-node metastasis from duodenal gastrinoma. The tumour cells form trabeculae (A) and are intensely NETs with a low-grade malignant potential
immunoreactive for gastrin (B). are those that invade beyond the submu-
cosa or show lymph-node or distant (liver)
metastases. Low-grade malignant NETs
gastrinomas and (400 μm diameter) neuroendocrine neoplasms {913}, contrary have been reported to comprise 10% of all
somatostatin-producing NETs, which there- to gastrointestinal NETs at other sites G cell duodenal-upper jejunal NETs {413},
fore represented true neoplasms. On the {3108}. Also, APC promoter methylation 58% of sporadic ZES cases {735} and 45%
contrary, LOH at 11q3 was not found in suggests a role for APC in Wnt activation of ZES–MEN1 cases {735}. Gastrinomas
hyperplastic gastrin and somatostatin cells. {2561}. Methylation of the 5’ region of the associated with overt ZES are prognosti-
CDKN2A (p16) tumour-suppressor gene cally less favourable than their nonfunc-
Neurofibromatosis type 1 (NF1) on chromosome 9p21 has been observed tioning counterparts, having a higher
Patients with von Recklinghausen disease in 52% of gastrinomas, including duode- frequency of metastases, and being deeply
are at significant risk of developing nal ones {2881}. Interestingly, promoter infiltrative {3011}. These findings suggest
ampullary and periampullary NETs {372, methylation of CDKN2A, APC, MEN1, that the natural history of G cell NETs is dif-
413, 1586, 3011} (Chapter 5). HIC1 and RASSF1A genes occurs more ferent for the two conditions. Nonfunction-
frequently in gastrointestinal neuroendo- ing neoplasms represent a generally
Von Hippel-Lindau (VHL) disease crine neoplasms than in pancreatic benign condition, while ZES neoplasms
A very rare case in which VHL disease neuroendocrine neoplasms {471}, indi- have a low-grade malignancy, especially
was associated with a duodenal function- cating that the CpG island methylator when arising in sites where G cells are not
ing somatostatin-producing NET with a phenotype (CIMP) is common among normally present, such as in the jejunum or
high level of plasma somatostatin has gastrointestinal neuroendocrine neoplasms pancreas {413}. Metastases in regional
been reported, indicating that VHL-asso- {146}. Microsatellite instability did not occur lymph nodes have been reported in 4 out
ciated NETs of the digestive system occur in any of the gastrointestinal neuroendo- of 8 cases of duodenal gastrinomas with
not only in the pancreas {1480}. crine neoplasms investigated {146}. ZES–MEN1 syndrome {2555}, in 2 out of 3
Incidental gastrin-producing (G cell) NETs cases of jejunal gastrinomas {413} and in
Molecular pathology do not overexpress either basic fibroblast 25% of 103 cases of duodenal neoplasms
In addition to MEN1-associated gastrino- growth factor (bFGF), acidic fibroblast with ZES, 24% of which also had MEN1
mas, the MEN1 tumour suppressor gene growth factor (aFGF), transforming growth syndrome {1225}.
is also involved in the pathogenesis of factor-α (TGFα), or their respective Lymph-node metastases of gastrinomas
sporadic duodenal gastrinomas. LOH at receptors FGFR4 and EGFR {1709}. On may be much larger than the primary,
the MEN1 locus was found in 60% of the contrary, these tumours overexpress which may be < 1 mm in size, and may
sporadic duodenal gastrinomas {3662} the β-subunit of activin, which may be erroneously be considered to be pancreatic
and MEN1 mutations were detected in involved in regulating the proliferation of
10–25% (40%) of sporadic duodenal gas- tumour cells {1708}.
trinomas {1003}. Mutations were clustered
between amino acids 66–166, unlike in Prognosis and predictive factors
patients with familial MEN1. The issue of TNM/Staging classification of
TP53 mutations are a rare event in neuroendocrine neoplasms is as yet unset-
sporadic neuroendocrine neoplasms of tled. The classification recently proposed
the digestive system {3221}. β-Catenin by the American Joint Committee on
mutations were reported in 8 out of 13 Cancer (AJCC) and the International Union
(61.5%) duodenal neuroendocrine neo- Against Cancer (UICC) and embraced by
plasms, with cytoplasmic and nuclear WHO is for “carcinoid”, i.e. well-differentiated
accumulation of β-catenin and overex- lesions only. Conversely, the classification
pression of cyclin D1 (CCND1), in the proposed by the European Neuro-
absence of APC gene mutation. These endocrine Tumor Society (ENETS) is also Fig. 6.09 Duodenal gastrinoma revealing immunoreactivity
results suggest that the Wnt pathway is meant for high-grade neoplasms {2685}. for somatostatin receptor 2A (SSTR2A); expression of
involved in the development of duodenal In addition, it is divided for the upper and SSTR2A is relevant for imaging and therapy.

neoplasms (especially if located at the

upper margin of the head of the pancreas
{735}), or as primary lymph-node gastri-
nomas {118}. Local lymph-node metastases
seem to have little influence on survival of
patients with ZES {689, 3477}. In a study
focusing on metastatic rate and survival
in patients with ZES, no difference was
found in the frequency of metastases to
lymph nodes {735}, when comparing
primary pancreatic (48%) and duodenal
(49%) neoplasms. In contrast, the same
study found a significantly higher
frequency of metastases to the liver in
patients with pancreatic gastrinomas than
in patients with duodenal gastrinomas
(52% vs 5%). The 10-year survival rate of
patients with duodenal gastrinomas (59%)
is significantly better than for patients with
pancreatic gastrinomas (9%) {3477}. The Fig. 6.10 Multiple enterochromaffin cell (EC cell, serotonin-producing) NET of the ileum with mesenteric lymph-node
more favourable prognosis for patients metastases.
with duodenal NETs is mainly linked to their
smaller size and less frequent association Epidemiology Localization
with liver metastases. Incidence and time trends In a series of 167 jejuno-ileal NETs, 70%
Somatostatin-producing NETs. About two The age-adjusted incidence of jejunum- were located in the ileum, 11% in the
thirds of these neoplasms were reported ileum NETs is 0.4 and 3.2, respectively jejunum, 3% in Meckel diverticulum {373}.
as low-grade malignant in one study, per 1 000 000 population {2854}. In the Most of these neoplasms are located in
despite their rather bland histological gastrointestinal tract, NETs occur pre- the distal ileum near the ileocaecal valve.
appearance {372, 666, 3011}. dominantly in the small intestine (44.7%)
Gangliocytic paragangliomas. Ganglio- followed in descending frequency by the Clinical features
cytic paragangliomas are usually benign, rectum (19.6%), appendix (16.7%), colon Patients with jejuno-ileal NETs present most
in contrast to G cell and somatostatin- (10.6%), and stomach (7.2%) {1951}. commonly with intermittent crampy abdo-
producing NETs that arise in the same Most small-intestinal NETs occur in the minal pain, suggestive of intermittent intes-
area. However, occasional large neo- ileum (49.9%). The incidence of ileal NETs tinal obstruction {2119}. Patients frequently
plasms (size, > 2 cm) may spread to local increased from 52% in 1973–1977 to have vague abdominal symptoms for
lymph nodes, mainly attributable to the 63.6% in 1998–2002), while the incidence several years before diagnosis, reflecting
endocrine component of the lesion {358, of adenocarcinomas has decreased from the slow growth rate of these neoplasms
1327} (see Chapter 5). 18.6% in 1973–1977 to 12.2% in 1998– {2119}. Pre-operative diagnosis is difficult
2002 {2111}. since standard imaging techniques rarely
NECs identify the primary tumour. Scintigraphic
NECs are high-grade malignant, poorly Age and sex distribution imaging with radiolabelled somatostatin
differentiated carcinomas that display a NETs of the distal jejunum and ileum are analogues (octreotide) is widely used to
high mitotic rate, tumour necrosis and almost equally distributed between males localize previously undetected primary or
usually deep mural invasion, angioinvasion, and females. NETs are diagnosed be- metastatic lesions {1701}. The “carcinoid
neuroinvasion, and poor survival {2099, tween the third and the tenth decades of syndrome” is found in 5–7.7% of patients
2254, 2817, 3670} (see Chapter 5). life, with a peak in the sixth and seventh with EC cell serotonin-producing NETs
decades {373, 1002, 2119, 3011}. {1002, 2119} that typically arise in the dis-
tal ileum and have already metastasized to
Neuroendocrine neoplasms of Etiology the lymph nodes and the liver. Symptoms
the distal jejunum and ileum Although neuroendocrine neoplasms of include cutaneous flushing, diarrhoea, and
lower jejunum and ileum are not generally fibrous thickening of the endocardium and
Neuroendocrine neoplasms of this seg- preceded by precursor lesions, there valves of the right heart.
ment of the small intestine are only NETs have been reports of focal microprolifera-
(carcinoids), mainly EC cell, serotonin- tions of EC cells in cases of multiple ileal Macroscopy
producing NETs and, less frequently, L neoplasms {2928} and of intraepithelial Jejuno-ileal NETs are multiple (2–100 neo-
cell, glucagon-like peptide and PP/PYY neuroendocrine cell hyperplasia in the plasms) in about 25–30% of cases {373,
(peptide YY)-producing NETs. NECs, mucosa adjacent to jejuno-ileal carci- 2119, 3099}. Size is < 1 cm in 13% and
poorly differentiated endocrine carcino- noids {2172}. < 2 cm in 47% of cases {373}. these neo-
mas, have not been reported. plasms usually appear as mucosal–
submucosal nodules with intact or slightly

A B
Fig. 6.11 Ileal enterochromaffin cell (EC cell) serotonin-producing NET. A The tumour is composed of cells with intense eosinophilic cytoplasm forming rounded nests with peripheral
palisading. B Note the nuclear immunoreactivity for CDX2.
eroded overlying mucosa. Deep infiltration 0–2% {405} and these neoplasms are thus Genetic susceptibility
of the muscular wall and peritoneum is G1 (see Chapter 1). In areas of deep inva- Unlike gastric ECL cell tumours and duo-
frequent. Extensive involvement of the sion with abundant desmoplastic reaction, denal G cell NETs, jejuno–ileal carcinoids
mesentery associates with considerable the cell nests may be oriented into cords are only occasionally associated with
fibroblastic or desmoplastic reaction, with and files. Mesenteric arteries and veins MEN1 {2431}. Rare examples of familial
consequent angulation and kinking of the located near the neoplasm, or away from occurrence of ileal EC cell carcinoids
bowel and obstruction of the lumen. In- it, may be thickened and their lumen have been reported {2117}.
farction of the involved loop of the small narrowed or even occluded by a peculiar
intestine may occur as a consequence of elastic sclerosis, which may lead to Molecular pathology
fibrous adhesions, volvulus, or occlusion ischaemic lesions in the intestine {127}. In a microarray analysis performed to
of the mesenteric blood vessels. Most tumour cells are strongly positive identify differentially expressed genes in
with Masson Fontana argentaffin stain pancreatic neuroendocrine neoplasms
Histopathology and strongly immunoreactive for chromo- and gastrointestinal NETs (mainly
Serotonin-producing (EC) cell NETs are granin A and B and synaptophysin. In represented by ileal invasive NETs), ileal
composed of rounded nests of closely about 30% of cases, a variable number of neoplasms exhibited a gene-expression
packed tumour cells that often show a cells is also reactive for prostatic acid profile that was significantly different from
typical peripheral palisading (Type A phosphatase {373}. that of pancreatic neuroendocrine neo-
according to Soga & Tazawa) {3001}. In the majority of cases, most tumour cells plasms {1799}.
Within the solid nests, rosette type, cribri- express serotonin. A variety of other neuro- Comparative genomic hybridization (CGH)
form and glandular-like structures are hormonal peptides or amines have been studies of ileal NETs have demonstrated
frequently detected. The tumour cells are detected in these neoplasms {267, 1005, losses of chromosome 9p, 18p, and 18q
uniform, with little or no pleomorphism or 1105, 1986, 3615}. Ileal serotonin-produc- in 21%, 38%, and 33% of case respec-
mitotic activity. The proliferative index ing (EC) cell NETs and their metastases tively {3268, 3704}, gains of chromosome
(Ki67-expressing cells) is very low at are positive for the transcription factor 17q and 19p in 57% of cases {3268} and
protein CDX2 {119} and > 90% of the neo- LOH of chromosome 18 has been de-
plasms show membranous labelling for tected in 88% of ileal NETs {1888}. Fur-
somatostatin receptor 2A {2450}. The thermore, 22% of ileal NETs showed
tumour cells may also express galectin 4 losses of 16q21 and an accumulation of
{2757} and cyclooxygenase-2 (COX2) genetic abnormalities mainly involving a
{1706}. In addition, carcinoembryonic loss of chromosome 16q and gain of
antigen (CEA) is found in approximately chromosome 4p was found in metas-
70% of neoplasms. Scattered between tases. High-resolution analysis of genetic
the tumour cells, S100-positive susten- alterations by single nucleotide polymor-
tacular cells may be observed {373}. phism confirmed that loss of all or most of
The rare jejuno-ileal NETs composed of chromosome 18 was the most frequent
glucagon-like peptide and PP/PYY-pro- aberration in ileal NETs {1546}; this strongly
ducing L cells feature a typical trabecular suggests that important candidate genes
structure and an immunoprofile similar to are located on this chromosome. In addi-
Fig. 6.12 Ileal enterochromaffin cell (EC cell), serotonin- the corresponding colorectal and appen- tion, losses of chromosome 18 are rare in
producing NET. Note the invasion of the perineural space. diceal NETs (see Chapters 7 and 8). bronchial and pancreatic neuroendocrine
neoplasms, suggesting a different genetic

background for these group of neoplasms of snail and sonic hedgehog in NETs of the
{1888, 3221, 3704}. ileum has been related to their metastatic
In contrast to foregut (gastric, duodenal spread, by a mechanism that leads to
and pancreatic) NETs, which show fre- downregulation of E-cadherin {833}.
quent deletions and mutations of the
MEN1 gene, midgut (mainly ileal) NETs Prognosis and predictive factors
rarely show involvement of MEN1 {683, The main criteria for considering a jejuno-
3253}. Mutations in APC but not in the ileal carcinoid to have malignant behaviour
β-catenin gene (CTNNB1) were found in are deep invasion of the wall (muscularis
ileal NETs showing nuclear translocation propria or beyond) and/or presence of
of β-catenin {2561}. Homeobox gene metastases. According to these criteria,
HOXC6 is upregulated in ileal NETs {912}. 141 out of 159 cases (89%) of jejuno-ileal
Interestingly, HOXC6 has been reported carcinoids in a large series were consid- Fig. 6.13 Ileal enterochromaffin cell (EC cell), serotonin-
as target of the MEN1 gene and also ered malignant {373}. The mortality rate producing NET displaying diffuse immunoreactivity for
upregulates CTGF, which encodes an was 21% for jejuno-ileal EC cell, serotonin- chromogranin A.
important growth factor in ileal NETs {912, producing NETs (carcinoids) compared
1537}. with 4% for duodenal, 6% for gastric, and Neuroendocrine tumours of
Accumulation of p53 has not been 3% for rectal carcinoids {373}. The overall
detected in EC cell NETs examined 5-year survival rate for patients with jejuno–
Meckel diverticulum
immunohistochemically, suggesting that ileal NETs is about 60% and the 10-year EC cell, serotonin-producing NETs occur
this tumour-suppressor gene is not impli- survival rate is 43% {373, 3099}. In patients rarely in Meckel diverticulum; 174 cases
cated in the pathogenesis of these neo- without liver metastases, the 5- and 10- have been reported {2116}. Meckel NETs
plasms {3011, 3441, 3478}. year survival rates are about 72% and prevail in males (three quarters of cases),
Several growth factors, such as TGFα and 60%, respectively, as opposed to 35% and with a reported age ranging from 14
IGF1, exert a proliferative effect reflected 15% for patients with liver metastases months to 82 years. About half of the pa-
by an increased mitotic index and signifi- {3099}, demonstrating the relatively slow tients present with symptoms such as
cantly increased DNA levels in primary rate of growth of some EC cell, serotonin- abdominal pain, nausea, diarrhoea, vom-
cell cultures of ileal NETs, suggesting the producing NETs. SEER data for 1973–2002 iting and haematochezia and already
involvement of an autocrine loop {44}. show that 5-year survival rates for small- have metastases {2289}. Because of their
PDGF, TGFα, bFGF, and aFGF seem to be intestinal NETs have remained unchanged considerable metastatic capacity, symp-
mainly involved in tumour stromal reac- over 30 years in the USA {2111}. Metas- tomatic NETs of Meckel diverticulum have
tion, including stromal desmoplasia {44, tases are generally confined to regional been equated to jejuno-ileal carcinoids
1703, 1709}, by acting on receptors lymph nodes and liver. Extra-abdominal {2171}. In contrast, tumours detected
expressed on fibroblasts or stimulating metastases are very rare {2119}. incidentally in asymptomatic patients are
the promotion of new vasculature and Tumour stage is the most important pre- usually not metastatic and are small in
tumour progression {44, 1703, 1709}. In dictor of survival. Patients with NETs and a size (< 1.7 cm). Histologically, Meckel
particular, EC cell NETs overexpress low Ki67 index live longer than those with NETs, like ileal NETs, show a characteris-
CTGF and TGFβ mRNA and synthesize a high Ki67 index {149}, indicating the tic type A pattern of growth, strong and
CTGF and TGFβ proteins that are signifi- importance of a proliferation-based grading diffuse expression of neuroendocrine
cantly elevated in patients with clinically system (see Chapter 1). Jejuno-ileal NETs markers and serotonin.
documented fibrosis {1537}. that are clinically nonfunctioning, 1 cm or
Neural adhesion molecule (NCAM/CNTN6), less in diameter and confined to the
a member of the immunoglobulin super- mucosa/submucosa are generally cured
family of cell-adhesion molecules, is by complete local excision, but invasion
highly expressed in ileal NETs {44}. Be- beyond the submucosa or metastatic
cause NCAM has not been shown in spread indicates that the lesion is malig-
normal gut neuroendocrine cells, the nant. The malignant potential is retained
novel expression of this adhesion mole- for ileal NETs > 1 cm but confined to the
cule in carcinoids may be of importance mucosa/submucosa.
for growth and metastases. Overexpression

B-cell lymphoma of the small intestine S. Nakamura

J. Delabie
Y.H. Ko
E.S. Jaffe
Definition represent different manifestations or phases

Primary small-intestinal B-cell lymphoma of the same disease. IPSID or αHCD occurs
is defined as an extranodal B-cell lym- predominantly in the Mediterranean area,
phoma arising in the small bowel with the but may be seen outside this region. It typ-
bulk of disease localized to this site. Con- ically affects young adults, while small-
tiguous lymph-node involvement and dis- intestinal lymphomas in North America and
tal spread may be seen, but the primary Europe increase in frequency with age,
clinical presentation is the small or large with peak incidence in the seventh dec-
intestine, with therapy directed to this site. ade of life. Most studies have shown a slight
predominance in males and an association
ICD-O codes with lower socioeconomic status {733}.
Burkitt lymphoma 9687/3 Burkitt lymphoma occurs in two major forms, Fig. 6.14 DLBCL of the small intestine. The gross specimen
B-cell lymphoma, unclassifiable, defined as endemic and sporadic. Endemic shows a large ulcerating tumour with luminal stricture.
with features intermediate Burkitt is found primarily in Africa and typ-
between diffuse large B-cell ically presents in the jaw, orbit or para-
lymphoma and Burkitt lymphoma 9680/3 spinal region, and is strongly associated
Diffuse large B-cell lymphoma with infection with Epstein-Barr virus (EBV).
(DLBCL) 9680/3 In other endemic regions, however, it is
Immunoproliferative small-intestinal relatively common for Burkitt lymphoma to
disease (IPSID) 9764/3 present in the small intestine, usually involv-
Follicular lymphoma 9690/3 ing the ileum, with preferential localization
Marginal zone lymphoma of to the ileocaecal region. In parts of the Middle
mucosa-associated lymphoid East, primary gastrointestinal Burkitt lym-
tissue (MALT lymphoma) 9699/3 phoma is a common disease of children.
Mantle cell lymphoma 9673/3 Sporadic or non-endemic Burkitt lymphoma
is a rare disease, not associated with EBV Fig. 6.15 Multiple lymphomatous polyposis with typical
Epidemiology infection, which frequently presents as polypoid mucosa.
In contrast to lymphomas involving the primary intestinal lymphoma. Burkitt lym-
stomach, primary small-intestinal B-cell lymphoma is also seen in the setting of infection
phomas are uncommon in North America, with human immunodeficiency virus (HIV), including congenital immune deficiency,
European and Asian countries {1622, 2219}. where it often involves the gastrointestinal iatrogenic immunodeficiency associated with
However, since epithelial and mesenchymal tract {420}. solid-organ transplantation, and acquired
tumours are uncommon in the small bowel, immuno-deficiency syndrome (AIDS) {626}.
lymphomas constitute a significant proportion Etiology In general, lymphomas associated with
(30–50%) of all malignant tumours at this site. Infection by Campylobacter jejuni has shown immunodeficiency show a predilection for
The most frequent histological type among to be associated with IPSID {1776}. Response extranodal sites, particularly the gastro-
intestinal B-cell lymphomas is diffuse large to treatment with antibiotics is typical of the intestinal tract, irrespective of the cause of
B-cell lymphoma (DLBCL), which accounts early phases of this disease. Chronic in- the immunodeficiency {1337, 1817}.
for 40–60% of cases in North America, flammatory bowel disease, including Crohn
European and Asian countries {733, 1622, disease and ulcerative colitis, are also risk Clinical features
2219}. Extranodal marginal-zone lymphomas factors for intestinal B-cell lymphomas, Symptoms produced by small-intestinal
of mucosa-associated lymphoid tissue some of which may be associated with lymphomas depend upon the specific
(MALT lymphomas) are also common lym- iatrogenic immunosuppression and EBV histological type. Indolent lymphomas of
phomas in the small intestine and col- {3350}. Some of these cases may resemble B-cell lineage typically present with abdo-
orectum (3–28%). classical Hodgkin lymphoma {1677}. How- minal pain, weight loss and bowel obstruction
Immunoproliferative small-intestinal disease ever, the risk for development of lymphoma {733}. Occasional cases present with nausea
(IPSID) is a unique form of intestinal MALT is much less than that associated with and vomiting; rarely, cases are discovered
lymphoma that occurs predominantly in coeliac disease and the development of pri- incidentally. More aggressive tumours,
the Middle East and Mediterranean. This mary T-cell lymphomas of the small bowel. such as Burkitt lymphoma, may present as
entity represents part of a spectrum of small- An increased incidence of lymphoma has a large intra-abdominal mass or acutely with
intestinal lymphoproliferations, including also been associated with both acquired intestinal perforation. IPSID often manifests
α heavy-chain disease (αHCD) and may and congenital immunodeficiency states, as abdominal pain, chronic severe intermittent

diarrhoea and weight loss. The diarrhoea The macroscopic appearance of IPSID IPSID/αHCD
is mainly the result of steatorrhoea, and a depends on the stage of disease. Early IPSID and αHCD are synonyms for a sub-
protein-losing enteropathy can be seen. on, the bowel may appear endoscopically type of small-intestinal MALT lymphoma
Peripheral oedema, tetany and clubbing normal, with infiltration apparent only on The histology of this subtype is charac-
are observed in as many as 50% of intestinal biopsy. The disease may then teristic of MALT lymphoma with marked
patients. Rectal bleeding is uncommon in progress to thickening of the upper plasma-cell differentiation. Three stages
small-bowel lymphoma, but is a common jejunum together with enlargement of the of IPSID are recognized.
presenting sign in primary colonic lym- mesenteric lymph nodes and the develop- In stage A, the lymphoplasmacytic infiltrate
phoma. Burkitt lymphoma is most fre- ment of lymphomatous masses. Typically, is confined to the mucosa and mesenteric
quently seen in the terminal ileum or the spleen is not involved and may even lymph nodes, and cytological atypia is not
ileocaecal region, and may cause intus- be small and fibrotic, as described for present. Although the infiltrate may obliter-
susception. coeliac disease. Distal spread beyond the ate the villous architecture, the endoscopic
abdomen is uncommon {1342}. examination appears normal. This phase
Imaging and endoscopy of the disease is typically responsive to
Radiological studies are useful adjuncts to Histopathology antibiotic therapy.
the diagnosis of small-intestinal lym- DLBCL In stage B, nodular mucosal infiltrates
phomas, including computed tomography DLBCL, with or without a MALT lymphoma develop and there is extension below the
(CT) and positron emission tomography component, is the dominant type of non- muscularis mucosae. The characteristic
(PET) scans. Most B-cell lymphomas Hodgkin lymphoma of the small intestine. features of MALT lymphoma are evident
manifest as exophytic or annular tumour The histological features of small intestinal and follicular colonization may be
masses in the ileum. Follicular lymphoma, DLBCL are similar to those of gastric marked. A minimal degree of cytological
mantle cell lymphoma, and MALT lym- DLBCL. In contrast to gastric lymphomas, atypia is apparent. This stage appears to
phoma may produce nodules or polyps DLBCLs arising in the small bowel are represent a transitional phase. Thickening
that can be seen both endoscopically and much commoner than low-grade B-cell of mucosal folds can be seen macro-
by imaging. Most small-intestinal lym- lymphomas of MALT type. Some intestinal scopically, and at this stage, the disease
phomas are localized to one anatomic site, DLBCLs may be associated with follicular is typically not curable with antibiotics.
but multifocal tumours are detected in lymphoma, which most often can be seen Stage C is characterized by the presence
approximately 8% of cases. in mesenteric lymph nodes. Focal areas of large masses and transformation to
Multiple lymphomatous polyposis (MLP) of follicular lymphoma may also be pres- DLBCL. Numerous immunoblasts and
consists of numerous polypoid lesions ent in the intestine, but such cases are plasmablasts are present. Marked cyto-
throughout the gastrointestinal tract. Most considered as nodal lymphomas with logical atypia is found, including Reed-
often, the jejunum and terminal ileum are spread to the intestine. Sternberg-like cells. Mitotic activity is
involved, but lesions can appear in the increased. Mesenteric lymph-node in-
stomach, duodenum, colon, and rectum. MALT lymphoma volvement occurs early in the course of
This entity produces a characteristic radi- The relative frequency of MALT lymphoma disease, with infiltration of nodal sinuses
ological picture that is virtually diagnostic. (other than IPSID) is much lower in the and marginal-zone areas. Immunohisto-
Most such cases have been considered to small intestine than the stomach. The chemical studies demonstrate the
be caused by mantle-cell lymphoma, but histological features of small-intestinal production of α heavy chain without light-
other subtypes of lymphoma, such as MALT lymphoma are similar to those of chain synthesis {1342}. IgA produced is
follicular lymphoma and MALT lymphoma, gastric MALT lymphoma, except that lym- almost always of the IgA1 type, with intact
may produce a similar radiological or phoepithelial lesions are less prominent. carboxy-terminal regions and deletion of
endoscopic pattern {1626}. most of the V and all of the CH1 domains.
A B
Fig. 6.16 DLBCL of the small intestine. Double-balloon Fig. 6.17 Mantle cell lymphoma of the duodenum with multiple lymphomatous polyposis. A Endoscopic appearance.
endoscopy reveals a large ulcerating tumour without B The spraying of indigo carmine highlights the presence of multiple lymphomatous polyposis.
epithelial irregularity or luminal stricture.
B-cell lymphoma 109

The molecular characterization of individ- B cells and express both CD19 and
ual cases is variable. The small lymphoma CD20. Characteristically the cells weakly
cells express CD19 and CD20, but fail to co-express CD5 and CD43. Surface
express CD5, CD10 and CD23, while the immunoglobulins found include both IgM
plasmacytic-cell component may only ex- and IgD. Light-chain restriction is present
press plasma-cell markers such as CD138. in most cases, with some studies demon-
strating a predominance of λ. CD10 and
Mantle cell lymphoma CD11c are virtually always negative. Cyclin
Mantle cell lymphoma typically involves D1 is found in virtually all cases and can
both spleen and intestines and may be demonstrated within the nuclei of the
present as an isolated mass or as multi- neoplastic lymphocytes in paraffin sec-
ple polyps throughout the gastrointestinal tions. Rare cases of mantle cell lymphoma Fig. 6.18 Multiple lymphomatous polyposis. Polypoid
tract where it is referred to as multiple lym- that are cyclin D1-negative may be inden- mantle cell lymphoma.
phomatous polyposis (MLP) {733, 2174}. tified by SOX11 overexpression {2175}.
Mantle cell lymphoma frequently expresses
α-4-β-7 integrin that facilitates homing to Follicular lymphoma
the gut. Importantly, other histological Follicular lymphoma occurs in the small
subtypes of non-Hodgkin lymphoma, such intestine, and involvement of the duode-
as follicular lymphoma and MALT lym- num is a frequent feature {2824, 2838}.
phoma, can also produce MLP. The Intestinal follicular lymphoma is predomi-
polyps range in size from 0.5 cm to 2 cm, nantly found in the second portion of the
with much larger polyps found in the duodenum, presenting as multiple small
ileocaecal region. polyps, often as an incidental finding on
The histology of mantle cell lymphoma endoscopy performed for other reasons.
involving the small bowel is identical to Recent developments in small-intestinal
that involving nodal sites {188}. The endoscopies, such as double-balloon or Fig. 6.19 Primary intestinal follicular lymphoma arising in
architecture is most frequently diffuse, but capsule endoscopy, have revealed that the jejunum.
a nodular pattern and a less common true the jejunum and ileum are also frequently
mantle-zone pattern are also observed. affected by follicular lymphoma, usually diminished distribution of follicular den-
Reactive germinal centres may be found presenting as MLP {1625, 2221}. Morpho- dritic-cell networks, in contrast to nodal
and are usually compressed by the logy is sometimes characterized by glove counterparts {3162}. Most patients have
surrounding lymphoma cells, thereby balloon-like villous hypertrophy caused by localized disease (stage IE or IIE), and sur-
appearing to replace the normal mantle extrafollicular infiltration of lymphoma vival appears to be excellent, even without
zones. Intestinal glands may be cells. The immunophenotype and genetic treatment. This localized polypoid form of
destroyed by the lymphoma, but typical features are similar to those of nodal follicular lymphoma appears to have a
lymphoepithelial lesions are not seen. The follicular lymphomas. The lymphoma cells very low risk of extra-intestinal disease.
low-power appearance is monotonous, co-express CD10, BCL2, and BCL6, but In contrast to the very localized and
with frequent epithelioid histiocytes, not CD5 or CD43. The expression of BCL2 limited involvement shown by some intes-
mitotic figures and fine sclerosis sur- in conjunction with strong CD10 is useful tinal follicular lymphomas, more extensive
rounding small blood vessels. The lym- for distinction from reactive follicles and involvement by primary nodal follicular
phoma cells are small to medium sized primary follicles, or marginal zone hyper- lymphoma also can be seen, associated
with irregular nuclear outlines, indistinct plasia. MIB1 shows a low proliferation rate. with mesenteric lymph-node involvement.
nucleoli and scant amounts of cytoplasm. Immunostaining to highlight follicular These more typical cases of follicular lym-
Large transformed cells are typically not dendritic cells (antibodies to CD21, CD23 phoma present with bulky disease. All cyto-
present. The lymphoma cells are mature or CD35) help to reveal the unusually logical grades may be seen: grades 1–2,
and grade 3A, or grade 3B. Progression
to DLBCL is present in some cases.
Burkitt lymphoma
The histology in all cases is identical and is
characterized by a diffuse infiltrate of
medium-sized cells with round to oval
nuclear outlines, two to five small but
distinct nucleoli and a small amount of
intensely basophilic cytoplasm. Numerous
mitotic figures and apoptotic cells are
present. The prominent “starry-sky” ap-
pearance is caused by benign phagocytic
Fig. 6.20 Mantle cell lymphoma. Immunostaining for Fig. 6.21 Burkitt lymphoma. Note the “starry-sky” effect histiocytes engulfing the nuclear debris
cyclin D1 shows nuclear positivity. caused by phagocytic histiocytes. resulting from apoptosis. Unusually for

lymphomas, thin sections often show that MALT lymphoma break-points are usually far 5’ of MYC,
the cytoplasmic borders of individual cells t(11;18)(q21;q21)/BIRC3-MALT1 is found while their chromosome 14 break-points
“square off” against each other; this indi- in one third of patients, with different most often occur in the location of the
cates a mature B-cell lymphoma and the frequencies found in primary and second- joining segments (IGHJ@); it is thus
neoplastic cells express pan-B-cell anti- ary intestinal MALT lymphomas (12.5% vs impossible in most cases to demonstrate
gens CD19, CD20, CD22, and CD79a. 57%) {3095}. t(1;14)(p22;q32)/BCL10- such rearrangements by Southern-blot
The neoplastic cells co-express CD10, but IGH@ and trisomy 3 or 18 are detected in analysis. In contrast, sporadic cases
fail to express CD5 or CD23. Expression 12.5% and 81% of primary intestinal MALT frequently have MYC break-points within
of surface immunoglobulins is moderately lymphomas, respectively, these frequencies noncoding introns and exons of the gene
intense and is nearly always IgM with being higher than those for gastric and itself (typically the first exon or intron, or
either κ or λ light-chain restriction. The secondary intestinal MALT lymphomas the 5’ flanking regions); such rearrange-
growth fraction, as assessed by Ki67 or {3095}. ments can be usually be detected by
MIB1, is nearly 100% of tumour cells. Southern blot {1126}. Fluorescence in situ
Burkitt lymphoma cells show positivity for IPSID hybridization (FISH) using break-apart
BCL6, but uniformly fail to express BCL2. No cytogenetic abnormalities have been probes for MYC detects most transloca-
consistently described in IPSID. Southern- tions. In cases lacking MYC rearrange-
B-cell lymphoma, unclassifiable, with blot analysis reveals clonal immuno- ments, aberrations in MYC-regulating
features intermediate between DLBCL globulin heavy-chain (IGH@) gene miRNAs have been found {1808A}.
and Burkitt lymphoma rearrangements.
Most tumours in this group have morpho- B-cell lymphoma, unclassifiable, with
logical features that are intermediate Mantle cell lymphoma features intermediate between DLBCL
between Burkitt lymphoma and DLBCL. Mantle cell lymphoma is cytogenetically and Burkitt lymphoma
Some of these cases were previously characterized by a t(11;14)(q13;q32) This category is cytogenetically hetero-
classified as Burkitt-like lymphoma. Other translocation that deregulates expression geneous and may contain three or more
cases may be morphologically more of the cyclin D1 (CCND1) oncogene on biological groups {2342}. Cases may be
typical of Burkitt lymphoma, but have an chromosome 11. double- or triple-hit lymphomas having
atypical immunophenotype or genetic translocations involving MYC, BCL2,
features that preclude a diagnosis of Follicular lymphoma and/or less frequently BCL6, and often
Burkitt lymphoma. Unlike Burkitt lymphoma, Follicular lymphoma is cytogenetically show a complex karyotype with multiple
these lymphomas do not have a predilec- characterized by the t(14;18)(q34;q21) abnormalities, in contrast to classical Burkitt
tion for the gastrointestinal tract of adults. translocation and BCL2 gene rearrange- lymphoma {3260}.
They also occur in the setting of HIV ment. Primary intestinal follicular lymphoma
infection. also features a high load of (ongoing) Prognosis and predictive factors
somatic mutations and a biased use of The main determinant of clinical outcome
Other B-cell lymphomas VH genes, in particular VH4, suggesting for small-intestinal lymphomas is histological
Although rare, any type of B-cell lym- a similar etiology to that of MALT lym- type {733}. Advanced age at diagnosis, an
phoma other than those described can phoma {2824, 3162}. acute presentation with perforation, and
present as a primary small-intestinal lym- the presence of multifocal tumours have an
phoma. Burkitt lymphoma adverse impact on survival. The prognostic
Indolent lymphomas such as small In most cases, Burkitt lymphoma demon- impact of concomitant MALT lymphoma for
lymphocytic lymphoma and lymphoplas- strates a consistent cytogenetic abnor- the behaviour of DLBCL is controversial
macytic lymphoma can present as mality that causes rearrangement of the {733, 2220}.
primary small-intestinal disease. MYC oncogene. The characteristic trans- Mantle cell lymphoma is an aggressive
Lymphoblastic lymphoma in rare cases location is t(8;14)(q24;q32), in which MYC neoplasm. A blastoid cytology, increased
may present as a mass in the ileocaecal is translocated from chromosome 8 to the mitotic index and peripheral-blood
region. Characteristic nuclear features IGH@ locus on chromosome 14. involvement are recognized as adverse
and the expression of terminal nucleotidyl The remaining cases show variant translo- factors {144}. Mutations in TP53 and
transferase may aid in establishing the cations including the immunoglobulin homozygous deletions of CDKN2A have
diagnosis. light-chain loci, t(2;8)(p12;q24) or t(8;22)- recently been shown to be associated
(q24;q11), involving κ and λ light-chain with poor prognosis {1177, 1899}. Patients
Molecular pathology genes, respectively. Thus part of the light- with intermediate lymphoma between
DLBCL chain constant region is translocated to DLBCL and Burkitt lymphoma, which
In primary intestinal DLBCL, transloca- chromosome 8, distal to the MYC gene. show dual translocations of both BCL2
tions involving IGH@, BCL6, BCL2, and MYC is deregulated by virtue of its juxta- and MYC, have markedly shortened over-
MYC are detected in 27%, 23–35%, 0–21%, position to the immunoglobulin light-chain all survival {1942, 3260}.
and 7% of cases, respectively {3649}. genes.
BIRC3-MALT1 translocation has been The molecular characteristics of the MYC
reported only a single case {3649}. translocation also differ between endemic
and sporadic cases. In endemic Burkitt
lymphoma, the (variable) chromosome 8
B-cell lymphoma 111

T-cell lymphoma H.K. Müller-Hermelink

J. Delabie
of the small intestine Y.H. Ko
E.S. Jaffe
S. Nakamura
Definition lymphoma, peripheral T-cell lymphoma

An intestinal lymphoma, most often unspecified – this term can be used only
derived from intraepithelial T lymphocytes, descriptively in the setting of incomplete
occurring as one of two subtypes: information and does not imply a disease
enteropathy-associated T-cell lymphoma entity.
(EATL) (about 80–90% of cases) and
monomorphic CD56+ (NCAM1) intestinal
T-cell lymphoma (about 10–20% of Enteropathy-associated intestinal
cases). Adjacent small intestinal mucosa T-cell lymphoma (EATL)
may show villous atrophy with crypt
hyperplasia, as well as increase of intra- Definition
Fig. 6.22 Intestinal T-cell lymphoma. Surgical specimen
epithelial lymphocytes and/or lymphoma EATL is an intestinal tumour of intra- showing intestinal perforation and severe acute peritonitis.
cells {540, 542}. epithelial T-lymphocytes composed of
large, often polymorphic lymphoid cells,
ICD-O codes which are negative for CD56. It is also 1020-fold in patients with protracted clinical
T-cell lymphoma 9702/3 referred to as Type I EATL coeliac disease {2536, 2854}. In a popula-
Enteropathy-associated T-cell tion-based registry of the Netherlands, the
lymphoma (EATL) 9717/3 Epidemiology annual incidence of EATL of the small in-
The disease is uncommon in most parts testine is estimated at 0.1 per 100 000
Synonyms of the world, but is seen with increasing overall and 2.08 per 100 000 in persons
Intestinal T-cell lymphoma (with and with- frequency in areas with a high prevalence aged > 50 years, with a male-to-female
out enteropathy). Since different T-cell of coeliac disease, e.g. Northern Europe. ratio of almost 3 : 1 in this age group. The
lymphoma subtypes can present with Conversely, EATL is extremely rare in the mean age at presentation is 64 years {3392}.
intestinal disease – extranodal natural oriental population where coeliac disease
killer/T-cell (NK/T-cell) lymphoma, γ-δ is also rare. The relative risk of EATL in the Etiology
T-cell lymphoma, anaplastic large cell small intestine is increased approximately This neoplasm is usually manifest in
patients with human leukocyte antigen
(HLA) haplotypes predisposing to coeliac
disease. Histopathological findings sug-
gest an association with coeliac disease
that is confirmed by positive serological
tests with anti-gliadin and anti-transgluta-
minase antibodies, HLA-DQ2 or HLA-DQ8
expression and associated clinical find-
ings such as dermatitis herpetiformis and
hyposplenism {720, 2785, 3368}. Over-
expression of interleukin 15 by enterocytes
in coeliac disease may play a role in the
A B
continuous stimulation of intraepithelial
lymphocytes {2047}.
Localization
The lymphoma occurs most commonly in
the jejunum or proximal ileum. Presentation
in the duodenum, stomach and colon or
outside the gastrointestinal tract may
occur but is rare {540}.
C D Clinical features
Fig. 6.23 Uninvolved mucosa adjacent to enteropathy-associated T-cell lymphoma (type I EATL). The intraepithelial A small proportion of patients with EATL
lymphocytes (A) may show an abnormal immunophenotype, with increased numbers being: B Positive for CD3; have a history of childhood-onset coeliac
C Negative for CD8; and D Negative for CD56 (NCAM). disease. Most show adult-onset disease

or are diagnosed as having coeliac

disease in the same clinical episode in
which the lymphoma is diagnosed.
Undetected coeliac disease has a higher
prevalence in the elderly population than
in the population in general (2.45% vs < 1%)
{3406}. Patients present with abdominal
pain, most often as emergencies associ-
ated with intestinal perforation and/or ob-
struction. In a proportion of patients there A B
is a prodromal period of refractory coeliac
disease that is sometimes accompanied
by intestinal ulceration (ulcerative jejunitis).
Macroscopy
In the affected bowel segment, the
tumour usually presents with a multifocal
involvement with multiple ulcerating
raised mucosal masses, but may present
as one or more ulcers with or without per-
foration or as a large exophytic mass. The C D
intact mucosa between the lesions may Fig. 6.24 Intestinal T-cell lymphoma (type I EATL). Cytomorphological polymorphism: A Immunoblastic morphology;
contain thickened folds or appear normal. B Pleomorphic morphology; and C Anaplastic morphology. D Intestinal T-cell lymphoma (type II EATL), monomorphic.
Histopathology Immunohistochemistry same monoclonal TCR gene rearrange-

The tumour forms an ulcerating mucosal In EATL, the tumour cells are CD3+, CD5–, ment and also gains of chromosome 1q
mass that invades the wall of the intestine. CD7+, CD8–/+, CD4–, CD103+, TCRß+/– as the subsequent T-cell lymphomas
There is a wide range of cytological pat- and contain cytotoxic granule-associated {154, 460, 461, 656, 3396}. Thus, RCD II
terns {1344, 3554}. Most commonly, the proteins (TIA1; granzyme B; perforin). In in which the intraepithelial lymphocytes
tumour cells are medium- to large-sized almost all cases, a varying proportion of show these immunophenotypical and
transformed lymphoid cells with roundish the tumour cells express CD30 {3040, genetic features can be considered as
or angulated vesicular nuclei, prominent 3554}. CD30+ cells are usually CD3–, examples of intraepithelial T-cell lymphoma
nucleoli and moderate to abundant, pale- CD4–,CD8– and predominate in the or, alternatively, EATL in situ. These atypi-
staining cytoplasm. Less commonly, the anaplastic variants of EATL. The intra- cal lymphoid cells are also not strictly con-
tumour exhibits marked pleomorphism epithelial lymphocytes in the adjacent fined to the intraepithelial component and
with multinucleated cells bearing a enteropathic mucosa may show an may even spread to distant locations, e.g.
resemblance to anaplastic large cell lym- abnormal immunophenotype, usually the skin {3393}. In retrospective analyses,
phoma. Most tumours show infiltration by CD3+, CD5–, CD8–, CD4– identical to that about 40% of RCD II develop overt EATL
inflammatory cells, including large num- of the lymphoma. EATL is usually CD56–. in a 5-year follow-up period {657, 1965}.
bers of histiocytes and eosinophils, and RCD I. In RCD I patients {1690}, intra-
in some cases these may be so abundant Precursor lesions epithelial lymphocytes express a normal
that they obscure the relatively small num- EATL may be preceded by refractory immunophenotype and are polyclonal.
ber of tumour cells present. Infiltration of coeliac disease with or without ulceration. These cases only rarely progress to EATL.
the epithelium of individual crypts is pres- This disease is divided into two variants, However, RCD I can also rarely progress
ent in many cases. Infiltration of the sur- RCD I and RCD II, according to the absence to RCD II {657}. Whether this is a neces-
face epithelium usually accompanies the or presence of intraepithelial lymphocytes sary intermediate in the multistep
destruction of enterocytes and ulceration. with an aberrant phenotype.
However, adjacent to the tumours, espe- RCD II. In RCD II, intraepithelial lympho-
cially to those in the jejunum, the intestinal cytes phenotypically show downregulation
mucosa usually shows enteropathy com- of CD8, as in mucosa adjacent to EATL
prising villous atrophy, crypt hyperplasia, {175, 461}. The intraepithelial lymphocytes
increased lamina propria lymphocytes also frequently show monoclonal T-cell
and plasma cells and intraepithelial rearrangement similar to the clonal re-
lymphocytosis. Intraepithelial lymphocytes arrangements that may be found in the
may be mixed with transformed lymphoid enteropathic mucosa adjacent to EATL
cells resembling the invasive part of the {1263}, suggesting that the immunopheno-
tumour. The degree of enteropathy is typically aberrant intraepithelial lymphocytes
highly variable and may consist only of an constitute a neoplastic population. In cases Fig. 6.25 Intestinal T-cell lymphoma. Low-power survey
increase in intraepithelial lymphocytes of RCD that subsequently develop into EATL, showing deep fissural ulceration and invasion of adjacent
without overt villous atrophy. the intraepithelial lymphocytes have the mucosa and deep intestinal wall layers.
T-cell lymphoma 113

proportion of cases of this lymphoma arises

outside the setting of coeliac disease, con-
firming the original clinical observation of a
lack of any anamnestic link {540}.
Localization
No significant differences from Type I EATL
have been reported, but monomorphic
CD56+ intestinal T-cell lymphoma more often
A B involves the deeper segments of the small
intestine, the ileocaecal region and even the
colon.
Histopathology
The neoplastic cells are small, round and
monomorphic with darkly staining nuclei
and a narrow rim of cytoplasm. There is
usually florid infiltration of intestinal crypt
epithelium and transmural spread. The
adjacent intestinal mucosa may show
C D villous atrophy and crypt hyperplasia with
Fig. 6.26 Cytomorphology and immunohistochemistry of type II EATL (monomorphic CD56+) primary intestinal T-cell striking intraepithelial lymphocytosis in-
lymphoma. A Monomorphic blastoid cytology. Note intraepithelial invasion of the mucosal surface. The tumours cells volving both crypt and surface epithelium.
are positive for CD3 (B), positive for CD8 (C) and positive for CD56 (D).
Immunohistochemistry
In monomorphic CD56+ intestinal T-cell
transformation process is presently not Monomorphic CD56+ intestinal lymphoma, the tumour cells are CD3+,
known. T-cell lymphoma CD4–, CD8+, NCAM1/CD56+ and TCRαß+
{540} and the intraepithelial lymphocytes
Molecular pathology Definition in the adjacent mucosa are immunophe-
TCRβ and TCRγ genes are clonally An intestinal tumour of intraepithelial notypically identical {175}. EBV-related
rearranged {1345, 2193}. Patients with T-lymphocytes composed of small- to antigen detection and EBV-encoded RNA
EATL frequently show a HLA-DQ8 and medium-sized monomorphic cytotoxic (EBER) in situ hybridization are negative,
HLA-DQ2, or HLA-DQB1 tumour genotype T-lymphocytes commonly expressing in contrast to nasal-type NK/T-cell lym-
pattern, which is associated with coeliac CD56. This lymphoma also has been phoma involving the small intestine.
disease {1263}. EATL frequently displays referred to as Type II EATL.
chromosomal gains in 1q32.2–q41 and Precursor lesions
5q34–q35.2 that may be found also in the Epidemiology No precursor lesions have yet been char-
intraepithelial lymphocytes of refractory This group comprises 10–20% of gastro- acterized.
coeliac disease {690, 3697, 3698}. In intestinal T-cell lymphomas {540, 690}.
contrast to primary nodal peripheral T-cell This type of lymphoma is also seen in Molecular pathology
lymphoma (PTCL), most EATL (58–70%) populations that are not exposed to nutri- TCRβ and TCRγ genes are clonally
harbour segmental gains of chromosome tional gluten and that have a very low rearranged {1345, 2193}. Like EATL, most
9q31.3–qter or deletions of 16q12.1 (23%). prevalence of coeliac disease, e.g. monomorphic CD56+ intestinal T-cell lym-
These features are prevalent in both sub- Taiwan (China) {3319} or Japan {57}. phomas (58–70%) harbour segmental
types of primary intestinal T-cell lymphoma gains of chromosome 9q31.3–qter or
(EATL and monomorphic CD56+ intestinal Etiology show deletions of 16q12.1. In contrast to
T-cell lymphoma) and form a common The etiology of this disease is unknown. Al- EATL, this lymphoma is more often char-
genetic link between the two types. though the mucosa adjacent to the invasive acterized by 8q24 (MYC) gains and lacks
tumour may show enteropathy-like changes, the segmental gains at 1q and 5q found
Prognosis and predictive factors the phenotype of intraepithelial lympho- in EATL and RCD II {690, 3697, 3698}.
Prognosis is usually poor, with death fre- cytes may be distinctly different from that for
quently resulting from abdominal compli- refractory coeliac disease {556}. There is Prognosis and predictive factors
cations in patients already weakened by also no clear genetic link with coeliac The clinical course of this disease is similar
uncontrolled malabsorption. Long-term disease; only 30–40% of Caucasian to that for Type I EATL; the prognosis for
survivals are recorded. Recurrences are patients have coeliac disease-associated overt lymphoma is very bad owing to intes-
most frequent in the small intestine. HLA-DQ2/HLA-DQ8, corresponding to the tinal complications (perforation, peritonitis)
normal prevalence of these HLA haplotypes or early spread with lung involvement.
in the Caucasian population {690}. Thus, in
contrast to Type I EATL, at least a substantial


C.D.M. Fletcher
of the small intestine L.-G. Kindblom
W.M.S. Tsui
ICD-O codes Macroscopy Positive immunolabelling for CD34 is less

Leiomyoma 8890/0 Occurring anywhere in the duodenum or common (50%) than in gastric GISTs.
Lipoma 8850/0 small intestine, GISTs vary from minimal
Angiosarcoma 9120/3 mural nodules to large complex masses, Genetic susceptibility
Gastrointestinal stromal tumour 8936/3 usually with predominant external exten- Multiple, often indolent, independent pri-
Kaposi sarcoma 9140/3 sion, which may be pedunculated. Some mary tumours occur in patients with neuro-
Leiomyosarcoma 8890/3 form dumb-bell shaped masses, typically fibromatosis type 1 (NF1). Patients with
with minor intraluminal and major extra- familial GIST syndrome can develop multi-
Gastrointestinal stromal tumour (GIST) luminal components. Large tumours are ple or diffuse GISTs {323, 1011, 2068, 3324}.
This category includes most smooth-mus- often cystic and haemorrhagic. Advanced
cle tumours of the small intestine defined tumours involve multiple loops of bowel Molecular pathology
before current concepts of GIST. Small- and develop diffuse or multifocal peri- KIT-activating mutations are typical of small-
intestinal and duodenal GISTs comprise toneal spread, often obscuring the intestinal GISTs. Substitutions and dele-
about 30% and 5%, respectively, of all primary site of origin. tions in KIT exon 11 mirror those reported
GISTs. in gastric GISTs, while insertions are rare.
Histopathology Duplication of AY502–503 in KIT exon 9 is
Clinical features Duodenal and small-intestinal GISTs are virtually specific for small-intestinal (vs
Duodenal and small-intestinal GISTs usually spindle cell tumours with diffuse gastric) GISTs, and occurs in up to 10% of
occur almost exclusively in adults, usually sheets or vague storiform arrangements of cases. Although not confirmed in one
aged > 50 years. Clinical presentation tumour cells. Tumours with low biological large study cohort, patients with these
resembles that of gastric GISTs, but acute potential often contain extracellular collagen mutations respond less well to imatinib,
complications more commonly include globules (“skeinoid fibres”). Anuclear areas prompting dose escalation or use of
intestinal obstruction and tumour rupture. are formed that resemble neuropil material alternative kinase inhibitors. Monosomy of
Smaller GISTs are detected incidentally in neuroblastoma. Nuclear palisading may chromosomes 14 and 22 also occurs
during endoscopy, surgery, or computed occur, but perinuclear vacuolization is rare. {597, 1750}. PDGFRA mutations occur only
tomography (CT). The frequency of clinical Regressive vascular changes (e.g. dilated in duodenal GISTs.
malignancy of small-intestinal GISTs is and thrombosed vessels, haemosiderin
approximately 35–40%, twice that of deposition, and fibrosis) are common. Nu- Prognostic factors, grade and stage
gastric GISTs; moreover, most intra- clear pleomorphism is rare, and mitotic rate The most useful and best studied prog-
abdominally disseminated GISTs appear is often low. Epithelioid morphology may be nostic factors are tumour size and mitotic
to originate in the small intestine. The associated with higher mitotic activity, activity, typically expressed as number of
metastatic pattern resembles that of reflecting malignancy. mitotic figures per 50 high power fields,
gastric GISTs. Although most localized Small-intestinal GISTS generally resemble (total area, 5 mm2). There is no formal
intestinal GISTs can be managed by gastric GISTs, except that immuno- grading system for GISTs; grading for
segmental resection, pancreaticoduo- labelling for KIT is almost uniformly posi- soft-tissue sarcoma is not applicable
denectomy may be necessary for duode- tive. DOG1-positivity is nearly consistent. because relatively low levels of mitotic
nal tumours abutting or involving the Immunolabelling for α-smooth muscle activity may confer high malignant poten-
pancreatic head. actin (SMA) and S100 is positive in 50% tial. Staging is based on size and mitotic
and 10–15% of cases, respectively. activity.
A B C
Fig. 6.27 Small-intestinal GISTs often form dumb-bell shaped masses with internal and external components (A, B). In larger GISTs, the external component usually predominates (C).

that for GIST. Often arising in young adults,

this sarcoma forms a mural mass of 2–5 cm
or larger that may be ulcerated. Metas-
tases to mesenteric lymph nodes and
liver are common and often detected at
presentation. Histologically, there are sheets
of rounded to mildly spindled cells, and
packeting to pseudoorganoid clusters is
not prominent (unlike peripheral clear cell
A A sarcoma). The presence of multinucleated
osteoclast-like histiocytic giant cells is a
common although not universal feature
{3675}. Immunohistochemically, the tumour
cells are positive for S100, but usually
negative for HMB45 (gp100), and Melan
A (MART1), in contrast to peripheral clear
cell sarcomas. Unlike GISTs, this tumour
is negative for KIT. The typical tumour
translocation is a EWSR1-CREB1 fusion
corresponding to t(2;22)(q32;q12) (unlike
B B peripheral clear cell sarcoma) {130}.
Fig. 6.28 Small-intestinal GIST. A Note the distinctive Fig. 6.29 Intramural leiomyoma. A The neoplasm forms
extracellular collagen globules (“skeinoid fibres”). B More a well-demarcated transmural mass. B It is composed Inflammatory fibroid polyp (IFP)
cellular examples contain uniform spindle cells and often of well-differentiated smooth-muscle cells with abundant This lesion occurs throughout the gastro-
anuclear areas of cell processes, resembling neuropil. eosinophilic cytoplasm and collagenous matrix. intestinal tract in adults of all ages, but in
the small intestine (most frequently in the
Smooth-muscle tumours may be multifocal and/or metastases, e.g. terminal ileum) more commonly forms a
Intramural leiomyomas similar to those from soft tissues of the head and neck. symptomatic mass causing obstruction by
seen in the stomach are very rare (about Histologically, the irregular anastomosing intussusception. The polyps usually meas-
1 per 100 GISTs). Muscularis mucosae vascular channels are lined by atypical ure 1–5 cm and are often pedunculated
leiomyoma, like that found more commonly spindled to epithelioid endothelial cells and project intraluminally, appearing grey-
in the colon and rectum, has also been with variable mitotic activity. Although white and glistening on sectioning. Mucosal
reported. Leiomyosarcomas are also rare. most are high-grade, isolated examples ulceration is possible. The histologically
Prognosis is better when grade and mitotic are well-differentiated and low-grade. typical appearance is oedematous with
rate are low {2078}. Immunolabelling is positive in nearly all spindled to epithelioid tumour cells
cases for CD31 (membrane pattern), but admixed with eosinophilic granulocytes
Angiosarcoma more variable for CD34 and FVIII-related and histiocytes and a prominent capillary
In rare instances, angiosarcoma can antigen. Keratins can be present, espe- network. In a minority of cases, the tumour
involve the small intestine or other parts of cially in epithelioid variants {95, 3207}. cells are (focally) positive for CD34 and
the gastrointestinal tract, particularly in SMA. They are negative for KIT and DOG1,
older adults with uterine or urinary bladder Gastrointestinal clear cell sarcoma but positive for PDGFRA. PDGFRA-activat-
cancer previously treated by irradiation. Most cases of this rare, recently recog- ing mutations (especially in exon 12) re-
Grossly, angiosarcoma forms a haemor- nized tumour occur in the intestine, sembling those seen in GISTs are present
rhagic, transmural, often ulcerated mass that although it is also reported in the stomach in > 50% of cases {1751, 2944}. Similar
often extends into mesentery. The lesions and colon. Clinical presentation resembles mutations also occur in gastric IFPs {2838}.

Desmoid can form an apparently intes-
tinal mass, despite originating in the
mesentery, and can arise in patients with
Gardner syndrome. Schwannomas of the
small intestine are very rare and resemble
those of the stomach. Calcifying fibrous
(pseudo)tumour can form a small intes-
tinal mass, but more often shows external
serosal involvement only. Inflammatory
myofibroblastic tumours may involve the
Fig. 6.30 Small-intestinal angiosarcoma contains Fig. 6.31 Inflammatory fibroid polyp: the loosely textured small intestine. Undifferentiated sarcomas
irregularly shaped vascular lumina lined by highly tissue contains oval to epithelioid tumour cells, eosinophilic are very rare; some may be related to
atypical endothelial cells with mitotic activity. granulocytes, small capillaries, and fibromyxoid matrix. dedifferentiated liposarcoma.

Secondary tumours C. Iacobuzio-Donahue

G.M. Groisman
of the small intestine
Definition no history of a primary tumour, the gen-

Tumours of the small intestine that origi- eral consensus is that they are virtually all
nate from an extra-intestinal neoplasm or metastases from a misdiagnosed or re-
that are discontinuous with a primary gressed primary melanoma {786, 1802}.
tumour elsewhere in the gastrointestinal
tract. Clinical features
Small intestinal metastases can cause
Epidemiology obstruction, perforation, intussusception,
In autopsy studies, secondary tumours of malabsorption and/or gastrointestinal
the small intestine are 2.5 times more bleeding {563, 949, 1239, 1306, 2725,
common than primary small-bowel carci- 3413}. Obstruction is more commonly
Fig. 6.32 High-grade retroperitoneal sarcoma metastatic
noma {725}. Metastatic spread to the seen in association with metastatic lobular
to the small intestine, gross micrograph. The metastasis
small intestine from either an intra- or forms an intraluminal mass with a smooth contoured breast carcinoma {1306}. Nonspecific
extra-abdominal primary site is more surface. symptoms associated with metastasis to
frequent than to any other site in the the small intestine include abdominal
tubular gastrointestinal tract {988, 1306}. discomfort, gas distension, and diarrhoea
small intestine, although testis, lung, {987}.
Origin breast and ovarian cancers also fre-
The routes by which secondary neoplasms quently involve the small intestine by Macroscopy
reach the small bowel include direct metastatic spread {725, 1306}. Melanoma, Typical features of intestinal metastases
extension (i.e. colonic, pancreatic and lung, breast and ovarian cancers also include intestinal-wall thickening, sub-
gastric cancers), intraperitoneal spread more frequently metastasize to the small mucosal spread, and ulcers {1306}.
(i.e. ovarian cancer) and lymphohaemato- intestine than to the stomach or colorec- Melanomas and sarcomas may appear
genous embolization (i.e. melanoma, lung tum {3461}. Primary melanomas of the as nodules or polyps {2444}.
and breast cancer). Melanoma is the most intestine are very rare. Although most
common malignancy to metastasize to the melanomas found in the small bowel have
Fig. 6.33 Metastatic high-grade serous ovarian carcinoma Fig. 6.34 Frequency of metastasis to the small intestine by site of the primary neoplasm. Data shown are based on
within the serosa of the small intestine secondary to findings of 3827 autopsies {735}. * Appendix, bile duct, bone, branchial cyst, duodenum, larynx, lip, penis, pleura,
intraperitoneal spread. The muscularis propria is present salivary gland, skin lower face, tonsil, vagina, vulva.
at the top of the image.

Histopathology
Metastases are typically located deep
within the submucosa or the muscularis
propria of the small bowel, with little
involvement of the mucosa. The lack of an
in situ component within the mucosa may
also serve as also a clue that the neo-
plasm is a metastasis, although metastatic
carcinoma may grow on the lumenal
surface and mimic an in situ neoplasm. A B
Obtaining appropriate clinical information
Fig. 6.35 Metastatic malignant melanoma in the small intestine. A Gross specimen. B Microscopic view.
about possible primary sites should be
the first step in the evaluation of a metas-
tasis. When a possible primary tumour
site has been identified, histological,
immunohistochemical and molecular
comparision of the metastasis with the
primary tumour may help to confirm the
origin of the metastasis. In difficult cases,
immunohistochemistry may help to differ-
entiate between primary small-bowel
cancer (positive for keratin 20 and CDX2),
metastatic melanoma (positive for
A B
Melan A and S100 protein), metastases Fig. 6.36 Metastatic adenocarcinoma in the small intestine. A The tumour lies beneath swollen mucosa.
B The tumour is situated in the muscularis propria. Submucosa is oedematous.
from ovary and breast (typically positive
for keratin 7 and estrogen/progesterone
receptors), lung (typically positive for
keratin 7 and thyroid transcription factor
1/TTF1) and those from liver, kidney and
prostate (typically negative for keratins 7
and 20 and positive for hepatocyte-paraf-
fin-1 antibody/HepPar1, PAX8 and prostate-
specific antigen [PSA], respectively) {551,
2380, 3267}. In contrast, the distinction
between multiple primary small-bowel
carcinoids and their metastases may not
be possible. This also applies to leiomyo-
sarcomas and other mesenchymal
neoplasms of the small intestine.

Intestinal metastases usually represent a
late stage of disease at which other
haematogenous metastases are also
frequently found. However, the prognosis
for patients with small-bowel metastasis
varies widely, partly according to the pri-
mary tumour type and patient-specific
factors {1306}. Metastatic melanoma or
renal carcinomas with isolated metastasis Fig. 6.37 Metastatic adenocarcinoma, small intestine. Fig. 6.38 Metastatic breast carcinoma in the colon.
to the small intestine may be associated The muscularis propria contains the tumour. The mucosa The tumour cells expand the submucosa.
with prolonged survival after resection {62}. is free of neoplasia

CHAPTER 7
Tumours of the appendix
Adenocarcinoma
Miscellaneous tumours
WHO classificationa of tumours of the appendix

Tubular 8211/0 Mixed adenoneuroendocrine carcinoma 8244/3
Villous 8261/0 EC cell, serotonin-producing NET 8241/3
Tubulovillous 8263/0 Goblet cell carcinoid 8243/3
L cell, Glucagon-like peptide-producing
Dysplasia (intraepithelial neoplasia), low grade 8148/0*
and PP/PYY-producing NETs 8152/1*
Dysplasia (intraepithelial neoplasia), high grade 8148/2
Tubular carcinoid 8245/1
Serrated lesions
Mesenchymal tumours
Hyperplastic polyp
Sessile serrated adenoma/polyp 8213/0* Leiomyoma 8890/0
Traditional serrated adenoma 8213/0 Lipoma 8850/0
Neuroma 9570/0
Carcinoma Kaposi sarcoma 9140/3
Adenocarcinoma 8140/3 Leiomyosarcoma 8890/3
Mucinous adenocarcinoma 8480/3
Low-grade appendiceal mucinous neoplasm 8480/1* Lymphomas
Undifferentiated carcinoma 8020/3 Secondary tumours
NET G2 8249/3
___________________________________________________________
EC, enterochromaffin ;
a
The morphology codes are from the International Classification of Diseases for Oncology (ICD-O) {904A} and the Systematized Nomenclature of Medicine
(SNOMED). Behaviour is coded /0 for benign tumours, /1 for unspecified, borderline or uncertain behaviour, /2 for carcinoma in situ and grade III intraepithelial
neoplasia, and /3 for malignant tumours.
b
The classification is modified from the previous (third) edition of the WHO histological classification of tumours {691} taking into account changes in our unde
standing of these lesions. In the case of neuroendocrine neoplasms, the classification has been simplified to be of more practical utility in morphological
classification.
120 Tumours of the appendix

TNM classificationa of tumours of the appendix

Carcinoma of the appendix
T – Primary tumour G – Histopathological grading
TX Primary tumour cannot be assessed GX Grade of differentiation cannot be assessed
T0 No evidence of primary tumour G1 Well differentiated Mucinous low grade
Tis Carcinoma in situ: intraepithelial or invasion of lamina propria G2 Moderately differentiated Mucinous high grade
T1 Tumour invades submucosa G3 Poorly differentiated Mucinous high grade
T2 Tumour invades muscularis propria G4 Undifferentiated
T3 Tumour invades subserosa or mesoappendix
T4 Tumour perforates visceral peritoneum, including mucinous
peritoneal tumour within the right lower quadrant and/or Stage grouping
directly invades other organs or structures
T4a Tumour perforates visceral peritoneum, including mucinous Stage T N M G
peritoneal tumour within the right lower quadrant
Stage 0 Tis N0 M0
T4b Tumour directly invades other organs or structures
Stage I T1, T2 N0 M0
Stage IIA T3 N0 M0
Stage IIB T4a N0 M0
Stage IIC T4b N0 M0
N0 No regional lymph node metastasis
Stage IIIA T1, T2 N1 M0
N1 Metastasis in 1 to 3 regional lymph nodes
Stage IIIB T3, T4 N1 M0
N2 Metastasis in 4 or more regional lymph nodes
Stage IIIC Any T N2 M0
Stage IVA Any T N0 M1a G1
Stage IVB Any T N0 M1a G2–G4
Any T N1, N2 M1a Any G
Stage IVC Any T Any N M1b Any G
M1a Intraperitoneal metastasis beyond the right lower
quadrant, including pseudomyxoma peritonei
M1b Nonperitoneal metastasis
Carcinoid of the appendixb
T – Primary tumour M – Distant metastasis

T1 Tumour 2 cm or less in greatest dimension
T1a Tumour 1 cm or less in greatest dimension
T1b Tumour more than 1 cm but not more than 2 cm Stage grouping
T2 Tumour more than 2 cm but not more than 4 cm or with
extension to the caecum Stage T N M
T3 Tumour more than 4 cm or with extension to the ileum Stage I T1 N0 M0
T4 Tumour perforates peritoneum or invades other adjacent Stage II T2, T3 N0 M0
organs or structures, e.g. abdominal wall and skeletal muscle Stage III T4 N0 M0
Any T N1 M0
N – Regional lymph nodes Stage IV Any T Any N M1
_____________
a
{762, 2996}
b
Neuroendocrine tumour (NET); well-differentiated neuroendocrine tumour/carcinoma. Goblet cell carcinoid is classified according to the scheme for carcinoma.
Classification 121
Adenocarcinoma of the appendix N.J. Carr

L.H. Sobin
Definition present within a hernia sac {440, 806,

A malignant epithelial neoplasm of the 2092, 3658}.
appendix with invasion beyond the mus-
cularis mucosae. Imaging
Adenomas and adenocarcinomas of the
ICD-O codes appendix can be demonstrated reliably
Adenocarcinoma 8140/3 by computed tomography (CT). They
Mucinous adenocarcinoma 8480/3 typically show cystic dilatation or a soft-
Low-grade appendiceal tissue mass. An appendix with a diameter
mucinous neoplasm 8480/1 of > 15 mm on CT is suspicious for the
Signet ring cell carcinoma 8490/3 presence of a neoplasm {2547}. Pseudo-
Undifferentiated carcinoma 8020/3 Fig. 7.01 Pseudomyxoma peritonei. Several loops of
myxoma peritonei is characterized by
bowel are encased in a multilocular mucinous mass.
low-attenuation mucinous ascites on CT,
Epidemiology although areas of high attenuation bowel, while large-volume disease is
Adenocarcinoma of the appendix occurs develop in large-volume disease {3127}. found in the greater omentum, beneath
in 0.1–0.2% of appendicectomies, corre- Scalloping of the outline of the liver and the right hemidiaphragm, in the right
sponding to an estimated incidence of 0.2 other viscera is characteristic. retrohepatic space, at the ligament of
per 100 000 per year {2282, 2985, 3237}. Treitz, in the left abdominal gutter and in
The median age at presentation is in the Macroscopy the pelvis {3117}.
sixth or seventh decade of life {440, 2092, In cases of primary adenocarcinoma, the In patients with both ovarian mucinous
3237}. Adenocarcinomas accounted for appendix may be enlarged, deformed or neoplasm and appendiceal mucinous
58% of malignant appendiceal tumours in completely destroyed {440, 441, 2092, adenocarcinoma, the appendix is almost
the United States Surveillance, Epidemio- 2722}. A cystic swelling of the appendix invariably the primary tumour and the
logy and End-Results (SEER) database, due to the accumulation of mucus within ovarian tumour is secondary, on the basis
the remainder being mostly carcinoids. the lumen can be termed mucocoele, but of molecular analysis {3149, 3632}.
The incidence rates for the carcinomas this is a purely descriptive term, not a Carcinoma of the appendix was included
stayed constant during 1973–1987 {3237}. pathological diagnosis {440, 441, 2435}. with colorectal carcinoma in the sixth
Males were more commonly affected than Rarely, the mucin forms small spheres, a edition of the TNM classification, but is
females, but a population study in the condition named myxoglobulosis {2814}. staged separately in the seventh edition.
Netherlands showed a predominance in The basic T, N, and M categories are
females {2985, 3237}. Tumour spread and staging essentially similar to those of the colon.
Low-grade appendiceal mucinous neo- The separation of mucinous from non-
Etiology plasms (LAMN) generally grow slowly, mucinous carcinomas is required, and T4
The causes of appendiceal adenocarci- and tend to produce the clinical picture of and M1 are modified to address the
noma are unclear. However, there is an low-grade pseudomyxoma peritonei in particular nature of mucinous carcinomas.
association with neoplasia elsewhere in which spread beyond the peritoneum or Grading was introduced to distinguish
the large intestine {1530, 2985}. Chronic nodal metastasis is unusual. High-grade between low-grade and high-grade
ulcerative colitis (UC) may also be a risk mucinous adenocarcinomas can also mucinous adenocarcinomas because of
factor; adenoma and adenocarcinoma of produce pseudomyxoma peritonei, but differences in behaviour and management.
the appendix have been described in pa- are more likely to invade the underlying The stage grouping is dependent on
tients affected by long-standing UC {2355}. organs and exhibit haematogenous and these grades. A distinction is made
lymphatic metastasis. On very rare occa- between mucinous peritoneal tumours
Clinical features sions, tumour growth in the retroperi- within the right lower quadrant (T4a) and
Many patients with appendiceal adeno- toneum may produce “pseudomyxoma intraperitoneal metastasis beyond the
carcinoma have clinical features that are retroperitonei” {393}. The behaviour of right lower quadrant, including pseudo-
indistinguishable from those of acute nonmucinous carcinomas resembles that myxoma peritonei (M1a) because of the
appendicitis. Others present with an of their colonic equivalents. favourable nature of the former compared
abdominal or pelvic mass. If spread to the A distinctive feature of pseudomyxoma with the latter {440}. The carcinoma stag-
peritoneal cavity, appendiceal adenocar- peritonei, especially when produced by ing scheme also applies to goblet cell
cinoma often produces pseudomyxoma low-grade neoplasms, is its distribution in carcinoids, but not to typical carcinoids.
peritonei, and the large volumes of mucus the abdomen. There is a tendency to
can cause abdominal distension or spare the peritoneal surfaces of the

Pseudomyxoma peritonei (mucinous

carcinoma peritonei). The term “pseudo-
myxoma peritonei” applies to the clinical
picture in which the growth of neoplastic
mucin-secreting cells within the peritoneal
cavity produces a slow but relentless
accumulation of mucin causing gelatinous
ascites. In LAMNs, cells may be very
scanty within this mucinous material. The
appendix is the primary site in the great A B
majority of cases. However, pseudomyx-
Fig. 7.02 Low-grade pseudomyxoma peritonei (low-grade mucinous carcinoma peritonei). A In some cases, the
oma can occasionally arise from mucinous malignant epithelium appears very bland. B Many lakes of mucin seem to lack epithelium.
adenocarcinomas of other organs, such
as colorectum, gallbladder, stomach,
pancreas, fallopian tube, urachus, lung,
and breast {607, 1686, 2017, 3676}. Evi-
dence now suggests that the ovary is only
the primary source on the very rare
occasions when a well-differentiated
mucinous adenocarcinoma of intestinal
type arises in a mature cystic teratoma
{1970, 2587, 2722, 3149, 3657}.
Using the criteria in Table 7.01, the lesion
causing the pseudomyxoma can be Fig. 7.03 Low-grade appendiceal mucinous neoplasm Fig. 7.04 Hyperplastic polyp of the appendix. There is
classified as low-grade or high-grade (LAMN). This undulating morphology can also be seen in no architectural or cytological atypia.
{321, 2092}. The terms “low-grade” and adenomas, but there is no lamina propria and the
“high-grade mucinous carcinoma peri- neoplastic epithelium rests on fibrous stroma.
tonei” can be used as alternatives {321}.
In general, low-grade pseudomyxoma
peritonei is associated with LAMNs, while Histopathology uncertain malignant potential” are included
high-grade disease is associated with Appendiceal adenocarcinomas are desig- in the LAMN category. LAMNs may have
mucinous adenocarcinoma, but discordant nated as mucinous if > 50% of the lesion villous, serrated or undulating morphol-
cases can occur {2092}. consists of extracellular mucin. The ogy but, unlike adenomas, they rest on
The term “disseminated peritoneal adeno- nomenclature of appendiceal mucinous fibrous tissue rather than lamina propria.
mucinosis” (DPAM) has been used for low- neoplasms is controversial, because low- Most non-carcinoid appendiceal neo-
grade pseudomyxoma peritonei arising grade neoplasms that morphologically plasms are LAMNs or mucinous adeno-
from LAMNs {2722}. The term DPAM should resemble adenomas can proliferate out- carcinomas {440}. They tend to involve the
be avoided, since low-grade and high- side the appendix in a malignant fashion, appendix in a circumferential fashion with
grade lesions represent a continuous producing pseudomyxoma peritonei and atrophy of the underlying lymphoid tissue
spectrum, and the concept of “ruptured even distant metastases {441, 957, 2092, {440, 2092}. The appendix may show
adenoma” does not adequately reflect the 2435}. It is best to diagnose these well- widespread epithelial denudation, espe-
clinical course that frequently causes death differentiated lesions as LAMNs, a term cially in well differentiated lesions, so that
through obstruction of abdominal viscera that avoids the use of “adenoma”, an multiple blocks may be required to
{321, 2092, 2435}. Likewise, the term inappropriate designation for a lesion that demonstrate tumour cells {441}. Non-
“borderline” is best not applied to appen- may produce widespread disease {441}. mucinous adenocarcinomas of the appen-
diceal LAMNs, since similar-appearing The classification of mucinous appendiceal dix resemble their colorectal counterparts.
borderline tumours of the ovary have a neoplasms is shown in Table 7.02. Lesions The term “mucinous cystadenocarcinoma”
more favourable prognosis {441, 2092}. designated as “mucinous tumours of has been used for well-differentiated
Table 7.01 Classification of pseudomyxoma peritonei.
Grade TNM classification Architecture Cellular features Intracytoplasmic mucin Mitoses
Low grade Mucinous, low grade Cells form strips or small islands. Cells Neoplastic cells in single layers, sometimes Variable Rare
may be very scanty; the mucin may appear with papillary tufting. Nuclei small and regular.
acellular. Low-grade dysplasia. Cells may be decep-
tively bland in appearance.
High grade Mucinous, high grade Cells form strips, small islands or cribriform High-grade dysplasia, at least focally. Variable. Signet-ring More com-
structures. Cells numerous. Extensive cells may be seen. mon. May be
invasion of underlying organs. atypical.
a
Use of the terms “low-grade dysplasia” and “high-grade dysplasia” is as for the large intestine.
Adenocarcinoma 123
A B C
Fig. 7.05 Goblet cell carcinoid. A Typical concentric mural distribution of tumour with preservation of the appendiceal lumen. Mucin-positive tumour nests (green) are seen with Movat
staining. The lumen is compressed, but intact. B Typical clusters of goblet cells. C The neoplasm consists of small clusters of cells and single cells, some infiltrating a nerve in the
centre of the field.
mucinous tumours with cystic structures; concentric manner, thus producing an ill- progression from a pre-existing goblet cell
however, such a diagnosis should be defined tumour mass {371}. The mucosa is carcinoid {3193}. Either a signet-ring cell type
avoided because this neoplasm does not characteristically spared, with the exception or poorly differentiated adenocarcinoma type
constitute a separate disease entity {441}. of areas of connection of tumour nests with may be encountered {3193, 3446}. The
Appendiceal adenocarcinomas regularly the base of the crypts. The tumour is com- latter type typically exhibits immunohisto-
express keratin 20 and CDX2; many posed of small, rounded nests of signet-ring- chemical expression of p53 and MUC1
express keratin 7 {2317}. They also express like cells resembling normal intestinal goblet together with loss of MUC2 {3193}. These
MUC2, a gel-forming mucin normally cells, except for the nuclear compression. carcinomas usually occur in the apparent
secreted by intestinal goblet cells {2317, Glandular lumina are infrequently observed. absence of neoplastic change in the
2337}. Comparison of well-differentiated The cells dispay mild-to-moderate atypia, mucosal epithelium {371}.
adenocarcinomas of the appendix and low mitotic activity with a Ki67 proliferation
colorectum shows similar expression of index < 20% {3193}. Lysozyme-positive Grading
p53 and CD44s, although the apoptotic Paneth cells as well as foci resembling Mucinous tumours are classified as low-
count is lower in appendiceal lesions {438}. Brunner glands may be present {1340}. grade (corresponding to a diagnosis of
Mucin staining is intensely positive within LAMN or low-grade pseudomyxoma peri-
Signet ring cell carcinoma goblet cells and extracellular mucin pools. tonei), or as high-grade (corresponding to
If signet-ring cells account for more than Immunohistochemically, the endocrine-cell a diagnosis of mucinous adenocarcinoma
50% of the neoplasm, the term “signet- component is positive for chromogranin A, or high-grade pseudomyxoma peritonei).
ring cell carcinoma” is appropriate. Such synaptophysin, CD56 (NCAM1), serotonin, The criteria for these diagnoses are
lesions should be included in the high- enteroglucagon, somatostatin, and/or PP discussed elsewhere in this chapter and
grade category. {1222, 1340, 3362}. The goblet cells ex- are shown in Tables 7.01 and 7.02. Non-
press CEA, keratins 19 and 20 and MUC2 mucinous adenocarcinomas of the
Undifferentiated carcinoma {3193, 3362}. Ultrastructurally, dense-core appendix can be graded using the criteria
Undifferentiated carcinomas occur in the endocrine granules and mucin droplets are for colorectal lesions (see Chapter 8).
appendix but are rare. Their histology both found {763, 1222}, occasionally within These designations are incorporated into
corresponds to that of undifferentiated the cytoplasm of the same cell {1340}. the grading scheme of the TNM classifi-
carcinomas of the colorectum. cation.
Mixed adenoneuroendocrine carcinoma
Goblet cell carcinoid (see Neuroendocrine neoplasms of the Precursor lesions
This tumour is characterized by predomi- appendix) By analogy with the rest of the large intestine,
nantly submucosal growth. It typically This term has been proposed to designate an adenoma–carcinoma sequence is
infiltrates the appendiceal wall in a carcinomas of the appendix that arise by assumed to occur in the appendix; the
Table 7.02 Classification of mucinous appendiceal neoplasms.

Neoplasm TNM classification Architecture Cellular features Intracytoplasmic mucin Mitoses
Low-grade appendiceal Mucinous, Villous, serrated or undulating architecture, Neoplastic cells in a single Large mucin vacuoles Rare
mucinous neoplasm low-grade often resembling adenoma. “Broad front layer; they may be columnar, common in columnar cells;
(LAMN) invasion” characterized by atrophy and cuboidal or flattened. Nuclei may compress the nuclei
fibrosis of underlying submucosa and small and regular. Low-grade to the cell base. Less
muscularis propria, but no desmoplasia. dysplasia. Cells may be de- mucin in cuboidal cells.
ceptively bland in appearance.
Mucinous Mucinous, Invasive pattern with desmoplastic stroma. High-grade dysplasia, at least Variable. Signet-ring cells More common.
adenocarcinoma high-grade Residual luminal mucinous tumour focally. may be seen. May be atypical.
resembling LAMN may be present.
a
Use of the terms “low-grade dysplasia” and “high-grade dysplasia” is as for the large intestine.

finding of a residual adenoma in some decreased expression of MLH1 and

cases of adenocarcinoma supports this MGMT together with BRAF mutations
contention. A few adenocarcinomas appear {3620}. However, KRAS mutations (mostly
to arise from goblet cell carcinoid tumours in codon 12 and a few in codon 13) are
{371, 440}. also common and are found in the majority
Adenomas are defined as lesions that are of appendiceal adenomas {1453, 3149}.
confined to the appendix with no evidence Appendiceal adenomas frequently show
of invasion {2434}. Most appendiceal loss of heterozygosity (LOH). In particular,
adenomas are low-grade; high-grade LOH at the 5q locus linked to the APC tu-
cytology and architectural complexity are mour suppressor gene is common {3149}.
only compatible with a diagnosis of ade- A study of appendiceal adenocarcinomas
Fig. 7.06 Sessile serrated adenoma/polyp of the appendix.
noma if the lesion resembles an adenoma showed frequent LOH of chromosome There is architectural complexity and serrations extend
of the colon and the muscularis mucosae 18q21 and 18q22, mutation of SMAD4/- into the crypt bases, which are dilated.
is clearly intact. The designation of ade- DPC4 in a minority of cases, and no
noma should imply that the lesion is cur- mutations of the β-catenin gene (CTNNB1)
able by complete excision {441, 2435}. {1992}. Whether mucinous or non-mucinous,
An alternative diagnosis, such as LAMN, is appendiceal adenocarcinomas appear to
appropriate if there is any doubt. In partic- be microsatellite-stable {1453}. Of the
ular, the presence of any mucin outside reported cases to date, only two lesions
the appendix (even if the mucin is acellu- showed microsatellite instability; one
lar) is incompatible with a diagnosis of showed loss of MSH2 and MSH6 that was
adenoma {2434}. ascribed to a germline defect {2090}, the
The classification of appendiceal adenomas other showed loss of MLH1 even though
is the same as that in the colon (tubular, the adjacent serrated polyp was micro-
tubulovillous, villous). The commonest satellite-stable {3620}. Thus, the available
premalignant lesion of the appendix is the evidence suggests that appendiceal Fig. 7.07 Serrated adenoma of the appendix with
sessile serrated adenoma/polyp {2547}, adenocarcinomas rarely develop via the undulating morphology. Note the intact muscularis
probably reported in the past as hyper- microsatellite-instability pathway. mucosae beneath the lesion. More typical serrated
plastic polyps or diffuse hyperplasia. In Unlike colonic adenocarcinomas, KRAS features were present elsewhere.
fact, although hyperplastic polyps of the mutations are rarely found in carcinoids or
appendix do occur, they are relatively goblet cell carcinoids, while p53 expression
unusual. A lesion that has villous structures, at immunohistochemistry or TP53 mutations
irregularly branched crypts or dilation at were detected in a fraction (25–31%) of
the base of the crypts is probably a goblet cell carcinoids {2624, 3362}. No
sessile serrated adenoma/polyp, not a mutations of CTNNB1 or DPC4/SMAD4
hyperplastic polyp. Traditional serrated were detected in goblet cell carcinoids
adenomas and mixed hyperplastic- {3056}. Finally, decreased expression of
adenomatous polyps form a significant NLRP1 was identified in goblet cell
proportion of lesions; the diagnostic criteria carcinoids {2112}.
are the same as elsewhere in the large
intestine {439, 3620}. We no longer Prognosis and predictive factors Fig. 7.08 Unusual adenoma of the appendix with serrated
recommend the use of “cystadenoma” as Features that have been associated with features. High-grade morphology is evident (right).
a diagnostic term at this site, since cystic a poor prognosis in appendiceal adeno-
change does not indicate a separate carcinoma include advanced stage, high
disease category. grade, and nonmucinous histology {606, In terms of aggressiveness, goblet cell
2308, 2434, 2989}. carcinoids are more aggressive than
Genetic susceptibility When pseudomyxoma peritonei is present, conventional carcinoids, but less than
Several cases of adenocarcinoma of the the distinction between low-grade and adenocarcinomas of the appendix.
appendix have been reported in familial high-grade pseudomyxoma has prognostic Metastases to the ovaries are not infre-
adenomatous polyposis, including one significance {192, 321, 2092, 2722}. The quently seen and may be confused with
with appendiceal adenocarcinoma as the spread of mucus beyond the right lower primary ovarian tumours {1265, 3193}.
presenting feature {2481}. quadrant of the abdomen is an inde- The 5-year survival of patients with goblet
pendent prognostic variable {440, 2434}. cell carcinoids is 86% for localized disease,
Molecular pathology If the mucin deposits appear acellular, the 74% for regional disease, and 18% when
Some hyperplastic polyps and sessile prognosis may be improved {440, 2092, distant metastases are present {2023}.
serrated adenomas of the appendix show 2434, 3621}.
Adenocarcinoma 125
Neuroendocrine neoplasms P. Komminoth

R. Arnold
of the appendix C. Capella
D.S. Klimstra
G. Klöppel
E. Solcia
G. Rindi
Definition Synonyms detection depending on careful histo-

Neoplasms with neuroendocrine differen- Synonyms for NET of the appendix logical examination. Most appendiceal
tiation, including neuroendocrine tumours include: carcinoid, well-differentiated NETs are asymptomatic and located in
(NET) and neuroendocrine carcinomas endocrine tumour/carcinoma {3013}. the distal end of the appendix {1004}. In a
(NEC) arising in the appendix. Mixed ade- Synonyms for NEC include: poorly differ- small number of cases, NETs involving the
noneuroendocrine carcinomas (MANEC) entiated endocrine carcinomas, high- remaining portions of the appendix may
have an exocrine and an endocrine com- grade neuroendocrine carcinoma, small obstruct the lumen and produce appen-
ponent, with one component exceeding cell and large cell endocrine carcinomas. dicitis {371, 1004}. A carcinoid syndrome
30%. MANECs develop from goblet cell is extremely rare and almost always
carcinoids. related to widespread metastases, usu-
ICD-O codes ally to the liver and retroperitoneum {2118,
Neuroendocrine tumour (NET) Epidemiology 3236}.
NET G1 (carcinoid) 8240/3 Incidence and time trends
NET G2 8249/3 NETs account for 50–77% of all appen- Macroscopy
Neuroendocrine carcinoma (NEC) 8246/3 diceal neoplasms {1934, 2118} and for NETs
Large cell NEC 8013/3 19% of all gastrointestinal NETs. They are For routine cases, it is recommended that
Small cell NEC 8041/3 found in 0.3–0.9% of patients undergoing the entire tip of the appendix (two longitu-
Mixed adenoneuroendocrine appendectomy {1324, 1995, 2023, 3209}. dinal pieces) be examined together with
carcinoma (MANEC) 8244/3 The annual incidence rate is 0.15 new the resection margin in one block and
EC cell, serotonin-producing NET 8241/3 cases per 100 000 population {3624}. several diametrical cuts through the rest
Goblet cell carcinoid 8243/3 However, this figure may be an underes- of the appendix in a second block.
L cell, Glucagon-like peptide timate, since not all cases are reported Appendiceal NETs are firm, greyish-white
and PP/PYY-producing NETs 8152/1 and some registries do not record (yellow after formalin fixation), and fairly
Tubular carcinoid 8245/1 “benign” neoplasms (e.g. NETs of < 1 cm). well-circumscribed, but not encapsulated.
NECs are exceedingly rare {2339, 2732}. In 80%, 14% and 6% of cases, the diameter
is < 1 cm, 1–2 cm and > 2 cm, respec-
Age and sex distribution tively {681, 3081}. Most neoplasms (75%)
The mean age at presentation is 32–43 are located at the tip of the appendix,
years (range, 6–80 years) {2115, 2118, followed by the middle appendix (15%)
2713}. Tubular NETs occur at a signifi- and the base (10%) {681, 3081}.
cantly younger age than goblet cell
carcinoids (average, 29 vs 53 years) {371}. MANECs
Appendiceal NETs occur more frequently MANECs (e.g. goblet cell carcinoids) of
in females than in males {1161}, which the appendix may be found in any portion
may reflect the greater number of inci- of the appendix and appear as an area of
Fig. 7.09 Neuroendocrine tumour (NET) G1 (carcinoid)
of the appendix, with typical yellow coloration.
dental appendicectomies performed in whitish, sometimes mucoid induration,
women; however, in the Surveillance, without dilatation of the lumen. They
Epidemiology and End Results (SEER) range in size from 1 to 5 cm, with a mean
database, the frequency of non-endocrine of 2 cm {100}, but may occasionally not
appendiceal neoplasms is similar in be assessed accurately because of their
males and females, suggesting that the diffuse infiltrative growth {371}. They are
higher rate of appendiceal NETs in discussed under Adenocarcinoma of the
women may not be due solely to higher appendix.
rates of appendectomy {2115, 2118}.
Furthermore, the prevalence of girls Histopathology
among children with appendiceal NETs Most NETs of the appendix are entero-
cannot be explained by differences in chromaffin (EC) cell, serotonin-producing
rates of appendectomy {1447, 2121}. tumours (see Table 7.03). Only a minority
are glucagon-like peptide, PP/PYY-
Clinical features producing or L cell NETs. Also relatively
Fig. 7.10 NET G1 (carcinoid ) of the appendix infiltrating Most appendiceal NETs are found rare are goblet cell carcinoids. Primary
the mesoappendix. incidentally in appendectomy specimens, NECs, either pure endocrine or MANEC,

are exceedingly rare in the appendix distant metastases {2023}. Like ileal EC characteristic trabecular pattern {1366,
{2339, 2732}. cell NETs, they stain for both serotonin 2911}. These neoplasms generally meas-
and substance P and may also exhibit ure only 2–3 mm in diameter and are the
NETs S100-positive sustentacular cells. How- appendiceal counterpart of L cell NETs in
EC cell NET. The tumour cells are ever, in contrast to ileal and colonic EC the rectum, showing a similar immuno-
arranged in rounded solid nests that cell NETs, which seem to develop from EC profile (see Chapter 8).
sometimes show peripheral-cell palisading. cells of the mucosal crypts {1914, 2172}, Tubular carcinoid. This neoplasm is often
Occasionally, there may also be glandular the S100-positive cells in appendiceal EC misdiagnosed as a metastatic adenocar-
formations, forming a tubular or acinar cell NETs may surround some nests of cinoma, because it does not resemble the
pattern. Tumour cells are uniform, with neoplastic cells, forming subepithelial typical EC cell NET and shows little
little or no pleomorphism or mitotic activity neuroendocrine complexes {1001, 1914}. contact with the mucosa. It is composed
and a Ki67 proliferative index of < 2% No other relevant histological, cytological, of small, discrete tubules, some with
{3362}, thus mostly belonging to the G1 or immunohistochemical differences be- inspissated mucin in their lumen. Short
class (for grading, see Chapter 1). NET tween ileal and appendiceal NETs have trabecular structures are frequent, but
with a predominantly clear cell phenotype been detected, despite their rather differ- solid nests are generally absent. Useful
may rarely be encountered and can easily ent clinical behaviour. Thus, the tumour criteria for diagnosing this neoplasm are
be confused with goblet cell carcinoids. cells are positive for chromogranin A, origin from the base of the crypts, integrity
Most EC cell NETs display invasion of the synaptophysin, keratins 8 and 19, CD56 of the luminal mucosa, orderly arrange-
muscular wall and also lymphatic and (NCAM1), CDX2 and usually negative for ments, and absence of cytological
perineural invasion. Subserosal/meso- keratins 7 and 20, CEA and TTF1 {100, abnormalities and mitoses. Immunohisto-
appendiceal fatty tissue is infiltrated in 3052, 3362}. chemically, the tumour cells are often
10–40% of cases {681, 3081}. Despite L cell NET. These rare NETs produce positive for chromogranin A, glucagon
such aggressive growth patterns, appen- glucagon-like peptides (GLP1, GLP2, and and serotonin, but negative for S100
diceal NETs, in contrast to ileal NETs, the enteroglucagons glicentin and oxyn- protein {371, 1001}.
infrequently present with lymph-node or tomodulin) and PP/PYY. They feature a
A B
Fig. 7.11 Tubular carcinoid of the appendix. Typical tubular pattern (A) with gland-like structures (B) arising at the tip of the appendix.
A B
Fig. 7.12 Neuroendocrine tumours (NETs) of the appendix. A L cell NET, low power. B Clear cell carcinoid.

Table 7.03 Types and characteristics of neuroendocrine neoplasms of the appendix. diameter, there is still significant uncer-
Type Subtype Characteristics tainty as to appropriate therapy in cases
where one of the aforementioned adverse
Neuroendocrine Enterochromaffin cell Majority of tumours
prognostic factors is present in a patient
tumour (NET) (EC cell) NET Produce serotonin, substance P; S100-positive
May show muscular invasion, lymphatic or perineural with a neoplasm of < 2 cm in diameter.
invasion and invasion of peritoneum For example, while some claim that meso-
appendiceal invasion in neoplasms of
L cell NET Minority of tumours < 2 cm has no prognostic impact and
Produce glucagon-like peptides, PP/PYY
simple appendectomy is sufficient {2733},
Tubular and trabecular pattern
Mostly 2–3 mm in size others perform right-sided hemicolec-
tomy and lymphadenectomy in such
Tubular carcinoid Affect younger patients (average age, 29 years) cases, since lymph-node metastases
Little contact with the mucosa may be found in about 1% of patients
Small tubules with mucin in lumina; no cell nests
{355, 681, 2191, 2566}. Location of neo-
Originate from base of the crypts
Produce glucagons, serotonin; no S100-positive cells plasms at the base of the appendix with
involvement of the surgical margin or
Mixed Goblet cell carcinoid Affect older patients (average age, 52 years) of the caecum is prognostically un-
adenoneuroendocrine Submucosal concentric growth favourable, requiring at least a partial
carcinoma (MANEC) Positive staining for mucin
Produce serotonin, somatostatin, carcinoembryonic
caecal resection to avoid residual tumour
antigen (CEA) or subsequent recurrence.
The 5-year survival of patients with
Neuroendocrine Small cell NEC Extremely rare appendiceal NETs is 88–94% for localized
carcinoma (NEC) Mostly associated with adenocarcinoma
disease, 78–83% for regional disease,
and 25–31% when distant metastases are
present {2023, 3624}.
NECs International Union Against Cancer Tubular NETs behave in a clinically benign
NECs (poorly differentiated endocrine (AJCC/UICC) classification for T (tumour) manner {371}.
carcinomas) are exceedingly rare in the is based on size only, while the ENETS Of the two cases of NECs in the appen-
appendix {2339, 2732}. Both the histology proposal considers invasion of subserosa/- dix so far reported, one was associated
and the immunoprofile are consistent with mesoappendix, an issue that requires with an adenocarcinoma and the patient
those reported for NECs at other sites of data confirmation. was alive 65 months after diagnosis, while
the gastrointestinal tract (see Chapters 2, The vast majority of patients with NETs of the other patient only survived 2 months
4, 6, 8). the appendix have a favourable prognosis. after surgery, which is consistent with the
Neoplasms of < 1 cm hardly ever metas- overall poor prognosis of pure NECs of
Goblet cell carcinoid. tasize. Nonfunctioning, non-angioinvasive other gastrointestinal sites.
See Adenocarcinoma of the appendix. neoplasms confined to the appendiceal Several studies have shown that patients
wall and of < 2 cm in diameter are gener- with appendiceal NETs exhibit an in-
Molecular pathology ally cured by complete local excision, the creased risk for other gastrointestinal
In contrast to other NETs of the gastro- risk for developing lymph-node metas- malignancies, which warrants follow-up of
intestinal tract, loss of heterozygosity tases being 1% or less. A risk of 21–44% all patients via colonoscopic screening
(LOH) at the MEN1 gene locus appears {2120} for metastatic spread to the lymph {356}.
to be rare {2528, 3056, 3253}. A gene- nodes {1936} has to be taken into
expression study identified overexpression account if the neoplasm exceeds 2 cm in
of NAP1L1, MAGED2 and MTA1 in size or invades deeply into the meso -
appendiceal NETs with lymph-node or appendiceal/subserosal fatty tissue or
liver metastases as well as in goblet cell shows angioinvasion {109, 183, 1936,
carcinoids, but not in incidentally 2120, 2773, 3147}. The significance of
detected small NETs. several other parameters, such as inva-
sion of peritoneum, an elevated prolifera-
Prognosis and predictive factors tion index, expression of additional
The issue of TNM/staging classification of immunohistochemical markers such as
neuroendocrine neoplasms is as yet p53 {2173}, localization of the neoplasm
unsettled. The classification presented in in the basis of the appendix, the distance
Chapter 1 is for “carcinoid”, i.e. well- from the meso-appendiceal resection
differentiated lesions only. Conversely, the margin are still unclear and remain to be
classification proposed by the European investigated in larger series.
Neuroendocrine Tumor Society (ENETS) While there is agreement that a right-
is also intended for high-grade neo- sided hemicolectomy (including lym-
plasms {2684, 2685}. In the appendix, the phadenectomy) should be performed in
American Joint Committee on Cancer/- patients with neoplasms of > 2 cm in

Miscellaneous tumours of the appendix N.J. Carr

L.H. Sobin
Neural proliferations
Neural proliferations are common in the
appendix. By far the most frequent is the
neuroma, also called neurogenic appen-
dicopathy or neurogenous hyperplasia
{441, 2401}. This lesion causes obliteration
of the appendiceal lumen by replacing
the normal mucosa and lymphoid tissue
with a proliferation of spindle cells that
immunoexpress S100 protein, together A B
with nerve fibres, neuroendocrine cells,
Fig. 7.13 Neuroma of the appendix. A The tumour occupies part of the lamina propria mucosae and comprises an
mast cells and eosinophils within a vari- eosinophilic bundle composed of fibroblastic cells with eosinophilic cytoplasm and spindle- or oval-shaped nuclei.
ably myxoid and collagenous stroma. B Immunohistochemical staining for S100 protein is positive.
These lesions were previously diagnosed
as fibrous obliteration. Occasionally, neu-
romas may be found in the mucosa or
submucosa without luminal obliteration.
Neuromas of the appendix can be
encountered in any age group, but their
prevalence increases with age; one study
found that 58% of appendices removed
at autopsy exhibited luminal obliteration
by this process {2401}.
Other neural proliferations, such as neuro-
fibroma, ganglioneuroma, schwannoma
Fig. 7.14 Burkitt lymphoma of the appendix. Fig. 7.15 Neuroma of the appendix. This lesion caused
and gangliocytic paraganglioma are rare
luminal obliteration. Spindle cells positive for S100 are
in the appendix {2076, 2400, 3363, 3679}.
intermingled with eosinophils.
Gastrointestinal stromal tumours are
probably the most frequent mesenchymal
neoplasm at this site {2076}. One are of Burkitt type {2180}. of the gastrointestinal and urogenital tract,
reported case had ganglion cells and Other rare primary appendiceal neo- breast, lung, and gallbladder. Metastatic
nerve fibres within the tumour {38}. plasms that have been described are thymoma and melanoma have also been
Kaposi sarcoma and small cell carcinoma reported {170, 959, 1032, 2727, 3066,
Lymphomas {710, 2339}. 3537}. A common pattern is serosal
Lymphomas involve the appendix usually involvement, presumably due to trans-
as part of more general intestinal spread. Secondary tumours coelomic spread. Endometriosis involving
Lymphomas presenting as primary Secondary tumours are unusual in the ap- the appendix wall may mimic metastatic
disease of the appendix are rare; some pendix. Primary sites include carcinomas adenocarcinoma.
Miscellaneous tumours 129

CHAPTER 8
Tumours of the colon and rectum
Carcinoma
Familial adenomatous polyposis
Lynch syndrome
MUTYH-associated polyposis
Serrated polyps and serrated polyposis
Juvenile polyposis
Peutz-Jeghers syndrome
Cowden syndrome
B-cell lymphoma
Mesenchymal tumours
WHO classificationa of tumours of the colon and rectum
Epithelial tumours Neuroendocrine neoplasmsb

Premalignant lesions Neuroendocrine tumour (NET)
Adenoma 8140/0 NET G1 (carcinoid) 8240/3
Tubular 8211/0 NET G2 8249/3
Villous 8261/0 Neuroendocrine carcinoma (NEC) 8246/3
Tubulovillous 8263/0 Large cell NEC 8013/3
Dysplasia (intraepithelial neoplasia), low grade 8148/0* Small cell NEC 8041/3
Dysplasia (intraepithelial neoplasia), high grade 8148/2 Mixed adenoneuroendocrine carcinoma 8244/3
EC cell, serotonin-producing NET 8241/3
Serrated lesions L cell, Glucagon-like peptide-producing and
PP/PYY-producing NETs 8152/1*
Hyperplastic polyp
Sessile serrated adenoma/polyp 8213/0*
Traditional serrated adenoma 8213/0*
Mesenchymal tumours
Hamartomas Leiomyoma 8890/0

Cowden-associated polyp Lipoma 8850/0
Juvenile polyp Angiosarcoma 9120/3
Peutz-Jeghers polyp Gastrointestinal stromal tumour 8936/3
Kaposi sarcoma 9140/3
Carcinomas Leiomyosarcoma 8890/3
Cribriform comedo-type adenocarcinoma 8201/3*
Medullary carcinoma 8510/3
Lymphomas
Micropapillary carcinoma 8265/3*
Serrated adenocarcinoma 8213/3*
Secondary tumours
Spindle cell carcinoma 8032/3
__________________________________________________________
EC, enterochromaffin.
a
The morphology codes are from the International Classification of Diseases for Oncology (ICD-O) {904A}. Behaviour is coded /0 for benign tumours, /1 for un
specified, borderline or uncertain behaviour, /2 for carcinoma in situ and grade III intraepithelial neoplasia, and /3 for malignant tumours.
b
The classification is modified from the previous (third) edition of the WHO histological classification of tumours {691} taking into account changes in our under
standing of these lesions. In the case of neuroendocrine neoplasms, the classification has been simplified to be of more practical utility in morphological
classification.
132 Tumours of the colon and rectum

TNM classificationa of tumours of the colon and rectumb
Carcinoma of the colon and rectum

Tis Carcinoma in situ: intraepithelial or invasion of lamina propria M1a Metastasis confined to one organ
T1 Tumour invades submucosa M1b Metastases in more than one organ or the peritoneum
T2 Tumour invades muscularis propria
T3 Tumour invades subserosa or into non-peritonealized
pericolic or perirectal tissues Stage grouping
T4 Tumour perforates visceral peritoneum and/or directly
invades other organs or structures Stage T N M
T4a Tumour perforates visceral peritoneum Stage 0 Tis N0 M0
T4b Tumour directly invades other organ or structures Stage I T1, T2 N0 M0
Stage II T3, T4 N0 M0
N – Regional lymph nodes Stage IIA T3 N0 M0
NX Regional lymph nodes cannot be assessed Stage IIB T4a N0 M0
N0 No regional lymph-node metastasis Stage IIC T4b N0 M0
N1 Metastasis in 1 to 3 regional lymph nodes Stage III Any T N1, N2 M0
N1a Metastasis in 1 regional lymph node Stage IIIA T1, T2 N1 M0
N1b Metastasis in 2 to 3 regional lymph nodes T1 N2a M0
N1c Tumour deposit(s), i.e. satellites, in the subserosa, or in Stage IIIB T3, T4a N1 M0
non-peritonealized pericolic or perirectal soft tissue T2,T3 N2a M0
without regional lymph-node metastasis T1,T2 N2b M0
N2 Metastasis in 4 or more regional lymph nodes Stage IIIC T4a N2a M0
N2a Metastasis in 4 to 6 regional lymph nodes T3, T4a N2b M0
N2b Metastasis in 7 or more regional lymph nodes T4b N1,N2 M0
Stage IVA Any T Any N M1a
Stage IVB Any T Any N M1b
Carcinoid of the colon and rectumc
T – Primary tumour Stage grouping

T0 No evidence of primary tumour Stage T N M
T1 Tumour invades lamina propria or submucosa and is no Stage I T1 N0 M0
greater than 2 cm in size Stage IIA T2 N0 M0
T1a Tumour less than 1 cm in size Stage IIB T3 N0 M0
T1b Tumour 1 to 2 cm in size Stage IIIA T4 N0 M0
T2 Tumour invades muscularis propria or is greater than 2 cm Stage IIIB Any T N1 M0
in size Stage IV Any T Any N M1
T3 Tumour invades subserosa, or non-peritonealized pericolic
or perirectal tissues
T4 Tumour perforates peritoneum or invades other organs

_____________
a
{762, 2996}
b
The TNM classification and stage grouping for GISTs of the colon and rectum can be found on page 47.
c
NET; well-differentiated endocrine tumour/carcinoma.
d
The term “carcinoma in situ” is not consistently used in diagnostic practice. The intraepithelial lesions are comprised in the dysplasia/intraepithelial neoplasia,
high-grade, category; when intramucosal invasive growth is encountered, the term used is “intramucosal carcinoma.”
Classification 133
Carcinoma of the colon and rectum S.R. Hamilton

F.T. Bosman
S.-I. Nakamura
P. Quirke
P. Boffetta E. Riboli
M. Ilyas L.H. Sobin
H. Morreau
Definition Higher rates occur in industrialized, high- incidence than in populations with a low
A malignant epithelial tumour originating resource countries of Europe, Australia, incidence {3697}.
in the large bowel. Metastasis, and there- New Zealand, North America and Japan The worldwide mortality rate is about half
fore the use of the term “carcinoma” for (about 40–60 per 100 000), and much the incidence rate (about 608 000 deaths
tumours of the colon and rectum, requires lower rates in other countries in Asia (e.g. from CRC in 2002), but there is wide vari-
invasion through the muscularis mucosae India) and Africa. The incidence, and ation in mortality rates according to avail-
into the submucosa. More than 90% of therefore the impact of CRC on the burden able treatment options, with lower rates in
colorectal carcinomas (CRC) are adeno- of cancer, are changing in many areas of countries with high incidences and high
carcinomas {319}. the world and will affect priorities for can- resources {319, 842}. Nonetheless, CRC is
cer control and cancer services. Incidence the most common cause of deaths from
ICD-O codes rates are rising in many countries where cancer that is not directly attributable to
Adenocarcinoma 8140/3 rates were previously low, but falling (e.g. tobacco usage in some of these countries.
Cribriform comedo-type North America), stabilizing (e.g. northern
adenocarcinoma 8201/3 and western Europe), or increasing only Etiology
Medullary carcinoma 8510/3 gradually in countries where rates were Diet, lifestyle, and other exposures
Micropapillary carcinoma 8265/3 previously high. Among immigrants and A high incidence of CRC is observed
Mucinous adenocarcinoma 8480/3 their descendants, incidence rates rapidly consistently in populations with a “Western-
Serrated adenocarcinoma 8213/3 approach those of their adopted countries, type” diet (highly caloric food rich in animal
Signet ring cell carcinoma 8490/3 indicating that lifestyle, dietary and fat) combined with a sedentary lifestyle.
Adenosquamous carcinoma 8560/3 perhaps other environmental factors are Epidemiological studies have indicated
Spindle cell carcinoma 8032/3 important risk factors {319}. that obesity, meat consumption, smoking
Squamous cell carcinoma 8070/3 Incidence increases with age {1816}, and and alcohol consumption are important
Undifferentiated carcinoma 8020/3 carcinomas are rare before the age of 40 modifiable risk factors. “Westernization” of
years, except in individuals with genetic previously low-incidence populations is
Epidemiology predisposition or predisposing conditions followed by increased incidence rates.
An estimated 1.23 million new cases of such as chronic inflammatory bowel Inverse associations in populations include
CRC occurred worldwide in 2008, repre- diseases in high-incidence countries. dietary consumption of fruits, vegetables,
senting about 9.7% of all new cancers. However, age-standardized incidence rates whole grains, calcium and vitamin D;
CRC ranks as the fourth most frequent among young patients are often higher in prolonged use of nonsteroidal anti-inflam-
cancer in men (after lung, prostate and low-incidence than in high-incidence matory drugs (NSAIDs); estrogen replace-
stomach cancer), and third in women populations {1650, 3016}. Rates of rectal ment therapy in women; and physical
(after cancers of the breast and uterine cancer are about 50% higher and colon activity. Numerous other putative protective
cervix) {319, 842}. However, the age-stan- cancer rates about 20% higher in men and predisposing dietary components and
dardized incidence of this cancer varies than in women. The ratio of colon to rectal exposures have been reported {319,
by at least 25-fold around the world. cancer is higher in populations with a high 882A, 1984A, 3360A}.
A B
Fig. 8.01 A Worldwide annual incidence (per 100 000) of cancer of the colon and rectum in men {842A}. Numbers on the map indicate regional average values and are higher in developed
countries {842A}. B Age-standardized incidence (per 100 000) of colorectal cancer in men in selected countries {842}.

A B C
Fig. 8.02 Advanced colorectal carcinomas. A Small depressed invasive carcinoma with a nearby protruding adenoma. B Advanced colorectal carcinoma, depressed type.
C Cross-section of adenocarcinoma with extension into the submucosa (pT1).
The molecular pathways underlying the Localization include fever, malaise, weight loss, and
epidemiological associations are poorly Most CRCs are located in the sigmoid abdominal pain.
understood because of complex interac- colon and rectum, but the proportion of
tions that probably involve dietary carcinomas that are more proximally Imaging
patterns, macro- and micronutrient com- located increases with age {3057}. Imaging techniques permit noninvasive
position of foodstuffs, food preparation Molecular pathology has site differences: detection and clinical staging. Barium
techniques, hormonal effects, genetic tumours with high levels of microsatellite enema has been replaced by computer
characteristics, and gene–diet and gene– instability (MSI-H) and CpG-island methy- assisted tomography (CT) that may be
gene effects. Research methodologies lation microsatellite-stable tumours are useful for screening (CT colonography).
are inadequate to characterize precisely frequently located in the caecum, Cross-sectional imaging by CT, magnetic
the various etiological components and ascending colon and transverse colon; resonance imaging (MRI), and transrectal
their interactions, contributing to the CpG-island methylation microsatellite- ultrasonography are used to estimate
insufficient levels of evidence upon which stable tumours in both the right and left depth of tumour invasion and the possibility
interventions could be based with confi- colon; and microsatellite-stable tumours of regional and distant metastases {722,
dence. Patients with colorectal adeno- without CpG-island methylation mainly in 2546}. Scintigraphy and positron emission
mas, known to be precursors to CRC, the left colon {227, 1317}. tomography (PET) are also used to assess
have been studied in clinical trials of pre- the spread of disease {1174, 1477}.
vention strategies. Dietary modifications, Clinical features
e.g. fibre supplementation and reduction Signs and symptoms Endoscopy
in fat, have been minimally effective {63, Some patients are asymptomatic and the Colonoscopy allows observation of the
2701} and supplemental folate that was neoplasm is identified by screening or mucosal surface of the entire large bowel.
expected to be protective may promote surveillance. Haematochezia and anaemia In addition, biopsy or therapeutic removal
neoplasia {579, 854}. In contrast, NSAIDs are common presenting features attribut- of identified lesions can be done by snare
{1102, 1736}, especially when combined able to bleeding from the tumour. Many polypectomy, endoscopic mucosal resec-
with an inhibitor of the polyamine pathway patients experience change in bowel tion or submucosal dissection, especially
{2058}, and dietary calcium supplemen- habits, especially constipation, because for adenomas and superficial carcinomas
tation {1052} have shown evidence of the solid faeces in the left colon are often {416, 3187}. Improved magnification,
chemopreventive activity. impeded by the mass. There may be chromoendoscopy employing dyes, and
associated abdominal distension, bowel confocal endoscopy improve visualization
Chronic inflammation obstruction or perforation. Rectosigmoid of non-protruding lesions. Other innovations
Chronic inflammatory bowel diseases are lesions can produce tenesmus and rectal such as narrow band imaging with different
etiological factors for CRC {1639, 3292} bleeding. Other nonspecific symptoms wavelengths of light, Raman spectroscopy
These diseases include ulcerative colitis
(UC), Crohn disease (CD), and Schisto-
soma mansoni infection {3653}. Despite
recurrent episodes of inflammation in
diverticular disease, diverticulitis is not a
specific risk factor for carcinoma {2054}.
Other risk factors

Rare but well-recognized etiological fac-
tors include therapeutic pelvic irradiation
{2632} and ureterosigmoidostomy {1000}.
A B
Fig. 8.03 CT scan of carcinoma of the colon and rectum. A Primary tumour (arrow) in the transverse colon.
B Metastases in the liver.
Carcinoma 135
A B C
Fig. 8.04 Mucinous adenocarcinoma. A Cut surface with gelatinous appearance. B Mucinous adenocarcinoma beneath high-grade dysplasia in ulcerative colitis. C Multilocular
mucin deposits with malignant epithelium.
and optical coherence tomography are of Tumour spread and staging breached and the submucosa is invaded.
unproven value {2433}. Following transmural direct extension Involvement of veins and venules that are
through the muscularis propria into periportal vein tributaries in the colon and
Macroscopy colic or perirectal soft tissue, carcino- vena cava tributaries in the rectum con-
Carcinomas have variable macroscopic mas may involve contiguous structures. tribute to haematogenous dissemination.
appearances: exophytic/fungating with The consequences depend on the
predominantly intraluminal growth, endo- anatomic site. Advanced rectal carcinomas Staging
phytic/ulcerative with predominantly intra- may extend into pelvic structures such as The classifications proposed by Cuthbert
mural growth, annular with circumferential the vagina and urinary bladder, but cannot Dukes in 1929–1935 for rectal cancer are
involvement of the colorectal wall and gain direct access to the peritoneal cavity the basis for many staging systems for
luminal stenosis, and, least commonly, when located distal to the peritoneal CRC, including the current TNM {89, 671}.
diffusely infiltrative/linitis plastica pattern. reflection. In contrast, colonic carcinomas This family of classifications for patients
Overlap among these types and ulceration can extend directly to the serosal surface who underwent resection of their primary
are common. Some cancers, usually with transcoelomic spread in the peri- with curative intent takes into account two
arising in a pedunculated adenoma, toneal cavity (peritoneal carcinomatosis) histopathological features: depth of pen-
occur on a stalk of uninvolved mucosa and/or perforation. Since the peritoneal etration relative to the muscularis propria
and submucosa and are amenable to surface infiltrated by tumour cells may and presence or absence of metastasis
colonoscopic polypectomy. Carcinomas become adherent to adjacent structures, in regional lymph nodes.
proximal to the splenic flexure tend to direct extension into adjoining organs can The TNM classification has now largely
grow as exophytic masses while those in also occur. Implantation attributable to sur- replaced other classifications thanks to its
the descending colon and rectum are gical manipulation, including laparoscopic greater utility and standardization. The
more often endophytic and annular. On resection, occurs only occasionally {103}. classification has undergone relatively
cut section, most CRCs have a relatively Spread via lymphatic or blood vessels few major modifications between the sixth
homogeneous grey/white appearance, can occur early in the natural history and (2002) and seventh (2009) editions, such
although a gelatinous cut surface can be lead to lymph node involvement and that the main T, N, and M categories and
seen in mucinous tumours. systemic disease. Despite the presence stages I to IV can be compared easily.
of lymphatic vessels in the colorectal In the T categories, the designations of
mucosa, lymphatic spread does not the subdivisions of T4 are reversed. The
occur unless the muscularis mucosae is N1 and N2 categories separating tumours
Fig. 8.05 Well-differentiated adenocarcinoma of the colon. Fig. 8.06 Clear cell carcinoma of the colon. Fig. 8.07 Rectal carcinoma with budding at invasive edge.

A B
Fig. 8.08 Adenocarcinoma in a pT4 stage category. A The tumour extends through the muscularis propria and subserosa and penetrates the serosa, accessing the peritoneal cavity.
The obliterated serosal surface does not represent a surgical margin of resection. B The tumour extends through the subserosa, which shows active inflammation and mesothelial
reaction on the serosal surface. Black ink was applied to the gross specimen to assist in histopathological identification of the serosa.
involving three or fewer lymph nodes and over the last 30 years. Molecular charac- Mucinous adenocarcinoma
four or more are retained, but further teristics and other histological features This designation is used if > 50% of the
subdivision by number of involved nodes such as extramural vascular invasion and lesion is composed of pools of extracellular
is added for finer distinction. The catego- depth of invasion in T1 carcinoma that are mucin that contain malignant epithelium as
rization of mesenteric tumour deposits or not included in the TNM classification but acinar structures, layers of tumour cells, or
satellites without identifiable residual lymph influence outcome and treatment are individual tumour cells including signet-
node is clarified. These may represent discussed below. ring cells. The level of maturation of the
discontinuous spread, venous invasion with epithelium determines differentiation, but
extravascular spread, or a totally replaced Histopathology many mucinous adenocarcinomas are
lymph node. Such a deposit, regardless The defining feature of CRC is invasion MSI-H {1061, 1804} and therefore low-
of size or configuration (used as criteria in through the muscularis mucosae into the grade. Mucinous adenocarcinomas that
the fifth and sixth editions, respectively), submucosa. More than 90% of CRCs are are microsatellite-stable (MSS) or have
is changed to equivalency to a lymph- adenocarcinomas {319}. Lesions with the low levels of instability (MSI-L) behave as
node metastasis, and in the absence of histopathological characteristics of adeno- high-grade lesions. Carcinomas with
lymph-node involvement is designated carcinoma that are confined within the mucinous areas of < 50% are categorized
N1c in the seventh edition to favour mucosa and completely removed have no as having a mucinous component.
treatment with postoperative adjuvant risk of metastasis even when intramu-
chemotherapy. This categorization leads to cosal invasion is present. Because these Signet ring cell carcinoma
the paradoxical situation in which in the lesions are cured when removed com- This variant of adenocarcinoma is defined
presence of a single lymph-node metastasis pletely, the terms “high-grade dysplasia” by the presence of > 50% of tumour cells
changes the category from N1c to N1a or “intramucosal carcinoma” are often with prominent intracytoplasmic mucin,
and therefore underestimates the prog- used to avoid inappropriate overtreatment typically with displacement and moulding
nostic influence of the mesenteric deposit for carcinoma, e.g. surgical resection of the nucleus. Signet-ring cells can occur
{2600, 2601, 3336}. {3024}. However, “intramucosal adeno- within the pools of mucinous adenocarci-
The M category is subdivided into a carcinoma” is used routinely with associ- noma or in a diffusely infiltrative process
category with distant metastasis confined ated treatment recommendations in the with minimal extracellular mucin in a
to one organ and potentially amenable to Guidelines for Treatment of Colorectal linitis-plastica pattern. Large signet-ring
surgical resection (although extent of Carcinoma edited by the Japanese cells can be termed “globoid cells”. Some
single-organ involvement, e.g. unilobar vs Society for Cancer of the Colon and signet ring cell carcinomas are MSI-H and
bilobar liver metastases, is not incorporated, Rectum {1391, 1392}.
and preoperative neoadjuvant chemother- Most colorectal adenocarcinomas are
apy may convert some tumours from negative for keratin 7 and positive for
unresectable to resectable) and a second keratin 20 by immunohistochemistry and
category with more widely disseminated also express CDX2 transcription factor. A
metastases in more than one organ or the proportion of tumours is negative for
peritoneum. The prefix “p” is used to keratin 20, and these tend to be MSI-H
indicate pathological, as contrasted with {2024}. Expression of CDX2 is not associ-
clinical or imaging, assessment. ated with MSI status {172, 2387}.
All the subdivisions of the T, N, and M
categories are expressed in subdivisions Other variants
of the stage groupings, generating three Several histopathological variants can be
subdivisions each for stages II and III and distinguished, some associated with Fig. 8.09 Intramucosal adenocarcinoma. Criteria of the
two subdivisions of stage IV, with compa- specific molecular characteristics. Japanese Society for Cancer of the Colon and Rectum
rability to previous TNM staging systems {1391, 1392}.
Carcinoma 137
Rare variants
There is an additional heterogeneous group
of very rare CRC variants, e.g. clear cell
carcinoma, that often have a component
of conventional adenocarcinoma or mimic
other types of cancers, e.g. choriocarci-
noma {1050}, Paneth cell-rich papillary
adenocarcinomas {2959}. The differential
diagnosis includes metastasis from else-
A B where or rare primary colorectal tumours,
Fig. 8.10 A Small adenocarcinoma arising in a depressed adenoma and invading the muscularis propria. B Early e.g. primary melanoma or nonepithelial
adenocarcinoma arising in a flat adenoma and invading the submucosa. cell types such as gastrointestinal stromal
tumours (GISTs).
are low-grade, but those that lack MSI-H Micropapillary adenocarcinoma Grading
are usually highly aggressive {2442}. Car- This rare variant has small clusters of tu- Colorectal adenocarcinoma was graded
cinomas with signet-ring cell areas of mour cells within stromal spaces mimick- traditionally as well-, moderately, poorly,
< 50% are categorized as adenocarcinoma ing vascular channels and has also been and undifferentiated on the basis of the
with a signet-ring cell component (signet described in breast and bladder cancer. percentage of gland formation. “Undiffer-
ring cell carcinoma). The pattern can be seen as a component entiated adenocarcinoma” is an oxymoron,
of conventional CRC. Immunohistochem- and “undifferentiated carcinoma” (grade
Medullary carcinoma istry shows a characteristic MUC1 staining 4) is now a term of exclusion reserved for
This rare variant is characterized by pattern {1211, 1687, 2780, 3283}. malignant epithelial tumours that show no
sheets of malignant cells with vesicular gland formation, mucin production, or
nuclei, prominent nucleoli and abundant Adenosquamous carcinoma neuroendocrine, squamous or sarcomatoid
eosinophilic cytoplasm exhibiting promi- This unusual tumour has features of both differentiation. The terms “low-grade” and
nent infiltration by intraepithelial lympho- squamous cell carcinoma and adenocar- “high-grade” are now favoured for clinical
cytes. It almost invariably has MSI-H and cinoma, either as separate areas within usage owing to the similar behaviour of
usually a favourable prognosis {1573, the tumour or admixed. This variant has well- and moderately differentiated carci-
2872}. more than just occasional small foci of nomas and greater reproducibility. Morpho-
squamous differentiation. Pure squamous logical grading of tumours applies only to
Serrated adenocarcinoma cell carcinoma is very rare. “Adenocarcinoma, NOS”. Other morpho-
This rare variant has architectural similarity logical variants carry their own prognostic
to a sessile serrated polyp with glandular Spindle cell carcinoma significance and grading does not apply.
serration that may be accompanied by This is a biphasic carcinoma with a spin- Adenocarcinomas and undifferentiated
mucinous, cribriform, lacy and trabecular dle-cell sarcomatoid component in which carcinomas that have MSI-H behave as
areas and a low nucleus-to-cytoplasm the tumour cells are at least focally low-grade.
ratio. These tumours can have MSI-L or immunoreactive for keratins {135, 1421, Carcinomas are sometimes heterogeneous,
MSI-H, BRAF mutations, and CpG island 1553}. and grading is then based upon the least
hypermethylation {1400, 1404, 1963}. differentiated component. The invading
Undifferentiated carcinoma edge of CRC is regarded as suboptimal to
Cribriform comedo-type adenocarcinoma These rare tumours lack morphological, evaluate tumour grade, but the presence of
This rare tumour has extensive large immunohistochemical, and molecular bio- “tumour budding” with poorly differentiated
cribriform glands with central necrosis logical evidence of differentiation beyond foci characterized by rudimentary gland
analogous to breast adenocarcinomas that of an epithelial tumour and have formation and individual invasive carcinoma
and is usually microsatellite-stable with variable histological features. Some of cells has been associated with aggressive
CpG island hypermethylation {528}. these tumours have MSI-H. behaviour {2360, 3452}. Classification of
morphologic variants and carcinomas other
than adenocarcinomas, e.g. NEC, as low-
Table 8.01 Criteria for histological grading of colorectal adenocarcinomas. or high-grade requires consideration of
Criterion Differentiation category Numerical gradea Descriptive grade specific criteria other than those for adeno-
carcinoma.
> 95% with gland formation Well-differentiated 1 Low
50–95% with gland formation Moderately differentiated 2 Low Precursor lesions

Aberrant crypt foci (ACF)
> 0–49% with gland formation Poorly differentiated 3 High
ACF are clusters of abnormal crypts seen
High level of microsatellite instabilityb Variable Variable Low on staining colorectal mucosa in resection
specimens with methylene blue or mucosal
a
The category “undifferentiated carcinoma” (grade 4) is reserved for carcinomas with no gland formation, mucin examination with a magnifying endoscope
production, or neuroendocrine, squamous or sarcomatoid differentiation; b MSI-H.
or chromoendoscopy. Increased numbers

of ACF are seen in association with neo-

plasia. Histopathology shows two main
types: those resembling hyperplastic
polyps that are common, and those with
dysplasia (microadenomas) that are rare,
except in familial adenomatous polyposis
(FAP) {531, 2326}. The clinical importance
of sporadic ACFs is uncertain {1088, 1737}.
Adenomas
Adenomas are defined by the presence of
dysplastic epithelium. This is characterized
histopathologically by enlarged, hyper- A B
chromatic nuclei, varying degrees of
Fig. 8.11 Endoscopic features of adenoma. A Polypoid. B Flat, slightly elevated.
nuclear spindling and stratification, and
loss of polarity. Dysplasia can be low-grade
or high-grade, depending on the degree of
architectural complexity, extent of nuclear
stratification, and severity of abnormal
nuclear morphology. Foci in invasive
growth can be encountered in an adenoma
with high-grade dysplasia. For such lesions,
the terms high-grade dysplasia as well as
intramucosal carcinomas are used. Paneth
cells, neuroendocrine cells and squamous-
cell aggregates may be seen in adenomas
{189, 1370, 3426}.
Macroscopically, most adenomas are poly-
poid with protrusion into the colorectal
lumen, either sessile with broad attachment
or on a stalk. A smaller number are flat or de-
A B
pressed {1734, 2469} and often recogniza- Fig. 8.12 Endoscopic features of adenomas highlighted with indigo carmine. A Two small flat adenomas; note the
abnormal tubular pit pattern. B Tubulovillous adenoma seen by magnifying video endoscopy; the cerebriform pattern is
ble macroscopically by mucosal reddening,
highlighted.
subtle changes in texture, or highlighting by
specialized endoscopic techniques.
Most adenomas are < 1 cm in size and colon, multiplicity of adenomas (five or cells with reactive changes.
have tubular architecture. Villous architecture more) or are male have more frequent The juvenile polyps in patients with juvenile
is defined as leaf- or finger-like projections development of a metachronous advanced polyposis syndrome often have a frond-
of epithelium overlying a small amount of adenoma or carcinoma {1991}. The clinical like growth pattern with less stroma, fewer
lamina propria. Tubulovillous adenomas implications of serration in adenomas and dilated glands and more proliferated
are defined by a mixture of tubular and vil- of sessile serrated adenomas/polyps are small glands (microtubular pattern) than
lous structures with arbitrary percentages not yet well-defined. the sporadic type. Dysplasia is rare in
in different studies, typically between 25% sporadic juvenile polyps, but there is an
and 75% villous component. Unusual Serrated lesions increased risk of colorectal carcinoma in
histopathological patterns such as micro- This is a heterogeneous group of lesions patients with juvenile polyposis syndrome
tubular adenoma occur. characterized morphologically by a {1280}.
The characteristics of adenomas are asso- serrated (sawtooth or stellate) architec-
ciated with the occurrence of synchronous ture of the epithelial compartment, and
and metachronous carcinoma. Adenomas includes the hyperplastic polyp, sessile
of larger size (1 cm), more extensive villous serrated adenoma/polyp and traditional
architecture, and high-grade intraepithelial serrated adenoma.
neoplasia/dysplasia, termed “advanced
adenomas” {1155}, and flat depressed Juvenile polyp
adenomas {1734} have a higher frequency Sporadic juvenile polyps occur most
of malignancy, although depressed ade- commonly in children {3451}. This lesion
nomas have a lower frequency of KRAS contains abundant stroma composed of
mutation than do polypoid adenomas inflamed, often oedematous, granulation
{2158}. Patients who have an adenoma of tissue that surrounds cystically dilated
20 mm or more with tubulovillous or villous glands containing mucin. The glands are Fig. 8.13 Frequency of colorectal adenocarcinoma in
architecture in a proximal location in the lined by cuboidal to columnar epithelial adenomas relative to size and architecture.
Carcinoma 139
A B
Fig. 8.14 Tubulovillous adenoma. A Partly sessile, partly pedunculated. B With pseudoinvasion. Small clusters of Fig. 8.15 Villous adenoma of the rectum and invasive
adenomatous cells produce multilocular, large mucin deposits that expand the stalk of the adenoma. This growth pattern adenocarcinoma.
can be mistaken for mucinous adenocarcinoma.
A B
Fig. 8.16 A Adenoma with low-grade dysplasia and well-maintained glandular architecture. B Low-grade dysplasia with Fig. 8.17 Flat “elevated” tubular adenoma showing low-
regular but slightly elongated, hyperchromatic nuclei. Cytoplasmic mucin is retained. grade dysplasia.
Peutz-Jeghers polyp of chronic inflammatory diseases includ- occur with prolapse in other sites, e.g.
These are hamartomatous gastrointestinal ing ulcerative colitis, Crohn colitis, diver- colostomy stomas. The features can be
polyps that preferentially affect the small ticulitis, and schistosomiasis {3574, 3653}. confused with inflamed adenoma or
intestine and that, together with muco- Mucosal prolapse changes/solitary rectal invasive adenocarcinomas and are an
cutaneous melanin pigmentation, are a ulcer syndrome/colitis cystica profunda. important cause of misdiagnosis of neopla-
component of the inherited predisposition Polyps, masses, erosions and ulcers sia. On the other hand, mucosal prolapse
syndrome, Peutz-Jeghers syndrome (PJS). characterized histopathologically by changes can occur due to an underlying
elongated, distorted regenerative glands neoplasm {1836}.
Other lesions surrounded by proliferated smooth-muscle In addition to mucosal prolapse changes/-
Reactive lesions/mimics of carcinoma fibres from the muscularis mucosae can solitary rectal ulcer syndrome/colitis cystica
Inflammatory polyp/“pseudopolyp.” These occur together with inflamed granulation profunda, misplacement of epithelium in
are composed of varying proportions of tissue and fibrosis in prolapsing mucosa the submucosa of adenomas (“pseudoin-
reactive epithelium, inflamed granulation and entrapped glands in deeper layers vasion”) {3198} and muciphages may be
tissue and fibrous tissue, often with morpho- {761, 2410, 2974}. When located in the misdiagnosed as carcinoma.
logical similarity to juvenile polyps. rectum, the lesion is termed solitary rectal
Inflammatory polyps are seen in a variety ulcer syndrome, but these findings can
A B C
Fig. 8.18 Adenomas with high-grade dysplasia. A Loss of normal glandular architecture, hyperchromatic cells with multi-layered irregular nuclei and loss of mucin, and a high
nucleus-to-cytoplasm ratio. According to Japanese criteria, this would be an intramucosal carcinoma. B Loss of polarity with little nuclear stratification; marked nuclear atypia with
prominent nucleoli (Japanese criteria: intramucosal adenocarcinoma). C Adenoma with focal cribriform pattern (Japanese criteria: adenocarcinoma in adenoma).

Neoplasia in chronic inflammatory bowel

diseases
The natural history and morphology of
CRC associated with chronic colitis differ
from those of sporadic carcinomas {45,
1164, 3723}. The risk in ulcerative colitis
and Crohn disease increases after 8–10
years and is highest in patients with early-
onset and extensive involvement of the
colorectum, especially pancolitis. A B
Fig. 8.19 Juvenile polyp. A Smooth eroded surface with numerous mucus retention cysts, typical of sporadic juvenile
Ulcerative colitis (UC) polyps. B Expanded inflamed stroma with distorted glands showing reactive changes.
This chronic inflammatory disorder of
unknown etiology affects children and
adults, with a peak incidence in the early similar {3443}, they seem to differ in Genetic susceptibility
third decade of life. A risk of CRC of 30% frequency and sequence: APC mutation Twin studies suggest that up to 35% of all
after 30 years is reported in patients with occurs late and TP53 mutation occurs CRCs can be ascribed to inherited
pancolitis in whom the inflammatory early in UC-associated CRC {3568}, and susceptibility {637}. Approximately 10–35%
disease began before the age of 15 MSI-H CRC is frequent {915}. Multiple of all CRC cases show familial clustering,
years. Population-based studies show a heterogeneous molecular alterations may and only a proportion can be explained
4.4-fold increase in mortality from CRC be found in the surrounding mucosa {582, by known syndromes. The currently
{771, 2039, 2532, 3078}, but in clinical 2476, 2693}, indicating field abnormalities known CRC-predisposition syndromes
studies, the increase in incidence is that explain the multiplicity. Use of molec- with high-risk germline mutations account
usually higher, up to 20-fold {1095, 1698}. ular markers, including transcriptome for < 6% of all cases {1}.
Involvement of more than half of the analysis, to allow early detection of The high-risk genetic diseases are
colorectum by UC is associated with a intraepithelial neoplasia/dysplasia in UC classified morphologically into polyposis
risk of developing carcinoma of approxi- has been extensively investigated, but to syndromes characterized by large numbers
mately 15%, whereas less extensive date no markers have achieved a level of of polyps (e.g. FAP) and nonpolyposis
left-sided disease has a lower risk of evidence to be included in follow-up syndromes characterized by a small num-
malignancy of about 5% {1801, 2915}, surveillance. ber of or absence of polyps, e.g. Lynch
and ulcerative proctitis is not associated syndrome. Although most of these syn-
with increased risk. Crohn disease dromes show autosomal dominant inheri-
UC-associated CRCs are often multiple, This disease is associated with an tance, recessive inheritance is evident in
flat, infiltrative, and mucinous or signet-ring increased risk of carcinoma in the small MUTYH-associated polyposis (MAP) due
cell type. Low-grade tubuloglandular ade- and the large intestine. The risk of CRC to mutation of the base excision-repair
nocarcinoma occurs almost exclusively in appears to be about threefold that in gene inherited from each parent {1906}.
UC or Crohn disease and is particularly individuals without chronic inflammatory For individuals from unexplained family
problematic to diagnose because of its bowel disease {890, 989}. Long duration clusters, the lifetime risk for CRC is more
well-differentiated nature {1815, 3341}. The and early onset of disease are risk than twice that of the general population
carcinomas evolve through low-grade and factors, as in UC. The characteristics of when these individuals have an affected
high-grade dysplasia that have heteroge- CRC in Crohn disease are similar to those first-degree relative, and more than three-
neous macroscopic appearances and in UC {2966}, but there is also an increased fold when the first-degree relative is
may be difficult to distinguish histopatho- frequency of adenocarcinoma within younger than 50 years {177, 388, 1435}.
logically from inflammation-induced reac- perianal fistulae and of squamous cell Some of the currently unexplained familial
tive epithelium. Flat lesions may be difficult carcinoma of the anus {1702}. risk could be attributable to as yet
to recognize endoscopically without chromo-
endoscopy {469}. Raised dysplastic lesions
(“dysplasia-associated lesion or mass”,
DALM) may present as polyps, plaques or
subtle velvety patches in inflamed areas.
Extensive biopsy sampling is therefore
essential. DALM is strongly associated with
carcinoma and considered an indication
for colectomy {1880}, but distinction of
colitis-associated dysplasia from a sporadic
adenoma that can be adequately treated
by polypectomy may be very difficult A B
{1880, 1882, 3370}. Fig. 8.20 Moderately differentiated adenocarcinoma with tubular adenoma, excised by endoscopic mucosal resection.
Although the molecular alterations in A Part of the adenocarcinoma invaded the lamina muscularis mucosae. B Immunohistochemical staining for desmin
sporadic and UC-related cancer are reveals entanglement of the tissues of the invading adenocarcinoma with muscle fibres of the muscularis mucosae.
Carcinoma 141
Fig. 8.21 Reactive epithelial changes in ulcerative colitis. Fig. 8.22 Low-grade dysplasia in ulcerative colitis. Note Fig. 8.23 Inflammatory polyp in ulcerative colitis.
the haphazardly arranged dysplastic glands.
unidentified highly penetrant genetic risk by GWAS collectively account for about Predisposition: germline (i.e. inherited)
factors. Another explanation could be the 6% of the risk of developing CRC. Low- variants that result in increased risk.
combination of several cancer-susceptibility penetrance alleles can act as modifiers in Profile: somatically mutated or altered in
alleles of low or moderate penetrance highly penetrant diseases {3505}. Func- expression within tumours.
{1251}. tional causal variants and genes and the Prognostic: associated with natural history
mechanisms of their actions are only partly and clinical outcome.
Unexplained high- or moderate-risk known. The novel variants may act as Predictive: associated with responsiveness
genetic predisposition regulatory elements of gene expression. or resistance of a tumour to specific
Evidence for additional high- or moderate- therapies.
risk alleles comes from the 30–40% of Genetic risk of CRC associated with other Pharmacogenomic: associated with me-
large families with CRC who fulfil the so- cancer syndromes or diseases tabolism and may affect levels and
called “Amsterdam” clinical criteria for Risk of CRC may be influenced by effectiveness of specific therapies
Lynch syndrome but lack a deficiency in germline defects that lead to cancer These five categories overlap, and many
mismatch repair and germline mutations syndromes not typically involving the genes and biomarkers are in more than
in mismatch-repair genes {669, 1863, colorectum, e.g. Li-Fraumeni syndrome, one category.
1864}. Such families have been termed characterized by germline mutation of
“familial colorectal cancer type X” {1862} TP53 {2367, 3544}, and BRCA1 hereditary Profile genes and biomarkers in the
or mismatch repair-proficient hereditary breast and ovarian cancer syndrome adenoma–adenocarcinoma sequence
nonpolyposis colorectal cancer (HNPCC). {648, 881}. Genetic polymorphisms or CRC is a paradigm for multistep carcino-
{2794}. Linkages with chromosomes 3q22 alterations in inflammatory-response genes genesis with morphological–genomic
and 9q22 have been reported {1517, are related to the occurrence of UC and associations in the adenoma–adenocar-
1519, 2447, 2545, 2983, 3502}. Crohn disease that in turn predispose to cinoma sequence, as introduced by
CRC. Alterations in TNF and NOD2/- Fearon and Vogelstein in 1990 {829,
Low-penetrance cancer-susceptibility CARD15 may influence the risk of CRC at 2199}. The body of evidence indicates
alleles older ages and with no relationship to that: (1) some alterations segregate
Numerous genome-wide polymorphic inflammatory bowel disease {1691, 3111}. together or inversely as part of a “genetic
genetic variations that may determine in- pathway” {1316}; and (2) functional path-
dividual susceptibility to cancer have been Molecular pathology ways can be disrupted at different points
studied in candidate-gene approaches Cancer-associated genes and biomarkers so that different alterations may have
and genome-wide association studies can be grouped into categories based functional “equivalence” in the same
(GWAS) {670, 2768, 3265}. Loci identified upon the types of information they provide: pathway {2493}.
Chromosomal instability pathway

Around 75% of sporadic CRCs in devel-
oped countries, a higher percentage in
low-incidence populations, and most syn-
dromic CRCs other than Lynch syndrome
develop along the chromosomal-instability
pathway {1046, 1486}. These cancers are
characterized by gross chromosomal
abnormalities, such as aneuploid kary-
otype, large chromosome-segment dele-
tions and duplications, and increased
Fig. 8.24 Crohn-like lymphoid reaction associated Fig. 8.25 Well-differentiated adenocarcinoma in Crohn nuclear DNA content. The tumours almost
with a colonic adenocarcinoma. disease, invading the wall beneath high-grade dysplasia with always have an APC mutation (> 90%)
villous architecture. while KRAS mutations occur in about 50%,

TP53 mutations in about 70%, and 18q Table 8.02 Genetic syndromes associated with a possible risk of colorectal carcinoma.
allelic loss in about 80%. Some tumours Syndrome Gene (chromosome) MIM No.
have a BRAF mutation as an alternative to
Autosomal dominant inheritable colorectal carcinoma
KRAS mutation {2887}. The molecular
characteristics of individual CRCs asso- No or few adenomatous polyps
ciate with DNA methylation status owing Lynch syndromea,b MLH1 (3p21–p23), 120435
to epigenetic and genomic interactions. MSH2 (2p21), MSH6 (2p21),
Mutations in PIK3CA are reported to PMS2 (7p22)
occur in about 25% of tumours and are
considered to be late events {2362}. Mu- Adenomatous polyps
tations in FBXW7/CDC4 are also reported Familial adenomatous polyposis (FAP)a and APC (5q21–q22) 175100
as late occurrences, and it is claimed attenuated FAP (AFAP)
these are responsible for aneuploidy Hamartomatous / mixed / hyperplastic polyps
{1518, 2618}, since adenomas are rarely Peutz-Jeghers syndrome (PJS) LKB1/STK11 (19p13.3) 175200
aneuploid. Low-frequency mutations are
Juvenile polyposis syndrome (JPS) SMAD4 (18q21.1) 174900
reported in mitotic checkpoint genes
BMPR1A (10q22.3)
such as CHEK2 {3519} and BUB1 {391}
Hereditary haemorrhagic telangiectasia syndrome (HHT)c ENG (9q33–q34.1), 187300
that also may contribute to aneuploidy.
ACVRL1 (12q11–q14)
Hyperplastic polyposis syndrome (HPS)c MUTYH (1p34.1; autosomal Unassigned
Microsatellite instability (MSI) pathway recessive), MBD4 (3q21.3)
Approximately 15% of sporadic CRCs in
Hereditary mixed polyposis syndrome (HMPS)c CRAC1 (15q13–q21) 601228
developed countries, a lower percentage
in low-incidence populations, and almost PTEN hamartoma syndrome (Cowden syndrome/ PTEN (10q23) 158350/153480
Bannayan-Ruvalcaba-Riley syndromes)c
all CRCs in HNPCC patients develop
along the MSI pathway {472, 1104}. Birt-Hogg-Dube syndromec FLCN (17p11.2) 135150
These tumours have lost the mismatch- Autosomal recessive inheritable colorectal carcinoma
repair function. Microsatellites are nucleo-
tide repeat sequences that are prone to Adenomatous, serrated adenomas and hyperplastic polyps
formation of insertion/deletion loops MUTYH-associated polyposis (MAP)b MUTYH (1p34.1) 608456
during DNA replication. Mismatch repair a
Turcot syndrome is a variant of Lynch syndrome, or FAP with brain tumours.
usually corrects insertion/deletion loops b
Muir-Torre syndrome is a variant of Lynch syndrome, or MAP with sebaceous gland tumours.
and keeps microsatellites at germline c
Risk of colorectal carcinoma is not clear.
length, whereas deficient repair allows
insertion/deletion loops to persist. After
additional rounds of replication without microsatellite, or as a result of germline often grouped with microsatellite-stable
mismatch repair, multiple alleles of varying mutation. tumours. Indirect diagnosis of MSI-H can
lengths develop, now termed MSI-H {227, Classification of MSI status is based on also be made using immunohistochem-
1317} and previously reported as ubiqui- altered size of various mononucleotide istry for loss of mismatch-repair proteins,
tous somatic mutations (USM) and DNA and dinucleotide repeat sequences (e.g. with greater accuracy for sporadic than
replication errors (RER). BAT25, BAT26, D5S346, D2S123, D17S250, for inherited cases {2420}.
In sporadic tumours, MSI-H and loss of known as the Bethesda panel) {296, Many genes contain small runs of
mismatch repair occur mainly due to 2977, 3342}. MSI-H is defined by altered nucleotide repeats in exonic coding re-
methylation of the MLH1 gene promoter size of at least two of the five (40%) gions, and consequently MSI-H tumours
with resultant epigenetic loss of protein microsatellite markers. Sporadic MSI-H frequently have frameshift mutations in
expression of MLH1 and its binding part- CRCs have more extensive alteration of these genes, e.g. TGFBR2, IGF2R, BAX,
ner PMS2. Sporadic MSI-H cancers microsatellites than Lynch syndrome TCF7L2, E2F4, PTEN, MSH6, MSH3, and
usually have global hypermethylation (i.e. CRCs. Most MSI-H cancers are diploid or CASP5 {916, 1434, 1978, 2627, 2862,
CpG island methylator phenotype, CIMP). near diploid, and the frequency of loss of 3027, 3592}. Instability in 3’ untranslated
In Lynch syndrome, loss of mismatch heterozygosity (LOH) is low, including regions can lead to loss of expression,
repair usually occurs because of germline chromosome 5q (962,841). Microsatellite- exemplified by BMPR2 {1623}. Numerous
mutation of one of four mismatch-repair stable tumours have no instability identi- single-nucleotide mismatches also persist.
genes (MSH2, MLH1, MSH6, or PMS2) or fied in the panel. Tumours with one The mutational profile of sporadic MSI-H
the TACSTD1 regulatory gene {1851}. abnormal marker among the five in the tumours includes APC, BRAF (approxi-
Usually, but not invariably, there is loss of panel (or more than one and < 40% of mately 50%), but rarely KRAS. Lynch syn-
expression of the corresponding gene markers in larger sets) are termed MSI-L. drome-associated cancers may contain
product in the case of MSH2 or MLH1 and The classification, and therefore the clini- CTNNB1 mutations {1437} as an alterna-
their binding partners (MSH6 and PMS2, cal significance, of MSI-L is controversial tive to APC, and never contain BRAF mu-
respectively). MSH6 can also be lost as a owing in part to lack of standardization of tation {732}, providing a useful marker to
result of defective mismatch repair the number and type of markers used, identify sporadic cases among those that
because the MSH6 gene itself contains a and this small subset of tumours is have lost MLH1. MSI-H tumours have a
Carcinoma 143
Table 8.03 Genes harbouring alleles that confer susceptibility to colorectal cancer, identified from candidate screens. mutation are referred to as CIMP1, whereas
Genetic pathway Gene variants References
CIMP tumours that are microsatellite-stable
with a high frequency of KRAS mutations
Carcinogen pathway NAT2, GSTT1 {670} are referred to as CIMP2, and CIMP-nega-
tive tumours are microsatellite-stable with
Folate pathway MTHFR {670, 1251A, 3473A}
frequent TP53 mutations {2918, 3115}.
Alcohol detoxification ALDH2 {670}
Noncoding RNAs
Oncogene HRAS1 {670, 1251A}
Small noncoding RNAs termed “micro-
Tumour-supressor genes APC, TCF7L2, TP53, CHEK2, BRCA1 {670, 877A, 1251A} RNAs” regulate gene expression, resulting
in loss of expression of tumour-suppressors
Others CaSR, AKAP9, PTGS1, TNFα, NOD2/CARD15 {1691, 2536A, 3111, 3473A} and expression of oncogenes. {2734}.
Table 8.04 Loci conferring susceptibility to colorectal cancer, identified from genome-wide association studies (GWAS). Stem-cell markers
Single nucleotide polymorphism (SNP) Chromosome Tagging gene Reference The cancer stem-cell hypothesis states
that a small number of stem cells undergo
rsl6892766 8q23.3 ElF3F {3265A} asymmetric division and are responsible
rs6983267/rs10505477 8q24.21 MYC {3265B, 3677A} for the generation of the bulk of the
tumour cells {92, 297}. Cancer stem cells
rs719725 9p24 {2583A} may be the counterparts of normal tissue
rsl075668 10p14 {3265A} stem cells and are proposed to be the
source of tumour recurrence and resist-
rs3802842 11q23.3 {2555B, 3212A} ance to chemotherapy, leading to thera-
rs4444235 14q22.2 BMP4 {1251B}
peutic strategies to attempt to specifically
target cancer stem cells. However, identi-
rs4779584 15q13.3 CRAC1 (HMPS) {1376A} fication of these cells is problematic since
they usually represent only a small
rs9929218 16q22.1 CDH1 {1251B}
fraction of the tumour cell population. In
rs4939827/rs12953717/rs4464148/Novel1' 18q21.1 SMAD7 {336A, 2555A, 3212A} addition, cancer stem cells may be in a
state of plasticity, rather than representing
rs10411210 19q13.1 RHPN2 {1251B}
a fixed tumour-cell subtype.
rs961253 20p12.3 {1251B} Several potential stem-cell markers that
have been proposed for CRC include
CD133, CD166, CD24, LGR5, DCAM
distinguishable gene-expression tran- analysis for total DNA content {476, 1526}, kinase-like II, Bmi, Musashi-1, and alde-
scriptome and microRNAome {1743}. evaluation of LOH at multiple loci, or array hyde dehydrogenase-1 {647, 2013, 2331,
Tumours with MSI-H, whether sporadic or comparative genomic hybridization. 2671, 3133, 3204, 3397}.
Lynch-associated, have morphological dif-
ferences from tumours with chromosomal CpG island methylator phenotype (CIMP) Prognosis and predictive factors
instability. They are frequently right-sided, Many genes contain areas rich in cytosine Anatomic extent of disease, i.e. tumour
mucinous or occasionally medullary type, and guanine dinucleotides, termed CpG stage, is the strongest prognostic factor for
associated with a Crohn-like peritumoral islands, within their promoter regions. CRC. Additional factors are summarized in
lymphocyte infiltrate and an intratumoral Methylation of the cytosine residues in Table 8.05 {675, 1022, 3462, 3725}:
lymphocyte infiltrate, devoid of “dirty” these CpG islands changes chromosomal
necrosis, and at lower stage and with structure and inhibits gene expression, Morphology
expansile growth and better stage-specific including that of tumour-suppressor genes, In addition to deeper invasion, especially
prognosis {952, 1416, 1548}. MSI-H tumours thereby allowing epigenetic loss of function serosal-surface involvement, greater extent
may be less responsive to certain chemo- without mutation. Methylation of gene of involvement of a particular layer of the
therapies, such as 5-fluorouracil {698, 2975}, promoters can occur as an age-related wall, an infiltrative pattern of the invasive
but more responsive to irinotecan {244}. phenomenon (called Type A methylation) edge and tumour budding as contrasted
but also occurs as a specific widespread with an expansile pattern, a microacinar
Microsatellite-stable and chromosome- phenomenon in certain cancers (called pattern with discrete small and relatively
stable tumours Type C methylation) {2361, 3282, 3724}. regular tubules {3499}, poor differentiation
Up to 15% of tumours do not show the Tumours with CIMP often have MSI-H including signet ring cell and mucinous
classical pathways of genome instability because of methylation of the MLH1 adenocarcinomas in the absence of MSI-H,
i.e. they will show neither MSI nor chromo- mismatch-repair gene; however, > 50% of and other histopathological types of
somal instability. These tumours are little CIMP carcinomas are microsatellite-stable. carcinoma (i.e. adenosquamous carcinoma
studied since demonstration of chromo- CIMP status clusters with MSI status and and small cell carcinoma) are associated
somal stability requires specialized tech- mutations in KRAS, BRAF, and TP53. with poorer prognosis {3437, 3438}.
niques such as flow cytometry or image Tumours with frequent MSI-H and BRAF

Additional lymph-node characteristics but none has been adopted into routine
Metastasis to numerous or a high proportion clinical practice. Tumour stage continues
of nodes, to those near the mesenteric to be the mainstay for patient-manage-
margin and/or at great distance from the ment decisions affected by prognostic
primary tumour, or to retrograde lymph considerations. This situation is attributable
nodes, and pathological examination of a to lack of the necessary levels of
smaller number of negative nodes (e.g. 12– evidence to support the use of potential
18) have been associated with poorer markers, as a consequence of lack of
prognosis {1043}. The prognostic value of cross-validation. The complexity of CRC
identification of isolated tumour cells or with the recognition of molecular subtypes
micrometastasis in lymph nodes by immuno- that often share markers despite very
Fig. 8.26 Adenocarcinoma within a lymphatic vessel.
histochemical or molecular techniques different biological behaviour contributes
remains controversial {2474}. to the lack of marker utility. In studies of
markers, variability in quality of pathology,
Extent of resection in protocols and methodologies used,
The term “margin” refers to the areas of a and in scoring or assessing markers,
resection or excision specimen that have under-powering due to sample size, ten-
been cut by the surgeon or gastroenterolo- dency to study single markers rather than
gist. Margins are not natural structures complete pathways, and the retrospective
such as the serosal surface. A short nature of the studies are problematic
longitudinal surgical resection margin (2– {2031}. The marker with the highest level
5 cm) reflecting the surgical technique em- of evidence is MSI-H for improved stage-
ployed and anatomical considerations has specific survival, with a hazard ratio of A
been associated with poor outcome. In rec- about 0.65 {2578}. Good prognosis is also
tal cancer, distance from the circumferen- reported where there is infiltration of
tial margin representing the adventitial soft tumours by cytotoxic T cells {3432}, a fea-
tissue margin closest to the deepest pene- ture of MSI-H. Reported markers for poor
tration of the tumour is important owing to prognosis include mutations of BRAF
the anatomical proximity of pelvic struc- {2788}, allelic imbalance at 18q {2577},
tures {2866}. For all segments of the large mutation of PIK3CA {2362}, or high
intestine that are either incompletely or not expression of CD133 stem-cell marker
enveloped by peritoneum, the circumfer- {297}, osteopontin {2703}, or CXCL12 {55}.
ential margin created by blunt or sharp dis-
section at operation is also important, as is Predictive genes and biomarkers
B
the mesocolic margin in colon cancer. The These genes or biomarkers that indicate Fig. 8.27 Well-differentiated adenocarcinoma that was
distance of the carcinoma from the margins likelihood of tumour response or resist- excised by endoscopical mucosal resection. A Veinous
invasion in a well-differentiated adenocarcinoma. B Elastic
in specimens from polypectomy, endo- ance to specific therapies and of their
(Van Gieson) stain reveals an artery that runs parallel to
scopic mucosal resection, submucosal toxicities must be used within the context the vein; the vein is invaded by adenocarcinoma.
excision, and transanal excision also has of the pathway that is being targeted, the
prognostic importance. combination of agents administered, and kinase inhibitors are inactive against CRC.
the clinical setting. Between 1995 and However, EGFR signals through the
Extramural venous invasion 2005, the number of efficacious thera- RAS/RAF pathway, and mutation in down-
Carcinomas sometimes invade muscular peutic agents for CRC increased from stream KRAS, leading to constitutive
veins. Many studies have shown that one (i.e. 5-fluorouracil) to seven (i.e. activation, renders tumours unresponsive
invasion of extramural (i.e. beyond the 5-fluorouracil, capecitabine, oxaliplatin, to upstream inhibition by anti-EGFR
muscularis propria) muscular veins is a irinotecan, bevacizumab, cetuximab, and antibodies {1847, 2321, 2810, 3025}.
poor prognostic feature {2599}. panitumumab), including the latter three Testing for KRAS mutation is therefore
targeted antibodies {2270}. Some of the required before the antibodies are used.
Other prognostic features best examples of predictive tumour mark- KRAS may be mutated at any of three
Angiolymphatic invasion and involvement ers are described below. potential hotspots (i.e. codons 12/13, 61
of perineural spaces and nerves are and 146) that should be tested. The role of
adverse features, whereas peritumoral KRAS mutation and epidermal growth BRAF mutation is less certain. EGFR also
lymphocytic response and tumour- factor receptor (EGFR) inhibitors signals through PIK3CA, and mutation of
infiltrating lymphocytes are favourable EGFR is expressed in most CRCs and, that gene and loss of PTEN expression
and often associated with MSI-H {939}. because it is located on the cell surface, may be adverse predictive markers.
it is an attractive target. The anti-EGFR Expression of epi- and amphiregulin
Prognostic genes and biomarkers monoclonal antibodies cetuximab and ligands and EGFR amplification are
The published literature is awash with panitumumab block ligand binding and potential favourable predictive markers.
studies reporting molecular or immuno- produce a dramatic response in some CRC
histochemical prognostic factors in CRC, patients, whereas small-molecule tyrosine
Carcinoma 145
Table 8.05 Prognostic factors not included in the TNM staging of carcinoma of the colon and rectum.
Adverse features of primary tumour Adverse vessel invasion Favourable host response Adverse surgical technique
Greater extent of circumferential involvement Muscular veins Intratumoral inflammation Short distance between resection margin and tumour
Bowel obstruction Lymphatic vessels Peritumoral inflammation Incomplete excision with residual tumour
Bowel perforation Perineural spaces Desmoplasia
Poor differentiationa Reactive lymph nodes
Infiltrative pattern of invasion/budding
Selected molecular characteristics
a
See Table 8.02 for exceptions related to high levels of microsatellite instability (MSI-H).
MSI-H and 5-fluorouracil, oxaliplatin and Other markers with mechanistic plausibil- Germline gene characteristics have the
irinotecan ity have been reported, including expres- potential to provide pharmacogenetic
MSI-H predicts poor response to 5-fluo- sion of thymidylate synthase (TYMS/TS), predictive biomarkers {2796}. Exposures
rouracil and oxaliplatin. Mismatch repair the target of 5-fluorouracil and of the fluo- including lifestyle factors such as diet
detects mutations produced by the ropyrimidine catabolizing enzymes dihydro- {2056}, physical activity {2055} and other
insertion of 5-fluorouracil into DNA and pyrimidine dehydrogenase (DPD) and drugs {2663} may also affect outcome
the formation of oxaliplatin adducts, and thymidine phosphorylase (TP). The re- after therapy. A large number of additional
then induces apoptosis if these alterations ported data are conflicting on the rela- agents directed at targets in CRC, e.g.
cannot be repaired. In the absence of tionship of expression to response to this MET and insulin-like growth factor 1
mismatch repair, apoptosis may not drug, which is the most commonly used receptor (IGF1R), are in the drug-devel-
occur, resulting in resistance to these therapeutic agent for CRC {328, 1917}. opment pipeline {474}. Research on
agents {3667}. Cell lines with MSI-H are Tumour topoisomerase I (Topo 1) expression genes and biomarkers for current and
usually sensitive to irinotecan {325}, and may predict a good response to irinotecan emerging therapeutic agents is targeted
the survival of patients with MSI-H colon and oxaliplatin. This enzyme unwinds DNA to providing personalized cancer therapy
cancers may be better survival after during replication and repair, and irinote- with optimal efficacy, toxicity and cost–
adjuvant therapy that includes this agent can is a Topo I inhibitor, but the mecha- effectiveness.
{244}. nistic link to oxaliplatin is uncertain {1741}.

Familial adenomatous polyposis F.M. Giardiello

R.W. Burt
H.J. Järvinen
G.J.A. Offerhaus
Definition in attenuated FAP averages approximately syndrome is fully developed {384, 3385}.
Familial adenomatous polyposis (FAP) is 30, while the number of polyps is extremely The finding of fewer adenomas in a first-
an autosomal dominant disorder charac- variable; the upper gastrointestinal polyps degree relative of an affected person is
terized by the development of hundreds to are similar to those arising in typical FAP. likewise diagnostic, especially in younger
thousands of colorectal adenomatous Extra-intestinal growths may occur in individuals. Histological confirmation of
polyps and the inevitable occurrence of attenuated FAP, but are far less common polyps as adenomas is required to distin-
colorectal adenocarcinoma if the colon is than in the classical form. guish FAP from other forms of polyposis,
not removed {384, 936, 3385}. Fundic including hamartomatous polyposes, lym-
gland polyps of the stomach and duodenal MIM No. phoid hyperplasia and lymphomatous
and small-bowel adenomas are also com- FAP (including Gardner syndrome polyposis. In cases in which the number
mon. FAP is caused by germline mutations and attenuated FAP) 175100 of synchronous adenomas is < 100, the
in the adenomatous polyposis coli (APC) Turcot syndrome 276300 possibility of MUTYH polyposis should
gene, which is located on the long arm of also be considered.
chromosome 5 (5q21–22) {378}. Synonyms A conclusive diagnosis of FAP is achieved
Gardner syndrome is a variant of FAP that Adenomatous polyposis coli, familial by demonstration of a disease-causing
includes epidermoid cysts, osteomas, polyposis coli, Bussey-Gardner polyposis, germline mutation in the APC gene {378}.
dental anomalies and desmoid tumours, in Gardner syndrome, familial multiple The rate of detection of such mutations in
addition to the expected gastrointestinal polyposis, multiple adenomatosis, familial an index case with the expected pheno-
polyps {947}. It is now more of historical polyposis of the colon and rectum, famil- type is 60–80%, but much lower for
interest, as these extra-intestinal growths ial polyposis of the gastrointestinal tract, attenuated FAP. Once the disease-causing
are known to correlate more with mutation familial adenomatous polyposis coli, etc. mutation is known in a family, genetic test-
location in the APC gene, rather than ing of family members for the presence or
occurring together in specific families. Incidence absence of that specific mutation is diag-
Nonetheless, the name persists and is Estimates of the incidence of FAP vary nostic with near 100% accuracy. The
often applied to families in which the extra- between 1 per 7000 and 1 per 30 000 presence of the mutation confirms the
intestinal manifestations of the disease are newborns. In general, FAP underlies < 1% diagnosis, while its absence rules out FAP.
particularly obvious and common. of all new cases of colorectal cancer. In patients for whom the fulfilment of the
The name “Turcot syndrome” is applied to Between 30% and 50% of new FAP clinical criteria remains doubtful and
a variant of FAP with typical intestinal patients are de novo cases, representing genetic diagnosis is not achieved, the find-
polyps but also brain tumours, almost new mutations of the APC gene or APC- ing of extracolonic features of FAP (e.g.
always medulloblastoma in type {1108, gene mosaicism in one of the parents epidermoid cysts, osteomas, desmoid
3321}, although the original Turcot family (much less common) {1179}. tumour, gastric fundic-gland polyps,
had Lynch syndrome (658). duodenal adenomas) may give additional
An attenuated form of FAP, called attenu- Diagnostic criteria diagnostic support. The following diag-
ated FAP or attenuated APC, has been Classical FAP is defined clinically by the nostic criteria have been established: (1)
distinguished from classic FAP {380, 1178, finding of at least 100 colorectal adeno- 100 or more colorectal adenomas; or (2) a
1619}. The number of colorectal adenomas matous polyps in a patient in whom the germline disease-causing mutation of the
A B
Fig. 8.28 Colectomy specimens from patients with familial adenomatous polyposis. A Multiple adenomas at different Fig. 8.29 Mesenteric fibromatosis (desmoid tumour) in a
stages of development. B Numerous small early (sessile) adenomas. patient with familial adenomatous polyposis. The lesion
entraps loops of small intestine.

APC gene; or (3) family history of FAP and the mean age at which symptoms appear
any number of adenomas at a young age. is 33 years and the mean age of diagnosis
Diagnostic criteria for attenuated FAP are is 36 years in unscreened/untreated FAP
more difficult to establish. An autosomal patients. Two thirds of patients diagnosed
dominant pattern of a smaller number of with FAP on the basis of symptoms already
adenomatous polyps is very suggestive have colorectal cancer, whereas cancer in
and best confirmed by genetic testing for asymptomatic members of known FAP fam-
mutations in expected areas of the APC ilies is very rare, if regular surveillance and
gene. As noted previously, the number of appropriate therapy have been undertaken.
adenomas averages 30, but is extremely The symptoms and signs of extra-intestinal
variable, making clinical diagnosis in a manifestations may sometimes precede
Fig. 8.30 A single crypt adenoma (aberrant crypt focus),
specific individual difficult. “Rectal sparing” those of the colorectum. Symptoms from be- the earliest microscopically recognizable adenoma in a
is common in patients with attenuated FAP. nign polyps of the upper gastrointestinal tract person affected by familial adenomatous polyposis.
are rare. Symptoms occur with gastric and
Localization duodenal cancers, but these virtually never Proliferation
Colorectal adenomas in FAP occur precede symptoms or cancer of the colon. The histologically normal intestinal mucosa
throughout the colon, but follow the gen- in FAP shows no increase in the rate of
eral distribution of sporadic adenomas, Macroscopy epithelial-cell proliferation {3459}. Mitotic
often with a slight excess of polyps in the Most polyps in FAP are small (usually activity is not increased {2218}, except in
left colon {384}. The distribution of cancers < 5 mm), sessile, and spherical, but may the adenomatous epithelium in which cell
follows that of the adenomas. This colonic be lobulated. Scattered larger peduncu- proliferation is identical to that in sporadic
distribution is reversed in attenuated FAP, lated polyps are much less common adenomas. Interestingly, in multiple intes-
with both adenomas and cancers exhibit- {979}. In the completely expressed dis- tinal neoplasia (Min) mice, a model for the
ing a more proximal colonic distribution ease, polyps often number hundreds or development of FAP, the histologically
with frequent “rectal sparing” {380}. thousands and may “carpet” the lining of normal-looking mucosa has an extended
the whole large bowel. The number of proliferative compartment and decreased
Clinical features adenomas per patient varies between rate of cellular crypt–villus migration
Age at clinical manifestation families, in some families being little more {1954}. Mutation of APC is associated
Colorectal adenomas become detectable than 100 even in adults, whereas most with a dominant-negative effect upon
at endoscopic examination in the second families are affected by profuse polyps, intestinal-cell migration {1954}. Studies on
or third decade of life, occurring at an numbering hundreds or thousands {979}. the cellular kinetics of proliferative pat-
average age of 15.9 years (range, 8–34 terns in the normal-looking colonic
years) {2537}. Polyps increase in number Histopathology mucosa of humans with FAP have also
and size with age. The most important Adenomas in FAP begin as dysplastic shown expansion of the proliferative com-
clinical feature of FAP is the almost invari- aberrant crypt foci, so-called “single- partment {699}. Moreover, the stem-cell
able progression of one or more colorec- crypt adenomas” {1414}. In practice, to dynamics of normal-appearing crypts in
tal adenomas to cancer. The mean age at find more than one of these in a colon is the colon of FAP patients indicate that
which cancer develops is about 40 years, considered virtually pathognomic for FAP. stem-cell survival is enhanced compared
but the risk of cancer is already 1–6% by By excessive and asymmetrical crypt fis- with unaffected individuals {1554}.
the age of 21 years {384}. By age 50 sion {3459} subsequent to loss of APC- These observations show that before
years, > 90% of untreated patients will controlled growth and tissue organization, somatic loss of the wild-type APC allele,
have colorectal cancer. Rare cases of these aberrant crypt foci develop into haploinsufficiency has apparently already
colorectal cancer have been reported in oligocryptal adenomas, which may not be lead to microscopically occult alterations
children with FAP. Extracolonic manifesta- visible as polyps before further growth in cell growth, differentiation and migration
tions such as epidermoid cysts, mandibular into grossly visible adenomatous polyps. in the colonic crypts of FAP patients, a
osteomas, desmoid tumours or congenital FAP adenomas have the same architec- phenomenon considered as pre-tumour
hypertrophy of the retinal pigment epithe- ture as their sporadic counterparts; most progression {394}.
lium (CHRPE) may present in children are tubular adenomas or, less frequently,
and can serve as markers of FAP. tubulovillous or villous. Nonpolypoid “flat” Small-intestinal polyps
adenomas account for approximately 5% Small-bowel polyps, particularly duode-
Symptoms and signs of colon adenomas in affected family nal polyps, are also adenomas. They
In the early phase of FAP, adenomas do not members {1997}. Adenomas and carci- develop preferentially in the periampullary
cause any symptoms. Specific symptoms nomas in FAP are histologically identical region of the duodenum, probably due to
attributable to colorectal adenomas do not to sporadic lesions. As for sporadic ade- a co-carcinogenic effect of bile {3043}.
usually occur until late in the second or nomas and colorectal carcinomas, the They become evident 10 years later than
early in the third decade of life and include incidence of malignancy depends on size colorectal polyps. Using side-viewing
rectal bleeding and diarrhoea, often and frequency. Adenomas in attenuated endoscopy, adenomas have been found
accompanied by mucous discharge and FAP show the same cytological features in 92% of patients with FAP at routine
abdominal pain. Such symptoms appear as adenomatous epithelium, but more screening {3047}. The severity of duode-
gradually and may be easily overlooked; often appear flat or depressed {598}. nal polyposis can be classified according

to Spigelman by the number, size, structure, Endocrine system. There is a definite but
and degree of dysplasia of adenomas relatively slight increase in the incidence of
{3047}. These adenomas increase in size neuroendocrine neoplasms in FAP, includ-
and number with time and carry a lifetime ing neoplasia of the pituitary, pancreatic
risk of duodenal or periampullary cancer of islets and adrenal cortex {1975}, as well as
4–10% {272, 1805}. Ampullary and peri- multiple endocrine neoplasia syndrome
ampullary adenocarcinoma is one of the (MEN), type 2b {2527}, but these are of
principal causes of death in patients who insufficient frequency or gravity to form
have undergone prophylactic proctocolec- part of a routine screening protocol. The
tomy {3047}. Adenomas develop rarely in best documented endocrine association is
the jejunum or ileum, but after prophylactic papillary carcinoma of the thyroid {464},
Fig. 8.31 Mesenteric fibromatosis (desmoid tumour) in a
proctocolectomy with ileoanal pouch, the patient with familial adenomatous polyposis. Note the which is largely restricted to women {364}.
prevalence of ileal adenomas may exceed collagen bands and small vessels. Nervous system. The concurrent presence
50% {252}. of a brain tumour and multiple colorectal
A desmoid is a mass of firm pale tissue, polyps constitutes Turcot syndrome. Some
Extraintestinal manifestations characteristically growing by expansion, individuals affected in this way have FAP
Several other organs are involved in FAP, usually rounded in shape. Desmoids begin and carry a germline defect in the APC
but extra-intestinal manifestations rarely as small scar-like foci of fibrosis in the gene. These are infants or young children
determine the clinical course of the retroperitoneal fat and, when large, typically who present with medulloblastoma and
disease, except for desmoid tumours. extend around and between other structures colorectal polyps {1108}. Other individuals
Stomach. Gastric adenomas do occur such as the small or large bowel, ureters, present later in life with a glioma, usually
with increased frequency {734}, but the and major blood vessels. Histologically, an astrocytoma or glioblastoma multiforme
most common abnormality is the fundic- these lesions are composed of sheets of that is usually associated with Lynch
gland polyp. This is a non-neoplastic elongated myofibroblasts, arranged in fas- syndrome rather than FAP {1900}.
mucus-retention type of polyp, grossly vis- cicles and whorls. The lesions have a dense,
ible as a smooth dome-shaped nodule in tough, consistency, and there is a variable Genetic susceptibility
the gastric body and fundus, and is usu- amount of collagen. They are well-vascu- Genetics
ally multiple. Histologically, the lesion is larized and contain numerous small blood FAP is an autosomal dominant disease
characteristically undramatic, consisting vessels that bleed profusely when incised. with almost complete penetrance by age
of gastric-body mucosa that is often normal Desmoid tumours may grow rapidly, but 40 years. In 1991, germline mutations in
apart from cystic dilatation of glands. can resolve spontaneously; some show the APC gene were identified as the
There is evidence for increased cell prolif- cycles of growth and regression, while cause of FAP by several investigators,
eration and dysplasia developing in these others remain stable {569}. Mesenteric including Kinzler, Groden, and Nishisho
polyps {3561}, but progression to adeno- and retroperitoneal desmoids may cause {1069, 1572, 2305}.
carcinoma is a rare occurrence {3728}. bowel or ureteric obstruction or other life-
Liver and biliary tract. There is an threatening complications. Gene structure and expression
increased incidence of hepatoblastoma in Bones. Bone lesions include exostoses The APC gene was localized to chromo-
male infants of families with FAP {980}. and endostoses. Endostoses of the some 5q21–22 by Bodmer et al. {291} and
Dysplasia has been demonstrated in the mandible are found in the majority of Leppert et al. {1806}. It was isolated by the
bile-duct and gallbladder epithelium in patients {365}. They are almost always group of White {1069} and by the laborato-
patients with FAP {2328}, and these small and symptomless. Exostoses may ries of Nakamura and Vogelstein {2305}. It
patients are at risk of developing adeno- be solitary or multiple and tend to arise in spans a region of 120 kb and is composed
carcinoma of the biliary tree {3044}. the long bones. of at least 21 exons, 7 of which are alterna-
Teeth. Dental abnormalities have been tively expressed {2798}. Sixteen APC tran-
Extra-gastrointestinal manifestations described in 11–80% of individuals with scripts that differ in their most 5’ regions
Soft tissues. Tissues derived from all three FAP {3503}. The abnormalities may be and arise by the alternative inclusion of six
germ layers are affected in FAP. As well as impaction, supernumerary or absent of these exons have been identified.
the endodermal lesions so far described, teeth, fused roots of first and second The APC gene is ubiquitously expressed
mesodermal lesions in the form of a fibro- molars or unusually long and tapered in normal tissues, with highest levels in
matosis unique to FAP, usually referred to roots of posterior teeth. the central nervous system. Tissue-
as desmoid tumour, develop in a substan- Eye. In 75–80% of patients, ophthal- specific differences have been observed
tial proportion of patients (10–25%) {245, moscopy reveals multiple patches CHRPE in the expression of APC transcripts with-
1752}. Desmoid tumours arise in either the {487}. Ultrastructurally, they are freckle- out exon 1, a coding region for a heptad
retroperitoneal tissues, mesenterium or in like plaques of enlarged melanin-contain- repeat that supports homodimerization of
the abdominal or thoracic wall. Trauma, ing retinal epithelial cells {2482}. Their value the APC protein.
previous surgery (at an early age), female for diagnosis is limited by inconsistency
sex, family history of desmoids, and the site and variation between families. Gene product and function
of the APC mutation beyond codon 1399 or Skin. Epidermal cysts, usually of the face The APC gene encodes a 2843 amino-
1444 are associated with an increased risk and often multiple, were first described in acid protein with a relative molecular
of desmoids {753}. FAP by Gardner {948}. mass of 309 000. The protein has several

family. The resulting complexes activate an affected member of the family to

MYC {1145} and transcription of the cyclin determine whether a detectable mutation
D1 gene {3224}. Lack of functional APC exists in the pedigree {622}. If a deleterious
can also cause unregulated intracellular mutation is found in an affected family
accumulation of β-catenin, and, thereby, member, then at-risk relatives can obtain
constitutive expression of MYC and of the true positive or negative test results. If a
cyclin D1 gene (CCND1) {3513}. In the mutation is not identified, testing at-risk
cytoplasm, β-catenin is involved in cyto- relatives should not be conducted because
skeletal organization with binding to micro- the results will be inconclusive {976} (in
tubules. It also interacts with E-cadherin, this situation, a negative test result for an
a membrane protein involved in cell at-risk individual could be a false negative
Fig. 8.32 Congenital hypertrophy of the retinal pigment
epithelium (CHRPE) in a 41-year-old man with familial adhesion. Unregulated concentrations of since the laboratory technology may not
adenomatous polyposis attributable to an APC gene β-catenin also perturb these processes. be of sufficient sensitivity to detect a mu-
mutation in exon 15, codon 1157. tation, if one is present). When an affected
Gene mutations family member is not available for evalua-
A deleterious germline mutation in APC is tion, testing of at-risk family members can
important structural areas {131}, including found in up to 95% of individuals with provide only positive or inconclusive
the oligomerization domain, armadillo classic FAP {1727}. Mutations in the base- results. In this case, a true negative test
region, 15 amino-acid repeat area, 20 pair excision gene MYH account for some result for an at-risk individual can only be
amino-acid repeat area, basic domain, of the remaining individuals {2961}. The given if another at-risk family member
end-binding protein 1 (EB1) binding site majority (95%) of APC mutations are non- tests positive for a deleterious mutation.
and the HDLG (homologue of the sense or frameshift mutations producing In patients with classic or the attenuated
Drosophila, discs large tumour-suppressor a truncated protein with abnormal func- FAP phenotype, in which no mutation in
protein) binding site. The oligomerization tion. About 10% of APC mutations are the APC gene has been found, MYH gene
domain is essential for the formation of large interstitial deletions that may involve testing should be considered.
dimers with wild-type and truncated the entire gene. Rare missense mutations,
mutant APC proteins. The armadillo region most with uncertain functional conse- Molecular pathology
binds the regulatory B56 subunit of protein quences, have been described. Also, In accordance with the two-hit model of
phosphatase 2A, the enzyme that also germline mutation in the APC promoter re- carcinogenesis, the wild-type APC allele
binds axin via its catalytic subunit. The 15 gion has been identified as a cause of is lost or mutated in most FAP-associated
amino-acid and 20 amino-acid repeat FAP {489}. More than 700 different dele- tumours, including colorectal adenoma
areas are essential for binding axin and terious APC gene mutations have been and carcinoma, desmoid tumours {2102},
β-catenin, respectively. The basic domains identified (primarily in the 5’ region of the medulloblastoma {364}, gastroduodenal
and EB1 binding-site complex with micro- gene), but those at codons 1061 and tumours {3281}, thyroid carcinoma {1368},
tubules. The HDLG binding site is involved 1309 account for 33% of all reported. and hepatoblastoma {1683}. Each colo-
in the inhibition of cell-cycle progression. The rate of germline mutation leading to rectal adenomatous polyp is a premalignant
The APC protein functions in tumour sup- a new deleterious APC allele is estimated lesion that may progress to carcinoma in
pression and is considered important in to be five to nine mutations per million an unpredictable fashion. In addition to
cell adhesion, signal transduction, and gametes. Consequently, individuals with no APC mutations, colon carcinomas in FAP
activation. The APC protein is a negative previous family history of FAP (de novo patients contain somatic mutations simi-
regulator in the Wnt signalling pathway. cases) are not uncommon, representing up lar to those found in sporadic colon
The domains described above act as to one quarter of propositi {266}. In addition cancers not associated with replication
binding and degradation sites for β-catenin to spontaneous mutation, gonadal mo- errors. TP53 mutation and 17p allele loss
and control the intracellular concentration saicism has been reported to account for are observed in 40% of invasive carcino-
of β-catenin {2742}. In the normal situation, about 10% of new cases of FAP {140, 2861}. mas {1541}. However, TP53 may not be
glycogen synthase kinase 3β (GSK3β) involved in some families {58}. Loss of
promotes phosphorylation of the protein Application of genetic testing alleles on chromosome 18 and 22 were
conductin/axin that is added to the APC– in the clinical setting observed in 46% and 33% of cases,
GSK3β complex {224}. Phosphorylated Genetic testing is the standard of care for respectively. The frequency of mutation of
axin recruits β-catenin, which is in turn screening at-risk members of families KRAS increases from 11% in moderately
phosphorylated and targeted for degrada- affected by FAP {975}. The indications for to 36% in severely dysplastic adenomas
tion through an APC-dependent ubiquitin– APC-gene testing include confirming the {58}. KRAS mutations may potentiate the
proteasome pathway {7}. When this diagnosis of FAP and pre-symptomatic transcription of cyclin D1 {1145}. Interest-
system is perturbed, β-catenin is not diagnosis of individuals aged 10 years or ingly, the type of APC germline mutation
degraded. This can occur when Wnt older at risk for this condition. Currently, may influence the mode of inactivation of
signalling inhibits GSK3β activity and commercial laboratories generally use the second APC allele {58}.
dephosphorylates axin. As a result, β-catenin sequencing for mutation analysis and
is released from the complex. Free β-catenin some additionally test for large-segment Animal model
shuttles to the nucleus where it binds to rearrangement. The strategy for testing an The first mouse model of APC mutation was
the transcription factors of the TCF/LEF at-risk individual begins with first testing developed via random mutagenesis {2164}.

on the presence and number of adenomas.

More intensive screening should probably
continue until age 50 or 60 years for persons
with this condition.
Colorectal therapy
Surgery can be anticipated once colonic
adenomas appear in a person with FAP
{1395, 1488, 2461}. In most cases, surgery
is delayed until the patient has completed
his/her secondary education, for psycho-
social reasons; however, annual surveil-
lance should be performed in these
persons to determine whether earlier
surgery is necessary. If colectomy has not
already been performed, it should certainly
Fig. 8.33 Structure of the protein encoded by the APC gene. αα, amino acid; EB1, end-binding protein 1; HDLG, be undertaken when approximately 100
homologue of Drosophila, discs large tumour-suppressor protein; NLS, nuclear localization signal. adenomas occur, when multiple adeno-
mas of more than 1 cm in diameter are
found, or if advanced histology appears
This Min mouse, designated APCmin, has more prevalent in persons with mutations in any adenoma. Surgical options include:
a heterozygous truncating mutation at after codon 1444 {450, 2290}. Multiplicity (1) restorative proctocolectomy; (2) colec-
codon 850 of the APC gene and develops of extracolonic manifestations appears to tomy with mucosal proctectomy, ileal
approximately 30 small intestinal adeno- occur more frequently in mutations that pouch construction and ileo-anal pouch
mas. Homozygous mutant embryos die are 3’ to codon 1445 {981}. No consistent anastomosis; and (3) colectomy with ileo-
before gastrulation {2164}. Other murine associations with tumours of the upper rectal anastamosis. Restorative procto-
APC models were subsequently con- gastrointestinal tract have been found. colectomy has the advantage that about
structed using gene-knockout technology 1 cm of low rectal tissue is left in place,
to create mutations in codons 716, 1638, Prognosis and management allowing the patient to distinguish air,
and 14; such mice have varying numbers Colorectal screening and surveillance liquid and solid material. It has the disad-
of small-bowel adenomas {3165}. Investi- Screening for FAP includes sigmoido- vantage, however, that residual rectal
gators have also created APC-mutant scopy or colonoscopy beginning at age tissue may form adenomas. Colectomy
mice carrying additional mutations that 10–15 years in individuals known to have a with ileo-anal pouch anastomosis is nec-
modify the number of intestinal polyps disease-causing mutation or in all children essary if adenomas are found at or near
and induce progression of adenomas to of an affected parent, if genetic testing is the dentate line at the anus before surgery.
cancer {2164, 3165}. not available or not informative {3385}. If a Colectomy with ileorectal anastomosis
mutation in APC has been detected in a can be done with rectal sparing and is
Genotype–phenotype relationships family member, genetic testing should be almost always the procedure of choice for
Several definitive associations exist offered to determine which relatives persons with attenuated FAP.
between specific APC-gene mutations require screening. Once adenomas are Surveillance is always necessary after
and colorectal and extracolorectal FAP detected, annual or biannual colonoscopy surgery, as adenomatous polyps may
phenotype {3048}. Attenuated FAP, char- should be continued until an appropriately develop in the ileal pouch or rectal tissue
acterized by patients with colorectal timed colectomy is completed. of any patient. The incidence of ileal can-
oligopolyposis (< 100 colorectal adeno- When genetic diagnosis is not possible, cer is low, but that of rectal cancer (when
mas) and later age of colorectal-cancer endoscopic surveillance should be contin- rectal tissue remains) is substantial if con-
development is caused by mutations ued at 1–2 year intervals up to the age of 40 tinued surveillance is not performed. An-
before codon 158 (5’ end of the gene), years. If FAP is not apparent by that age, nual or 6-monthly flexible sigmoidoscopy
after codon 1595 (3’ end of the gene) or in screening as per persons with an average can be done, depending on the number
the alternatively spliced region of exon 9 risk of colon cancer can then be performed. of polyps observed. Polyps should be
(codons 312–412) {332, 974}. Severe In persons at risk or with a genetic diagno- removed or ablated. Some patients with a
colorectal polyposis (> 1000 adenomas) sis of attenuated FAP, colonoscopy should remaining rectum or rectal cuff will even-
correlates with mutations between codons always be used in view of the more proximal tually need completion surgery because
1250 and 1464 {2207}. CHRPE is associ- distribution of polyps {380}. Colonoscopy of adenomas or advanced adenomas that
ated with mutations between codons 311 should start late in the second decade of life are not well-controlled endoscopically.
and 1444, and desmoid tumours may be and be repeated every 1–2 years, depending

Lynch syndrome P. Peltomaki

G.J.A. Offerhaus
H.F.A. Vasen
Definition constitutes a heterogeneous group of

Lynch syndrome (previously “hereditary families. In about half of the families with
nonpolyposis colorectal cancer”, HNPCC) HNPCC, neither microsatellite instability
is an autosomal dominant disorder (MSI) in tumours nor a germline defect in
caused by a defect in a DNA mismatch an MMR gene could be identified {1864,
repair (MMR) gene. The syndrome is 3506}. Such families are referred to as
characterized by the development of colo- having “familial colorectal cancer type X”
rectal carcinoma, endometrial carcinoma {1864}, “non-Lynch syndrome colorectal
and other cancers. cancer predisposition” {738} or just “familial
colorectal cancer” {3386}. The genetic
MIM No. 120435-6 basis for this disease is still unknown
Fig. 8.34 Mucinous adenocarcinoma from a patient with
{3383}. Lynch syndrome.
Diagnostic criteria Currently, the term “Lynch syndrome” is
Before the discovery of the DNA MMR-gene reserved for families with an identified of the MutL homologue 1 (MLH1) promotor
defects responsible for Lynch syndrome in pathogenic germline mutation in one of in the germline have also been reported
the 1990s, clinical diagnostic criteria (the the DNA MMR genes {295}. In addition, {1213, 2143} and may be designated as
“Amsterdam criteria”) were used to identify patients with inactivation of MutS homo- having Lynch syndrome, although segre-
families with a presumably inherited form of logue 2 (MSH2) due to a deletion of the 3’ gation and penetrance in subsequent gen-
colorectal carcinoma {3384, 3388}. Families exons of the TACSTD1 gene (tumour- erations remain unclear. Patients without
that met these criteria were referred to as associated calcium signal transducer 1) an identified germline defect in a DNA
having HNPCC. Further molecular genetic are considered to have Lynch syndrome MMR gene but with a tumour showing MSI
analysis, however, showed that HNPCC {1851}. Recently, patients with methylation and absence of immunohistochemical
expression of the MMR proteins are very
Table 8.06 Overview of clinical criteria for Lynch syndrome: Amsterdam I and II and revised Bethesda criteria. likely to have Lynch syndrome if other
causes of MSI, such as methylation of the
Amsterdam criteria I
There should be at least three relatives with CRC; all the following criteria should be present:
MLH1 promoter, are excluded.
1. One should be a first-degree relative of the other two In 2004, a set of clinical guidelines (the re-
2. At least two successive generations should be affected vised Bethesda guidelines) was proposed
3. At least one CRC should be diagnosed before the age of 50 years that can be used to select individuals for
4. Familial adenomatous polyposis should be excluded MSI analysis {3342}. Individuals that meet
5. Tumours should be verified by pathological examination one of these criteria are suspected to have
Lynch syndrome.
Amsterdam criteria II
There should be at least three relatives with a Lynch syndrome-associated cancer (CRC, cancer of the
endometrium, small bowel, ureter or renal pelvis); all of the following criteria should be present: Clinical features
1. One should be a first-degree relative of the other two Carriers of a pathogenic mutation in a DNA
2. At least two successive generations should be affected MMR gene have a high lifetime risk of de-
3. At least one should be diagnosed before the age of 50 years veloping colorectal carcinoma (10–53%),
4. Familial adenomatous polyposis should be excluded in the CRC case(s) if any endometrial carcinoma (15–44%), and
5. Tumours should be verified by pathological examination
certain other cancers (< 15%) {178, 509,
Revised Bethesda criteria 2877, 3471}. The risk of developing can-
1. CRC diagnosed in a patient of less than 50 years of age cer depends on sex, type of gene involved
2. Presence of synchronous, metachronous colorectal, or other Lynch syndrome-related tumours,a and environmental factors. Colorectal
regardless of age carcinomas are often diagnosed at an
3. CRC with MSI-H phenotype diagnosed at less than 60 years of age
early age (mean, 45–50 years), and are
4. Patient with CRC and a first-degree relative with a Lynch syndrome-related tumour, with one of the
cancers diagnosed before the age of 50 years
located in the proximal part of the colon in
5. Patient with CRC with two or more first-degree or second-degree relatives with a Lynch syndrome- about two thirds of patients. Synchronous
related tumour, regardless of age. or metachronous colorectal carcinoma is
present in 18% of patients {3382}. In almost
CRC, colorectal cancer. all cases, MSI is evident. The adenomas
a
Lynch syndrome-related tumours include colorectal, endometrial, stomach, ovarian, pancreas, ureter, renal
that occur in Lynch syndrome tend to
pelvis, biliary-tract and brain tumours, sebaceous gland adenomas, keratoacanthomas and carcinoma of the
small bowel. b MSI-H, high level of microsatellite instability. develop at an early age, have villous
components and are more dysplastic than

Table 8.07 Current terminology for families with inherited colorectal cancer without polyposis.
Terminology Clinical definition Molecular genetic analysis
Hereditary nonpolyposis colorectal cancer (HNPCC) Amsterdam criteria I and II Defined solely by clinical criteriaa
Familial colorectal cancer (type X) Amsterdam criteria I Genetic basis unknown; no evidence for defects in DNA MMR genes
Non-Lynch syndrome colorectal cancer predisposition
Lynch syndrome Familial clustering of colorectal cancer and/or Presence of pathogenic germline defects in DNA MMR genes
other cancers Germline methylation of the MLH1 promoter
Inactivation of MSH2 due to deletion of 3’ exons of the EPCAM
(TACSTD1) gene
Probable Lynch syndrome Familial clustering of colorectal cancer and/or Presence of microsatellite instability and absence of expression of
other cancers DNA MMR proteins in tumours
Additionally, no evidence for methylation of the MLH1 promoter
Suspected Lynch syndrome Revised Bethesda criteria, Defined solely by clinical criteriaa
Amsterdam criteria I and II
MMR, mismatch repair, a This terminology is used if no molecular genetic data are available.
adenomas detected in the general popu- on the one hand and familial adenomatous occur in the proximal colon. Gross
lation {668, 2678}. Although multiple polyposis (FAP) on the other {1108}. appearances have not been studied in
adenomas may be observed in Lynch detail. However, since HNPCC and MSI-H
syndrome, florid polyposis is not a feature. Pathology colorectal carcinomas show a consistent
Patients with mutations of MSH6 and PMS2 Although the pathogenesis and also certain trend towards good circumscription
may present at an older age with more left morphological features differ between Lynch {1402, 2909}, they are more likely to pres-
sided tumours than those with mutations of tumours and sporadic colorectal cancers ent as polypoid growths, plaques, ulcers
the other genes. with a high frequency of MSI (MSI-H) or bulky masses and less likely to present
Extracolonic lesions include cancer of the {1398}, the pathology of Lynch tumours is as diffuse growths or tight strictures. Ade-
endometrium, renal pelvis/ureter, stomach, very similar to that of sporadic colorectal nomas are not numerous, but are likely to
small bowel, ovary, brain, hepatobiliary carcinoma with MSI-H. Many studies make be more frequent in subjects with Lynch
tract, and also sebaceous tumours. Of no distinction between familial and non- syndrome than in age-matched controls
these, the relative risk of carcinoma of the familial carcinomas with MSI-H. Therefore, {1405}. Colonoscopic studies indicate
endometrium, ovaries, ureter, renal pelvis, the following descriptions apply to all carci- that the distribution of adenomas in Lynch
and small bowel is highest, and these nomas with MSI-H, but highlight subtle dif- syndrome may not mirror the proximal
tumours are therefore the most specific for ferences between cancers from the Lynch colonic predilection of carcinoma {1405}.
Lynch syndrome {3471}. The occurrence syndrome and their sporadic counterparts, This could be due to the occurrence of
of sebaceous gland tumours together with where these are known. sporadic distal adenomas in older sub-
Lynch syndrome-type internal malignancy jects with Lynch syndrome or because
is referred to as the Muir-Torre syndrome Macroscopy proximal adenomas are more likely to
{577}. The association of primary brain Lynch syndrome-associated cancers show progress to cancer. It is considered that
tumours (usually glioblastomas) with multi- a predilection for the proximal colon, colorectal carcinomas in Lynch syndrome
ple colorectal adenomas is referred to as including the caecum, ascending colon, arise from conventional adenomas, while
Turcot syndrome {3321}. The latter has a hepatic flexure and transverse colon the precursors of sporadic MSI-H tumours
shared genetic basis with Lynch syndrome {1933}. At least 60% of such cancers are serrated polyps {1398}
A B
Fig. 8.35 Abundant lymphocytes infiltrate the neoplastic epithelium in poorly differentiated (A) and moderately differentiated (B) adenocarcinomas from patients with Lynch syndrome.
Lynch syndrome 153

Histopathology reaction may be present. This subtype has with haematoxylin and eosin, lymphocytes
No individual microscopic feature is been described as medullary or “undiffer- are difficult to discern when the percentage
specific to Lynch syndrome, but particular entiated”, although most of these tumours of CD3-positive lymphocytes (out of all
groups of features are diagnostically contain subclones in which glandular epithelial nuclei) is less than about 5%. CD3
useful {1416, 2909, 3297}. Similar features differentiation is evident. This subtype may counts in excess of 5% occur in about 70%
are found in the 10–15% of sporadic be more common in subjects with a muta- of MSI-H cancers. CD3 counts in excess of
colorectal cancers that show MSI-H tion in MSH2 {2909}. In general, colorectal 10% are highly specific for MSI-H cancers,
{1402}. However, sporadic MSI-H cancers cancers showing TIL and/or a Crohn-like and are the best predictors. The feature of
present in older subjects lacking a family lymphocytic reaction appear to be more TIL does not, however, distinguish between
history of bowel cancer. Colorectal cancers common in subjects with a germline Lynch tumours and their sporadic MSI-H
from Lynch syndrome fall into different mutation in MLH1 {2909}. Poor differentiation counterparts {1061, 1416, 3297}. The
groups on the basis of site and micro- is another microscopic feature that is more nodular arrangements of lymphocytes
scopic criteria. frequent in sporadic MSI-H tumours than in occurring peri-tumourally or within the
their Lynch-syndrome counterparts {1061, serosa (Crohn-like reaction) are B-lympho-
Proximally located mucinous 1398}. cytes surrounded by T-lymphocytes.
adenocarcinomas
These are usually well circumscribed and Adenomas in Lynch syndrome Molecular pathology
well- or moderately differentiated. Lympho- These are more likely to show features Acquired genetic changes in
cytic infiltration is not prominent, but indicative of increased risk of cancer, Lynch-syndrome cancers
tumour-infiltrating (intraepithelial) lympho- including villosity and high-grade intra- The demonstration of MSI serves as an
cytes (TIL) may be evident in nonmucinous epithelial neoplasia {1405}. Immunohisto- important biomarker for cancers associ-
areas. There may be tubulo-villous or chemical staining to demonstrate loss of ated with Lynch syndrome. Lynch-syndrome
villous adenomatous remnants adjacent expression of MMR proteins (MLH1, MSH2, cancers and sporadic MSI-H cancers
to the cancer. Mucin production may be postmeiotic segregation 2 [PMS2], MutS share the mutator pathway.
more common in subjects with a germline homologue 6 [MSH6]) may assist in
mutation in MSH2 {2909}. Sporadic MSI-H pinpointing the underlying germline muta- Mode of inheritance, chromosomal
tumours more often show a mucinous tion. However, immunoreactivity may be location, and structure
appearance than their Lynch-syndrome retained in the case of MLH1, even if Lynch syndrome is transmitted as an
counterparts {1061}. genetic changes result in the production of autosomal dominant trait. It is associated
a nonfunctioning protein {3233}. Virtually with heterozygous germline mutations in
Proximally located, poorly differentiated all sporadic MSI-H carcinomas lose MLH1 one of five genes with a verified or puta-
adenocarcinomas through methylation; BRAF mutations are tive function in DNA MMR, namely MLH1,
Poor differentation indicates failure of gland also largely restricted to the sporadic MSI-H MSH2, MSH6, PMS2, and MLH3 (MutL
formation, the malignant epithelium being tumours and are not found in Lynch- homologue 3). Biallelic mutations cause a
arranged in small clusters, irregular trabec- syndrome tumours {1398}. Immunohisto- syndrome of constitutional deficiency in
ulae or large aggregates. These tumours chemical staining of MSI-H colorectal MMR, which is characterized by child-
are well-circumscribed and lack an abun- cancers confirms that most TIL are CD3- hood cancers of the haematological sys-
dant desmoplastic stroma. Some are pep- positive T cells and most are cytotoxic tem and brain, in addition to early-onset
pered with TIL. A Crohn-like lymphocytic (CD8-positive) {731}. In sections stained colorectal cancer {3524}. Furthermore,
most patients with biallelic mutations
show signs of neurofibromatosis type 1
(NF1).
Gene product
Lynch-syndrome-associated DNA MMR
genes are ubiquitously expressed in adult
human tissues; the expression pattern there-
fore does not seem to explain the selective
organ involvement observed in this syn-
drome. Expression is particularly prominent
in the epithelium of the digestive tract as well
as in testis and ovary {862, 1774, 3523}.
In the intestine, expression is confined to
the replicating compartment, i.e. the
bottom half of the crypts. Immunohisto-
chemical staining of MMR proteins shows
nuclear localization. Mutations typically
A B lead to the absence of the respective MMR
Fig. 8.36 Tubular adenoma from a patient with Lynch syndrome. A Immunostaining for MLH1. B Immunostaining for protein (and occasionally, other MMR
MSH2; the neoplastic epithelium shows loss of MSH2 expression (upper portion). proteins, in a defined pattern {1166}).

Function Table 8.08. Characteristics of Lynch syndrome-associated human DNA mismatch repair genes.
The protein products of genes involved in Gene Chromosomal Length of No. of Genomic References
Lynch syndrome are key players in the location cDNA (kb) exons size (kb)
correction of mismatches that arise during
MLH1 3p21–p23 2.3 19 58–100 {339, 1112, 1635, 1861, 1869, 2446}
DNA replication {1831}. Two different
MutS-related heterodimeric complexes MSH2 2p21 2.8 16 73 {869, 1636, 1773, 1871, 2515, 2847}
are responsible for mismatch recognition:
MSH2–MSH3 and MSH2–MSH6. While MSH6 2p21 4.2 10 20 {21, 2847, 2441, 2280}
the presence of MSH2 in the complex is PMS2 7p22 2.6 15 16 {2279, 2281}
mandatory, MSH3 can replace MSH6 in
the correction of insertion–deletion mis- MLH3 14q24 4.4 12 36 {1866}
matches, but not single-base mispairs.
Following mismatch binding, a hetero- presently known that are likely to be Lynch syndrome that meet the Amsterdam
dimeric complex of MutL-related proteins, pathogenic {2517, 3547}. While > 80% of criteria and show MSI in tumours {1870}.
MLH1–PMS2 (and possibly another alter- mutations are specific to each family, The occurrence of these mutations is
native complex formed by MLH1–MLH3) prevalent founding mutations occur in cer- clearly lower (< 30%) in kindreds not meet-
is recruited, and this larger complex, tain populations {2517}. As a rule, the mu- ing the Amsterdam criteria {2329, 3504}.
together with numerous other proteins, tations are scattered throughout the genes.
accomplishes MMR. The observed func- Most mutations in MSH2 and MLH1 are Prognosis and predictive factors
tional redundancy in the DNA MMR protein truncating {2517, 3547}. However, one MLH1 and MSH2 mutations have a high
family may help explain why mutations in third of the mutations in MLH1 are penetrance, with > 80% of carriers devel-
MSH2 and MLH1 are prevalent in families missense, which constitutes a diagnostic oping some form of cancer during their
with Lynch syndrome, while mutations problem concerning their pathogenicity. lifetime {3387}. There is no clear-cut
in MSH6, PMS2, and MLH3 are less Commonly used theoretical criteria in correlation between the involved gene,
frequent, and no Lynch-syndrome- support of pathogenicity include the mutation site within the gene, or mutation
associated germline mutations in MSH3 following: the mutation leads to a non- type vs clinical features. MSH2 mutations
have been reported. MMR deficiency conservative amino-acid change, the may confer a higher risk of extracolonic
gives rise to MSI, and as such may aid in involved codon is evolutionarily conserved, cancer than do MLH1 mutations, while
the diagnosis of this syndrome {2}. How- the change is absent in the normal popu- MSH6 mutations may be associated with
ever, MSI is not specific to Lynch syn- lation, and it segregates with the disease atypical clinical features, including an
drome since it also occurs in 10–15% of phenotype. However, functional testing is elevated occurrence of endometrial can-
apparently sporadic colorectal and other often mandatory for the proper assign- cer relative to colorectal cancer as well as
tumours {296}. Correction of biosynthetic ment of pathogenicity to unclassified late age of onset {1166}. PMS2 mutations
errors in the newly synthesized DNA is not variants. Characteristics of variants with are associated with a lower penetrance
the only function of the DNA MMR system. reported results of functional and/or in and variable clinical phenotypes ranging
In particular, it is also able to recognize silico testing can be viewed in a database from early- or late-onset, apparently spo-
lesions caused by exogenous mutagens (http://www.mmruv.info; {2419}). Functional radic colorectal cancer (heterozygosity
and mediate DNA-damage signalling {1831}. studies have shown that Lynch syndrome- for germline mutations {2877, 3296}) to
associated mutations in DNA MMR genes Turcot syndrome or a distinct childhood-
Gene mutations can be pathogenic in multiple ways cancer syndrome (homozygosity or
The International Society for Gastrointestinal {2398, 2615}. Furthermore, the mecha- compound heterozygosity for germline
Hereditary Tumours (InSiGHT) maintains a nism behind constitutional inactivation of mutation {3524}). Kindreds with the Muir-
central database for Lynch syndrome- a DNA MMR gene is not always genetic Torre phenotype {1666} as well as a sub-
associated mutations and polymorphisms (point mutation or large rearrangement) set of those with Turcot syndrome {1108}
(http://www.insight-group.org). Most are but may be epigenetic (germline epimu- show predisposing mutations similar to
found in MLH1 and MSH2, with fewer tation) {1212, 1851}. those observed in classical Lynch syn-
mutations in MSH6, PMS2 and MLH3. Mutations in DNA MMR genes account for drome (with the distinction that in Turcot
More than a thousand mutations are two thirds of all families with classical syndrome the mutations are often biallelic).
Lynch syndrome 155

MUTYH-associated polyposis H. Morreau

R.H. Riddell
S. Aretz
Definition adenomas, Lynch syndrome (hereditary patients with colorectal adenomatous

MUTYH-associated polyposis (MAP) is an nonpolyposis colorectal cancer, HNPCC) polyposis who are negative for APC
autosomal recessive disorder character- should be considered {1166}. Since mutations, depending on the inclusion
ized by a variable number of colorectal hyperplastic polyps and sessile serrated criteria applied, the methods used for
polyps with different histological pheno- adenomas are a common finding in MAP mutation screening, and the patient’s
types, that have a tendency to progress to {302, 2340} and the occurrence of ethnic background {1863}.
malignancy. Since the disorder was not colorectal cancer in the absence of col-
recognized until 2002 {60}, the full spectrum orectal polyps has been reported {571, Localization
of MUTYH-associated phenotypes and the 1906}, the clinical presentation could be MAP polyps are located throughout the
prediction of risk associated with MUTYH misdiagnosed as hyperplastic polyposis colon, but also in the small intestine
mutations are still being elucidated and are or sporadic colorectal cancer in some (mostly duodenum) and stomach. Simi-
the subject of ongoing debate. patients. In patients of any age with few larly, MAP carcinomas can be found
Characteristically, > 10 polyps are found, adenomas, without an overt family history throughout the colorectum; however,
although in population-based series of (and no carcinoma), the likelihood of when all reported cases are compiled,
colorectal cancer (CRC) up to one third of identifying MAP, AFAP or Lynch syndrome MAP carcinomas are more often found in
patients with biallelic MUTYH mutations is very small. the right side of the colon compared with
have no or < 10 polyps at presentation sporadic CRCs {142, 1867, 2283, 2340}.
{142, 163, 180, 571, 621, 822, 1075, Epidemiology MAP carcinomas can also be found in the
2284, 2583, 2790, 2961, 3369, 3448}. The prevalence of MAP is yet unknown. duodenum {360, 2286, 3408}.
Small-intestinal (mostly duodenal) and Assuming that the frequency of carriers of
stomach polyposis is part of the MAP a heterozygous MUTYH mutation is Clinical features
spectrum and extra-intestinal manifesta- approximately 2% in Caucasian popula- Colorectal manifestations
tions of MAP might occur {3408}. tions, the incidence of biallelic mutations Most clinical information on carriers of bial-
is about 1:10 000 in Europe and North lelic MUTYH mutations has come from stud-
MIM No. America. According to studies on large ies of polyposis cohorts, which are biased
MAP 608456 population-based cohorts of patients with in favour of description of a more severe
MUTYH 604933 colorectal cancer (CRC), biallelic carriers phenotype. According to this clinic-based
account for < 1% of cases of CRC {571, approach, MAP is characterized by the
Synonyms 1906}, but can be identified in 3–42% of occurrence of tens to a few hundreds of
The approved abbreviation of the
syndrome is MAP, the approved gene
symbol is MUTYH. The terms MYH and
MYH-associated polyposis should no
longer be used.
Diagnostic criteria
MAP is suspected in patients with multiple
(> 10) synchronous colorectal adenomas
of rather late onset in the absence of a
germline mutation in the adenomatous
polyposis coli (APC) gene and a pedigree
suggestive of autosomal recessive inher-
itance. However, since most MAP patients
present as seemingly sporadic cases and
pseudo-dominant families have also been
reported, genetic testing by screening for
MUTYH mutation is imperative to guaran-
tee a confident diagnosis {2790}.
The most important differential diagnosis
is the APC-related attenuated or atypical
form of familial adenomatous polyposis Fig. 8.37 Age at diagnosis of colorectal cancer (CRC) in patients with MUTYH-associated polyposis (MAP); the age at
(AFAP). In cases where there are few diagnosis ranged from 21 to 70 years. Modified from Sampson & Jones {2790}.

colorectal polyps throughout the colorec- gland tumours do not seem to be

tum; around two thirds of patients have restricted to germline mutations of mis-
< 100 polyps at diagnosis {2790}. How- match repair genes (Muir-Torre syndrome)
ever, a proportion of patients have > 100, but might also serve as marker lesions in
sometimes even up to 1000 polyps, but a small subset of MAP patients.
do not have the carpets seen in some
variants of FAP in which some folds are Implications of heterozygous
studded with polyps. MUTYH mutations
About 60% of MAP patients are diag- The clinical relevance of monoallelic
nosed with CRC at first presentation; in MUTYH mutations is still controversial.
large population-based series, the pene- According to studies on large (partly
trance of biallelic mutations has been population-based) series using different
estimated to be around 70% at age 70 approaches, carriers of heterozygous Fig. 8.38 Sebaceous gland adenomas of the forehead in
years {1906}. Colorectal polyps and CRC mutations have a modest and late-onset a patient with proven biallelic MUTYH mutations
usually manifest between the fourth and increase in the risk of CRC (odds ratio, (a patient with MUTYH-associated polyposis). Reprinted
from Ponti et al. {2575A}.
seventh decades of life, with a mean age 1.5–2.1) comparable to that of first-
at diagnosis of 45 years {2285}. Even in degree relatives of individuals with
patients with > 100 polyps, the mean age apparently sporadic CRC {571, 822, Colon carcinomas
at diagnosis is significantly older than that 1442}. In contrast, another large population- So far, there are no established histologi-
for classic FAP {142}. based study and a meta-analysis of 11 cal features that differentiate MAP carci-
According to recent studies on large pop- case–control series failed to identify a nomas from FAP or sporadic carcinomas
ulation-based cohorts of persons with significantly increased risk of CRC {1906}. {2340}. However, it has been suggested
CRC, up to one third of carriers of biallelic In the latter, however, screening for that MAP CRCs can show similarities to
MUTYH mutations exhibit CRC in the MUTYH mutations was restricted to the microsatellite-unstable cancers (such as
absence of multiple adenomas {571}, c.536A>G;p.Tyr179Cys (Y179C) and predilection for the proximal colon, a more
suggesting that a substantial number of c.1187G>A;p.Gly396Asp (G396D) muta- often mucinous histotype, presence of
patients are not identified by current tions. tumour-infiltrating lymphocytes or intra-
screening strategies. Considerable inter- epithelial lymphocytes) and a Crohn-like
and intra-familial variability in phenotype Macroscopy infiltrate {2283}). A small proportion of
expression was recognized, even between Polyps and carcinomas MAP carcinomas also has a high level of
patients carrying the same mutations. The gross appearance of MAP adenomas microsatellite instability (MSI-H) owing to
usually resembles attenuated FAP (< 100 sporadic promoter hypermethylation of
Extracolonic manifestations polyps); indeed, up to 40% of cases of MLH1 {580, 1795}. Although initially
Extracolonic manifestations have been AFAP have been attributed to MAP. For reported, there is no consensus that
described only in several case reports reporting, it is thus important to count the immunohistochemical staining of MUTYH
and small sample series suggesting number of polyps as accurately as possi- is helpful in the diagnosis of MAP {714,
coincidence with limited clinical relevance ble. Apart from the greater tendency of 2340, 3360}. Aberrant immunohistochemical
{2583}. A systematic retrospective evalu- MAP cancers to be located in the proxi- staining of other molecules such as p53
ation in a large cohort of MAP patients mal colon, no characteristic macroscopic or β-catenin (CTNNB1), differs in fre-
(n = 276) recruited from a European mul- features have yet been described. quency in MAP carcinomas in compari-
ticentre study identified a moderate but son to sporadic CRC, but is not helpful in
significant over-representation of several Histopathology the identification of MAP carcinomas.
extracolonic tumours {3408}. Gastric Colon polyps
lesions occurred in 11% of examined Conventional adenomas (mostly of low Duodenal carcinomas
MAP cases. The majority had fundic gland grade) are the predominant type of To date six duodenal carcinomas have
polyps only, but a few gastric adenomas polyps found in MAP {1863, 1867, 2961}. been described in MAP patients in the
were described. The incidence of gastric The unexpected feature of MAP is their context of duodenal polyposis {360, 2286,
cancer was not significantly increased. association with serrated polyps of all 3408}. In two of those that were analysed
Duodenal polyposis was seen in 17% of kinds, which also resemble their non-MAP further, a typical c.34G>T KRAS tranver-
cases and the relative risk of duodenal counterparts. While hyperplastic polyps sion mutation was found, providing
cancer was high. The incidence of (usually less than five) are usually only evidence that the duodenal lesions were
extraintestinal malignancies was almost found occasionally, some MAP patients indeed induced by a MUTYH deficiency.
twice that of the general population and have an excess of hyperplastic polyps Duodenal carcinomas were also observed
the lifetime risk was almost 40%, although and, to a much lesser extent, sessile in the absence of duodenal adenomas.
no predominant tumour and no shift serrated adenoma/polyps (SSA/P), some
towards early onset was observed. The of which fulfil the criteria for serrated poly- Stomach polyps
tumour spectrum is wide and points to a posis (see Serrated polyps of the colon Fundic-gland polyps and adenomas can
certain phenotypic overlap with Lynch and rectum and serrated polyposis) {302, be found {2583, 3408}.
syndrome that may reflect shared aspects 2340}.
of pathophysiology. In particular, sebaceous

A B
Fig. 8.39 Histology of colorectal cancer in patients with MUTYH-associated polyposis (MAP). A Mucinous carcinoma in the ascending colon of a MAP patient with a p.G396D/p.P405L mutation
in MUTYH. Reprinted from Nielsen et al., 2009 {2283} . B Adenocarcinoma in the ascending colon with tumour-infiltrating lymphocytes (arrows) in a patient with p.Y179C/p.Y179C mutation
in MUTYH.
Genetic susceptibility c.494A>G;p.Tyr165Cys and c.1145G>A;p.- there is a high occurrence of these trans-
MUTYH gene Gly382Asp, respectively) account for versions at GAA sites, especially in the
MAP is caused by biallelic germline around 70% of all mutant alleles. However, APC gene, leading to selection of the stop
mutations of the base excision repair (BER) ethnic and geographic differences in the codon TAA. The finding of such somatic
gene MUTYH on chromosome 1p34.1, pattern of MUTYH mutations are evident APC mutations in adenomas has led to the
the human homologue of the Escherichia and point to founder events. To date, few elucidation of the underlying cause of MAP
coli mutY gene {60}. MUTYH consists of missense changes have been character- in humans {60}. The requirement for two
16 exons encompassing 1650 bp and ized by functional assays. rather than a single somatic APC mutation
encodes a highly conserved DNA glyco- for initiation of adenoma might be the rea-
sylase that is responsible for removing Recurrence risk and predictive testing son for the more attenuated colorectal
adenine residues mismatched with 8-oxo- Genetic counselling should be offered to phenotype in MAP compared with classic
7,8-dihydro-2’-deoxyguanosine (8-oxoG), all patients with suspected or proven FAP {142, 2790}. In MAP adenomas and
the most stable product of DNA damage monogenic disease and to their relatives, carcinomas (in the latter with a frequency
caused by reactive oxygen species. in particular in a setting of predictive of up to 64%), but also in SSA/P/Ls and
genetic testing. Siblings of MAP patients hyperplastic polyps of MAP patients, a
Mutation spectrum have a recurrence risk of 25%, thus, characteristic c.34G>T;p.Gly12Cys KRAS
By 2009, > 100 different MUTYH muta- predictive testing is reasonable once the tranversion mutation in codon 12 is found
tions had been reported in a variety of mutations are identified in the index case. {60, 302, 1867, 2961}. This mutation is
biallelic combinations in MAP patients Due to a heterogeneous carrier frequency infrequent in consecutive series of spo-
worldwide (Human gene mutation data- of MUTYH mutations of around 2% in the radic CRC {115} and thus can be used to
base, www.hgmd.org; Leiden open vari- Caucasian general population, children of identify (atypical) MAP patients {3369}.
ation database, www.lovd.nl/MUTYH, a MAP patient have a low but not negligible The c.35G>T; p. Gly>Val KRAS transver-
{877}). The current annotation for the risk (approximately 1%) of carrying two sion is not typically associated with MAP
description of MUTYH mutations (Gen- mutations; screening of the spouses of and occasionally c.39G>A; p. Gly>Asp is
Bank: NM_001128425) extends the MAP patients and MUTYH heterozygotes found in adenomas. In other genes often
numbering after nucleotide position c.157 for MUTYH mutation should thus be implicated in colorectal tumorigenesis,
by 42 nucleotides (14 amino acids) considered {2790}. such as TP53 and SMAD4, G>T transver-
compared to the originally introduced ref- sions are found but to a lesser extent than
erence sequence (GenBank: U63329.1). Molecular pathology other types of mutations, which might
The predominant mutation type (about Oxidative DNA damage (especially with indicate a predominant MUTYH effect in
50% of cases) is missense changes 8-oxoG) is not readily repaired in the ab- early carcinogenesis {1867, 2283}.
followed by protein-truncating mutations sence of functional MUTYH base-excision As the APC gene is a preferred target of
that span the whole gene, except the most repair {2583}. A defect in the latter leads to somatic mutations caused by insufficient
3ánd 5énds {2583, 2790}. Large genomic increased misincorporation of adenine MUTYH activity, consequently MAP-asso-
deletions do not seem to contribute sub- opposite 8-oxo-guanine and is thereby ciated adenomas and carcinomas are ex-
stantially to the mutation spectrum. In associated with increased frequency of pected to use the chromosomal-instability
Caucasian populations, the two missense G:C > T:A transversions in tumour-sup- pathway associated with the Wnt sig-
mutations c.536A>G;p.Tyr179Cys (Y179C) pressor genes and oncogenes in daugh- nalling pathway, and therefore should
in exon 7 and c.1187G>A;p.Gly396Asp ter cells, leading to the formation of resemble typical sporadic adenomas and
(G396D) in exon 13 (previously designated intestinal adenoma. For unknown reasons, carcinomas. However, in contrast to most

sporadic forms of CRC, about half of MAP

carcinomas are close to diploid. Although
MAP CRCs are without alterations that are
detectable with array comparative genomic
hybridization, loss of heterozygosity (LOH)
is present at different loci, owing to wide-
spread copy-neutral LOH {1867, 2062}.
For MAP adenomas, the picture is less
clear as near diploid and aneuploid
adenomas have been identified using
different technical platforms {422, 1439}.
Loss of human leukocyte antigen (HLA)
class I is a frequent event in MAP carcino-
mas, similarly to mismatch repair-deficient
tumours {673}. This can be explained by
the loss of caretaker functions leading to
abundance of somatic mutations in the
genome and resulting in presentation of
aberrant peptides at the cell surface in the
context of HLA. The latter most likely trig-
gers a strong selective pressure by the
immune system favouring outgrowth of Fig. 8.40 The 8-oxoG repair system of Escherichia coli. The 8-oxoG is denoted by a red dot next to the G. The human
cells with an immune evasive phenotype. homologues of the three E. coli DNA glycosylases MutY, Mut and MutM are termed MUTYH, MTH1 and OGG1,
respectively. GMP, guanine monophosphate; GTP, guanine triphosphate. From Cheadle & Sampson {499A}.
Surveillance and predictive testing
The gastrointestinal surveillance protocol
applied in AFAP has been suggested for genotype–phenotype correlation has measures similar to those offered to first-
MAP by a European expert panel {3385}. It been established: Y179C homozygotes degree relatives of patients with sporadic
includes complete colonoscopy at biannual present earlier and have a higher risk of CRC seem to be appropriate {1442}.
intervals starting from age 18–20 years and developing CRC than do Y179C/G396D Prognostic and predictive factors for
gastroduodenoscopy starting at age 25–30 compound heterozygotes and G396D MAP-associated CRC are under study.
years. Accordingly, predictive genetic test- homozygotes {2285}. In the light of The timing and procedure for colorectal
ing should be performed at these ages. current data, intense surveillance for surgery are similar to those for FAP and
However, these recommendations might be extra-intestinal tumours is unlikely to offer must be determined on an individual
modified as the full clinical spectrum great benefit {3408}. In heterozygous basis {2790}.
becomes better understood. A significant relatives of MAP patients, CRC screening

Serrated polyps of the colon and rectum D.C. Snover

D.J. Ahnen
and serrated polyposis R.W. Burt
R.D. Odze
Sporadic serrated polyps Clinical features be flat and are often covered with yellow-
Hyperplastic polyps (HPs) ish mucus.
Definition HPs are most frequent in the distal colon
This is a heterogeneous group of lesions and rarely cause symptoms {198}. Histo- Sessile serrated adenomas/polyps (SSA/P)
characterized morphologically by a ser- logically, several subtypes have been SSA/Ps rarely cause clinical symptoms.
rated (sawtooth or stellate) architecture of recognized that differ slightly in terms of They are more likely to be located in the
the epithelial compartment. The lesions morphology, distribution and molecular proximal colon. Their average size is
include hyperplastic polyps (HPs), sessile characteristics, but without clinical rele- larger than that of hyperplastic polyps;
serrated adenoma/polyp (SSA/P) and vance as yet. Goblet-cell rich hyperplastic more than half of SSA/Ps measure
traditional serrated adenomas (TSA). Def- polyps (GCHP) are almost exclusively > 5 mm and 15–20% are > 10 mm {3049}.
initions of the subtypes of serrated polyps seen in the left colon, whereas micro- They appear flat to sessile, with a soft,
of the large intestine and of serrated vesicular hyperplastic polyps (MVHP) are smooth-appearing surface. They are
polyposis are summarized in Table 8.09. more widely distributed. often covered with mucus, giving them an
HPs are typically sessile lesions of 1–5 mm initial yellow appearance {2332}. When
ICD-O codes in size and rarely > 1 cm. It is not uncommon the mucus is washed off, the underlying
Sessile serrated adenoma/polyp 8213/0 for distal HPs to be multiple (10–20). They polyp may be similar in colour to the
Traditional serrated adenoma 8213/0 are generally described as looking like adjacent mucosa or may be reddish.
pearl-coloured dew drops, tend to flatten When viewed by chromoendoscopy or
Synonyms and are more difficult to see when the narrow-band imaging, the surface char-
At the present time, “hyperplastic polyp” lumen is fully distended. Using newer acteristics of SSA/Ps are similar to those
without a modifier (i.e. microvesicular) is high-definition endoscopes and chro- of MVHPs {1394}.
acceptable since there is no known clini- moendoscopy, the polyp surface has
cal utility to distinguishing subtypes. Sessile been described as having crypt openings Traditional serrated adenoma (TSA)
serrated adenoma (SSA) and sessile that are larger than the surrounding nor- TSAs are much less common than other
serrated polyp (SSP) are currently con- mal crypts, with lumens that are rounded serrated polyps, are usually found in the
sidered synonyms and both are accept- in GCHP and stellate in MVHP {2333, distal colon and rarely cause clinical
able diagnostic terms. Filiform serrated 3109}. These techniques may make endo- symptoms. Although there are limited en-
adenoma may be a subset of TSA. It is scopic diagnosis of HPs and other ser- doscopic data, TSAs have been described
recommended that giant hyperplastic rated polyps feasible, but the current as having an endoscopic appearance that
polyp, variant hyperplastic polyp and standard for diagnosis is polypectomy resembles that of conventional colonic
serrated adenoma (without a modifier) and histology. HPs in the proximal colon adenomas, which are more commonly red-
should not be used since they are poten- are larger, on average, than those in the dish and protuberant than SSA/Ps {1192,
tially misleading and evolving concepts distal colon. Large proximal HPs may be 1277, 2006}. The endoscopic surface
have led to new nomenclature. difficult to visualize because they tend to appearance of TSAs is not well character-
ized.
Histopathology
The distinction of HP from SSA/P and TSA
is based mainly on architectural criteria,
although cytological features play a more
important role in TSA {757, 2994, 2993,
3274}. SSA/P and TSA can develop addi-
tional cytological features indicative of
progression toward the development of
carcinoma. It is recognized that not all
serrated lesions are easily classified,
often because of sampling issues or poor
orientation of the specimen. In such
A B cases, the term “serrated polyp, unclas-
Fig. 8.41 Typical endoscopic appearance of sporadic serrated polyps in the sigmid colon. A Hyperplastic polyp (HP). sified” may be used.
The lesion (arrow) is sessile and pearly white. B Sessile serrated adenoma/polyp (SSA/P). The lesion is somewhat larger
than a typical hyperplastic polyp, sessile and has a yellow mucus cap.

Hyperplastic polyps (HP) mucin with or without interspersed goblet the precursor to sporadic carcinomas
HPs are the most common serrated cells and tend to show more prominent with microsatellite instability (MSI) and is
lesions, accounting for > 75% of all serrations. GCHPs are mostly composed probably also the precursor for CpG
serrated polyps. Three types have been of goblet cells and show much more island-methylated microsatellite-stable
described: the microvesicular (MVHP), subtle serrations. Both MVHP and GCHP carcinomas {1399}. Like HP, SSA/P has
goblet-cell rich (GCHP) and mucin-poor have bland nuclei without atypia. MPHPs bland cytology and elongation of crypts
types (MPHP) {3274}. The subtypes have are mucin-depleted, may show prominent with prominent serration. The distinguishing
demographic and molecular differences serration and may show reactive-appear- feature of SSA/P is an overall distortion of
{2333}. All three types are characterized ing nuclear atypia. MVHP is the most the normal architecture resulting from
by elongation of the crypts with variable common, followed by GCHP. MPHP is alterations of the proliferative zone {3276}.
degrees of serration. The crypts are very rare and little is currently known The proliferative zone is often not located
straight and proliferation is located in the about this variant. in the base of the crypts but rather on one
lower third of the crypts, with serration or the other side of the crypts and is often
developing in the more luminal aspects SSA/P asymmetrical. Ki67 staining emphasizes
{3276}. The bases of the crypts are nar- SSA/P constitutes about 15–25% of all this abnormal proliferation and reveals
row and lined with undifferentiated cells serrated polyps and in one prospective cells with goblet-cell or gastric-foveolar
with interspersed neuroendocrine cells. study was found in 9% of all patients un- differentiation at the base of the crypts.
MVHPs are characterized by epithelial dergoing screening colonoscopy {1021, The crypts are often dilated and assume
cells with microvesicular (small-droplet) 3049, 3274}. This lesion is thought to be abnormal shapes including L-shaped and
Table 8.09 Histological and genetic features distinguishing different types of sporadic serrated polyps and serrated polyposis.
Type Synonyms Histological featuresa Genetic featuresb
Crypts Proliferation Cytological Mucin type BRAF KRAS CIMP MLH1

dysplasia mutation mutation methylation
MVHP Hyperplastic polyp; Straight with Located uniformly in No Microvesicular or +++ – + –
metaplastic polyp serrations toward basal portion of crypts mixed goblet cell
lumen & microvesicular
GCHP Hyperplastic polyp; Straight, serrations Located uniformly in No Pure goblet cells – +++ U –
metaplastic polyp may be minimal the basal portion of
crypts
MP/HP Hyperplastic polyp; Straight, Located uniformly in Atypia present None U U U U

metaplastic polyp serration toward the basal portion of but appears
lumen crypts reactive
SSA/P Serrated polyp with Crypts distorted, Proliferation abnormally No Usually +++ – +++ –
abnormal proliferation; often dilated near located often away microvesicular,
giant hyperplastic base, excess from the base of the sometimes with
polyp; variant serration near crypts, variable from goblet cells or
hyperplastic polyp base crypt to crypt gastric foveolar
differentiation
SSA/P with Mixed hyperplastic- As for SSA/P As for SSA/P but with Present As for SSA/P +++ – +++ ++
cytological adenomatous more proliferation in
dysplasia polyp; advanced cytologically dysplastic
SSA/P areas
TSA Serrated adenoma; Hyperserrated in Proliferation present at May be present, None or goblet +c +c ++ –
filiform serrated part owing to base of ectopic crypts usually in the cells
adenoma formation of form of cells
ectopic crypts with
eosinophilic
cytoplasm
Serrated Hyperplastic poly- Mostly SSA/P with As per polyp subtype Present as As per polyp ++ c +c +++ +
polyposis posis; giant hyper- some MVHP disease subtype
plastic polyposis advances
CIMP, CpG island methylator phenotype; GCHP, goblet cell-rich hyperplastic polyp; MPHP, mucin-poor hyperplastic polyp; MVHP, microvesicular hyperplastic polyp; SSA/P,
Sessile serrated adenoma/polyp; TSA, traditional serrated adenoma.
a
Please see text for details of histology. b –, not present; +, present often to a limited extent or in some cases; ++ and +++, present extensively; U, unknown. c KRAS and
BRAF mutations are mutually exclusive. Individuals only carry a mutation in one of these two genes.
Serrated polyps of the colon and rectum and serrated polyposis 161
quite different from the dysplasia of

conventional adenomas or of SSA/P with
cytological dysplasia {2994, 3274}. The
lesion reported as “filiform” serrated
adenoma may represent a subset of TSA
{3619}. TSAs are uncommon, making up
< 1% of all polyps.
The original definition of TSA referred to a
lesion with a protuberant although sessile
A B growth pattern with an overall complex,
often villiform configuration. In many
Fig. 8.42 Hyperplastic polyps. A Microvesicular hyperplastic polyp (MVHP). The crypts are elongated but relatively
straight, with serrations that are visible mainly near the luminal end of the crypts. B Goblet cell-rich hyperplastic polyp examples, the villi are lined with a very
(GCHP). The crypts are elongated and slightly serpiginous, but generally straight. Serrations are minimal in most cases. characteristic cell – a tall columnar cell
with a narrow pencillate nucleus and
eosinophilic cytoplasm, often refered to
inverted T-shaped. Serration may be very literature; however, the term “SSA/P with as a “dysplastic” cell. Mitoses are very
prominent and is often seen at the base of cytological dysplasia” is preferred since rare in these cells, unlike the dysplastic
the crypts, rather than superficially, as for biologically the cytologically dysplastic cells of conventional adenoma, and there
HPs. There is often subtle nuclear atypia, part of these lesions is not the same as is no proliferation according to Ki67 stain-
usually in the form of vesicular nuclei with conventional adenoma, essentially never ing. These cells are, therefore, not “dys-
prominent nuclei, and mitoses may be with mutation of the APC gene but rather plastic” in the same sense as the
seen anywhere in the crypts, including in with MSI resulting from methylation of “dysplastic” cells of conventional ade-
the upper third. Some areas of SSA/P may MLH1. The behaviour of these lesions noma or SSA/P with cytological dysplasia,
have straight crypts similar to those of may be more aggressive than that of and appear to be senescent. Conven-
MVHP; however, usually the straight crypts conventional adenoma. tional or serrated dysplasia can occur in
account for less than half of the lesion and TSA, probably reflecting progression
if more than two or three contiguous crypts TSA toward carcinoma. Recent studies have
demonstrate features of SSA/P, the lesion The term “serrated adenoma” was initially suggested that the cytological features of
should be classified as SSA/P. coined for any lesion showing serration the individual cells of TSA may not be the
Cytological dysplasia is not present in and cytological dysplasia {1891}. As it best defining feature, but rather that TSA
uncomplicated SSA/P, but develops with turns out, several disparate lesions fulfil differs from HP and SSA/P in that the
progression toward carcinoma, often in this definition, including the lesions now crypts have lost their anchoring to the un-
conjunction with methylation of the MLH1 known as TSA, SSA/P with cytological derlying muscularis mucosae, leading to
gene and with the development of MSI dysplasia and some conventional adeno- the formation of “ectopic” crypts {3276}.
{1019, 2927}. In addition to dysplasia mas with an overall serrated architecture. If the presence of ectopic crypts is con-
resembling that of conventional adenomas Because of this potentially confusing sidered to be the defining feature of TSA,
(with narrow elongated hyperchromatic ambiguity, it is recommended that the lesions having the overall growth pattern
nuclei and basophilic cytoplasm) more term “serrated adenoma” never be used of TSA but with a predominance of goblet
cuboidal cells with eosinophilic cytoplasia without a qualifier. The most unique lesion cells may also be categorized as TSA.
and more vesicular nuclei with prominent falling under this category, TSA, is a TSA has some features in common with
nucleoli may occur, referred to as “serrated lesion characterized by an overall SSA/P, but the lesions have more differ-
dysplasia”. These advanced lesions have complex and villiform growth pattern, ences than similarities, including consid-
been referred to as “mixed SSA/P-tubular often with cells showing cytological erable differences in histology, location,
adenomas” (or mixed HP-TA) in the older features characterized as “dysplasia”, but progression and molecular pathology.
A B C
Fig. 8.43 Hyperplastic polyps: all types have crypts with narrow bases and a component of undifferentiated small proliferating cells as well as a variable number of interspersed goblet
cells. A Microvesicular hyperplastic polyp (MVHP) generally has a higher proportion of proliferating cells than goblet cell-rich hyperplastic polyps (GCHP). B In MVHP, the maturing
cells near the lumen contain very small droplets of mucin. C In GCHP, the primary maturing cell is the goblet cell and there are no microvesicular cells.

TSA is generally not associated with

carcinoma with high MSI but may be
associated with low MSI {757}.
Molecular pathology
The serrated pathway involves a sequence
of genetic and epigenetic alterations that
lead to the development of sporadic
carcinomas with MSI and probably also
microsatellite stable CpG island-methylated A B
carcinomas (CIMP+ MSS). An early event
Fig. 8.44 Sessile serrated adenoma/polyp (SSA/P), high-power view. A Mature cells are often seen at the base of the
in the pathway involves activating muta- crypts; in this case, they mainly resemble gastric foveolar cells. Note the dilated, distorted appearance of the crypt,
tions of the BRAF gene, a pro-proliferative, sometime referred to as “anchor-shaped”. B In this case, the crypts are uniformly dilated and there are goblet cells at
anti-apoptotic serine-threonine kinase. the crypt bases.
Mutations of BRAF are present in the
majority of SSA/Ps and are also common
in MVHP. This explains why some sporadic
MSI-H adenocarcinomas (but not Lynch
syndrome-associated MSI carcinomas)
contain BRAF mutatations. GCHPs tend to
carry KRAS mutations. The serration of
both SSA/P and MVHP is thought to be
attributable to failure of apoptosis, which
leads to the accumulation of mature cells
that pile up into serrations. Although it has
been speculated that MVHP may be a A B
precursor lesion to SSA/P, there are several Fig. 8.45 Sessile serrated adenoma/polyp (SSA/P), low-power view. A Note that although the crypts still reach the
arguments against this possibility, including muscularis mucosae, they are generally distorted and dilated, L-shaped, inverted T-shaped or anchor-shaped. B SSA/P
the marked difference in distribution of the with excess serration at the base of a crypt.
lesions and the fact that SSA/Ps can
occasionally be only two or three crypts in that of adenomas in patients with Lynch it is likely that many of the cases in which
size. Therefore, this possibility remains to syndrome. The MLH1 gene is not methylated BRAF is mutant are SSA/P with cytological
be clarified. in CIMP-H microsatellite-stable carcinomas dysplasia, rather than TSA. TSA does show
It is clear that SSA/P acts as a more imme- and the specific genes and sequence of increased methylation, but essentially never
diate precursor to carcinoma. SSA/Ps are events that drive the progression from shows methylation of MLH1, and is never
prone to methylation of the promoter regions SSA/P to CIMP-H microsatellite-stable associated with CIMP-H MSI carcinomas.
of a number of genes, the most important of carcinomas is unknown. It has been suggested that TSA may be
which is MLH1, a DNA mismatch repair TSA shows considerable differences from the precursor to MSI-L carcinoma by way
gene. SSA/Ps without cytological dysplasia SSA/P in terms of mutation and methylation of methylation of the MGMT promoter.
are generally not methylated at MLH1, and status {757}. Although many TSAs are Much remains to be learned about TSA,
hence are not MSI. When methylation of reported to have BRAF mutations, at least which has only recently been distin-
MLH1 occurs, the polyp becomes MSI, and 25% of TSAs have mutations of KRAS, not guished from the other serrated lesions.
at this point has a propensity to develop into BRAF. Since such mutation studies have not
carcinoma, probably at a rate similar to always used the current definition of TSA,
A B C
Fig. 8.46 Sessile serrated adenoma/ polyp (SSA/P) with cytological dysplasia. A At low power, the SSA/P on the left is sharply demarcated from the cytologically dysplastic area on
the right. B Here the cytological dysplasia resembles that of a conventional adenoma, although the molecular profile of this lesion is likely to be very different. C The cytological dysplasia
in this example is slightly different from that of a conventional adenoma; the cells are shorter, and the nuclei have more open chromatin and prominent nucleoli. The cytoplasm tends
to be more eosinophilic (less amphophilic) than that found in conventional adenomas. This is sometimes referred to as “serrated” dysplasia.
with serrated polyposis; or (3) > 20 ser-

rated polyps of any size, but distributed
throughout the colon {1106, 2636, 1401}.
Clinical features
Serrated polyposis occurs in males and
females and at any age, although it is
more often reported in middle and later
life {845, 1296, 2636, 2658, 2744}. It is
A B generally asymptomatic, but larger
polyps may bleed. The condition is most
often identified unexpectedly at screen-
ing colonoscopy. The polyps are most
often sessile and < 1 cm in diameter, with
rare larger pedunculated lesions. Small
polyps are often distributed throughout
the colon while larger polyps are usually
found in the proximal colon. One or
several cytologically dysplastic lesions
are often found in this condition during
C D surveillance. Serrated polyps have been
Fig. 8.47 Traditional serrated adenoma (TSA). A At low power, TSA often appears very complex with a prominent observed to progress to high-grade
“villiform” or “filiform” configuration. B In many cases, the cells lining the villi are predominantly tall and columnar with dysplasia. Extracolonic or extraintestinal
eosinophilic cytoplasm and oval nuclei, which are typically minimally pseudostratified and generally show little if any manifestations have not been observed.
mitotic activity (and are usually negative for the proliferation marker Ki67). C Note the presence of small abortive or Two clinical variants are recognized,
“ectopic” crypts (seen protruding from the surface) that do not extend to the muscularis mucosae. This detachment of although overlap may be present {381,
crypts from the muscularis mucosae may allow these lesions to become villiform. D At higher power, the cells of these
1401}. In type 2, numerous small (usually
ectopic crypts are differentiated near the surface, but proliferating and undifferentiated at the base.
5 mm or smaller) classical hyperplastic
polyps are present throughout the colon
Prognosis and predictive factors SSA/P with cytological dysplasia be and the risk of cancer is modestly
The current recommendation is to remove considered as a histologically advanced increased, if at all {1401}. In type 1, multi-
all polyps when technically possible lesion, given the likelihood that it is MSI, ple SSA/Ps occur that can be larger and
{2664}, except where there are many and that a 1-year post-intervention exam- often more proximal {1401}. The risk of
diminutive (< 5 mm) distal HP-appearing ination should be considered to guaran- cancer is substantial for type 1. Ultimately,
polyps that can be sampled (six to eight tee complete removal of the lesion, with a molecular genetic alterations may define
polyps biopsied) to confirm that they are subsequent surveillance interval of 3 these two and possibly other variants.
HPs). Diminutive distal HPs are thought to years, but this approach has not been rig-
have little or no malignant potential and orously tested. Histopathology
their presence does not otherwise affect The lesions of serrated polyposis are
screening for colorectal cancer and inter- predominately SSA/P, with fewer MVHPs,
vals for colonoscopic surveillance. Serrated polyposis which may be larger than typical HPs
Follow-up recommendations for individu- {3275, 757, 1401}. With progression,
als with large (> 1 cm) HPs are not clearly Synonyms SSA/Ps with cytological dysplasia appear,
defined but, given that many SSA/Ps will Historically, serrated polyposis has been at which point carcinoma may develop
have areas that are histologically indistin- called hyperplastic polyposis; however, quickly. Lesions that are indistinguishable
guishable from HPs, complete excision is the term “serrated polyposis” is preferred, from conventional adenoma are some-
important, if possible, to assure accurate given the common presence of SSA/P in times present, and may represent SSA/P
diagnosis. Surveillance recommendations this process {3275}.
for SSA/Ps and TSAs are not standardized
nor validated. Two groups have published Diagnostic criteria
similar recommendations based on cur- Differing criteria to define serrated poly-
rent terminology and predicted behaviour, posis have been suggested, although all
but they have not been tested {757, are empirical and the described cate-
2994}. Recommended surveillance inter- gories may represent different diseases.
vals may be partly based on the number Definitions include: (1) at least five
and size of the polyps (5-year surveil- serrated polyps proximal to the sigmoid
lance for one or two small [< 1 cm] colon with two or more of these being
polyps; 3-year surveillance for any large > 10 mm; (2) any number of serrated
[> 1 cm] lesion or for three or more of any polyps proximal to the sigmoid colon in an
size). Some authors recommend that any individual who has a first-degree relative Fig. 8.48 Serrated polyposis in a colectomy specimen.

Fig. 8.49 Schematic representation of the development of sporadic colorectal carcinoma with microsatellite instability (MSI) via methylation of the MLH1 gene. The earliest steps in
the progression from normal mucosa to sessile serrated adenoma/polyp (SSA/P) are currently under debate (dotted lines).
that has been overtaken by cytologically of the phenotype {544}. It has been sug- dysplasia is observed, then colectomy
dysplastic cells and hence are not tech- gested that the lesions in type 2 serrated with ileo-rectal anastamosis should be
nically conventional adenomas. polyposis generally have KRAS mutations recommended, followed by regular rectal
while lesions in type 1 serrated polyposis clearing of new polyps. The presence of
Genetic suscepibility tend to have mutant BRAF {1401}. multiple, large proximal colonic serrated
Relatives have not generally been exam- polyps, which can be difficult and risky to
ined for polyposis. Few cases of familial Prognosis and predictive factors remove by colonoscopy, is a common
serrated polyposis have been described Untreated serrated polyposis is thought to reason to move to surgery, although large
{1401}. be associated with a substantial (although numbers of polyps may also lead to this
undetermined) increased risk of develop- decision. Screening colonoscopy should
Molecular pathology ing colon cancer {3275, 845, 1138, 1296, probably also be offered to first-degree
The genetic etiology and pathogenesis of 1403, 1401, 1796, 2658, 2744}. Suggested relatives, particularly those aged > 40
serrated polyposis is not known. The management is colonoscopy for polyp re- years, in view of the possible familial risk
serrated pathway, described for sporadic moval every 1–3 years, depending on the {1719, 3635}. Properly managed patients
polyps, is certainly one possibility {1406, number of polyps present {845, 1719, with serrated polyposis appear to have a
1465, 3656}. Additional pathways have 2744, 3635}. Polyps of < 3–4 mm can prob- very good prognosis. Some cases of
been postulated, suggesting that the ably safely be observed with annual ex- MUTYH-associated polyposis are also
disease may be heterogeneous {1401, amination, although larger polyps should reported to have SSA/P.
2636}. MUTYH gene-associated poly- be removed. If colonoscopic manage-
posis has occasionally been reported to ment becomes technically difficult or inef-
include multiple serrated polyps as part fective, or if any progression to cytological
Juvenile polyposis G.J.A. Offerhaus

J.R. Howe
Definition seventh decade {1258}. Although epi-

Juvenile polyposis is a familial cancer demiological data are limited, incomplete
syndrome with an autosomal dominant penetrance and approximately equal
trait. It is characterized by multiple juve- distribution between males and females
nile polyps of the gastrointestinal tract, can be presumed.
predominantly the colorectum, but also
the stomach and small intestine. Localization
Polyps occur with equal frequency
MIM Nos 174900, 175050, 612242 throughout the colon and range in num-
ber from 1 to > 100. Some patients de-
Fig. 8.50 Juvenile polyposis. The contours of the multiple
Synonyms velop polyps of the upper gastrointestinal polyps are highly irregular and fronded, unlike those of
Generalized juvenile polyposis; juvenile tract, most often the stomach, but also solitary sporadic juvenile polyps.
polyposis coli; juvenile polyposis of in- small intestine. Generalized juvenile
fancy; juvenile polyposis of the stomach; gastrointestinal polyposis is defined by
familial juvenile polyposis; hamartoma- the presence of polyps in the stomach, commonly diffuse. Biopsy or excision of
tous gastrointestinal polyposis; combined small intestine and colon {2770}. polyps by colonoscopy can be both
juvenile polyposis/hereditary haemorrhagic diagnostic and therapeutic. Endoscopic
telangiectasia (Osler-Weber-Rendu) syn- Clinical features screening of the colorectum and upper
drome. Signs and symptoms gastrointestinal tract is recommended at
Patients usually present with gastrointestinal age 15 years or at the time of first symp-
Diagnostic criteria bleeding, manifesting as haematochezia. toms {344, 1259} and should be repeated
After the initial report by McColl in 1964 Melaena, prolapsed rectal polyps, passage every 2–3 years.
{2020}, the following diagnostic criteria of tissue per rectum, intussusception,
were established: (1) more than three to abdominal pain, and anaemia are also Extraintestinal manifestations
five juvenile polyps of the colorectum; or common. Congenital anomalies have been reported
(2) juvenile polyps throughout the gastroin 11–15% of patients with juvenile poly-
intestinal tract; or (3) any number of juve- Imaging posis {572, 1226}, mostly in sporadic
nile polyps with a family history of juvenile Air-contrast barium enema and upper cases {385}. These anomalies most com-
polyposis {978, 1407}. Other syndromes gastrointestinal series may reveal filling monly involve the heart, central nervous
involving hamartomatous gastrointestinal defects, but are non-diagnostic for juve- system, soft tissues, gastrointestinal tract
polyps should be ruled out clinically or by nile polyps. and genitourinary system {572, 2020}.
pathological examination. Several patients have been reported with
Endoscopy. Small juvenile polyps may re- ganglioneuromatous proliferation within
Epidemiology semble hyperplastic polyps, while larger juvenile polyps {2042, 2539, 3483}. An as-
Incidence polyps generally have a well-defined stalk sociation exists between juvenile polyposis
Juvenile polyposis is ten times less com- with a bright red, rounded head, which and hereditary haemorrhagic telangiectasia,
mon than familial adenomatous polyposis may be eroded. In the stomach, polyps characterized by vascular malformations
(FAP) {1397}, with an incidence of 0.6–1 are less often pedunculated and are more affecting many organs {938}, and various
case per 100 000 population in European
countries and North America {379}. In less
developed countries, however, juvenile
polyposis may be the most common
gastrointestinal polyposis syndrome
{2662, 3515}. About half of cases arise in
patients with no family history {572}.
Age and sex distribution

Two thirds of patients with juvenile poly-
posis present within the first two decades
of life, with a mean age at diagnosis of A B
18.5 years {572}, although some present Fig. 8.51 A, B Juvenile polyposis with low-grade dysplasia: the bizarre architecture is unlike the round, uniform structure
in infancy, and others not until their of sporadic juvenile polyps.

reports of patients with juvenile polyposis

who have pulmonary arteriovenous
malformations and hypertrophic osteo-
arthropathy have been published {174,
611, 2972}.
Macroscopy
Most subjects with juvenile polyposis
have 3–200 polyps throughout the
colorectum. The rare and often lethal form
occurring in infancy may be associated
with diffuse gastrointestinal polyposis
{2770}. In cases presenting in later child-
hood to adulthood, completely unaffected
mucosa separates the lesions. This is
unlike the dense mucosal carpeting that
is characteristic of FAP. The polyps are
usually pedunculated, but can be sessile
in the stomach. Smaller examples have
the spherical head of a typical solitary
Fig. 8.52 Juvenile polyp with low-grade dysplasia and an area of early adenocarcinoma (arrow).
juvenile polyp. They may grow up to 5 cm
in diameter, with a multilobulated head.
The individual lobes are relatively smooth disruption of signalling by intestinal bone Prognosis and predictive factors
and separated by deep, well-defined morphogenetic protein (BMP) leads to the The most severe form of juvenile polypsis
clefts. The multilobulated polyp therefore development of neoplasia in the polyps presents in infancy, with diarrhoea,
appears as a cluster of smaller juvenile {1122}. anaemia, and hypoalbuminaemia; these
polyps attached to a common stalk. Such patients rarely survive past age 2 years.
multilobulated or atypical juvenile polyps Molecular pathology Although polyps in patients with juvenile
account for about 20% of the total number Germline mutations in SMAD4 or BMPR1A polypsis are considered to be hamar-
of polyps {1407}. are identified causes of juvenile polyposis tomas, they do have malignant potential.
in 50–60% of patients {893, 1254, 1261, A recent analysis found a cumulative life-
Histopathology 2736}. Most such alterations are point time risk of colorectal cancer of 39% and
Smaller polyps are indistinguishable from mutations or small base-pair deletions that a relative risk of 34 for patients with
their sporadic counterparts, i.e. they have can be detected by conventional sequence juvenile polyposis {343}. The lifetime risk
an eroded surface, abundant oedema- analysis; however, about 5–15% are deletions of other cancers of the stomach, small
tous stroma with inflammatory cells and of one or more exons, or the entire SMAD4 bowel and pancreas has been reported
cystically dilated glands with reactive or BMPR1A gene. To analyse such large as 10–15% {1258}. The typical age at
epithelium. In the multilobulated or atypical genomic deletions, techniques such as diagnosis is between 35 and 45 years
variety, the lobes may be either rounded multiplex ligation-dependent probe ampli- (range, 15–68 years) for colon carcinoma
or finger-like. There is a relative increase fication (MPLA) are necessary {141, 401, and 58 years (range, 21–73 years) for
in the amount of epithelium vs stroma. 3365}. upper gastrointestinal carcinoma {1258,
Glands show more budding and branch- Since the molecular cause of juvenile 1407}. Most cases occur in patients who
ing but less cystic change than the polyposis remains unknown in about half have not been screened radiologically or
classical solitary polyp {1407}. of cases, other candidate genes, mostly endoscopically, suggesting that cancers
those involved in the TGFβ/BMP pathway, may be preventable by close surveil-
Neoplastic potential. There are two histo- have been investigated. Germline mutation lance. Prophylactic surgery should be
genetic explanations for the well-docu- of the TGFβ coreceptor endoglin (ENG) considered for patients who cannot be
mented association between juvenile has been reported in two patients with managed endoscopically and have
polyposis and colorectal cancer, which juvenile polyposis {3144}, but since no polyps with dysplasia or who have a
could (1) arise in co-existing adenomas; ENG mutations were found in an additional strong family history of colorectal cancer.
or (2) develop via neoplastic change 65 patients, the role of this gene in suscep- Mutations in SMAD4 and BMPR1A may
within a juvenile polyp. While both tibility is under debate {1255}. No germline be associated with phenotypic differ-
mechanisms may apply, pure adenomas mutations have been found in SMAD1–3, ences in severity {1116}. In general,
appear to be uncommon in juvenile poly- SMAD5, SMAD7, BMPR2, BMPR1B, carriers of SMAD4 mutations are more
posis. In contrast, foci of dysplasia are ACVRL1, TGFBR2 or CDX2 {345, 3365}. likely to develop polyps and cancers of
regularly seen, particularly in atypical or Although one unconfirmed report has the upper gastrointestinal tract {894,
multilobulated juvenile polyps {1407, suggested a role for PTEN {2399}, the 2831} and hereditary haemorrhagic
3546}. Additional support for the second present notion is that individuals with PTEN telangiectasia {938}, while carriers of
mechanism comes from a transgenic- mutations should be considered as having BMPR1A mutations are more likely to
mouse model of juvenile polypsis in which Cowden syndrome {795}. have cardiac defects.
Juvenile polyposis 167

Peutz-Jeghers syndrome G.J.A. Offerhaus

M. Billaud
S.B. Gruber
Definition of polyps that come to clinical attention

Peutz-Jeghers syndrome (PJS) is an (e.g. upon intussusception) might mis-
inherited cancer syndrome characterized represent the true number and distribution
by mucocutaneous melanin pigmentation of polyps {3331}.
and hamartomatous gastrointestinal
polyposis, which preferentially affects the Clinical features
small intestine. PJS patients also have an Signs and symptoms. These include
increased risk of extraintestinal cancer, abdominal pain, intestinal bleeding,
including tumours of the ovary, uterine anaemia, and intussusception, which
cervix, testis, pancreas and breast. typically manifest in the first two decades
Fig. 8.53 Peutz-Jeghers syndrome. Note the pigmentation of life {344}. The characteristic pigmenta-
MIM No. 175200 of the lips, peri-oral skin, tongue and fingers. tion, if present, allows diagnosis of
asymptomatic patients in familial cases,
Synonyms and historical annotation but the hamartomatous PJS polyps
The syndrome was first described by or (2) any number of Peutz-Jeghers polyps constitute the main clinical hallmark.
Peutz in 1921 {2538} and later by Jeghers with a family history of PJS; or (3) charac-
in 1949 {1411}. The pedigree of the Dutch teristic, prominent, mucocutaneous pig- Imaging. The presence of polyps may be
family described by Peutz continues to be mentation with a family history of PJS; or detected by upper-gastrointestinal and
followed {3492}. Several designations (4) any number of Peutz-Jeghers polyps small-bowel contrast radiography, and by
have been used synonymously, including and characteristic, prominent, mucocuta- air-contrast barium enema. Periodic small-
Peutz-Jeghers polyposis, periorificial neous pigmentation. Some melanin pig- bowel X-ray examination is advisable in
lentiginosis, and polyps-and-spots syn- mentation is also regularly seen in the follow-up of affected patients. Endo-
drome. unaffected individuals, hence the empha- scopy is superior to radiological imaging
sis on the prominence of the pigmentation. since simultaneous polypectomy can be
Incidence Moreover, the pigmentation in PJS patients used for diagnostic and therapeutic
As this condition is rare, well-documented may disappear with time or can, in rare purposes. Current recommendations
incidence data are not available. Based cases, be absent altogether. include biannual endoscopy of the upper
on numbers of families registered in the gastrointestinal tract and colonoscopy
Finnish Polyposis Registry, the incidence Intestinal neoplasms with polypectomy, and small-bowel X-ray
of PJS is roughly one tenth that of familial Penetrance appears to be high and series {982}. Since the enteroscope is
adenomatous polyposis (FAP), with an males and females are equally affected rarely able to view the full length of the
estimated prevalence of 1 per 50 000 to {1160}. Polyps are most common in the bowel, imaging remains an integral com-
1 per 200 000 births. small intestine, but may occur anywhere ponent of clinical management, although
in the gastrointestinal tract. Polyps in PJS solid evidence on the impact of surveil-
Diagnostic criteria have also been described at locations lance strategies in these patients is
The following diagnostic criteria are outside the gastrointestinal tract, such as lacking.
recommended: (1) three or more histo- the gallbladder, bladder and nasopharynx
logically confirmed Peutz-Jeghers polyps; {1515}. Note that counting only the number Macroscopy
On gross inspection, the surface of Peutz-
Jeghers polyps shows coarse lobulation
somewhat resembling that of an adenoma
but with larger lobules and in marked
contrast to the smooth surface of a
juvenile polyp. The stalk is generally short
and broad or absent. Polyp size can vary
from 5–50 mm.
Histopathology
A typical Peutz-Jeghers polyp has a diag-
A B nostically useful central core of smooth
Fig. 8.54 A Lobulated Peutz-Jeghers polyp of the small intestine, gross specimen. B Small-intestinal Peutz-Jeghers muscle that shows tree-like branching.
polyp with haemorrhagic infarction caused by intussusception. This is covered by the mucosa native to

A B
Fig. 8.55 Peutz-Jeghers polyp of the small intestine. A Whole mount. B Pseudoinvasion characterized by benign Fig. 8.56 Peutz-Jeghers polyp of the colon. Arborizing
mucinous cysts extending through the bowel wall into mesentery. The patient was well 10 years after removal of the polyp. smooth muscle separates colonic glands into lobules
(Masson trichrome stain).
the region, heaped into folds producing a question of whether or not the hamar- Extraintestinal manifestations
villous pattern {1385}. Diagnosis may be tomatous Peutz-Jeghers polyp is itself pre- Predisposition to cancer of multiple organ
complicated when there is secondary cancerous has proved difficult to resolve. systems is an important feature of PJS
ischaemic necrosis, which can arise when Epithelial misplacement has apparently {977}. The most well-documented extra-
a polyp has caused intussusception, a been overdiagnosed as cancer in the intestinal neoplasms include sex-cord
common form of presentation. Occasion- past {2923}, and it is questionable tumours with annular tubules (SCTAT) of
ally, polyps (especially smaller ones) lack whether the increased risk of malignancy the ovary {3659}, adenoma malignum of
diagnostic features. Epithelial misplace- in the stomach, small bowel and colon is the uterine cervix {3659}, Sertoli cell
ment involving all layers of the bowel wall attributable to malignant progression from tumours of the testis {3521}, carcinoma of
(“pseudoinvasion”) has been described in hamartoma to adenocarcinoma. Intraep- the pancreas {980}, and carcinoma of the
up to 10% of intestinal PJS polyps {2923}. ithelial neoplasia (dysplasia) is very un- breast {2680}. The risk of breast cancer in
Mechanical forces associated with intus- common in PJS polyps {1865, 2923}, female PJS patients is comparable to that
susception and episodes of mucosal pro- although it has been described occasion- of carriers of BRCA1 or BRCA2 mutations
lapse {1385} is the likely explanation for this ally {573, 2534}. Human PJS polyps ap- {1146}. Cutaneous melanin pigmentation
observation. Epithelial misplacement may pear to be polyclonal {672}, while murine occurs typically around the mouth as
be florid and extend into the serosa, thereby PJS models have demonstrated that loss freckle-like spots. Other sites commonly
mimicking a well-differentiated adenocarci- of the wildtype LKB1/STK11 allele, the affected are the digits, palms and feet,
noma. Useful discriminatory features are the gene responsible for PJS, is not a prereq- buccal mucosa, and anal region. While
lack of cytological atypia, presence of all uisite for polyp formation {2731}. The in- dramatic pigmentation is a helpful sign, it
the normal cell types, mucinous cysts and cidence of adenomas in PJS patients may fade with time, and some affected
haemosiderin deposition {2923}. remains ill-defined, although an increased individuals never display pigmentation.
risk of developing adenoma has been re-
Intraepithelial neoplasia (dysplasia) and ported {2021}. It is conceivable that pro- Genetic susceptibility
cancer in Peutz-Jeghers polyps. lapse of a well-formed adenoma may PJS is an autosomal dominant trait with
While PJS is associated with a 10- to 18- mimic the histopathology of dysplasia in nearly complete penetrance. The PJS
fold excess of gastrointestinal and non- a hypothetically pre-existing hamartoma- gene, LKB1/STK11, maps to 19p13.3.
gastrointestinal cancers {977, 3045}, the tous PJS polyp. Although some initial evidence suggested
A B
Fig. 8.57 Peutz-Jegher polyp of the small intestine. A Note the branching muscularis mucosae with overlying small-intestinal mucosa. B The small-intestinal mucosa is essentially
normal and overlies an arborized muscularis mucosae.
Peutz-Jeghers syndrome 169

during spermiogenesis {3280}. Homologues

of LKB1 have been identified in several
species, including mouse, Xenopus,
Drosophila and Caenorhabditis elegans
{2987, 3106, 3472}. Unlike most kinases,
LKB1 is not activated by phosphorylation
of its activation loop by an upstream
kinase, but by binding to the adapter
proteins STRAD and MO25. Formation of
this trimeric complex stabilizes and
activates LKB1. LKB1 is a master kinase
that regulates cell polarity and energetic
metabolism {879}. Although the crucial
downstream target of LKB1 remains to be
defined, it has been shown that LKB1 can
effectively phosphorylate AMPK, a key
sensor of cellular energy status that relays
LKB1 tumour-suppressor activity in inver-
A B tebate models {879}. Furthermore, the
Fig. 8.58 Peutz-Jeghers polyp of the large intestine. A Note the arborizing muscularis mucosae with overlying relatively LKB1–AMPK signalling cascade nega-
normal colonic mucosa. B At high power, the appearance of the mucosa is nearly normal. tively regulates the mTOR pathway, which
is a major regulator of cell growth and is
constantly hyperactivated in hamartoma-
locus heterogeneity {2034}, the advent of Germline mutations tous polyposis syndromes, including PJS
novel molecular techniques for the analysis Germline mutations are usually truncating, {1329}. These findings suggest that
of large genomic deletions (e.g. multiplex but missense mutations have also been topical inhibition of mTOR with rapamycin
ligation probe amplification), PJS in most described {1159, 1417}. Since wildtype analogues may prove beneficial in the
families can now be linked to pathogenic LKB1 is capable of autophosphorylation treatment of PJS-associated tumours
germline mutations in LKB1/STK11 {671, {2034, 3642}, the effect of missense {2889}. In humans, the AMPK family in-
1147}. However, the identification of a mutations occurring in the kinase domain cludes 14 kinases that are involved in a
germline mutation in the gene encoding can be evaluated in assays for autophos- wide array of functions ranging from
smooth-muscle myosin (MYH11) in a PJS phorylation. Interestingly, inactivating control of cell metabolism to the regulation
patient suggests that alterations in genes mutations in PJS patients and in sporadic of cellular polarity {1386}. The LKB1 protein
other than LKB1/STK11 may also be cases are not restricted to the kinase behaves as a tumour suppressor in
involved in this disease {89}. domain {86, 1494} and functional analyses various model systems and, curiously,
have revealed that such mutations hemi-allelic inactivation has been shown
Gene structure interfere with LKB1-mediated regulation to accelerate tumour formation in murine
The LKB1 gene spans 23 kb and com- of AMPK and cell polarity {880}. Recent models {1424}, suggesting that LKB1
prises 11 exons, 9 of which are coding. It research shows that LKB1/STK11 is may be haplo-insufficient for suppression
is transcribed in the telomere-to-centro- frequently targeted for inactivation in pul- of neoplastic transformation under certain
mere direction. The open reading frame monary cancers in patients with sporadic conditions.
consists of 1302 base pairs, correspon- tumours, particularly the most frequent
ding to 433 amino acids. Codons 50–337 subtype, adenocarcinoma {1424, 2793}. Prognosis and predictive factors
encode the catalytic kinase domain of the While intussusception has been a major
protein, which is most similar to the SNF1/- Gene product source of mortality in PJS kindreds {3492},
AMP-activated protein kinase (AMPK) The human LKB1 gene is ubiquitously surgery constitutes an effective treatment.
family. Two alternatively spliced forms of expressed in fetal and adult tissues The prognosis for individuals affected by
LKB1 exist: in LKB1 long (LKB1L), the C- {1159, 1417}. LKB1L is a 50 kDa protein PJS is thus mainly determined by the risk
terminal sequence is encoded by exon that possesses a serine/threonine kinase of malignancy {977}. Although little infor-
9B, while in the recently desccribed LKB1 domain framed by a short N-terminus mation on prognosis is available, one
short (LKB1S) this sequence is encoded sequence (48 residues) and a more report suggests that PJS-associated
by exon 9A {3280}. In LKB1S, the 63 extended C-terminus region of 122 amino cancers are particularly aggressive
residues of LKB1L are substitued by a 39- acids that contains five phosphorylation {3045}. Research shows that a diagnosis
residue unique sequence. sites and a farnesylation motif {1159, of PJS has great psychosocial impact
1417}. LKB1S lacks two phosphorylation {3545}, although the physical impact on
sites and the prenylation motif; it is mostly the patient is not greater than that in the
expressed in the testis where it is required general population.

Cowden syndrome Ch. Eng

C. Eng
R.W. Burt
Definition florid and unusual families or case reports hyperplasia {424, 3476}. These polyps
Cowden syndrome (CS), also known as by subspecialists interested in their are found in the stomach, duodenum,
PTEN hamartoma syndrome, is an auto- respective organ systems, the spectrum small bowel and colon. Those in the colon
somal dominant disorder characterized of component signs is unknown. Despite and rectum usually measure 3–10 mm in
by multiple hamartomas involving organs this, the most commonly reported mani- diameter, but can reach 2 cm or more.
derived from all three germ-cell layers. festations are mucocutaneous lesions, Some of the polyps are no more than tags
The classical hamartoma associated with thyroid abnormalities, fibrocystic disease of mucosa, but others have a more
CS is trichilemmoma. Affected family and carcinoma of the breast, gastro- definite structure. Examples containing
members have a high risk of developing intestinal hamartomas, multiple, early- adipose tissue have been described. The
breast and epithelial thyroid carcinomas. onset uterine leiomyoma, macrocephaly mucosal glands within the lesion are nor-
Other clinical manifestations include (specifically, megencephaly) and mental mal or elongated and irregularly formed,
mucocutaneous lesions, nonmalignant retardation {1119, 1895, 3058, 3683}. but the overlying epithelium is normal and
thyroid abnormalities, fibrocystic disease includes goblet cells and columnar cells
of the breast, gastrointestinal hamar- Epidemiology {424}. Some ganglion tissue is not
tomas, early-onset uterine leiomyomas, The single most comprehensive clinical unusual in the juvenile-like polyps, but
macrocephaly, mental retardation and epidemiological study estimated the lesions in which autonomic nerves are
dysplastic gangliocytoma of the cerebel- prevalence to be 1 per million population predominant, giving a ganglioneuroma-
lum (Lhermitte-Duclos disease). The {3058}. After identification of the gene for like appearance, have been described
syndrome is caused by germline muta- CS {1842}, a molecular-based estimate of but seem to be exceptional {1749}.
tions of the phosphatase and tensin prevalence in the same population was The vast majority of CS hamartomatous
homologue (PTEN) gene. A subset of 1 : 200 000 {2262}. Because of difficulty in polyps are asymptomatic, although anec-
individuals with CS and CS-like symptoms recognizing this syndrome, prevalence dotally, adenomatous polyps and colon can-
without germline PTEN mutations have figures are likely to be underestimates. cers have been observed in young patients
been found to habour germline variants of with this condition {3684}. The association
dehydrogenase complex subunits B Intestinal neoplasms and risk of gastrointestinal malignancy with
(SDHB) or D (SDHD). Hamartomatous polyps CS is unknown, but appears to be likely. In a
In a small but systematic study compris- study of nine CS individuals, glycogenic
MIM No. 158350 ing nine well-documented individuals with acanthosis of the oesophagus was found in
CS, seven of whom had a germline muta- six out of seven individuals with PTEN
Synonyms tion in PTEN, all nine had hamartomatous mutation {3476}. It is likely that many more
Cowden disease; multiple hamartoma polyps {3476}. Several varieties of hamar- CS patients will be identified in the future
syndrome. tomatous polyps are seen in this syn- with ongoing screening for colon cancer,
drome, including hamartomas most which should allow a more precise charac-
Diagnostic criteria similar to juvenile polyps composed of a terization of the phenotypic gastrointestinal
Because of the variable and broad mixture of connective tissues normally features of this disease and possible risk of
expression of CS and the lack of uniform present in the mucosa, principally smooth gastrointestinal cancer.
diagnostic criteria prior to 1996, the Inter- muscle in continuity with the muscularis In order to determine the prevalence of
national Cowden Consortium {2263} com- mucosae, along with lipomatous and gan- PTEN germline mutations in an unselected
piled operational diagnostic criteria for CS glioneuromatous lesions and lymphoid series of individuals with hamartomatous
on the basis of the published literature
and their own clinical experience {793,
3683}. Trichilemmomas and papilloma-
tous papules are particularly important to
recognize. CS usually presents within the
third decade of life. It has variable and
broad expression and an age-related
penetrance. By the third decade of life,
99% of affected individuals have devel-
oped mucocutaneous stigmata, although
any of the other features could already be
present. Because the clinical literature on A B
CS consists mostly of reports of the most Fig. 8.59 A, B Colonic polyps in Cowden syndrome. Distorted glands and fibrous proliferation in the lamina propria.
Cowden syndrome 171

Table 8.10 International Cowden Consortium diagnostic infancy, this deletion also involved are follicular adenomas and multinodular
criteria for Cowden syndrome and operational diagnosis. BMPR1A upstream of PTEN. Subse- goitre of the thyroid. An unusual tumour of
Diagnostic criteria quently, germline deletion involving both the central nervous system, cerebellar
PTEN and BMPR1A was shown to char- dysplastic gangliocytoma or Lhermitte-
Pathognomonic criteria
Mucocutanous lesions: acterize at least a subset of juvenile poly- Duclos disease, has recently been
Trichilemmomas, facial posis of infancy {692}. associated with CS {794, 1900, 2432}.
Acral keratoses Interestingly, adult-onset Lhermitte-Duclos
Papillomatous papules Extraintestinal manifestations disease, even in the absence of other fea-
Mucosal lesions Breast cancer tures or family history, is highly predictive
The two most commonly recognized can- of finding a germline mutation in PTEN
Major criteria
cers in CS are carcinoma of the breast {3713}. Other malignancies and benign
Breast cancer
Thyroid cancer, especially follicular carcinoma and thyroid {3058, 3683}. In the general tumours have been reported in patients or
Macrocephaly (megencephaly) (≥ 97th percentile) population, lifetime risks of breast and families with CS. Some authors believe
Lhermitte-Duclos disease thyroid cancers are approximately 11% that endometrial carcinoma could also be
(in women), and 1%, respectively. Breast a component tumour of CS. It remains to be
Minor criteria cancer has been observed rarely in men shown whether other tumours (sarcomas,
Other thyroid lesions (e.g. adenoma or with CS {1979}. In women with CS, esti- lymphomas, leukaemia, meningiomas)
multinodular goitre)
Mental retardation (IQ ≤ 75)
mates of lifetime risk of breast cancer are true components of CS.
Gastrointestinal hamartomas range from 25% to 50% {793, 1119, 1895,
Fibrocystic disease of the breast 3058, 3683}. The mean age at diagnosis Genetic susceptibility
Lipomas is likely to be 10 years earlier than for Chromosomal location and mode of
Fibromas breast cancer occurring in the general transmission
Genitourinary tumours (e.g. uterine fibroids) or population {1895, 3058}. Although Rachel CS is an autosomal dominant disorder,
malformation
Cowden died of breast cancer at the age with age-related penetrance and variable
Operational diagnosis in an individual of 31 years {349, 1875} and the earliest expression {794}. The CS susceptibility
recorded age at diagnosis of breast gene, PTEN, resides on 10q23.3 {1834,
1. Mucocutaneous lesions alone if:
(a) there are six or more facial papules, of which cancer is 14 {3058}, the great majority of 1842, 2263}.
three or more must be trichilemmoma; or breast cancers are diagnosed after the Pilot data suggest that a subset of indi-
(b) cutaneous facial papules and oral mucosal age of 30–35 years (range, 14–65 years) viduals with CS and CS-like features, who
papillomatosis; or {1895}. The predominant histology is are negative for PTEN mutations, harbour
(c) oral mucosal papillomatosis and acral ductal adenocarcinoma. Most CS breast germline variants of SDHB (on 1p35–p36)
keratoses; or carcinomas occur in the context of ductal or SDHD (on 11q23), both of which have
(d) palmoplantar keratoses, six or more.
carcinoma in situ (DCIS), atypical ductal been shown to affect the same down-
2. Two major criteria but one must include hyperplasia, adenosis and sclerosis stream signalling pathways as PTEN (AKT
macrocephaly or Lhermitte-Duclos disease {2856}. and MAPK) {2277}.
3. One major and three minor criteria. Thyroid cancer Gene structure
The lifetime risk of epithelial thyroid PTEN/MMAC1/TEP1 consists of nine exons
4. Four minor criteria.
cancer can be as high as 10% in males spanning 120–150 kb {1834, 1979, 3063}.
and females with CS. Because of small It is believed that intron 1 occupies much
Operational diagnosis in a family where one numbers of cases, it is unclear whether of this genomic distance (approximately
individual is diagnostic for Cowden the age of onset is truly earlier than that of 100 kb). PTEN is predicted to encode a
1. At least one pathognomonic criterion. the general population. Histologically, 403 amino-acid phosphatase. Similar to
thyroid cancer is predominantly follicular other phosphatase genes, PTEN exon 5
2. Any one major criterion with or without minor criteria.
carcinoma, although papillary histology specifically encodes a phosphatase core
3. Two minor criteria. has also been rarely observed {1119, motif. Exons 1 to 6 encode amino acid
1968, 3058, 3683}. Medullary thyroid sequence that is homologous to tensin
carcinoma has not been observed in and auxilin {1830, 1834, 3063}.
polyps, a prospective pilot series of 49 patients with CS.
individuals who had five or more colonic Gene product
polyps, at least one of which was hamar- Benign tumours PTEN is virtually ubiquitously expressed
tomatous or hyperplastic, were accrued The most important benign tumours are {3063}. Detailed studies of expression in
irrespective of age or family history trichilemmomas and papillomatous human development have not been
{3144}. Of these 49 individuals, approxi- papules of the skin. Apart from those of performed. Only a single study has
mately 20% were found to have germline the skin, benign tumours or disorders of examined expression of PTEN protein
mutations in PTEN, SMAD4, BMPR1A or breast and thyroid are most frequently during human embryogenesis using a
STK11. Of these eleven germline muta- noted and probably represent true com- monoclonal antibody against the terminal
tions, four involved PTEN – two intragenic ponent features of this syndrome. 100 amino acids of PTEN {992}. This
mutations and two large deletions {3144}. Fibroadenomas and fibrocystic disease of study revealed high levels of expression
In a child with juvenile polyposis of the breast are common signs of CS, as of PTEN protein in the skin, thyroid and

Gene mutations PTEN is associated with cancer strongly

Approximately 85% of CS cases, as suggest that CS and BRRS are allelic and
strictly defined by the Consortium criteria, part of a single spectrum at the molecular
have a germline mutation in PTEN, includ- level. The aggregate term of PTEN
ing intragenic mutations, promoter muta- hamartoma tumour syndrome (PHTS) has
tions and large deletions/rearrangements been suggested {1982}, and has become
{1842, 1979, 3714}. If the diagnostic criteria more germane when germline mutations
are relaxed, then mutation frequencies in PTEN were subsequently identified in
drop to 10–50% {1925, 2264, 3303}. A for- autism spectrum disorder with macro-
mal study that ascertained 64 unrelated cephaly, Proteus syndrome and VATER
CS-like cases revealed a mutation fre- (association of birth defects) with macro-
quency of 2% if the criteria were not met, cephaly {386, 2643, 3712}. The identifi-
even if the diagnosis were made short of cation of a germline intragenic mutation in
one criterion {1980}. However, it should PTEN in a patient previously thought to
be noted that this study only looked at the have juvenile polyposis {2399} excludes
Fig. 8.60 Schematic representation of the PI3K-Akt- nine exons of PTEN, and it would be pre- that specific clinical diagnosis, and points
mTOR signalling pathway. When PTEN is downregulated, dicted that further mutations would have to the correct molecular designation of
Akt is upregulated, leading to upregulation of mTOR.
been identified in the promoter or in PHTS {795, 1260, 1261, 1689, 1983,
Reprinted by permission from Macmillan Publishers Ltd:
European Journal of Human Genetics, Blumenthal GM
SDHB/SDHD. A single research-centre 2408}. This has been further borne out by
et al. {287A}, Copyright 2008. study involving 37 unrelated CS families, finding germline mutations/deletions of
ascertained according to the strict diag- PTEN in individuals with juvenile polyps
nostic criteria of the Consortium, revealed and of large deletions involving both
central nervous system, organs that are a mutation frequency of 80% {1979}. Ex- PTEN and BMPR1A in juvenile polyposis
affected by the component neoplasias of ploratory genotype–phenotype analyses of infancy {692, 3144}. A significant finding
CS. It also revealed prominent expression revealed that the presence of a germline of the polyp-ascertainment study was that
in the developing autonomic nervous sys- mutation was associated with a familial risk the reasons for referral based on original
tem and gastrointestinal tract. Moreover, of developing malignant breast disease pathology readings were often incorrect,
early embryonic death in pten -/- mice {1979}. Further, missense mutations and/- suggesting that re-review of all polyp
also imply a crucial role for PTEN in early or mutations 5` of the phosphatase core histologies by gastrointestinal patholo-
development {713, 2569, 3138}. PTEN is motif seem to be associated with a surro- gists based in major academic medical
a tumour suppressor and a dual-speci- gate for disease severity (multi-organ centres is vital for focusing on the correct
ficity lipid phosphatase that plays multiple involvement). A small study comprising 13 genetic etiology {3144}.
roles in the cell cycle, apoptosis, cell families with 8 PTEN mutation-positive
polarity, cell migration and even genomic members could not find any genotype– Prognosis and predictive factors
stability {2200, 2919, 3683}. The major phenotype associations {2262}, but this There have been no systematic studies to
substrate of PTEN is phosphatidylinositol- may be due to the small sample size. indicate whether the prognosis for CS
3,4,5-triphosphate (PIP3) which lies in the patients who have cancer is different from
PI3 kinase pathway {643, 926, 1833, Bannayan-Riley-Ruvalcaba syndrome that of their counterparts with sporadic
1949, 3053}. When PTEN is ample and (BRRS) cancer.
functional, PIP3 is converted to 4,5-PIP2, Previously thought to be clinically distinct, When activated mTOR signalling was
which results in hypophosphorylated BRRS (MIM 153480), characterized by uncovered as an important downstream
AKT/PKB, a known cell-survival factor. macrocephaly, lipomatosis, haemangio- response to PTEN dysfunction or defi-
Hypophosphorylated AKT is apoptotic. matosis and speckled penis, is likely to be ciency, mTOR inhibition was shown to be
When PTEN is in the cytoplasm, it pre- allelic to CS {1981}. Approximately 60% effective in vitro and in animal models
dominantly signals via its lipid phos- of BRRS families and isolated cases com- {3051}. In fact, rapamycin was shown to be
phatase activity down the PI3K-AKT bined carry a germline mutation in PTEN effective in a child with Proteus syndrome
pathways {2082}. In contrast, when PTEN {1982}. There were 11 cases classified as who also carried a germline mutation in
is in the nucleus, it predominantly signals true CS–BRRS overlap families in this PTEN {1984}. An open label phase II trial of
via protein phosphatase activity down the cohort, and 10 of these had a PTEN mTOR inhibitor is currently underway for
cyclin D1/MAPK pathway, eliciting G1 mutation. Another 10% of BRRS individuals human CS with demonstrated germline
arrest at least in breast and glioma cells were subsequently shown to harbour PTEN mutation (NCI-08-C-0151).
{926, 927, 1833, 2082}. It is also believed larger germline deletions of PTEN {3714}.
that PTEN can dephosphorylate focal The overlapping mutation spectrum, the
adhesion kinase (FAK; PTK2B) and inhibit existence of true overlap families and the
integrin and mitogen-activated protein genotype–phenotype associations suggest
(MAP) kinase signalling {1078, 3179}. that the presence of germline mutation of
Cowden syndrome 173

Neuroendocrine neoplasms D.S. Klimstra

R. Arnold
of the colon and rectum C. Capella
G. Klöppel
P. Komminoth
E. Solcia
G. Rindi
Definition Islanders, Native Americans, and African

Neoplasms with neuroendocrine differen- Americans {3624}.
tiation including neuroendocrine tumours NECs are rare in the large bowel, but
(NET) and neuroendocrine carcinomas more common in this location than else-
(NEC) arising in the large intestine and where in the intestines. NECs comprise
presacral region; mixed adeno-neuro- approximately 0.6% of all carcinomas of
endocrine carcinomas (MANEC) have an the large bowel {243}.
exocrine and a neuroendocrine compo-
nent, with one component exceeding 30% Age and sex distribution
(see Chapter 1). The reported average age at diagnosis is
56 years for rectal NETs, and 66 years for Fig. 8.61 Endoscopically resected rectal neuroendocrine
Synonyms colonic NETs, and the male-to-female tumour (NET) invading the mucosa–submucosa, but not
Synonyms for colon and rectum NET ratio is 1.02 and 0.66, for rectal and the muscularis propria.
include: carcinoid, well differentiated colonic NETs, respectively {620, 815, 1738,
endocrine tumour/carcinoma {3013}. 2115}. Although colorectal NETs are rare
Synonyms for NEC include: poorly differ- in childhood, they make up 34% of solid
entiated endocrine carcinomas, high colorectal neoplasms in patients aged
grade neuroendocrine carcinoma, small < 20 years {3617}.
cell and large cell endocrine carcinomas. The average age of patients with NECs of
the large bowel is 61.5 years, and the
ICD-O codes male-to-female ratio is essentially 1 : 1,
Neuroendocrine tumour (NET) similar to the values for large-bowel
NET G1 (carcinoid) 8240/3 adenocarcinomas {243, 3071}.
NET G2 8249/3
Neuroendocrine carcinoma (NEC) 8246/3 Etiology Fig. 8.62 Surgically resected neuroendocrine tumour
Large cell NEC 8013/3 Some colorectal neuroendocrine neo- (NET) invading the mucosa–submucosa, but not the
Small cell NEC 8041/3 plasms, including both NETs and NECs, muscularis propria.
Mixed adenoneuroendocrine have been reported in the large bowel of
carcinoma (MANEC) 8244/3 patients with ulcerative colitis {995, 1062} or adenocarcinomas and presumably
EC cell, serotonin-producing NET 8241/3 or Crohn disease {1062, 1188, 1220, share some molecular alterations and
L cell, Glucagon-like peptide 2965}. In association with these conditions, etiological associations with conventional
and PP/PYY-producing NETs 8152/1 the neoplasms tend to be multiple {2029}. colorectal adenocarcinomas.
However, there appears to be no evi- Patients with colorectal NETs are reported
Epidemiology dence to substantiate a direct association to have an increased risk of other malig-
Incidence and time trends between inflammatory bowel disease and nancies, including carcinomas of the gastro-
The annual incidence of NETs of the colon neuroendocrine oncogenesis, because intestinal tract, lung, and prostate {3246},
is 0.11 to 0.21 cases per 100 000 popula- almost all cases are found incidentally and metachronous or synchronous non-NET
tion {2115} and NETs make up 0.4% of after surgery for inflammatory bowel neoplasms are found in 13% of cases {2115}.
colorectal neoplasms {1648}. NETs of the disease {1062}. A case of rectal NET in a
caecum to transverse colon (midgut) patient with Peutz-Jeghers syndrome has Localization
represent about 8% of all gastrointestinal also been reported {3425}. Multiple rectal NETs are more common in the rectum
NETs, while NETS of the descending colon NETs have been reported in diffuse (54% of cases), followed by the caecum
and rectosigmoid (hindgut) represent ganglioneuromatosis {1121}. (20%), sigmoid colon (7.5%), rectosigmoid
about 27% {2113, 2115}. Rectal NETs Rarely, NETs or so-called “microcarcinoids” colon (5.5%) and ascending colon (5%)
have an annual incidence of 0.14–0.76 (microscopic NET cell nests) are found {2115, 3013}. A NET arising in a caecal
cases per 100 000 population. In the 40 associated with adenomatous polyps of duplication cyst has been reported {1379}.
years between 1950 and 1991, the pro- the large bowel {1924, 2598}, but there is NECs can arise in either the right colon or
portion of caecal NETs, among NETs of all no evidence that the majority of colorectal the rectosigmoid {3071}. Most NECs of
sites, nearly doubled, as did the propor- NETs are etiologically related to adeno- the anal canal are small cell carcinomas,
tion of rectosigmoid lesions {2115, 3440}. mas or adenocarcinomas of the large whereas those of the colon and rectum
It has been suggested that rectal NETs bowel. In contrast, high-grade NECs com- may be small cell, large cell, or have
are particularly prevalent in Asian/Pacific monly arise in association with adenomas mixed features {2932}.

Clinical features be fixed to the rectal wall. In the majority

Symptomatic patients with colonic NETs of cases, the neoplasm is found 4–13 cm
most commonly present in the seventh above the dentate line and on the anterior
decade of life with symptoms of abdomi- or lateral rectal walls {396}.
nal pain and weight loss, although some
present at a late stage with liver metas- NECs
tases {2730}. Less than 5% of patients NECs of the colorectum are grossly simi-
present with the carcinoid syndrome {234, lar to conventional adenocarcinomas. If
2730}. an associated adenoma is present, they
Half of rectal NETs are asymptomatic and may be polypoid; if not, they are typically
are discovered at routine rectal examina- ulcerated neoplasms with a raised border,
Fig. 8.63 NET of the rectum, with a trabecular pattern,
tion or endoscopy {1699}, while the other and on cut section they are infiltrative. typical of L cell NET.
half give rise to symptoms, typically rectal
bleeding, pain or constipation {1423, 3080}. Histopathology
Rectal NETs are practically never associ- NETs chromatin pattern. Most colorectal NETs
ated with the carcinoid syndrome {1423, Since the large bowel is derived from both have minimal if any necrosis. The mitotic
3080}. the embryonic midgut and hindgut, NETs rate is, by definition, < 20 per 10 high power
NECs are aggressive neoplasms and can of the colon can be either midgut-type fields (HPF), but most cases have very few
present with symptoms attributable to serotonin (enterochromaffin, EC) cell mitoses (< 2 per 10 HPF), corresponding to
local disease or to widespread metastases. NETs (in the caecum and ascending grade G1 {2685}. Typically (but not always),
colon) or hindgut-type NETs that arise in a slightly higher mitotic rate is found in
Macroscopy the more distal colon and rectum and are larger (> 2.0 cm) colorectal NETs.
NETs L cell (glucagon-like peptide-producing Immunohistochemically, colorectal NETs
The majority of colonic NETs are detected and PP/PYY-producing) NETs {864}. stain for the neuroendocrine markers
in the right colon {234, 2730} and are Colonic EC cell serotonin-producing NETs chromogranin A and synaptophysin,
larger than their counterparts in the small show histological, cytological, cytochem- keratins (especially Cam5.2, low-molecular-
intestine, appendix, and rectum. The ical, and ultrastructural features that are mass keratins 8–18), NCAM1/CD56 and
average size has been reported as identical to those of jejuno–ileal EC cell for a variety of peptide hormones {831}.
4.9 cm {234}. serotonin-producing NETs {3013}. L cell, About 80% of rectal NETs display more or
Rectal NETs appear as solitary submu- glucagon-like peptide and PP/PYY- less abundant glucagon-like peptides
cosal nodules, sometimes polypoid, often producing NETs are characterized histo- (GLP-1, GLP-2, glicentin) and/or PP/PYY
with intact overlying epithelium {2936}. logically by the predominance of a immunoreactivity typical of intestinal L
Larger neoplasms may be ulcerated trabecular pattern, often admixed with cells, whereas only 30% show serotonin
{2936}. Up to half of rectal NETs are tubuloacini or broad, irregular trabeculae immunoreactivity and 20% somatostatin
< 1.0 cm in diameter, perhaps because with rosettes, and only occasionally with immunoreactivity, usually in only a few cells
they are more readily detected on physi- solid nests {3001}. These patterns are {864, 3011}. Although there is a prevalence
cal examination or endoscopy than those different from those of EC cell serotonin- of L cells in these neoplasms, minority
that are more proximally located {396, producing NETs, in which solid nests populations of substance P, insulin,
1699}. Reviewing 356 cases reported in prevail. The cytological features resemble enkephalin, β-endorphin, neurotensin,
the literature, Caldarola et al. {396} found those of other gastrointestinal NETs, with and motilin immunoreactive cells have
that only 13% of rectal NETs measured uniform round to oval nuclei having also been identified {831, 3011}. The vast
> 2 cm in diameter. Larger lesions tend to indistinct nucleoli and a coarsely granular majority (82%) of colorectal NETs tested
A B
Fig. 8.64 Neuroendocrine tumour (NET) of the rectum. A Note the trabecular arrangement of cells in the submucosa. B High-power view of the trabecular growth pattern.

A B
Fig. 8.65 Small cell neuroendocrine carcinoma (NEC) arising in a tubulovillous adenoma of the sigmoid colon (A). B Typical oval or moulded nuclei with diffuse chromatin, scant
cytoplasm and little stroma.
in one series of 84 cases showed immuno- The mitotic rate is very high, averaging 65 chromogranin A, or CD56) must be
reactivity for prostatic acid phosphatase, per 10 HPF {2932}. One quarter of cases diffusely positive to establish a diagnosis
a finding that is unusual in other gut NETs have a minor component (< 30%) of of large cell NEC. CDX2 may also be
and is possibly related to the common adenocarcinoma or (in the anal canal) expressed, but TTF1 usually is not {1498}.
origin of the rectum and prostate from squamous cell carcinoma {2932}. Small
cloacal hindgut {831}. Most midgut NETs cell carcinomas typically express chromo- MANECs
are positive for CDX2, whereas hindgut granin A, synaptophysin and CD56, Although examples have been reported of
NETs are rarely positive {193, 801, 3052}. although less consistently or diffusely NETs or neuroendocrine micronests aris-
TTF1 is negative in colorectal NETs and than NETs {1045}. Seventy-five percent ing in adenomatous polyps {1924, 2598},
keratin 20 may be positive in 24% of express either chromogranin A or synap- NETs arising in association with adeno-
cases {392}. The Ki67-labelling index, like tophysin and 95% express at least one of carcinomas are exceedingly rare {107,
the mitotic rate, is defined as < 20% the above three markers {2932}. Keratins 1220, 1429, 1618}. Thus, most bona fide
{2685}, and most cases a Ki67 index of are also expressed, often dot-like {933}. MANECs of the large bowel consist of
1–2%, corresponding to G1. The Ki67-labelling index is usually > 50% components of adenocarcinoma (or, in the
and may be nearly 100%. One out of five anal canal, squamous cell carcinoma)
NECs colorectal small cell carcinomas stains for mixed with high-grade NEC, which can be
These are morphologically similar to small CDX2 {801}. Keratin 20 may also be either small cell or large cell {1964, 2932}.
cell carcinoma and large cell NEC of the expressed {1498}. TTF1 is also expressed in In fact, as mentioned above, many high-
lung, and correspond to class G3 {2682, some colorectal small cell carcinomas, lim- grade NECs have minor exocrine compo-
2685}. They are usually found in the right iting its use to define the site of origin {523}. nents, and an origin in association with
colon, and are frequently associated with Large cell NEC. These neoplasms show adenomatous polyps is frequent {2081}.
an overlying adenoma or adenocarcinoma organoid, nesting, trabecular, rosette-like Conversely, immunohistochemically de-
{2081, 2932}, but not associated with NETs and palisading patterns that suggest neu- tectable neuroendocrine cells are found in
(carcinoid tumours) {368, 2932}. In the roendocrine differentiation, which must be up to 41% of colorectal adenocarcinomas,
colon and rectum, 75% of NECs are large- confirmed by immunohistochemistry or most of which have no morphological
cell type, whereas in the anus most are electron microscopy {613}. In contrast to suggestion of a discrete neuroendocrine
small cell carcinomas {2932}. Primary small cell carcinoma, the neoplastic cells component {1328, 3130, 3623}.
NECs in the colon without an associated have more abundant cytoplasm, more A neoplasm with morphologically recog-
adenoma component must be distin- vesicular nuclei, and often prominent nizable adeno- and neuroendocrine
guished from metastases of pulmonary nucleoli {2932, 3289}. A component of phenotypes is defined as carcinoma since
neuroendocrine carcinomas or cutaneous adenocarcinoma is relatively common both components are malignant and
Merkel cell carcinomas {1281, 1755}. (61%), and in some cases this component should be graded. The identification of
Small cell NEC. Small cell carcinomas exceeds 30% of the neoplasm, qualifying scattered neuroendocrine cells by immuno-
have a diffuse or nesting growth pattern for a diagnosis of MANEC {2932}. The histochemistry in adenocarcinoma does
and are composed of small to medium Ki67 labelling index is usually very high not qualify for this definition. A squamous
sized cells with minimal cytoplasm and (30–80%) {2103}. At immunohistochem- cell carcinoma component is rare.
have fusiform nuclei with granular chro- istry, pure neuroendocrine areas are
matin and inconspicuous nucleoli. Some diffusely positive for synaptophysin and Molecular pathology
larger cells or occasional cells with nucleoli usually for chromogranin A, although to a Loss of heterozygosity at the MEN1 gene
(< 25% of the neoplastic population) are lesser extent {243, 2932}. At least two locus is rare {683, 1380, 3253} and colo-
acceptable findings. Necrosis is common. neuroendocrine markers (synaptophysin, rectal NETs do not represent an integral

part of the MEN1 syndrome {2431}. presence of > 2 mitoses per 10 HPF (and
Colorectal NECs, like NECs developing at thus fitting the G2 class), and DNA aneu-
other gastrointestinal sites, display higher ploidy {3301}. A scoring system based on
frequency of allelic imbalances than size, depth of invasion, lymph-node
NETs, the most frequent abnormality metastases, and distant metastases that
involving the p53 and CDKN2/Rb path- accurately stratifies prognosis has been
ways, FHIT (3p), DCC/SMAD4 (18q) and developed for rectal NETs {1738}. Some
MEN1 {924, 2560}. NECs may share authors suggest that rectal NETs measur-
some molecular features with adenocar- ing < 1.0 cm with no lymphatic invasion
cinomas of the colorectum, with which have a low enough rate of metastasis to
they may be associated, suggesting a justify endoscopic local resection as
Fig. 8.66 Rectal neuroendocrine tumour (NET) showing
common origin {3325, 3422}. In contrast definitive therapy {1648, 519}, although one diffuse and intense immunoreactivity for prostatic acid
to colorectal adenocarcinoma, however, case of a rectal NET of < 0.5 cm with liver phosphatase.
they often demonstrate loss of expression metastases has been reported {3304}.
of the Rb gene product (especially small Although rectal NETs limited to the
cell carcinomas), a feature they share with mucosa and submucosa generally do not presenting with mass-related symptoms
their pulmonary counterparts {1583, 1754}. metastasize, the size of the neoplasm re- and often pain. Neuroendocrine neoplasms
DNA mismatch repair proteins are intact mains important, since those measuring of the presacral region are NETs display-
in most NECs {3071}. > 1.0 cm have a greater metastatic rate ing histological and immunohistochemical
than stage-equivalent adenocarcinomas features similar to those of rectal NETs,
Staging, prognosis and predictive factors {3000}. Immunoexpression of peripherin, with trabecular-gyriform structure, bland
The issue of TNM/staging classification of a type-III neuronal intermediate filament, cytology and immunoreactivity for chro-
neuroendocrine neoplasms is as yet had been reported to be more consistent mogranin A and synaptophysin {746}.
unsettled. The classification presented in in rectal NETs without metastases than in One case also showed positive nuclear
this book is for “carcinoid”, i.e. well-differ- those with metastases {1353}. immunohistochemistry for estrogen and
entiated, lesions only. Conversely, the NECs of the large bowel are highly progesterone receptors {1840}. The low
classification proposed by the European aggressive, and 70% of patients have mitotic rate, the absence of necrosis and
Neuroendocrine Tumor Society (ENETS) metastases at presentation; median the low Ki67 index reported qualify most
is also meant for high-grade neoplasms survival is 10.4 months, 2-year survival is presacral region NETS as G1 (for grading,
{2684, 2685}. In the large intestine, both 25%, and 5-year survival is 13% {243, see Chapter 1) {746, 1561, 1840}. Malig-
classifications are largely concordant. 329, 933, 2932}. Mixed adenoneuroendo- nant NETs with proven metastatic capac-
Colonic EC cell serotonin-producing NETs crine neoplasms are so rare that general- ity also displayed foci of necrosis,
frequently show malignant behaviour; izations about behaviour are not possible. angioinvasion and increased Ki67 index,
local spread is found in 36–44% of Those cases with a high-grade NEC qualifying these NETs as G2 {1916, 3017}.
patients and distant metastases in 38% component are aggressive, similar to the Patients with sacrococcigeal NETs in gen-
{2115, 2730}. The reported 5-year and pure high-grade NECs, one case being eral have a good prognosis, largely
10-year survival rates are 25–42% and reported with liver metastases in the depending on appropriate management
10%, respectively {2115, 2730}. Modlin presence of invasion limited to mucosa- with either surgery or local radiation ther-
found that metastatic neoplasms represent submucosa {3325}. apy, one patient being alive and well after
82% of caecal NETs, but only 11–18% of 28 years of evolution {746}. A poor
rectal NET patients develop metastases Neuroendocrine neoplasms of the outcome is reported for G2 cases {1840,
{815, 831, 1699, 2113, 2115}. Patients presacral region 1916, 3017}.
with rectal NETs generally have a good Neuroendocrine neoplasms of the pre-
prognosis, with a 5-year survival rate of sacral region are rare, with only 25 cases
72–89% {2113, 2115}, which is better than reported in the English literature {746,
the 5-year survival rate of 60% for patients 1561, 1840, 1916, 3017}. An origin from hind-
with jejuno–ileal NETs {373}. gut remnants in the region has been pro-
Recognized risk factors for malignant posed, 12 of the reported cases being
behaviour include: size > 2 cm {1423, associated with teratoma or tailgut cysts,
1585, 2256}, invasion of the muscularis one case being associated with imperfo-
propria {1423, 2256}, lymphatic invasion rate anus {1561}. Patients are more often
{815, 1648}, atypical histology {1659}, female, age ranging from 18 to 72 years,

B-cell lymphoma H.K. Müller-Hermelink

J. Delabie
of the colon and rectum Y.H. Ko
E.S. Jaffe
J.H. van Krieken
S. Nakamura
Definition type, follicular lymphoma, mantle cell

Primary B-cell lymphoma of the colorectum lymphoma and Burkitt lymphoma {1093}.
is defined as an extranodal lymphoma The frequencies in Asia are similar {1629}.
arising in either the colon or rectum with In mantle cell lymphoma, colonic involve-
the bulk of disease localized to this site ment by systemic lymphoma is frequent
{1341}. Locoregional lymph-node involve- and detected by colonoscopy in 88% of
ment and distal spread may be seen, but cases {2718}.
the primary clinical site of presentation is
the colon and/or rectum. Etiology
The main risk factors are medical immuno-
ICD-O codes suppression, e.g. long-term treatment with
B-cell lymphoma, unclassifiable, with corticosteroids and inhibitors of tumour
features intermediate between necrosis factor α (TNFα), and immunode-
diffuse large B-cell lymphoma and ficiency associated with human immuno-
Burkitt lymphoma 9680/3 deficiency virus (HIV). The standardized
Burkitt lymphoma 9687/3 incidence rate of malignant non-Hodgkin
Diffuse large B-cell lymphoma 9680/3 lymphoma in HIV-seropositive individuals
Mantle cell lymphoma 9673/3 has declined considerably as a result of
Marginal zone lymphoma of the use of highly active antiretroviral ther-
mucosa-associated lymphoid apy (HAART). Colorectal lymphomas in
tissue (MALT lymphoma) 9699/3 HIV-infected patients were more common
in the pre-HAART era {2498}.
Epidemiology Inflammatory bowel disease, Crohn dis-
Primary lymphomas arising in the large ease and ulcerative colitis in their natural Fig. 8.67 Malignant lymphoma of the rectum.
intestine are less frequent than either course are not thought to be associated
gastric or small bowel lymphomas {1344}. with increased frequency of lymphoma;
They account for < 10% of gastrointestinal however, the incidence of treatment- Clinical features
lymphomas and most commonly (73%) related lymphomas has increased. Recent The presenting features are very similar to
occur in the caecum. The incidence of reports suggest that patients receiving those of epithelial neoplasms at this site.
colonic lymphoma is increasing owing to anti-TNFα therapy might have a higher The most frequent clinical signs are ab-
increased numbers of cases associated chance of developing non-Hodgkin lym- dominal pain, palpable mass, anaemia,
with acquired or iatrogenic immunodefi- phoma, but this remains to be firmly weight loss, rectal bleeding, diarrhoea or
ciency {1093}. Most colorectal malignant established {1726}. Colonic B-cell lym- constipation, irregular bowel habit and
lymphomas are B-cell lymphomas, but a phomas associated with inflammatory worsening of the symptoms of ulcerative
higher prevalence of T-/NK-cell lymphomas bowel disease frequently harbour Epstein- colitis. Occasional cases are found inci-
of the colon and rectum may also account Barr virus (EBV) {3542}. EBV-associated dentally, while an acute presentation with
for a slightly higher incidence in Asian colonic large B-cell lymphomas and pri- rupture of the colon is distinctly uncom-
countries {1472}. Primary lymphomas mary Hodgkin lymphoma may also occur mon {1042, 1563, 2925}. Colorectal lym-
account only for about 0.2–0.4% of all in age-related immunodeficiency, long- phomas are usually diagnosed using
malignant neoplasms at this site. There is term medical immunosuppression or HIV- endoscopy and biopsy. Computerized
a male predominance with a male :female associated acquired immunodeficiency. tomography (CT) and barium enema have
ratio of 2 : 1. a role in diagnosis and determining the
The mean age at presentation of colonic Localization extent of disease and staging. Multiple
B-cell lymphomas is between 50 and 70 Most colorectal lymphomas involve the lymphomatous polyposis has a charac-
years, presentation at a younger age is caecum or ascending colon, followed by teristic radiological picture with numerous
common in immunodeficient individuals. the rectum. There is a preference for polyps of variable size throughout the
The majority (54.7%) of these neoplasms rectal lymphoma in heavily immunodefi- colon. Transrectal ultrasonography may
are diffuse large B-cell lymphoma cient patients infected with HIV {1337, also be a useful adjunct for diagnosis.
(DLBCL), which includes immunodefi- 1817}. Multifocal involvement is uncom-
ciency-associated cases, followed by mon, with the exception of multiple lym- Macroscopy
marginal zone B-cell lymphoma of mu- phomatous polyposis {2925}. Most low-grade lymphomas present as
cosa-associated lymphoid tissue (MALT) well-defined protuberant growths that

deeply invade the bowel wall. DLBCL and lesions are less prominent than in the
Burkitt lymphoma tend to form larger stomach. Multiple gastrointestinal involv-
masses with stricture and ulcer formation ement of more than one anatomical site is
involving long segments of the colorec- frequent {1622}.
tum. Low-grade and aggressive MALT The immunophenotype is positive for
lymphomas typically remain localized for CD20, negative for CD10 and BCL6; CD5
prolonged periods, but may spread to is usually negative but may be weakly
involve locoregional lymph nodes. Mantle expressed in rare cases; CD21 is often
cell lymphoma may present as an isolated expressed, but CD23 is usually negative.
mass or as multiple polyps producing the Plasma-cell differentiation may be
clinical picture of multiple lymphomatous detected by immunoglobulin light-chain
Fig. 8.68 Mantle cell lymphoma predominantly infiltrating
polyposis {3485}. In most cases, the restriction. the submucosa, thereby causing a polypoid lesion.
colon is more significantly involved than
the small bowel. The polyps range in size Mantle cell lymphoma
from 0.5 cm to 2 cm, with much larger The morphology of mantle cell lymphoma colorectal tumour in the HAART era, as
polyps found in the ileocaecal region involving the large bowel is identical to these lymphomas have also been
{1343, 2174}. Although multiple lympho- that of mantle cell lymphoma at nodal observed in immunocompetent patients
matous polyposis is characteristic of sites {188}. The architecture is most fre- in the past {419, 3032}. The details of the
mantle cell lymphoma, it may also be quently diffuse, but a nodular pattern and histology, immunophenotype, cytogenet-
found in other lymphoma entities, and a less common true mantle-zone pattern ics and molecular genetics of these tu-
more than half of patients with mantle cell are also seen. Intestinal glands may be mours are described in detail for the small
lymphoma show subclinical involvement destroyed by the lymphoma, but typical intestine (Chapter 6).
of the colonic mucosa without any visible lymphoepithelial lesions are not seen. The
abnormality {2718}. low-power appearance is monotonous B-cell lymphoma, unclassifiable, with
with dispersed histiocytes, while mitotic features intermediate between DLBCL
Histopathology and immunohistochemistry figures may be more frequent than in and Burkitt lymphoma
Diffuse large B-cell lymphoma (DLBCL) MALT lymphomas. The lymphoma cells B-cell lymphomas with morphological and
DLBCL is the most frequent malignant are small- to medium-sized with irregular genetic features intermediate between
lymphoma found in the colon. In contrast nuclear outlines, indistinct nucleoli and DLBCL and Burkitt lymphoma for clinical
to gastric DLBCL, low-grade components scant amounts of cytoplasm. Large trans- and biological reasons should be diag-
are rarely seen and if present may repre- formed cells are typically not present. nosed separately and not included in one
sent a follicular lymphoma component. The lymphoma cells are mature B cells of these categories {3145}. The so-called
The lymphoma forms large ulcerating expressing both CD79a and CD20. Char- “double-hit” lymphomas showing a BCL2
tumours with transmural infiltration by acteristically the cells weakly co-express translocation with a MYC translocation, as
tumour cells. Sporadic DLBCL of the colon CD5 and CD43. Surface immunoglobulin well as cases with MYC translocations
shows often centroblastic morphology is found, including both IgM and IgD. involving partners other than immuno-
and its variants (multilobulated, monomor- Light-chain restriction is present in most globulin genes. Cases are often found at
phic, polymorphic). In the setting of cases, with a predominance of lambda. extranodal sites and are resistant to
immunodeficiency-associated DLBCL, CD10 and CD11c are virtually always current therapies.
the lymphoma cells are more often negative. Cyclin D1 is found in almost all
immunoblastic or even plasmablastic. cases and can be seen within the nuclei Other B-cell lymphomas
Association with EBV is frequent and is in- of the neoplastic lymphocytes in paraffin Most subtypes of B-cell lymphoma {3349}
vestigated by EBV-encoded RNA (EBER) sections. The Ki67-defined proliferation can present primarily as colorectal tumour
hybridization. These DLBCLs also show rate is an important predictive marker and may mimic the clinical appearance of
an inflammatory component consisting of {1584}, since the proliferation-signature lymphomas or other neoplasms that are
activated T cells, macrophages, polytypic gene score has been shown to be the more frequent in this site. Chronic lym-
plasma cells and eosinophils. The phe- most important prognostic factor on phocytic leukaemia involving the colonic
notype is that of a mature B cell, being gene-expression profiling {1128}. Rare mucosa may mimic mantle cell lymphoma
positive for CD20 and CD79a. cases of mantle cell lymphoma that are or MALT lymphoma. Rectal involvement of
negative for cyclin D1 may be identified plasmablastic lymphoma is difficult to dis-
MALT lymphoma by SOX11 overexpression {2175}. tinguish from undifferentiated carcinoma
Marginal zone B-cell lymphoma of MALT- or malignant melanoma. Intestinal T-cell
type (MALT lymphoma) may occur as soli- Burkitt lymphoma lymphoma may present as multiple lym-
tary mass or nodular lesion in the caecum Typical Burkitt lymphoma as primary colo- phomatous polyposis. Therefore biopsies
or rectum {1341}. The histological and rectal lymphoma is rare. The caecum and that are suspicious for a lymphoprolifera-
immunophenotypical features are dis- ascending colon may be involved {1629}. tive disease should be thoroughly investi-
cussed in detail with tumours of the stom- Sporadic cases of childhood Burkitt lym- gated by immunophenotyping. In the
ach (Chapter 4). Low-grade colorectal phoma in the rectum have been described diagnostic work-up of large cell lymphoma
MALT lymphomas resemble those of the {827, 960}. Burkitt lymphoma in HIV- also EBER in situ hybridization and
small intestine in that lymphoepithelial infected individuals may still present as a genetic studies by fluorescent in situ
B-cell lymphoma 179

Fig. 8.69 MALT lymphoma of the rectum with Fig. 8.70 Burkitt lymphoma of the colon. Malignant cells Fig. 8.71 Mantle cell lymphoma of the colon.
lymphoepithelial lesions. infiltrate the lamina propria and produce lymphoepithelial
lesions.
hybridization (FISH) techniques for MYC lymphomas are incompletely investigated. heavy-chain locus on chromosome 14. In
rearrangement and/or other breakpoints The presence of t(11;18)(q21;q21) and the variant translocations, a part of the
(BCL2, BCL6) are often necessary for the corresponding molecular abnormali- light-chain constant region is translocated
definitive classification. ties, rearrangement of BCL10 or BIRC3- to chromosome 8, distal to the MYC gene.
MALT, have been seen rarely at this site, Thus, in the variant translocations, MYC
Genetic susceptibility sometimes together with a gastric tumour remains on chromosome 8 and is dereg-
Lymphomas have been considered to be and multiple intestinal involvement. Trisomy ulated by virtue of its juxtaposition to the
part of the Lynch syndrome-associated of chromosome 3 has also been seen in immunoglobulin light-chain genes.
tumour spectrum, described earlier in this colonic MALT lymphoma. The molecular characteristics of the MYC
chapter, as a childhood cancer syndrome translocation also differ between endemic
with biallelic homozygous or compound Mantle cell lymphoma and sporadic cases. In endemic Burkitt
heterozygous mutations in DNA mismatch MCL is characterized by a recurrent cyto- lymphoma, the chromosome 8 break-
repair genes. Rarely, these lymphomas genetic abnormality, t(11;14)(q13;q32). points are variable and usually far 5’ of
may arise within the gastrointestinal tract This translocation deregulates expression MYC, while the chromosome 14 break-
and show the underlying genetic defect of the cyclin D1 oncogene on chromo- points most often occur in the location of
in DNA mismatch repair {1199, 2551}. some 11. the IGHJ@ gene joining segments. FISH
analysis using break-apart probes for
Molecular pathology Burkitt lymphoma MYC detects most translocations. In
Genetic information is included in the def- Burkitt lymphoma demonstrates a consis- cases without MYC rearrangements,
inition of lymphoma entities and found in tent cytogenetic abnormality in most aberrations in miRNA regulating MYC
the WHO classification of haematopoietic cases, with rearrangement of the MYC have been found {1808A}.
and lymphoid tumours, fourth edition oncogene on chromosome 8. The char-
{3145}. acteristic translocation, t(8;14)(q24;q32), Prognosis and predictive factors
is seen in most cases; the remainder Prognostic factors for colorectal lym-
MALT lymphoma shows variant translocations including the phoma are similar to those for lymphoma
Genetic alterations and the frequencies of immunoglobulin light-chain loci, t(2;8)- of the small intestine (Chapter 6).
distinct types of balanced translocation (p12;q24) or t(8;22)(q24;q11), involving
show a site specific variation in MALT kappa and lambda light-chain genes,
lymphomas. The cytogenetic and molec- respectively. In the classical t(8;14), MYC
ular features of low-grade colorectal MALT is translocated from chromosome 8 to the


C.D.M. Fletcher
of the colon and rectum L.-G. Kindblom
W.M.S. Tsui
ICD-O codes when detected, and have a poor prognosis.

Leiomyoma 8890/0 The behaviour of rectal GISTs is often
Lipoma 8850/0 aggressive, and even small tumours of
Gastrointestinal stromal tumour 8936/3 < 2 cm in size with mitotic activity can
Angiosarcoma 9120/3 recur and metastasize. Pelvic extension
Kaposi sarcoma 9140/3 and liver metastasis is common, and bone
Leiomyosarcoma 8890/3 metastases may develop more often than
in gastric and small-intestinal GISTs.
Definition
Gastrointestinal stromal tumour (GIST) Smooth muscle tumours A
For definition, terminology and incidence, A distinctive type of leiomyoma that usu-
we refer to the chapters on gastric and ally occurs in the colon and rectum is that
small-intestinal GISTs (Chapter 4 and 6). of the muscularis mucosae. These tumours
GISTs are very rare in the colon (about 1% are roundish nodules that usually measure
of all GISTs) and have a predilection for the < 1 cm and not more than 2 cm. They are
sigmoid. However, microscopic GISTs have usually incidental endoscopic findings in
been detected in 0.2% of retrospectively older adults and are clinically indolent.
examined sigmoid-colon resections. Rectal Histologically, these tumours are com-
GISTs comprise 4% of all GISTs and occur posed of bundles of well-differentiated
in any segment. These tumours vary from smooth muscle that merge into the mus-
incidentally detected small mural nodules cularis mucosae. Although focal nuclear B
to large, complex pelvic masses that can atypia may be present, mitotic activity is Fig. 8.72 Leiomyoma of muscularis mucosae. A The
cause intestinal obstruction or gastro- not detectable. tumours forms a sharply demarcated mucosal mass that
intestinal bleeding. Those with anterior Immunohistochemical features are typical merges with muscularis mucosae layer. B It is composed
extension can abut the prostate gland and of well-differentiated smooth muscle of well-differentiated smooth muscle cells.
clinically simulate prostate cancer {39, tumours: positive for SMA and desmin,
1131, 2064, 2074}. and negative for CD34, S100 protein, KIT,
The histological features of colonic GISTs are and DOG1 {2072}.
generally similar to those of small-intestinal Intramural leiomyomas are rare. They usu-
GISTs. While most have spindle-cell mor- ally measure 1–3 cm, and are composed
phology, some are epithelioid. Skeinoid of well-differentiated smooth muscle cells
fibres may occur. Nuclear palisading is a with limited, if any, atypia and virtually no
common feature, whereas perinuclear mitotic activity, although tumours with both
vacuolization is not usually prominent. atypia and mitotic activity are more appro-
Rectal GISTs are usually highly cellular spin- priately designated as leiomyosarcomas.
dle cell tumours, and many contain nuclear Leiomyosarcomas occur both in the colon
palisades, whereas perinuclear vacuolization and rectum. They are often obstructing Fig. 8.73 Leiomyosarcoma. Note the cigar-shaped nuclei.
and skeinoid fibres do not occur. Occasional polypoid intraluminal masses. Prognosis
epithelioid examples have been reported. varies, but may be good after complete
Immunohistochemically, colonic GISTs are excision, despite high-grade histology.
similar to small-intestinal ones, whereas Histological and immunohistochemical
rectal GISTs resemble gastric GISTs by features are similar to those of leiomyosar-
being consistently positive for KIT, DOG1, comas at other sites {2064}.
and CD34 and usually negative for
smooth-muscle antigen (SMA). Schwannoma
The KIT mutation spectrum of colorectal Schwannomas similar to those in the stom-
GISTs is similar to that of small-intestinal ach occur in the colon and rectum, usually
GISTs, with a majority of cases showing in older adults. Presentations include
mutations in exon 11 and a minority show- gastrointestinal bleeding and a polypoid, Fig. 8.74 Schwannoma: this colonic mucosal nerve
ing mutations in exons 9, 13 or 17 {1131, obstructing, intraluminal mass. The histo- sheath tumour contains mildly palisaded spindle-cell
2064, 2074}. logical features of these tumours are infiltration between crypts. The inset shows positivity for
Most colonic GISTs are advanced tumours similar to those in the stomach, with the S100 protein.

A B
Fig. 8.75 Colonic perineurioma contains uniform spindle Fig. 8.76 Mucosal ganglioneuroma. The tumour forms a small polyp (A) that contains spindled Schwann cells, ganglion
cells spaced between crypts. This tumour was positive for cells, and often also eosinophilic granulocytes (B). The inset shows positivity for S100 protein.
epithelial membrane antigen (EMA).
A B
Fig. 8.77 Colonic lipoma. Fig. 8.78 Kaposi sarcoma. A Submucosal infiltrate. B Vascular slit pattern.
typical features including peritumoral lym- Ganglioneuroma The neoplastic component consists of
phoid cuff and microtrabecular architec- Most gastrointestinal ganglioneuromas large cells with small nuclei and abundant,
ture. Small mucosal nerve sheath tumours occur in the colon with a predilection to the granular cytoplasm that is positive for PAS
occur in the colon and rectum. The desig- left side and the rectum, and a few are and S100 protein {2040, 3004}.
nation “mucosal Schwann cell hamartoma” seen in the appendix. They are seen at a
has also been used for apparently similar wide range of ages and equally in men and Lipoma
lesions. These tumours are clinically indo- women. The usual presentation is a small Submucosal lipomas occur especially in
lent and are not associated with neuro- mucosal polyp of < 1–2 cm, or sometimes the colon, usually detected in older adults
fibromatosis type 1 (NF1) {985, 2075}. multiple polyps. They are usually sporadic as an incidental finding. Larger tumours
and indolent. However, diffuse murally may cause obstruction, ulcerate and
Perineurioma extending ganglioneuromas (ganglioneuro- undergo necrosis resulting in gastro-
Perineuriomas in the gastrointestinal tract matosis) have a high association with NF1 intestinal haemorrhage. Histologically,
usually occur in the colon and are most and multiple endocrine neoplasia type 2b there is mature adipose tissue without
often identified by chance as a small (MEN2B) syndromes {436, 2914}. significant atypia. Thick-walled dilated
sessile polyp in adults. Most measure Histologically, there are large numbers of blood vessels are often present in these
< 0.5 cm, rarely being larger. Histologically, mucosal ganglion cells and spindled lipomas, although they differ from periph-
these are typically intramucosal lesions, Schwann cells, often with numerous eral angiolipomas.
which fill and expand the lamina propria, eosinophilic granulocytes. Cystic glands
entrapping crypts. They are composed of can be present, imparting a resemblance Other mesenchymal tumours
uniform spindle cells with short tapering to juvenile polyp in some cases. Immuno- A wide spectrum of vascular tumours
nuclei and indistinct eosinophilic cyto- histochemically, the ganglion cells are such as haemangiomas, lymphangiomas,
plasm, often arranged in a whorled fashion positive for neuron-specific enolase (NSE), angiosarcoma and Kaposi sarcoma may
within a delicate collagenous stroma. neurofilaments, and synaptophysin, occur in the colon and rectum. Mesen-
Perineuriomas are consistently immuno- whereas the Schwannian components are teric desmoid can involve the colonic
positive for EMA and less often claudin- positive for S100 protein and often also for wall, potentially simulating a GIST. Rare
positive. They show no evident tendency glial fibrillary acidic protein (GFAP). undifferentiated, phenotypically nonspe-
to recur {1241}. Lesions formerly known cific sarcomas occur in the colon, and
as fibroblastic polyps of the colon appear Granular cell tumour these should be separated from GISTs.
to represent intramucosal perineuriomas These tumours usually present as small Variably HMB45-positive PEComas (spin-
{1071}. mucosal nodules incidentally detected at dle cell and epithelioid variants, related to
endoscopy. Multiple lesions can be pres- angiomyolipoma family) may occur in the
ent, and occurrence together with periph- colon. The pathology of these neoplasms
eral granular cell tumours is also possible. is discussed in Chapter 10.

CHAPTER 9
Tumours of the anal canal
Squamous cell carcinoma
Adenocarcinoma
Basal cell carcinoma of the anal margin
Paget disease
Other lesions
WHO classificationa of tumours of the anal canal

Epithelial tumours
Premalignant lesions Neuroendocrine neoplasmsb
Anal intraepithelial neoplasia (dysplasia), low grade 8077/0* Neuroendocrine tumour (NET)
Anal intraepithelial neoplasia (dysplasia), high grade 8077/2 NET G1 (carcinoid) 8240/3
NET G2 8249/3
Bowen disease Neuroendocrine carcinoma (NEC) 8246/3
Perianal squamous intraepithelial neoplasia Large cell NEC 8013/3
Paget disease 8542/3 Small cell NEC 8041/3
Carcinoma
Squamous cell carcinoma 8070/3 Mesenchymal tumours
Verrucous carcinoma 8051/3
Undifferentiated carcinoma 8020/3 Secondary tumours
___________________________________________________________
a
Morphology code of the International Classification of Diseases for Oncology (ICD-O) {904A}. Behaviour is coded /0 for benign tumours, /1 for unspecified, bor-
derline or uncertain behaviour, /2 for carcinoma in situ and grade III intraepithelial neoplasia, and /3 for malignant tumours.
b
The classification is modified from the previous (third) edition of the WHO histological classification of tumours {691} taking into account changes in our under-
standing of these lesions. In the case of neuroendocrine neoplasms, the classification has been simplified to be of more practical utility in morphological classifi-
cation.
TNM classificationa of carcinoma of the anal canal

Tis Carcinoma in situ, Bowen disease, high-grade squamous
intraepithelial lesion (HSIL), anal intraepithelial neoplasia
II–III (AIN II–III) Stage grouping
T1 Tumour 2 cm or less in greatest dimension
T2 Tumour more than 2 cm but not more than 5 cm in greatest Stage T N M
dimension
Stage 0 Tis N0 M0
T3 Tumour more than 5 cm in greatest dimension
Stage I T1 N0 M0
T4 Tumour of any size invades adjacent organ(s), e.g. vagina,
urethra, bladder (direct invasion of rectal wall, perianal skin, Stage II T2, T3 N0 M0
subcutaneous tissue or the sphincter muscle(s) alone is not Stage IIIA T1, T2, T3 N1 M0
classified as T4) T4 N0 M0
Stage IIIB T4 N1 M0
N – Regional lymph nodes Any T N2, N3 M0
N1 Metastasis in perirectal lymph node(s)
N2 Metastasis in unilateral internal iliac and/or inguinal lymph
node(s)
N3 Metastasis in perirectal and inguinal lymph nodes and/or
bilateral internal iliac and/or bilateral inguinal lymph nodes
____________________
a
{762, 2996}
A helpdesk for specific questions about the TNM classification is available at http://www.uicc.org.
184 Tumours of the anal canal

Tumours of the anal canal M.L. Welton

R. Lambert
F.T. Bosman
Topographic definition of the anal canal,

anal margin and perianal region
The anal canal is defined as the terminal
part of the large intestine. The uppermost
boundary of the anal canal is defined by
the passage of the rectum through the
proximal portion of the anorectal ring,
usually 1–2 cm above the dentate line.
The large bowel passes through the
muscular diaphragm of the sphincter
mechanism and terminates at the inter-
sphincteric groove, which is created by
the termination of the circular muscle of
the large bowel. This anatomic landmark
correlates roughly with the transition from
the highly specialized squamous mucosa
of the anal canal to the perianal skin. The Fig. 9.01 Anatomy of the anal canal. The light blue area is the anal transitional zone. Reproduced from Sternberg SS,
dentate (pectinate) line denotes the Histology for pathologists, 2nd edition {835}, with permission.
mucosal transition from rectum to anus
that occurs on average 1–2 cm proximal
to the termination of the anal canal. The hair follicles, apocrine glands and sweat ICD-O code 8070/3
proximal anal canal is lined with colorectal glands. The perianal skin is denoted by
mucosa. This colorectal mucosa may be the appearance of these skin appendages. Epidemiology
involved with squamous metaplasia These landmarks, the dentate line and the The age-standardized rate of incidence of
resulting in a “transformation zone” blurring anal verge, have historically been used to anal SCC is < 1 per 100 000. Most anal
the original dentate line. define cancers of the anal canal and anal cancers occur among patients in the sixth
This transformation zone is particularly margin. Unfortunately, much confusion or seventh decade of life {903}. However,
susceptible to involvement with human has persisted, leading to miscategoriza- in individuals with cellular immune incom-
papillomavirus (HPV). Immediately proxi- tion of tumours and quite possibly petence, anal cancer may occur at a
mal to the dentate line and extending by overtreatment. young age {2036}.
0–12 mm is a variably present anal tran- Recently, new definitions have been The incidence of anal cancer is higher in
sitional zone (ATZ) of specialized epithe- proposed to simplify classification: anal females than in males {592, 903, 2037},
lium that is similar to urothelium {835, canal, perianal and transformation zone. with a male-to-female ratio of 0.81. Anal
3240}. The distal anal canal extends from A tumour of the anal canal is defined as a cancer is more common in females of all
the dentate line downwards to the muco- tumour that cannot be seen in its entirety, ages and basaloid tumours in particular
cutaneous junction with the perianal skin, or at all, when gentle traction is placed on are more frequent in women. The evolution
the anal verge. It is lined with a highly the buttocks. A perianal cancer is found of sexuality, HPV infection and sex
specialized nonkeratinizing squamous within a 5 cm radius of the anus and is hormones play a causal role in the
mucosa, formerly termed pectin, lacking seen completely when gentle traction is increasing predominance of females
placed on the anus. The rectal transfor- {901}; the latter as estrogen and andro-
mation zone represents the area of distal gen receptors are present in the support-
rectal mucosa proximal to the dentate line ive tissue of anal mucosa {2358}.
involved with squamous metaplasia. Anal cancer has increased in incidence
during recent decades by about 2.5-fold
in men and 5-fold in women {903, 1240,
Squamous cell carcinoma 1436, 2037, 3487}. The risk is higher in
urban than in rural areas {903, 2037}. The
Definition overall incidence of invasive and in situ
Squamous cell carcinoma (SCC) of the anal carcinoma increased to about 2.5
anal canal is a malignant epithelial neo- per 100 000 {1436}.
plasm that is frequently associated with Racial differences exist: the age-stan-
Fig. 9.02 Normal histology of the anal transition zone. chronic infection with HPV. dardized incidence in the USA is 1.4 and
Tumours of the anal canal 185

1.9 per 100 000 for white men and HPV infection
women, respectively, and 1.6 per 100 000 The association between HPV infection
for African-American men and women and anal cancer has been extensively
{1240}. analysed and included in the burden of
Geographic variations in the respective HPV-related cancers {2484}. HPV infection
proportion of SCC and adenocarcinoma is also associated with development of
exist: for SCC, the age-standardized rate anal squamous intraepithelial neoplasia in
of incidence is < 0.5 per 100 000 men but persons with immunodeficiency. Sexually
> 0.5 per 100 000 women {634}. transmissible HPV can be detected in the
The age-standardized rate of incidence majority of anal SCCs in more developed
for adenocarcinoma varies from 0.1 to 0.5 countries {900, 1180, 1230, 2784, 3151}.
Fig. 9.03 Squamous cell carcinoma arising at the dentate
per 100 000 men and from 0.1 to 0.2 per line of the anal canal. Different results have been reported in
100 000 women. The proportion of Asia; in China, only a single case involving
adenocarcinoma is particularly low in HPV type 16 DNA was detected among
Northern Europe, constituting < 15% of all American men and of 69.5 and 58.5 for 72 anal cancers {1724}. HPV was detected
cases {634}. Adenocarcinoma is more Caucasian women and African-American in 90% of women and 63% of men with
frequent in some African or Asiatic coun- women, respectively. The 5-year relative invasive anal cancer {898}. In women,
tries and represents the majority of anal survival for localized anal cancer (48% and HPV-associated gynaecological (cervical,
cancers in Japan. 42% of the registered cases for white and vulvar, vaginal) cancer has been reported
African-American people, respectively) to be strongly associated with anal cancer
Mortality was slightly more than 81% for Caucasian {1431, 3079}. While many HPV types can
The rate of mortality is significantly lower people and 67% for African American peo- infect the genital mucosa, their potential to
than the rate of incidence. In the USA in ple. The 5-year relative survival with induce malignancy differs. The prevalence
2002–2006, the age-standardized rate of extensive disease is around 15%. of HPV16 and HPV18 DNA was 72% in
mortality was 0.2 per 100 000. In 1980– invasive cancer, 69% in high-grade squa-
2006 in the USA, a significant annual Etiology mous intraepithelial neoplasia and 27% in
increase in mortality occurred in females Several recent studies have identified risk low-grade intraepithelial neoplasia {1237}.
{1240}. factors for anal SCC, including infection Low-risk HPV types are identified in anal
with HPV, immunodeficiency with human lesions with low-grade dysplasia and high-
Survival immunodeficiency virus (HIV) seropositivity, risk types (HPV types 16, 18, 31, 33, 35,
The prognosis for patients with anal a low CD4-T-cell count, immunosuppres- 39, 45, 50, 51, 53, 56, 58, 59 and 68) occur
cancer varies according to the stage of sion following solid-organ transplantion, in high-grade anal intraepithelial neoplasia
the tumour at detection. In the USA, the anoreceptive sexual intercourse, and (AIN) or invasive cancer {3682}. HPV-16 is
SEER survival monograph {1943} reports tobacco-smoking {3346}. detected in around 70% of cases {649,
a relative 5-year survival rate of 60.2 for 900}. Involvement of high-risk HPV is less
Caucasian men and 47.0 for African- frequent in lesions confined to the perianal
skin {898}.
HIV and immunosuppression

Homosexual men who are infected with
HIV appear to be at a particularly high risk
of developing anal cancer {1015, 2036,
2438}. Development of squamous intra-
epithelial lesions is inversely related to
CD4-T-cell count. The risk of HPV-related
cancers was analysed in the USA in
nearly 500 000 individuals diagnosed with
acquired immunodeficiency syndrome
(AIDS); the incidence of invasive anal
cancer was increased in men with a CD4-
T-cell count of < 100 per mm3. Incidence
was also higher during 1996–2004 than in
1990–2005, suggesting that prolonged
survival attributable to antiretroviral
treatment may be associated with an
increased risk of developing HPV-associ-
ated cancer {498}. Antiretroviral treat-
ments do not seem to decrease the risk
of anal cancer, suggesting that a vaccine
Fig. 9.04 In situ hybridization for human papilloma virus HPV16/18 is positive in this anal carcinoma. against HPV (now available) could prove

A B
Fig. 9.05 Squamous cell carcinoma of the anus. A The tumour shows a combination of basaloid features and keratinization. B Note the large cells that are poorly differentiated.
to be protective {886}. The association Anal cancer was also found to be more bleeding, fissure, or fistula. The initial non-
between HIV infection and anal cancer is common in women practising anal inter- specificity of clinical features combined
subject to confounding factors because course. with physician and patient reluctance to
HIV-positive patients are often infected examine and discuss anal diseases
with more than one HPV type {2438}. The Other factors contribute to a delay in diagnosis {2139A}.
role of HIV infection in the development of Several studies have identified smoking The clinical diagnosis of an anal tumour
malignancy is proposed to be through as a risk factor for the development of should always be confirmed by histo-
HPV infection {902}. anal cancer {901, 1231}. Case–control logical examination. A forceps or needle
Patients receiving long-term immunosup- studies estimate the relative risk of anal biopsy is usually sufficient to establish the
pressive therapy after solid-organ trans- cancer in smokers at 3.0–7.7 for women diagnosis. The biopsy should be accom-
plantion are at a higher risk of developing and 3.9–9.4 for men {649}. Haemorrhoids panied by an exact description of the
SCC {2519}, with a increased risk of 100- and fissures, fistulae and abcesses in the location and appearance of the biopsy
fold after renal transplantation {568}. An anal region had been considered as site. An excisional biopsy may be inad-
increased risk of anal cancer has also predisposing factors, but at the present visable, because delay in wound-healing
been reported in patients receiving time three case–control studies {650, 899, may postpone optimal chemoradiothera-
immunosuppressive therapy with corti- 1231} and two cohort studies {904, 1857} peutic treatment. However, small lesions
coids for other indications {649}. have failed to support this association. may lend themselves to local excision
Crohn disease of long duration has also more readily and the wound is often small
Sexual practices been implicated in the etiology of anal enough to be of little clinical impact.
The risk of anal cancer is linked to sexual SCC according to some case reports Enlarged lymph nodes, if symptomatic,
practice. Homosexual men constitute a {1702}. The association was not confirmed may be excised, but are generally
high-risk group {900, 903, 2037}. In the in a controlled study addressing this issue included in the planned radiation fields. If
USA, the incidence of anal SCC has been {899}. An increased risk of anal cancer is lymph-node biopsy is necessary for plan-
estimated to be 11–34 times higher in reported in persons with longstanding ning, needle aspiration under radiological
homosexual men than in the general male perianal Crohn disease {707}, but the guidance is often useful.
population and approximately as high as majority of cases concern adenocarci-
the incidence of cervical cancer before noma. In addition, the occurrence of an Imaging
the introduction of cervical cytology adenocarcinoma is not an unusual com- Computed tomography (CT) scan, mag-
screening {2437}. plication at the ileo-anal anastomosis after netic resonance imaging (MRI), and fine-
A population-based study {650} has establishment of an ileal pouch. needle aspiration may be used to
shown an increased risk in men who are establish inguinal and pararectal node
not exclusively heterosexual and in those Clinical features involvement. Endo-anal ultrasound is
practicing anal intercourse. A further Symptoms and signs useful in the follow-up of irradiated carci-
study of the same group {649} has shown AIN is often an unexpected finding in nomas {1985}. CT scan and MRI allow
that the odds ratio for anal cancer in men minor surgical specimens. Clinical mani- detection of involved lymph nodes and
who are not exclusively heterosexual was festations of anal cancer are often late and distant metastases {3078}.
17.3. The risk is also increased when nonspecific and are mainly related to
there is a history of genital warts, with an tumour size and extent of infiltration. They Exfoliative cytology
odds ratio of 7.4. Other factors include include anal pruritus, discomfort in the In patients with an increased risk, such as
number of sexual partners, receptive anal sitting position, sensation of a pelvic mass, those with HIV, those who are immuno-
intercourse, and coinfection with other pain, change in bowel habit, incontinence compromised (kidney transplant patients),
sexually transmitted diseases {900}. caused by sphincter infiltration, discharge, or women with SCC of the genital tract,

and chemotherapy, sometimes in combi-

nation with local excision. Large surgical
specimens are therefore rare. The exami-
nation should include resection lines in all
directions and a careful search for lymph
nodes. Clinical results for the combined
treatment regimes are comparable or
better than those for surgery alone, but
detection of residual disease can be more
difficult using imaging techniques owing
to local fibrosis. The question of persistent
versus recurrent disease often arises in
the first months after combined modality
therapy has been completed. Serial
digital rectal examination with anoscopy
and ultrasound is recommended for mon-
itoring. Routine biopsy is discouraged as
non-healing painful ulcers often result,
requiring abdominal–perineal resection
Fig. 9.06 Carcinoma of the anal canal. Note the small neoplastic glands that resemble anal glands.
for “benign” disease {2737}. Larger
lesions may take 6–8 months to resolve
the use of anal smears taken with a cyto- mucosa may appear somewhat granular and patience is encouraged as long as
logy brush from the area above the and friable or may be completely invisible the lesion continues to decrease in size.
dentate line is recommended {895, 2851}. and only detected upon palpation or with In 15–20% of cases, the lesion may infil-
the aid of high-resolution anoscopy trate the lower rectum and the neighbour-
Macroscopy (HRA). In HRA, a magnified view of the ing organs, including the rectovaginal
The entire anal canal and distal rectum anus is augmented by the painting of the septum, bladder, prostate and posterior
must be considered at risk. A digital rectal anal canal and distal rectal mucosa with urethra, sometimes with suppuration and
exam may detect a tiny lump, or ulceration acetic acid. Ulceration and infiltration result fistulas. The vulva is usually spared.
in the distal rectal mucosa or a fissure in bleeding and fixation. Lymphatic spread occurs in up to 40% of
with slightly exophytic and indurated cases {2472}. Tumours proximal to the
margins. Inspection may reveal an irregular Tumour spread and staging pectinate line drain into the pelvis along
thickening of the anoderm and anal mar- Anal SCC should be staged according to the middle rectal vessels to the pelvic
gin with chronic dermatitis. The lesion in the TNM (tumour, node, metastasis) system side walls and internal iliac chains and
the anal mucosa and perianal skin may {1107}. Treatment for anal SCC has now superiorly via the superior rectal vessels
have a different colour from the surrounding changed from surgery alone to sphincter- to the periaortic nodes. Tumours distal to
tissue and the lesion in the distal rectal preserving procedures, including radiation the dentate line drain along cutaneous
pathways to the inguinal and the femoral
nodal chains. Inguinal nodes are involved
in about 10–20% of cases {966, 2472}.
Inguinal lymph nodes can be involved
bilaterally in a small number of cases at
time of presentation. Retrograde lym-
phatic drainage occurs in advanced cases
when the lymphatics are obstructed by
malignant spread {2472}.
Histopathology
SCC of the anal canal
Anal SCC may show homogeneous histo-
logical characteristics, but most tumours
exhibit a mixture of areas with different
histological features. One pattern is that
of large, pale eosinophilic cells and
keratinization of either lamellar or single-
cell type. Another is that of small cells with
palisading of the nuclei in the periphery
of tumour-cell islands. The latter often
contain necrotic eosinophilic centres.
Fig. 9.07 Verrucous carcinoma (giant condyloma). Intermediate stages between these two

extremes are often present. Tubular nuclear moulding, high mitotic rate,
architecture or spindle-cell transformation extensive apoptosis and diffuse infiltration
may be found. The invasive margin can in the surrounding stroma. This has been
vary from well-circumscribed to irregular, called small cell (anaplastic) carcinoma
and a lymphocytic infiltrate may be {2922}, but should not be confused with
pronounced or absent. None of these small cell carcinoma (poorly differentiated
features have been shown to have any neuroendocrine carcinoma).
prognostic significance; histological
features do not consistently correlate with Perianal SCC
HPV type {1892, 3151}. The usual patterns The distinction between anal canal and
of immunoexpression are summarized in perianal SCC may be difficult, as tumours
Fig. 9.08 High-grade intraepithelial neoplasia adjacent
Table 9.01 {2210}. often involve both areas at the time of to normal rectal epithelium.
The second edition of the WHO classifi- diagnosis. This may account for the varying
cation of SCC of the anal canal included data on prognosis; however, prognosis is
the large cell keratinizing subtype, the generally better for patients with perianal Cytologically, the epithelial cells appear
large cell nonkeratinizing subtype, and SCC than with anal-canal SCC, in partic- benign. Large nuclei with prominent
the basaloid subtype, often referred to as ular if local resection is possible {2510}. nucleoli may be present, but cytonuclear
cloacogenic carcinoma. The value of this Perianal SCC is often the large cell variant atypia is usually minimal and mitoses are
classification of anal SCC has been ques- {898, 2510}. restricted to the basal layers {1892}.
tioned in recent years. Many tumours Some verrucous carcinomas contain HPV,
show more than one subtype. Thus in a Verrucous carcinoma the most common types being HPV6 and
study of 100 cases of anal carcinomas, 99 In the anogenital area, this tumour is also HPV11. They are regarded as an interme-
showed some features of squamous dif- called giant (malignant) condyloma or diate state between the ordinary condy-
ferentiation (keratinization, stratification Buschke-Löwenstein tumour {1077}. It has loma and SCC, and the clinical course is
and prickles), 65 showed basaloid features a cauliflower-like appearance, is larger typically that of local destructive invasion
(small cell change, palisading, retraction than the usual condyloma (with a diameter without metastases {248, 1892}. The pres-
artefact and central eosinophilic necrosis) of up to 12 cm), and fails to respond to ence of severe cytological changes,
and 26 showed focal evidence of ductal conservative treatment. In contrast to an unequivocal invasion or metastases
proliferation and occasionally positive ordinary condyloma, it is characterized by should lead to the diagnosis of SCC and
staining for periodic acid–Schiff (PAS) a combination of exophytic and endo- to the appropriate therapy.
after diastase digestion {3517}. Further- phytic growth. Histologically, it shows
more, the diagnostic reproducibility of acanthosis and papillomatosis with orderly Grading
these subtypes is low {837}. This is prob- arrangement of the epithelial layers and an Poor prognosis has been related to poor
ably the reason that the proportion of intact but often irregular base with blunt differentiation {298}, especially if this was
basaloid carcinoma in larger series has downward projections and keratin-filled defined only by the degree of dissociation
varied from 10% to almost 70%, and that cysts. The endophytic growth may repre- of tumour cells {1016}. However, such
no significant correlation between histo- sent invasive activity, but convincing differences may be related to tumour
logical subtype and prognosis has been evidence of invasive growth is rare. stage in multivariate analysis {2926}.
established. In addition, histological
diagnosis is nowadays nearly always per- Table 9.01. Immunoreactivity profiles for anal tumours.a
formed on small biopsies, that may not be Keratins
representative of the whole tumour, and Tumour Mucin CEA Vimentin Others
8 + 18 7 / 20 5 + 14
therapy is not influenced by histological
Colorectal adenocarcinoma + –/+ – + + – —
subtype {837}. Therefore, it is recom-
mended that the generic term “squamous Squamous cell variants – –/– + – – – Keratin 13 / 19
cell carcinoma” be used for these tumours, Basal cell carcinoma – –/– + – – – Ber-EP4b
accompanied by a comment describing
Neuroendocrine tumour (NET) + –/– – – – – Chrom / Synap
those histopathological features that may
possibly affect the prognosis, i.e. size of Malignant melanoma – –/– – – – + S100, HMB45c
predominant neoplastic cell, basaloid fea- Bowen (also pigmented) – –/– + – – –
tures, degree of keratinization, adjacent
Paget cells (local) + +/– – + + – GCDFP-15
squamous intraepithelial neoplasia, pres-
ence of mucinous microcysts or degree Paget cells (from colorectal carcinoma) + +/+ – + + –
of differentiaton {258}. Prostatic carcinoma + –/– – – – – PSA, PSAP
Apart from the verrucous carcinoma men- Malignant lymphoma – –/– - - - + LCA and others
tioned below, the only rare histological
subtype that seems to have a different bi- CEA, carcinoembryonic antigen; Chrom, chromogranin A; GCDFP, gross cystic disease fluid protein, a marker for
ological course, having a less favourable apocrine cells; LCA, leukocyte common antigen; PSA, prostate-specific antigen; PSAP, prostate-specific acid
phosphatase; Synap, synaptophysin. a Exceptions occur, especially among keratins and mucin; b Antibody to
prognosis, is characterized by a rather epithelial cell-adhesion molecule; c Melanocyte-specific antibody.
uniform pattern of small tumour cells with

Grading on the basis of biopsies is not in mild, moderate and severe should be production of inactive p53 or, less
recommended, as these may not be abandoned because reproducibility stud- frequently, by means of deletions in the
representative of the tumour as a whole. ies have shown considerable variation relevant area of chromosome 17p {1180}.
between observers {446}. Expression of More typically, p53 inactivation occurs at
Precursor lesions CDKN2A (p16) and assessment of prolif- the protein level through formation of a
Chronic HPV infection erative activity according to the Ki67- complex between the viral protein E6
Warts in the perianal skin and lower anal labelling index can assist in grading {3439}. (expressed by “high-risk” HPV types) and
canal (condyloma acuminatum) show the a cellular protein, the E6-associated
same histology as their genital counter- Perianal squamous intraepithelial neoplasia protein, which when bound to p53 leads
parts. Flat koilocytic lesions also occur. (PSIN, previously known as Bowen to rapid proteolytic degradation of p53
They should always be totally embedded disease) {3491}. The level of p53 expression does
and examined histologically for possible Clinically, this presents as a white or red not correlate with HPV status {1180}. The
presence of intraepithelial neoplasia. area in the perianal skin that may be in E7 protein of high-risk HPV types binds to
continuity with dysplastic lesions in the the retinoblastoma protein, pRb {755},
Intraepithelial neoplasia anal canal. HPV DNA is sometimes disrupting signals that normally restrict
Precancerous AIN in the ATZ and the detected, including HPV types 16 and 18, proliferation to the basal epithelial layer.
squamous zone has also been termed among others. Histologically, it shows full- The resulting increased proliferation
dysplasia, carcinoma in situ and anal thickness dysplasia of the squamous and increases the risk of malignant transfor-
squamous intraepithelial lesion (ASIL) sometimes the pilosebaceous epithelium, mation on exposure to DNA-damaging
{839, 2438}. The corresponding lesions in with disorderly maturation, mitoses at all stimuli. The combination of increased cell
the perianal skin are commonly referred levels and dyskeratosis. Occasionally, proliferation (pRb inactivation) and
to as Bowen disease. This terminology is atypical keratinocytes may resemble Paget impaired ability to induce cell-cycle arrest
complicated by the fact that the precan- cells, but are negative for low relative- or apoptosis following DNA damage (p53
cerous changes are not always restricted molecular-mass keratins and for mucin. In inactivation) are two central mechanisms
to one area. pigmented PSIN, the neoplastic cells are through which high-risk types of HPV
Given the confusion engendered by invariably negative for S100 protein and increase the risk of anogenital cancer.
multiple terms referring to the same HMB45. PSIN has a strong tendency to Additional gene alterations appear to be
pathology, the American Joint Committee recur after local treatment, but only a few involved in malignant progression and
on Cancer (AJCC) has recommended percent of cases will progress to SCC. This invasion. Amplification of the MYC gene
using simply “low-grade squamous tendency is higher in immunocompromised was found in 30% of anal SCCs {623}.
intraepithelial lesion” (LSIL) and “high- patients who develop PSIN {2850} Furthermore, gains in chromosomes 3q,
grade squamous intraepithelial lesion” 17, and 19 as well as losses in chromo-
(HSIL). The term preferred by WHO is AIN Genetic susceptibility somes 4p, 11q, 13q, and 18q, loss of
(see Chapter 1). “Leukoplakia” is a Human leukocyte antigens (HLAs) are in- heterozygosity at the APC, DCC/SMAD4
clinical term and should not be used as a volved in the presentation of viral antigens and D2S123 gene loci and epigenetic
histological diagnosis. to the immune system. Since the etiology alterations such as inactivation of the
of most anal SCCs involves HPV infection TSLC1 tumour-suppressor gene occur
Anal squamous intraepithelial neoplasia {898}, susceptibility to cancer develop- with increased frequency in SCC {969,
(ASIN) ment might be HLA type-dependent. 1180, 2179, 3064}.
Most cases of ASIN are incidental findings However, no study has addressed the
in specimens taken during minor surgery association between specific HLA class I Prognosis and predictive factors
for benign conditions. When detected or II alleles and risk, and attempts to iden- The most important prognostic factors
macroscopically, ASIN may present as an tify other genetic susceptibility markers reported in recent larger series of SCC of
eczematoid or papillomatous area, or as for anal SCC have so far been unsuc- the anal canal are tumour stage and nodal
papules or plaques. The latter may be cessful {501, 502}. status {258, 892, 2511, 2926}. Perianal
irregular, raised, scaly, white, pigmented SCC has a slightly better prognosis, which
or erythematous and occasionally fissured. Molecular pathology depends only on inguinal-node involve-
Induration or ulceration may indicate HPV DNA is detectable in most anal ment {2510}. DNA ploidy status has only
invasion. SCCs; in a large population-based series been shown to be of independent
Histologically, ASIN is characterized by of anal SCCs in Denmark and Sweden, prognostic significance in one of three
varying degrees of loss of stratification 84% contained HPV DNA, with higher larger series {1016, 2867, 2926}. Expres-
and nuclear polarity, nuclear pleomor- proportions of HPV DNA-positive cancers sion of p53, cyclin A, tumour-budding and
phism and hyperchromatism, and in- among women and homosexual men than tumour-infiltrating T-cells have been found
creased mitotic activity with presence of among non-homosexual men {898}. Loss to be of prognostic significance {1044,
mitoses high in the epithelium. The sur- of functional tumour-suppressor protein 2292, 2293}.
face may or may not be keratinized, and p53 appears to play a central role in the
koilocytic changes may be present. ASIN development of anal and anogenital
should be graded as either ASIN-L (low- SCCs {623, 624, 1180, 1793}. Inactivation
grade) or ASIN-H (high-grade) and the of p53 (TP53) may occur at the gene level
terminology of dysplasia and the grading through point mutations leading to the

Adenocarcinoma in these two locations show the same Basal cell carcinoma of the anal
profile with regard to mucin composition margin
Definition {836} and keratin expression {1217,
Adenocarcinoma of the anal canal is an 3518}. Basal cell carcinoma, the most common
adenocarcinoma arising in the epithelium skin cancer, is primarily found on areas of
of the anal canal, including the mucosal Adenocarcinoma within anorectal fistulae the skin that are exposed to the sun, and
surface, the anal glands and the lining of These tumours develop in pre-existing little more than 100 cases have been
fistulous tracts. anal sinuses or in fistulae {129}. Some are reported to occur in the anal area {984,
associated with Crohn disease {707, 2287}. The etiology is unknown and there
ICD-O code 8140/3 1702}. Others may contain epithelioid is no evidence for a role of infection by
granulomas, often related to foci of HPV {2261}. The tumour commonly presents
Clinical features inflammation or extravasated mucin, but as an indurated area with raised edges
The clinical features of anal adenocarci- without other signs of inflammatory bowel and central ulceration, located in the
noma of colorectal type do not differ from disease {1440}. Rarely, the tumours may perianal skin, but occasionally involves the
those of anal squamous cell carcinoma be related to fistulae lined by normal squamous zone below the dentate line.
(SCC). Perianal adenocarcinomas may rectal mucosa, including muscularis Histologically, it can show the same vari-
present as submucosal tumours, sometimes mucosae, most likely representing ability in morphology as basal cell carci-
in combination with fistulae. Occasionally, adenocarcinomas arising in congenital noma elsewhere, most reported cases
there may be associated Paget disease of duplications {1440}. Histologically, carci- having had a solid or adenoid pattern.
the anus. Tumour spread and staging nomas arising in fistulae usually are of the
largely correspond to that for anal SCC. mucinous type, but tubular adenocarci-
nomas and squamous neoplasia can also
Histopathology be found {1702, 3636}.
Adenocarcinoma arising in anal mucosa
Most adenocarcinomas found in the anal Adenocarcinoma of anal glands
canal represent downward spread from Only a few cases have been reported in
an adenocarcinoma in the rectum or arise which convincing evidence for origin in an
in colorectal-type mucosa above the anal gland has been demonstrated by
dentate line. Macroscopically and histo- continuity between anal-gland epithelium
logically, they are indistinguishable from and tumour {209, 1099, 2490, 3486,
ordinary colorectal-type adenocarcinoma, 3540}. With a single exception {1099},
and do not seem to represent a special these patients have had no history of
entity, except for their low location. previous or concomitant fistula. The
Adenocarcinoma in the ATZ may develop tumours were all characterized by a
after restorative proctocolectomy for ductular architecture with scant production
ulcerative colitis {2878}. of mucin. Pagetoid spread was present in
at least one case {3540}. Carcinomas of
Extramucosal (perianal) adenocarcinoma the anal gland express keratin 7 as well
Approximately 200 cases of extramucosal as keratin 5/6 and show a loss of p63
adenocarcinoma have been reported, the expression, which may be helpful in
largest series unfortunately with insuffi- diagnosis {1217, 1868}.
cient histological data {5}. A minimum
criterion for diagnosis is an overlying non- Grading
neoplastic mucosa, which may be Anal adenocarcinomas are graded in the
ulcerated. Recent reports indicate that same way as colorectal adenocarcino- Fig. 9.09 Paget disease of the anal canal. Large Paget
about two thirds of these tumours mani- mas. cells are distributed throughout the non-neoplastic
fest in men with a mean age of about 60 squamous epithelium.
years. Reliable data for the prognosis for Precursor lesions
such patients have not been identified. Anal adenocarcinomas without predis-
Difficulties in establishing the correct posing conditions as described above
diagnosis may delay proper treatment. are rare. They can arise from adenomas
Extramucosal adenocarcinomas seem to {584A}, which can be graded as for the
fall into two groups on the basis of their colorectum.
association with either fistulae or rem-
nants of anal glands. At present, no labo- Prognosis and predictive factors
ratory methods can distinguish between The prognosis for anal adenocarcinoma
these two groups. The epithelium of seems to be related only to stage at
persistent anal fistulae is most often of the diagnosis and is poorer than that for SCC
same type as that found in the anal {209, 481, 513, 1585, 2201}.
glands and ATZ {1915}, and the epithelia Fig. 9.10 Paget disease of the anal canal.

Other lesions
Squamous cell papilloma, papillary
hidradenoma, keratoacanthoma, mes-
enchymal tumours, neurogenic tumours
and lymphomas rarely involve the anal
canal and perianal region. Patients with
AIDS have an increased risk of developing
lymphoma and Kaposi sarcoma. Neuro-
A endocrine neoplasms of the anal canal
are conventionally classified as rectal and
are discussed in Chapter 8.
Squamous cell papilloma of the anal

canal
Rarely, papillomatous processes covered
by normal, more or less keratinized squa-
mous epithelium can be found in the
anus. Such lesions should be tested for
the presence of HPV. Lesions that are
B negative for HPV are commonly regarded
Fig. 9.11 Malignant melanoma of the anus with typical Fig. 9.12 Malignant melanoma of the anus. A Polypoid as “burned-out” condylomas.
polypoid appearance. growth is frequent. B Epitheloid melanoma cells with
prominent nucleoli. Papillary hidradenoma
This rare tumour arises in the perianal
Basal cell carcinoma is treated ade- erythematous eczematoid plaque that may apocrine glands, typically in middle-aged
quately by local excision and metastases extend up to the dentate line {2808}. Histo- women and only exceedingly rarely in
are extremely rare. It is therefore impor- logically, the basal part or whole thickness men {1877}. It presents as a circum-
tant to distinguish basal cell from of the squamous epithelium is infiltrated by scribed nodule approximately 1 cm in
squamous cell carcinoma; this may be large cells with abundant pale cytoplasm diameter and may resemble a haemor-
particularly difficult when relying solely on and large nuclei. Occasional cells have the rhoid. Histologically, it consists of a papil-
small biopsies. Both types of tumours can appearance of signet rings. Paget cells lary mass with a cyst-like capsule. The
be found in the squamous zone, and both invariably react positively for mucin stains papillae are lined by a double layer of
can show a combination of basaloid, and nearly always for keratin 7, but Merkel epithelial cells, the outer layer being
squamous and adenoid features and an cells and Toker cells may also be positive composed of cells containing mucin. The
inflammatory infiltrate in the stroma {101}. for the latter. tumour does not express the eccrine
Numerous and even atypical mitoses may Paget disease of the anus appears to marker IKH4, but it must be remembered
be present in basal cell carcinomas represent two entities. About half of the that adenocarcinoma metastases are also
{2593}. However, basaloid areas in cases are associated with a synchronous negative for this marker {1357}. Convincing
squamous carcinoma usually show less or metachronous malignancy, most often examples of anal apocrine adenocarci-
conspicuous peripheral palisading, more a colorectal adenocarcinoma. Such noma have not been published.
cellular pleomorphism, and often large, cases can be regarded as a pagetoid
eosinophilic necrotic areas. Immunohisto- extension of the tumour. They usually Keratoacanthoma
chemistry may be helpful in establishing react positively for keratin 20 and nega- There are a few reports on keratoacan-
the diagnosis. Basal cell carcinoma is tively for gross cystic-disease fluid thoma arising in the perianal skin {783}.
positive for Ber-EP4 and negative for protein-15 (GCDFP-15), a marker for
keratins 13, 19 and 22, and for carcino- apocrine cells. This is in contrast to the Neuroendocrine tumours
embryonic antigen (CEA), epithelial mem- other half of the cases, which are not Neuroendocrine tumours may arise in the
brane antigen (EMA), erythroid band 3 associated with internal malignancies but anus {838, 1243}. They are, however,
(AE1) and Ulex europaeus agglutinin 1 have a high rate of local recurrence and conventionally classified as rectal. An
(UEA1), while basaloid variants SCC may become invasive {1976}. Only the immunohistochemical study of 17 rectal
usually show the opposite pattern {101}. latter entity can be regarded as a true neuroendocrine tumours showed that
epidermotrophic apocrine neoplasm most were of L cell type {519} (see
{145, 215, 1012, 2325}. Recently, it has Chapter 5).
Paget disease been proposed that this disease arises
from adnexal stem cells residing in the Malignant melanoma
Extramammary Paget disease usually infundibulo-sebaceous unit of hair follicles Anal melanoma is rare, representing 1–3%
affects sites with a high density of apoc- and adnexal structures, on the basis of of all anal tumours. Patients most com-
rine glands, such as the anogenital region, expression of keratins 15 and 19 {2652}. monly present in the fifth or sixth decades
where it presents as a slowly spreading, of life with pain, rectal bleeding or a mass.

Macroscopy. Lesions may be polypoid or but much more common in patients with
sessile and infiltrating. Pigmentation of the AIDS, particularly homosexual men. All
lesion is often apparent. Satellite nodules are of B-cell type, the most common types
may occur. being large cell immunoblastic or pleo-
morphic {1154, 1336}. Langerhans-cell
Histopathology. The features are similar histiocytosis has been described in chil-
to those of cutaneous melanomas that dren {1051, 1454} and in an adult {587}.
express S100 protein. Most cases show a
junctional component adjacent to the Secondary tumours
invasive tumour, and this finding is Metastases to the anal canal and
evidence that the lesion is primary rather perineum are rare and present as any
Fig. 9.13 Inflammatory cloacogenic polyp. Dilated
than metastatic. other lesion involving this region with pain, elongated hyperplastic glands showing regenerative
bleeding, a mass, or altered bowel control. atypia. Surface erosion is a constant feature.
Prognosis. Anal melanomas spread by Most primaries are found in the rectum or
lymphatics to regional nodes, and colon, but occasionally also in the respi-
haematogenously to the liver and thence ratory tract, breast and pancreas {662, slightly hyperplastic and may be kera-
to other organs. Metastases are frequent 834, 1474, 2986}. There are few reports of tinized. The stroma may be more or less
at time of presentation, and the prognosis metastatic squamous cell carcinoma dense and often contains fibroblastic
is poor; 5-year survival is < 20% {3087}. {965}. Malignant lymphoma, leukaemia cells with two or more nuclei and a con-
Outcomes do not support radical surgery, and myeloma may infiltrate the anal canal, siderable number of mast cells {1070}.
except for the purposes of palliation in the and eosinophilic granuloma has also Neuronal hyperplasia is a common
unusual cases that present at an early been described {834}. feature {840}.
stage {292, 322}.
Neoplasia-like lesions / Fibroepithelial Inflammatory cloacagenic polyp
Mesenchymal and neurogenic tumours polyp Inflammatory cloacagenic polyps, first
These are all rare and the exact point of Also called fibrous polyp or anal tag, this described in 1981 {1878}, are commonly
origin may be difficult to establish. is one of the most frequent anal lesions associated with mucosal prolapse and
Reports on tumours in the anorectal and and is found at the dentate line, anal sometimes with haemorrhoids {520,
perianal area include haemangioma, lym- mucosa or in the perianal skin {3501}. 1812}. These polyps arise in the ATZ and
phangioma {653}, haemangiopericytoma Fibroepithelial polyps may be associated form a rounded or irregular mass meas-
{804}, leiomyoma, malignant fibrous histio- with local inflammation such as fissure or uring 1–5 cm in diameter. Histologically,
cytoma and leiomyosarcoma {1913}, fistula {1879}. Granulomas can be found the polyp consists of hyperplastic rectal
rhabdomyoma in a newborn {1744}, and in about one third of skin tags in cases of mucosa, partly covered with ATZ-type or
rhabdomyosarcoma in childhood {2631} Crohn disease {3208}. Others may repre- squamous epithelium. The surface is
and adulthood {1524}, fibrosarcoma, sent the end stage of a thrombosed typically eroded and the stroma shows
neurilemmoma and neurofibroma {961}, haemorrhoid, but remnants of haemor- oedema, vascular ectasia, inflammatory
granular cell tumour (myoblastoma) rhoidal vessels or signs of previous bleed- cells and granulation tissue. Vertically
{1438}, spindle cell lipoma and aggres- ing are rarely found. Most are probably of oriented smooth-muscle fibres are found
sive angiomyxoma {852} and extraspinal idiopathic nature as the incidence is between the elongated and tortuous
ependymoma in a newborn {3475}. Per- rather similar in patients with or without crypts. It can be confused with a
sons infected with HIV may, in addition to anal diseases {3501}. prolapsed rectal adenoma {2464}.
the increased risk of squamous neopla- Grossly, the polyp is spherical or elon-
sia, develop Kaposi sarcoma in the peri- gated with a greater diameter ranging Malacoplakia
anal area {202}. from a few millimetres up to 4 cm. The Cutaneous malacoplakia may arise in
surface is white or grey and may show immunocompromised patients and pres-
Lymphoma superficial ulceration. Histologically, it ent as perianal nodules {1903}.
Primary lymphomas of the anorectal consists of a fibrous stroma covered by
region are rare in the general population, squamous epithelium, which usually is a

CHAPTER 10
Tumours of the liver and intrahepatic bile ducts
Focal nodular hyperplasia and hepatocellular adenoma
Hepatocellular carcinoma
Intrahepatic cholangiocarcinoma
Combined hepatocellular-cholangiocarcinoma
Hepatoblastoma
Mucinous cystic neoplasms
Lymphoma
Mesenchymal tumours
Secondary tumours
Diagnostic algorithms
WHO classificationa of tumours of the liver and intrahepatic bile ducts

Epithelial tumours: hepatocellular Malignancies of mixed or uncertain origin
Benign Calcifying nested epithelial stromal tumour 8975/1*
Hepatocellular adenoma 8170/0 Carcinosarcoma 8980/3
Focal nodular hyperplasia Combined hepatocellular-cholangiocarcinoma 8180/3
Malignancy-associated and premalignant lesions Hepatoblastoma, mixed epithelial-mesenchymal 8970/3
Large cell change (formerly “dysplasia”) Malignant rhabdoid tumour 8963/3
Small cell change (formerly “dysplasia”)
Dysplastic nodules
Mesenchymal tumours
Low grade
High grade Benign
Angiomyolipoma (PEComa) 8860/0
Malignant
Cavernous haemangioma 9121/0
Hepatocellular carcinoma 8170/3
Infantile haemangioma 9131/0
Hepatocellular carcinoma, fibrolamellar variant 8171/3
Inflammatory pseudotumour
Hepatoblastoma, epithelial variants 8970/3
Lymphangioma 9170/0
Lymphangiomatosis
Mesenchymal hamartoma
Epithelial tumours: biliary Solitary fibrous tumour 8815/0
Benign Malignant
Bile duct adenoma (peribiliary gland hamartoma Angiosarcoma 9120/3
and others) 8160/0
Embryonal sarcoma (undifferentiated sarcoma) 8991/3
Microcystic adenoma 8202/0
Epithelioid haemangioendothelioma 9133/3
Biliary adenofibroma 9013/0
Premalignant lesions Leiomyosarcoma 8890/3
Biliary intraepithelial neoplasia, grade 3 (BilIN-3) 8148/2* Rhabdomyosarcoma 8900/3
Intraductal papillary neoplasm with low- or Synovial sarcoma 9040/3
intermediate-grade intraepithelial neoplasia 8503/0
Intraductal papillary neoplasm with high-grade
intraepithelial neoplasia 8503/2*
Germ cell tumours
Mucinous cystic neoplasm with low- or
intermediate-grade intraepithelial neoplasia 8470/0 Teratoma 9080/1
Mucinous cystic neoplasm with high-grade Yolk sac tumour (endodermal sinus tumour) 9071/3
intraepithelial neoplasia 8470/2
Malignant Lymphomas
Intrahepatic cholangiocarcinoma 8160/3
Intraductal papillary neoplasm with an associated Secondary tumours
invasive carcinoma 8503/3*
Mucinous cystic neoplasm with an associated
invasive carcinoma 8470/3
____________________
PEComa, perivascular epithelioid cell tumour.

a
The morphology codes are from the International Classification of Diseases for Oncology (ICD-O) {904A} and the Systematized Nomenclature of Medicine
(SNOMED). Behaviour is coded /0 for benign tumours, /1 for unspecified, borderline or uncertain behaviour, /2 for carcinoma in situ and grade III intraepithelial neo-
plasia, and /3 for malignant tumours.
196 Tumours of the liver and intrahepatic bile ducts

TNM classificationa of tumours of the liver and intrahepatic bile ducts

Hepatocellular carcinoma Carcinoma of the intrahepatic bile ductsb
T – Primary tumour T – Primary tumour

TX Primary tumour cannot be assessed TX Primary tumour cannot be assessed
T0 No evidence of primary tumour T0 No evidence of primary tumour
T1 Solitary tumour without vascular invasion Tis Carcinoma in situ (intraductal tumour)
T2 Solitary tumour with vascular invasion or multiple tumours, T1 Solitary tumour without vascular invasion
none more than 5 cm in greatest dimension T2a Solitary tumour with vascular invasion
T3 Multiple tumours any more than 5 cm or tumour involving a T2b Multiple tumours, with or without vascular invasion
major branch of the portal or hepatic vein(s) T3 Tumour perforates the visceral peritoneum or directly
T3a Multiple tumours any more than 5 cm invades adjacent extrahepatic structures
T3b Tumour involving a major branch of the portal or T4 Tumour with periductal invasion (periductal growth pattern)
hepatic vein(s)
T4 Tumour(s) with direct invasion of adjacent organs other than N – Regional lymph nodes
the gall bladder or with perforation of visceral peritoneum
Stage grouping
Stage grouping
Stage T N M
Stage I T1 N0 M0
Stage T N M
Stage II T2 N0 M0
Stage I T1 N0 M0
Stage III T3 N0 M0
Stage II T2 N0 M0
Stage IVA T4 N0 M0
Stage IIIA T3a N0 M0
Any T N1 M0
Stage IIIB T3b N0 M0
Stage IVB Any T Any N M1
Stage IIIC T4 N0 M0
Stage IVA Any T N1 M0
____________________
a
{762, 2996}
b
The classification applies to intrahepatic cholangiocarcinoma, cholangiocellular carcinoma, and combined hepatocellular and cholangiocarcinoma (mixed
hepatocellular-cholangiocellular carcinoma).
Classification 197
Focal nodular hyperplasia and P. Bioulac-Sage

C. Balabaud
hepatocellular adenoma I. Wanless
Focal nodular hyperplasia 90% of cases, FNH is discovered in

women in their third or fourth decade of
Definition life. Three quarters of women with FNH
Focal nodular hyperplasia (FNH) is not a have been long-term users of oral contra-
true neoplasm, but a regenerative hyper- ceptives (OC) suggesting that female hor-
plastic response of hepatocytes, second- mones play a role in the pathogenesis of
ary to localized vascular abnormalities FNH {973}, although use of OC did not
{3456}. correlate with the size or number of le-
sions, making it unlikely that this is an im-
Epidemiology portant risk factor {2000}. In countries
FNH is the second most frequent benign where OC use is less prevalent (e.g.
Fig. 10.02 Focal nodular hyperplasia. Fibrous septa
liver nodule (after haemangioma) and has China), FNH tends to be a lesion found in
separate hepatocellular nodules of different sizes that
been reported to occur in 0.8% of an men or children of either sex {1860}. resemble cirrhosis (Masson trichrome).
adult autopsy population {3455}. In 80–
Etiology
Pathogenesis
While the pathogenesis of FNH is not fully
established, the association with condi-
tions in which there are vascular anom-
alies (e.g. hereditary haemorrhagic
telangiectasia) and the presence of un-
usually large vessels within the lesions
has led to the belief that FNH is a
response to focally increased blood flow
{3456}. The presence of focal hepatic Fig. 10.03 Focal nodular hyperplasia. The arteries in the
A vein obstruction and association with central scar are variably thick-walled (arrows).
Budd-Chiari syndrome suggest a role for
outflow obstruction. A current hypothesis
is that the primary lesion is outflow ob- rial imaging {1681, 2373}, although histo-
struction and the secondary congestive logical proof is absent.
injury results in parenchymal collapse and The background liver is usually normal;
fibrosis, arteriovenous shunting, and loss however, classical FNH, and especially
of portal veins and ducts. The sequential FNH variants, can occur in abnormal liv-
loss of portal veins and ducts and the reers with vascular alterations (Table 10.01)
placement of congested tissue with fibro- {1843, 3186, 3454, 3455}.
sis explain the spectrum of histological FNH is associated with hepatic haeman-
B findings (Table 10.01). Since all histologi- gioma in 20% of cases. Coexistence with
cal features are local events in or adjacent hepatocellular adenoma (HCA) is rare.
to individual, lesional portal tracts, mixed Associated vascular lesions outside the
forms occur within this spectrum. liver have also been reported.
Clinical features Macroscopy

In two thirds of cases, FNH is solitary On cut section, classical FNH is a pale,
{3455}. Most lesions are asymptomatic firm mass, ranging from a few millimetres
and discovered incidentally during sur- to > 10 cm in diameter. The margin is
gery, autopsy, or imaging for unrelated well-delimited, lobulated, and non-en-
C symptoms. Large lesions can present capsulated. The lesion is composed of
Fig. 10.01 Focal nodular hyperplasia. A MRI: fat-suppressed with abdominal pain or compression of component nodules each measuring 2–
gadolinium-enhanced T1-weighted sequence (arterial adjacent organs. Rare reports of haemor- 3 mm, separated by zones of atrophy giv-
phase). B Fresh specimen: note the multinodularity and rhage or malignant transformation still re- ing a multinodular appearance. The
central stellate scar (arrow). C Small lesion without stellate quire confirmation. FNH lesions may lesion characteristically has a central or
scar, but with focal areas of congestion. regress with age, as documented by se- excentric stellate scar with radiating

extensions that partially surround some Table 10.01 Histological criteria for classical focal nodular hyperplasia (FNH) and its variants.
component nodules. FNH variants, in- Criterion Classical FNHa FNH variantsb
complete or early forms may lack a cen-
tral scar and have variably prominent Fibrosis +++ – to ++
regions of congestion. Duct loss and ductular reaction (keratin 19+) +++ – to +
Sinusoidal dilatation +/– to + – to ++
Histopathology Large positive anastomosing
Glutamine synthetase immunostaining Few data available
Classical FNH lesions are composed of areas, often around central veins
benign hepatocellular nodules arranged Background liver Normalc Normal or abnormald
in plates no more than two cells thick. + , positive; –, negative.
Steatosis, usually focal, may occur. The a
Fibrous scar or ductular reaction may be absent, particularly in a biopsy.
central scar contains one or more large b
These variants are rare compared with classical FNH and include a variety of benign nodules considered to be
dystrophic vessels and numerous small regenerative in nature and containing portal tracts. These have been classified over the years under a variety of
arterioles. The large vessels have irregu- names that are not yet universally accepted, including early FNH, pre-FNH, subtle FNH, FNH-like nodules,
telangiectatic FNH, large regenerative nodules, or partial nodular transformation. These lesions may have a focal
lar, fibrous, intimal thickening with focal
component of classical FNH.
medial attenuation. The internal elastic c
Steatosis may be seen in the otherwise normal liver.
lamina is poorly formed and duplicated. d
In addition to possible steatosis, livers may show vascular disorders, including portal thrombosis or atresia, patent
Portal veins are absent. The radiating ductus venosus, hepatic vein thrombosis, hereditary haemorragic telangiectasia, or cirrhosis.
branches of scar contain portal tract-like
structures with arteries unaccompanied
by portal veins or ducts. When fibrous universally accepted terminology awaits In FNH lesions, the β-catenin pathway is
septation is prominent, the appearance further characterization of the FNH vari- activated, including the downstream tar-
may be indistinguishable from cirrhosis, ants using modern techniques of imag- get, glutamine synthetase {2646}, which
especially in biopsy specimens. Stromal ing, immunohistochemistry and molecular explains the expansion of hepatocytes
inflammatory infiltrates, lymphocytic or analysis {264, 2456, 3608}. expressing glutamine synthetase that is
mixed, are frequent. At the stromal- so useful for histological diagnosis. While
parenchymal interface, cholate stasis Molecular pathology the molecular mechanisms of this activa-
and/or ductular reactions are often present. Clonal analysis using the human andro- tion are uncertain, they do not involve
Sinusoids adjacent to arterial sources are gen receptor (HUMARA) test demon- demonstrable mutations in β-catenin
lined by CD34-positive endothelium. Im- strates the reactive, polyclonal nature of (CTNNB1) or axin 1 (AXIN1).
munostaining reveals broad, anastomos- FNH liver cells in 50–100% of cases {264,
ing (“map-like”) areas of (hepatocellular) 2459}. Recent studies have shown that Prognosis and predictive factors
expression of glutamine synthetase, often mRNA expression of the angiopoietin In centres with experience in this field,
adjacent to hepatic veins {263}. genes (ANGPT1 and ANGPT2) involved an accurate diagnosis can be made
In addition to classical FNH, other nod- in vessel maturation is altered, with the using imaging techniques in 90% of
ules thought to be regenerative in nature ratio of ANGPT1 to ANGPT2 being in- cases. Contrast-enhanced ultrasonography
have been reported under many different creased compared with normal liver, cir- (CEUS) is the modality of choice {376,
names {1335, 2274, 3455}. The existing rhosis, and other liver tumours {2457, 1562}. Magnetic resonance imaging
literature concerning these rare FNH vari- 2645}, supporting the importance of vas- (MRI) and triple-phase computed tomog-
ants is confusing because diagnostic cri- cular alterations in the pathogenesis of raphy (CT) are useful when CEUS is not
teria have not been standardized; a FNH. available. In < 10% of cases, the differential
Fig. 10.04 Focal nodular hyperplasia displaying cholate stasis in periseptal hepatocytes, Fig. 10.05 Focal nodular hyperplasia. Immunostaining for keratin 7 highlights the prominent
ductular reaction at stromal–parenchymal interface, and septal inflammation. ductular reaction at the septal–parenchymal interface.
Focal nodular hyperplasia and hepatocellular adenoma 199

Table 10.02 Typical features of focal nodular hyperplasia (FNH) with various imaging modalities. tocytes and must be supplied by altered
Imaging modality Main nodule Central scar region
portal tracts. Ensuring that the biopsy in-
cludes the lesion may be difficult, since
Magnetic resonance imaging (MRI) cirrhosis attributable to any cause may
T1-weighted Iso- or slightly hypointense Hypointense
closely resemble FNH. It is therefore rec-
Chemical shift sequences No signal dropout
ommended that a biopsy be accompa-
T2-weighted Iso- or slightly hyperintense Hyperintense
nied by a sample of nonlesional liver.
Gadolinium-enhanced imaging
Arterial phase Hyperintense Hypointense
HCA is the most frequent lesion to be dis-
Portal venous phase Isointense Hypo-, iso-, or hyperintense tinguished from FNH. In most cases this
Delayed phase Isointense Hyperintense is straightforward because adenomas are
Baseline grey-scale ultrasonography Slightly hypoechoic, isoechoic, or Slightly hyperechoica supplied by isolated arteries, not portal
hyperechoic tracts. A source of difficulty in this regard
Colour Doppler is the presence of ductular elements that
Vascularity Hypervascular are positive for keratin 7 in HCA of the in-
Arteries Feeding arterya Central stellate vasculaturea flammatory type. The key feature is that
Veins Peripheral draining veinsa expression of glutamine synthetase
Contrast-enhanced ultrasonography (CEUS) shows a distinctive map-like distribution
Arterial phase Hypervascular Central scar not visualized adjacent to hepatic veins in FNH, while
Filling pattern Centrifugal expression is diffusely positive in β-
Portal venous phase Iso- or hyperechoic Hypoechoica catenin-activated HCA and mostly nega-
Delayed phase Isoechoic Hypoechoica tive in other types of HCA.
a
Inconsistent HCC may mimic FNH by the presence of
focal scarring, arterialized sinusoids, and
residual portal-tract remnants. Warning
diagnosis of FNH, hepatocellular ade- problem cases. Differential diagnosis may signs of malignancy include nuclear
noma (HCA), and hepatocellular carci- be impossible on the basis of biopsy only; pleiomorphism, wide plates, a high
noma (HCC) cannot be solved by if the result is not definitive, surgery may nucleus-to-cytoplasm ratio, mitotic figures
imaging alone. A biopsy with standard be advocated. in the lesion and often cirrhosis in the
and/or immunohistochemical stainings, The histological diagnosis of FNH re- background liver.
interpreted by an experienced liver quires two main criteria: the lesion must
pathologist, can resolve most of these be composed of benign-appearing hepa-
Hepatocellular adenoma
Definition
Hepatocellular adenoma (HCA) is a be-
nign liver neoplasm composed of hepa-
tocytes.
ICD-O code 8170/0
Epidemiology
The incidence of HCA is about 3–4 per
100 000 population in Europe and North
America {2723} but lower in Asia. Eighty-
A B five percent of cases occur in young
Fig. 10.06 Small steatotic focal nodular hyperplasia. A Surgical specimen. B Masson trichrome staining. women; HCA is rare in children, men, and
the elderly.
Normal liver Normal liver
Etiology
The major risk factor for HCA is exposure
FNH FNH to estrogenic or androgenic steroids. In
young women with HCA, 80% have been
users of oral contraceptives (OC) and risk
increases with duration of use. The preva-
lence appears to be declining as low-es-
trogen preparations become more
A B widespread. The lesions usually shrink
Fig. 10.07 A Focal nodular hyperplasia (FNH). B Immunolabelling for glutamine synthetase reveals a broad, after stopping OC or after menopause.
anastomosing “map-like” pattern of staining within the lesion and the normal, perivenular pattern outside. Most men developing HCA have been

users of anabolic steroids for the purpose

of bodybuilding. Patients taking andro-
gens for Fanconi anaemia or acquired
aplastic anaemia are also at risk {3389}.
Nonhormonal risk factors include
glycogenosis type 1 (von Gierke disease)
or 3 (Forbes disease), galactosaemia, ty-
rosinaemia, familial polyposis coli, and
hepatic iron overload with β-thalassemia
{2960}. Obesity has recently been shown A B C
to be a risk factor for a particular HCA Fig. 10.08 HNF1α-inactivated hepatocellular adenoma. MRI: Homogeneous segment IV lesion displaying isointensity
subtype. on T1W image (A) and critical homogenous signal drop-out on phased opposed T1W image (B) due to massive fat
component. C Fresh specimen: yellowish tumour (arrows).
Clinical features
Clinical presentation may include abdom-
inal pain, abdominal mass, intraperitoneal ally one or at most two cells thick. There Mitoses are extremely rare in HCA and
haemorrhage, abnormal liver tests, or a may be very focal pseudogland forma- their presence indicates that HCC should
liver mass found incidentally during an tion. Tumour hepatocytes have cytoplasm be considered. Arterialized sinusoids
imaging study. HCA can be single or mul- that may be normal, clear (glycogen-rich), (CD34+) are almost always found in
tiple. When 10 or more adenomas occur, steatotic, or contain pigment in lyso- HCCs, but may also be found in some
the condition is known as “adenomatosis” somes. Nuclear atypia and mitoses are HCAs. Cytoplasmic pigment, when pres-
{873, 3400}. Clinically significant haemor- unusual. The tumour parenchyma is sup- ent, suggests that the lesion is slow-grow-
rhage is observed in 20–25% of cases; plied by isolated arteries unaccompanied ing and thus favours HCA over HCC.
the risk being highest when the tumours by bile ducts. Variations in this typical pat- Angiomyolipoma may also resemble
are > 5 cm. Malignant transformation to tern are frequently seen in some of the HCA, but can be differentiated by im-
hepatocellular carcinoma (HCC) is rare subtypes. munohistochemistry.
but well-documented, occurring in up to As the deviation from normal liver histol-
7% of cases reported from referral cen- ogy may be minimal, it is very important Molecular pathology
tres {260, 730, 2059}. The risk of transfor- to obtain a simultaneous biopsy of nontu- HCA represents a heterogeneous entity,
mation varies with HCA subtype and with moral liver, to confirm the presence or ab- recently subclassified into several groups
clinical association, being higher in pa- sence of cirrhosis in particular. according to genotype and phenotype.
tients with glycogenosis or androgenic– These subtypes vary greatly in their clini-
anabolic steroid use. Differential diagnosis cal, pathological, and radiological fea-
Fibrosis or the presence of ductules within tures {265, 1757, 3727}.
Macroscopy the lesion, particularly in inflammatory
HCAs are typically large, globular tu- HCA, may hinder differential diagnosis HNF1α-inactivated HCA
mours with prominent vessels in the over- with FNH. In such cases, the identification The HNF1A gene encodes hepatocyte
lying hepatic capsule. On cut section, the of FNH or HCA by immunostaining for glu- nuclear factor 1 (HNF1α), a transcription
parenchyma is soft and relatively uniform, tamine synthetase is very useful. factor that is involved in hepatocyte
although congestion, necrosis, haemor-
rhage, or fibrosis are frequent. The mar-
gins of the lesion are ill-defined, grossly
and microscopically, with little or no fi-
brous capsule. Size varies from micro-
scopic to 20 cm in diameter. In livers with
adenomatosis, hundreds of lesions may NTL HCA
be visible grossly as minute ill-defined
nodules or only microscopically. HCA
may be similar in colour and texture to the
background liver, but steatosis, major
congestion and haemorrhage or degen-
erative changes can make it distinct. The
background liver is usually normal or al-
tered in colour related to associated fatty-
liver disease, glycogen-storage disease,
or iron overload.
Fig. 10.09 HNF1α-inactivated hepatocellular adenoma. Fig 10.10 HNF1α-inactivated hepatocellular adenoma. In
Histopathology Benign, steatotic hepatocytes are intermingled with isolated contrast to the adjacent nontumoral liver (NTL), the steatotic
HCA is typically composed of benign he- thin-walled arteries. and nonsteatotic tumoral hepatocytes lack normal expression
patocytes arranged in regular plates, usu- of L-FABP.

Table 10.03 Histological features of subtypes of hepatocellular adenoma (HCA). differentiation. Biallelic inactivating muta-
HNF1α− β-Catenin- Inflammatory Unclassified tions of this gene are found in approxi-
Histological feature mately 35–40% of HCA; 90% of HNF1A
inactivated HCA activated HCA HCAa HCA
mutations are somatic, while the remain-
Usually +++ – to ++
Steatosis Rarely + – (heterogeneous) +/– ing 10%, are constitutional (germline)
Extremely rarely – rarely +++ {288}. Heterozygous germline mutations
in HNF1A are responsible for an autoso-
Sinusoidal dilatation and peliosis – to + – to +/- – to +++ – to ++
mal dominant form of diabetes, MODY3
Ductular reaction – – +/– to +++ – (maturity-onset diabetes of the young
type 3). Patients with MODY3 and HCA
Abnormal thick arteries – – + to ++ – to +/– carry an additional somatic mutation of
Inflammatory reaction – to +/– – + to +++ –/+
the second allele. In rare cases, germline
mutations of HNF1A could cause genetic
Cytological abnormalities – + – b
– predisposition to the development of HCA
Remodelling (necrosis, haemorrhage, fi- via a carcinogenic pathway other than the
– to +/– – to +/– – to ++ – to +/– complete inactivation of HNF1α. Germline
brotic bands)
heterozygous mutations in CYP1B1 could
also participate in genetic predisposition
L-FABPc – + + + to the development of HNF1α-inactivated
Glutamine synthetased – + –b –
HCA {1410}.
β-Catenin (aberrant nuclear expression) – + –b –
SAA/CRPe – – + to +++ – HNF1α-inactivated HCAs represent a ho-
mogeneous group of tumours with lobu-
L-FABP, liver fatty acid-binding protein; HNF1α, hepatocyte nuclear factor 1 α; SAA/CRP, Serum amyloid A/C
reactive protein. Grading: +, mild; ++, moderate; +++, severe; –, absent. lated contours, showing typically marked
a
Can also have mutant β-catenin; b Except if β-catenin is mutated; c Normally expressed in nontumoral liver; and diffuse steatosis, and absence of sig-
d
Glutamine synthetase is occasionally expressed at the periphery and around veins of any HCA without β-catenin nificant inflammation or nuclear atypia.
mutation; FABP1, encoding L-FABP (liver fatty-acid
e
Rarely, only one is expressed; occasionally, both can be overexpressed in nontumoral liver as a general inflammatory binding protein), a gene that is positively
reaction (i.e. in response to bleeding). regulated by HNF1A, is expressed in nor-
mal liver tissue and clearly downregulated
in this HCA subtype. Immunohistochemi-
cally, there is nearly complete absence of
L-FABP staining, in contrast to the nontu-
moral surrounding liver, which appears
homogeneously, although faintly stained.
Therefore, lack of L-FABP expression is
an excellent diagnostic argument for
HNF1α-inactivated HCA. Furthermore,
the downregulation of L-FABP may con-
tribute to the fatty phenotype through im-
paired fatty-acid trafficking {2647}. HCA
associated with mutant HNF1A occurs al-
most exclusively in women. Nodules can
be solitary or multiple. Most adenomato-
sis contains mutant HNF1A. Constitutional
Fig. 10.11 Inflammatory hepatocellular adenoma. Note the sinusoidal dilatation, inflammatory infiltrates (asterisks) and mutations can affect both sexes, and can
thick-walled artery (arrow). be discovered in children, sometimes in a
familial form or in association with MODY3
{173}.
β-Catenin-activated HCA
An activating mutation in β-catenin is
found in 10–15% of HCA cases. GLUL,
which encodes glutamine synthetase, a
HCA HCA
target of β-catenin, is also upregulated.
This HCA subtype is often associated with
specific conditions (i.e. glycogenosis, ad-
A B ministration of male hormones) and male
Fig. 10.12 Inflammatory hepatocellular adenoma (HCA). A The limits of the tumour (arrows) are ill-defined on sex. The lesions are usually solitary (ex-
haematoxylin & eosin staining. B Amyloid A is strongly overexpressed by adenomatous hepatocytes, clearly demarcated cept in glycogenosis) and have an in-
from the nontumoral liver (arrows). creased risk of malignant transformation,

compared with the other subtypes.

Steatosis and inflammation are usually
absent. Since nuclear atypia and a
pseudoglandular growth pattern are fre-
quent in this subtype, distinguishing
β-catenin-activated HCA from well-differ-
entiated HCC may be very difficult.
By immunohistochemistry, glutamine syn-
thetase is usually strongly expressed in a
diffuse pattern, associated with aberrant
cytoplasmic and nuclear β-catenin. When
glutamine synthetase staining is hetero-
A geneous and β-catenin staining is non-
conclusive, molecular techniques can
identify the presence of mutations in β-
catenin. Fig. 10.15 Inflammatory hepatocellular adenoma.
Immunostaining for keratin 7 highlights ductular reaction.
Inflammatory HCA
Inflammatory HCA, also known as telang-
iectatic adenoma {2458}, represents more 10% of inflammatory HCAs.
than half of HCA cases. IHCA is charac- Most patients with this subtype are women.
terized by increased expression of in- Obesity and fatty-liver disease are frequent
B flammation-associated proteins such as {260, 2458}. In 50% of cases, serum levels
Fig. 10.13 Inflammatory hepatocellular adenoma. A On amyloid A (SAA) and C-reactive protein of CRP are elevated and erythrocyte sedi-
the fat-suppressed T2-weighted MRI sequence, the (CRP), at both the mRNA and protein lev- mentation rate is increased, in rare cases,
tumour displays a high signal intensity, especially at the els. About 60% of these adenomas have in association with fever and anaemia;
periphery. B The resected specimen shows an ill-defined mutations in gp130 {2644}; β-catenin mu- these features can regress after resection.
tumour with congested areas. tations coexist with gp130 mutations in Nodules can be solitary or multiple.
Genetic predisposition and risk factors Classification Main clinical-pathological characteristicsc
Constitutional L-FABP: negative

mutation of HNF1A
Women
MODY3 HNF1α Marked steatosis
inactivation Adenomatosis
Constitutional
35-40%
mutation
of CYP1B1
GS: positive
β-catenin: positive Men
Cytological abnormalities
β-catenin Pseudogland formation
activation: positive
10–15% High risk of HCC
Oral contraception
Glycogenosis
SAA/CRP: positive
Women and men
Inflammatory HCAa
Obesity
Alcohol
Inflammatory infiltrates
45–60% Thick-walled arteries
gp130 mutationb Sinusoidal dilation
Unclassified
10%
Fig. 10.14 Classification of hepatocellular adenoma (HCA) by genotype and phenotype.

GS, glutamine synthetase; HCC, hepatocellular carcinoma; SAA/CRP, serum amyloid A/C-reactive protein.
a
10% of HCAs also have mutant β-catenin; b Mutations in the gene encoding gp130 are found in 60% of inflammatory HCAs; c These characteristics are frequent, but not exclusive.

A C
Fig. 10.16 Hepatocellular adenoma with mutant β-catenin Fig. 10.17 Hepatocellular adenoma (HCA) with mutant β-catenin (A). B Note the strong and diffuse overexpression
in a young boy treated with androgens for anaplastic of glutamine synthetase, contrasting with normal expression in centrilobular hepatocytes (arrow) of nontumoral liver
anaemia. There are mild cytological and architectural (NTL). C There is aberrant cytoplasmic and nuclear expression of β-catenin in the tumoral hepatocytes.
abnormalities, including rare pseudoglands (arrow).
Histologically, inflammatory HCA typically Unclassified HCA absence of cirrhosis and history of hor-
exhibits focal or diffuse inflammation, si- HCAs without distinguishing histological mone exposure is often helpful, but can-
nusoidal dilatation, congestion and peli- features and without known mutations not be definitive. Biopsy fulfils two goals:
otic areas, numerous thick-walled arteries represent < 10% of all cases. to make the differential diagnosis be-
often in association with ductular reaction, tween HCA, FNH, and well-differentiated
lying in small amounts of connective tis- Prognosis and predictive factors HCC, and to classify HCA subtypes.
sue. There may be focal steatosis. Radiological diagnosis can be difficult Recognition of β-catenin-activated HCA is
Immunohistochemistry reveals strong ex- owing to the variable and nonspecific fea- important for patient management {260}.
pression of SAA and CRP in tumour he- tures of HCA. However, the two major Patients with large (> 5 cm) nodules, ei-
patocytes. Micronodules can also be HCA subtypes (i.e. HNF1α-inactivated ther HCA or unclassified, should be
detected by immunostaining for SAA and and inflammatory) can now be identified treated (surgery, radiofrequency, em-
CRP in the liver parenchyma, outside the using magnetic resonance imaging (MRI), bolization); but tissue should be taken for
main tumours {261}. There is a risk of ma- which has greatly helped the diagnosis of confirmation of diagnosis {260, 730}.
lignant transformation, particularly for HCA {324, 1757, 1824}.
cases in which β-catenin is also mutant. Clinical or biological context, including

N.D. Theise Y.N. Park

Hepatocellular carcinoma M.P. Curado M. Sakamoto
S. Franceschi M. Torbenson
P. Hytiroglou A. Wee
M. Kudo
Definition logically specified tumours are exceptional,

A malignant tumour with hepatocellular e.g. Lampang, Thailand, where intrahep-
differentiation. atic cholangiocarcinoma is predominant
owing to infection by endemic liver fluke
ICD-O codes (Opisthorchis viverrini) {2487}.
Hepatocellular carcinoma 8170/3
Fibrolamellar variant 8171/3 Geographical distribution
Undifferentiated carcinoma 8020/3 Rates of HCC are highest in East Asia
(China, Japan), but are also moderately
Epidemiology high in Italy. With annual age-standard-
Primary liver cancer is the second most ized incidence rates (ASIR, standardized
common cancer in Asia and the fourth to world population) of < 7 per 100 000,
most common in Africa. In 2002, the low-risk areas include North and South Fig. 10.19 Age-specific incidence of liver cancer in men in
global number of new cases in males was America, South–Central Asia, Northern selected countries {842A}.
estimated at 442 119; there were 416 882 Europe, Australia and New Zealand. With
deaths, 94% of which occurred in the first > 80% of reported global cases, less de- population) reflect the sero-prevalence of
year after diagnosis. For females, there veloped countries carry the greatest bur- antibodies to HCV among blood donors
were an estimated 184 043 new cases den of disease. {122, 2488, 3183, 3314}.
globally, most of which occurred in east- Geographical variations in HCC incidence
ern regions of Asia {634, 842}. and mortality are ascribed to different levels Time trends
Hepatocellular carcinoma (HCC) is the of exposure to HCC-associated risk fac- The overall incidence of HCC remains
most common histological type of primary tors: chronic infection with hepatitis B virus high in developing countries and is
liver cancer. Population-based cancer (HBV) or hepatitis C virus (HCV) and expo- steadily rising in most industrialized coun-
registries show that the incidence of HCC, sure to aflatoxin in developing countries, tries {2903}. In Asia, incidence rates are
as a percentage of histologically speci- smoking and alcohol abuse in developed highest in China, but a slight decrease
fied tumours, is higher in North America countries {2389, 2509, 2605}. In Japan, has been reported for the period 1998–
and Europe than in Asia. Regions where local differences in the age-standardized 2002 {3701}. A decrease in incidence
the incidence of HCC is < 30% of histo- mortality rate (ASMR, standardized to world rates has also been observed in other re-
gions of Asia {2489}.
In the United States of America (USA),
there has been an increase of about 80%
in the annual incidence of HCC, and this
has been more marked in African Ameri-
cans. Similar increases have been re-
ported in the United Kingdom (UK),
Canada and Australia. These changes
may, at least in part, be ascribed to in-
creases in chronic infection with HCV.
Age and sex distribution

Age-specific incidence rates differ signif-
icantly between countries. In males aged
25–49 years, liver cancer is the second
most common tumour in Asia and the
third most common in Africa, while in
males aged 50–69 years, liver cancer
ranks as the second most common tu-
mour in Africa and the third in Asia. In fe-
males, liver cancer is the fifth most
common in Africa in those aged 50–69
Fig. 10.18 Worldwide annual age-standardized incidence (per 100 000) of liver cancer in men. Numbers on the map years and the third most common cancer at
indicate regional average values {842A}. age 70 years. The geographical distribution
Hepatocellular carcinoma 205

of HCC, accounting for approximately

85% of cases {2483, 2641}. Alcohol-in-
duced liver injury constitutes the most im-
portant nonviral risk factor {887}.
Tobacco-smoking has also been recently
recognized as a risk factor for HCC
{1333}. In southern China and sub-Saha-
ran Africa, high dietary ingestion of afla-
toxin is an environmental hazard,
A B particularly in individuals infected with
HBV {1331}. Iron overload, particularly in
the context of hereditary haemochro-
matosis, is also an exogenous risk factor
{1528}. α-1-Antitrypsin deficiency greatly
increases the risk of developing HCC. It
has become apparent that obesity, with its
accompanying problems of diabetes mel-
litus and nonalcoholic steato-hepatitis,
can increase the risk of HCC, even with-
out viral infection {781, 2570}. The risk of
C D acquiring HCC increases if multiple risk
Fig. 10.20 Hepatocellular carcinoma. A Nodular type. B Massive type. C Diffuse type. D With multiple (“satellite”) factors are present {887, 3131}.
nodules of intrahepatic metastases.
Liver cirrhosis
The major clinical risk factor for HCC is
of HCC is similar for males and females, A similar pattern is found for females in liver cirrhosis, largely independently of its
although males have a considerably the same regions; however, the highest etiology, though cirrhosis itself is now not
higher risk of developing HCC. Data for rates are about 14 per 100 000 {634, 842}. considered premalignant, but rather a
2002 show that ASIR reaches 50–25 per parallel process to malignant transforma-
100 000 males in East Asia (China, Etiology tion in the setting of chronic liver disease
Japan), while rates in Europe reach about Chronic viral infection (HBV or HCV or {3229}.
25 per 100 000 in some regions of Italy. coinfection) is the most important cause
HBV
HBV is a DNA virus belonging to the he-
padnavirus group. The virus consists of
an outer envelope, composed mainly of
hepatitis B surface antigen (HBsAg), and
N1 an internal core (nucleocapsid), which
contains hepatitis B core antigen
(HBcAg), a DNA polymerase/reverse
transcriptase, and the viral genome. The
N2 genome comprises a well-characterized,
N3 partly double-stranded, circular DNA mol-
ecule of about 3200 base pairs. Se-
quencing of HBV genomes and the S
gene has revealed eight genotypes (A–H)
and several subgenotypes {2320}; the
N1 distribution of the different types and sub-
types differs according to geographical
location and the predominant transmis-
sion modality and can affect response to
antiviral treatment with lamivudine.
N5
N4 The World Health Organization (WHO) es-
N2 timates that about 350 million people are
chronically infected with HBV worldwide.
HBV is the predominant cause of HCC in
most Asian, African, and Latin American
countries {2641}. Epidemiological studies
Fig. 10.21 Multicentric development of five nodules of hepatocellular carcinoma (N1 to N5), including two early show a convincing link between chronic
hepatocellular carcinomas (N4 and N5). HBV infection and HCC development.

The incidence of HCC in individuals who padnavirus infection; and (4) the declin- clear whether chronic HDV infection in-
are chronically infected with HBV is ap- ing incidence of HCC after mass HBV creases the risk of developing HCC over
proximately 100 times higher than in the vaccination {484}. that for HBV infection alone {825}.
uninfected population, and the lifetime
risk of HCC in males infected at birth ap- HCV Alcohol
proaches 50%. Several lines of evidence HCV has a single-stranded RNA genome In the USA and northern Europe, alcohol-
support a direct oncogenic role for HBV that codes for a single polyprotein con- induced liver injury is a leading cause of
in the development of HCC: (1) the inte- sisting of 3010–3033 amino acids. Post- chronic liver disease and liver cirrhosis
gration of HBV DNA into the chromosomal translational processing yields the {2641}. Heavy alcohol consumption in
DNA of HCCs; (2) the role of the HBV X structural protein C (RNA-binding nucle- men {3681} and even moderate con-
gene in the pathogenesis of HBV-associ- ocapsid protein), E1 and E2 envelope sumption (two or more drinks per day) in
ated HCCs, in particular, binding to and proteins, and nonstructural proteins NS1– women {93} are associated with a two-
inactivation of p53; (3) the development NS5, including RNA-dependent RNA fold increased risk of acquiring HCC. Pa-
of HCC in animal models of chronic he- polymerase {3241}. HCV isolated from tients who drink heavily and have
various geographical regions shows coexisting liver disease from other causes
marked genetic heterogeneity, with at have the highest risk of developing HCC
least six different genotypes in distinct {887}.
patterns of geographical distribution. The
HCV genome readily mutates, with the Tobacco
genes for the envelope proteins E1 and An association between tobacco-smoking
E2 appearing to be particularly variable. and HCC has been established recently
Rapid replication and lack of proofread- {1333}. Independently of alcohol use or
ing function – characteristics that are typ- viral infection, the risk of acquiring HCC
ical of RNA viruses – explain the has been shown to increase with duration
enormous genetic variability of HCV and of smoking and number of cigarettes
the difficulties encountered in eradicating smoked per day.
Fig. 10.22 Well-differentiated hepatocellular carcinoma: HCV infection, even with multidrug therapy.
the cohesive clusters of malignant hepatocytes appear There is no prophylactic vaccine against Aflatoxin B1 (AFB1)
as slender arborizing cords (Papanicolaou). HCV. WHO estimates that about 180 mil- AFB1 is a potent liver carcinogen {2485}
lion people are infected with HCV world- produced by the moulds Aspergillus par-
wide, but there is evidence that the asiticus and A. flavus. Under hot and
prevalence of HCV is greatly underesti- humid tropical conditions, these moulds
mated and is still increasing in some less can contaminate grain, particularly
developed countries {2641}. ground nuts (peanuts). Dietary ingestion
HCV is more commonly found than HBV
in patients with HCCs in Europe, Japan
and the USA, but also in a few less de-
veloped countries (e.g. Egypt, Mongolia
and Pakistan) {2641} where HCV is
spread through unscreened blood and
Fig. 10.23 Moderately differentiated hepatocellular non-sterile injections {2586}.
carcinoma: the cohesive clusters of malignant hepatocytes HCV-associated HCCs typically develop
with broad cords (more than five cells thick) are wrapped 20–30 years after infection and are usu-
by endothelium. Note the granular cytoplasm, increased ally, but not always, preceded by cirrho-
nucleus:cytoplasm ratio, centrally placed round nuclei sis. Thus far, there is no evidence to
with well-delineated nuclear membrane, granular chromatin
suggest a direct, molecular role for HCV
and distinct nucleolus (Papanicolaou).
in the pathogenesis of HCC. Rather, HCC
develops via HCV-induced chronic liver
injury in parallel with progression to fibro-
sis and cirrhosis. The average time from
infection to onset of cirrhosis in published
studies was 13–25 years and time to
onset of liver cancer 17–31 years {1841}.
The risk of liver cancer among individuals
with HCV-related cirrhosis ranged be-
tween 1% and 7% per year.
Hepatitis D virus (HDV) Fig. 10.25 Hepatocellular carcinoma with fatty change,
Fig. 10.24 Hepatocellular carcinoma with trabecular HDV (“delta”) is an RNA-defective virus bile and giant cells. Dissociated malignant hepatocytes
arrangement and clear cell change (Papanicolaou). requiring HBV for infection {2695}. It is un- show pleomorphism and multinucleation (Papanicolaou).

of high levels of aflatoxins, particularly in els may also be found in liver disease Macroscopy
the context of coexisting chronic HBV in- without HCC. AFP levels, therefore, have Most HCCs are nodular lesions. The
fection {2133, 3131}, increases the risk of to be interpreted individually in the con- macroscopic features vary according to
HCC by more than 50-fold. AFB1 is me- text of other clinical symptoms and signs, tumour size and the presence or absence
tabolized by cytochrome P450 enzymes as well as imaging studies. of liver cirrhosis. In the presence of cir-
to its reactive form, AFB1-5,9-oxide. Bind- There are also uncommon paraneoplas- rhosis, HCC often has a fibrous pseudo-
ing to DNA at the N7 position of guanine tic syndromes, such as erythrocytosis, hy- capsule, while in livers without cirrhosis
preferentially causes a G:C > T:A muta- poglycaemia or hypercalcaemia. HCC tends to be unencapsulated. HCCs
tion in codon 249 of the TP53 tumour-sup- are typically softer than the background
pressor gene, resulting in the substitution Imaging liver and may be unifocal or multifocal.
of arginine for serine {333}, which is most Imaging studies are important in patient Multifocality is defined as tumour nodules
often found in areas of the world with the management for the identification and lo- clearly separated by intervening non-neo-
highest levels of food contamination with calization of HCC. Useful techniques in- plastic liver. Multifocal tumours may rep-
AFB1 {2133}. Use of low-technology ap- clude ultrasonography (US), colour Doppler resent either independent HCCs arising
proaches at the subsistence-farm level in US, contrast-enhanced US, computed to- simultaneously (i.e. multicentric HCC), or
sub-Saharan Africa reduces exposure to mography (CT), lipiodol CT, magnetic reso- intrahepatic metastases from a primary
aflatoxins {3323}. nance imaging (MRI), angiography, CT tumour. Unifocal tumours may grow as
during hepatic arteriography (CTHA), and single nodules or as clusters of closely
Clinical features CT during arterial portography (CTAP). approximated and contiguous individual
Symptoms and signs The standard imaging techniques are US, nodules.
The presenting signs and symptoms in CT and MRI. In most cases, these allow The term “massive type” has been used
patients with HCC may be caused by the detection and staging of HCC. Typical for HCC growing as a large dominant
tumour itself or by an advanced stage of findings associated with HCCs that have mass, with or without smaller satellite
chronic liver disease predisposing to ma- progressed are arterial hypervascularity nodules. Another subtype, peduncu-
lignancy. Thus, symptoms include ab- with venous wash-out on dynamic CT, dy- lated HCC, is defined as a tumour mass
dominal pain, general malaise, anorexia namic MRI or contrast-enhanced US protruding outside of the liver, with or
or weight loss, and nausea or vomiting. {352, 1672}. without a pedicle. Pedunculated HCC
Common clinical signs include he- However, early HCC (vaguely-nodular was initially reported to have a good
patomegaly, ascites, fever, jaundice, and type HCC) presents a different dynamic prognosis, although this has not been
splenomegaly. imaging pattern: isovascular, hypovascu- confirmed in all studies. HCC metasta-
The laboratory findings are partly deter- lar, or rarely hypervascular arterial supply tic to the right adrenal gland can mimic
mined by the underlying liver disease and on dynamic CT, dynamic MRI, or CTHA and should be distinguished from pe-
may be reflected in changes in the results associated with preserved portal supply dunculated HCC. Diffuse or cirrhoto-
of blood tests for liver enzymes, which are on CTAP. A problematic issue in the diag- mimetic HCC is a rare HCC growth
not, however, HCC-specific. A signifi- nosis of early HCC via imaging is that pattern in which numerous small tumour
cantly raised serum level of α-fetoprotein these findings are frequently shared by nodules are distributed throughout the
(AFP) of > 400 ng/ml, or a continuous rise dysplastic nodules (DN) {125, 1672}. Of liver in a diffuse pattern that closely
even if < 100 ng/ml, strongly suggests the existing imaging modalities, gadolin- mimics the regenerative nodules of liver
HCC. However, most HCCs are not asso- ium-ethoxybenzyl DTPA (Gd-EOB-DTPA) cirrhosis. The macroscopic appearance
ciated with elevated AFP levels, particu- MRI seems to be the most sensitive im- of HCC can be further modified by
larly as HCC lesions are detected at aging tool for the differentiation of early varying degrees of necrosis and tumour
earlier stages, and mildly raised AFP lev- HCC from DN {1671A}. involvement of portal and hepatic veins.
A B
Fig. 10.26 Histological features of hepatocellular carcinomas. A Trabecular pattern. B Pseudoglandular or acinar pattern.

In addition, the production of bile or fat sue; however, at the tumour periphery, en- The gland-like structures are referred to
and the accumulation of cytoplasmic ma- trapped portal tracts may be seen among as “pseudoglands” or “pseudoacini” be-
terial such as glycogen can affect the invasive neoplastic cells. cause they are not true glands but actu-
macroscopic findings. HCCs vary architecturally and cytologi- ally modified, abnormal bile canaliculi
cally. The different architectural patterns formed between tumour cells. The struc-
Tumour spread and cytological variants frequently occur ture is formed mostly by a single layer of
HCC may spread by lymphatic and in combination. Immunohistochemically, tumour cells. Pseudoglands frequently
haematogenous routes. Intrahepatic HCC is characterized by cytoplasmic contain proteinaceous fluids, which often
spread via the portal veins is common positivity with antibodies to carbamoyl stain with periodic acid–Schiff (PAS), but
and its frequency increases with tumour phosphate synthetase-1 (HepPar1). It has not with mucicarmine or Alcian blue. Bile
size. Tumour invasion into the major bile been reported that about 90% of all HCCs may be present. Cystic dilatation of the
ducts is infrequent clinically, but found in are positive for HepPar1; positivity is less pseudoglands sometimes occurs and
about 5% of autopsy cases. In clinical fol- frequent in poorly differentiated or scir- may occasionally be formed by the de-
low-up studies, the lungs are the most rhous HCCs {552}. Canalicular patterns generation of thick trabeculae. Generally,
common target for extrahepatic metasta- may be seen with immunohistochemical the pseudoglandular structures are
sis (47% of metastatic HCCs), followed staining with polyclonal antibodies to car- smaller in well-differentiated tumours
closely by the lymph nodes (45%), bone cinoembryonic antigen(CEA) or antibod- than in moderately differentiated tu-
(37%), and the adrenal glands (12%) ies to CD10 or ABCB1/MDR1. HCC is also mours.
{3338}. often positive for AFP, fibrinogen, and ker- Compact pattern. Sinusoid-like blood
atins 8 and18, but usually negative for spaces are inconspicuous and slit-like,
Histopathology keratins 19 and 20 and epithelial mem- giving the tumour a solid appearance.
Classical HCC brane antigen. The compact pattern is common in poorly
HCCs consist of tumour cells that usually differentiated tumours.
resemble hepatocytes. The stroma is Architectural patterns
composed of sinusoid-like blood spaces Trabecular (plate-like) pattern. This pat- Cytological variants
lined by a single layer of endothelial cells. tern is the most common in well- and Pleomorphic cells. Tumour cells show
Unlike the sinusoidal endothelial cells in moderately differentiated HCCs. Tumour marked variation in cellular and nuclear
normal liver tissue, those of HCC show cells grow in cords of variable thickness size, shape, and staining. Bizarre multin-
changes of “capillarization”, i.e. they re- that are separated by sinusoid-like blood ucleated or mononuclear giant cells are
semble normal capillaries, including spaces. Well-differentiated tumours have often present, and osteoclast-like giant
immunohistochemically demonstrable a thin trabecular pattern and trabeculae cells are rarely seen. Generally, pleomor-
CD34, factor-VIII-related antigen and become thicker with de-differentiation. Si- phic tumour cells lack cohesiveness, do
subendothelial laminin and type IV colla- nusoid-like blood spaces sometimes not show a distinct trabecular pattern and
gen. Ultrastructural observation confirms show varying degrees of dilatation, or are common in poorly differentiated tu-
a basement-membrane-like structure be- may be difficult to recognize owing to mours.
tween the endothelial cells and tumour- compression by tumour cells. Reticulin Clear cells. Tumour cells have clear cyto-
cell trabeculae {797, 1565, 1569}. The staining or CD34 immunostaining is help- plasm owing to the presence of abundant
blood supply of HCCs is derived from ful in the recognition of a trabecular pat- glycogen. If the tumour consists predom-
newly formed arteries, which are termed tern. inantly of this type, it is sometimes difficult
“unpaired” or “nontriadal” arteries be- Pseudoglandular or acinar pattern. HCC to distinguish from metastatic renal cell
cause they are not part of portal tracts. frequently has a gland-like pattern, usu- carcinoma of clear-cell type. Clinical
Portal tracts are not present in HCC tis- ally admixed with the trabecular pattern. information and immunohistochemical
A B
Fig. 10.27 Histological features of hepatocellular carcinomas. A Thick trabecular growth with clear cells. B Fatty change.

round, homogeneous, strongly aci-

dophilic, PAS-positive and stains orange
to red with Masson trichrome stain. Im-
munohistochemically, they are often pos-
itive for α-1-antitrypsin.
Pale bodies. These are intracytoplasmic,
round to ovoid, amorphous, and lightly
eosinophilic. They consist of amorphous
material accumulated in cystically dilated
endoplasmic reticulum, and often contain
immunostainable fibrinogen {3100}. They
are commonly seen in the fibrolamellar
variant of HCC but are also found in the
common types of HCC and in scirrhous
HCC.
A B
Ground glass inclusions. Like those of
Fig. 10.28 Histological features of hepatocellular carcinomas. A Multinucleated giant cell. B Trabecular and pseudoglandular HBsAg-positive hepatocytes, these are
pattern with bile plugs.
rarely also observed in neoplastic cells of
HCC arising in HBsAg-positive patients.
They stain with modified orcein, Victoria
blue, aldehyde fuchsin, and with im-
munohistochemistry.
Special types of carcinoma

Fibrolamellar carcinoma. Fibrolamellar
carcinomas (FLC) are distinctive liver
cancers of children and young adults that
differ from classical HCC at the clinical,
histological, and molecular levels {3270}.
FLC account for 0.5–9.0% of primary liver
cancers in various case series, with re-
ported frequency being influenced by
country and study design. Overall, FLC
appears to be less common in Asia and in
A B
Africa than in North America and Euro-
Fig. 10.29 Special types of hepatocellular carcinomas. A Sarcomatoid hepatocellular carcinoma. B Scirrhous pean countries. FLC arises in non-cir-
hepatocellular carcinoma.
rhotic livers; etiology and risk factors are
not known. There is no strong gender
stains can be helpful in this regard. infrequent in advanced tumours. Meta- predilection. The age at presentation
Spindle cells. Spindle cells are observed bolic disorders related to hepatocarcino- shows a unimodal distribu tion peaking at
in sarcomatoid HCC, which is discussed genesis and insufficient blood supply in age 25 years and 85% of all FLC occur in
in the section on special types. the early neoplastic stages have been individuals aged 35 years or younger.
Fatty change. Diffuse fatty change is most suggested as possible mechanisms un- Two-thirds of cases involve the left lobe of
frequent in small, early-stage tumours derlying fatty change in small tumours. the liver. Grossly, FLC tend to be yellow to
(< 2 cm in diameter). Its frequency de- Bile production. Bile is occasionally ob- pale tan and are firm to hard. A central
clines as tumour size increases and it is served, usually as plugs in dilated canali- scar may be found in about 75% of cases,
culi or pseudoglands. When bile but FLC do not appear to be etiologically
production is prominent, the tumour is yel- related to focal nodular hyperplasia.
lowish in colour and turns green after for- Histologically, FLC typically grow with
malin fixation. broad pushing borders and benign portal
Hyaline bodies. Mallory-Denk bodies tracts can occasionally be found en-
(reticular hyaline bodies) are intracyto- trapped within the growing tumour front.
plasmic, irregular in shape, eosinophilic FLC are made up of large polygonal cells
and PAS-negative. Some take a globular with abundant eosinophilic (oncocytic)
shape and are called globular hyaline cytoplasm, large vesicular nuclei, and
bodies. They consist of aggregated inter- large nucleoli. These distinctive cytologi-
mediate filaments and show immunohis- cal findings in conjunction with the lamel-
tochemical positivity with antibodies to lar fibrosis are the defining features of
Fig. 10.30 Poorly differentiated hepatocellular carcinoma ubiquitin and keratins. However, another FLC. The eosinophilic cytoplasm is rich in
with no evidence of trabecular arrangement. type of globular hyaline body is small, mitochondria. In a subset of FLC, areas of

gland-like formation are present, with tu-

mour cells lining circular or ovoid
spaces, some of which may contain mu-
cicarmine and/or alcian blue-positive
secretions. Such cases can be misclas-
sified as combined hepatocellular-
cholangiocarcinoma in the absence of
careful attention to the complete histo-
logical findings. Other findings include
calcifications, either in stroma or as lu- A B
minal calcification of pseudogland se- Fig. 10.32 Fibrolamellar carcinoma (FLC). A Intratumoral fibrosis often runs in parallel bands separating nests of
cretions. “Pale bodies” and/or “hyaline oncocytic hepatocytes. B The diagnosis depends on the diffuse presence of oncocytic hepatocytes, as well as fibrous
bodies” may be found, as in classical bands. The vesicular nuclei and large nucleoli are important diagnostic features. Pale bodies are also present in this field.
HCC. The prognosis for FLC is better
than for typical HCC that arises in cir-
rhotic livers, but similar to typical HCC Undifferentiated carcinoma. Undifferenti- apy or transarterial chemoembolization
that arises in non-cirrhotic livers. ated carcinomas are tumours that are pri- {1634}.
Scirrhous HCC. About 5% of HCCs show mary to the liver and can be diagnosed
a scirrhous growth pattern characterized as carcinomas based on immunohisto- Grading
by marked fibrosis along the sinusoid-like chemistry, but cannot be further classi- Histological grading of HCC is based on
blood spaces with varying degrees of at- fied. Undifferentiated carcinoma is rare, tumour differentiation: well-differentiated,
rophy of tumour trabeculae {1688}. Most accounting for < 2% of epithelial liver tu- moderately differentiated, poorly differen-
of these tumours arise immediately below mours. There is a male preponderance, tiated, and undifferentiated types are rec-
the liver capsule. In cases of multifocal but data on geographical distribution are ognized.
carcinoma, some tumour foci may show a not available. Localization, clinical fea-
scirrhous growth pattern while others tures, symptoms and signs, and diagnos- Well-differentiated HCC
show a classical HCC pattern. A better tic procedures display no differences Well-differentiated HCC is most common
prognosis has been reported in some, but compared with hepatocellular carcinoma. in small, early-stage tumours of < 2 cm,
not all studies. The scirrhous type of HCC Undifferentiated carcinomas are postu- and is rare in advanced tumours. The
should not be confused with cholangio- lated to have a worse prognosis (com- lesions are composed of cells with
carcinoma or FLC. In addition, similar fi- pared with HCC), although greater case mild atypia and increased nucleus-to-
brotic changes can occur following numbers to support this are not available cytoplasm ratio in a thin trabecular
chemotherapy, radiation, and transarter- {614, 1349}. pattern, often with pseudoglandular struc-
ial chemoembolization. Such post-thera- Lymphoepithelioma-like carcinoma. Lym- tures. Fatty change is frequent. In most
peutic fibrosis should be distinguished phoepithelioma-like carcinoma is a rare tumours of > 3 cm in diameter, well- dif-
from the scirrhous variant. The term “scle- type of HCC with pleomorphic tumour ferentiated carcinoma is observed only in
rosing hepatic carcinoma”, has been cells intermixed with numerous lympho- the periphery, if at all.
used to designate a variety of tumours cytes {2265}. The tumour cells tend to
arising in non-cirrhotic livers that can be be small with focal syncytial growth. In Moderately differentiated HCC
associated with hypercalcaemia, but some but not all cases, the tumour cells Moderately differentiated HCC is most
does not constitute a distinct histopatho- are positive for Epstein-Barr virus (EBV). common in tumours of > 3 cm in diame-
logical entity {1349}; some of these Because of the rarity of this tumour type, ter and is characterized by trabecular
tumours appear to be hepatocellular, information regarding histological find- growth of three or more cells in thickness.
but others are intrahepatic (peripheral) ings, clinical features and prognosis is Tumour cells have abundant eosinophilic
cholangiocarcinomas. limited. cytoplasm and round nuclei with distinct
Sarcomatoid hepatocellular carcinoma.
Occasionally, HCC is partially or fully
comprised of malignant spindle cells, and
may be difficult to distinguish from various
sarcomas. When such sarcomatoid fea-
tures are prominent, the tumour is called
sarcomatoid HCC. Most sarcomatoid
HCCs have areas of more typical HCC
identified by sufficient sampling; however,
immunohistochemical stains and clinico-
pathological correlation are also of value
in correctly classifying such tumours, es-
Fig. 10.31 Hepatocellular carcinoma: immunostaining with pecially when the histological material is
polyclonal antibodies to carcinoembryonic antigen (CEA) limited. Sarcomatoid change is more fre- Fig. 10.33 Lymphoepithelioma-like carcinoma of the liver.
shows a characteristic canalicular pattern. quent in HCC with repeated chemother-

Fig. 10.34 Small cell change in hepatocytes. Fig. 10.35 Large cell change in hepatocytes.
nucleoli. A pseudoglandular pattern is arteries and capillarization of sinusoids, in been associated with carcinogenesis in
also frequent, and pseudoglands often parallel with increased arterial supply on chronic liver disease include small cell
contain bile or proteinaceous fluid. radiological imaging. change, large cell change, and iron-free
foci.
Poorly differentiated HCC Precursor and early lesions Small cell change, originally described as
Poorly differentiated HCC, which is ex- Precancerous lesions of HCC include: (1) small cell dysplasia {3466}, is defined as
tremely rare in small, early-stage tumours, cytological changes indicative of hepato- hepatocytes showing decreased cell vol-
grows in a solid pattern without distinct si- cellular dysplasia, often occurring as ex- ume, increased nucleus : cytoplasm ratio,
nusoid-like blood spaces; only slit-like pansile foci (seen on microscopic, but not mild nuclear pleomorphism and hyper-
blood vessels are observed in large tu- on gross examination), termed “dysplas- chromasia, and cytoplasmic basophilia,
mour nests. The neoplastic cells show an tic foci”; and (2) nodular lesions de- giving the impression of nuclear crowd-
increased nucleus : cytoplasm ratio and tectable on gross and, often, on ing. Small cell change is characterized by
frequently moderate to marked pleomor- radiological examination, characterized higher proliferative activity than surround-
phism. by cytological or structural atypia and ing hepatocytes, chromosomal gains and
termed “dysplastic nodules” (DN). Re- losses, telomere shortening with p21-
Undifferentiated HCC cently, international consensus has been check-point inactivation, a morphological
Undifferentiated tumour cells contain little reached regarding the histological fea- resemblance to early HCC, and a histo-
cytoplasm, are spindle or round-shaped, tures of early HCC, which is a low-grade, logical continuum to HCC {24, 1298,
and exhibit solid growth. early-stage tumour. 1977, 2565, 3466}. These data support
Edmondson and Steiner classified HCCs the precancerous nature of small cell
on a scale ranging from grade 1 to grade Hepatocellular changes and dysplastic foci change.
4, on the basis of nuclear and cellular Hepatocellular changes that have mostly Large cell change, originally termed “liver
atypia. However, approaches using nu-
clear/cytological grading and/or prolifer-
ative index are not widely used in routine
diagnostic practice for HCC.
It should be kept in mind that HCC often
varies histologically even within a single
nodule. In terms of histological grade,
most primary cancer nodules of < 1 cm in
diameter are uniformly well-differentiated,
while approximately 40% of nodules of
1.0–3.0 cm in diameter consist of different
types of neoplastic tissue with different
histological grades {1520}. Less differen-
tiated tissues are always located inside,
surrounded by well-differentiated tumour
on the outside; these less differentiated
areas come to predominate as tumours
enlarge to 3 cm {2153, 2381}. Stromal Fig. 10.36 Dysplastic nodule in a cirrhotic liver. Fig. 10.37 High-grade dysplastic nodule with cytological
changes during tumour progression in- and structural atypia, including high cell density, two-to-three-
clude increasing frequency of unpaired cell thick plates, small cell change and focal fatty change.

A B C
Fig. 10.38 Early hepatocellular carcinoma (HCC). A An early HCC with fatty change arising in a cirrhotic liver affected with chronic hepatitis B. Note the indistinctly nodular outline of
the lesion. B Low-power view of an early HCC. C At high power, the cell plates at the border of early HCCs can be seen to be composed both of hepatocytes and neoplastic cells.
cell dysplasia” {128}, is defined as hepa- foci arising in livers with hereditary liver disease without developed cirrhosis
tocytes with both nuclear and cellular en- haemochromatosis are precancerous, i.e. {125, 1298, 1335, 1633}. They may be
largement (therefore, a preserved dysplastic foci {705}. Other cytological single or multiple, and may have distinct
nucleus : cytoplasm ratio), nuclear pleo- changes that may be seen in dysplastic or indistinct margins on gross examina-
morphism, frequent nuclear hyperchro- foci of humans almost certainly exist, but tion. Their size varies from few millimetres
masia, and multinucleation. The data for are still under investigation; as discussed to few centimetres, but most are < 15 mm
the nature of such change have been above, a subset of large cell change may in diameter. On the cut surface of the liver,
conflicting and suggest that large cell represent such lesions. The efforts to DNs differ from the surrounding cirrhotic
change may be a heterogeneous entity study the biological nature of dysplastic nodules because of their size, colour, tex-
{311, 1299, 1787, 1977, 2479, 2565, foci have been limited by the inability to ture, or degree of bulging. Nevertheless,
3220}. This change has been linked to follow these lesions over time. However, identification of these lesions relies on his-
cellular senescence {1787} and cholesta- from a practical point of view, identifica- tological examination. According to inter-
sis {2255}; however, large cell change in tion of small or large cell change, or iron- national consensus {1335}, DNs are
chronic hepatitis B appears to be a tu- free foci in liver biopsy specimens classified as low-grade (LGDN) or high-
mour-related lesion {1549}. Actually, the signifies an increased risk of HCC. grade (HGDN), depending on degree of
presence of large cell change in cirrhosis atypia.
associated with chronic hepatitis B or C Dysplastic nodules (DN) On microscopic examination, DNs often
has been reported to be an important in- DNs are usually detected in cirrhotic livers, appear hypercellular when compared
dependent risk factor for subsequent de- but are occasionally found with chronic with the adjacent hepatic parenchyma;
velopment of HCC {310, 941}. Thus, there
is consensus that large cell change is at
Low-grade High-grade
least an indication of chronic injury that Feature Well-differentiated Moderately
dysplastic nodule dysplastic nodule
predisposes to hepatocarcinogenesis; HCC differentiated HCC
(LGDN) (HGDN)
whether there are subtypes of large cell Anatomical change
change that are directly premalignant re-
mains uncertain.
The term “dysplastic focus” was intro-
duced by an international consensus arti-
cle published in 1995 {1335}, and has
been subsequently used to describe Pathological features:
groups of hepatocytes with features sug- Gross appearance Vaguely nodular Distinctly nodular
gestive of precancerous change, which Stromal invasion (–) (–) +/– +/–
are incidentally discovered on histological
examination. According to the original Imaging:
definition, dysplastic foci measure < 1 mm Iso- / hypo- / rarely
Arterial supplya Iso- / hypovascular Iso- / hypovascular Hypervascular
in diameter; this arbitrary size criterion is hypervascular
related to the fact that these microscopic Portal-vein supply + + + –
lesions are usually contained within a
Clinico-pathological Premalignant Early HCC Progressed HCC
single hepatic lobule or cirrhotic nodule.
Dysplastic foci are mostly identified
Intratumoral portal tract Unpaired artery Fibrous pseudocapsule
in livers with cirrhosis, and are often
multiple.
Fig. 10.39 International consensus on the classification of small nodular lesions in cirrhotic liver: clinical and pathological
Histologically, most recognizable dys- correlations. The diagnosis must also consider the context of the lesion, especially the presence of cirrhosis, imaging findings,
plastic foci consist of expansile groups of and growth rate.
hepatocytes with small cell change HCC, hepatocellular carcinoma. a Hypovascularity, hypervascularity, and isovascularity refer to density or signal intensity
{1298}. At least a subset of iron-free in the arterial phase of contrast-enhanced imaging relative to the nontumoral liver {125}.

A B
Fig. 10.40 Early hepatocellular carcinoma. A Immunostaining for glypican-3 (GPC3) reveals pericanalicular and Fig. 10.41 Early hepatocellular carcinoma. Absence of
cytoplasmic patterns of expression. B Immunostaining for heat-shock protein-70 (HSP70) is positive in tumour cells, ductular reaction in an area of stromal invasion
including nuclei, and in biliary epithelium, but negative in non-lesional hepatocytes. (immunostaining for keratin 19).
such increase in cell density can be oped immunohistochemical markers may acteristic features, often seen in combi-
marked in HGDN {125}. Both LGDN and be of assistance in this regard. nation, include: (1) increased cell density,
HGDN may exhibit features suggesting At the other end of the spectrum, there is more than twice that of the surrounding
the presence of a clonal cell population, currently consensus that distinction be- liver, with increased nucleus : cytoplasm
such as iron or copper accumulation, or tween LGDN and large regenerative nod- ratio; (2) irregular thin trabecular pattern
steatosis in a liver without significant fatty ules of cirrhotic livers cannot be made of growth; (3) pseudoglandular structures;
change. DNs may derive their blood sup- confidently by morphology alone, remain- (4) fatty change; (5) unpaired arteries;
ply both from portal vessels and from ing a task for future resolution {125}. How- and (6) intratumoral portal tracts {125,
newly formed arteries (termed “unpaired” ever, presence of unpaired arteries or 1633}. Any of these features may be pres-
or “nontriadal” arteries) {2480, 2721, evidence of a clone-like cell population in ent diffusely in the tumour, or may be seen
3332}. Portal tracts are commonly seen, a large nodule indicate that the nodule is in an expansile subnodule. Because the
but may be few and scarred. Unpaired ar- dysplastic rather than regenerative. The histological features listed above may be
teries of DN are least prominent in LGDN, practical implication of this diagnosis is observed both in early HCC and in
both in number and in size, and increase that the patient is at increased risk of de- HGDN, distinction between the two types
through HGDN and early HCC develop- veloping HCC. Useful histological fea- of lesion may sometimes be impossible,
mental stages. Therefore, in the arterial tures for the differential diagnosis among especially in biopsy material {1641}. How-
phase of contrast-enhanced hepatic im- large regenerative nodule, FNH-like nod- ever, detection of stromal invasion quali-
aging, DNs usually appear isovascular or ule, LGDN, HGDN, early HCC and classifies a lesion as HCC {125}. If the presence
hypovascular, as compared to the sur- cal HCC are presented in the section on of invasion is questionable, detection of a
rounding parenchyma. Algorithmic approach to diagnosis of liver ductular reaction by immunohistochemi-
Diffuse or focal small cell change is com- tumours. cal stains for keratins 7 or 19 will favour
monly found in HGDN. Other cytological pseudoinvasion rather than true invasion
changes that are indicative of atypia, dis- Early hepatocellular carcinoma {2478}.
tinguishing HGDN from LGDN, include Early HCC is a low-grade, early-stage tu- It should be emphasized that not all small
clear cell change, focal fatty change with mour that may be difficult to recognize HCCs (defined by the international con-
Mallory-Denk bodies and resistance to both grossly and microscopically. Al- sensus article of 1995 as HCCs measur-
iron accumulation. HGDN may also though the pathological features of early ing < 2 cm {1335}) represent early HCC.
demonstrate evidence of structural HCC have been well described by Japan- As a rule, distinctly nodular small HCCs
atypia, such as thick cell plates (up to ese authors during the last two decades have similar histological features to those
three cells in thickness), occasional {1642, 2242, 2781, 2782}, international of larger examples of classical HCC, in-
pseudoglandular structures, and expan- consensus regarding the biological na- cluding: variably differentiated neoplastic
sile subnodules (foci), often differing from ture of this lesion and its distinction from cell populations; well-developed trabecu-
the remaining nodule in degree of cyto- HGDN has only recently been achieved lar architecture, pseudoglandular struc-
logical atypia or cell proliferation rate. In {125}. Grossly, early HCC usually is a tures and unpaired arteries; absence of
order to make a diagnosis of HGDN, the poorly defined nodular lesion measuring portal tracts; and presence of fibrous
atypia observed in the lesion should be < 2 cm in diameter (hence the terms pseudocapsule at the tumour margin.
insufficient for a confident diagnosis of “vaguely nodular small HCC” and “small Thus, distinctly nodular small HCCs are
HCC. Sometimes, a subnodule with fea- HCC with indistinct margins” that have biologically progressed lesions, as evi-
tures diagnostic for HCC may be seen in been used for this tumour in the litera- denced by the presence of portal vein
a DN; the most appropriate term for such ture). branch invasion and intrahepatic metas-
lesions is “HCC arising in DN”. On other On microscopic examination, early HCC tases in a significant proportion of cases
occasions, definite distinction between is a well-differentiated neoplasm, com- {125, 1633}. Although early HCC is con-
HGDN and well-differentiated HCC may monly composed of small hepatocyte-like sidered to be an earlier stage of tumour
be difficult or impossible, especially on cells that merge imperceptibly with the than distinctly nodular HCC, it should also
needle biopsy material. Recently devel- surrounding hepatic parenchyma. Char- be noted that the characteristic histologi-

mutations, loss of heterozygosity, global

DNA hypomethylation and promoter hy-
permethylation {1759, 2089, 3242}. These
changes derange several signal trans-
duction pathways, each with a relatively
low frequency; therefore, HCC is charac-
terized by remarkable molecular hetero-
geneity. The Wnt/β-catenin pathway is
commonly disrupted in HCC, mostly as a
result of mutations in CTNNB1 or AXIN1,
epigenetic silencing of CDH1, or changes
in the expression of Frizzle receptors
{1759, 2089}. Activation of this pathway
causes accumulation of nuclear β-
catenin, where it regulates specific onco-
genes, including CCND1, MYC and
BIRC5. The p53 and Rb1 pathways are
also often disturbed in HCC, p53 particu-
larly by aflatoxin exposure (although also
by other mechanisms) {2427}, and Rb1
Fig. 10.42 Early hepatocellular carcinoma. High cell density and irregular thin trabecular pattern with occasional by mutation, loss or silencing of RB1 or
pseudoglands are typical features. CDKN2A, or due to reduced expression
of other genes, such as CDKN1A {137}.
The PI3K/Akt/mTOR pathway is also com-
cal features of early HCC may sometimes progenitor cells. When cirrhosis develops, monly disrupted {3404}, sometimes due
be seen in tumours measuring > 2 cm in the likelihood of HCC is increased, re- to abnormal activation of tyrosine kinase
diameter, suggesting that some HCCs flecting an increase in cell proliferation receptors, or to constitutive activation of
have a slow biological evolution. (owing to architectural remodelling and PI3K following loss of function of the tu-
The differences in vascular supply be- vascular alterations) and, possibly, mour-suppressor gene PTEN. Derange-
tween early HCC (portal vessels, variable replicative senescence. Nevertheless, the ments of other signal transduction
number of unpaired arteries) and dis- early molecular alterations leading to he- pathways, such as the MAPK pathway
tinctly nodular HCC (no portal vessels, patocarcinogenesis appear before cir- and the TGFβ pathway, also play roles in
well-developed unpaired arteries) are re- rhosis is established and are epigenetic hepatocarcinogenesis {137, 2427}. Fi-
flected in their imaging findings: early in nature, including overexpression of nally, mutations of the KRAS oncogene in
HCCs usually appear iso- or hypovasular growth factors, such as TGFα and IGF-2, HCC are associated with exposure to
when compared with the surrounding as well as gene inactivation by promoter vinyl chloride {3484}.
parenchyma, while distinctly nodular methylation {1645, 3242}. In addition, in
HCCs appear hypervascular on the arte- chronic hepatitis B, viral X protein acts as Molecular diagnosis of early HCC
rial phase and hypovascular on the ve- an oncoprotein, while HBV DNA integra- Most early HCCs are negative for serum
nous phase. Consequently, an early HCC tion in the host genome induces genomic markers (AFP and PIVKA-II ), lack typical
with a subnodule of classical HCC may instability and deregulates genes in- radiological findings and show relatively
provide a nodule-in-nodule pattern on im- volved in cell signalling and replication, mild histological atypia. The lack of typical
aging studies {765, 1142}. such as the gene encoding cyclin A and features of classical HCC causes difficulty
the human telomerase reverse transcrip- in the detection and accurate diagnosis
Hepatocellular adenoma tase (TERT) gene {712, 1759}. Other of early HCC. Therefore, large-scale
Transformation of hepatocellular ade- structural DNA changes, such as allelic methods of gene expression have been
noma to HCC has been considered rare. deletions, also occur in livers with chronic employed to identify easily applicable im-
However, recent molecular studies have hepatitis, with or without cirrhosis. How- munomarkers to aid the diagnosis of car-
identified a subset of adenomas with an ever, the incidence of genomic changes cinoma in these tumours.
increased risk of malignant transforma- escalates rapidly from chronic hepatitis The mRNA and protein expression of
tion, which are characterized by activat- and cirrhosis to dysplastic lesions and heat-shock protein 70 (HSP70) is upregu-
ing mutations in the gene encoding HCC {3242}. lated in early HCC, increasing in a step-
β-catenin {265}. Clonal expansion is enhanced by telom- wise manner in the multistage process of
erase activation with diminished apopto- hepatocarcinogenesis. Normal HSP70 im-
Molecular pathology sis. Active telomerase has been detected munoreactivity of biliary epithelium serves
The great majority of HCCs develop in pain cirrhotic nodules, DN and HCC {1297, as an internal positive control (nontumor-
tients with chronic liver disease as a re- 1658}. A large variety of genetic and epi- ous hepatocytes are negative). Positive
sult of accumulating genetic and genetic changes have been identified in expression (defined as immunopositivity
epigenetic changes in concert with clonal precancerous hepatic lesions and HCC, of at least 10% of tumour cells) was re-
expansion of hepatocytes and/or hepatic including chromosomal amplifications, ported in about 80% of early HCC and

A B C
Fig. 10.43 Nodule-in-nodule type of hepatocellular carcinoma. A Macroscopy. B Low-power view. C Note the border between the early (right side) and advanced (left side) components.
only exceptionally in DNs or other non- Molecular diagnosis of multicentric HCC and presence of a TP53 gene mutation
cancerous nodules {557, 718}. Glypican- HCCs frequently occur as multiple intra- {94, 3126}. Cases of morphologically pure
3 (GPC3), an oncofetal protein, is hepatic nodules, synchronously or HCC (i.e. without the morphological fea-
expressed abundantly in fetal liver, is in- metachronously. Genetic analysis of the tures of combined hepatocellular cholan-
active in the normal adult liver, and is fre- HBV integration pattern, chromosomal al- giocarcinoma), but which demonstrate
quently reactivated in HCC {418}. lele loss, and mutational inactivation of tu- significant (5% of tumour cells or greater)
Immunohistochemical expression of mour-suppressor genes has often immunostaining for keratin 19 have been
GPC3 is much higher in small HCCs than indicated multicentric, independent de- found to have a poorer prognosis and
in cirrhosis and DNs. GPC3 has a re- velopment of these nodules {2349, 2783}. higher rates of recurrence and lymph-
ported sensitivity of 77% and specificity These studies have shown that nodules node metastasis than keratin 19-negative
of 96% in the diagnosis of small HCC. The apparently growing from portal-vein tu- HCC {3335}. Spontaneous regression has
expression of glutamine synthetase, a tar- mour thrombi or satellite nodules sur- been reported rarely. Most studies report
get of β-catenin signalling, also increases rounding a large main tumour represent a 5-year survival rate of < 5% in patients
in a stepwise fashion from precancerous intrahepatic metastases, whereas other with symptomatic HCC.
lesions to advanced HCC, as seen by im- nodules can be considered to be multi- Established HCCs are largely resistant to
munohistochemistry {2412}. Glutamine centric HCCs. The following histological radio- and chemotherapy, although a sub-
synthetase is expressed in hepatocytes criteria are proposed to recognize multi- set of patients have shown a response to
surrounding the terminal hepatic venules centric HCC in routine practice: (1) multi- sorafenib, a new agent that inhibits sev-
in normal livers, while positive areas comple early HCCs or concurrent early HCCs eral tyrosine protein kinases, a success
prise < 10% of the parenchyma in cir- and classical HCCs; (2) presence of pe- that gives hope that novel efficacious
rhotic livers; therefore, staining in 10% of ripheral areas of well-differentiated HCC agents will be developed based on bet-
cells or more is considered suggestive of in the smaller lesions; and (3) multiple ter knowledge of the molecular mecha-
malignancy. HCCs of obviously different histology. nisms responsible for HCC development
Applying the above markers (HSP70, Multicentric HCC appears to be most fre- {314}. Currently, however, long-term sur-
GPC3, glutamine synthetase) as a panel quent with HCV infection {2381}. vival is likely only in patients with small,
can raise the diagnostic accuracy in tu- asymptomatic HCCs that can be treated
mour biopsy specimens, particularly Prognosis and predictive factors by resection, including liver transplanta-
when definite stromal invasion is not seen The prognosis for patients with classical tion, or by nonsurgical methods, includ-
{717, 2478}. Investigation of additional HCC is generally very poor, particularly ing percutaneous ethanol or acetic acid
markers holds promise for the future. for cases in which AFP levels are injection and percutaneous radiofre-
> 100 ng/ml at the time of diagnosis, par- quency thermal ablation.
tial or complete portal vein thrombosis,

Intrahepatic cholangiocarcinoma Y. Nakanuma

M.-P. Curado
W.M.S. Tsui
A. Wee
S. Franceschi
G. Gores
V. Paradis
B. Sripa
Definition An associated invasive carcinoma demic {532, 1855, 3468}. The age-spe-
Intrahepatic cholangiocarcinoma (ICC) is 8503/3 cific incidence of this tumour is consis-
an intrahepatic malignancy with biliary ep- Intrahepatic cholangiocarcinoma 8160/3 tent with a linear increase with age,
ithelial differentiation. ICC can arise in any being highest in the oldest age group
portion of the intrahepatic biliary tree, from Epidemiology (≥ 85 years) {2022}.
the segmental and area ducts and their Incidence and geographical distribution
major branches to the smallest bile ducts ICC is a relatively infrequent tumour in Time trends
and ductules {1106, 2390, 2499}. ICC aris- most populations, but is the second most The incidence of ICC is increasing in
ing from the intrahepatic small bile ducts common primary hepatic malignancy many regions, including non-endemic
is often called “peripheral ICC”, but use of after hepatocellular carcinoma (HCC); areas {1531, 1621, 2499, 2898, 3489}. In
this term is discouraged. about 5–15% of primary liver cancers are the USA, a nearly three-fold increase was
Cholangiocarcinoma arising from the right estimated to be ICCs {1967, 3489, 3602}. reported in the diagnosis of ICC between
and left hepatic ducts at or near their junc- ICC is sometimes coded by cancer reg- 1975 and 1999.
tion is referred to as “hilar CC” (often istries together with liver cancer, and this
called “Klatskin tumour”) and is consid- can lead to an underestimation of the true Etiology
ered to be an extrahepatic lesion {3489}, incidence of this tumour. The technologi- Although the etiology of most cases of
although the differentiation of hilar cholan- cal requirements for morphological sam- ICC remains obscure, some cases are as-
giocarcinoma from ICC arising from the in- pling of ICC means that verification is low sociated with prior biliary or hepatic dis-
trahepatic large bile ducts (perihilar ICC) in areas where incidence is high {634}. ease and a number of other risk factors
is usually controversial at advanced The prevalence of ICC shows a wide geo- {488}. For example, case–control studies
stages, and such cases could be in- graphic variation, and the highest inci- in the USA have shown that several risk
cluded in the definition of perihilar ICC dence is reported in areas of Asia where factors, including nonspecific cirrhosis,
{1106, 2248}. Likewise, it should be kept in Opisthorchis viverrini (Thailand and Laos alcoholic liver disease, hepatitis C virus
mind that the distinction of hilar from peri- {1855}) and Clonorchis sinensis (southern (HCV) infection, human immunodefi-
hilar depends on the pathological exami- China and the Republic of Korea {3468}) ciency virus (HIV) infection, diabetes mel-
nation of resected specimens. The uses are endemic. The age-standardized inci- litus, and inflammatory bowel diseases
and meanings of the terms “hilar” and dence of ICC in Khon Kaen (Thailand) are significantly more prevalent among
“perihilar” therefore may differ between was 88 per 100 000 in males and 37 per patients with ICC {2899}.
pathologists, surgeons and radiologists. 100 000 in females {2486}.
In the United States of America (USA), Chronic inflammatory biliary disease
ICD-O codes considered to be a low-risk population, Some cases of ICC are preceded by a
Biliary intraepithelial neoplasia, the incidence of ICC from 1976 to 2000 chronic inflammatory process of the bile
grade 3 (BilIN-3) 8148/2 was greatest in men of African descent. ducts. Carcinogenesis is probably related
Intraductal papillary neoplasm with: to the duration and severity of bile-duct in-
Low- or intermediate-grade Age distribution flammation, and ICC tends to proliferate
intraepithelial neoplasia 8503/0 Patients with ICC are usually elderly, and spread along the affected intrahep-
High-grade intraepithelial with a slight male dominance, in areas atic bile ducts.
neoplasia 8503/2 where liver flukes are or are not en-
A B C
Fig. 10.44 Predisposing conditions for intrahepatic cholangiocarcinoma. A Hepatolithiasis with intrahepatic cholangiocarcinoma (arrow, stone). B Opisthorchis viverrini (liver fluke)
in an intrahepatic bile duct. C Fibropolycystic disease of the liver with features of Caroli disease and of congenital hepatic fibrosis.
Intrahepatic cholangiocarcinoma 217

virus (EBV) infection and genetic

haemochromatosis are rare risk factors
{511}.
Clinical features
ICC is an aggressive cancer, with high
mortality and poor survival rates {1080}.
The site of the tumour in the liver, its
growth pattern and the presence or ab-
A B sence of strictures of the biliary tree relate
to the clinical features of ICC.
Symptoms and signs

Clinical features are dependent on the
anatomical location, growth pattern and
stage of disease {762, 1967, 2996}. ICC
without central bile-duct obstruction and
presenting as mass(es) often go unno-
ticed until attaining a large size. General
malaise, night sweats, right upper-quad-
C D rant abdominal pain and weight loss are
Fig. 10.45 Macroscopic features of intrahepatic cholangiocarcinoma. A Mass-forming type. B Periductal infiltrating type. frequent clinical symptoms. The liver itself
C Periductal-infiltrating and mass-forming type. D Intraductal growth type. is enlarged to a lesser extent, ascites is
uncommon, and signs of portal hyperten-
sion are absent or minimal. Perihilar ICC
Primary sclerosing cholangitis (PSC) sis ranges from 2.7 to 6.5 {634, 3468}. usually presents with cholestasis {758}.
PSC with or without inflammatory bowel Liver flukes, especially O. viverrini and C. Other symptoms that may coexist are re-
disease, usually ulcerative colitis, is a sinensis, are risk factors for ICC {532, lated to hepatitis viral infection, cirrhosis,
common risk factor for ICC in North Amer- 1855, 3468}. The presence of parasites in and prior biliary diseases such as PSC, or
ica and European countries, and the the biliary tree leads to a chronic inflam- systemic metastases.
prevalence of ICC in PSC is 5–15% with a matory response and bile-duct epithelial
cumulative risk of 1.5% per year {238, hyperplasia with an increased risk of ICC Imaging
289}. This risk is higher in northern Euro- {2818}. Imaging is essential for diagnosis. The
pean countries. Clinically undetected ICC mass-forming type of ICC is expansile,
or precursor lesions are occasionally en- Biliary malformations and other lesions and the borders between the cancer and
countered in explanted livers at liver ICC may arise in fibropolycystic disease of non-neoplastic tissues are relatively clear
transplantation. the liver, including congenital segmental or {1106, 3604}. On arterial dominant phase
multiple dilatation of the intrahepatic bile of dynamic enhanced computed tomog-
Hepatolithiasis ducts (Caroli disease), choledochal cysts, raphy (CT) or magnetic resonance imag-
Hepatolithiasis, which is not rare in the Far solitary unilocular or multiple liver cysts, ing (MRI), usually only the periphery of the
East, is the primary independent risk fac- and congenital hepatic fibrosis {3606}. tumour enhances; the centre of the tu-
tor for ICC {1778}; about 7% of patients mour (with few cells and abundant
with hepatolithiasis eventually develop Non-biliary cirrhosis stroma) remains poorly enhanced. The
ICC {526} and 27–65% of ICCs are asso- Non-biliary cirrhosis, particularly hepatitis centre of the tumour gradually enhances
ciated with hepatolithiasis {507, 508}. Cal- virus-related cirrhosis, is known as a on equilibrium phase (late phase, de-
cium bilirubinate stones predominate, but background lesion of ICC {2899, 3597}. layed enhancement). This progressive
some ICCs are associated with choles- HCV infection may play a role in the de- contrast enhancement from early to late
terol stones {526}. The hepatic lobe or velopment of ICC {1621, 3488}. In Japan, phase differs from that commonly seen in
segments containing calculi involved by patients with cirrhosis attributable to HCV HCC (which shows early enhancement
ICC are sometimes atrophic. The calculi- have a 1000-fold risk of ICC compared and a delayed contrast washout) {2681}.
containing bile ducts have a proliferative with the general population {1621}. In The periductal-infiltrating type of ICC de-
epithelial lining and, not infrequently, dys- areas where both HBV and ICC are en- velops along the intrahepatic bile ducts
plasia {3694}. demic, the two may also be related {1778, and appears as a solid mass extending
1791}. Such ICCs are usually smaller, along portal tracts, showing delayed en-
Parasitic biliary infestation mass-forming types, when clinically de- hancement on contrast-enhanced CT or
Epidemiological studies, such as a case– tectable, and are frequently associated MRI. Endoscopic retrograde cholan-
control study in an endemic area (Pusan) with neutrophilic infiltration {2237}. giopancreatography (ERCP) reveals sec-
in the Republic of Korea and Hong Kong ondary dilatation of the upstream ducts as
(China), have shown that the relative risk Other risk factors a result of tumoral obstruction, and the
of ICC in persons infected with C. sinen- Deposition of thorotrast, Epstein-Barr anatomical location of the involved ducts

can be evaluated by calibre changes or common, and mucin may be visible on

duct rigidity. the cut surfaces.
Intraductal tumours are confined within
the dilated part of an intrahepatic large Tumour spread and staging
bile duct, commonly showing contrast-en- ICC directly invades the surrounding he-
hanced papillary mural nodules with no or patic parenchyma and may spread along
mild extension beyond the bile-duct walls. the portal pedicles. The IG type often
Marked, localized dilatation of affected spreads intraluminally along the ducts. In-
ducts caused by mucin hypersecretion is trahepatic metastases develop in nearly
identifiable by all imaging modalities, es- all advanced cases. The incidence of
pecially ultrasound and MR cholangiog- metastases to regional lymph nodes is
Fig. 10.46 Macroscopic features of intrahepatic
raphy (MRCP). Cholangiography reveals higher than in HCC. Blood-borne metas- cholangiocarcinoma, advanced stage.
filling defects in the biliary tract, which are tases occur later, particularly to the lungs;
caused by polypoid tumours and/or hy- other sites of metastasis include bone,
persecreted mucin. adrenals, kidneys, spleen, and pancreas. from the hepatic progenitor cells {1778,
Advanced cases of ICC often have a The TNM (tumour, node, metastasis) clas- 2237}.
mixed pattern of growth with central sification of extrahepatic bile-duct carci-
necrosis and/or intrahepatic metastases. noma (sixth edition) has divided these Adenocarcinoma
Secondary dilated bile ducts around the carcinomas into perihilar and distal bile- Most ICCs have a tubular pattern of
tumour are more frequently detectable by duct types. The perihilar classification ap- growth with variable-sized lumina, though
CT, MRI and ultrasonography. plies to carcinomas of the right, left, and micropapillary, acinar or cord-like pat-
common hepatic ducts, i.e. those proxi- terns also occur. The neoplastic cells are
Macroscopy mal to the origin of the cystic duct usually small or medium-sized, cuboidal
ICC often develops in a non-cirrhotic liver. (Klatskin tumour). or columnar, and can be pleomorphic.
ICC is grossly classifiable into three They have small nuclei and nucleoli, and
types: mass-forming (MF) type, periductal Histopathology most have pale, slightly eosinophilic or
infiltrating (PI) type and intraductal-growth Most ICCs are adenocarcinomas with vacuolated cytoplasm. The neoplastic
(IG) type {1106, 3604}. The MF type pres- variable differentiation and fibroplasia, re- cells may sometimes have clear and
ents a nodular or mass lesion in the he- sembling adenocarcinoma of the hilar abundant cytoplasm or resemble goblet
patic parenchyma, and the carcinoma is and extrahepatic bile ducts or pancreas. cells. These features resemble cholan-
grey to grey-white, firm and solid. The PI There is no dominant histological type in giocytes (lining epithelium of the bile
type spreads along the portal tracts with cases associated with preceding biliary ducts), while some cases resemble bile
narrowing of the involved ducts. Periph- disease, while ICC arising in non-biliary ductules.
eral bile ducts show obstructive dilatation cirrhosis frequently presents with bile- A variable and occasionally abundant
and cholangitis. The IG type is a polypoid ductule differentiation, possibly arising fibrous stroma is an important characteristic
or papillary tumour within the dilated bile-
duct lumen, and this type represents ma-
lignant progression of intraductal papillary
neoplasm (IPN) of the bile duct. These
three types may overlap in the same
case. According to recent experience in
North America and European countries,
the MF type was present in 34 patients
(65%), the MF + PI type in 13 patients
(25%), the PI type in 3 patients (6%), and
the IG type in 2 patients (4%) {1080}. Fi-
brous encapsulation is not seen in any A B
type.
ICC arising in the intrahepatic small bile
ducts or ductules usually presents as MF
type {2237}, while ICC arising in the intra-
hepatic large bile ducts (perihilar ICC)
presents as any of the three types. ICC
cases involving the hepatic hilum are as-
sociated with cholestasis, biliary fibrosis,
and cholangitis of the intrahepatic bile
ducts. At more advanced stages, ICCs
consist of variably sized nodules, usually C D
coalescent. The MF type can be quite Fig. 10.47 Cytology of intrahepatic cholangiocarcinoma according to fine-needle aspiration. A Malignant epithelial cells.
large. Central necrosis or scarring are B Differentiated carcinoma. C Less well-differentiated carcinoma. D Intraductal papillary neoplasm.

A B
C D
Fig. 10.48 Intrahepatic cholangiocarcinoma. A Well-differentiated adenocarcinoma. B Moderately differentiated adenocarcinoma. C Well-differentiated tubular cholangiocarcinoma.
D Well-differentiated papillotubular adenocarcinoma.
of ICC. Usually, the centre of the tumour bile ducts are often associated with a and poorly differentiated adenocarcinoma
is more sclerotic and hypocellular, the noninvasive IPN. Once there is invasion of according to their morphology. Most ICCs
neoplastic cells appearing lost in the the ductal wall, the lesion may be well- to are well-differentiated tubular adenocarci-
dense, hyaline stroma. There may be moderately differentiated adenocarcinoma with or without micropapillary struc-
focal calcifications in these areas. The noma, with considerable desmoplasia tures. Moderately differentiated carcinomas
periphery of the tumours contains more and stenosis of the bile-duct lumen. In the are composed of moderately distorted tu-
abundant, proliferating cells. ICC often IG type of invasive carcinoma, a grossly bular glands with cribriform formations
extends by compressing hepatocytes, by visible papillary tumour growing in the and/or a cord-like pattern, while the poorly
infiltrating along sinusoids, or directly re- duct lumen is supported by fine fibrovas- differentiated cancers are recognized by
placing adjoining hepatocytes in their cular cores, and the surrounding mucosa distorted tubular or cord-like structures with
trabeculae. As a result, portal tracts may is frequently replaced by superficial marked cellular pleomorphism.
be incorporated within the tumour and ap- spreading carcinoma.
pear as tracts of elastic fibre-rich con- ICC arising from the intrahepatic peribil- Histological variants
nective tissue. ICC also frequently iary glands is also recognized and mainly The following rare variants of ICC are rec-
infiltrates the portal tracts, and invades involves these glands, sparing the lining ognized: adenosquamous and squamous
portal vessels (lymphatics and portal epithelial cells at an early stage. The tu- carcinoma, mucinous carcinoma, signet-
venules). This pattern of invasion is a fre- mour cells can also infiltrate the peribiliary ring cell carcinoma, clear cell carcinoma,
quent and relatively early histological find- glands of the intrahepatic large bile ducts mucoepidermoid carcinoma, lymphoepi-
ing, suggesting the development of early and their conduits, and this lesion should thelioma-like carcinoma, and sarcomatous
metastasis. Infiltrating, well-differentiated be differentiated from invasion of carci- ICC. Adenosquamous and squamous car-
tubular carcinoma must be differentiated noma in the portal connective tissue. Oc- cinoma are occasionally seen at ad-
from the non-neoplastic pre-existing small casionally it may be difficult to distinguish vanced stages of ICC. Mucinous
bile ducts and ductules. ICC also often in- this lesion from reactive proliferated peri- carcinoma is not infrequently associated
filtrates intrahepatic nerves, frequently biliary glands. with the IG type of ICC, particularly cases
forming variably-sized glands surround- with intestinal differentiation. EBV-
ing the nerve. Grading encoded nuclear RNAs have been
ICCs arising from the large intrahepatic ICCs can be graded as well-, moderately, demonstrated in lymphoepithelioma-like

carcinoma {511, 1272, 3420}. Sarcoma-

tous ICC shows spindle-cell areas
resembling spindle cell sarcoma or fi-
brosarcoma or with features of malignant
fibrous histiocytoma. Carcinomatous foci,
including squamous cell carcinoma, are
scattered focally.
The production of mucin can be demon- A B
strated in most ICCs by staining with mu-
cicarmine, diastase-PAS or Alcian blue,
though the amount of mucin is usually
small and especially negligible in carci-
noma resembling bile ductules. Mucin
core (MUC) proteins 1, 2, and 3 are de-
tectable in the carcinoma cells {2811,
2812}. ICC cells are often immunoreactive
for keratins 7 and 19, carcinoembryonic
antigen (CEA), epithelial membrane anti-
gen (EMA), and blood group antigens. C D
EMA is expressed on the luminal surface Fig. 10.49 Intrahepatic cholangiocarcinoma. A Poorly differentiated adenocarcinoma with pleomorphic pattern.
of carcinoma cells with ductular features. B Poorly differentiated adenocarcinoma with solid growth pattern. C Cells of poorly differentiated adenocarcinoma in
A keratin profile is useful for the differenti- B are positive for epithelial membrane antigen (EMA). D Adenocarcinoma with cord-like and solid pattern.
ation of ICC from metastatic carcinoma:
Keratin 7 is constantly expressed in ICC, sampled for cytology. In routine cytology, niques such as fluorescent in situ hy-
while keratin 20 is constantly expressed epithelial cells with prominent nucleoli, bridization (FISH), for evaluation of aneu-
in metastatic colon carcinoma {2756}. thickening of the nuclear membrane and ploidy, increases both sensitivity (up to
increased chromatin are diagnostic for 34%) and specificity (up to 98%) {200,
Cytopathology malignancy, with sensitivity varying from 1572A}. Percutaneous or endoscopic
Bile and suspicious lesions encountered 9% to 24% and specificity from 61% to ultrasound-guided fine-needle aspiration
during biliary instrumentation can be 100% {1125}. Advanced cytological tech- (FNA) cytology can be used to sample
ICCs, especially the MF type {499, 625,
785}. Cellularity varies with degree of
desmoplasia. In well-differentiated ICCs,
sheets of cuboidal or columnar epithelial
cells show a honeycomb appearance
with round to eccentric nuclei, fine chro-
matin, small to inconspicuous nucleoli
and ample, lacy or vacuolated cytoplasm.
However, there is disorderly growth with
crowding, piling up and loss of nuclear
polarity. Characteristically, cell and nu-
A B clear enlargement can be abrupt, with an
Fig. 10.50 A Intraductal papillary biliary neoplasm (IPBN) showing a multilocular pattern; this growth pattern, which can increased nucleus-to-cytoplasm ratio, ir-
be mistaken for mucinous cystic neoplasm (cystadenocarcinoma), can be distinguished histologically by the absence regular nuclear contour, hyperchromasia
of ovarian-like stroma. B IPBN showing a unilocular cystic pattern and filled with carcinoma and mucin. and distinct nucleolus. Less differentiated
ICCs exhibit greater pleomorphism. Squa-
mous features with dense cytoplasm and
distinct cell borders may be seen. In IPN
of the bile ducts, the hypercellular aspi-
rates are composed of broad and often
double-cell layered sheets of ductal
columnar epithelium with distinctive,
three-dimensional, complex and branch-
* ing papillary configurations {3310}.
A B Differential diagnosis
Fig. 10.51 Intraductal papillary biliary neoplasm of the bile duct (IPBN). A Microscopic papillary lesion remote from the Bile duct adenoma (BDA) is usually sin-
main lesion (multifocal occurrence). B Intraductal in situ-like spread of the small bile duct (*) and also large bile duct (L). gle, usually < 1 cm in size, and is sub-

premalignant neoplasm.
Von Meyenburg complex (biliary micro-
hamartoma) is small, up to several mil-
limetres in diameter. These lesions are
usually multiple and are adjacent to a por-
tal tract and, if widespread, may be an in-
dication of fibropolycystic disease of the
liver. Within a fibrous or hyalinized stroma,
they present as irregular or round ductal
A B structures that appear somewhat dilated
and have a flattened or cuboidal epithe-
lium. The lumina contain proteinaceous or
bile-stained secretions.
Intrahepatic peribiliary cysts are usually
found in chronic advanced liver disease,
in syndromes with biliary anomalies, and
also in normal livers. Multiple cysts may
be seen around the intrahepatic large bile
ducts {2236}. They are visible by ultra-
sound or CT and are thought to derived
C D from peribiliary glands and should be dif-
ferentiated from ICC clinically and histo-
logically. Multicystic biliary hamartoma
consists of ductal structures, periductal
glands, and fibrous connective tissues
containing blood vessels {3695}. Smooth
muscle bundles focally surrounded
ductal structures. Ductal epithelium and
periductal glands resemble biliary epi-
thelium and peribiliary glands, respec-
E F tively.
Multifocal hyperplasia of peribiliary
glands comprises macroscopically rec-
ognizable dilatation and hyperplasia of
the peribiliary glands of intrahepatic and
extrahepatic bile ducts in apparently nor-
mal livers and also in acquired liver dis-
eases {748}. Some ducts may be
cystically dilated. Lack of familiarity with
this lesion could lead to an erroneous di-
agnosis of a well-differentiated cholan-
G H giocarcinoma.
Fig. 10.52 A Normal biliary epithelial cells of the intrahepatic large bile duct. B Hyperplastic biliary epithelial cells of
the intrahepatic large bile duct. C, D Biliary intraepithelial neoplasia 1 (BilIN-1). E, F Biliary intraepithelial neoplasia 2 Precursor and early lesions
(BillN-2). G, H Biliary intraepithelial neoplasia 3 (BillN 3). Two types of precursor lesions are pro-
posed for the development and progres-
sion of ICC arising from the intrahepatic
capsular and well-circumscribed but non- a peribiliary gland hamartoma {253}. large bile ducts: flat biliary intraepithelial
encapsulated. BDA is composed of a pro- Biliary adenofibroma is characterized by neoplasia (BilIN) and papillary intraductal
liferation of small, uniform small-sized a complex tubulocystic biliary epithelium papillary neoplasm (IPN) of the bile duct.
ducts with cuboidal cells that have regu- without mucin production, together with Molecular and genetic alterations related
lar nuclei. These ducts have no or little abundant fibroblastic stromal compo- to cholangiocarcinogenesis have been
lumen and can elaborate mucin. Their as- nents. There is evidence that this might described in these lesions {2235, 3689,
sociated fibrous stroma shows varying be related to Von Meyenburg complex 3691, 3694}.
degrees of chronic inflammation and colon the basis of similar morphological ar-
lagenization. Enclosed in the lesion are chitecture and epithelial expression of Biliary intraepithelial neoplasia
normally spaced portal tracts. BDA and D10, but not 1F6 {3380}. Because of its BilIN is not infrequently encountered in
peribiliary glands share common anti- size, proliferative activity and im- the intrahepatic large bile ducts in chronic
gens, suggesting a common line of differ- munopositivity for p53, biliary adenofi- biliary diseases such as hepatolithiasis
entiation and leading some to consider it broma is believed to be a potentially {3689}. BilINs are characterized by atypical

epithelial cells with multilayering of nuclei

and micropapillary projections into the
duct lumen {3688, 3689}. The atypical
cells have an increased nucleus-to-
cytoplasm ratio, partial loss of nuclear po-
larity, and nuclear hyperchromasia. They
are divisible into BilIN-1, BilIN-2 and BilIN-
3 according to degree of atypia: BilIN-1
and BilIN-2 correspond to low- and inter-
mediate-grade lesions (ICD-O code,
8148/0), and BilIN-3 to high-grade lesions
(ICD-O code, 8148/2) {3688}. Some peri-
biliary glands in chronic hepatobiliary dis-
eases may show BilIN lesions. BilINs are
also seen in the hilar and extrahepatic bile
ducts. Interestingly, similar intraepithelial
biliary lesions are also encountered in the
small intrahepatic bile ducts in livers with
chronic hepatis C, alcoholic cirrhosis,
thorotrast deposition, and PSC, suggest-
ing that they may be precursor and early
lesions of ICC arising from small bile
ducts and ductules {876, 3273}. Exten-
sive intraductal spread of BilINs along the Fig. 10.53 Intraductal papillary biliary neoplasm (IPBN) showing papillary-villous growth in the cystically dilated bile duct.
intrahepatic bile ducts without grossly vis-
ible tumour lesions has been reported
{48}. in the pancreas, when associated with an tic neoplasm (biliary cystadenoma/cyst-
invasive carcinoma, the pancreatobiliary adenocarcinoma) applying the criteria
Intraductal papillary neoplasms type of bile-duct IPN is usually associated used in the differentiation of IPMN of pan-
IPN of the bile ducts includes the previ- with a tubular adenocarcinoma, while the creas from pancreatic mucinous cystic
ous categories of biliary papilloma and intestinal type of bile-duct IPN is usually neoplasm, namely the presence of ovar-
papillomatosis, and is characterized by associated with a colloid type of invasive ian-type stroma and female sex are sup-
dilated intrahepatic bile ducts filled with a carcinoma {1611, 2933}. portive of biliary mucinous cystic
noninvasive papillary or villous biliary IPN with cystic luminal dilatation can be neoplasm, while luminal communication
neoplasm covering delicate fibrovascular distiniguished from biliary mucinous cys- with the bile ducts and absence of
stalks {11, 12, 510, 1364, 3690, 3691,
3694}. Dilated bile ducts are fusiform or
cystic (unilocular or multilocular). The
papillary lesions are soft and white, red or
tan. Similar neoplasia can develop in the
hilar and extrahepatic bile ducts, and syn-
chronous and metachronous IPNs can
develop in the intrahepatic and extrahep-
atic biliary tree. About one third of IPNs
secrete mucin in the duct lumen (mucin
secreting biliary tumour) {2933, 3691}.
Although IPN of the bile ducts is usually A B
not so mucinous, there are a number of
parallels between IPN of the bile ducts
and intraductal papillary mucinous neo-
plasm (IPMN) of the pancreas {1611,
2933, 3690, 3691}. Both lesions are papil-
lary and intraductal, both show similar
range of possible differentiation of the
neoplastic cells (pancreatobiliary type,
intestinal type, oncocytic type, and
gastric type), and both have similar types
of assocated invasive carcinomas {3691}. C D
The pancreatobiliary type is the most Fig. 10.54 Phenotype of intraductal papillary neoplasia. A Pancreatobiliary type. B Intestinal type. C Oncocytic type.
common type of IPN of the bile ducts. As D Gastric type.

on growth type: the 5-year survival rate is

39% in patients with the MF type and 69%
for the IG type, while the PI type shows a
poor prognosis; no patients with the MF +
PI type survived more than 5 years {1426,
3141, 3599}. Patients with mucinous car-
cinoma of the IG type have a better prog-
nosis after surgical resection, when
compared with conventional adenocarci-
noma {2933, 3691}. These growth types
reflect different biological behaviours: the
MF + PI tumours had a positive lymph-
node metastasis rate of 50% and a
macroscopic vascular involvement rate of
61%, and perineural infiltration was higher
A B in MF + PI types (80%) than in the MF
group (33%). ICC arising in non-biliary
Fig. 10.55 Bile duct adenoma. A A proliferation of normal-appearing, small bile ducts is surrounded by connective tissue
with an entrapped portal tract. B Bile-duct cells stain positively for epithelial membrane antigen. cirrhosis is usually detectable as a small
nodule during follow-up of hepatitis virus-
related cirrhosis, and is treatable with
ovarian-type stroma support the diagno- {2045, 3120}. IL6 can also regulate the hepatectomy {3597}. Concomitant hepa-
sis of IPN {3690, 3691}. activity of DNA methyltransferases, and tolithiasis prevents precise diagnosis pre-
IPN of the bile ducts is classifiable as low, overexpression results in methylation of operatively, with a poor prognosis {1426}.
intermediate or high grade on the basis of the promoters of several genes, including Lymph-node spread, macroscopic vas-
degree of cellular and nuclear atypia the epidermal growth factor receptor cular invasion, positive surgical margins
{2235, 3690, 3691}. IPNs are not infre- (EGFR) {2045}. Telomerase activity is de- and bilobar distribution are associated
quently associated with invasive carci- tectable in carcinoma cells of almost all with a high recurrence rate and a poor
noma (IPN with an associated invasive ICC cases {2423}. EGFR expression is a prognosis {1426, 3598}. In addition, intra-
ICC). IPN with an associated invasive ICC significant prognostic factor and also a hepatic metastasis, macroscopic vascu-
in the intrahepatic bile ducts corresponds risk factor for tumour recurrence {3650}. lar invasion, noncurative resection and
to the IG type of ICC. When an invasive Increased gene signals of proto-onco- advanced TNM stage are associated with
carcinoma is present, it should be sepa- gene ERRB2 (human epidermal growth a poor prognosis {1426}. Poor histologi-
rately designated and staged. factor receptor-2, HER2) have been re- cal differentiation and squamous-cell or
ported in ICC and may relate to progres- sarcomatous elements confer a poor
Molecular pathology sion {3339}. Promoter mutations leading prognosis. The mucin phenotype is also
Cholangiocytes are continuously exposed to loss of transcriptional activity of of prognostic significance: MUC2 expres-
to genotoxic insults such as chronic in- CDKN2A/p16INK4a occur in PSC-associ- sion is relatively frequent in well differen-
flammation, oxidative stress and hy- ated cholangiocarcinoma {3194}, while tiated ICC, suggesting a favourable
drophobic bile acids, predisposing them overexpression of polycomb group pro- prognosis {1189}, while MUC5AC was
to genetic and epigenetic alterations tein EZH2 may induce methylation of the more often associated with aggressive tu-
{2167}. There are also accompanying in- CDKN2A promoter followed by de- mour development. In a single-centre ex-
creases of inflammatory mediators creased expression of CDKN2A in hepa- perience, liver transplantation for highly
{1967}. Decreased membranous expres- tolithiasis-associated ICC {2813}. selected patients with perihilar CC with
sion of E-cadherin, α-catenin, and β- neoadjuvant chemoirradiation has a 5-
catenin leads to weaker intercellular Prognosis and predictive factors year disease-free survival of > 80%
adhesion {790}, correlating with high- ICC is associated with a high rate of fa- {1424}.
grade ICC and related to invasiveness tality because of early invasion, wide-
{153, 1364}. spread metastasis, and lack of effective
IL6 appears to play an important role in therapeutic modalities. Few patients are
cholangiocarcinogenesis; tumour cells candidates for surgical resection as many
constitutively secrete IL6, which activates patients present with advanced disease
cell survival pathways and enhances tu- {2390, 2499, 3489}. The postoperative
mour growth via autocrine mechanisms prognosis for patients with ICC depends

Combined hepatocellular- N.D. Theise

O. Nakashima
cholangiocarcinoma Y.N. Park
Y. Nakanuma
Definition ally highlighted by immunostains; these cinomas, there are foci of intermediate
A tumour containing unequivocal, intimately do not however confirm biliary differentia- morphology at the interface of the HCC
mixed elements of both hepatocellular carc- tion, as hepatocellular components may and ChC components; immunohisto-
inoma (HCC) and cholangiocarcinoma also be positive for these antigens {723, chemistry often provides confirmatory evi-
(ChC). This tumour should be distin- 3335}. dence of mixed phenotypes in these
guished from separate HCC and ChC In many of these mixed hepatobiliary car- regions. Cells that have phenotypical or
arising in the same liver {1030}. Such tu-
mours may be separated or intermixed
(“collision tumour”).
ICD-O code 8180/3
Epidemiology
This tumour type comprises < 1% of all
liver carcinomas. Age- and sex-specific
incidence and variations in geographical
distribution of this tumour are similar to
those for HCC.
Macroscopy
The gross morphology of this tumour is
not significantly different from that of HCC.
In tumours with a major component of
ChC with fibrous stroma, the cut surface A B
is firm and fibrotic. Fig. 10.56 Combined hepatocellular-cholangiocarcinoma. A The classical type shows a border zone between an
hepatocellular carcinoma component with thick trabeculae (upper right) and a cholangiocarcinoma component with
malignant glands in an abundant fibrous stroma (lower left). B The transitional area between the two components often
Histopathology
shows mixed features with intermediate morphology.
Combined hepatocellular-cholangiocarci-
noma, classical type
The most typical form of combined hepato-
cellular-cholangiocarcioma contains areas
of typical HCC and areas of typical ChC.
The hepatocellular component may be well-
, moderately or poorly differentiated. Con-
firmation of hepatocellular differentiation is
easily provided by immunohistochemical
staining, e.g. with HepPar1 (granular cyto-
plasmic staining) or specific canalicular
staining with anti-CD10 and/or rabbit poly-
clonal antibody to carcinoembryonic anti-
gen (CEA) {309, 1123, 1803, 2455, 3244,
3567}. α-Fetoprotein may or may not be
present. Bile may be produced, highlighted
if necessary by Prussian blue stain or histo-
chemical staining.
The biliary component is usually a typical
adenocarcinoma, well-, moderately, or
poorly differentiated, often accompanied
by abundant stroma. Mucin may be Fig. 10.57 Combined hepatocellular-cholangiocarcinoma with stem-cell features, typical subtype. In addition to
demonstrated histochemically (periodic components of hepatocellular and cholangiocarcinoma (not shown), these tumours have nests of mature appearing
acid–Schiff stain after diastase digestion, hepatocytes with peripheral, small, stem/progenitor-like cells, which may be positive for keratin 19, neural cell adhesion
mucicarmine). Keratins 7 and 19 are usu- molecule (NCAM1/CD56), KIT and/or EpCAM.
Combined hepatocellular-cholangiocarcinoma 225

Combined hepatocellular-cholangiocellular
carcinoma with stem-cell features, typ-
subtype demonstrates nests of mature
appearing hepatocytes with peripheral
clusters of small cells which have high nu-
cleus : cytoplasm ratio and hyperchro-
matic nuclei {910, 3231}. These cells are
positive for keratins 7 and 19, nuclear cell
adhesion molecule (NCAM1/CD56), KIT
A B and/or epithelial cell adhesion molecule
(EpCAM), thus recapitulating the mor-
phological features and immunohisto-
chemical profile of stem/progenitor cells.
These nests may be separated by suffi-
cient stroma to impart a schirrous ap-
pearance. In some cases, the
hepatocytes in the centre of the nests
show clear cell change.
noma with stem-cell features, intermedi-
C D ate-cell subtype consists of tumour cells
Fig. 10.58 Combined hepatocellular-cholangiocarcinoma with stem-cell features, typical subtype. Carcinoma cells at the with features intermediate between hepa-
periphery of tumour cell nests are small, dark-stained and face the fibrous septa (A). These cells are immunopositive for keratin tocytes and cholangiocytes {1550}. These
19 (B), neural cell adhesion molecule (NCAM1/CD56) (C), and epithelial cell adhesion molecule (EpCAM) (D). tumour cells are small and oval-shaped
with hyperchromatic nuclei and scant cy-
toplasm. They are arranged in trabeculae,
solid nests or strands and set within a
background of marked desmoplasia.
Elongated, ill-defined gland-like struc-
tures may be present, but well-defined
glands are not seen. Cellular atypia is not
marked and mucin production is not pres-
ent. The tumour cells show simultaneous
cytoplasmic expression of hepatocytic
(HepPar1 or α-fetoprotein) and cholan-
A B
giocytic markers (keratin 19 or CEA),
much like ductular reactions in non-neo-
plastic, diseased liver; KIT expression is
common.
noma with stem-cell features, cholangi-
olocellular type has populations of small
cells with high nuclear:cytoplasmic ratio
and hyperchromatic, oval nuclei, growing
in a tubular, cord-like, anastomosing
C D pattern, the so-called “antler-like” pattern
Fig. 10.59 Combined hepatocellular-cholangiocarcinoma with stem-cell features, intermediate-cell type. A Tumour cells {1638, 2953}. They are embedded in a
are small and oval-shaped with scant cytoplasm and arranged in solid nests and strands within fibrotic stroma. There fibrous stroma, and appear to recapitulate
is simultaneous expression of HepPar-1 (B), α-fetoprotein (C), and keratin 19 (D). the canals of Hering or cholangioles.
These tumour cells may be immunohisto-
chemically positive for keratin 19, KIT,
immunophenotypical features of stem/- have been highlighted in the literature, al- NCAM and EpCAM. Cellular atypia is
progenitor cells may also be present; if though they are not at this time considered usually mild and mucin production is
these predominate, classification as one to be distinctive clinicopathological entities, absent. HCC-like and/or ChC-like areas
of the subtypes “combined hepatocellu- since it is as yet uncertain whether there are are frequently present at the periphery of
lar-cholangiocarcinoma with stem-cell biological differences between them. There- the tumours, where the tumour cords are
features” should be considered. fore, the clinical term “combined hepato- continuous with the nontumoral liver-cell
cellular-cholangiocarcinoma with stem-cell cords in a replacing pattern of growth.
Subtypes with stem-cell features features” includes all these subtypes and This tumour has traditionally been classi-
Three specific forms of stem-cell features any other as yet unidentified variants. fied as a special type of cholangio-

A B C
D E F
G H I
Fig. 10.60 Combined hepatocellular-cholangiocarcinoma with stem-cell features, cholangiolocellular type. Tumour cells are arranged in a tubular, cord-like, “antler-like” pattern with
marked fibrous stroma (A, D). The tumour cords are continuous with the nontumoral liver-cell cords in a replacing growth pattern (G). There is no mucin production (B) and tumour cells
are usually immunohistochemically positive for keratin 7 (E) and keratin 19 (H), and also frequently show a positive but variable reaction for KIT (C), NCAM1/CD56 (F) and EpCAM (I).
carcinoma, but is now considered a stem- out stem cell features is thought to be 3335, 3605}. Long-term follow-up of
cell subtype of combined hepatocellular- worse than for pure HCC {1489}. Progno- larger cohorts of strictly categorized tu-
cholangiocarcinoma. sis for combined hepatocellular-cholan- mours is needed to adequately define the
giocarcinoma with stem-cell features is clinical and biological behaviour of all the
Prognosis and predictive factors unknown, with conflicting evidence based combined variants.
The prognosis for patients with combined on small series and numbers of patients
hepatocellular-cholangiocarcinoma with- {723, 1550, 1638, 2386, 2606, 3231,
Combined hepatocellular-cholangiocarcinoma 227

Hepatoblastoma A. Zimmermann
R. Saxena
Definition tropin, causing precocious puberty.

A primary malignant blastomatous tumour A marked elevation of serum α-fetoprotein
of the liver characterized by various com- (AFP) is noted in up to 90% of cases; a
binations of several epithelial and mes- subgroup of hepatoblastomas show low
enchymal cell lineages. The epithelial or normal levels of serum AFP. The latter
lineages recapitulate early hepatic onto- are associated with an aggressive course
genesis and include immature cells, em- {680} and high-risk histologies such as
bryonal and fetal hepatoblasts, and more small cell undifferentiated (SCUD) hepa-
mature hepatocyte-like cells. toblastoma and tumours with rhabdoid
features. AFP levels markedly decrease
ICD-O codes or fall to normal after chemotherapy-in-
Fig. 10.61 Epithelial hepatoblastoma presenting as a
Hepatoblastoma duced regression or complete removal of
large, well-demarcated lesion with central haemorrhage.
Epithelial variants 8970/3 the tumour and rise with recurrence of
Mixed epithelial-mesenchymal 8970/3 disease. It should be borne in mind that
Calcifying nested epithelial clear; therapeutic agents used to main- “adult” levels of AFP (< 25 ng/mL) are not
stromal tumour 8975/1 tain low-birth-weight infants possibly play normally reached until approximately 6
a role. months of age.
Epidemiology
A rare tumour with 1 case per 1–1.5 mil- Localization Imaging
lion population, hepatoblastoma is the Hepatoblastomas occur as a single mass Ultrasonographically, most hepatoblas-
most frequent liver tumour in children; in 80–85% of cases, involving the right tomas present as hyperechoic masses.
80–90% of hepatoblastomas present be- lobe in 55–60% of cases, the left lobe in Computed tomography (CT) shows well-
fore the age of 5 years, 70% present in 15% of cases, and both lobes in the rem- delineated single or multiple masses that
the first 2 years of life, and 4% are pres- aining cases. Multiple masses may occur are hypoattenuated compared with the
ent at birth. Prenatal presentation with in either or both liver lobes. surrounding liver. Up to 50% of tumours
placental metastasis has been reported. appear calcified or ossified. Magnetic
There is a slight male predominance Clinical features resonance imaging (MRI) in combination
(1.5–2 : 1). Hepatoblastomas are often noted by a par- with CT can help to differentiate hepato-
ent or physician as an enlarging abdomen blastoma from infantile haemangioen-
Etiology in the infant or small child, often accompa- dothelioma, mesenchymal hamartoma,
The strong association of hepatoblastoma nied by anorexia or weight loss. Nausea, undifferentiated (embryonal) sarcoma,
with prematurity and low birth weight vomiting and abdominal discomfort or pain and hepatocellular carcinoma by demon-
{2026, 2667, 2984, 3037} was first re- may be present. Jaundice is seen in < 5% strating cystic or vascular features pecu-
ported in a study from Japan {3197}, of patients. Hepatoblastoma is often asso- liar to each lesion {3372}. MRI may also
which found that hepatoblastomas ac- ciated with haematological paraneoplastic be used to characterize epithelial and
counted for 58% of all malignancies in syndromes, including anaemia and throm- mesenchymal components of hepato-
children with birth weights of < 1000 g. bocytosis {2891}. Very rarely, hepatoblastoma.
The underlying etiopathogenesis is not blastomas may produce chorionic gonado-
Macroscopy
Table 10.04 Histopathological patterns in hepatoblastoma. Hepatoblastomas often present as well-
circumscribed, single or multiple lesions
Histological type Subtype varying from 5 cm to > 20 cm in size, and
Wholly epithelial type Fetal from 150 to about 1500 g in weight. He-
Mixed fetal and embryonal patoblastomas are often nodular and
Macrotrabecular
bulge from the cut surface. An irregular,
usually thin pseudocapsule formed by
Small cell undifferentiated (SCUD)
compressed liver may be present. The
Mixed epithelial and mesenchymal (MEM) typea Without teratoid features texture and colour of the cut surface de-
With teratoid features pends on the tumour components; and
Hepatoblastoma, not otherwise specified presence or absence of necrosis and
a
The epithelial component should be specified according to the category listed under wholly epithelial type. haemorrhage. Fetal hepatoblastomas dis-
play a tan-brown colour similar to that of
228 Tumours of the liver

normal liver. In the other subtypes, the cut

surface is often variegated, with soft or
gelatinous, brown to red areas {3082}.
When osteoid is present, the tumour is
typically gritty and the cut surface exhibits
multiple whitish and slightly transparent
speckles which may be clustered in a
focal area. A standardized protocol for the
examination of surgically resected hepa-
toblastoma specimens has been pub- A B
lished {861}.
Fig. 10.62 Pure fetal epithelial hepatoblastoma. A Variable concentrations of glycogen and lipid within tumour cells
sreate dark and light areas. B At higher magnification, the marked difference between the glycogen-rich clear cells
Histopathology (left) and the glycogen-poor dark cells (right) is evident.
Hepatoblastomas and related tumours
display a distinct variety of histological
patterns that may be present in varying
proportions {6, 2739}. These tumours are
classified as wholly epithelial or mixed epi-
thelial and mesenchymal types; the most
widely-used classfication is given in Table
10.04. A more extended classification,
based on the concept of a hepatoblas-
toma family of tumours and containing
variants of hepatoblastoma and hepato-
blastoma-related neoplasms, has been
published {3720}.
Fig. 10.63 Pure fetal epithelial hepatoblastoma. Cuboidal Fig. 10.64 Fetal hepatoblastoma expressing β-catenin
cells form trabeculae. Immunoreactivity for α-fetoprotein is on the cell surface, as on normal hepatocytes.
Wholly epithelial types of hepatoblastoma
present in most tumour cells. A cluster of haematopoietic
Fetal subtype cells is present, lower centre.
Accounting for nearly one third of hepa-
toblastomas, the fetal subtype presents
as thin plates or nests of small- to and the DNA content is diploid {2755}. A clei with coarse chromatin, thus resem-
medium-sized cells resembling hepato- subset of fetal hepatoblastomas shows bling blastemal cells found in other
cytes of the developing fetal liver. The cy- significant mitotic activity (> 2 per 10 high blastomatous tumours, such as nephrob-
toplasm is either finely granular and power fields) and is associated with lastoma. The cells are arranged as solid
eosinophilic or clear, reflecting variable larger, more pleomorphic nuclei and de- nests or glandular/acinar structures,
amounts of glycogen and lipids, which creased cytoplasmic glycogen, creating sometimes with papillary profiles and for-
impart a characteristic "light and dark" a crowded, cellular appearance. This mation of pseudorosettes. The mitotic ac-
pattern at low magnification. The cells variant is termed “crowded fetal”. Hepa- tivity is more pronounced than in the
contain a small round nucleus with fine toblastomas with an exclusively fetal mor- embryonal areas. Foci of extramedullary
nuclear chromatin and an indistinct nu- phology and absence of crowding have haematopoiesis are rarely present {1575}.
cleolus. They are arranged in trabecula, been termed “pure fetal hepatoblas- Immunohistochemistry for β-catenin
and canalicular domains may develop, toma”. shows normal membranous staining of
with visible bile droplets. The intervening Immunohistochemically, fetal hepatoblas- the fetal cells while the less mature cells
thin-walled sinusoid-like vascular chan- tomas may express AFP and show mem- often show nuclear staining.
nels are lined by endothelial cells that branous expression of β-catenin. A subset of fetal and fetal/embryonal
demonstrate diffuse CD34 immunostain- hepatoblastomas contain (sometimes
ing in contrast to the focal staining of si- Mixed fetal and embryonal subtype numerous) roughly spherical foci of pale,
nusoidal endothelium in normal liver This subtype of hepatoblastoma accounts small cells. These foci may be sur-
{2746}. The tumours may contain vascular for about 20% of cases. Apart from a few rounded by a rim of embryonal-looking
areas that may be mistaken for portal tumours post-chemotherapy, embryonal cells, followed by fetal-type cells. It has
tracts, especially in needle biopsies, but components do not usually occur alone, been shown that these foci consist of
that lack bile ducts. Foci of ex- but develop in combination with the fetal poorly differentiated cells with marked nu-
tramedullary haematopoiesis composed phenotype. The morphology of embryonal clear expression of β-catenin and very
mainly of clusters of erythroid precursors hepatoblastoma resembles that of the low proliferative activity. In contrast, the
are seen, more often in pretreatment biop- liver at 6–8 weeks of gestation. Embryonal embryonal cells surrounding these pale
sies {3417}. hepatoblasts have scant, dark granular foci have very high proliferative activity,
In the typical fetal subtype, mitotic figures cytoplasm devoid of visible glycogen (no are rich in mitochondria, and exhibit a
are commonly < 2 per 10 high power periodic acid–Schiff, PAS, staining) and mixed nuclear and cytoplasmic/membra-
fields, the PCNA proliferative index is low lipid droplets; and contain enlarged nu- nous pattern of β-catenin staining. The
Hepatoblastoma 229
cellular carcinoma. It has been proposed

that macrotrabecular hepatoblastoma be
divided into MT-1, consisting exclusively
of hepatocyte-like cells and suspected to
have a more aggressive course; and MT-
2, consisting of fetal/embryonal cells as-
sumed to have biologically standard risk.
The MT-1 phenotype may be difficult to
distinguish from hepatocellular carcinoma
occurring in older children {3720}.
Small cell undifferentiated (SCUD) subtype

Approximately 2–3% of epithelial hepato-
blastomas are composed entirely of non-
Fig. 10.65 Mixed fetal and embryonal hepatoblastoma. Fig. 10.66 Macrotrabecular hepatoblastoma. The tumour cohesive sheets of small cells resembling
Embryonal epithelial cells occur singly and in glandlike structures. consists of macrotrabeculae (left). the cells of neuroblastoma or other so-
called small cell blue tumours. Formerly
termed anaplastic hepatoblastoma, this
variant is now called SCUD hepatoblas-
toma {1026}. In contrast to other epithelial
hepatoblastomas, this subtype shows low
or normal levels of serum AFP and is re-
garded as the least differentiated form of
hepatoblastoma.Tumours consisting ex-
clusively of small undifferentiated cells are
very rare (2% or less) but foci of SCUD
A B are common in other subtypes of hepato-
Fig. 10.67 Hepatoblastoma, small cell undifferentiated subtype (SCUD). A Small immature cells with increased blastoma. The SCUD phenotype, is an
nucleus : cytoplasm ratio form a diffuse growth pattern. B Clusters of small cells are embedded in a myxoid matrix adverse prognostic factor, even when
(myxoid/mucoid variant). present focally {1096}.
This tumour grows diffusely and is highly
invasive. The cells are arranged as solid
sheets with abundant apoptosis, necrosis
and numerous mitotic figures. Sinusoids
are present but decreased in amount
compared with fetal-type tumours, and
there is pronounced expression of distinct
extracellular matrix proteins {2745}. Im-
munostaining shows reactivity for keratin
8, sometimes for vimentin, and rarely for
A B CD99, but not for AFP. In the Ki67 im-
Fig. 10.68 Mixed epithelial and mesenchymal (MEM) hepatoblastoma. A Areas showing mesenchymal tissue and foci munostain, the proliferation fraction usu-
of osteoid-like material are present, together with areas of epithelial hepatoblastoma. B MEM type with teratoid features. ally exceeds 80%.
There are numerous dark-brown melanin granules within the mesenchyme and in osteoblast-like cells. Similiar to certain subsets of neuroblas-
toma and medulloblastoma, some SCUD
peripheral rim of fetal-type cells demon- denotes a growth pattern and not a dis- hepatoblastomas contain tumour cells of
strate low proliferation and membranous tinct differentiation pathway. The term intermediate or even large size (interme-
β-catenin staining {3720}. These findings “macrotrabecular” is applied only to those diate cell and large cell undifferentiated
suggest microheterogeneity in some ep- tumours in which the pattern is a promi- hepatoblastoma; ICUD and LCUD)
ithelial hepatoblastomas, with formation of nent feature of the lesion. When present {3720}. In addition, SCUD hepatoblas-
distinct proliferation and differentiation focally, the tumour is classified according toma sometimes exhibits rhabdoid fea-
“pacemakers” possibly driven by clones to its predominant components. tures, histologically resembling malignant
of mutated progenitor cells. The trabeculae are composed of fetal and extrarenal rhabdoid tumour. A pathogenic
embryonal epithelial cells and a third, connection between these two lesions is
Macrotrabecular subtype larger cell type resembling hepatocytes. suspected, since some liver neoplasms
Macrotrabecular hepatoblastomas ac- Fetal and embryonal cells show the same that histologically qualify as SCUD are im-
count for 3% of tumours and display tra- morphological and proliferative features munohistochemically SMARCB1(INI1)-
becula that are 6–12 or more cells in as described above, while the hepato- negative, a bone fide feature of rhabdoid
thickness; the pattern is best appreciated cyte-like cells with vesicular nuclei and tumours {3294, 3294, 3427}.
on a reticulin stain. This subtype therefore prominent nucleoli may resemble hepato-

A B C
Fig. 10.69 Microheterogeneity in some fetal and mixed fetal/embryonal hepatoblastomas. A Foci of immature-looking cells, but with inconspicuous nuclei, are seen embedded in
fetal or mixed fetal and embryonal tissue. B Mitochondrial immunostain: the cells of the nests have a poor organelle complement, whereas the surrounding, rapidly proliferating cells
are rich in mitochondria. C Ki67 immunostain: the nest of progenitor cells exhibits very low proliferative activity, the surrounding rim of cells shows marked proliferation and the
hepatoblastoma tissue shows low proliferation.
Mixed epithelial and mesenchymal (MEM) not related to teratomas, which are germ borders. The cut surface of such tumours
type cell tumours. There is, however, a report is typically nodular; most of the nodules
MEM type without teratoid features. MEM of a discrete cystic teratoma contiguous consist of firm fibrotic tissue intermingled
hepatoblastomas account for 45% of he- to a hepatoblastoma. Between 3% and with necrosis and/or haemorrage. Micro-
patoblastomas and consist of epithelial 20% of MEM hepatoblastomas display scopically, small foci of residual tumour
(usually fetal or mixed fetal/embryonal) endodermal, neuroectodermal (melanin- may be detectable; the amount of de-
elements admixed with neoplastic mes- producing cells, glial elements and neu- tectable residual tumour depends upon
enchymal components, i.e. not tumour-in- ronal cells), and complex mesenchymal the extent of sampling {2830}. Adequate
duced stroma. Most of these tumours tissues, including striated muscle cells sampling may be guided by careful in-
(about 80%) contain mature and imma- {3084}. Melanin granules may be seen in spection of the cut surfaces; viable ep-
ture fibrous tissue, osteoid or osteoid-like osteoblast-like cells situated in osteoid, ithelial tumour appears as pale friable foci
tissue, and rarely hyaline cartilage. The but the mere presence of osteoid does located within fibrotic nodules, whereas
other 20% display more complex heterol- not qualify a tumour as teratoid. Similarly, MEM tumour remnants may be seen as
ogous tissues of all germ layers, and are stratified squamous epithelium, seen in white specks of osteoid. Histologically,
termed MEM hepatoblastomas with tera- tumours subsequent to chemotherapy, is residual embryonal, macrotrabecular and
toid features. The fibrous mesenchyme not a teratoid feature. The pathogenesis small cell components can be identified
may be rich in glycosaminoglycans, proof teratoid MEM is not established, but a without difficulty, but the small nests of
ducing a myxoid appearance, but it also role for pluripotent stem/precursor cells is clear and dark cells of fetal hepatoblas-
contains myofibroblast-like cells and bun- hypothesized. The prognostic signifi- toma embedded in fibrous tissue may be
dles of collagen fibres. Islands of osteoid- cance of teratoid features is not clear. difficult to distinguish from entrapped and
like tissue composed of a hyaline matrix damaged benign hepatocytes.
containing lacunae filled with one or more Pathology of hepatoblastoma subsequent Chemotherapy causes complex second-
cells are the hallmark of MEM hepato- to chemotherapy ary changes in tumour cells, including cell
blastoma. Rarely, they are the only mes- Pre-surgical or pre-transplantation enlargement with or without ballooning,
enchymal component noted in a chemotherapy, a common therapeutic fatty change and marked nuclear anom-
predominantly fetal hepatoblastoma. strategy in the treatment of hepatoblas- alies precluding proper identification of
There is strong evidence that the cells lo- tomas {2525}, induces shrinkage of the cell types. In some treated hepatoblas-
cated within lacunae and osteoblast-like tumour which aquires a more spherical tomas, only crowded foci of osteoid may
cells at the border of osteoid are derived configuration with more clearly delineated remain without any epithelial tumour
from epithelial cells, because: (1) they
may blend with adjacent fetal/embryonal
hepatoblastoma cells; (2) they show im-
munostaining for keratin 8 and epithelial
membrane antigen, in addition to AFP
and vimentin {6, 3457}; and (3) the os-
teoid cells share molecular abnormalities
of the β-catenin gene and expression/sig-
nalling pathways with epithelial hepato-
blastoma cells.
Mixed epithelial and mesenchymal (MEM) A B

type with teratoid features. This subtype, Fig. 10.70 A Hepatoblastoma with post-chemotherapy alterations. Immunostaining for keratin 8 shows residual fetal-
so-named owing to the variable presence type tumour cells adjacent to a scar. There is admixed inflammation. B Several typical foci of partly keratinized squamous
of diverse heterologous components, is epithelium in an inflammatory tissue.
Hepatoblastoma 231
foreign-body giant-cell reaction. Com- Hepatocellular adenoma is rarely found

pletely regressed tumour often shows fi- in the first 5–10 years of life, but may be
brous spheres containing scarred difficult to differentiate from a pure fetal
vessels, necroses, old blood and hepatoblastoma on the basis of imag-
haemosiderin granules. ing. Mesenchymal neoplasms such as
hepatic angiomyolipomas or other
Differential diagnosis perivascular epithelioid cell tumours
Hepatoblastoma must be differentiated (PEComas) occurring in children are,
from other liver tumours and pseudotu- owing to their imaging morphology and
mours that occur in the same age group. anatomical localization, relatively easy
Modern imaging techniques, especially to differentiate from malignant liver-cell
Fig. 10.71 Cholangioblastic hepatoblastoma.
MRI, allow distinction from infantile hae- tumours.
mangioendothelioma, which presents al-
most exclusively in the first year of life as Variants of hepatoblastoma and tumours
an asymptomatic liver mass or masses related to hepatoblastoma
with or without shunting phenomena and Hepatoblastomas and related tumours
heart failure {2870}. with cholangiocellular components
Mesenchymal hamartoma, a benign but A proportion of hepatoblastomas are
sometimes very large lesion, occurs dur- characterized by the presence of cholan-
ing the first 2–3 years of life and presents giocellular elements with or without form-
as a rapidly enlarging mass owing to cyst ation of bile duct-like structures
formation {3086}, a feature not encoun- (hepatoblastoma with cholangioblastic
tered in hepatoblastoma. Rapid enlarge- features; cholangioblastic hepatoblas-
Fig. 10.72 “Ductal-plate tumour.” In this hepatoblastoma ment may also be seen in undifferentiated toma) {3719}. Duct-like profiles may be
variant, nests of nodules of hepatoid epithelial cells embryonal sarcoma, which however oc- seen on staining with haematoxylin and
encircled by keratin 7-positive cholangiocytes often form curs in older children than for mesenchy- eosin, while cholangiocellular elements
duplicated profiles with slits, mimicking the ductal plate. mal hamartoma and hepatoblastoma. may be revealed by immunostaining for
Focal nodular hyperplasia (FNH) may be keratins 7 and 19. In rare instances, slit-
seen in the first few years of life, but is like ductular structures surround nodules
elements. Keratinized squamous epithe- more common in older children; the of immature hepatoblasts or hepatocytes,
lium is a typical post-chemotherapy fea- radiological features of this lesion are mimicking an abortive ductal plate (“ductal
ture, and is often accompanied by a distinctive. plate tumours”) {1035}.
A B C
Fig. 10.73 Transitional liver cell tumour (TLCT). A Tumour composed of large hepatoid cells, few giant cells and smaller cells growing in a trabecular to diffuse pattern. B Note the
very large multinuclear tumour giant cells and a few hepatoblastoma-like cells. C After immunostaining for β-catenin, TLCTs often show a mixed pattern, i.e. nuclear, cytoplasmic,
and membranous staining.
A B C
Fig. 10.74 Calcifying nested stromal epithelial tumour. A A nest of epithelial cells, reminiscent of immature hepatoid cells, is surrounded by a mantle of spindle cells. B The epithelial
cells show prominent nuclear immunostaining for β-catenin. C The mesenchymal elements of the tumour are positive for smooth muscle actin.

Transitional liver cell tumour Table 10.05 The Pretreatment Extent of Disease (PRETEXT) staging system {2706}.
Transitional liver cell tumour (TLCT) is a
PRETEXT I One sectiona is involved and three adjoining sections are free.
recently characterized malignant hepato- PRETEXT II One or two sections are involved, but two adjoining sections are free
cellular neoplasm {2595} that occurs in PRETEXT III Two or three sections are involved, and no two adjoining sections are free.
older children and young adolescents, PRETEXT IV All four sections are involved.
and is distinct in regard to clinical pres-
entation, histopathology, immunohisto- Additional criteria for liver tumour
chemistry and treatment response. The Caudate lobe involvement (C)
term “transitional” implies a putative inter- C0 Caudate lobe not involved
mediate position of the neoplastic cells C1 Tumour involving the caudate lobe
between hepatoblasts and hepatocytes. Tumour focality (F)
Clinically, TLCT presents as large or very F0 Patient with solitary tumour
large, expanding masses commonly lo- F1 Patient with two or more discrete tumours
cated in the right liver lobe. These masses Additional criteria for venous involvement
are hypo-dense and non homogeneous in
Portal-vein involvement (P)
CT scans and may demonstrate extensive P0 No involvement of the main portal vein or its left or right branches
central necroses. Very high levels of P1 Involvement of either the left or the right branch of the portal vein
serum AFP are typical. Histologically, the P2 Involvement of the main portal vein
growth pattern is more often diffuse than a Suffix “a” if intravascular tumour is present (e.g. P1a)
trabecular, lacking a prominent sinusoidal
vascular network or prominent stroma. Involvement of the inferior vena cava (IVC) and/or hepatic veins (V)
The tumour cells represent a mixture of V0 No involvement of the hepatic veins or IVC
V1 Involvement of one hepatic vein but not IVC
cells resembling those of hepatocellular
V2 Involvement of two hepatic veins but not the IVC
carcinoma, hepatoblastoma-like cells V3 Involvement of all three hepatic veins and/or the IVC
(mainly with a fetal morphology), and
a Suffix “a” if intravascular tumour is present (e.g. V1a)
multinucleated giant cells. Acinar struc-
tures staining for keratins 7 and 19 may Additional criteria for abdominal involvement
also be encountered. The tumour cells ex- Tumour rupture or intraperitoneal haemorrhage (H)
press β-catenin, in a mixed nuclear and H0 No evidence of tumour rupture or intraperitoneal haemorrhage
cytoplasmic pattern. H1 Imaging and clinical findings of intraperitoneal haemorrhage
TLCT are very aggressive neoplasms that Extrahepatic abdominal disease (E)
pursue a rapid course and do not re- E0 No evidence of abdominal involvement (except M1 or N1)
spond to chemotherapy. E1 Direct extension of tumour into adjacent organs or diaphragm
E2 Peritoneal nodules
Calcifying nested stromal epithelial a Suffix “a” if intravascular tumour is present (e.g. E1a)
tumour of the liver Additional criteria for metastases
This neoplasm is an unusual, probably Distant metastases (M)
favourable hepatic tumour in children of M0 No metastases
young to older age {1149, 1194}. It is M1 Any metastases except E and N
characterized histologically by nested Lymph-node metastases (N)
spindle and epithelioid cells and some- N0 No nodal metastases
times marked desmoplasia. The nests of N1 Metastases in abdominal lymph nodes only
epithelioid cells resemble immature, ker- N2 Metastases in extra-abdominal lymph nodes
atin 8- and epithelial membrane antigen- (with or without abdominal lymph-node metastases)
positive hepatoid cells with eosinophilic a
PRETEXT groups the liver into four sections: left lateral section (segments 2 and 3); left medial section (segments
cytoplasm. These nests are surrounded 4a and 4b); right anterior section (segments 5 and 8); right posterior section (segments 6 and 7). The term “section”
by spindle cells that stain for vimentin and is synonymous with the previously used term “sector.”
α-smooth muscle actin. Calcifications and
bone formation may occur. An possible Table 10.06 Children’s Oncology Group (COG) staging of hepatoblastoma {2666}.
relationship to mixed blastomatous tu-
mours of the paediatric liver is uncertain, Stage Criterion
but, like hepatoblastomas, the epithelioid Stage I Tumour completely resected with no microscopic residual disease
cells in nested tumours have nuclear pos-
Stage II Microscopic residual disease present
itivity for β-catenin, suggesting a patho-
genic role for mutations in the β-catenin Preoperative or intraoperative rupture
gene. Stage III Tumour unresectable
Tumour resected with grossly visible residual disease
Tumour spread and staging Nodal involvement
Some 40–60% of hepatoblastomas are ei-
Stage IV Distant metastases
ther very large or involve both liver lobes
Hepatoblastoma 233
Table 10.07 Molecular findings in hepatoblastoma.
Gene or genetic pathway Alteration References
Chromosomal changes Gain or loss of 1q, 2q, 4q, 8, 11q, 17q and 20
Microsatellite instability {635}
TGFB1 (TGFβ) Upregulation {25}
PPARA Upregulation {25}
Adipocytokine signalling Upregulation {25}
Extracellular matrix-receptor interaction Upregulation {25}
Apoptopic pathways Downregulation {25}
Upregulation of the WNT β-catenin signalling pathwaya {25}
CTNNB1 Mutation; deletions in exons 3 and 4 {1897, 635}
AXIN1 and AXIN2 Mutations {3427}
APC Mutations (found in hepatoblastoma associated with familial adenomatous polyposis {1208}
Upregulation of cell-cycle pathways and loss of check-point control
PLK1 (polo-like kinase-1) Upregulation {3579}
CDKN2A (p16) Promoter methylation {2936A}
CDKN1B (p27/KIP1) Loss of expression {345A}
DLK1, the NOTCH ligand Upregulation {1897}
Dysregulation of insulin-like growth factor (IGF) signalling {1053, 3414, 3264}
PLAG1 Overexpression {3681A}
11p15 gene cluster Imprinting errors (found in hepatoblastoma associated with Beckwith-Wiedemann syndrome) {595}
Molecular markers with prognostic significance
PLK1 Expression is an indicator of poor prognosis {3579}
RASSF1A Methylation suggests that tumour is less likely to respond to preoperative chemotherapy {1232}
a
Seen on immunohistochemistry as nuclear localization of β-catenin.
at presentation, rendering them unre- the initiation of any therapy and has been Genetic susceptibility
sectable {3084}. However, preoperative shown to correlate with overall and event- Congenital anomalies are noted in ap-
chemotherapy, such as employed in trials free survival. It is also useful in assessing proximately 5% of patients and include
by the International Childhood Liver the efficacy of neoadjuvant chemotherapy renal malformations such as horseshoe
Tumor Strategy Group (SIOPEL), reduces and predicting surgical resectability. The kidney, renal dysplasia and duplicated
the size of the tumour masses in > 80% of COG system assesses completeness of ureters, gastrointestinal malformations
patients, allowing complete resection. resection, which is the single most impor- such as Meckel diverticulum, inguinal
{860, 2057, 2525, 2707}. Tumour spread tant prognostic factor in hepatoblastoma. hernia and diaphragmatic hernia, and
includes local extension into the hepatic It is therefore designed for post-surgical other disparate malformations such as
veins and the inferior vena cava. The lung staging of the tumour and is more appro- absent adrenal gland, heterotopic lung
is the most frequent site of remote metas- priate for use in treatment protocols that tissue and hemihypertrophy. Other syn-
tases; approximately 10–20% of patients favour surgery immediately after diagno- dromes with an increased incidence of
have pulmonary metastases at diagnosis. sis. hepatoblastoma include Beckwith-Wiede-
Hepatoblastomas also metastasize to the The PRETEXT stage consists of a num- mann syndrome, trisomy 18, trisomy 21,
skeleton, brain, ovaries, and the eye. Pre- ber from 1 to 4, which indicates the ex- Acardia syndrome, Goldenhar syndrome,
natally developing hepatoblastomas may tent of liver involvement by tumour, plus Prader Willi syndrome, type-1a glycogen
metastasize to the placenta {318, 789, several additional criteria {2706}. The storage disease {2677} and familial ade-
2698}. PRETEXT number is derived by sub- nomatous polyposis (FAP). FAP kindreds
There are two main systems for staging of tracting the number of contiguous sec- include patients with hepatoblastoma
hepatoblastoma; the first is the PRETEXT tions not involved by tumour from 4 who have a mutation at the 5' end of the
(pretreatment extent of disease) system (Table 10.05). When assigning this num- APC gene {463, 983}. Alterations in APC
formulated by SIOPEL and the second is ber, it is important to distinguish actual have also been noted in cases of hepato-
the COG (Children’s Oncology Group) involvement of the section from mere blastoma in patients with nonfamilial ade-
system adopted by the American Chil- compression by an adjacent tumour. nomatous polyposis {2347}.
dren’s Oncology Group. The PRETEXT The COG staging system is shown in
system is used for staging tumours before Table 10.06 {2666}.

Molecular pathology Table 10.08 Correlation of molecular changes with histological subtypes of hepatoblastoma.
Genetic and molecular studies of hepato-
blastoma have identified gains or losses Histological subtype Molecular change References
of several chromosomes as well as alter- Small cell undifferentiated (SCUD) Differential overexpression of MAPK pathway genes {25}
ations in pathways affecting cell fate, hepatoblastomaa
growth, apoptosis, signalling and differ- Loss of CDKN1B (p27/KIP1)
entiation (Table 10.07) {1054}. Of these, Overexpression of FOXG1 {26}
the two most commonly implicated path- Decreased expression of HES1 (a NOTCH target gene) {1897}
ways are the Wnt/β-catenin and the in-
Decreased expression of GLUL (encoding glutamine synthetase) {1897}
sulin growth factor signalling pathways.
Approximately 70% of sporadic hepato- Fetal hepatoblastoma a
Large deletions in exons 3 and 4 of the β-catenin gene (CTNNB1) {1897}
blastomas show accumulation of β- Upregulation of genes involved in extracellular matrix-receptor
catenin {635} and a common deletion in Mesenchymal hepatoblastoma {25}
interaction pathways
exon 4 of the CTNNB1 gene was demon- MAPK, mitogen-activated protein kinase.
strated in 86% of hepatoblastomas a
Molecular changes for SCUD are compared to those for fetal hepatoblastoma and vice versa.
{1897}. There appears to be some corre-
lation between molecular patterns and
histological subtypes, with the most sig- ing and rendering it resectable {1244, for various events in mitotic progression.
nificant differences being observed at the 2525}. High initial (PRETEXT) tumour In one study, higher mRNA levels correl-
two ends of the differentiation spectrum of stage, low serum AFP, vascular invasion ated with poor outcome: the 5-year
hepatoblastoma, namely the fetal subtype and certain histological subtypes (SCUD; survival rate was 56% for high expression
and SCUD subtype (Table 10.08). In gen- rhabdoid features; TLCT) are powerful versus 87% for low expression {3579}. A
eral, fetal hepatoblastomas show more predictors of aggressive biology (high- separate study showed that hepato-
molecular evidence of differentiation than risk tumours), whereas low stage and blastomas with RASSF1A methylation
SCUD hepatoblastomas. purely fetal morphology are favourable (RAS association domain family protein 1)
prognostic factors (standard risk) {3416}. are less likely to respond to preoperative
Prognosis and predictive factors Serum AFP levels are useful in predicting chemotherapy than those without
Prognosis is directly affected by the abil- outcome by monitoring the response of RASSF1A methylation {1232}.
ity to completely resect the lesion {591, AFP-producing tumours to surgery and
1097, 3418}. Modern treatment strategies chemotherapy {3371}.
developed and tested in large interna- Of all the molecular markers studied, only
tional trials during the past years have im- Polo-kinase 1 expression has been re-
pressively improved the prognosis and ported to have prognostic value inde-
outcome of hepatoblastoma, primarily by pendent of β-catenin mutation, age, stage
shrinking the tumour, thereby downstag- or histology {3579}. This protein is crucial
Hepatoblastoma 235
W.M.S. Tsui
Mucinous cystic neoplasms of the liver N.V. Adsay
J.M. Crawford
R. Hruban
G. Klöppel
A. Wee
Definition
A cyst-forming epithelial neoplasm, usually
showing no communication with the bile
ducts, composed of cuboidal to columnar,
variably mucin-producing epithelium, as-
sociated with ovarian-type subepithelial
stroma. This neoplasm occurs almost ex-
clusively in women. Noninvasive mucinous
cystic neoplasms (MCN) are categorized on
the basis of the highest degree of cytoar-
chitectural atypia into MCN with low-grade
Fig. 10.75 Mucinous cystic neoplasm, high grade, with Fig. 10.76 Biliary adenofibroma. Circumscribed tumour
dysplasia, MCN with intermediate-grade invasive carcinoma (biliary cystadenocarcinoma). with solid and spongy areas formed by microcysts.
dysplasia, and MCN with high-grade dys- Multiloculated cystic tumour with solid fleshy nodules
plasia. If there is a component of invasive arising in the wall.
carcinoma, the lesion should be designated
as MCN with an associated invasive carci-
noma. MCNs occur principally in the liver
and occasionally in the extrahepatic biliary
system (including the gallbladder).
ICD-O codes
MCN with low- or intermediate-grade
MCN with high-grade
intraepithelial neoplasia 8470/2 A B
MCN with an associated invasive carcinoma
8470/3
Synonyms
These lesions have previously been re-
ferred to as cystadenoma and cystade-
nocarcinoma.
Epidemiology
MCNs are rare {706}. Without an associ-
C D
ated invasive carcinoma they are seen al-
most exclusively in women. Cases of Fig. 10.77 Mucinous cystic neoplasm, low grade (biliary cystadenoma). A Multiple locules among a compacted cellular
stroma with an outer fibrous capsule. B The columnar lining epithelium is mucin-secreting and lies on an ovarian-like
“cystadenocarcinoma” have been re-
stroma. C Carcinoembryonic antigen (CEA) is focally expressed on the luminal border of dysplastic epithelium. D The
ported in males and females with equal ovarian-like stroma is immunoreactive for estrogen receptors.
frequency; however, based on the current
requirement for the presence of ovarian-
type stroma, it is likely that many of these the time of presentation, typically abdom- internal septation, and papillary projec-
neoplasms would now be classified as in- inal pain and swelling. Biliary obstruction tions observed in the malignant tumours.
traductal papillary neoplasms (IPN) of the with resultant jaundice and ascending in-
bile ducts with marked cystic changes. Pa- fection, haemorrhage, rupture, vena- Macroscopy
tients who present with MCN with an asso- caval obstruction and biliary calculi Most MCNs are multilocular and range in
ciated invasive carcinoma tend to be older formation have also been reported. size from 2.5 to 28 cm {706}. The fluid con-
(mean age, 59 years) than patients with Serum levels of the tumour marker CA19- tent of locules is usually thin and watery, but
noninvasive MCN (mean age, 45 years). 9 may be elevated, particularly if there is it can also be haemorrhagic or composed
an associated invasive carcinoma. Imag- of a mucinous semi-solid material. The cysts
Clinical features ing techniques show a multilocular cystic typically do not directly communicate with
MCNs nearly always cause symptoms at mass, with irregular thickness of the wall, the larger bile ducts. When an associated

invasive carcinoma is present, there may be

a large papillary mass as well as solid areas
of grey-white tumour in a thickened wall.
Tumour spread and staging

MCNs are slow-growing, frequently reach-
ing a large size. They can progress to in-
vasive carcinoma over a period of many
years. When present, an associated inva-
sive carcinoma is usually limited to within
A B
the primary neoplasm so that complete
Fig. 10.78 Mucinous cystic neoplasm with high-grade intraepithelial neoplasia (biliary cystadenocarcinoma). A Transition
surgical removal is often feasible. How-
from normal to dysplastic epithelium. B Complex papillary projections and crypt-like invaginations in the area of
ever, invasive carcinoma can sometimes high-grade neoplasia.
spread to the parenchyma of the liver, or
metastasize to regional lymph nodes in
the hepatoduodenal ligament. Distant epithelial cells in most hepatic cases have characterized by significant architectural
metastases most frequently involve the pale eosinophilic cytoplasm and basally atypia, such as exophytic papillae with
lungs, pleura and peritoneum. Staging fol- oriented nuclei, and express biliary-type back-to-back glands, as well as nuclear
lows the protocol of TNM (tumour, node, keratins (7, 8, 18, 19), epithelial mem- pleomorphism and numerous mitotic fig-
metastasis) classification for intrahepatic brane antigen (EMA), and focally carci- ures. Most associated invasive carcino-
cholangiocarcinoma noembryonic antigen (CEA). Gastric and mas are ductal adenocarcinomas with
intestinal differentiation and squamous tubulopapillary or tubular growth patterns.
Histopathology metaplasia may also occur. About half of Although often multifocal, malignant foci
These tumours should be extensively the tumours contain scattered endocrine may be focal, and these neoplasms there-
sampled for microscopy, especially in cells, as identified by expression of chro- fore need to be extensively sampled
areas with papillary projections and mural mogranin and synaptophysin {3213}. {706}.
nodules. By microscopy, noninvasive Subjacent to the basement membrane is
MCNs are usually multilocular and are a cellular, compact, ovarian-like, mes- Cytopathology
well-defined by a fibrous capsule, which enchymal stroma, which in turn is sur- Diagnostic fine-needle aspiration (FNA)
may contain smooth muscle fibres. The rounded by looser fibrous tissue. The cytology samples are characterized by
inner surface of the cysts are lined by stromal cells are spindle-shaped or rarely aggregates of cuboidal to columnar ep-
columnar, cuboidal, or flattened, mucus- oval, and may be focally luteinized. They ithelium with occasional papillary
secreting epithelial cells resting on a express vimentin, actin and desmin. This arrangement. The background can be
basement membrane; polypoid or papil- mesenchymal component is immunore- watery, or composed of abundant thick
lary projections may be present. A muci- active with estrogen and progesterone mucin containing degenerated cellular
carmine stain can highlight the mucin, receptors, and α-inhibin {3}. A xan- debris and macrophages. The neoplas-
particularly when the neoplastic epithelial thogranulomatous reaction, with foam tic cells show varying degrees of
cells are columnar. Compared with MCNs cells, cholesterol clefts and pigmented architectural and nuclear atypia corre-
of the pancreas, hepatic MCNs more lipofuscin-containing macrophages, may sponding to heterogeneity of the cyst lin-
commonly have cuboidal, non mucinous be present in the cyst wall. ing. The ovarian-type stromal component
epithelium. However, the presence of Foci of epithelial dysplasia comprising mi- is usually not seen {1884, 3479}. The cy-
ovarian-type stroma defines these neo- cropapillary projections or crypt-like in- tological features overlap with those of
plasms as MCN. The use of the term vaginations, nuclear enlargement and IPN, in which papillary clusters with fi-
“serous cystadenoma” for neoplasms with hyperchromasia, multilayering, and mito- brovascular cores and nuclear grooves
ovarian-type stroma is inappropriate. The sis may be seen. Severe dysplasia is are abundant {3310}.
A B C
Fig. 10.79 Fine-needle aspirate of mucinous cystic neoplasm, low grade (biliary cystadenoma). A Mucinous background with some cellular debris and muciphages (Papanicolaou).
B A sheet of columnar cells with bland nuclei in basal location (Papanicolaou). C Cell block reveals a short strip of columnar cells with basally oriented nuclei and mucin-positive
apical cytoplasm (mucicarmine).

tumours, is basically a solid tumour with

some microcystic spaces, comprising mi-
crocystic and tubuloacinar glandular struc-
tures lined by non-mucin-secreting biliary
epithelium and supported by a fibroblastic
stromal scaffolding {3311}.
Endometriosis with its specialized stroma
can mimic MCN, as can adult mesenchy-
mal hamartoma with multicystic appear-
A B ance. In cases where the mesenchymal
stroma is lacking, distinction of MCN from
Fig. 10.80 Fine-needle aspirate of mucinous cystic neoplasm with high-grade intraepithelial neoplasia (biliary cystadenocarcinoma).
A Sheets of moderately dysplastic epithelium with larger nuclei, nuclear crowding, and irregular nuclear membrane.
non-neoplastic bile duct cysts and other
B Clusters of malignant cells with much enlarged, pleomorphic hyperchromatic nuclei, prominent nucleoli and pale cytoplasm. large cystic lesions can be problematic.
Bile duct cysts (simple hepatic cysts) are
characterized by flat to columnar lining epi-
thelium and absence of mucin-secretion;
accompanying von Meyenburg complexes
and corpora albicans-like collapsed cysts
are common when multiple bile duct cysts
are present in the liver.
Intrahepatic cystic carcinomas that com-
municate with bile ducts and do not con-
tain ovarian-like stroma are most likely to
A B be associated with IPN {132, 2238}. Peri-
Fig. 10.81 Peribiliary cysts. A Large cysts in the connective tissue of the hilus; the background liver shows advanced biliary cysts comprising cystically dilated
cirrhosis. B Variably sized cysts are intermingled with peribiliary glands. peribiliary mucin-secreting glands may
simulate MCN. In fact, it is currently
thought likely that MCN originates from
peribiliary glands, considering the site of
occurrence, histological morphology, close
relationship with these glands, and fre-
quent presence of endocrine cells.

The prognosis for patients with a nonin-
vasive biliary MCN is excellent if complete
resection is possible. The prognosis for
patients with an invasive adenocarcinoma
arising in association with MCN is much
harder to predict. In the past, a variety of
different carcinomas were lumped to-
Fig. 10.82 Cystic variant of intraductal papillary neoplasm (IPN) closely mimicking high-grade mucinous cystic neoplasm gether under this designation, including
(right side) but lacking the ovarian-like stroma. Note the intraductal papillary neoplasm (IPN) in the adjacent dilated bile carcinomas arising in association with
duct (left side). MCN with ovarian stroma, carcinomas
arising in the context of fibropolycystic
In practice, FNA lacks sensitivity owing to form mucin-containing cysts lined by a disease, carcinomas arising in congenital
sampling problems and often cannot dif- cuboidal to columnar neoplastic epi- liver cysts, and carcinomas in the hepa-
ferentiate between the various types of thelium. Communication with the bile ducts toduodenal ligament {706, 3230}.
hepatobiliary cysts. The findings usually and absence of ovarian-like stroma favour Additional data are needed to define
only permit distinction between benign a diagnosis of IPN of the bile ducts {3114, more precisely the prognosis for patients
cyst contents or adenocarcinoma. Stains 3690}. with MCN with an associated invasive
for mucin can help distinguish mucinous Hepatic microcystic serous cystadenoma carcinoma when current definitions,
from nonmucinous cystic lesions. The of pancreatic type is characterized by mul- specifically inclusive of the requirement
cyst fluid can be also assayed for CA19- tiple small locules lined by a single layer of for ovarian-like stroma, are rigorously ap-
9 and CEA to distinguish a mucinous glycogen-rich cuboidal cells with clear cy- plied. At present, it appears that invasive
neoplasm from non-neoplastic lesions toplasm and lacking the ovarian-type mes- adenocarcinomas arising in association
{1627}. enchymal stroma. This benign tumour is with biliary MCN have a better prognosis
exceedingly rare in the liver {706, 1350, than do pure cholangiocarcinomas, high-
Differential diagnosis 1564}. Biliary adenofibroma, another rare lighting the importance of this distinction.
MCN and IPN of the biliary tree can both member of the group of benign bile-duct

E.S. Jaffe
Lymphoma of the liver H.K. Müller-Hermelink
J. Delabie
Y.H. Ko
S. Nakamura
Definition liferative disease of childhood) may pres-

Primary hepatic lymphoma is defined as ent with abnormal results for serum liver
an extranodal lymphoma arising in the enzyme tests {2610}. Most cases are soli-
liver, with the bulk of the disease localized tary or multiple masses within the liver,
to this site. More often, the liver is a sec- sometimes misdiagnosed as primary he-
ondary site of involvement by lymphoma. patocellular or metastatic cancer {2041}.
Some rare lymphomas, such as he- Some cases have been reported with dif-
patosplenic T-cell lymphoma, may pres- fuse infiltration of the liver associated with
ent with dominant manifestations in the hepatomegaly, but without a discrete
liver, but the disease is in reality systemic. mass, simulating hepatic inflammation.
T-cell/histiocyte-rich large B-cell lym-
Epidemiology phomas often present with marked
Primary lymphoma of the liver is rare hepatomegaly, but the disease is usually A
{1341} and mainly a disease of middle- disseminated with splenic and bone-mar-
aged men {2041}, although occasional row involvement {455}.
paediatric cases are reported. Most are In contrast to primary lymphoma, sec-
diffuse large B-cell lymphomas (DLBCL), ondary liver infiltration is a frequent oc-
mucosa-associated lymphoid tissue currence in many low-grade B-cell
(MALT) lymphomas are second most malignancies, including chronic lympho-
common. Hepatosplenic T-cell lymphoma cytic leukaemia and follicular lymphoma,
is a disease that mainly affects young and is an indication of stage IV disease.
adult males (male : female ratio, approxi- Hepatosplenic T-cell lymphomas present
mately 5 : 1) {593}. Predominantly paedi- with hepatosplenomegaly, usually without B
atric lymphomas, such as Epstein-Barr peripheral lymphadenopathy or lympho-
Fig. 10.83 Diffuse large B-cell lymphoma (DLBCL). A
virus (EBV)-positive T-cell lymphoprolifer- cytosis. There is almost always thrombo-
MRI for the patient shown in B. Multiple filling defects are
ative disease of childhood, are also rec- cytopenia and most patients are anaemic. seen in the liver. B HIV-associated. Sheets of abnormal
ognized {2610}. The results of tests of liver function are lymphoid cells diffusely infiltrate the hepatic parenchyma.
usually abnormal, with moderate eleva-
Etiology tion of levels of transaminases and
A proportion of cases are associated with alkaline phosphatase. Serum lactate de-
infection with hepatitis C virus, with or hydrogenase levels may be very high
without mixed cryoglobulinaemia {114, {593}. Evidence of hepatic failure is com-
152, 652, 677, 2122, 2197, 2741}. Other mon in lymphomas associated with a
lymphomas have been reported arising haemophagocytic syndrome, most often
within a background of infection with hep- EBV-positive T-cell or natural-killer cell
atitis B virus {1999, 2424}, HIV {2544, (NK) malignancies {1323, 1383}.
2835} or primary biliary cirrhosis {2584}.
Hepatosplenic T-cell lymphomas have Histopathology
been linked to iatrogenic immunosup- B-cell lymphoma Fig. 10.84 Hepatosplenic T-cell lymphoma. Abnormal
pression, especially in children with Crohn The majority of primary hepatic lym- lymphoid cells with abundant pale cytoplasm infiltrate
disease {2257, 3228, 3394}. EBV infection phomas are DLBCLs and are composed hepatic sinusoids.
of T cells is found in systemic EBV-posi- of a monotonous proliferation of large
tive T-cell lymphoproliferative disease of cells expressing CD20 and other B-cell-
childhood, and may follow chronic active associated antigens, with formation of a lymphoid infiltrate within the portal tracts.
EBV infection in some cases {576, 2375}. destructive mass lesion. T-cell/histiocyte- The atypical lymphoid cells have centro-
rich large B-cell lymphomas involve the cyte-like cell morphology and surround
Clinical features liver more diffusely, usually with infiltration reactive germinal centres. Lymphoepithe-
The most frequent presenting symptoms of portal triads. Occasional cases of lial lesions may involve the bile-duct epi-
are right upper-abdominal/epigastric pain Burkitt lymphoma have been described thelium, and these may be highlighted by
or discomfort, weight loss and fever {1276}, usually presenting as a solitary staining with antibodies to keratins {1574,
{2041}, although some patients (e.g. mass. Low-grade B-cell lymphomas of 1950}. IgG4-associated sclerosing cholan-
those with EBV-postiive T-cell lymphopro- MALT type are characterized by a dense gitis should be considered in the differential
Lymphoma 239
diagnosis of hepatic MALT lymphoma and

is usually associated with autoimmune
pancreatitis {702}.
Secondary involvement of the liver by low-
grade B-cell malignancies shows prefer-
ential involvement of the portal triads, with
the morphology and phenotype related to
the specific entity.
T-cell lymphoma A B
Hepatosplenic T-cell lymphoma is charac-
Fig. 10.85 Aggressive NK-cell leukaemia with prominent sinusoidal infiltration. A Neoplastic cells infiltrate the sinuses.
terized by infiltration of the sinusoids by B In situ hybridization shows that tumour cells are positive for Epstein-Barr virus-encoded RNA (EBER).
a monomorphic population of medium
sized cells with a moderate amount of
eosinophilic cytoplasm. The nuclei are than portal tracts. Systemic EBV-positive T- cases {98}. For other lymphoma sub-
round or slightly indented with moderately cell lymphoproliferative disease of child- types, the genetics are specific to the par-
dispersed chromatin and contain small, hood and aggressive NK-cell leukaemia ticular diagnosis, with no features specific
usually basophilic, nucleoli. Portal infiltra- are both sinusoidal in distribution and often for cases with hepatic involvement.
tion is variable, but generally not promi- associated with haemophagocytic syn-
nent. A similar sinusoidal pattern of drome. In haemophagocytic syndrome, Prognosis and predictive factors
infiltration is seen in the spleen and bone Kupffer cells show erythrophagocytosis The prognosis for patients with primary
marrow, both of which are usually involved and bile stasis is usually evident. Extran- hepatic lymphoma relates to the specific
by the lymphoma at diagnosis {593, 819}. odal NK/T-cell lymphoma also has a high disease entity. DLBCL is an aggressive
The cells are most often of γ δ T-cell deri- frequency of hepatic infiltration, with or disease, with the international prognostic
vation with a minority derived from α β T- without haemophagocytic syndrome. index providing guidance for expected
cells. They are cytotoxic, but with an treatment response and outcome {2041,
immature or inactivated phenotype {225, Molecular pathology 2954}. Liver involvement is indicative of
593, 819}. Hepatic MALT lymphomas have been as- stage IV disease. Hepatosplenic T-cell
Systemic T-cell malignancies, including T- sociated with a translocation involving lymphomas are very aggressive, with a
cell large granular lymphocytic leukaemia, IGHα and MALT1 {3094}. Hepatosplenic mean patient survival time of 1 year {225,
and adult T-cell leukaemia/ lymphoma usu- T-cell lymphomas are associated with 593}.
ally involve the sinuses more prominently isochromosome 7q and trisomy 8 in most

Mesenchymal tumours of the liver M. Miettinen

C.D.M. Fletcher
L.G. Kindblom
A. Zimmermann
W.M.S. Tsui
Definition
A group of benign or malignant tumours
with specific mesenchymal cell differenti-
ation or lack of specific differentiation (un-
differentiated sarcoma).
ICD-O codes
Angiomyolipoma (PEComa) 8860/0
Cavernous haemangioma 9121/0
Infantile haemangioma 9131/0
A B
Lymphangioma 9170/0
Solitary fibrous tumour 8815/0
Angiosarcoma 9120/3
Carcinosarcoma 8980/3
Embryonal sarcoma
(undifferentiated sarcoma) 8991/3
Epithelioid
haemangioendothelioma 9133/3
Leiomyosarcoma 8890/3
Malignant rhabdoid tumour 8963/3 C D
Rhabdomyosarcoma 8900/3 Fig. 10.86 Mesenchymal hamartoma. A The cut surface shows cysts and tan-white tissue. B Mixture of bile ducts,
Synovial sarcoma 9040/3 mesenchymal tissue and blood vessels. C Bile ducts display a ductal plate malformation; the primitive mesenchymal
tissue consists of loosely arranged stellate cells. The tumour contains liver cells (top) in addition to blood vessels. D Fluid
Mesenchymal hamartoma accumulation in the mesenchyme mimics lymphangioma, but the spaces lack an endothelial lining.
Mesenchymal hamartoma (MH) of the
liver is a benign tumour-like lesion that de-
velops before birth and is characterized all liver tumours and pseudotumours from 22% of all benign liver neoplasms. About
by a commonly multicystic and well-de- birth to age 21 years, but represents 12% 85% of affected children present before
lineated hepatic mass {600, 686, 1712, of all liver tumours and pseudotumours the age of 3 years, and < 5% of MHs are
3083, 3086, 3098}. It accounts for 8% of arising during the first 2 years of life, and diagnosed after the age of 5 years {693}.
About 15% of cases have been observed
Table 10.09 Mesenchymal tumours of the liver. in the neonatal period {2183}. The lesion
is slightly more common in boys than in
Mode of presentation Examples
girls. In contrast, the rare MHs occurring
Asymptomatic (incidental finding) Any in adults are more frequent in women
Upper abdominal mass +/- hepatomegaly Any {3637}.
Sudden increase in size of tumour Mesenchymal hamartoma, cavernous haemangioma
Febrile illness with weight loss Inflammatory pseudotumour, embryonal sarcoma, angiosarcoma Clinical features
Acute abdominal crisis from rupture Cavernous haemangioma, infantile haemangioma, angiomyolipoma, Clinically, MH typically presents with ab-
angiosarcoma, epithelioid haemangioendothelioma dominal distension and an upper abdom-
Budd-Chiari syndrome Epithelioid haemangioendothelioma
inal mass, although some cases are
found incidentally. Pain is rarely a domi-
Congestive heart failure Infantile haemangioma
nant feature, and only few patients show
Cardiac tumour syndrome Embryonal sarcoma anorexia, vomiting or failure to thrive
Consumption coagulopathy Cavernous haemangioma, infantile haemangioma {693}. Abdominal distention may rapidly
Hypoglycaemia Solitary fibrous tumour progress owing to fluid accumulation in
Portal hypertension Epithelioid haemangioendothelioma, inflammatory pseudotumour the loose tissues and in cysts and may
Liver failure Epitheliod haemangioendothelioma, angiosarcoma cause respiratory distress. Large MH in
neonates and infants may compromise
Obstructive jaundice Inflammatory pseudotumour
blood circulation and evolve into life-
Lung metastases Epithelioid haemangioendothelioma, angiosarcoma threatening lesions. Specifically, tumoral

arteriovenous shunts may induce heart Histopathology 19q13.4 might be a common clonal ab-
failure. A complication of macrocystic MH The lesion is composed of loose con- normality in MH {2902}.
is cyst rupture followed by neonatal as- nective tissue and epithelial bile duct- or
cites {964}. MH is sometimes associated ductule-like in varying proportions. The Prognosis
with malformations, including defects in mesenchyme is typically loose and myx- As a rule, MH has a benign course in the
the common mesentery and mesenchy- oid, or collagenous and arranged con- absence of complications, with good
mation, such as protrusion through the centrically around the the ductules. The prognosis if the mass is resected {3633}.
chest wall. It may also sometimes be latter may be tortuous and occasionally Exceptions are patients with severe car-
associated with mesenchymal stem villus dilated. These biliary cell profiles are diopulmonary complications and the rare
hyperplasia/dysplasia of the placenta often arranged in a ductal-plate malfor- instances of evolution into undifferentiated
{444, 1711}. A subset of MHs is already mation pattern. Islets of liver cells with- (embryonal ) sarcoma {1487, 2622}.
detectable prenatally (fetal mesenchymal out an acinar architecture may be
hamartoma), usually diagnosed by fetal present. MH usually contains foci of ex- Infantile haemangioma
ultrasonography and/or computed to- tramedullary haematopiesis (in > 85% of Infantile haemangioma (formerly often
mography (CT) in the last trimester of cases). designated as infantile haemangioen-
pregnancy. The results of liver-function dothelioma) is a benign vascular tumour
tests are usually normal, but serum levels Molecular pathology similar to capillary haemangioma of the
of α-fetoprotein (AFP) may be slightly ele- On the basis of analyses of cytogenetics skin in infancy. It is the most common
vated owing to AFP production by regen- and DNA, there is some evidence that a mesenchymal tumour of the liver in infants
erating hepatocytes located around the neoplastic process may be involved. This and children, accounting for about 20%
tumour mass {299}; in exceptional cases, has received some support from the ob- of all liver tumours arising between birth
MH is associated with high levels of servation of evolution of undifferentiated and age 21 years. The clinically signifi-
serum AFP, a phenomenon that poses dif- sarcoma from MH. Chromosomal aberra- cant cases usually present in the first 2
ferential diagnostic problems in regard to tions in MH include balanced transloca- years of life, when infantile haemangioma
hepatoblastoma {891, 1084, 3344}. tions between chromosomes 15 and 19 represents 40% of all tumours and 70% of
Ultrasonography and CT reflect the main {3038} and chromosomes 11 and 19 with benign tumours {3084}. It occurs more
gross components of MH, ranging from a a break-point at 19q13.4 {1998}, intersti- frequently in females (63%) than in males.
predominantly cystic lesion or multicystic tial deletion involving chromosome band Patients usually present with an enlarging
mass to a complex solid mass, which is 19q13.4 {3175}, and a complex translo- abdomen, some may develop congestive
usually hypodense and hypovascular and cation between chromosomes 11, 17 and heart failure or consumption coagulopathy
often multiloculated {1559}. Calcification 19 {2196} termed “MHLB1” (mesenchy- {687, 2870}, and about 10% have
(usually peripheral) may occur {3069}. mal hamartoma of the liver breakpoint 1) haemangiomas in the skin or other sites.
Cysts are commonly septated, with mo- {2619}, suggesting that the break-point There may be a variety of associated con-
bile septa. These features are, together
with parietal solid and nodular compo-
nents, very suggestive of MH {1464,
2820, 3633}.
Macroscopy
Grossly, MH occur in the right liver lobe in
75% of cases, the left lobe in 22% of
cases, and both lobes in 3% of cases.
Most present as expanding, well-delim-
ited masses without a capsule, but with
perifocal liver atrophy. Very large tumours A B
may involve both lobes or even most of Fig. 10.87 Infantile haemangioma (infantile haemangioendothelioma). A A red and brown tumour with focal haemorrhage.
the organ. Few to multiple cystic spaces B Multiple brown cavitary lesions.
lacking a communication with bile ducts
are noted on cut surfaces (85% of cases).
Very young patients show fewer cysts and
a more solid phenotype, suggesting that
cysts develop in parallel with progressive
tumour growth; in some cases cysts may
reach > 10 cm in size and contain an
amber fluid or a gelatinous mass. In one
series, 41% of tumours were solid and
59% were cystic {483}. Similar to other he- A B
patic tumours, a subset of MH shows a Fig. 10.88 Infantile haemangioma (infantile haemangioendothelioma). A The tumour is well-circumscribed but not
pedunculated growth pattern, usually sit- encapsulated, and consists of small vessels. B Vessels are lined by a single layer of plump endothelial cells surrounded
uated at the inferior surface of the liver. by a scant fibrous stroma; note the scattered bile ducts (Masson trichrome stain).

A B C
Fig. 10.89 Cavernous haemangioma. A Diffuse haemangiomatosis showing numerous dark blood-filled vessels extending beyond the central spongy mass and involving the whole
liver lobe. B Multilocular blood-filled structures with pale solid areas. C Note the large thin-walled vascular spaces.
genital anomalies, including hemihyper- within the advancing edges, and foci of tions of the endothelial lining; and solid
trophy and Cornelia de Lange syndrome. extramedullary haematopoiesis. Endothe- cellular masses with whorls of spindle
lial cells in the tumour express factor VIII- cells and Kaposiform features: this is now
Macroscopy related antigen, CD31 and CD34. classified as angiosarcoma. There are
The tumours are single in 55% and multi- Distinction from congenital vascular mal- also occasional reports of transformation
ple in 45% of cases. Single tumours are formation with capillary proliferation has of infantile haemangioendothelioma to
as large as 15 cm and located equally in been advocated, using GLUT1 as an angiosarcoma {2870}.
both lobes. Multiple lesions are often immunomarker that is only positive in
< 1 cm in size and frequently involve haemangioma {2110}. Cavernous haemangioma
large portions of the liver. The large, sin- This is the most common benign tumour
gle lesions are red-brown or red-tan, often Prognosis of the liver {262}. The reported incidence
with haemorrhagic or fibre-optic centres This benign tumour exhibits rapid post- varies from 0.4% to 20% in autopsy stud-
and focal calcification. The small lesions natal proliferation, and then maturation, ies, the highest figure being the result of a
appear spongy and red-brown on sec- followed by slow involution during child- thorough prospective search {1484}. It
tioning. hood. Yet deaths are not uncommon, with occurs at all ages, but is more commonly
an overall survival of 70%; adverse risk seen in young adult females. It is known
Histopathology factors include congestive heart failure, to increase in size or even rupture during
The tumour, especially the peripheral por- jaundice, multiple tumours and absence pregnancy, and also may enlarge or recur
tion, is composed of numerous small vas- of cavernous differentiation {2870}. Clini- in patients on estrogen therapy. Haeman-
cular channels (capillary-like) lined by cal management takes account of possi- giomas are symptomatic only when they
plump endothelial cells usually arranged ble spontaneous regression and the are > 4 cm in size, leading to pain or a
in a single layer. The vessels are sup- severity of associated complications. The mass syndrome. Rupture or acute throm-
ported by a scanty fibrous stroma that first line of treatment is with drugs, fol- bosis are exceptional, as well as the se-
may be loose or compact. Larger cav- lowed in the nonresponders by surgical vere Kasaback-Merritt syndrome with
ernous vessels lined by flat endothelium resection, hepatic-artery ligation or trans- consumptive coagulopathy.
and increased stromal fibrosis are often arterial embolization, with liver transplan-
present in the centre of the larger lesions, tation being the last resort {548}. Macroscopy
corresponding to tumour regression. “Infantile haemangioendothelioma” was Cavernous haemangiomas vary from a
These vessels may undergo thrombosis classified into two histological types few millimetres in size to huge tumours
with infarction, haemorrhage and calcifi- {687}. The histologically more aggressive that can replace most of the liver. They are
cation. Other characteristic features are type 2 was characterized by nuclear usually single, and soft or fluctuant. When
small bile ducts and hepatocytes trapped atypia, multilayered and papillary projec- sectioned, they partially collapse owing to
the escape of blood and have a spongy
appearance. Recent haemorrhages, or-
ganized thrombi, fibrosis and calcification
may be seen.
Histopathology
Lesions are typically composed of vary-
ing sized blood-filled vascular channels
lined by a single layer of flat endothelial
cells and separated by fibrous septa of
various thicknesses. Small arborizing ves-
sels may be present in the fibrous stroma.
Fig. 10.90 Sclerosed haemangioma. Pale hyalinized Fig. 10.91 Lymphangioma. The lymphatic channels of Although grossly well-circumscribed,
nodule with remnants of obliterated vessels. variable size contain clear pink-staining fluid. microscopic extension of dilated vascular

or diffuse lesions must be differentiated

from peliosis hepatis and hereditary
haemorrhagic telangiectasia.
Lymphangioma and lymphangiomatosis

Lymphangioma is a rare benign tumour
that is usually observed in children and
adolescents. It may occur as a solitary
mass or more commonly as multiple
A B masses composed of multiple endothe-
lial-lined spaces that vary in size from
capillary channels to large, cystic spaces
containing clear pink-staining lymph. The
vascular spaces are lined by a single
layer of endothelial cells. The supporting
stroma is usually scanty and may contain
lymphoid tissue.
Hepatic lymphangiomas extremely rarely
occur in isolation; they are often accom-
panied by lymphangiomatosis of the
C D spleen, skeleton, and other tissues, and
may represent a malformation syndrome.
Diffuse lymphangiomatosis involving the
liver and multiple organs is associated
with a poor prognosis {655}. Single lesions
have been successfully resected {2897}.
Angiomyolipoma and lipomatous lesions

Angiomyolipoma is defined as a benign
tumour composed of variable admixtures
E F of adipose tissue, smooth muscle (spin-
dled or epithelioid), and thick-walled
blood vessels {1029}. It is currently re-
garded as a tumour of perivascular epi-
thelioid cells (PEComa) exhibiting dual
myomatous and lipomatous differentiation
and melanogenesis {1987, 3309}. This tu-
mour occurs principally in adults, with a
wide age range (10–86 years) and female
predominance (female-to-male ratio, 2 : 1
to 5 : 1). An association with tuberous
G H sclerosis is recognized (5–10%); these
Fig. 10.92 Angiomyolipoma of the liver. A Cirumscribed tumour with variegated appearence including yellowish fatty patients have coexisting renal tumours
areas. B Classic mixed tumour with admixture of myoid and fat cells. C Trabecular pattern featuring epitheloid myoid and often multiple liver tumours. Most pa-
cells arranged in trabeculae separated by sinusoids. D Inflammatory infiltrate among spindle-cell stroma resembling tients are asymptomatic, and the tumours
inflammatory pseudotumour. E Epithelioid clear myoid cells with perinuclear condensation of cytoplasm. F Oncocytic are found incidentally. Large lesions may
myoid cells with abundant eosinophilic granular cytoplasm. G Lipomatous tumour with diffuse sheets of adipocytes and cause epigastric pain. Rarely, rupture with
scanty myoid cells resembling a tumour originating from adipose tissue. H This neoplasm can easily be mistaken for haemoperitoneum occurs in large sub-
liposarcoma owing to the presence of lipoblast-like cells.
capsular tumours.
spaces into adjacent hepatic parenchyma are only rarely recorded in adult livers. Macroscopy
may be observed {1547}. Thrombi in vari- Cavernous haemangiomas are not known Angiomyolipomas are usually single and
ous stages of organization with areas of to undergo malignant change. Only large variable in size (0.8–36 cm). They are
infarction may be present, and older le- symptomatic tumours require surgical ex- sharply demarcated but not encapsu-
sions show dense fibrosis and calcifica- cision. Extremely rarely, diffuse and multi- lated, fleshy or firm and, when sectioned,
tion. In sclerosed haemangiomas, most or ple lesions (diffuse hemangiomatosis) with a homogeneous yellow, yellow-tan or
all of the vessels are occluded and some- with progressive development do occur tan appearance, depending on their fat
times are only demonstrable by stains for {1797}; some cases are associated with content. Larger tumours may have grossly
elastic tissue. Capillary-type haemangiomas involvement of multiple organs. Multiple evident necrosis or haemorrhage.

Histopathology desmin and vimentin expression is vari- different appellations and even liposarco-
The components of smooth muscle, adi- able. The microscopic appearances are mas are all basically angiomyolipomas
pose tissue and thick-walled, sometimes extensively varied and may imitate hepato- with varying proportions and/or unusual
hyalinized blood vessels occur in varying cellular carcinoma, sarcomas or even morphology of the different components.
proportions, and are responsible for vascular malformation. The correct terminology should be
the protean morphological appearance Angiomyolipomas are benign neoplasms, adopted, as with the soft-tissue tumours
{3309}. The smooth muscle is the only despite their occasional large size, infil- in other organs.
specific diagnostic component, compris- trative margins and pleomorphic appear- Pseudolipoma is believed to represent an
ing mainly epithelioid cells in sheets and, ance. Rare malignant examples are being appendix epiploica attached to the Glis-
to a lesser extent, spindle-shaped cells recognized, with monotypic epithelioid son capsule after becoming detached
arranged in bundles. The epithelioid cells morphology, necrosis, marked nuclear from the large bowel. Lesions are usually
may be clear (sugar cell), oncocytic, or atypia, and high proliferation activity sug- a small, encapsulated mass of fat located
pleomorphic. Unusual growth patterns gested as potentially ominous features in a concavity on the surface of the liver,
(trabecular, pelioid, inflammatory) may be {651, 696, 2276, 2463}. the fat typically showing necrosis and cal-
seen, especially in myomatous tumours cification {1483}.
with few or no fat cells. Extramedullary Lipomatous tumours and lesions Focal fatty change of the liver is not a
haematopoiesis is a frequent and char- Traditionally, the lipomatous tumours of mesenchymal lesion, but may be mis-
acteristic feature of hepatic tumours. Im- the liver are designated according to the taken for lipomatous lesions on imaging. It
munohistochemically, the defining myoid elements present, e.g. lipoma, hiber- is characterized by multiple, contiguous
cells are consistently positive for HMB45 noma, angiolipoma, myelolipoma, an- acini showing macrovesicular steatosis of
and other melanogenesis markers (e.g. giomyelolipoma. In fact, some of the hepatocytes, with preservation of acinar
Melan A) {1962}; S100, CD117, actin, lipomatous tumours reported under these architecture. About 45% of cases in a se-
ries of focal fatty change occurred in pa-
tients with diabetes mellitus {1072}.
Distinction has to be made from steatotic
microadenomas in liver adenomatosis as-
sociated with mutations in hepatocyte nu-
clear factor 1α (HNF1α) {1807}.
Solitary fibrous tumour

Solitary fibrous tumour (previously also
known as localized fibrous tumour and lo-
calized fibrous mesothelioma) originates
A B from the submesothelial tissue of the liver.
Fig. 10.93 Solitary fibrous tumour of the liver. A Cellular area comprising uniform spindle cells in patternless architecture. It occurs in patients aged 16–84 years
B Spindle cells are separated by keloid-like collagen. (mean, 55 years) {2145, 2526} and with a
female-to-male predominance of 2 : 1.
Clinical presentation includes mild ab-
dominal discomfort and presence of a
solid abdominal mass. Some cases are
associated with hypoglycaemia caused
by the production of an insulin-like growth
factor.
Macroscopy
A B Lesions vary considerably in size, from 2–
32 cm in diameter. They arise in either
lobe and are occasionally pedunculated.
The external surface is smooth and the
consistency firm. They are sharply de-
marcated but not encapsulated. Cross
sections show a light tan to almost white
colour with a whorled texture.
Histopathology
Solitary fibrous tumour is composed of
C D bland uniform fibroblast-like spindle cells
Fig. 10.94 Inflammatory pseudotumour of the liver. A The tumour forms a circumscribed yellowish-tan mass. in a collagenized stroma and often shows
B Mononuclear inflammatory cells in a stroma of spindle cells. C Note the presence of obliterative phlebitis. alternating hypocellular and hypercellular
D There are many IgG4-positive plasma cells among the inflammatory infiltrate. areas. There are accompanying branching

haemangiopericytoma-like vessels. Nu- tious and inflammatory causes being dense fibrosis of hilar and extrahepatic
clei of the spindle cells are uniform and proposed. bile ducts and obliterative phlebitis, and
lack pleomorphism, but these tumours responds to steroid therapy {3692, 3693}.
may undergo malignant change as evi- Macroscopy
denced by the presence of infiltrative Inflammatory pseudotumours are solitary Differential diagnosis
margins, high cellularity, prominent cellu- (about 80% of cases) or less often multi- The clinical presentation and gross ap-
lar atypia, tumour necrosis, and increased ple (about 20% of cases) and usually pearance of inflammatory pseudotumour
mitotic activity (> 4 mitoses per 10 HPF) intrahepatic, but some can involve the may mimic that of malignant tumours, and
{473, 2145}. The tumour cells character- hepatic hilum (about 10% of cases). the lesion may be mistaken for a sarcoma.
istically express CD34 and often CD99. About half of the solitary tumours are On the contrary, other neoplasms with an
located in the right lobe. They vary in size inflammatory infiltrate are not uncom-
Inflammatory pseudotumour from 1 cm to large masses involving an monly misdiagnosed as inflammatory
This lesion is defined as a benign, non- entire lobe, and are firm, tan, yellow-white pseudotumours. Examples include follic-
neoplastic, non-metastasizing mass com- or white in colour. ular dendritic tumour harbouring Epstein-
posed of fibrous tissue and proliferated Barr virus (EBV) {524, 2873}, inflammatory
myofibroblasts, with a marked inflamma- Histopathology myofibroblastic tumour/low-grade inflam-
tory infiltration, predominantly plasma The lesions are composed of inflammatory matory fibrosarcoma {3107}, and the in-
cells. It has been described under many cells in a stroma of interlaced bundles of flammatory type of angiomyolipoma
other names, such as plasma cell granu- myofibroblasts, fibroblasts, and collagen. {1632, 3309}.
loma, pseudolymphoma, fibroxanthoma, Most of the inflammatory cells are mature
and histiocytoma, a reflection of the vari- polyclonal plasma cells, but lymphocytes Embryonal sarcoma
ability of its appearance. In liver lesions, (and occasional lymphoid aggregates or Undifferentiated (embryonal) sarcoma of
there is a 3 : 1 predominance in males, follicles), as well as eosinophils and neu- the liver (UES; synonym: malignant mes-
and mean age at presentation is 37 years trophils, may be present. Macrophages, enchymoma of the liver) is a malignant
(range, 1–83 years) {2913}. Most patients sometimes showing xanthomatous hepatic tumour that is composed of un-
present with recurrent fever, weight loss changes, occasional granulomas and, differentiated mesenchymal cells and that
and abdominal pain; jaundice develops rarely, phlebitis involving portal vein chiefly occurs in older children.
in a minority. branches or outflow veins, may be seen. More than 75% of cases of UES have
The etiology of this lesion remains un- Lately, IgG4-related disease turns out to been diagnosed in children aged 6–15
known, although the myofibroblastic be an important subgroup, which features years {3082}. Few cases occur in adults.
nature of the spindle cells has been a fibroblastic mass with marked lympho- It has been estimated that UES ranks as
well established. Most probably it is a plasmacytic infiltration, many eosinophils, the third most common primary malignant
heterogenous lesion, with various infec- numerous IgG4-positive plasma cells, paediatric liver tumour, after hepato-
A B
C D
Fig. 10.95 Undifferentiated embryonal sarcoma of the liver. This neoplasm shows varying cellularity with formation of pleomorphic and giant cells (A). Focally, a myxoid matrix is seen
(B). The presence of cytoplasmic (C) or extracellular (D) hyaline globules is a typical feature of this tumour.

detected, including vimentin (the most

consistent reaction) {1811}, desmin (highly
variable), keratins, α-smooth muscle
actin, α-1-antitrypsin and α-1-anti-
chymotrypsin, CD10, CD68 and calponin
{1536, 1715, 1811, 2065, 2304, 2465,
3482}. MyoD1 is not detectable in UES,
an important feature for distinguishing
UES from hepatobiliary rhabdomyosar-
A B coma {2278}. In contrast to many hepato-
blastomas, UES does not show nuclear
Fig. 10.96 Kaposi sarcoma. A Multiple dark-brown lesions are centred in large portal areas. B Spindle cells and slit-
like vascular spaces.
expression of β-catenin {3603}.
Molecular pathology
blastoma and hepatocellular carcinoma, myxoid tissue containing an immature- The etiology and pathogenesis of UES
representing 9–15% of hepatic tumours in looking population of spindle, stellate, are unknown. Cytogenetically, UES are
this age group {3085}. The incidence in polymorphous and giant cells. These diploid or aneuploid {543, 1811}, and
males and females is equal. There is no cells form a diffuse growth, but cellularity there is evidence for extensive chromo-
pre-existing liver disease. may be higher around blood vessels and somal rearrangements {1315}. Compara-
Clinically, affected children show abdom- entrapped bile ducts. Tumour cells often tive genomic hybridization (CGH) has
inal pain and enlargement, weight loss display prominent anisonucleosis with demonstrated several chromosomal
and fever, and may be severely sick at hyperchromasia. The giant cells are iso- gains and deletions, but without a specific
presentation, with systemic signs of ma- lated or form small clusters; they may be pattern {3029}. Together, these findings
lignancy. Levels of serum AFP are not el- multinucleated and often contain bizarre suggest marked and probably progres-
evated {1715}, or only to a minimal nuclei with massively deranged chromatin sive genomic instability. In a few in-
degree owing to hepatocyte regeneration. structure, anomalies resembling those stances, UES evolves in connection with
A few patients exhibit spontaneous tu- produced by ionizing radiation. A charac- pre-existing MH of the liver {667, 1762}.
mour rupture followed by haemato- teristic feature is the presence of Cytogenetic analysis of UES secondary to
peritoneum and haemorrhagic shock sometimes numerous eosinophilic intra- MH showed a translocation at 19q13.4, a
{1304, 1715, 3085}. UES may invade the cytoplasmic globules of variable size, lo- potential marker of MH {1762} and termed
inferior vena cava and grow into the right cated mainly in large and polymorphous MHLB1 {2619}, suggesting the involve-
atrium, producing a cardiac murmur. cells and in giant cells. These globules ment of a common pathogenic pathway
Imaging shows that UES is located more are strongly positive on periodic acid- in these two lesions. In a case of UES aris-
frequently in the right liver lobe {1715}. Ul- Schiff (PAS) (diastase-resistant) staining ing in mesenchymal hamartoma and
trasonographically, > 80% of these tu- and seem ultrastructurally to represent showing t(11;19)(q13;q13.4 ), the break-
mours are solid, whereas CT and electron-dense lysosomes with dense point at 11q13 occurred in the MALAT1
magnetic resonance imaging (MRI) have precipitates {40}. gene, which is known to be rearrranged
shown low-attenuation masses with a cys- Some UES show a storiform pattern re- in a subset of renal tumours {2619}.
tic appearance {1158, 2138, 2724}. It has sembling malignant fibrous histiocytoma
been shown that the CT/MR findings for {1511} or haemangiopericytoma-like Prognosis
cysts do not correlate well with patholog- areas. Spindle cells suggesting a myoid Until recently, the prognosis for patients
ical findings {361}, most of the cystic differentiation may occur {3433}, and a with UES has been poor, with a median
structures not being true cysts but liqui- subset of UES displays anaplastic com- survival of < 1 year after diagnosis. With
fied necroses and blood clots {3085}. ponents (mainly in adult patients) {2304} considerable improvements in recent
However, true cystic spaces may also or small undifferentiated cells {3433} years, long-term survival has been
occur {3663}, sometimes with intracystic resembling those in undifferentiated achieved after combined modality treat-
septa suggesting echinococcosis at hepatoblastoma or some rhabdoid tu- ments {269, 1545, 2430}. .
imaging {1449}. mours. Osteoid formation has been re-
ported {1715}. UES contains bile duct-like Kaposi sarcoma
Macroscopy profiles, sometimes with dilated lumina, Disseminated Kaposi sarcoma involving
Macroscopically, UES varies from 10 to and hepatocyte nests, both structures the liver, mostly associated with AIDS, is
20 cm in diameter. It is typically well-de- being thought to be entrapped pre-exist- usually an incidental finding on autopsy
marcated but not encapsulated. Gross ing structures. detected in 15% of patients with AIDS. In
sections reveal a variegated cut surface Immunohistochemically, the reaction pro- the liver, Kaposi sarcoma typically in-
with glistening, solid, grey-white tumour file seems to represent an immature phe- volves portal and periportal areas, often
tissue alternating with fluid-rich and gelat- notype involving putative precursors of grossly detectable as red-brownish foci.
inous areas, necroses and haemorrhage. both mesenchymal and epithelial line- Histologically, these tumours typically
ages and possibly reflecting abnormal show poorly vasoformative spindle-cell
Histopathology mesenchymal–epithelial transition (MET). proliferation accompanied by haemor-
UES is chiefly composed of a loose or Positivity for several markers has been rhage and focal deposition of

complicated by Budd-Chiari syndrome been shown to be a useful marker for he-

{1143} or by hepatic-vein invasion with a patic EHE {911}. An endothelium-related
venoocclusive disease (VOD)-like pres- cell seems to be involved, also supported
entation. by the finding of Weibel-Palade bodies in
Radiologically, EHE presents as nodular the tumour cells {2865}.
and solitary lesions at early stages, often
changing into multiple lesions. On MRI Prognosis
images, the nodules may show a multi- EHE of the liver generally behaves as a
layered target appearance with prominent low-grade malignant neoplasm with slow
peripheral rim with high signal intensity on progression, but appears to be resistant
T1-weighted and very low signal intensity to chemotherapy and may undergo a fatal
Fig. 10.97 Epithelioid hemangioendothelioma with strong
positivity for CD34. on T2-weighted images (the bright-dark course {3328}, frankly malignant behav-
ring sign), corresponding to thrombosed iour also occurring rarely in children and
vascular channels {760}. In the largest adolescents {1490, 3154}. Tumour-related
published series, 82% of hepatic EHE death has also been reported after EHE
were manifest as multiple tumours {1961}. recurrence subsequent to liver transplan-
About 20% of these lesions exhibit focal tation {1679}. So far, there is no standard-
calcifications, sometimes resulting in ized effective therapy, but the results of
subtotal liver calcification {695}. surgical resection in cases of localized
and monolobar intrahepatic disease
Macroscopy {2166} and liver transplantation are en-
Grossly, hepatic EHE presents as pale or couraging {1808, 2327}.
whitish and firm to rubbery nodules with
Fig. 10.98 Hepatic angiosarcoma showing strong infiltrative borders. Subcapsular tumours Angiosarcoma
membrane positivity for CD31. may show typical umbilication. Solitary le- This is a variably vasoformative malignant
sions have an average diameter of neoplasm composed of spindled or epi-
5.6 cm, and multiple lesions range in dia- thelioid endothelial cells. The typical oc-
haemosiderin. Cytoplasmic eosinophilic meter from 0.2 cm to 14 cm {1961}. currence is in patients aged > 60 years
hyaline globules are a typical finding, and and there is a 3 : 1 predominance in men.
immunohistochemical demonstration of Histopathology However, angiosarcomas occur even in
membranous/cytoplasmic CD31 and The neoplastic cell exhibits epithelioid, children with a very low frequency. Known
CD34, and nuclear human herpesvirus 8 dendritic, or intermediate features {1351}. etiological factors (seen in 20% of hepatic
(HHV-8) are diagnostic {2310}. The characteristic, slightly eosinophilic angiosarcomas) include occupational ex-
epithelioid cells occur in all cases and posure to vinyl chloride monomer, ar-
Epithelioid haemangioendothelioma may show vacuolated signet ring-cell-like senic, and androgenic-anabolic steroids.
A tumour of variable malignant potential features representing intracytoplasmic lu- Iatrogenic thorium oxide (thorothrast), an
that is composed of spindle or epithelioid mina sometimes containing erythrocytes. α particle-radiating substance previously
cells growing along preformed vessels or Epithelioid cells typically invade the liver used as a radiological contrast medium,
forming new vessels. sinusoids, causing marked hepatocyte is historically important, but presently a
Epithelioid haemangioendothelioma (EHE) plate atrophy and destruction. Dendritic very rare etiological factor.
of the liver acquired its name because of cells display a spindle or stellate mor-
the involvement of a neoplastic cell with phology with interdigitating processes Clinical features
an epithelioid morphology, but the neo- and may also contain intracytoplasmic Patients with angiosarcoma present with
plasm is clearly not epithelial. It is an un- vacuoles. The third cell type, intermediate abdominal pain, ascites, or sometimes
common tumour that presents between cell, is cytologically situated between the with acute abdomen caused by tumour
the ages of 12 and 86 years. The overall other two types {1351}. The mitotic rate rupture. Prognosis is poor, and most pa-
incidence of this tumour is unknown, but varies considerably; no mitoses were tients die within 1 year.
more hepatic EHEs are reported in fe- found in 58% of tumours {1961}. EHE re-
males (about 60%) than in males (about veals a sometimes marked desmoplastic Macroscopy
40%), in contrast to EHEs arising in soft stromal reaction, more pronounced in the Grossly, hepatic angiosarcomas are typi-
tissues. Most patients are adults; of 137 tumour centre. cally ill-defined masses that often involve
patients with EHE of the liver, only seven Immunohistochemically, EHE cells are re- much of the liver. Many also involve the
patients were aged 20 years or < 20 active for vimentin, factor VIII-associated spleen. On sectioning, the tumour varies
years {1961}. antigen, CD31 and CD34 {1143, 1351, from greyish-white to haemorrhagic and
1961, 3434}, CD34 reactivity is a particu- focally cystic.
Clinical features larly useful marker {694}. Some of the tu-
Apart from asymptomatic patients (42%), mour cells are positive for keratins, in Histopathology
hepatic EHE may present with abdominal particular, keratin18 {1961, 2063}, but this Microscopically, angiosarcomas can
pain, jaundice, and ascites {230, 1961}. observation does not prove an epithelial show solid and pseudopapillary patterns
In rare circumstances, the tumour may be lineage. Podoplanin (D2-40 antibody) has with formation of irregular vascular chan-

nels lined by variably atypical endothelial opment and growth of a usually embry- tissue with interspersed spindled or stel-
cells that often show multilayering and mi- onal-type rhabdomyosarcoma along the late neoplastic cells. These cells have a
totic activity. The tumour cells frequently biliary tract in children {659, 1714}. Al- sparse cytoplasm and small and dense
line pre-existing vascular channels and though rare, this neoplasm is the most nuclei, in the absence of easily recogniz-
hepatic sinusoids. Cases associated with common tumour of the biliary tract in chil- able mitotic figures, potentially causing
thorothrast often contain portal fibrosis, dren, representing 1% of all paediatric misinterpretations in small biopsies. A
with granules of thorothrast present in rhabdomyosarcomas. The tumour occurs characteristic feature is the rather low cel-
these areas. predominantly in infants, with a marked lularity in deeper parts of the tumour and
male preponderance, and about 2% of le- a band of higher cellularity immediately
Molecular pathology sions are present at birth. beneath the biliary epithelium, the
Mutations in the TP53 gene have been ex- so-called “cambium” layer. Diagnosis re-
amined in angiosarcomas that are asso- Clinical features quires immunohistochemistry, the neo-
ciated or otherwise with exposure to vinyl Clinical presentation is dominated by the plastic cells being immunoreactive for
chloride. The former were found to have sequelae of the tumour’s intrabiliary desmin, myogenin and MyoD.
A to T transversion missense mutations in growth, i.e. mainly intermittent obstructive
codons 249 and 255 (two out of four jaundice, but fever and nonspecific ab- Prognosis
cases), whereas the latter lacked such dominal manifestations may also occur. For treatment, chemotherapy with or with-
mutations and instead had G to A transi- The tumour can involve the extrahepatic out surgery has been performed, leading
tions in codons 141 and 136 (2 out of 21 and/or the intrahepatic bile ducts. In lo- to complete tumour regression in some
cases) suggesting that vinyl-chloride as- calized disease, hepatobiliary RMS is patients and avoiding aggressive surgery,
sociated angiosarcomas may have a dis- classified as stage I according to the In- but treatment strategies and results are
tinctive TP53 mutation profile {1228, tergroup RMS Study Group/COG {1767}. constantly changing owing to improved
3008}. KRAS mutations seem to be com- A novel classification of risk associated imaging procedures for staging and novel
mon in both sporadic and thorothrast- with RMS has recently been formulated therapy regimes {619, 1283, 1990, 2573,
and vinyl-chloride associated hepatic an- {1144}. 2763, 2800, 3050, 3436}
giosarcomas {2596}. Ultrasonography shows an intraductal
stenosing mass causing biliary dilatation, Extrarenal malignant rhabdoid tumour of
Carcinosarcoma and CT reveals hypodense and hetero- the liver
These neoplasms are currently under- geneous attenuation patterns. The typical Malignant rhabdoid tumour (RT) primary
stood to be carcinomas that have under- cholangiographic finding is that of varie- to the liver is a rare and highly aggressive
gone sarcoma-like differentiation (sarco- gated filling defects representing the in- tumour that is characterized by a diffuse
matoid carcinoma). The sarcomatoid com- traductal tumour masses {963, 2705, growth of undifferentiated cells with so-
ponent represents clonal evolution from 2708}. called rhabdoid features and a distinct
the differentiated component (hepatocel- molecular change in some cases.
lular or cholangiocarcinoma). Morphology Macroscopy The concept of rhaboid tumour or of tu-
varies from spindled to epithelioid and Grossly, hepatobiliary RMS forms soft and mours with rhabdoid features is based on
pleomorphic. Mitotic rare is usually high, often transparent masses that grow into the observation of intracellular filamen-
and atypical mitoses are frequent. These the biliary lumina, producing polypoid tous aggregates manifest as distinct
are clinically aggressive tumours with a and grape-like masses (botryoid growth paranuclear spherical inclusions {1027},
poor prognosis. pattern). rendering the cell asymmetrical and
somewhat resembling a rhabdomyoblast.
Hepatobiliary rhabdomyosarcoma Histopathology However, the cell lineage involved in RT
Hepatobiliary rhabdomyosarcoma (RMS) Hepatobiliary RMS commonly exhibits the has nothing to do with rhabdomyosar-
is a clinically and pathologically distinct morphology of embryonal RMS, charac- coma, and the cell type involved is still un-
tumour entity characterized by the devel- terized by a loose and sometimes myxoid known.
RT is a well-known entity in the kidney, but
primary hepatic RT is a rare high-risk lesion
of still unknown frequency {1289, 2466}.
Clinical features
Clinically, hepatic RT presents in a similar
fashion to other malignant liver tumours in
childhood, but serum AFP levels are con-
sistently normal, an important differential
diagnostic feature. RT of the liver can un-
dergo spontaneous rupture {565}.
A B Grossly, RT of the liver are often large or
Fig. 10.99 Hepatobiliary rhabdomyosarcoma. A This neoplasm is characterized by the typical loose tissue of the very large tumours predominantly located
embryonal variant. It is covered by atrophic biliary epithelium and forms the mucosal surface of a duct. Note the subepithelial in the right liver lobe, forming lobulated
hypercellular band of tumour tissue, the “cambium.” B Spindle cells and stellate cells show marked positivity for desmin. masses with necrosis and haemorrhage.

tumours are caused by loss of function of

the SMARCB1 component of the SWI/SNF
chromatin-remodelling complex {1628}. It
is thought that this loss of function affects
key regulator proteins of cell-cycle pro-
gression and cell-cycle check-point (G1/S
transition) control, as this protein regu-
lates the activities of cyclin D1, CDKN2A
A B (p16INK4A) and pRb(f). However, it has
been reported that SMARCB1-deficient
tumours and rhabdoid tumours are con-
vergent, but not fully overlapping entities
{315}.
Prognosis
RT (including primary hepatic RT) are
generally highly aggressive lesions. Mod-
ern chemotherapy regimes have deliv-
C D ered promising results {1409, 1499}.
Fig. 10.100 Malignant rhabdoid tumour of the liver. A There is a diffuse growth of rather large cells with partly vesicular
nuclei. In some (rhabdoid) cells, the nucleus is excentrically placed, caused by a paranuclear inclusion. B, C The
Leiomyosarcoma
paranuclear bodies of rhabdoid cells are better visualized after immunostaining for vimentin. D Unlike the normal
Conventional leiomyosarcomas are al-
surrounding cells, the nuclei of the neoplastic cells fail to stain for SMARCB1/BAF47.
most always metastatic when involving
the liver, and search for a primary tumour
Histopathology detected by immunohistochemistry using in locations such as the retroperitoneum
RT shows a diffuse growth pattern, the le- the BAF47 antibody {1450}, which shows is always necessary. EBV-associated
sion being composed of noncohesive loss of nuclear immunostaining in the nu- leiomyosarcomas/smooth-muscle tu-
small- to medium-sized undifferentiated clei of RT cells, including those of the liver mours can form primary hepatic masses.
cells with a generally inconspicuous cy- {3427, 3562}. These tumours occur in patients with im-
toplasm. Some of the cells display the A fraction of hepatic RTs consist of small munosuppression, either acquired
rhabdoid feature described above. The and anaplastic-looking cells, easily con- (HIV/AIDS-associated) or iatrogenic (usu-
recognition of these paranuclear bodies founded with small cell undifferentiated ally transplant-associated). In liver-trans-
seems to depend on a good fixation and hepatoblastoma; these cells are plant patients, occurrence from donor
high-quality haematoxylin and eosin stain- SMARCB1-negative, suggesting that a cells has been reported in allografts, and
ing of the tissue. Immunohistochemically, subset of undifferentiated hepatoblas- occurrence from recipient cells outside
RT are polyantigenic, with immunoreac- tomas have rhabdoid features {3294, the graft.
tivity to a wide array of antibodies against 3427}. Histologically, these tumours are typically
mesenchymal, epithelial, neural, glial and less differentiated than typical leiomyosar-
myogenic markers {2466, 2837}, but they Molecular pathology comas, composed of oval to spindled
commonly express vimentin (mainly in the Most RT show a characteristic molecular mesenchymal cells with immunoreactivity
paranuclear inclusion, resulting in a char- feature, i.e. loss of the SWI/SNF related, for α smooth muscle actin, but usually not
acteristic “dot”) and sometimes epithelial matrix associated, actin-dependent regu- for desmin. Demonstration of nuclear
markers such as keratins (in particular, lator of chromatin SMARCB1 (INI1). In the EBER is diagnostic.
keratins 8 and 18, but not keratins 1, 10, regulation of gene expression, chromatin Tumour behaviour is unpredictable, and
13–17 or 20) {3666} and epithelial mem- organization in nuclei is a crucial mecha- multifocal lesions do not necessarily indi-
brane antigen. It has been reported that nism. Complexes of the SWI/SNF cate metastasis, but are a feature of this
intracytoplasmic inclusion-body formation (SMARCA1/SMARCB1) family of proteins tumour {3249}. In some cases, antiviral
in RT may be related to mutations in the control or alter chromatin structure via treatment and restoration of immune re-
keratin 8 gene {2955}. Loss of SMARCB1 ATP-dependent nucleosome remodelling sponse have resulted in tumour regres-
(caused by truncating mutations) can be {2129, 3088}. Most malignant rhabdoid sion and long-term survival {300}.

Secondary tumours of the liver C. Iacobuzio-Donahue

L. Ferrell
Definition does excess consumption of alcohol hepatic metastases at presentation, but

Malignant neoplasms that have metasta- {1947}. In most patients, metastases to 34% have hepatic metastases at autopsy
sized to the liver from extrahepatic pri- the liver are a manifestation of systemic, {1393}.
mary tumours. disseminated disease. Colorectal carci-
noma, neuroendocrine neoplasms, and Clinical features
Epidemiology renal cell carcinoma are exceptions, as Signs and symptoms
Metastases predominate over primary he- these neoplasms sometimes produce iso- In many patients, the presence of a
patic tumours in a ratio of 40 : 1 in Europe lated, even solitary, deposits {102, 2015}. hepatic metastasis is asymptomatic.
and North America {235, 2548} and by Patients with symptomatic hepatic metas-
2.6 : 1 in Japan {2548}. In contrast, pri- Origin of metastases tases often present with ascites, he-
mary hepatic tumours are more common The most frequent secondary neoplasms patomegaly or abdominal fullness,
than metastases in south-east Asia and of the liver are carcinomas followed by hepatic pain, jaundice, anorexia, and
sub-Saharan Africa {2168} owing to the melanomas {725, 2973}. Hepatic involve- weight loss. There may be constitutional
high incidence of hepatocellular carci- ment by lymphomas or sarcomas is un- symptoms, such as malaise, fatigue and
noma (HCC), shorter life expectancy common {1377, 1881, 3062}. In autopsy fever {2893}. On examination, nodules or
(common extrahepatic carcinomas affect studies in North America and Europe, the a mass are felt in up to 50% of cases, and
older age groups) and the low incidence frequency of hepatic metastases per pri- a friction bruit may be heard on ausculta-
of certain tumour types (e.g. carcinomas mary site is greatest for testicular, ocular tion. Symptomatic presentation is associ-
of the lung and colorectum). Autopsy (uveal melanoma) and pancreaticobiliary ated with bulky, rapidly progressing
studies in Japan and the USA have cancers. Breast, lung and colorectal car- tumours with a poor prognosis {2893}.
shown that up to 40% of patients with an cinomas also frequently metastasize to Rarely, patients present with fulminant he-
extrahepatic primary tumour have hepatic the liver {725}. In terms of absolute num- patic failure {2620} caused by diffuse in-
metastases {614, 725, 2548}. bers, the most common metastases to the filtration of the liver, most often seen in
liver are derived from breast, colorectal association with metastatic small cell car-
Etiopathogenesis and gastric carcinomas {725}. Hodgkin cinoma. Patients with functioning neuro-
The liver has a rich systemic (arterial) and and non-Hodgkin lymphomas may involve endocrine carcinomas that metastasize to
portal (venous) blood supply, providing a the liver in up to 20% of patients at pres- the liver may present with carcinoid syn-
fertile environment for entrapping circu- entation and 55% at autopsy {1377}. Only drome {231}. “Carcinomatous cirrhosis”
lating neoplastic cells. The arrest of such 6% of patients with sarcoma may have with jaundice, ascites, and bleeding
cells is controlled by Kupffer cells in the
sinusoids {217, 1469} and may be
enhanced by growth factors such as
transforming growth factor α (TGFα)
{3453}, tumour necrosis factor (TNF)
{1581}, or insulin-like growth factor-1 (IGF-
1) {2215}, chemokines such as CXCR4
{951} and adhesion molecules such as in-
tegrin αb6 {3614}. As tumour deposits
enlarge, they induce angiogenesis using
native sinusoidal endothelium, thus en-
hancing their chances of survival {970}.
Most metastases from unpaired abdomi-
nal organs reach the liver via the portal
vein, and from other sites via the systemic
arterial circulation. Lymphatic spread is
less common and extension to the liver
via the peritoneal fluid is rare {614}. Cir-
rhosis provides a measure of relative pro-
tection against seeding by secondary
tumours {2522}. In contrast, experimental
models suggest that steatohepatitis pro-
motes metastatic formation {3376}, as Fig. 10.101 Frequency of metastasis to the liver according to site of the primary neoplasm. Data from 3827 autopsies {725}.

cess relies on the fact that tumours are

not fed by portal-vein blood, so that
metastases appear as filling defects. In-
traoperative ultrasound, capable of de-
tecting lesions of 2–4 mm in diameter,
delineates the anatomical location of tu-
mours in relationship to major vascular
and biliary structures and provides guid-
ance for intraoperative needle biopsies. It
A B is the definitive step for determining re-
sectability at the time of exploratory la-
parotomy or laparoscopy. Although the
use of angiography has declined in
recent years, it is helpful in defining
vascular anatomy for planned hepatic
resections, selective chemotherapy,
chemo-embolization, or devascularization
procedures, for assessing whether there
is metastatic involvement of the portal ve-
nous system and/or hepatic veins, or for
C D differentiating between benign and ma-
Fig. 10.102 Gross specimens. A Metastatic colon carcinoma showing umbilication and hyperaemic borders. B Metastatic lignant vascular lesions when other imag-
small cell carcinoma of the lung forming innumerable small nodules. C,D Metastatic large-intestinal carcinoma, cut surfaces. ing studies have yielded equivocal
results.
varices due to diffuse infiltration of the screening tool. The administration of Macroscopy
liver has also been described {2815}. intravenous contrast permits the detection Some studies suggest that right-sided
Laboratory studies: Levels of alkaline of tumours as small as 0.5 cm in diame- colon cancers predominantly metastasize
phosphatase and serum transaminase, ter {2981}. Most metastases display de- to the right lobe of the liver, while left-
although nonspecific, are elevated in creased vascularity in comparison to the sided colon cancers metastasize to both
about 80% and 67% of patients respec- surrounding hepatic parenchyma and lobes, supporting the existence of the
tively, and probably represent the effects thus appear as hypodense defects. Tu- “streaming” effect in the portal vein
of hepatic parenchymal infiltration by the mours that are hypervascular (e.g. {1649}. Metastases may be multinodular,
tumour and of generalized wasting. Ele- melanoma, carcinoids and some breast diffusely infiltrative, or solitary. Very large
vated levels of lactic dehydrogenase are cancers) or calcified (e.g. colorectal car- solitary metastases are most often seen in
relatively specific for the presence of cinoma) are better delineated by non- association with metastatic colorectal or
metastatic melanoma. Tests of synthetic contrast views. Magnetic resonance renal cell carcinoma. Umbilication (a cen-
function, e.g. prothrombin time and levels imaging (MRI) is more sensitive than CT tral depression on the surface of a
of serum albumin, may be normal despite in the detection of hepatic tumours and metastatic deposit) is caused by necrosis
extensive metastatic involvement. Levels can detect additional lesions, too small to or scarring and is typical of metastatic
of α-fetoprotein (AFP) may be slightly to be seen via CT. Positron emission tomog- adenocarcinomas from the stomach, pan-
moderately elevated, but very high con- raphy (PET) can detect metastatic dis- creas or colorectum. A vascular rim
centrations are more consistent with a ease in the liver and elsewhere. The around the periphery of the metastatic le-
diagnosis of HCC {3710}. Levels of carci- radiolabelled glucose analogue 2-(18)flu- sion is often seen. Mucin-secreting ade-
noembryonic antigen (CEA), which are oro-2-deoxy-D-glucose (F-18 FDG) can nocarcinomas appear as glistening,
raised in as many as 90% of patients with be used with PET to highlight metaboli- gelatinous masses, while well-differenti-
metastases from colorectal carcinoma, cally active tissues. Through co-regis- ated keratinizing squamous cell carcino-
can be useful in monitoring patients after tration with anatomical studies like CT or mas are granular. Metastatic carcinoid
resection of the primary tumour, together MRI, viable malignant tumours can be tumours are typically solid but can form
with routine clinical and imaging follow-up differentiated from benign or necrotic le- pseudocysts {697}. Extensive haemor-
studies {3181}. sions {111}. However, a high rate of rhage is more frequently seen in metasta-
Imaging studies: Ultrasound can identify false-negatives has been shown for PET tic choriocarcinoma, carcinomas of the
tumours measuring 1–2 cm in size, differ- when evaluating mucinous carcinomas thyroid or kidney, neuroendocrine neo-
entiate solid from cystic lesions, and pro- {236}. plasms, or vascular leiomyosarcomas.
vide guidance for percutaneous needle Preoperative CT arterial portography or Diffusely infiltrating neoplasms, such as
biopsy. However, it provides poor anatom- intraoperative ultrasound is associated small cell carcinoma, lymphoma and sar-
ical definition and frequently misses with the highest sensitivities {3031}. The coma may have a soft, opaque, fleshy ap-
smaller lesions. Computed tomography former is capable of detecting lesions of pearance. Rarely, metastatic breast
(CT), using contrasted and non-con- 15 mm, although a false-positive rate of carcinoma can produce extensive fibro-
trasted images, can also serve as a 17% has been reported {3030}. Its suc- sis simulating cirrhosis. Calcification of

{1803, 2380}. The presence of high-grade tophysin and neuron-specific enolase.

intraepithelial neoplasia within intrahep- Islet cell tumours also produce specific
atic bile ducts near an adenocarcinoma hormones, e.g. insulin, glucagon, gastrin,
is strong evidence that the neoplasm is a vasoactive intestinal peptide and somato-
primary cholangiocarcinoma; without this statin, which either give rise to clinical syn-
finding, panels of immunohistochemical dromes or can be detected in the blood or
stains are required. tumour tissue. In some instances, the site
Cholangiocarcinoma may assume any of of origin of the neuroendocrine neoplasm
the histological patterns of a metastatic (e.g. gastrointestinal vs pulmonary) can be
adenocarcinoma; it is usually tubular but identified by nuclear positivity for CDX2 or
may be mucinous, signet-ring, papillary, TTF1, respectively {2801}.
cystic, or undifferentiated. Some metas- Although uncommon, most sarcomas that
tases form reproducible patterns that may metastasize to the liver are gastrointesti-
provide clues to their primary origin, e.g. nal stromal tumours (typically positive for
Fig. 10.103 Metastatic colorectal carcinoma. The tumour small tubular or tubulo-papillary glands CD34 and KIT) or uterine leiomyosarco-
is necrotic and the cell type is typically columnar. frequently derive from the pancreaticobil- mas (that may be positive for desmin or
iary system, while a signet ring-cell ap- muscle-specific actin) {3062}. Some car-
pearance suggests a gastric or breast cinomas, notably of the kidney, may be
hepatic metastases may be seen in asso- primary. sarcomatoid in their morphology. Sarco-
ciation with a variety of primary neo- Perhaps the easiest pattern to recognize matoid renal cell carcinomas nonetheless
plasms. In colon cancer, calcifications as metastatic in origin is that exhibited by retain PAX8 expression {3267}.
within hepatic metastases are associated adenocarcinomas of the colon and rec- Leukaemias, myeloproliferative disorders,
with a better prognosis {756}. tum, which nearly always show glands of Hodgkin and non-Hodgkin lymphomas
variable size and shape, lined by tall may involve the liver at advanced stages
Histopathology and differential diagnosis columnar cells, with lumina containing of disease. Leukaemias tend to produce
Metastatic neoplasms to the liver are usu- abundant necrotic debris. Metastases diffuse sinusoidal infiltrates. Hodgkin and
ally histologically similar to their primary from the colorectum frequently have well- high-grade non-Hodgkin lymphomas pro-
tumour of origin and to related metas- defined edges whereas those from other duce tumour-like masses, while low-grade
tases at other organ sites. glandular sites tend to be more diffuse. Of nonHodgkin lymphomas produce diffuse
Metastases arising from renal cell carci- note, some metastatic colonic adenocar- portal infiltrates {1377}.
noma, adrenocortical carcinoma or cinomas are associated with prominent Rarely, carcinomas of the thyroid, prostate
melanoma may mimic HCC, which can intrabiliary ductal growth that mimics and testis may metastasize to the liver. In
usually be distinguished by its trabecular high-grade intraepithelial neoplasia of in- these cases, the diagnosis can be con-
structure and presence of sinusoids, ab- trahepatic bile ducts {2689}. Cholangio- firmed by immunohistochemical detection
sence of mucin secretion or desmoplastic carcinomas typically express keratins 7 of thyroglobulin, prostate-specific antigen
stroma, bile production, and the demon- and 19 but not 20, while colorectal carci- and AFP and bHCG, respectively. Squa-
stration of bile canaliculi by polyclonal nomas are typically negative for keratins 7 mous cell carcinomas of the head and
CEA antisera (specific for a liver-cell and 19 and positive for keratin 20 {1948, neck seldom involve the liver.
origin). Other useful immunophenotypic 2756}. Nuclear positivity for CDX2 is also The presence of a characteristic histolog-
features are the presence of liver a marker for gastrointestinal origin {3490}. ical triad of features – proliferating bile
export proteins (albumin, fibrinogen, Metastases from the breast may be iden- ducts, leukocytes and focal sinusoidal di-
α-1-antitrypsin) and expression of hepa- tified by immunostains for gross cystic latation – in a core biopsy suggests that a
tocyte-paraffin-1 (HepPar1), AFP and the disease fluid protein 15, estrogen and metastatic deposit (a space-occupying
oncofetal protein glypican-3 {1458}. Of progesterone receptors {2335}. Metasta- lesion) has been missed by the biopsy
note, AFP and glypican-3 also stain germ tic adenocarcinoma from the lung is typi- needle. Three lesions – bile duct ade-
cell tumours, and glypican-3 can also be cally positive for TTF1; however, occult noma, sclerosed haemangioma, and lar-
positive in melanoma. Moreover, AFP is breast or lung carcinoma with hepatic val granuloma – may resemble metastatic
expressed in only a minority of HCCs, and metastases as the initial presentation is tumours at laparotomy {3573}.
glypican-3 is often not positive in well-dif- rare. The same applies to squamous cell
ferentiated HCCs {1849, 2892}. Adreno- carcinomas of the oesophagus and Prognosis
cortical carcinomas are typically positive cervix. In patients presenting with hepatic In most patients, the presence of hepatic
for inhibin and melanA {2189, 2659}, and metastasis, the most common primary is metastasis indicates an advanced and
renal cell carcinomas are typically posi- a small cell carcinoma of the lung, char- disseminated stage of disease that pre-
tive for paired box gene 8/PAX8 {3267}. acteristically producing an enlarged liver cludes surgical intervention. However, for
Amelanotic melanoma is easily identified caused by diffuse infiltration {2620}. patients with colorectal carcinoma and
by positive immunolabelling for S100 pro- Neuroendocrine/islet cell/carcinoid tu- low-burden metastatic disease, 5-year
tein and HMB45 {2380}. mours are easily identified by their survival can be as high as 40%. Without
The distinction between cholangiocarci- organoid nesting pattern, uniform cytol- surgical therapy, median survivals of < 12
noma and metastatic adenocarcinomas is ogy and vascularity, and positive months should be expected.
much more difficult, if not impossible immunostaining for chromogranin, synap-

Diagnostic algorithms for tumours of R. Saxena

J. Albores-Saavedra
the liver P. Bioulac-Sage
P. Hytiroglou
M. Sakamoto
N.D. Theise
W.M.S. Tsui
Introduction tion are mesenchymal hamartoma, undif- giosarcoma.

Hepatocellular carcinoma (HCC) and ferentiated embryonal sarcoma, HCC Tumours with predominant hepatocytic
metastatic tumours constitute the vast ma- post-embolization and large cavernous phenotype may contain a variety of intra-
jority of clinically significant liver tumours haemangioma. cellular inclusions such as ground glass
worldwide. The most common liver tumour The diagnosis of a liver tumour is facili- inclusions, pale bodies, eosinophilic glob-
is cavernous haemangioma, which is most tated by four vital pieces of clinical and ules and Mallory-Denk hyalin. The cells
often discovered incidentally during im- radiological information: the age of the are arranged in trabeculae with interven-
aging for unrelated conditions. patient; whether the tumour is solid or ing endothelium-lined sinusoids, a pattern
An important consideration in the differen- cystic; whether the tumour is single or that recapitulates the architecture of the
tial diagnosis of a liver tumour is whether multicentric; and whether there is under- normal liver. These tumours may also form
the background liver is cirrhotic. While ex- lying fibrotic chronic liver disease. While gland-like structures that do not contain
ceptions occur, a malignant tumour in a imaging studies offer clues about the na- mucin (pseudoglands or acini) but may
cirrhotic liver in children or adults is HCC, ture of a liver tumour, they offer a specific have bile (biliary rosettes), a pattern re-
and needs to be differentiated from large diagnosis only in a subset of HCCs aris- capitulating the biliary canalicular system
regenerative nodules and dysplastic nod- ing in the cirrhotic liver. This includes of the normal liver. The presence of bile is
ules, which also form distinctive nodules lesions > 2 cm in diameter that demon- the most convincing evidence of hepato-
in the cirrhotic liver. In contrast, there are strate radiological features specific for cellular differentiation on an haematoxylin
major geographic differences in the types HCC by one dynamic imaging modality or and eosin stain. Immunohistochemical
of tumours that occur in the non-cirrhotic lesions < 2 cm in diameter that demon- evidence of hepatocyte lineage is
liver; in adults, HCC is the most common strate these specific features by two dy- provided by cytoplasmic positivity for
liver tumour in South-East Asia and sub- namic imaging modalities {352}. hepatocyte-specific antigen (carbomyl
Saharan Africa, while metastatic tumours Radiological findings considered specific phosphate synthetase-1, recognized by
and benign hepatocellular lesions (focal for HCC in a cirrhotic liver are “rapid HepPar1 antibody) and α-fetoprotein
nodular hyperplasia and hepatocellular wash-in” during arterial phase followed (AFP); and by canalicular positivity for
adenoma) outnumber HCC in the USA by “rapid wash-out” during early-late CD10 and polyclonal antibody to carci-
and Europe. In children, paediatric tu- portal phases. A confirmatory biopsy is noembryonic antigen (pCEA). The latter
mours such as hepatoblastoma, mes- not needed in these cases of HCC, rep- cross-reacts with a biliary glycoprotein
enchymal hamartoma and infantile resenting perhaps the only instance in present in the canalicular membrane of
haemangioma account for the majority of which diagnosis of malignancy is es- hepatocytes; cytoplasmic reactivity with
tumours arising in non-cirrhotic livers. tablished by radiology alone. These either pCEA or monoclonal antibody to
While HCCs do occur in children, only 20– noninvasive criteria do not apply for the CEA (mCEA) is evidence against HCC.
30% occur in a background of cirrhosis in diagnosis of HCC in a non-cirrhotic Immunohistochemical evidence for the
contrast to 80–90% in adults, at least in liver. hepatocellular phenotype is useful in two
European countries and North America. situations: first, in the distinction of well-
Similarly, the fibrolamellar variant of HCC Cellular lines of differentiation of liver differentiated HCC from other tumours
occurs in non-cirrhotic livers of older chil- tumours that may show large eosinophilic cells
dren and young adults. The repertoire of primary epithelial liver tu- with or without a trabecular architecture
The vast majority of cystic liver lesions are mours is largely limited to tumours that (Table 10.10); and second, in the distinc-
either developmental or infectious in na- display hepatocytic and/ or cholangio- tion of poorly differentiated HCC from
ture, which thus form an important differ- cytic phenotypes. This rather small group other poorly differentiated tumours, in-
ential diagnostic consideration with cystic of primary tumours is matched by an al- cluding metastatic carcinomas.
liver neoplasms. True primary cystic neo- most indefinite variety of metastatic tu- Tumours with predominant cholangiocytic
plasms of the liver, i.e. neoplasms with epi- mours. Mesenchymal tumours of the liver phenotype form ductal and/or glandular
thelium-lined cysts, are few and include are similar to those arising elsewhere in structures of varying complexity and are
biliary intraductal papillary neoplasm, mu- the body except for mesenchymal hamar- usually associated with a fibrous stroma
cinous cystic neoplasm and cystic toma, which is specific to the liver. (bile duct adenoma, intrahepatic cholan-
cholangiocarcinoma. On the other hand, Mesenchymal tumours that occur prefer- giocarcinoma). These tumours may
almost any solid tumour can undergo cys- entially in the liver include inflammatory contain mucin and demonstrate immuno-
tic degeneration; in these tumours, the pseudotumour, cavernous haemangioma, histochemical positivity for keratins AE1,
cystic cavities are not lined by epithelium. angiomyolipoma, infantile haemangioma, 8/18, 7, and 19, and for epithelial mem-
Solid neoplasms most likely to appear epithelioid haemangioendothelioma, un- brane antigen (EMA), pCEA, MOC31 and
cystic on radiological or gross examina- differentiated embryonal sarcoma and an- MUC1; however, none of these markers
254 Tumours of the liver

Table 10.10 Differential diagnosis of hepatocellular carcinoma (HCC) and its mimics: useful histological and immunohistochemical features.a
Features HCC AdCa RCC ACC OCT NET / NEC AML MEL
Histological / histochemical
Trabecular architecture ● ● ● ● ● ● ●
Pseudoglandular structures ● ● ● ●
Bile production ●
Tubuloglandular architecture ● ●
Desmoplastic reaction ● ● ●
Organoid pattern ● ● ●
Cytoplasmic fat in tumour cells ● ● ● ●
Mucin ●
Immunohistochemical b
α-Fetoprotein ●
HSA / carbamoyl phosphate synthetase-1 ●
CEA, canalicular staining ●
CEA, cytoplasmic staining ●
Glypican-3 ● ●
Keratins 8/18 ● ● ● ● ●
Keratins 7/19 ● ● ●
MOC31 ● ●
Epithelial membrane antigen ● ● ● ●
Vimentin ● ● ● ● ●
PAX2 ●
Inhibin ●
Melan A ● ● ●
Chromogranin ●
Synaptophysin ● ●
Smooth muscle actin ●
HMB45 antigen ● ●
TTF1 nuclear staining ●c ● ●c
Thyroglobulin ●
ACC, adrenocortical carcinoma; AdCa, adenocarcinoma; AML, angiomyolipoma, epithelioid variant; CEA, carcinoembryonic antigen; HCC, hepatocellular carcinoma;
HSA, hepatocyte-specific antigen (HepPar1 antibody); MEL, melanoma; NET/NEC, neuroendocrine tumour/ neuroendocrine carcinoma;
OCT, follicular carcinoma of thyroid, oncocytic variant; RCC, renal cell carcinoma.
a
The selection of features was based on utility, not completeness. Dots indicate features that are commonly present in each tumour. Absence of a dot signifies that the
specific feature is either absent or uncommonly present in the specific tumour.
b
Other immunohistochemical markers may be useful in specific situations (see Table 10.13), e.g. metastatic colorectal adenocarcinomas are usually keratin 20-positive, CDX-2
positive, MUC2-positive, and keratin 7-negative; HCCs arising in patients with chronic infection with hepatitis B virus (HBV) occasionally express hepatitis B surface antigen
(HBsAg); CDX-2 may be positive in NET/NEC of the gut.
c
Positive in adenocarcinoma and NET/NEC of the lung, and in small cell NEC of other organs.
are specific for cholangiocytic differentia- chronic liver disease help to significantly rhabdoid tumour and rhabdomyosar-
tion. The diagnosis of intrahepatic cholan- narrow the differential diagnosis. Tumours coma. Tumours in children aged
giocarcinoma necessitates exclusion of that may present at birth include mes- > 2 years include undifferentiated em-
morphologically similar and more fre- enchymal hamartoma, hepatoblastoma bryonal sarcoma, calcifying nested ep-
quently occuring metastatic adenocarci- and infantile hemangioma. A large tumour ithelial stromal tumour, transitional liver
nomas; both lesions usually occur in in a child aged < 6 months with a hyper- cell tumour and HCC (Table 10.14). In a
non-cirrhotic livers (Table 10.13). dynamic circulation or consumptive child with a cirrhotic liver, the differential
thrombocytopenia (Kassabach-Merritt diagnosis of a distinctive liver nodule is
Clues from the clinical picture syndrome) is most likely to be an infantile the same as in adults and includes large
Information on age, sex, multicentricity haemangioma. Other tumours that occur regenerative nodule, dysplastic nodule
and the presence or absence of fibrotic in children aged < 2 years are malignant and HCC.

Table 10.11 Differential diagnosis of well-differentiated hepatocellular tumours arising in non-cirrhotic liver: useful gross, microscopic and immunohistochemical features.
Tumour Gross characteristics Microscopy Immunohistochemistry
Focal nodular hyperplasia Firm, multinodular mass, well-limited, Nodules of benign hepatocytes, separated Overexpression of glutamine synthetase,
(FNH) non-encapsulated; often central stellate by fibrous bands radiating from stellate scar; forming large interconnected areas in a
fibrous scar (classical FNH); any size; thick, dystrophic arteries, ductular reaction “map-like” pattern; keratin 7 or 19 to highlight
single (in about two thirds of cases) or and lymphocytic infiltration in fibrosis ductular reaction
multiple (classical FNH)
Hepatocellular adenoma Soft, non-encapsulated mass, often Benign hepatocytes, isolated arteries and The following panel is useful in
(HCA)a necrotic and haemorrhagic; any size; arterioles. subclassification of HCA: b
single (in about two thirds of cases) or
multiple Subtypes:
HNF1α-inactivated
Steatosis, usually marked Loss of L-FABP in tumoral hepatocytes
β-Catenin-activated
Focal, mild to moderate nuclear atypia and Glutamine synthetase: strong, diffuse
pseudoglands overexpression;
β-Catenin: aberrant, often focal, nuclear and
cytoplasmic expression
Inflammatory HCAc
Inflammatory infiltrate, thick arteries, ductular Serum amyloid A, C-reactive protein: diffuse
reaction; often prominent sinusoidal dilata- overexpression
tion and peliotic areas
Well-differentiated Soft tumour, often encapsulated, Trabecular architecture (plates often more Glypican-3: for this differential diagnosis, this
hepatocellular carcinoma a often large than two to three cells thick), pseudoglands; stain is useful only if positive
variable nuclear atypia; bile production AFP: useful if positive, but usually negative
(common); numerous isolated arteries; de-
creased reticulin network
Fibrolamellar hepatocellular Large, firm, variegated tumour with Large, eosinophilic (oncocytic) hepatocytes; Keratin 7: useful, if strongly and diffusely
carcinoma fibrous scar; calcifications (imaging) thick plates separated by thick parallel positive
fibrous lamellae; cytoplasmic inclusions
common
Hepatoblastoma, fetal type Large, variegated tumour, often Small hepatocytes in two-cell thick plates; AFP: positive
haemorrhagic little to no pleomorphism; ‘”light” and “dark”
areas; extramedullary haematopoiesis
AFP, α-fetoprotein; L-FABP, liver fatty acid-binding protein.

a
The differential diagnosis of HCA and well differentiated HCC may be impossible. Often additional clinical information, radiological examination (including assessment of
rapid growth), and/or more extensive sampling are necessary for diagnosis.
b This panel may also be used for distinguishing FNH from HCA (in FNH, L-FABP is normally expressed, i.e. diffusely positive, and β-catenin is exclusively membranous,
whereas C-reactive protein and serum amyloid A are negative).

c
10% of inflammatory HCAs are also β-catenin-activated.
A young woman taking the contraceptive more, as in the pancreas, a number of “cystadenoma” and “cystadenocarci-
pill who presents with acute abdominal cystic, mass-like lesions do not show an noma” without the typical “ovarian-like”
haemorrhage is most likely to have a he- “ovarian-like” stroma and are lined by stroma, are more appropriately termed
patocellular adenoma. A cystic tumour in papillary epithelium, which may be biliary, “biliary intraductal papillary neoplasms”
a young woman is likely to be a mucinous mucinous or oncocytic in nature. Like (whether cystic or not) in alignment with
cystic neoplasm, formerly referred to as their pancreatic counterparts, they arise intraductal papillary tumours of the pan-
“biliary cystadenoma.” If the tumour from biliary intraductal papillary lesions creas. In contrast to intraductal papillary
demonstrates areas of invasion, it is (biliary papilloma/biliary papillomatosis) neoplasms of the pancreas, which are
called a mucinous cystic neoplasm asso- and become cystic as they enlarge and most often lined by mucinous epithelium,
ciated with invasive carcinoma; a term obstruct the ducts of origin. These cystic the vast majority of intraductal papillary
that is preferred to the formerly used “ bil- neoplasms occur with equal frequency in neoplasms of the biliary tree are lined by
iary cystadenocarcinoma.” These cystic men and women and are distinct from the biliary epithelium. Oncocytic variants are
neoplasms are analogous to their coun- mucinous cystic neoplasms with “ovarian- rare at both sites.
terparts in the pancreas and, as in that like” stroma in both the pancreas and liver The new suggested terminology acknowl-
organ, their defining feature is the pres- {257, 1837, 2250}. Thus, these tumours, edges the similarities between cystic tu-
ence of “ovarian-like” stroma. Further- originally thought to represent variants of mours arising in the pancreas and the liver

and their respective ductal systems, and Table 10.12 Differential diagnosis of distinctive hepatocellular nodular lesions arising in cirrhotic liver: useful histologi-
distinguishes the two distinct clinico- cal and immunohistochemical features.
Hepatocellular lesion
pathological groups of cystic tumours in
the liver; those that have an intraductal ori- Histological feature FNH-
LRN LGDN HGDN eHCC clHCC
gin and those that do not {2719}. like
The presence of underlying chronic liver Features characteristic of carcinoma
disease, especially when there is ad-
Cell plates more than three cells in width – – – – +/– +
vanced fibrosis or cirrhosis, represents
high odds for the presence of HCC. In ad- Moderate nuclear-contour irregularities – – – – + +
dition, HCC may arise in the context of Stromal invasion – – – – +/– +/–
haemochromatosis and chronic hepatitis
Vascular invasion – – – – – +/–
B infection even in the absence of cirrho-
sis; this is especially true in areas with Widespread loss and irregularity of reticulin framework – – – – – +/–
high incidence of HCC, such as South-
Other features
East Asia and sub-Saharan Africa, where
a male preponderance is noted. Cell density more than twice that of the surrounding
– – – +/– + +/–
parenchyma (reflecting increased nucleus : cytoplasm ratio)
Clues from the radiological and gross ap- Pseudogland formation in the absence of cholestasis – – – +/– +/– +/–
pearance of liver tumours
Expansile subnodules (foci) – – – +/– +/– +/–
Most liver tumours are solid in appear-
ance but cystic changes may occur in Nuclear hyperchromasia – – – + + +
any tumour, including HCC. Cystic Mild nuclear-contour irregularities – – – + + +
changes are rare in cholangiocarcino-
Cytoplasmic basophilia – – – +/– +/– +/–
mas, which usually are white, firm masses
Prominent steatosis
without significant necrosis or haemor- (more than in the background liver)
– ? +/– +/– +/– +/–
rhage. The presence of fibrosis in these
Prominent hepatocellular siderosis
tumours leads to delayed central en- – – +/– +/– – –
(more than in the background liver)
hancement on dynamic computed to-
Resistance to iron accumulationa – – – +/– + +
mography (CT) and magnetic resonance
imaging (MRI); this feature when associ- Portal tracts within the nodule + +/– + + +/– –
ated with biliary dilatation is strongly sug- Unpaired arteries – + +/– +/– +/– +
gestive of cholangiocarcinoma. Almost
any tumour can cause compression of the Immunohistochemical stains
bile ducts, but an abrupt biliary stricture α-Fetoprotein – – – – –b +/–
is indicative of cholangiocarcinoma, es-
Three-marker panel:c
pecially when there are known predis-
posing factors such as primary sclerosing Glypican-3 –b ? –b +/– +/– +/–
cholangitis. While both focal nodular hy- Heat shock protein 70 – ? –b –b +/– +/–
perplasia and fibrolamellar carcinoma Glutamine synthetase
– – – – +/– +/–
occur in non-cirrhotic livers and show a (diffuse pattern, not just perivenular)
central stellate scar, focal nodular hyper-
FNH-like, focal nodular hyperplasia-like nodule; HGDN, high-grade dysplastic nodule; LGDN, low-grade dysplastic
plasia has a soft appearance while fibro- nodule; LRN, large regenerative nodule; eHCC, early hepatocellular carcinoma; clHCC: “classic” hepatocellular
lamellar carcinoma is firm. A yellow colour carcinoma.
representing underlying steatosis is more –, absent; +, present; +/–, can be absent or present; ?, not known.
common in focal nodular hyperplasia. a
“Resistance to iron accumulation” refers to an iron-free focus in an otherwise siderotic nodule.
b
Most primary liver tumours are solitary; Rarely positive.
c
HCC may show multiple satellite nodules Currently, positive immunostaining for any two markers of the three-marker panel is considered strong suggestive
evidence for hepatocellular carcinoma (either early or classic).
situated around the main tumour at a dis-
tance of 1 cm or less. On the other hand,
the presence of multiple tumours, both
solid and cystic, is suspicious for masses in a non-cirrhotic liver of an eld- appear spongy and beefy-red on gross
metastatic disease, especially when they erly individual are distinctive for epithe- examination. The latter also show periph-
arise in older individuals without cirrhosis. lioid haemangioendothelioma. eral puddling of contrast material on im-
Bile duct adenomas are often multiple Different types of cysts cannot be reliably aging studies, the intensity of which is the
and appear as tiny, subcapsular lesions distinguished from one another by radio- same as that of the aorta, an important di-
measuring 1–5 mm. They raise alarm for logical or gross examination, except in the agnostic feature. When imaging shows
metastatic disease during abdominal sur- case of hydatid cysts which have pearly multiple liver cysts, developmental cysts
gery and account for a significant number white, slimy walls and characteristic im- or metastatic disease are the major con-
of intraoperative consultations. Multiple, aging features. Large cavernous haeman- siderations. Liver tumours that are entirely
centrally calcified or ossified tumour giomas with cystic degeneration typically or predominantly intraductal include

258
Solid lesion
Hepatocytes
Immature-appearing cells Hepatocytes or other large eosinophilic cells Ducts/glands/mucin
and ducts/glands/mucin
In fibrotic/cirrhotic In the absence of

background significant fibrosis
Hepatocytes with
any of the following:
HSA Any of the following: Any of the following: bile, HSA, CD10, pCEA,a
Tumours of the liver and intrahepatic bile ducts

α-Fetoprotein bile, HSA, CD10, pCEAa bile, HSA, CD10, pCEAa and
ducts/glands/mucin/keratin 7
Positive Negative Positive Negative Positive Negative Benign Malignant

Hepatoblastoma Metastasis Large regenerative nodule Metastasis Focal nodular hyperplasia Metastasis Bile duct adenoma Cholangiocarcinoma Combined hepatocellular-
except fetal type Metastasis cholangiocarcinoma
See Table 10.10 See Table 10.10 Peribiliary gland
Dysplastic nodule Hepatocellular adenoma See Table 10.13
hamartoma
Biliary
Hepatocellular carcinoma Hepatocellular carcinoma
adenofibroma
See Table 10.12 See Table 10.13

Fibrolamellar carcinoma
Hepatoblastoma, fetal type

See Table 10.11
Fig. 10.104 Diagnostic algorithm of liver lesions with solid mass.

a
Only the canalicular pattern of staining for CD10 and pCEA is specific for the hepatocellular phenotype; this may, however, coexist with a membranous pattern
pCEA, polyclonal antibody to carcinoembryonic antigen; HSA, hepatocyte-specific antigen, recognized by HepPar1 antibody, corresponds to cytoplasmic carbamoyl phosphate synthetase-1.
Cystic lesion
Epithelium-lined Without epithelial lining
Cuboidal / Biliary/mucinous/oncocytic
Ciliated Neoplastic Non-neoplastic
low columnar (with or without papillary architecture)
Laminated Inflammation and

With ovarian-like stroma Without ovarian-like stroma wall necrosis
No epithelial Epithelial No epithelial Epithelial

invasion into invasion into invasion into invasion into Benign Malignant
wall wall wall wall
Ciliated Mucinous Mucinous cystic Biliary intraductal Malignant biliary Mesenchymal Undifferentiated
Solitary bile duct cyst Hydatid cyst Amoebic abscess Haemorrhagic
foregut cyst cystic neoplasm with papillary neoplasmd intraductal papillary hamartoma embryonal
cystf
neoplasmc an associated neoplasme sarcoma
Fibropolycystic liver Cavernous
invasive Pyogenic abscess
Intrahepatic haemangioma
disease,b with or Cystic

carcinomag
without associated cholangiocarcinoma Cystic degeneration
renal disease with cystic change Hydatid cyst
degeneration in any tumour
in any tumour
Obstructive dilatation Necrotizing
of bile duct eosinophilic
granulomaa
Fig 10.105 Diagnostic algorithm of cystic lesions of the liver.
a
This does not refer to Langerhans cell histiocytosis, but to an inflammatory lesion, often associated with parasitic infections.
b
259
Inclusive of Caroli disease; c Biliary cystadenoma; d Biliary papilloma or papillomatosis, with low- or high-grade dysplasia; e Biliary papillomatosis with invasion; f Cystic haematoma; g Biliary cystadenocarcinoma.
Table 10.13 Differential diagnosis of solid, benign and malignant, biliary and gland-forming lesions of the liver: useful gross, histological and immunohistochemical features.
Solid glandular lesion Gross characteristics Histological and immunohistochemical characteristics
von Meyenburg complex Multiple discrete nodules, related to portal tracts; may Irregular or rounded ductal structures lined by flattened or cuboidal epithelium; lumina
(bile duct microhamartoma) contain bile; usually < 0.5 cm may contain proteinaceous fluid or bile concretions; dense fibrous stroma; usually
portal or periportal; expresses keratins 7 and 19.
Bile duct adenoma Solitary subcapsular, whitish firm discrete nodule; Small, round tubules, lined by cuboidal epithelium,a may contain mucin; often contains
(peribiliary gland hamartoma) usually < 2 cm normal portal tracts; expresses keratins 7 and 19.
Biliary adenofibroma Circumscribed, whitish tumour; may contain microcystic Complex tubulo-cystic structures with complex branching; single-layered biliary epithelium
areas; may be as large as 16 cm. of variable height, sometimes with mitotic activity; lumina may contain cellular debris or
proteineous fluid; abundant fibroblastic stroma and/or areas of hyalinization; expresses
keratins 7 and 19.
Serous cystadenoma (micro- Circumscribed, sponge-like tumour, with microcysts Multiple small cysts separated by thin fibrous septa, lined by a single layer of clear, glyco-
cystic adenoma) filled with clear, watery fluid; any size. gen-rich cuboidal cells; expresses keratins 7 and 19, and occasionally CA19-9 and B72.3.
Cholangiocarcinoma Variable appearances; any size: Adenocarcinoma, often with abundant desmoplastic stroma, perineural invasion and/or
• Single firm nodule; mucin secretion.
• Multiple nodules (mimicking metastases); Immunoprofile: keratins 7 and 19, EMA, and CEA: usually positive; keratin 20: positive in
• Diffuse growth; 20% of cases.
• Irregular periductal thickening; (Epithelioid hemangioendothelioma may mimic cholangiocarcinoma, but is negative for
• Intraductal polypoid mass; epithelial immunomarkers and positive for endothelial markers, e.g. CD31 and CD34)
• Any combination of the above.
Metastatic pancreatobiliary Single or multiple firm nodules of any size. Adenocarcinoma indistinguishable from cholangiocarcinoma either by morphology or
ductal carcinoma by immunohistochemistry.
Metastatic colorectal adeno- Single or multiple nodules of any size, often with Adenocarcinoma, often with garland pattern and central “dirty” necrosis.
carcinoma central necrosis. Immunoprofile: keratin 20, CDX2, MUC2 and CEA: positive; keratin 7: negative.
Metastatic adenocarcinoma Single or multiple nodules of any size. Adenocarcinoma with variable appearance.
from other sites Immunoprofile: first segregate according to pattern of keratins 7 and 20; then apply
markers according to the suspected primary site.
CEA, carcinoembryonic antigen; EMA, epithelial membrane antigen.

a
The rare clear cell variant may be easily confused with metastatic renal cell carcinoma or cholangiocarcinoma, clear cell type.
biliary intraductal papillary neoplasm and positivity for hepatocyte-specific antigen fibrolamellar carcinoma and hepatoblas-
embryonal rhabdomyosarcoma. and AFP {824}. When the tumour demon- toma (Table 10.11). The differential diagno-
strates hepatocellular phenotype or large sis of metastatic lesions with a hepatocytoid
The diagnostic algorithm eosinophilic cells, the differential diagno- appearance is listed in Table 10.10.
The diagnosis of liver tumours initially re- sis differs significantly in cirrhotic versus When a tumour is composed of ducts
quires that the lesion be identified as pre- non-cirrhotic livers. The overwhelming and/or glands with or without mucin pro-
dominantly cystic or solid; this information majority of distinctive nodules in a cir- duction, the first step is to determine
is available either from the radiology re- rhotic liver are indeed of hepatocellular whether the ductal/glandular structures
port, in the case of a biopsy specimen, or origin and demonstrate differentiation fea- are benign or malignant. Benign lesions
from the gross findings, in the case of a tures of this phenotype, such as presence usually demonstrate a biliary phenotype
surgically resected specimen. of bile, cytoplasmic positivity for hepato- and are often accompanied by a fibrous
cyte-specific antigen and canalicular pos- stromal background. The differential di-
Solid lesions itivity for pCEA and CD10. Such lesions agnosis of malignant gland-forming and/
If the tumour is solid in appearance, the may represent large regenerative nod- or mucin-producing lesions in the liver in
next step is to determine the nature of the ules, dysplastic nodules or hepatocellular one of the most difficult in diagnostic sur-
cells and/or architecture on low-power carcinomas (Table 10.12). gical pathology. It encompasses the
microscopic examination. This leads to In a non-cirrhotic liver, the presence of large distinction of intrahepatic cholangiocarci-
four possible observations, as noted hepatocyte-like eosinophilic cells with or noma from metastatic adenocarcinoma
in the algorithm for solid tumours. without a trabecular pattern may represent and in the latter case, the identification of
When the tumour is composed predomi- true hepatocytic differentiation or be effec- the primary site of origin. This can be ac-
nantly of immature-appearing cells, the tively mimicked by metastatic tumours from complished in most cases by correlation
differential diagnosis includes hepato- other organs. The former group of lesions of the histological features with the stain-
blastoma and metastasis; the former can demonstrate markers of hepatocytic differing profile for keratins 7 and 20, com-
be differentiated from morphologically entiation and include focal nodular hyper- bined with the application of site-specific
similar appearing metastatic tumours by plasia, hepatocellular adenoma, HCC, antibodies. In this context, it is pertinent

that cholangiocarcinomas may be posi- neoplasia. These neoplasms may show epi- Table 10.14 Age at presentation of liver tumours in infants
tive for keratin 20 in about 40%, and for thelial invasion into the cyst walls, giving rise and children.
CDX2 in about 20% of cases, making dis- to their malignant counterpart, malignant bil- Age < 2 years
tinction from metastatic colonic adeno- iary intraductal papillary neoplasm (biliary
Infantile haemangioma
carcinoma difficult. However, in contrast papillomatosis with invasion). Uncommonly, Mesenchymal hamartoma
to intrahepatic cholangiocarcinoma, the intrahepatic cholangiocarcinoma may Hepatoblastoma
latter usually shows abundant necrosis demonstrate cystic change and may be dif- Hepatic malignant rhabdoid tumour
and no desmoplasia. The morphological ficult to differentiate from malignant biliary in- Rhabdomyosarcoma
and immunohistochemical profile of pan- traductal papillary neoplasm.
Age > 2 years
creatic adenocarcinoma is identical to that Liver cysts not lined by epithelium may
for intrahepatic cholangiocarcinoma and represent cystic change in solid tumours Focal nodular hyperplasia
the two cannot be distinguished without or necrosis in inflammatory lesions; the Hepatocellular adenoma
additional clinical and radiological data. first step is therefore to distinguish be- Fibrolamellar carcinoma
Hepatocellular carcinoma
A tumour containing both hepatocytes tween neoplastic and non-neoplastic le-
Transitional liver cell tumour
and ducts/glands is most commonly a sions. Almost any tumour may be seen Calcifying nested epithelial stromal tumour
combined hepatocellular-cholangiocarci- but those most prone to appear cystic on Undifferentiated embryonal sarcoma
noma (mixed hepatobiliary carcinoma). radiological and gross examination are
These tumours show immunopositivity for mesenchymal hamartoma, undifferenti-
hepatocyte markers in the hepatocellular- ated embryonal sarcoma and large cysts that form mass lesions are included
looking areas and for cholangiocytic cavernous haemangioma. Mesenchymal since they outstrip cystic neoplasms in inci-
markers in the ductal and glandular ele- hamartoma occurs at < 2 years of age dence. Similarly, the algorithm outlines the
ments. Cholangiocarcinoma with reported and contains abundant myxoid tissue, most common pathways of tumour mor-
positivity for hepatocellular markers such while undifferentiated embryonal sarcoma phology and behaviour; and does not in-
as hepatocyte-specific antigen, CD10 occurs more commonly at > 2 years of clude rare morphological and biological
and AFP (2–5% of cases), probably rep- age and shows undifferentiated, obvi- variants.
resent examples of this tumour. ously malignant cells with eosinophilic in- It is pertinent to note that although immuno-
tracytoplasmic globules. A cyst showing histochemical stains form an important part
Cystic lesions a laminated wall of acellular eosinophilic of the diagnostic algorithm, they are neither
The first step in the diagnosis of a liver material, often lined by a germinal layer, sensitive nor specific. The sensitivity of he-
cyst is to determine whether it is a true is a hydatid cyst. The presence of inflam- patocyte-specific antigen for diagnosis of
cyst, i.e. whether the cystic space is lined mation and necrosis should raise suspi- HCC is 70–90% {818, 1735, 1911} and
by epithelium. When lined by epithelium, cion of an infectious process, e.g. a seems to decrease with the degree of dif-
the nature of the epithelium is assessed. pyogenic abscess, amoebic abscess, hy- ferentiation of the tumour {552}. This marker
Cysts lined by cuboidal or low columnar datid cyst or necrotizing eosinophilic is also positive in gastric, pulmonary, ovarian
epithelium are common and the vast ma- granuloma. The latter term is used to de- and pancreatobiliary carcinomas {1735}.
jority are developmental in origin; a mi- note inflammatory nodules with central AFP is detectable by immunohistochemistry
nority are a result of biliary obstruction. If necrosis that are usually associated with in only 30–40% of HCCs {552, 3271} and
the lining epithelium is ciliated, the cyst parasitic infections and systemic symp- approximately 50–60% of hepatoblastomas
represents a ciliated foregut cyst and will toms and should not be confused with {2628}. On the other hand, approximately
usually show smooth muscle in its wall. A Langerhans cell histiocytosis {1475}. It is 10–20% of HCCs may be positive for ker-
benign cyst with a mucinous or biliary lin- uncertain whether the solitary necrotic atins 7 and 20. The issue of immunohisto-
ing epithelium and ovarian-like stroma in nodule is also related to necrotizing chemical sensitivity and specificity is
the wall is a mucinous cystic neoplasm eosinophilic granuloma {3715}. Large particularly compounded in poorly differen-
(formerly, biliary cystadenoma). These haematomas may sometimes appear as tiated tumours that display aberrant pheno-
cysts occur almost exclusively in women cystic tumours and are easily identified by types as they diverge markedly from normal
and the stroma is immunohistochemically the presence of organizing blood and differentiation pathways. Many of these tu-
positive for estrogen and progesterone re- absence of epithelial lining, neoplastic mours may morphologically appear as solid
ceptors. Uncommonly, these tumours tissue and inflammatory reaction. sheets of cells, which do not indicate a def-
may undergo malignant change mani- inite differentiation pathway.
fested by invasive epithelial growth into Comments A biopsy aimed at a mass lesion in the liver
the cyst wall (mucinous cystic neoplasm The diagnostic algorithm focuses on com- may miss its target and instead sample ad-
with invasive carcinoma; formerly, biliary monly encountered lesions and does not in- jacent compressed hepatic parenchyma,
cystadenocarcinoma). clude rare epithelial tumours (microcystic which shows a characteristic triad of histo-
A cyst lined by biliary or mucinous epithe- adenoma), rare variants of epithelial tumours logical findings. These include sinusoidal di-
lium in papillary configurations is a biliary in- (cholangiocellular variants of hepatoblas- latation, ductular reaction, and portal
traductal papillary neoplasm, biliary or toma, transitional liver cell tumour), mixed inflammation and oedema. These features
mucinous type, respectively. Rare cases epithelial-mesenchymal tumours (calcifying reflect obstruction of bile and blood flow by
may be lined by oncocytic cells. The epi- nested stromal epithelial tumour) and mes- an adjacent space-occupying lesion, thus
thelium in these cysts may show low-, inter- enchymal tumours (angiomyolipoma and suggesting the presence of such a lesion
mediate-or high-grade intraepithelial others). On the other hand, non-neoplastic {967}.

CHAPTER 11
Tumours of the gallbladder

and extrahepatic bile ducts
Carcinoma
Mesenchymal tumours
Lymphoma
Secondary tumours and melanoma

WHO classificationa of tumours of the gallbladder and

extrahepatic bile ducts
Epithelial tumours
Premalignant lesions Neuroendocrine neoplasmsb
Adenoma 8140/0 Neuroendocrine tumour (NET)
Tubular 8211/0 NET G1 (carcinoid) 8240/3
Papillary 8260/0 NET G2 8249/3
Tubulopapillary 8263/0 Neuroendocrine carcinoma (NEC) 8246/3
Biliary intraepithelial neoplasia, grade 3 (BilIN-3) 8148/2 Large cell NEC 8013/3
Intracystic (gallbladder) or intraductal (bile ducts) Small cell NEC 8041/3
papillary neoplasm with low- or intermediate-grade Mixed adenoneuroendocrine carcinoma 8244/3
Goblet cell carcinoid 8243/3
Intracystic (gallbladder) or intraductal (bile ducts)
papillary neoplasm with high-grade intraepithelial Tubular carcinoid 8245/1
neoplasia 8503/2*
Mucinous cystic neoplasm with low- or Mesenchymal tumours
intermediate-grade intraepithelial neoplasia 8470/0
Mucinous cystic neoplasm with high-grade Granular cell tumour 9580/0
intraepithelial neoplasia 8470/2 Leiomyoma 8890/0
Carcinoma
Leiomyosarcoma 8890/3
Rhabdomyosarcoma 8900/3
Adenocarcinoma, biliary type 8140/3
Adenocarcinoma, gastric foveolar type 8140/3
Lymphomas
Adenocarcinoma, intestinal type 8144/3
Clear cell adenocarcinoma 8310/3
Secondary tumours
Intracystic (gallbladder) or intraductal (bile ducts)
papillary neoplasm with an associated invasive
carcinoma 8503/3*
Mucinous cystic neoplasm with an associated
invasive carcinoma 8470/3*
____________________
a
b
The classification is modified from the previous WHO histological classification of tumours {691} taking into account changes in our understanding of these
lesions. In the case of neuroendocrine neoplasms, the classification has been simplified to be of more practical utility in morphological classification.
264 Tumours of the gallbladder and extrahepatic bile ducts

TNM classificationa of tumours of the gallbladder and

extrahepatic bile ducts
Carcinoma of the gallbladder
T – Primary tumour N – Regional lymph nodes
TX Primary tumour cannot be assessed NX Regional lymph nodes cannot be assessed
T0 No evidence of primary tumour N0 No regional lymph-node metastasis
Tis Carcinoma in situ N1 Regional lymph-node metastasis (including nodes along the
T1 Tumour invades lamina propria or muscular layer cystic duct, common bile duct, hepatic artery, and portal vein).
T1a Tumour invades lamina propria M – Distant metastasis
T1b Tumour invades muscular layer M0 No distant metastasis
T2 Tumour invades perimuscular connective tissue; no extension M1 Distant metastasis
beyond serosa or into liver
T3 Tumour perforates the serosa (visceral peritoneum) and/or Stage grouping
directly invades the liver and/or one other adjacent organ or
structure, such as stomach, duodenum, colon, pancreas, Stage 0 Tis N0 M0
omentum, extrahepatic bile ducts Stage I T1 N0 M0
T4 Tumour invades main portal vein or hepatic artery or invades Stage II T2 N0 M0
two or more extrahepatic organs or structures Stage IIIA T3 N0 M0
Stage IIIB T1, T2, T3 N1 M0
Stage IVA T4 Any N M0
Carcinoma of the distal extrahepatic bile ductsb

Tis Carcinoma in situ
Stage grouping
T1 Tumour confined to the bile duct
T2 Tumour invades beyond the wall of the bile duct Stage 0 Tis N0 M0
T3 Tumour invades the gallbladder, liver, pancreas, duodenum Stage IA T1 N0 M0
or other adjacent organs Stage IB T2 N0 M0
T4 Tumour involves the coeliac axis or the superior mesenteric Stage IIA T3 N0 M0
artery Stage IIB T1, T2, T3 N1 M0
N – Regional lymph nodes Stage III T4 Any N M0
Carcinoma of the perihilar extrahepatic bile ductsc

T – Primary tumour NX Regional lymph nodes cannot be assessed
TX Primary tumour cannot be assessed N0 No regional lymph-node metastasis
T0 No evidence of primary tumour N1 Regional lymph-node metastasis including nodes along the
Tis Carcinoma in situ cystic duct, common bile duct, hepatic artery, and portal vein
T1 Tumour confined to the bile duct, with extension up to the
muscle layer or fibrous tissue M – Distant metastasis
T2a Tumour invades beyond the wall of the bile duct to surrounding M0 No distant metastasis
adipose tissue M1 Distant metastasis
T2b Tumour invades adjacent hepatic parenchyma
T3 Tumour invades unilateral branches of the portal vein or Stage grouping
hepatic artery Stage 0 Tis N0 M0
T4 Tumour invades the main portal vein or its branches bilaterally; Stage I T1 N0 M0
or the common hepatic artery; or the second-order biliary
radicals bilaterally; or unilateral second-order biliary radicals Stage II T2a, T2b N0 M0
with contralateral portal-vein or hepatic-artery involvement Stage IIIA T3 N0 M0
Stage IIIB T1, T2, T3 N1 M0
Stage IVA T4 N0, N1 M0
____________________
a
{762, 2996}; b The classification applies to carcinomas of the extrahepatic bile ducts distal to the insertion of the cystic duct. Cystic duct carcinoma is included
under gallbladder; c The classification applies to carcinomas of the extrahepatic bile ducts of perihilar localization (Klatskin tumour). Included are the right, left,
and common hepatic ducts, i.e. those proximal to the origin of the cystic duct.
Classification 265
Carcinoma of the gallbladder and J. Albores-Saavedra

N.V. Adsay
G. Klöppel
B. Sripa
extrahepatic bile ducts J.M. Crawford
D.S. Klimstra
W.M.S. Tsui
V. Paradis
Carcinoma of the gallbladder eastern Europe and in parts of Asia junction between the pancreatic and
{1800, 2630}. common bile ducts and cancer of the
Definition gallbladder and the extrahepatic bile
A malignant epithelial neoplasm, usually Etiology ducts {2105}. Of patients with gallbladder
with biliary, intestinal, foveolar or squamous The most important risk factors for carci- carcinoma, those with an abnormal chole-
differentiation, arising in the gallbladder. noma of the gallbladder are genetic back- dochopancreatic junction are on average
ground (described later), gallstones and 10 years younger than those with a
ICD-O codes an abnormal choledochopancreatic junc- normal junction {2105}.
Adenocarcinoma 8140/3 tion. A small number of patients with familial
Biliary type 8140/3 Gallstones are present in > 80% of gall- adenomatous polyposis (FAP) will
Gastric foveolar type 8140/3 bladders harbouring a carcinoma {70}. develop dysplasia and carcinoma of the
Intestinal type 8144/3 However, the overall incidence of carci- gallbladder {1198}.
Clear cell adenocarcinoma 8310/3 noma of the gallbladder in patients with The inflammatory disorders ulcerative co-
Mucinous adenocarcinoma 8480/3 cholelithiasis is < 0.2% {70}, so although litis and primary sclerosing cholangitis
Signet ring cell carcinoma 8490/3 gallstones are considered to be a con- have also been reported to be associated
Adenosquamous carcinoma 8560/3 tributing risk factor, most individuals with with carcinoma of the gallbladder,
Intracystic (gallbladder) or gallstones never develop gallbladder car- although less frequently than with carci-
intraductal (bile ducts) papillary cinoma. Correlation between gallstone noma of the extrahepatic bile ducts
neoplasm with an associated size and the risk of cancer is suspected, {1826, 3601}.
invasive carcinoma 8503/3 but has not been confirmed {70}.
Mucinous cystic neoplasm with an Diffuse calcification of the gallbladder Clinical features
associated invasive carcinoma 8470/3 wall (“porcelain gallbladder”) is present in Currently, close to 50% of gallbladder car-
Squamous cell carcinoma 8070/3 < 1% of cholecystectomy specimens and cinomas are diagnosed incidentally in
Undifferentiated carcinoma 8020/3 8–10% of such resected specimens cholecystectomy specimens from pa-
(some estimates reaching 13–62%) har- tients with symptoms attributed only to the
Epidemiology bour a carcinoma {631, 3075, 3279}. presence of gallstones (cholelithiasis)
Most patients with carcinoma of the gall- Some studies have suggested that selec- {745}. Unfortunately, gallbladder carci-
bladder are in the sixth or seventh tive mucosal calcification poses a signifi- noma usually presents at a late stage,
decade of life. From 1985 to 2005, the in- cant cancer risk, while diffuse intramural even when found incidentally. The signs
cidence of invasive carcinoma of the gall- calcification does not {3075}. In studies in and symptoms are not specific, often re-
bladder in the USA was 0.9 per 100 000 which such an association was reported, sembling those of chronic cholecystitis.
males and 1.6 per 100 000 females, ac- the carcinomas detected included not Right upper-quadrant pain is common.
counting for 0.16% and 0.39% of all can- only well-differentiated adenocarcinoma Computed tomography (CT) and ultra-
cers in males and females, respectively but also mucinous and squamous cell sonography aid detection of the neoplasm.
{1240}. The female-to-male ratio is 1.77. carcinomas {70}. Less than 1% of patients with carcinomas
Cancer of the gallbladder accounts for Data reported largely from Japan indicate of the gallbladder present with a parane-
51% of all cancers arising in the biliary an association between an abnormal oplastic syndrome that may be the first
tract in women and 28% in men. The inci-
dence of this cancer decreased between
1973 and 2005 {1240}.
The incidence of carcinoma of the gall-
bladder varies geographically and also in
different ethnic groups within the same
country. In the USA, it is more common in
American Indians and Hispanic Ameri-
cans than in whites or African Americans
{70, 708, 2890}. Recent studies indicate
that rates are declining in American Indi-
ans, possibly because of the increasing
use of cholecystectomy {191}. High rates Fig. 11.01 The white, irregular cut surface of an Fig. 11.02 Well-differentiated adenocarcinoma infiltrating
are also found in certain populations in intracystic papillary neoplasm projecting into the the wall of the gallbladder, biliary type.
Mexico, Central and South America, gallbladder lumen next to a large gallstone.

A B
Fig. 11.03 Adenocarcinoma of the gallbladder, intestinal type. A Note the tubular glands similar to those seen in colonic adenocarcinoma. B Goblet-cell variant.
manifestation of the neoplasm {3345}. of intracystic papillary neoplasms and bil- neoplasm is not warranted. Rarely, Paneth
Adenocarcinomas of the gallbladder have iary intraepithelial neoplasia (BilIN) with cells may be seen. Adenocarcinomas
been reported in association with acan- those of the intrahepatic biliary tree and may contain osteoclast-like giant cells
thosis nigricans {2623}, bullous pemphy- the pancreas. Two new histological types, {52} or show focal cribriform or angiosar-
goid-type lesions {70}, the Leser-Trelat cribriform carcinoma and the benign comatous patterns {70, 185}. They may
sign {70}, dermatomyositis {3640} and giant cell tumour, have been added also contain cyto- and syncytio-tro-
Guillain-Barré syndrome {2540}. {69, 71}. phoblast cells {20, 70}.
Gallbladder adenocarcinomas tend to
Macroscopy Adenocarcinoma, biliary type be more poorly differentiated and show
Carcinoma of the gallbladder usually Well- to moderately differentiated invasive less desmoplasia than their counter-
forms an infiltrating grey-white mass. adenocarcinomas of biliary type are the parts in the extrahepatic bile ducts.
Some carcinomas cause diffuse thicken- most common malignant epithelial neo- Most adenocarcinomas of the gallbladder
ing and induration of the entire gallblad- plasms of the gallbladder. They are com- are immunoreactive for carcinoembryonic
der wall. The gallbladder may be posed of short or long tubular glands antigen (CEA), MUC1, MUC2, p53 and
distended by the tumour, or collapsed lined by cells that vary in height from keratin 7 {76, 77, 214, 660, 754, 1790,
owing to obstruction of the neck or cystic cuboidal to tall columnar, superficially re- 2011, 2779, 3177, 3530, 3596}.
duct. It can also assume an hourglass de- sembling biliary epithelium. Cytoplasmic
formity when the neoplasm arises in the and luminal mucin is frequently present Adenocarcinoma, intestinal type
body and constricts the lateral walls. Car- {1745}. Rarely, the extracellular mucin Two morphological variants of invasive
cinomas arising in association with intra- may become calcified. About one third of adenocarcinoma of intestinal type have
cystic papillary neoplasms are usually the well-differentiated adenocarcinomas been described in the gallbladder. The
sessile and exhibit a polypoid or cauli- show focal intestinal differentiation and most common is composed of tubular
flower-like appearance. Mucinous and contain goblet and neuroendocrine cells glands closely resembling those of
signet ring cell carcinomas have a mu- {76, 3582, 3596}. These sometimes colonic adenocarcinomas. The glands
coid or gelatinous cut surface. numerous neuroendocrine cells may be im- are lined predominantly by columnar
munoreactive for serotonin and peptide hor- cells with pseudostratified ovoid or elon-
Tumour staging mones, but a diagnosis of neuroendocrine gated nuclei. The second variant con-
The TNM (tumour, node, metastasis) clas- sists of glands lined predominantly of
sification for the gallbladder also applies goblet cells usually with a variable num-
for carcinomas of the cystic duct. ber of neuroendocrine and Paneth cells
Changes in the classification of regional {70, 75}. Both variants label with anti-
lymph nodes and stage grouping oc- bodies to CDX2, MUC2, CEA and keratin
curred between the sixth and seventh edi- 20.
tions of TNM {2996}.
Adenocarcinoma, gastric foveolar type
Histopathology This unusual but distinctive, well-differen-
The WHO histological classification of tu- tiated variant is composed of tall colum-
mours of the gallbladder is based on pre- nar cells with basally oriented nuclei and
vious classifications published by WHO abundant mucin-containing cytoplasm; it
{1106} and by the Armed Forces Institute usually labels with antibodies to MUC5A.
of Pathology (AFIP) in 2000 {70} and has Fig. 11.04 Intestinal-type adenocarcinoma of the common Combined forms (adenocarcinoma or
been updated to align the nomenclature hepatic duct showing diffuse nuclear expression of CDX2. adenosquamous carcinoma with foveolar
Carcinoma 267
Fig. 11.05 Adenosquamous carcinoma of the gallbladder, composed of gland-forming Fig. 11.06 Squamous cell carcinoma of the gallbladder.
elements alternating with solid, squamous nests.
differentiation) have been reported in the Carcinosarcoma Cribriform carcinoma

gallbladder {70}. The epithelial (carcinomatous) elements Cribriform carcinoma is a distinctive inva-
usually predominate in the form of glands, sive neoplasm of the gallbladder that re-
Adenosquamous carcinoma but may be arranged in cords or sheets. sembles cribriform carcinoma of the
The extent of differentiation of the two ma- Foci of squamous differentiation are re- breast, but accounts for < 1% of all gall-
lignant components, glandular and squa- ported. The sarcomatous component can bladder carcinomas {71}. Patients are
mous, varies, but in general they tend to include heterologous elements such as younger than those with conventional
be moderately differentiated {54, 69, 475, chondrosarcoma, osteosarcoma, and adenocarcinoma of the gallbladder and
1856, 2088, 2295}. Keratin pearls are rhabdomyosarcoma. Keratin and CEA are the neoplasms are usually associated
often present in the squamous compo- absent from the mesenchymal compo- with cholelithiasis. In addition to typical
nent, and mucin is usually demonstrable nent, helping to distinguish carcinosarco- cribriform growth, high-grade tumours
in the neoplastic glands. mas from undifferentiated spindle and have large vesicular nuclei with prominent
giant cell carcinomas {70}. nucleoli and show comedo-type necrosis.
In contrast to cribriform carcinomas of the
breast, the gallbladder carcinomas are
negative for estrogen and progesterone
receptors and behave aggressively, like
conventional adenocarcinomas of the
gallbladder {71}.
Clear cell adenocarcinoma

This rare malignant neoplasm is com-
posed predominantly of glycogen-rich
clear cells with well-defined cytoplasmic
borders and central hyperchromatic nuclei
arranged in glandular or other growth pat-
Fig. 11.07 Carcinosarcoma of the gallbladder. The tumour Fig. 11.09 Signet ring cell carcinoma of the gallbladder.
has malignant glandular elements and a sarcomatous
terns {73, 270, 3139, 3377}. Some cells
component with osteoid formation. contain eosinophilic granular cytoplasm.
Foci of conventional adenocarcinoma with
mucin production are usually found and
can distinguish primary carcinomas from
metastatic clear cell carcinomas of the kid-
ney. Exclusion of renal cell carcinoma is
also accomplished by immunohistochem-
ical labelling for PAX8 and RCC {162}. In
some clear cell adenocarcinomas, the
columnar cells contain subnuclear and
supranuclear vacuoles similar to those
seen in secretory endometrium. Produc-
Fig. 11.08 High-grade cribriform carcinoma of the Fig. 11.10 Mucinous adenocarcinoma. Clusters of tion of α-fetoprotein has been documented
gallbladder with comedo-type necrosis. malignant epithelial cells are surrounded by abundant in clear cell carcinomas with or without he-
extracellular mucin. patoid differentiation {2107, 3465}.

Hepatoid adenocarcinoma
This is an exceedingly rare neoplasm of
the gallbladder that closely mimics hepa-
tocellular carcinoma {2779, 3356}. For di-
agnosis, > 50% of the neoplasm should
be composed of hepatoid cells usually
arranged in a trabecular pattern. The neo-
plastic hepatoid cells label with HepPar1
antibody and rarely with α-fetoprotein. A
minor component of conventional adeno-
carcinoma has been reported in all of
these carcinomas. The biological behav-
iour of hepatoid adenocarcinoma ap-
pears to be similar to that of conventional
adenocarcinoma.
Fig. 11.11 Undifferentiated carcinoma of the gallbladder, spindle cell and giant cell type; note the absence of glandular
Mucinous adenocarcinoma differentiation.
These neoplasms are more common in
the gallbladder than in the extrahepatic
bile ducts, and are similar to those that
arise at other anatomical sites. By con-
vention, > 50% of the tumour contains ex-
tracellular mucin {70, 72}. Mucinous
carcinoma should be distinguished from
a benign mucocele. The abundant extra-
cellular mucin present in a mucocele may
be recognized grossly in the gallbladder A B
wall as nodules of different sizes. The
Fig. 11.12 Tubular adenoma, pyloric-gland type, of the gallbladder. A A vague lobular patern is seen at low magnification.
mucin can extend to the serosa through
B Tubular glands are lined by mucin-containing columnar cells with basally placed, uniform vesicular nuclei.
the Rokitansky-Aschoff sinuses and in-
duce a histiocytic response. The histio-
cytes may phagocytize mucin and be dominate in some poorly differentiated ocytic neoplasm, can be distinguished
confused with signet ring cells. Immuno- squamous cell carcinomas, which may be from carcinoma with osteoclast-like giant
labelling for keratin and CEA is positive in confused with sarcomas {3137}. Immuno- cells by immunohistochemical assessment
mucinous carcinoma and negative in labelling for keratin and p63 may clarify of CD163, CD68, HAM56, and keratins {69}.
mucocele. Ruptured, mucin-containing, the diagnosis in these spindle-cell cases.
Rokitansky-Aschoff sinuses with abun- The carcinoma may arise from areas of Precursor lesions
dant extracellular mucins having small squamous metaplasia or high-grade Adenoma
benign glandular and papillary structures intraepithelial neoplasia {70}. Most gall- Adenomas are benign neoplasms of glan-
should not be confused with mucinous bladder carcinomas with squamous dif- dular epithelium that are typically poly-
carcinoma {68}. ferentiation represent adenosquamous poid, single and well-demarcated. They
carcinomas, and the glandular compo- are more common in women than in men,
Signet ring cell carcinoma nent may be very focal; thorough exami- and most occur in adults {85, 3531}. They
Cells containing intracytoplasmic mucin nation is required before a diagnosis of are found in 0.3–0.5% of gallbladders
displacing the nuclei toward the peri- pure squamous cell carcinoma can be removed for cholelithiasis or chronic
phery predominate in this variant of established.
adenocarcinoma. A variable amount of
extracellular mucin is usually present. Lat- Undifferentiated carcinoma
eral spread through the lamina propria is This neoplasm is more common in the
a common feature. A diffusely infiltrating gallbladder than in the extrahepatic bile
linear pattern resembling linitis plastica ducts. Characteristically, glandular struct-
(diffuse-type adenocarcinoma) of the ures are few or absent. There are sev-
stomach has been observed {70}. eral histological variants: spindle cell,
giant cell (including those with osteo-
Squamous cell carcinoma clast-like giant cells), small cell (non-
This malignant epithelial neoplasm is neuroendocrine), and a nodular/lobular
composed entirely of squamous cells with type that superficially resembles breast
highly variable degrees of differentiation. carcinoma {70, 73, 721, 1085, 1124, 2231, Fig. 11.13 Papillary adenoma of the gallbladder, intestinal
Keratinizing and nonkeratinizing types 2298}. The recently described benign giant type. Note the pseudostratified columnar cells with
exist {136, 954, 3137}. Spindle cells pre- cell tumour of the biliary tree, a true histi- scattered goblet and Paneth cells.
Carcinoma 269
{70, 239, 240, 290, 743, 991, 1139, 1492,

1729, 1910, 2234, 2253, 3137}.
BilIN is usually not recognized on macro-
scopic examination because it often occurs
in association with chronic cholecystitis. The
mucosa may be granular, nodular, plaque-
like, or trabeculated. BilIN-1 and 2 of the
gallbladder is characterized by mild cy-
toarchitectural atypia including enlarge-
ment of cells, pseudostratification of nuclei
and hyperchromatism. It is typically de-
Fig. 11.14 Low-grade intraepithelial neoplasia (BilIN-1) of Fig. 11.15 High-grade intraepithelial neoplasia (BilIN-3)
the gallbladder adjacent to intestinal metaplasia with of intestinal type in the gallbladder. tected incidentally and is of no established
numerous mature goblet cells. clinical significance.
BilIN-3 usually arises in a background of
pyloric and intestinal metaplasia {70, 743,
cholecystitis. Adenomas are often small, Intestinal-type adenoma is a rare benign 1216, 1725}. Occasional goblet cells are
asymptomatic, and usually discovered in- neoplasm composed of dysplastic tubu- found in one third of cases. An abrupt
cidentally during cholecystectomy, but lar glands lined by cells with an intestinal transition between columnar cells of nor-
they can be multiple, fill the lumen of the phenotype, which closely resembles mal appearance and dysplastic cells is
gallbladder and be symptomatic. Occa- colonic adenomas. seen in nearly all cases. Five cell pheno-
sionally, adenomas of the gallbladder Foveolar-type adenoma has a tubulopap- types are recognized: biliary, intestinal,
occur in association with Peutz-Jeghers illary architecture and consists of tall oncocytic, squamous and signet ring cell
syndrome {884} or Gardner syndrome columnar cells with small basal hyper- {70, 75, 812}. When associated with an in-
{3201, 3435}. While a significant number chromatic nuclei and abundant mucin- vasive cancer, the morphological type of
of adenomas in the gallbladder are asso- containing cytoplasm {70}. Rarely, these BilIN-3 does not always correspond with
ciated with lithiasis, those of the extra- adenomas arise from the epithelial in- that of the carcinoma. BilIN-3 may arise
hepatic bile ducts are not. vaginations of adenomyomatous hyper- from or extend into Rokitansky-Aschoff si-
Adenomas can be divided into three plasia. Foveolar-type adenomas label with nuses, a feature that should not be con-
types on the basis of growth pattern: tu- antibodies to MUC5AC and occasionally fused with stromal invasion {80}. If BilIN-3
bular, papillary, and tubulopapillary {70}. MUC6. is found, multiple sections should be
Cytologically, they are classified as: py- There is also an exceedingly rare biliary- taken to exclude invasive cancer. The
loric-gland type, intestinal type, foveolar type adenoma lined by cytologically nor- dysplastic cells immunolabel for CEA
type and biliary type. Pyloric and intes- mal-appearing biliary epithelium. {77}, S100 A4 {3703}, CA19-9 {70} and
tinal-type adenomas are more common in p53 {3530}. Cholecystectomy with nega-
the gallbladder than in the extrahepatic bile Biliary intraepithelial neoplasia tive margins is a curative surgical proce-
ducts {85}. A small proportion of adenomas BilINs are characterized by atypical epi- dure for patients with BilIN-3 or with
progress to invasive carcinoma {85, 1540}. thelial cells with multilayering of nuclei invasive carcinoma limited to the lamina
Tubular adenoma, pyloric-gland type (py- and micropapillary projections into the propria {70}.
loric-gland adenoma) is the most com- gallbladder lumen {3688, 3689}. The BilIN is often encountered in the setting
mon variant of gallbladder adenoma. It is atypical cells have an increased nucleus- of chronic cholecystitis and may coexist
composed of lobules of closely packed to-cytoplasm ratio, partial loss of nuclear with reactive epithelial changes. In con-
pyloric-type glands, some of which may polarity, and nuclear hyperchromasia. trast to BilIN, these changes (“atypia of
be cystically dilated, often covered by BilIN-1 and BilIN-2 correspond to low- repair”) involve a heterogeneous cell
normal biliary epithelium. Squamoid grade and intermediate-grade lesions population containing columnar mucus-
morules characterized by nodular aggre- and BilIN-3 corresponds to high grade le- secreting cells, low cuboidal cells, at-
gates of cytologically bland spindle cells sions {3688}. The incidence of BilIN-3 rophic-appearing epithelium, and
with eosinophilic cytoplasm but no kera- parallels that of invasive carcinoma and pencil-like cells. In addition, reactive
tinization are also seen {1693, 2300}. its prevalence is higher in countries in changes show a gradual transition be-
Paneth cells and neuroendocrine cells are which gallbladder carcinoma is endemic tween cellular abnormalities, in contrast
often present. By definition, pyloric-gland than in countries in which it is sporadic. to the abrupt transition seen in BilIN. The
adenomas have at least low-grade in- The incidence of BilIN-3 in gallbladders expression of TP53 is more extensive
traepithelial neoplasia. Larger adenomas with lithiasis varies from 0.5% to 3% {70}. and more common in BilIN than in reac-
may have high-grade intraepithelial neo- This variation in the incidence of BilIn-3 is tive epithelia {70}.
plasia or may be associated with foci of partially attributable to a lack of uniformity
invasive carcinoma. As they enlarge, in morphological criteria and sampling Intracystic papillary neoplasms
some develop a pedicle and project into methods. In addition to cholelithiasis, Intraluminal papillary neoplasms of the
the lumen. Rarely, they extend into or BilIN-3 occurs in the mucosa adjacent to extrahepatic biliary tree are referred to as
arise from Rokitansky-Aschoff sinuses, a most invasive carcinomas and can be “intracystic” in the gallbladder and “intra-
finding that should not be mistaken for in- found in patients with FAP, sclerosing ductal” in the extrahepatic bile ducts.
vasive carcinoma {85}. cholangitis and pancreatobiliary reflux Similar to intraductal papillary neoplasms

Fig. 11.16 High-grade intraepithelial neoplasia (BilIN-3) of the gallbladder, with biliary phenotype. A At low magnification, the dysplastic epithelium lines the mucosal villi. B At high
magnification, there is complete loss of nuclear polarization and the round nuclei are markedly pleomorphic.
described in the extrahepatic and intra- Mucinous cystic neoplasms (MCNs)

hepatic biliary tree, intracystic papillary These neoplasms resemble their intra-
neoplasms of the gallbladder may occur hepatic counterparts. MCNs are seen
as pancreatobiliary or intestinal pheno- predominantly in adult females and are
types, the latter with goblet, Paneth, usually symptomatic. Some MCNs meas-
and/or serotonin-containing cells. Previ- ure up to 20 cm in diameter and cause
ously, the low-grade lesions were some- obstructive jaundice or cholecystitis-like
times designated “papillary adenoma” symptoms. More common in the extra-
and the high-grade lesions as “noninva- hepatic bile ducts than in the gallbladder,
sive papillary carcinoma.” These neo- MCNs are multiloculated neoplasms that
plasms often arise in a background of contain mucinous or serous fluid and are
pyloric-gland metaplasia. Intracystic pap- lined by columnar epithelium reminiscent Fig. 11.17 Intracystic papillary neoplasm projecting into
the lumen, but without invasion of the wall of the
illary neoplasms of the gallbladder may of bile duct or foveolar gastric epithelium
gallbladder.
be associated with invasive adenocarci- {706}. Neuroendocrine cells are occa-
noma, which should be separately re- sionally present. By definition, the cellular
ported and staged. When an invasive subepithelial stroma resembles ovarian
carcinoma arises in association with an in- stroma and is immunoreactive for estro-
tracystic papillary neoplasm, the lesion gen and progesterone receptors. The
usually has high-grade intraepithelial neo- stroma is also variably fibrotic. Invasive
plasia, which is characterized by complex carcinomas that arise in association with
papillary structures lined by cuboidal or MCNs of the gallbladder should be des-
low columnar biliary-type cells or colum- ignated MCN with an associated invasive
nar intestinal-type cells, often containing carcinoma {706} and clearly described in
variable amounts of mucin. The invasive terms of grade and extent; staging is only
component is usually a tubular adenocar- required for the invasive component.
cinoma, although mucinous carcinoma,
undifferentiated carcinoma, small cell car- Genetic susceptibility
cinoma, and large cell neuroendocrine Carcinoma of the gallbladder is concen-
carcinoma have also been described trated in certain racial and ethnic groups.
{1215}. Familial aggregation has been recorded
Distinguishing intracystic papillary neo- in the USA and elsewhere {1163, 3285}.
plasms from papillary adenomas may be In addition, a high prevalence of gallstone
difficult. The vast majority of intracystic disease has been associated with spe-
papillary neoplasms have a biliary phe- cific human leukocyte antigen (HLA) alle-
notype whereas papillary adenomas ex- les that are more common in Native
hibit an intestinal phenotype. High-grade Americans {2043}. Although a person’s
intracystic papillary neoplasms show genetic background may increase the
greater architectural compliexity and cy- propensity to develop gallstones and thus
tological atypia than papillary adenomas. indirectly increase susceptibility to gall-
{74, 84, 1215}. Mitotic figures are more bladder cancer, no genetic traits specific Fig. 11.18 Intracystic papillary neoplasm with associated
common in intracystic papillary neo- to gallbladder oncogenesis have been invasive carcinoma. The noninvasive component is
plasms than in adenomas. identified. papillary whereas the invasive component is tubular.
Carcinoma 271
Molecular pathology gardless of size, cell phenotype and de- jaundice, which can rapidly progress or
Mutations of the KRAS, TP53 and gree of differentiation, rarely metastasize fluctuate. Jaundice usually appears while
CDKN2A genes have been reported in in- and therefore have the best prognosis. In the neoplasm is relatively small and pre-
vasive carcinomas of the gallbladder contrast, carcinomas metastasize and cedes widespread dissemination. Other
{414, 1114, 1187, 1318, 1668, 1966, 2494, are associated with a poor prognosis if symptoms include right upper-quadrant
3529, 3532}. The incidence of KRAS mu- they infiltrate the entire thickness of the pain, malaise, weight loss, pruritus,
tations and loss of SMAD4 expression is gallbladder wall (10-year relative survival anorexia, nausea, and vomiting. If cholan-
low in carcinomas arising in the gallblad- rate, 52% {77, 85}. The 10-year relative gitis develops, chills and fever appear. In
der {143, 2679, 3465}, although KRAS survival rate for patients with undifferenti- patients with carcinoma of the proximal
mutations are more frequent in gallblad- ated carcinoma spindle cell and giant bile ducts (right and left hepatic ducts,
der carcinomas associated with an anom- cell types is 0% {66}. common hepatic duct), the intrahepatic
alous junction of the pancreaticobiliary bile ducts are dilated, the gallbladder is
duct {2634}. Amplification of the ERBB2 not palpable and the common duct often
gene was detected in 30 out of 43 inva- Carcinoma of the extrahepatic collapses. Patients with carcinoma in the
sive carcinomas of the gallbladder bile ducts common or cystic ducts have a distended
{1780}; however, there was no correlation and palpable gallbladder as well as a
between ERBB2 amplification and prog- Definition markedly dilated proximal duct system,
nosis. A malignant epithelial neoplasm usually as may be shown by ultrasonography
The molecular pathology of adenomas of with biliary, intestinal, foveolar or squa- and computed tomography. Transhepatic
the gallbladder differs from that of inva- mous differentiation, arising in the extra- cholangiograms and endoscopic retro-
sive carcinomas. None of 16 adenomas hepatic bile ducts. grade cholangiopancreatography (ERCP)
showed TP53 or CDKN2A gene muta- are essential to localize carcinomas of the
tions, which are common in carcinomas Epidemiology extrahepatic bile ducts. Like carcinoma of
{3531}. Several studies have investigated Most patients with extrahepatic biliary the gallbladder, carcinomas of the extra-
mutations and immunohistochemical ex- carcinoma are in the sixth or seventh hepatic bile ducts may rarely present with
pression of β-catenin in adenomas and decades of life. Except for the Republic paraneoplastic syndromes.
carcinomas of the gallbladder {482, 2634, of Korea, where incidence is somewhat
3612}. Mutations in β-catenin were found higher, there is no geographical variation Macroscopy
in 57–63% of tubular adenomas (pyloric- in the incidence of extrahepatic bile-duct Carcinomas of the extrahepatic bile ducts
gland type), and in 0–9% of carcinomas carcinoma. In the USA, for example, ex- have been divided into polypoid, nodular,
{2711}. These studies provide additional trahepatic bile-duct carcinoma accounts scirrhous constricting, and diffusely infil-
support for the hypothesis that pyloric- for 0.16% of all invasive cancers in males trating types. While this categorization
gland adenomas play a minor role in gall- and 0.15% in females in the general can provide a guide to the most appro-
bladder carcinogenesis {70}. population {70}. From 1985 to 2005, the priate operative procedure, extent of
A high incidence of loss of heterozygosity incidence of extrahepatic bile-duct carci- resection, and prognosis, it is rarely pos-
(LOH) at the TP53 gene locus has been noma in the USA was 1.1 per 100 000 sible in practice (except for the polypoid
reported in BilIN; other molecular abnor- males and 0.7 per 100 000 females tumours) because of overlap in the gross
malities include LOH at 9p and 8p loci {1240}. features of each type. The nodular and
and the 18q gene. These abnormalities scirrhous types tend to infiltrate surround-
are early events and probably contribute Etiology ing tissues and are difficult to resect. The
to the pathogenesis of gallbladder carci- Risk factors for carcinoma of the extra- diffusely infiltrating types tend to spread
noma. However, no KRAS mutations were hepatic bile ducts include primary scle- linearly along the ducts.
detected in BilIN-3 {3529, 3530}. rosing cholangitis, ulcerative colitis,
abnormal choldedochopancreatic junc- Tumour staging
Prognosis and predictive factors tion and, in south-east Asia, infestation The seventh edition of the TNM classifi-
The prognosis for patients with carci- with Clonorchis sinensis or Opisthorcis cation divides extrahepatic bile-duct car-
noma of the gallbladder depends prima- viverrini {534, 634, 1855, 3285, 3468}.
rily on the extent of disease and Unlike in the gallbladder, choledocholithi-
histological type {74, 85}. For example, asis does not play a role in the pathogen-
the vast majority of adenocarcinomas of esis of carcinomas of the extrahepatic
the gallbladder confined to the lamina bile ducts. Choledochal cysts are of par-
propria do not metastasize and simple ticular note as 2.5–15% of adult patients
cholecystectomy appears to be curative. with choledochal cysts develop carcino-
In contrast, the 10-year relative survival mas {70}, most commonly adenocarci-
rate for invasive adenocarcinomas that noma of intestinal type.
extend through the entire thickness of the
gallbladder wall is 30% {74, 85}. Nonin- Clinical features
vasive intracystic papillary neoplasms Unlike those of the gallbladder, carcino-
and minimally invasive carcinomas aris- mas of the extrahepatic bile ducts usually Fig. 11.19 Adenocarcinoma of the distal common bile
ing in association with such lesions, represent relatively early with obstructive duct infiltrating the duodenal wall.

A B C
Fig. 11.20 Diffuse intraductal papillary neoplasm (“biliary papillomatosis”) in the bile ducts. A Papillary (villous) pattern. B Villous pattern. C There is no invasive carcinoma associated
with the intraductal neoplasm.
cinoma into perihilar and distal bile duct Precursor lesions tic factors. Therefore, when an invasive
{2996}. The distal classification applies to Two types of precursor lesions are carcinoma is present, it should be desig-
carcinomas that are distal to the insertion thought to precede the development and nated (e.g. “intraductal papillary neo-
of the cystic duct. progression of extrahepatic bile duct ade- plasm with an associated invasive
nocarcinoma: BilIN and intraductal papil- adenocarcinoma”) and staged sepa-
Histopathology lary neoplasms {12, 2235, 3689, 3691, rately. The prognosis is excellent if an in-
The WHO histological classification of 3694} (see Chapter 10). traductal papillary neoplasm without an
carcinomas derives from prior classifica- associated carcinoma is localized and
tions and includes the concepts of the Biliary intraepithelial neoplasia can be completely resected, but more
precursor lesions intraductal papillary BilINs of the extrahepatic and intrahepatic widely distributed disease may be difficult
neoplasms and BilIN, and new entities. biliary tree share clinical, morphological, to eradicate surgically and behave more
and immunophenotypical features. aggressively {3639}.
Adenocarcinoma, biliary type
Extrahepatic bile-duct adenocarcinomas Intraductal papillary neoplasms Molecular pathology
tend to be better differentiated and show Intraductal papillary neoplasms may di- The incidence of KRAS gene mutations,
more desmoplasia than their counterparts late the bile ducts, and luminal accumu- immunolabelling for p53 protein, and loss
in the gallbladder, but are similar in all lation of mucin may occur {2933, 3691}; of SMAD4 expression in carcinomas of
other ways, including immunoreactivity. the latter is much less common in biliary the extrahepatic bile ducts increases from
lesions than in pancreatic intraductal pap- proximal to distal bile duct {143, 2679,
Adenocarcinoma, gastric foveolar type. illary mucinous neoplasms (IPMNs). As 3465}. As for IPN of the extrahepatic bil-
This unusual, distinctive, well differenti- with pancreatic IPMNs, four phenotypes iary tree, but unlike conventional adeno-
ated variant is composed of tall columnar of epithelium are recognized: pancreato- carcinoma of the extrahepatic bile ducts,
cells with basally oriented nuclei and biliary (the most common in the biliary a low frequency of KRAS mutations has
abundant mucin-containing cytoplasm, tree), intestinal, oncocytic, and gastric been detected in IPNs of the extrahepatic
which usually label with MUC5AC. Unlike types (the two latter types are rare) {1611, biliary tree {12}. Microsatellite instability
in the gallbladder, where mixed forms are 2738, 2933, 3691}. The clinicopathologi- occurs in only 10% of IPNs of the extra-
seen, the pure form of foveolar adenocar- cal condition previously referred to as “bil- hepatic bile ducts {11}.
cinoma has been described in the extra- iary papillomatosis” is characterized by
hepatic bile ducts {70}. multiple, recurring intraductal papillary Prognosis and predictive factors
neoplasms that may involve extensive The prognosis for patients with neo-
Intestinal-type adenocarcinoma, squamous areas of the extrahepatic bile ducts and plasms of the extrahepatic biliary tract de-
cell carcinoma, adenosquamous carcinoma, even extend into the gallbladder and in- pends primarily on the extent of disease
carcinosarcoma, clear cell adenocarcinoma, trahepatic ducts {11, 1790}. The disease and histological type {1170, 1171, 2378,
squamous cell carcinoma affects males and females equally, most 3251}. Carcinomas arising in association
These neoplasms share the histological being between the ages of 50 and 70 with an intraductal papillary neoplasms
and immunophenotypical characteristics years. In the Republic of Korea, Taiwan have the potential to metastasize and are
of those arising in the gallbladder. (China) and Japan, about 30% of cases associated with a poor prognosis; when
are associated with stones and 25% with the carcinoma is localized to the ductal
Mucinous adenocarcinoma and flukes {1790}. Invasive carcinoma may wall, the relative 10-year survival rate is
undifferentiated carcinoma occur in association with intraductal pap- 21% {77, 85}. Perineural invasion and
These carcinomas share the histological illary neoplasms {3690, 3691}. Once in- lymphatic permeation are common and
and immunophenotypical characteristics vasive carcinoma develops, prognosis is are significant prognostic factors {706,
of those arising in the gallbladder, but are related to the stage of the invasive com- 2205, 3531}.
less common. ponent and other conventional prognos-
Carcinoma 273
Neuroendocrine neoplasms of the P. Komminoth

R. Arnold
G. Rindi
J. Albores-Saavedra
gallbladder and extrahepatic bile ducts C. Capella
D.S. Klimstra
E. Solcia
G. Klöppel
Definition Neuroendocrine carcinoma (NEC) 8246/3 Etiology

Neoplasms with neuroendocrine differen- Large cell NEC 8013/3 The cause of NETs of the extrahepatic bil-
tiation, including neuroendocrine tumours Small cell NEC 8041/3 iary tract and the gallbladder is not known.
(NET) and neuroendocrine carcinomas Mixed adenoneuroendocrine NECs (poorly differentiated endocrine
(NEC) arising in the extrahepatic bile carcinoma (MANEC) 8244/3 carcinomas) seem to be associated with
ducts or gallbladder. Mixed adenoneu- Goblet cell carcinoid 8243/3 gallstones {2559}.
roendocrine carcinomas (MANECs) have Tubular carcinoid 8245/1
both exocrine and endocrine compo- Localization
nents, with each component exceeding Epidemiology All types of neuroendocrine neoplasms
30%. NETs (carcinoids) of the bile duct and the are more commonly located in the gall-
gallbladder are very rare. There were 19 bladder than in the extrahepatic bile
Synonyms gallbladder NETs and one bile-duct NET ducts {70, 2115, 3595}. Both NETs and
Synonyms for NETs of extrahepatic bile recorded in a series of 8305 cases of all NECs can involve any portion of the gall-
ducts or gallbladder include: carcinoid, sites, representing 0.2% and 0.01% of bladder (fundus, body, or neck). NETs in
well-differentiated endocrine tumour/car- cases {2115}. NETs are equally distrib- the extrahepatic bile ducts may arise any-
cinoma {3013}. Synonyms for NEC in- uted between males and females and where within the biliary tree, including the
clude: poorly differentiated endocrine present at an average age of 60 years. common hepatic duct (33%), the cystic
carcinomas, high-grade neuroendocrine NECs represent 4% of all malignant neo- duct (11%), and the upper or lower com-
carcinoma, small cell and large cell en- plasms of the gallbladder {83, 2296}. mon bile duct (58%) {468, 774, 2590}. In-
docrine carcinomas. NECs are slightly more common in fe- volvement of the site of confluence of bile
males (male-to-female ratio, 1 : 1.8) and ducts (cystic duct and common hepatic
ICD-O codes present at an average age of 65 years duct, or right and left hepatic ducts) or ori-
Neuroendocrine tumour (NET) (range, 43–83 years) {2296}. gin within the intrapancreatic distal com-
NET G1 (carcinoid) 8240/3 mon bile duct, appear to be most
NET G2 8249/3 common {1544}. NECs of the bile ducts
tend to be located distally, only one case
A B C
Fig. 11.21 Neuroendocrine tumour (NET) G1 (carcinoid) of the common bile duct. A A band of fibrous tissue separates the tumour from normal bile-duct epithelium. B Carcinoid
cells with round nuclei and eosinophilic cytoplasm. C The NET cells are immunoreactive for serotonin.

has been reported in the cystic duct

{1248, 3021}.
Clinical features
Gallbladder NETs usually lack specific
symptoms. In most instances, they are
detected incidentally after cholecystec-
tomy. Occasionally, they cause recurrent
upper-quadrant pain. NETs of the extra-
hepatic bile ducts typically produce either
sudden onset of biliary colic or painless
obstructive jaundice {2754}. Rare cases
of primary, functioning, gastrin-producing
NET (gastrinoma) of the common hepatic
duct with Zollinger-Ellison syndrome have
been reported {1988, 2590}.
The chief complaint of patients with NEC Fig. 11.22 Small cell neuroendocrine carcinoma (NEC) lying below normal gallbladder epithelium.
is abdominal pain. Other clinical features
include abdominal mass, jaundice, and
ascites {2296}. In addition, rare cases of Histopathology
hormonal syndromes have been reported NETs Small cell NECs. These neoplasms are
associated with NECs, one patient with NETs are composed of cells that are uni- composed of round or fusiform cells
Cushing syndrome due to an adrenocor- form in size, with round or oval nuclei, in- arranged in sheets, nests, cords, and
ticotropic hormone (ACTH)-secreting conspicuous nucleoli, and eosinophilic festoons. Characteristic nuclear “mould-
small cell carcinoma {3039} and one suf- cytoplasm. NET cells are arranged in ing” is demonstrable on high-power ex-
fering from paraneoplastic sensory neu- combined patterns with trabecular anas- amination. Rosette-like structures and
ropathy {3345}. tomosing structures, tubular structures tubules are occasionally present. Ex-
and solid nests {529, 1028, 2754, 2999}. tensive necrosis and subepithelial
Macroscopy Tumour cells are immunoreactive for growth are constant features. In necrotic
NETs of the gallbladder are usually small synaptophysin {1957} chromogranin A areas, intense basophilic staining of the
(generally < 2 cm), grey-white or yellow, {116, 2754}, neuron-specific enolase blood vessels occurs. Tumour cells
submucosal nodules or polyps, some- (NSE) {116, 203, 348}, keratins (keratin 7 have round or ovoid hyperchromatic nu-
times infiltrating the muscular wall {70, and AE1/AE3) {2976}, and several hor- clei with inconspicuous nucleoli. Occa-
774, 1957, 2388, 2754}. Some are pe- mones, including serotonin {116, 203, sionally, tumour giant cells {70, 2296}
dunculated {1456, 2388}. Multifocality has 1957}, gastrin {201, 1957, 1972, 1988}, and focal areas of glandular or squa-
been reported, but is rare {2425}. NETs somatostatin {116, 1028, 1957} and pan- mous differentiation are observed
measuring 0.3–0.5 cm can easily be over- creatic polypeptide {1183, 1647, 1957}. {1310, 1958, 2296}. Mitotic figures are
looked on gross examination of cholecys- Clear cell NETs of the gallbladder are frequent and reported to range from 15
tectomy specimens {2580}. characterized by cells with abundant cy- to 206 (mean, 75) per 10 high power
Bile-duct NETs are usually small, submu- toplasm containing small lipid vacuoles, fields (HPF) {2296}. NECs of small cell
cosal nodules with variable amounts of imparting a foamy appearance. Periodic type show diffuse positivity for synapto-
sclerosis. Although they are often grossly acid-Schiff demonstrates neither glyco- physin and NSE and often contain scat-
circumscribed, they have infiltrative growth, gen nor mucin in the clear cells. This NET tered chromogranin A-positive cells. In
grossly resembling primary adenocarcino- variant can be either sporadic or associ- addition, tumour cells express epithelial
mas of the bile ducts {1957}. There is less ated with von Hippel-Lindau (VHL) dis- markers such as epithelial membrane
tendency to invade adjacent structures, ease {1647, 2976, 3252}. Neoplasms antigen (EMA), keratin AE1/AE3 and
however, and the size of these neoplasms associated with VHL disease are positive carcinoembryonic antigen (CEA). A few
averages only 2.0 cm (range, 1.1–5.4 cm) for inhibin, while sporadic neoplasms are cells may stain for serotonin, somato-
{849, 1957}. Some are polypoid, resembling negative for inhibin {1647, 3252}. statin, and ACTH {70, 2296}. Overex-
papillary bile-duct neoplasms {1284, 3252}. pression of p53 has been detected in
NECs and MANECs appear as a nodular NECs 83% and loss of pRb in 67% of cases
mass or neoplasm diffusely infiltrating the NECs of the gallbladder and extrahepatic {2494}. Ultrastructurally, a small number
gallbladder or bile-duct wall {2296}. A sig- bile ducts encompass small cell and of dense-core secretory granules can
nificant proportion of NECs of both the large cell variants. In the small cell type, be found {70, 83}.
gallbladder and bile ducts have a poly- the cell population and the growth pattern
poid appearance {1420, 1560, 1685, are similar to those of small cell carci- Large cell NECs. These neoplasms dis-
3595}. Although they average 3.0 cm in noma of the lung {1685, 1958, 2296}. play an organoid growth pattern often
size {1958}, these neoplasms can be Small cell carcinomas appear to be more with rosette formation composed by large
quite large and may extensively invade common in the gallbladder than in the ex- cells characterized by vesicular nuclei
the liver and adjacent tissues {1535}. trahepatic bile ducts. with prominent nucleoli and a variable

amount of cytoplasm {1451, 2451}. Tu- Genetic susceptibility sive growth, including invasion of the
mour cells are positive for keratins, chro- NETs of the gallbladder and extrahepatic muscularis propria or beyond {116, 117,
mogranin A and synaptophysin. The bile ducts are infrequently associated with 2027}, and neural invasion {2027}. The
proliferative rate (Ki67 immunostain) is VHL syndrome {2202, 2976} and multiple risk of malignant behaviour largely de-
> 50%. Foci of adenocarcinoma may be endocrine neoplasia type 1 (MEN1) pends on tumour size, since NETs meas-
present. {2590}. uring 0.3–0.5 cm usually do not show
metastases {70}, while NETs > 2 cm often
MANECs Molecular pathology extend into the liver and/or metastasize
A significant number of cases reported in Few studies have addressed genetic al- {2294}. The percentage of gallbladder
the older literature as NETs, including the terations in neuroendocrine neoplasms of NETs showing regional and distant metas-
cases reviewed by Yamamoto et al. the gallbladder and extrahepatic bile tases has been estimated as approxi-
{3593, 3595}, are in fact MANECs. These ducts {1848}. Mutations of TP53, KRAS mately 44% and 11%, respectively {774,
are composite neoplasms in which areas and SMAD4 appear not to play a signifi- 2115}. The 5-year survival rate is 41% ac-
of adenocarcinoma or squamous cell car- cant role in the pathogenesis of NETs cording to Surveillance, Epidemiology nd
cinoma intermingle with areas of NET or {1957}. Accumulation of p53 and inacti- End Results (SEER) data for the USA. Ap-
NEC, each comprising at least 30% of the vation of the pRb/p16 pathway has been proximately one third of patients with bile-
neoplasm, by arbitrary definition. The found in most NECs of the gallbladder duct NETs exhibit metastases at
neuroendocrine components display fea- {2296, 2494}. Expression of SMAD4 pro- diagnosis {774}. Aggressive surgical ther-
tures overlapping those described in pure tein is usually retained and KRAS muta- apy offers the only chance for cure and
NETs or NECs, being formed by solid tions are rare {1958, 2494}. should be considered whenever possible
and/or trabecular structures with argyro- {1092, 1373}. Five-year survival rates
phylic cells that are immunoreactive for Prognosis and predictive factors range from 60% to 100% {2116}.
NSE, chromogranin A, CD56/NCAM1, In contrast to other gastrointestinal sites, The prognosis for patients with NEC either
serotonin and gastrin {803, 2296, 2372, there is no proposal for a TNM/staging of small or large cell type is poor {83,
2385, 2661, 2947, 3307, 3595}. The ade- classification of neuroendocrine neo- 1451}. About 40–50% of patients have
nocarcinoma component is usually tubu- plasms of the gallbladder and bile ducts. disseminated disease at the time of diag-
lar or papillary, formed by columnar cells, The relative rarity of NETs and NECs at nosis {907}. Small cell NEC of the gall-
goblet cells and sometimes Paneth cells. these sites may account for this. Given bladder appears to be highly responsive
Squamous elements appear as circum- the limits of differences in tumour biology, to chemotherapy as well as radiotherapy,
scribed nests of squamous cells, some- for practical purposes staging may be and survival times of > 1 year have been
times with keratinization, that have an performed according to the TNM classifi- reported using regimens similar to those
abrupt transition to the surrounding NEC cation for adenocarcinomas of the gall- used for small cell carcinoma of the lung
elements. A case of MANEC of diffuse bladder and bile duct. {907}.
type with mucin-containing signet ring Malignant behaviour of NETs of gallblad- MANECs behave as adenocarcinomas
cells and clear neuroendocrine cells has der and bile ducts is defined by the pres- and should be managed accordingly,
also been reported {2454}. ence of regional or distant metastases being clinically more aggressive than
{116, 2027} and/or signs of local aggres- NETs.

Mesenchymal tumours of the M. Miettinen

C.D.M. Fletcher
gallbladder and extrahepatic bile ducts L.-G. Kindblom
ICD-O codes tween normal paraganglionic structures Ganglioneuromatosis

Granular cell tumour 9580/0 and a very small paraganglioma. Diffuse ganglioneuromatosis can involve the
Leiomyoma 8890/0 gallbladder in patients with MEN2B. The le-
Kaposi sarcoma 9140/3 Granular cell tumour sions contain Schwann-cell elements ad-
Leiomyosarcoma 8890/3 Although rare, granular cell tumour is the mixed with scattered ganglion cells
Rhabdomyosarcoma 8900/3 most commonly diagnosed benign nonep- involving the entire wall of the gallbladder
ithelial tumour of the gallbladder and extra- {437}. Diffuse or plexiform neurofibromas
Paraganglioma hepatic biliary tract. In the gallbladder, such can also involve the biliary tract in patients
This generally benign neural tumour is tumours are usually incidental microscopic with neurofibromatosis type 1 (NF1) {2095}.
composed of nests of neural cells (chief findings, whereas granular cell tumours in
cells) often lined by Schwann cell-related the bile ducts can cause symptomatic bil- Rhabdomyosarcoma
sustentacular cells. The former are im- iary obstruction that clinically mimics bile In young children, embryonal (botryoid)
munohistochemically positive for chromo- duct carcinoma {3210}. rhabdomyosarcoma occurs in the extra-
granin A and synaptophysin and negative Granular cell tumours can be multicentric, hepatic bile ducts and rarely in the gall-
for keratins and S100 protein, whereas the involving different visceral sites as well as bladder, where it can secondarily extend
latter are positive for S100 protein and the skin and peripheral soft tissues. Involve- into the hepatic hilus and often manifests
often for glial fibrillary acidic protein ment of the bile ducts often results in a con- with biliary obstruction. Rhabdomyosar-
(GFAP). The tumour is usually located in centric or eccentric mass that variably coma forms a mass composed of multiple
the outer wall of the gallbladder, but can obliterates the lumen. Histologically, granu- filiform, polypoid intraluminal protrusions in-
also involve the extrahepatic bile ducts. It lar cell tumours contain clusters or sheets of volving the bile ducts {1714, 59A}. Rhab-
is usually an incidental microscopic find- polygonal cells with abundant periodic domyoblastic differentiation is variable, and
ing in cholecystectomy specimens. Some acid–Schiff (PAS)-positive granular cyto- coexpression of desmin and myogenic reg-
cases occur in association with multiple plasm and small nuclei. The cells are im- ulatory proteins (MYOD1, myogenin) is di-
endocrine neoplasia (MEN) syndromes munohistochemically positive for S100 agnostic. Prognosis is reasonably good with
{2035}. It can be difficult to distinguish be- protein and α-inhibin {2188}. modern combined chemotherapy and sur-
gery regimens; in one study, the estimated
5-year survival was 66% {2278}.
Other sarcomas and benign

mesenchymal tumours
Epstein-Barr virus (EBV)-associated leiomyo-
sarcoma/smooth muscle tumour rarely in-
volves the gallbladder wall. These tumours
are described in Chapter 10. Other sarco-
mas involving the gallbladder and biliary
ducts are undifferentiated pleomorphic sar-
A A coma and myxofibrosarcoma (malignant fi-
brous histiocytoma), angiosarcoma {59A}. In
addition, Kaposi sarcoma, abdominal li-
posarcomas and leiomyosarcomas can sec-
ondarily involve gallbladder and bile-duct
system. Sarcomatoid carcinoma, (metasta-
tic) melanoma and dedifferentiated liposar-
coma have to be ruled out before diagnosing
an undifferentiated sarcoma in the gallblad-
der. Lipomas, lymphangiomas, and hae-
B B mangiomas rarely involve the gallbladder
Fig. 11.23 Epstein-Barr virus-associated leiomyosarcoma. Fig. 11.24 Embryonal (botryoid) rhabdomyosarcoma.
{414}. Despite occasional reports in the liter-
A The neoplasm forms a transmural mass involving the A The neoplasm contains multiple polypoid protrusions ature, we have doubts concerning the oc-
gallbladder wall. B It is composed of spindled to oval cells projecting into the bile-duct lumen. B At higher currence of true gastrointestinal stromal
that are less differentiated than the smooth muscle in magnification, elongated rhabdomyoblasts can be seen tumours of the gallbladder that are compara-
typical leiomyosarcoma. as a minor component among less differentiated cells. ble to those found in the gastrointestinal tract.

Lymphoma of the gallbladder and E.S. Jaffe

S. Nakamura
extrahepatic bile ducts Y.H. Ko
J. Delabie
In common with lymphoma elsewhere in mucosa-associated lymphoid tissue testinal lymphomas, and have included
the digestive system, primary lymphomas (MALT) in the gallbladder have been de- cases of lymphomatous polypopsis, ex-
of the gallbladder and extrahepatic bile scribed {256, 268, 2019}. Such tumours tracavitary primary effusion lymphoma
ducts are defined as extranodal lym- may arise within the context of acquired and plasmablastic lymphoma {1972A}.
phomas arising in and localized to this re- MALT lymphoma, which is frequently en- Other lymphoma subtypes that have been
gion {1341}. Contiguous lymph-node countered in the gallbladder associated reported in the gallbladder, with involve-
involvement and distant spread may be with chronic cholecystitis {268, 3266}. ment of the extrahepatic ducts in rare in-
seen, but the primary clinical presentation The morphology and genetics of lym- stances, are follicular lymphoma and
is in the gallbladder or, even more rarely, phoma of the gallbladder appear to be diffuse large B-cell lymphoma {843, 1282,
in the extrahepatic bile ducts. Lym- similar to those of gastric MALT lym- 1412, 3118}. Rarely, other forms of lym-
phomas with this localization are ex- phomas, including the presence of the fu- phoma or lymphoblastic leukaemia may
tremely rare, with fewer than 40 reported sion gene BIRC3-MALT1 in at least one be seen initially at this site {1412, 2097}.
cases {160, 256, 497, 1495, 2019, 2402}. reported case {268}. Other types of pri-
A few instances of primary lymphoma of mary gall bladder lymphoma resemble in-
Secondary tumours and melanoma of the C. Iacobuzio-Donahue
gallbladder and extrahepatic bile ducts
Incidence and origins tion are the presence of junctional activity described {1944}. Primary melanoma of
Metastases to the gallbladder and extra- in the epithelium adjacent to the tumour the gallbladder is most often seen as an
hepatic biliary tree are uncommon. Al- {442, 2670}, and the absence of a primary intraluminal polypoid mass {676, 2772,
though virtually any primary malignancy melanoma elsewhere in the body. How- 2789}.
can metastasize to the gallbladder or bil- ever, junctional activity has been reported
iary tract {725}, melanoma accounts for in metastatic melanoma of the gallbladder. Histopathology
> 50% of all reported cases of metastasis The features of metastases to the gall-
to the gallbladder and biliary tract {442}, Clinical features bladder and extrahepatic biliary tree are
followed by carcinomas of the stomach Metastases to the gallbladder or extra- similar to those observed for metastases
and breast {725}. Secondary involvement hepatic biliary tract are most often asymp- to other organs. Primary melanomas of
of the gallbladder or extrahepatic biliary tomatic. In patients who do have the gallbladder and extrahepatic biliary
tract may result from transcoelomic symptoms, the most common presenta- tree may have evidence of melanoma in
spread in the setting of peritoneal carci- tions are biliary colic {182}, acute chole- situ (junctional activity) adjacent to the in-
nomatosis, or by direct extension from cystitis {676, 3398}, or biliary obstruction filtrating component {442, 2670}.
carcinomas of adjacent organs. {942, 1944}.
Primary malignant melanoma of the gall-
bladder or extrahepatic biliary tract is Macroscopy
even more rare than metastatic melanoma Both intraluminal metastases and diffuse
{442, 2772, 2789, 3460}. Features that wall infiltration or stricture formation by
favour a primary melanoma in this loca- metastases to the gallbladder have been

CHAPTER 12
Tumours of the pancreas
Ductal adenocarcinoma
Ductal adenocarcinoma variants and mixed neoplasms
Serous neoplasms
Mucinous cystic neoplasms
Intraductal neoplasms
Acinar cell neoplasms
Pancreatoblastoma
Solid-pseudopapillary neoplasms
Mesenchymal tumours
Lymphoma
Secondary tumours
WHO classificationa of tumours of the pancreas

Epithelial tumours Mixed acinar-ductal carcinoma 8552/3
Benign Mixed acinar-neuroendocrine carcinoma 8154/3
Acinar cell cystadenoma 8551/0 Mixed acinar-neuroendocrine-ductal carcinoma 8154/3
Serous cystadenoma 8441/0a Mixed ductal-neuroendocrine carcinoma 8154/3
Mucinous cystic neoplasm with
Premalignant lesions an associated invasive carcinoma 8470/3
Pancreatoblastoma 8971/3
Pancreatic intraepithelial neoplasia, grade 3
(PanIN-3) 8148/2 Serous cystadenocarcinoma 8441/3
Intraductal papillary mucinous neoplasm with Solid-pseudopapillary neoplasm 8452/3
low- or intermediate-grade dysplasia 8453/0
Intraductal papillary mucinous neoplasm with
high-grade dysplasia 8453/2 Pancreatic neuroendocrine microadenoma 8150/0
Intraductal tubulopapillary neoplasm 8503/2* Neuroendocrine tumour (NET)
Mucinous cystic neoplasm with Nonfunctional pancreatic NET, G1, G2 8150/3
low- or intermediate-grade dysplasia 8470/0 NET G1 8240/3
Mucinous cystic neoplasm with NET G2 8249/3
high-grade dysplasia 8470/2
Neuroendocrine carcinoma (NEC) 8246/3
Malignant Large cell NEC 8013/3
Ductal adenocarcinoma 8500/3 Small cell NEC 8041/3
Adenosquamous carcinoma 8560/3 EC cell, serotonin-producing NET (carcinoid) 8241/3
Colloid carcinoma (mucinous noncystic carcinoma) 8480/3 Gastrinoma 8153/3
Hepatoid carcinoma 8576/3 Glucagonoma 8152/3
Medullary carcinoma 8510/3 Insulinoma 8151/3
Signet ring cell carcinoma 8490/3 Somatostatinoma 8156/3
Undifferentiated carcinoma 8020/3 VIPoma 8155/3
Undifferentiated carcinoma with
osteoclast-like giant cells 8035/3 Mature teratoma 9080/0
Acinar cell carcinoma 8550/3 Mesenchymal tumours
Acinar cell cystadenocarcinoma 8551/3
Lymphomas
Intraductal papillary mucinous neoplasm with
an associated invasive carcinoma 8453/3 Secondary tumours
____________________
EC, enterochromaffin; VIP, vasoactive intestinal peptide. a The morphology codes are from the International Classification of Diseases for Oncology (ICD-O)
{904A}. b The classification is modified from the previous WHO histological classification of tumours {691} taking into account changes in our understanding of
these lesions. In the case of neuroendocrine neoplasms, the classification has been simplified to be of more practical utility in morphological classification.
TNM classificationa of tumours of the pancreasb

T0 No evidence of primary tumour MI Distant metastasis
Tis Carcinoma in situ, includes PanIN-3c
T1 Tumour limited to the pancreas, 2 cm or less in greatest
dimension Stage grouping
T2 Tumour limited to the pancreas, more than 2 cm in greatest Stage T N M
dimension Stage 0 Tis N0 M0
T3 Tumour extends beyond pancreas Stage IA T1 N0 M0
T4 Tumour involves coeliac axis or superior mesenteric artery Stage IB T2 N0 M0
Stage IIA T3 N0 M0
N – Regional lymph nodes Stage IIB T1, T2, T3 N1 M0
NX Regional lymph nodes cannot be assessed Stage III T4 Any N M0
N0 No regional lymph-node metastasis Stage IV Any T Any N M1
____________________
a
{762, 2996}; b The classification applies to carcinomas of the exocrine pancreas and pancreatic neuroendocrine tumours; c PanIN, pancreatic intraepithelial
neoplasia. A helpdesk for specific questions about the TNM classification is available at http://www.uicc.org.
280 Tumours of the pancreas

Ductal adenocarcinoma of the pancreas R.H. Hruban

P. Boffetta
G. Klöppel
A. Maitra
N. Hiraoka G.J.A. Offerhaus
C. Iacobuzio-Donahue M.B. Pitman
Y. Kato
S.E. Kern
D.S. Klimstra
Definition ported incidence and mortality rates. and declined over recent years {1814}.
An infiltrating epithelial neoplasm with The highest rates of pancreatic ductal Incidence is higher in urban populations
glandular (ductal) differentiation, usually adenocarcinoma are recorded among than in rural populations, but this may re-
demonstrating luminal and/or intracellular African Americans (about 12 per 100 000 flect differences in the quality of diagno-
production of mucin, and without a pre- men and 10 per 100 000 women) and sis. Studies of migrant populations have
dominant component of any other histo- among indigenous populations in Ocea- shown that, after 15–20 years, first-gener-
logical type. An abundant desmoplastic nia. The lowest rates (< 2 per 100 000 ation migrants from low-risk to high-risk
stromal response is a typical feature of men and 1 per 100 000 women), which areas experience rates that are higher
this neoplasm. may be partly attributable to under-diag- than those of the country of origin, sug-
nosis, are recorded in India, northern and gesting an important role for environmen-
ICD-O codes central Africa and south-east Asia. In the tal exposures occurring late in life {110}.
Ductal adenocarcinoma 8500/3 USA, rates are about 50–100% higher in
Pancreatic intraepithelial neoplasia African Americans than in whites living in Etiology
grade 3 (PanIN-3) 8148/2 the same areas {634}. Worldwide, there The best-known risk factor for pancreatic
were an estimated 230 000 new cases in cancer is tobacco smoking. The risk in
Synonyms 2002, 60% of which occurred in high-re- smokers is two- to three times greater
Tubular adenocarcinoma, infiltrating duct source countries {842}. Incidence is than in nonsmokers, there is a dose–
carcinoma, not otherwise specified (NOS) about 50% higher in men than in women. response relationship, and smoking ces-
Most patients are between 60 and 80 sation has been shown to lower risk in
Epidemiology years of age. Given the very poor survival, many populations {1338}. The proportion
The epidemiological study of this disease mortality rates closely parallel incidence of cases of pancreatic cancer attributable
is complicated by significant geographi- rates. to tobacco smoking has been estimated
cal and temporal variations in the sensi- Diagnostic improvements are partly re- at 20–30% in men and 10% in women
tivity and specificity of clinical diagnosis sponsible for the increase in reported in- {1333}. Some, but not all, of the features
and in the proportion of cases that are his- cidence and mortality rates that has taken of the descriptive epidemiology of pan-
tologically verified. Differences in access place since the 1970s, particularly in Eu- creatic cancer (i.e. the higher incidence
to health care (e.g. for different social rope; however, incidence and mortality in African Americans than in white Amer-
classes or age groups) can affect re- rates in western Europe have levelled off icans, and the higher risk in men and
urban residents) can be explained by dif-
ferences in smoking habits {148, 2967}.
Use of smokeless tobacco products has
also been linked to an increased risk of
pancreatic cancer {1334}.
It has been suggested that pancreatic
cancer is associated with nutritional and
dietary factors, including obesity and low
physical activity, high intake of fats, espe-
cially saturated fats, and low intake of
vegetables and fruit {3548, 149A}.
Early reports of an association between
coffee consumption and risk of pancreatic
cancer were of questionable quality and
have not been confirmed by larger, more
recent investigations. Heavy drinking of
alcohol may weakly increase risk {3286}.
Of the medical conditions that have been
studied {110}, a history of chronic pan-
creatitis is associated with an increased
risk of pancreatic cancer of more than 10-
fold. The risk is particularly high in indi-
Fig. 12.01 Worldwide age-standardized annual incidence (per 100 000) of pancreatic cancer in men (2008). Note the viduals with hereditary pancreatitis
areas of high incidence in North America, Europe, and the Russian Federation {842A}. {1901}. Diabetes mellitus has also been
Ductal adenocarcinoma 281

invasion of adjacent organs (duodenum)

or involvement of the peritoneal cavity
(ascites). Occasionally, patients present
with acute pancreatitis {1059}, migratory
thrombophlebitis {1534}, hypoglycaemia,
or hypercalcaemia {2127}. Depression
that is out of proportion to the severity of
the disease can be a presenting symptom
{434, 2497}.
A
Imaging and laboratory tests
Fig. 12.03 Ductal adenocarcinoma. An ill-defined
Computed tomography (CT) is one of the scirrhous carcinoma of the head of the pancreas
best imaging modalities for the pancreas infiltrating the duodenum.
and pancreatic adenocarcinomas appear
as hypodense masses in up to 92% of
cases {286, 1461, 2775}. Diffuse tumour in-
volvement is found in about 4% of cases.
Early findings on CT include abrupt cut-off
and dilatation of the pancreatic duct {940}.
The “double-duct sign” – dilatation of both
the biliary and pancreatic ducts – points to
cancer arising in the head of the pancreas.
On endoscopic ultrasonography (EUS),
most ductal adenocarcinomas produce
B echo-poor and nonhomogeneous mass le- Fig. 12.04 Infiltrating ductal adenocarcinoma. Note the
sions. About 10% of tumours appear echo- metastasis to a lymph node (arrow).
Fig. 12.02 A Computed tomography (CT) scan of a ductal rich. With increasing size, tumours tend to
adenocarcinoma of the body and tail of the pancreas with
become heterogeneous, with cystic and
numerous liver metastases. B Coronal CT scan revealing
echo-rich areas. Indirect signs of a pan-
a large ductal adenocarcinoma in the head of the
pancreas. Note the secondary dilatation of the pancreatic creatic tumour (dilatation of pancreatic
and intrahepatic bile ducts, as well as the massive and/or common bile duct) are usually
enlargement of the gallbladder. found upstream of tumours > 3 cm in size.
Lymph-node metastases appear as en-
larged echo-poor nodes on EUS. Biopsies
associated with an increased risk of pan- performed through the endoscope can be
creatic cancer (relative risk, 1.5–2-fold). used to establish the diagnosis.
Gastrectomy patients have a three- to Endoscopic retrograde cholangiopancre-
fivefold risk of pancreatic cancer; the as- atography (ERCP) may demonstrate dis- Fig. 12.05 Ductal adenocarcinoma in the tail of the
sociation does not appear to be con- placement, narrowing, or obstruction of the pancreas. Note the normal duct (left) downstream from
founded by tobacco smoking. pancreatic duct. the carcinoma (centre), and the small retention cyst
Additional valuable techniques include upstream from the tumour (right).
Localization magnetic resonance imaging (MRI)
Most (60–70%) pancreatic ductal adeno- and serum tumour-marker determination
carcinomas arise in the head of the gland, (CA19-9, carcinoembryonic antigen [CEA]). Macroscopy
and the remainder in the body (5–15%) or Because of significant false-positive and Ductal adenocarcinomas are firm, scle-
tail (10–15%). The vast majority of pan- false-negative rates, serum tumour mark- rotic and poorly defined masses that re-
creatic cancers are solitary, but multifocal ers are not useful in screening the general place the normal lobular architecture of
disease can occur {1270, 3012}. Very population. the gland. The cut surfaces are yellow to
rarely, heterotopic pancreatic tissue can Positron emission tomography (PET) scan- white. Haemorrhage and necrosis are un-
give rise to a carcinoma {1014, 3196}. ning may have diagnostic value, but is of common, but microcystic areas may
uncertain additional clinical utility beyond occur, particularly in larger tumours. In
Clinical features that of the conventional imaging modali- surgical series, most carcinomas of the
Signs and symptoms ties {2875}. pancreatic head measure 1.5–5.0 cm,
Clinical features include back pain, unex- The sensitivity and specificity of any one with a mean diameter of 2.5–3.5 cm,
plained weight loss, jaundice and pruritus of these tests alone range from 55% to while carcinomas of the body/tail are usu-
{1229}. Diabetes mellitus is present in 95%, but applying combinations can ally larger. Cancers measuring < 2 cm
70% of patients, and new-onset diabetes achieve accuracy rates of > 95%, al- are infrequent {1176} and may be difficult
may be the first manifestation of pancre- though tissue diagnosis remains the gold to recognize on gross inspection. Carci-
atic cancer {490}. Later symptoms are standard {2775}. nomas of the pancreatic head usually in-
related to liver metastasis and/or vade the common bile duct and/or the

main pancreatic duct and produce steno- usually clinically detected {3638}. In ad- Histopathology
sis that results in proximal dilatation of dition to peripancreatic lymph nodes, car- Most ductal adenocarcinomas are com-
both duct systems. More advanced pan- cinomas of the pancreatic head typically posed of well- to moderately developed
creatic carcinomas in the head of the involve the chains of lymph nodes along glandular and duct-like structures, which
gland can involve the ampulla of Vater the superior mesenteric artery, the com- infiltrate the pancreatic parenchyma,
and/or the duodenal wall. Carcinomas in mon hepatic artery and the hepatoduo- grow in a haphazard pattern, are associ-
the body or tail obstruct the main pan- denal ligament {1577}. The carcinoma ated with a desmoplastic stroma and pro-
creatic duct, but typically do not involve may metastasize more distantly to lymph duce sialo-type and sulfated acid mucins
the common bile duct. Stenosis of the nodes in the ligamentum hepatoduode- that stain with Alcian blue and periodic
main pancreatic duct can produce nale, the coeliac trunk, and in para-aortic acid-Schiff (PAS). Poorly differentiated
secondary changes in the upstream area at the level of the renal arteries. Car- ductal adenocarcinomas form small,
pancreatic parenchyma, including duct cinomas of the body and tail are particu- poorly formed glands composed of cells
dilatation, retention-cyst formation and fi- larly prone to metastasize to the superior with pleomorphic nuclei, individual infil-
brous atrophy of the parenchyma (i.e. ob- and inferior body and tail lymph-node trating cells, and solid cellular areas. They
structive chronic pancreatitis). Gross groups and to the splenic hilus lymph produce much less mucin than more dif-
distinction of chronic pancreatitis from in- nodes, and may also spread via lym- ferentiated carcinomas.
vasive ductal adenocarcinoma is often phatic channels to the pleura and lung
difficult, making the limits of the neo- {1974}. Haematogenous metastasis oc- Well-differentiated carcinomas
plasm hard to define. curs, in decreasing order of frequency, to These carcinomas are composed of hap-
the liver, lungs, bones and adrenals hazardly arranged infiltrating duct-like
Tumour spread and staging {3573}. structures and medium-sized neoplastic
At diagnosis, the vast majority of pancre- Particularly problematic is the diagnosis glands. The contours of the duct-like
atic cancers have spread beyond the of metastasis to the ovary, which can structures may be angular or irregular,
pancreatic parenchyma {3007}. Carcino- mimic a primary ovarian mucinous neo- such irregular contours are especially
mas of the head commonly extend into plasm {3374, 3375, 3632}. Pancreatic pronounced in the “large-duct” variant
the duodenum and the ampulla of Vater cancers metastatic to the ovary are typi- {1653}. Perineural or vascular invasion are
(causing ulceration), the intrapancreatic cally cystic, large, and bilateral; they in- both highly diagnostic of an invasive can-
portion of the common bile duct (causing volve the surface and hilum of the ovary, cer, and “ruptured” or “incomplete” ducts
stenosis), and into peripancreatic or and are characterized microscopically by (which lack a portion of epithelium and in-
retroperitoneal adipose tissue. Perineural nodularity, and a haphazard infiltrative stead are partially lined by cellular stro-
invasion is a common mechanism by pattern of growth {3374, 3375, 3632}. Im- mal tissue) are highly suggestive of an
which pancreatic cancers reach these munolabelling with a panel of antibodies invasive cancer. Non-neoplastic ducts, as
structures and may precede the develop- to keratins 7 and 20, SMAD4/DPC4, well as remnants of acini and individual
ment of peripancreatic lymph-node CDKN2A (p16) and CDX2 may help to est- islets of Langerhans, are typically inter-
metastases {1509, 2204}. Invasion into ablish the diagnosis {3374, 3375, 3632}. spersed among the neoplastic glands,
the spleen, stomach, left adrenal gland, Pancreatic cancers are staged according and some neoplastic glands may even in-
colon, and peritoneum tends to be more to the seventh edition of the TNM system filtrate into non-neoplastic islets of
common among carcinomas of the body {2996}. A slightly modified classification Langerhans. Only in exceptional cases
and tail because of the proximity of these has been proposed by the Japanese Pan- do neuroendocrine cells constitute a sec-
structures to the tail of the pancreas and creas Society {1347}. ond neoplastic cell component of ductal
the late stage at which such cancers are carcinomas.
A B
Fig. 12.06 A Ductal adenocarcinoma, well-differentiated, showing intensive desmoplastic stromal reaction. B Ductal adenocarcinoma, large-duct type. Note the microcystic
well-differentiated neoplastic duct structures.

the vast majority of cases, the neoplastic

cells that invade the nerves show glandu-
lar differentiation. Benign ducts are rarely
encountered in the vicinity of a nerve and
a non-neoplastic glandular inclusion in a
nerve is exceedingly uncommon, al-
though non-neoplastic islet cells may in-
volve nerves. Lymphatic invasion is
another very common finding and is as-
sociated with lymph-node metastasis.
Carcinoma may invade the wall of blood
vessels (e.g. the portal vein), or the neo-
plastic cells may penetrate the lumen,
causing thrombosis. In some cases, the
neoplastic epithelium can entirely replace
the endothelium and re-line the vessel,
producing a vessel lined by well-differen-
tiated epithelial cells; such structures can
mimic PanIN.
Neoplastic glands may also infiltrate the
Fig. 12.07 Poorly differentiated ductal adenocarcinoma. Note the irregularly structured neoplastic glands showing distinct peripancreatic adipose tissue without fol-
pleomorphism of the lining cells. lowing pre-existing structures. Typically
these glands lie individually as naked
glands within the fat, either directly abut-
The neoplastic cells are cuboidal to They may also invade the common bile ting adipocytes or surrounded by inflam-
columnar, and form a single cell layer, al- duct, the ampulla, and the duodenal mu- matory cells. If infiltrating neoplastic
though papillary projections can be seen. cosa, typically following pre-existing glands reach the mucosa of the distal
The cytoplasm is usually eosinophilic, but structures such as ducts, nerves and ves- common bile duct, the ampulla and/or the
a pale or even clear appearance may sels. Cancerization of the pancreatic duodenum, the neoplastic cells may re-
sometimes be prominent. The nuclei are ducts, particularly the medium-sized in- place the normal epithelium, mimicking a
round to oval and may be three to four terlobular ducts, is not uncommon, and primary neoplasm of the involved site.
times larger than non-neoplastic nuclei. may extend far beyond the main neo-
Importantly, the size, shape, and location plastic mass {1613}. In these cases, the Moderately differentiated carcinomas
of the nuclei vary among cells within the normal epithelium is replaced by atypical These carcinomas are largely identical to
individual neoplastic glands. The nuclear columnar cells that often form papillary well-differentiated adenocarcinomas in
membranes are sharp and the distinct nu- projections without fibrovascular stalks. growth pattern and behaviour, except that
cleoli are often large. Mitoses are not This change is usually accompanied by a they produce a mixture of medium-sized
common. ductocentric desmoplasia, and can be duct-like structures and small tubular
At the time of diagnosis, virtually all carci- virtually indistinguishable from high-grade glands of variable size and shape (some
nomas deeply infiltrate the surrounding pancreatic intraepithelial neoplasia are incompletely formed, others create a
pancreatic tissue and the adjacent peri- (PanIN-3). Perineural invasion is seen in cribriform pattern). Moderately differenti-
pancreatic adipose tissue. The infiltrating almost all cases within the pancreas itself, ated carcinomas are also characterized
malignant glands are often found in ab- and invasive carcinoma typically extends by a greater variation in nuclear size,
normal locations, such as immediately into the retroperitoneal fatty tissue behind chromatin structure and prominence of
adjacent to muscular blood vessels; a the head of the pancreas and around the nucleoli and more mitotic figures. The cy-
finding that may be diagnostically useful. bile duct, where nerves are abundant. In toplasm is usually slightly eosinophilic,
but clear cells are occasionally abundant.
Mucin production appears to be de-
creased. Foci of poor and irregular glan-
dular formation are often found at the
leading edge of the neoplasm, particu-
larly where the carcinoma invades the
peripancreatic tissue.
Poorly differentiated ductal

adenocarcinomas
These neoplasms are composed of a mix-
ture of densely packed, small irregular
Fig. 12.08 Infiltrating ductal adenocarcinoma with Fig. 12.09 Ductal adenocarcinoma with venous invasion, glands, solid sheets and nests, as well
perineural invasion. mimicking pancreatic intraepithelial neoplasia (PanIN). as individual cells. The desmoplastic

response to the neoplasm can be minimal

and foci of necrosis and haemorrhage
may occur. The cells forming glands and
solid cellular sheets show marked nuclear
pleomorphism (occasionally with squamoid
or spindle-cell differentiation), little or no
mucin production, and brisk mitotic activ-
ity. Intraductal extension of the carcinoma
is seen less often than in more differenti-
ated carcinomas, while perineural, lym-
phatic, and blood-vessel invasion are
equally frequent.
Many ductal adenocarcinomas obstruct
the main pancreatic duct, causing up-
stream obstructive chronic pancreatitis.
Complete obstruction usually results in
the upstream duct becoming markedly di-
lated, the pancreatic parenchyma is atro-
phied, and there can be a marked
clustering (“aggregation”) of the residual
islets, which can mimic a neuroendocrine Fig. 12.10 Well-differentiated infiltrating ductal adenocarcinoma of the pancreas. Glands adjacent to muscular vessels
neoplasm. The intraductal calcifications suggest the diagnosis.
that are typically seen in alcoholic chronic
pancreatitis are generally absent.
producing adenocarcinomas, notably bile creatic ducts to some extent, particularly
Grading duct carcinomas, although some markers in chronic pancreatitis.
The grading of ductal adenocarcinoma is can be useful {1270}. Ductal adenocarcinomas are usually
based on combined assessment of histo- Ductal adenocarcinomas express the negative for vimentin {2858}. With rare
logical and cytological features and mi- same keratin types as normal pancreatic exceptions (e.g. mixed ductal neuro-
totic activity (see Table 12.01) {1612, duct epithelium, i.e. keratins 7, 8, 18 and endocrine carcinoma), they also fail to
1921}. If there is intratumour heterogene- 19. More than 50% of ductal adenocarci- label with neuroendocrine markers such
ity, i.e. variation in the degree of differen- nomas also express keratin 4 {2858}, as synaptophysin and chromogranin A,
tiation and mitotic activity, the higher while keratin 20 is often not expressed although they may contain scattered
grade and activity is to be reported. This {2125}, or less widely than keratin 7. This non-neoplastic neuroendocrine cells in
rule also applies if only a minor compo- pattern of keratin expression contrasts close association with neoplastic cells,
nent (less than half the carcinoma) is of with that observed in non-ductal pancre- particularly if the carcinoma is well-
lower grade. Histological grade correlates atic neoplasms (i.e. acinar cell carcino- differentiated {2369}. Ductal adenocarci-
with survival when the system illustrated mas and neuroendocrine neoplasms, nomas generally do not express pancre-
is employed {1612, 1921}. which express keratins 8 and 18 and atic exocrine enzymes such as trypsin,
sometimes 19) and gut carcinomas chymotrypsin and lipase {1235, 2161}.
Immunohistochemistry (which express keratins 8, 18, 19 and 20). Immunolabelling for the SMAD4/DPC4
There is as yet no immunohistochemical Most ductal adenocarcinomas express protein is lost in 55% of carcinomas, and
marker that can be used to unequivocally MUC1, MUC3, MUC4 and MUC5AC, but the p53 protein is expressed at immuno-
distinguish pancreatic ductal adenocarci- not MUC2 {2208, 3216, 3645}. They also histochemically detectable levels in most
noma from reactive glands, nor can im- express glycoprotein tumour antigens cases {1270}.
munostains be used to unequivocally such as CEA, B72.3, CA125 and CA19-9 Among the growth factors and adhesion
distinguish pancreatic ductal adenocarci- {2884, 3163}. Several of these markers molecules that are overexpressed by
noma from other extrapancreatic mucin- also label the epithelium of normal pan- pancreatic ductal adenocarcinomas are
Table 12.01 Histopathological grading of ductal adenocarcinoma of the pancreas.a
Tumour Glandular differentiation Mucin production Mitoses Nuclear features

grade (per 10 HPF)
Grade 1 Well-differentiated Intensive 5 Little polymorphism, polar arrangement
Grade 2 Moderately differentiated duct-like structures and tubular glands Irregular 6–10 Moderate polymorphism
Grade 3 Poorly differentiated glands, abortive mucoepidermoid and Abortive > 10 Marked polymorphism and increased size
pleomorphic structures
a
HPF, high power field. Grade is assigned on the basis of the feature of highest grade {1921}.

carcinoma is more challenging as the as-

pirated neoplastic ductal cells must be
distinguished from atypical but reactive
ductal cells {700, 1665}, as well as from
gastrointestinal contamination from the
EUS biopsy procedure {2258}. Cytologi-
cal criteria for well-differentiated adeno-
carcinoma include irregular spacing of
cells in a cohesive group, anisonucleosis
of 4 : 1 in a single group, parachromatin A
clearing and irregular nuclear mem-
Fig. 12.11 Cancerization of preexisting duct in the
pancreas. Immunolabelling for SMAD4 (DPC4) showing branes {1859, 2556, 2700}. Variants such
complete loss of expression in the neoplastic cells. as adenosquamous carcinoma, undiffer-
entiated carcinoma and undifferentiated
carcinoma with osteoclast-like giant cells
epidermal growth factor and its receptor, can also be recognized by their unique
ERBB2 (c-erbB-2), transforming growth cytological features {1768, 2616}.
factors α and β {665, 2828}, platelet-de-
rived growth factors A and B, vascular en- Ultrastructure
dothelial growth factor and its receptors, Ductal adenocarcinoma cells are charac-
metallothionein {2376}, and CD44v6 {454, terized by mucin granules in the apical B
3158}. A membranous pattern of labelling cytoplasm, irregular microvilli on the lumi- Fig. 12.12 Direct smear of ductal adenocarcinoma of the
is usually seen with antibodies to E-cad- nal surface, and a more or less polarized pancreas. A Moderately differentiated adenocarcinoma
herin; however, this expression is often arrangement of the differently sized nuclei displaying enlarged, hyperchromatic, crowded and disordered
lost in poorly differentiated carcinomas {1270}. Loss of differentiation is charac- nuclei with some dyshesion (Diff-Quik®). B Well-differentiated
{3527, 2550}. Other more recently dis- terized by loss of cell polarity, disappear- adenocarcinoma displaying nuclei with irregular spacing,
anisonucleosis of 4 : 1, parachromatin clearing and
covered markers include mesothelin, ance of a basal lamina, appearance of
irregular nuclear membranes (Papanicolaou).
prostate stem-cell antigen, claudins 4 and irregular luminal spaces, and loss of
18, annexin A8, ADAM9, KOC, S100A4, mucin granules.
S100A6 and S100P {410, 739, 1478, involves the pancreas more diffusely
2379, 2556, 2979, 3622}. Histological variants than carcinoma. The ducts may be di-
The variants that appear to have dis- lated and lithiasis can occur. The texture
Cytopathology tinct clinical or prognostic features of the gland is more rubbery than in car-
Cytological diagnosis is most often ob- include adenosquamous carcinoma, cinoma, which has a more gritty consis-
tained by fine-needle aspiration (FNA), in- colloid (mucinous noncystic) adeno - tency.
creasingly performed endoscopically carcinoma, hepatoid, medullary, signet Autoimmune pancreatitis is an exception
using EUS guidance {197, 3322}. Tech- ring cell carcinoma, undifferentiated car- to these rules, and it can both clinically
niques of pancreatobiliary-duct brushing cinoma, and undifferentiated carcinoma and grossly mimic pancreatic cancer,
have improved {3326}, but brushing with osteoclast-like giant cells. These are often being grossly discrete and tumour-
cytology has a lower sensitivity for discussed in the next section, Ductal ade- like, and ductal dilatation is not common.
malignancy than FNA, averaging 50% nocarcinoma variants and mixed neo- The characteristic microscopic features of
compared with 80% for EUS-FNA {228, plasms. Histological types that are not autoimmune pancreatitis include dense
3322}. considered among the variants are the inflammation with abundant plasma cells
The smear pattern of adenocarcinomas is ductal adenocarcinomas with a foamy concentrated around pancreatic ducts, a
one of scattered cellular glandular clus- gland pattern {33}, with clear cell features cellular fibroinflammatory stroma with a
ters admixed with single cells. This con- {1922} and with large-duct features {503, storiform appearance, and obliterative
trasts with the diffuse, uniform solid 628, 1617, 1653}; these latter types have venulitis, although these features maybe
cellular smear pattern produced by the no prognostic significance and are less obvious in biopsies than in resection
parenchymal-rich, stromal-poor neo- typically found within ductal adenocarci- specimens. Increased numbers of plasma
plasms such as acinar cell carcinomas nomas with otherwise conventional histo- cells expressing IgG4 (> 10–50 cells per
and well-differentiated neuroendocrine logical features. high power field) is typical of autoim-
neoplasms {2556}. mune pancreatitis, as are elevations in
Moderately to poorly differentiated carci- Differential diagnosis serum IgG4 {491, 703, 2163, 2617,
nomas have overt features of malignancy. Chronic pancreatitis 3700}.
Nuclei are enlarged, hyperchromatic and The most significant differential diagno- The microscopic findings most helpful in
display irregular nuclear membranes; the sis for conventional (tubular-type) pan- distinguishing adenocarcinoma from re-
cytoplasm ranges from scant and non- creatic adenocarcinoma is chronic active glands are the location and archi-
mucinous to abundant and mucinous pancreatitis {31, 1665}. From the gross tecture of the glands, and the cytological
{2556, 2700, 3641}. perspective, chronic pancreatitis of al- features. The ductal system of the normal
The recognition of well-differentiated adeno- coholic or obstructive etiology usually pancreas has a lobular architecture, and

this lobular pattern is retained in chronic Pancreatic intraepithelial neoplasia (PanIN) a problem if radiographic and clinical
pancreatitis, with a central more dilated The distinction between PanIN and inva- findings are integrated with the pathology.
duct surrounded by a cluster of smaller sive carcinoma is based on the shape However, some infiltrating carcinomas
ductules and atrophic acini. In contrast, and location of the glands. Distinguishing form massively dilated invasive glands
carcinoma has a haphazard arrangement high-grade PanIN (PanIN-3) from invasive that can simulate a cystic neoplasm. This
of glands, with loss of the normal lobularity. carcinoma on the basis of cytological ap- pattern has been designated the “large-
The abnormal presence of glands within pearance can be very difficult. Of note, it duct type” of infiltrating carcinoma {1270}
the duodenal muscularis or submucosa, is very unusual to encounter PanIN-3 in and is generally not associated with gross
or immediately adjacent to a muscular the absence of invasive carcinoma, es- cyst formation. The cystic glands are irreg-
vessel is highly suggestive of carcinoma pecially when there is a mass lesion in the ular, do not communicate with the native
{30, 2908}. Profound atrophy of the pan- pancreas. ducts, have an associated desmoplastic
creas can juxtapose benign glands and Reactive glands and low-grade PanIN le- stromal response, and lack the ”ovarian-
vessels {3423}, but only in the most ex- sions do not express tumour-associated like” subepithelial stroma of MCNs.
treme cases of atrophic pancreatitis. glycoproteins (CEA, B72.3, and CA125),
Perineural and intravascular invasion are p53, mesothelin, claudin 4, S100A4, or Neuroendocrine neoplasms
almost diagnostic of carcinoma. It is ex- 14-3-3σ {41, 1133, 1242, 1270, 1956}. Paradoxically, poorly differentiated ductal
ceptional to find benign glands within the Positive immunolabelling for any of these adenocarcinomas can resemble well-
perineurium {1270}, and true vascular in- markers favours a diagnosis of carci- differentiated pancreatic neuroendocrine
vasion does not occur in benign condi- noma, although the sensitivity of these neolasms, especially neuroendocrine
tions. Other helpful features are “naked markers varies widely. Loss of immunoex- neolasms with nuclear pleomorphism
glands in fat” – individual glands touch- pression of SMAD4 in the face of intact {3687}. The sclerotic (rather than desmo-
ing adipocytes without any intervening fi- expression in normal cells also strongly plastic) nature of the stroma, nuclear fea-
brotic stroma {31, 1606} – and glands with supports a diagnosis of carcinoma {1242, tures of neuroendocrine differentiation,
irregular contours, luminal necrosis, and 1275}, but is only found in about half of in- organoid architectural patterns, and a
incomplete glands lacking epithelium on filtrating ductal adenocarcinomas {3202}. lack of mitotic activity all suggest that a
one edge {1606}. A nuclear size variation neuroendocrine neoplasm should be con-
of 4 : 1 within a single duct is considered Precursor lesions sidered. Immunohistochemical labelling
virtually diagnostic {1270}. Mitotic figures, The macroscopic presence of a recog- for chromogranin and synaptophysin help
especially if atypical, are also helpful, as nized precursor (intraductal papillary mu- to establish this diagnosis. Non-neoplas-
are very prominent nucleoli. Other fea- cinous neoplasm [IPMN] or mucinous tic islets in chronic pancreatitis can also
tures that point to a malignant diagnosis cystic neoplasm [MCN]) to infiltrating car- simulate carcinoma, as they can assume
are necrotic luminal debris and stromal cinoma increases the chances that a solid a pseudo-infiltrative appearance within fi-
desmoplasia (as opposed to the usually mass may be an infiltrating carcinoma. brotic stroma once the acinar elements
dense and hyalinized stroma of chronic The distinction between infiltrating carci- have completely atrophied {205}. The nu-
pancreatitis). noma and these mass-forming cystic neo- clei remain bland, however, and immuno-
plasms (MCN and IPMN) is generally not histochemistry is helpful in difficult cases.
Table 12.02 Morphological features of pancreatic intraepithelial neoplasia (PanIN).

Epithelial lesion Morphological features
Normal The normal ductal and ductular epithelium is a cuboidal to low-columnar epithelium with amphophilic cytoplasm. Mucinous cytoplasm, nuclear
crowding, and atypia are not seen.
Squamous (transitional) A process in which the normal cuboidal ductal epithelium is replaced by mature stratified squamous or pseudostratified transitional epithelium
metaplasia without atypia.
PanIN-1A These flat epithelial lesions are composed of tall columnar cells with basally located nuclei and abundant supranuclear mucin. The nuclei are small
and round-to-oval in shape. When oval, the nuclei are oriented perpendicular to the basement menbrane. There may be considerable histological
overlap between non-neoplastic, flat, hyperplastic lesions and flat, neoplastic lesions without atypia; the modifier term “lesion” (“PanIN/L-1A”) may
be used to acknowledge that the neoplastic nature of many PanIN-1A cases has not been unambiguously established.
PanIN-1B These epithelial lesions have a papillary, micropapillary, or basally pseudostratified architecture but are otherwise identical to PanIN-1A.
PanIN-2 These mucinous epithelial lesions may be flat but are mostly papillary. By definition, PanIN-2 lesions must have some nuclear abnormalities, which
may include some loss of polarity, nuclear crowding, enlarged nuclei, pseudostratification, and hyperchromatism, but to a lesser degree than in
PanIN-3. Mitoses are rare, but when present are non-luminal (not apical), and are not atypical. True cribriform structures with luminal necrosis and
marked cytological abnormalities are generally not seen and, when present, should suggest a diagnosis of PanIN-3.
PanIN-3 These lesions are usually papillary or micropapillary, but may rarely be flat. True cribriforming, the appearance of “budding off” of small clusters of
epithelial cells into the lumen, and luminal necrosis all suggest a diagnosis of PanIN-3. PanIN-3 lesions are characterized by loss of nuclear polarity,
dystrophic goblet cells (goblet cells with nuclei oriented toward the basement menbrane), occasionally-abnormal mitoses, nuclear irregularities,
and prominent (macro) nucleoli. Resembling carcinoma at the cytonuclear level, there is, however, no invasion of the basement membrane.
PanIN, pancreatic intraepithelial neoplasia. Adapted with permission from {1271}.

Fig. 12.13 Small low-grade pancreatic intraepithelial neoplasia (PanIN) lesion surrounded Fig. 12.14 High-grade pancreatic intraepithelial neoplasia (PanIN 3).
by a larger area of lobulocentric atrophy.
Extrapancreatic metastatic mucin, PanINs are divided into three itself. In patients that have a familial pre-
adenocarcinoma grades according to the degree of cyto- disposition to pancreatic cancer, PanIN
It is not uncommon to encounter a logical and architectural atypia. Lesions lesions, and the resulting lobulocentric at-
metastatic adenocarcinoma in an extra- with minimal, moderate or marked atypia rophy, tend to be multifocal in the pan-
pancreatic location for which the pan- are designated PanIN-1, PanIN-2, and creatic parenchyma {353}. It is possible
creas appears to be a possible primary; PanIN-3, respectively. PanIN-1 lesions are to detect this distinctive change in imag-
however, there are no pancreas-specific further subdivided into flat (PanIN-1A) ing studies, such as EUS, suggesting a
immunohistochemical stains to prove and papillary types (PanIN-1B). potential screening tool for identification
pancreatic origin. A common immuno- Multiple lines of evidence support the of individuals with a higher risk of devel-
phenotype for ductal adenocarcinomas of hypothesis that PanINs are bona fide oping invasive carcinoma {407}.
the pancreas is positive for keratins 7 and precursors of infiltrating ductal adeno-
19, CEA, B72.3; focally positive or nega- carcinoma. PanINs (especially higher- Genetic susceptibility
tive for keratin 20, and negative for CDX2, grade lesions) are more common in Up to 10% of patients with pancreatic
TTF1, and hormone receptors. This la- pancreata with adenocarcinoma than cancer have a family history of this dis-
belling profile is shared by primary carci- without {108, 1662}, with at least one ease {207, 844, 1162, 1269, 1926, 1927}.
nomas of the upper gastrointestinal tract, study identifying PanIN-3 exclusively in Some pancreatic cancers arise in patients
biliary tree, gallbladder, and some pul- pancreata with an invasive carcinoma with recognized genetic syndromes, but
monary and mammary carcinomas. Im- {627}. As is true for ductal adenocarci- in most instances the genetic basis for the
munolabelling for the SMAD4 protein can noma, the incidence of PanINs increases familial aggregation of pancreatic carci-
be helpful, as this is lost in 55% of inva- with age, and PanINs are more common nomas has not yet been identified. Stud-
sive ductal adenocarcinomas of the panin the head than in the tail of the pancreas ies of extended families have suggested
creas, but only rarely in carcinomas {1268, 1662}. Although rare, patients have an autosomal-dominant mode of inheri-
arising outside of the pancreatobiliary been reported who had a residual high- tance {1587}. Having one, two or three
tree. grade PanIN lesion at the surgical margin first-degree relatives with pancreatic can-
of a partial pancreatectomy for benign cer increases the risk of developing pan-
Precursor lesions disease and then, several months to creatic cancer by 2.3-fold, 6-fold and
The most common precursor lesions of years after surgery, developed invasive 32-fold, respectively {106, 1588}. Having
pancreatic ductal adenocarcinoma are adenocarcinoma in the remnant pancreas a member of the family with young-onset
PanIN lesions. Less frequently, macro- {327, 336}. Perhaps the most compelling pancreatic cancer confers an added risk
scopic (cystic) precursor lesions, includ- evidence comes from the demonstration in kindreds in which multiple family mem-
ing MCNs and IPMNs, may also progress that PanINs and invasive ductal adeno- bers have been diagnosed with pancre-
to ductal adenocarcinoma. carcinomas share critical genetic abnor- atic cancer {354}.
malities.
PanINs FAMMM syndrome
As defined by published consensus Lobulocentric atrophy. PanIN lesions are Familial atypical multiple mole melanoma
guidelines {1271}, PanINs are micro- associated with lobulocentric atrophy in (FAMMM) is associated with germline mu-
scopic papillary or flat, noninvasive epi- the immediately adjacent pancreatic tations in the CDKN2A tumour suppressor
thelial neoplasms that are usually < 5 mm parenchyma {353, 704, 2929}. Although gene on chromosome 9p. Affected indi-
in diameter and confined to the pancre- the exact pathogenesis of lobulocentric viduals have an increased risk of devel-
atic ducts. Composed of columnar to atrophy remains uncertain, these foci of oping both melanoma and pancreatic
cuboidal cells with varying amounts of atrophy are larger than the PanIN lesion carcinoma {1017, 1928, 2165, 3495}.

Patients have a 20–34-fold risk of pan- (PALB2), which encodes a BRCA2-bind- genes, including MSH2 on chromosome
creatic cancer, and the risk appears to ing protein, has also been identified as a 2p and MLH1 on 3p {1773, 1870, 3470}.
be particularly high in carriers of a spe- familial susceptibility gene for pancreatic It has been suggested that individuals
cific 19-base-pair deletion in CDKN2A cancer {1443, 3146, 3250}. with Lynch syndrome have an increased
(p16-Leiden deletion) {678}. Carriers of Germline BRCA1 mutations have also risk of pancreatic cancer, and microsatellite
this particular mutation have a 15% been associated with an increased risk of instability has been reported to occur in
lifetime risk of developing pancreatic pancreatic cancer {1846}, although some about 4% of pancreatic carcinomas {1007,
carcinoma. studies have not found this link to be 1491, 1933, 2516}. Pancreatic cancers
strong {165}. with microsatellite instability are often
BRCA2 and other Fanconi anaemia microscopically distinct and have a
complementation (FANC) genes Peutz-Jeghers syndrome characteristic “medullary” histological
The discovery of the second breast can- Patients with Peutz-Jeghers syndrome appearance.
cer gene (BRCA2) on chromosome 13q have a highly increased risk (> 100-fold)
was made possible largely as a result of of developing pancreatic carcinoma ABO blood group
the discovery of a homozygous deletion {977}, and bi-allelic inactivation of the A genome-wide association study has
in a pancreatic carcinoma {2859}. Pan- STK11 gene has been demonstrated in a linked variants in the ABO blood group
creatic carcinomas have been reported in pancreatic carcinoma arising in a patient locus to susceptibility to pancreatic can-
some kindreds with BRCA2 gene muta- with Peutz-Jeghers syndrome {980, cer, with individuals with blood group O
tions {807, 1008, 2542, 3243}, and pa- 3105}. having a lower risk than those with groups
tients with identified germline mutations in A or B {105}.
BRCA2 have a 3- to10-fold increased risk Hereditary pancreatitis
of pancreatic cancer {1846}. The pene- This disease is caused by germline mu- Molecular pathology
trance of these germline mutations is tations in the cationic trypsinogen gene The alterations reported in pancreatic
incomplete and many patients with pan- PRSS1 or in the serine peptidase inhibitor cancers include losses and gains of ge-
creatic ductal carcinoma who carry such SPINK1 {1901, 3496}. Patients develop netic material as well as generalized chro-
mutations do not have a strong family his- recurrent episodes of pancreatitis starting mosome instability {326, 1037, 1065,
tory of breast or pancreatic carcinoma at a young age, and 25–40% will develop 1066, 2888}. These consist of very high
{1008}. A number of patients with BRCA2 pancreatic cancer by the age of 70 years, rates of loss at chromosomes 18q (90%
mutations and pancreatic cancer are of the risk increasing if the patient is also a of cases), 17p (90%), 1p (60%) and 9p
Ashkenazi Jewish descent {1008, 2426}; cigarette smoker {1902}. (85%), and moderately frequent losses at
a founder BRCA2 mutation, 1674 delT, is nearly a dozen additional sites (25–50%
present in about 1% of the Ashkenazi Lynch syndrome of cases). Comprehensive sequencing of
Jewish population. The BRCA2 gene in- This syndrome is associated with an in- the genomic exons of a series of 24 pan-
teracts with the products of the FANC creased risk of developing carcinoma of creatic cancers revealed that an average
genes, and germline mutations in the the colon, endometrium, stomach, and of five dozen intragenic mutations had ac-
FANCC and FANCG genes have been re- ovary {3470}. Lynch syndrome can be cumulated in each cancer {1444}. Most of
ported in young patients with pancreatic caused by germline mutations in any one the genes mutated are infrequently in-
cancer {609, 3359}. Recently, FANCN of a number of DNA mismatch repair volved, and thus it is assumed that most
Table 12.03 Genetic syndromes associated with an increased risk of pancreatic cancer.
Syndrome (MIM No.)a Mode of inheritance Gene Lifetime risk of References

(chromosome arm) pancreatic cancer (age)
Lynch syndrome (120435, 609310) Autosomal dominant MSH2 (2p), MLH1 (3p) 1.3–4% (70 years) b {1007, 1491, 1933}
and others
Familial breast cancer and other Fanconi Autosomal dominant BRCA2 (13q), PALB2 (16p), 3.5–10% for BRCA2 c {609, 807, 1008, 1443, 1846,
anaemia genes (612555, 610832, FANCC (9q), FANCG (9p), 2542, 3243, 3250, 3359}
227645) and possibly BRCA1 (17q)
Familial pancreatic cancer (three or more Autosomal dominant Unknown 9–38% (80 years) b {106, 1588, 3449}
relatives with pancreatic cancer)
Familial atypical multiple mole melanoma, Autosomal dominant CDKN2A (9p) 10–17% c (70 years) {678, 1017, 1298, 2165, 3495}
FAMMM (606719)
Hereditary pancreatitis (167800, 167790) Autosomal dominant (PRSS1) PRSS1 (7q), SPINK1 (5q) 25–40% (60 years) {1264, 1901}
or autosomal recessive (SPNK1)
Peutz-Jeghers syndrome (175200) Autosomal dominant STK11 (19p) 30–60% (70 years) {977, 980, 3105}
a
Mendelian inheritance in man (MIM): www.ncbi.nlm.nih.gov/omim; b Calculated empirically; c Extrapolated from relative rates.

Table 12.04 Genetic alterations identified in ductal adenocarcinoma of the pancreas. occasional mutation or amplification of
Gene Chromosome Mechanism of alteration Frequency various growth-stimulating genes, and
overexpression of ERBB2 on chromo-
Oncogenes some 17q in 70% of pancreatic carcino-
KRAS 12p Point mutation > 90% mas {97, 517, 665, 971, 1279, 1444,
2100}. Mutations of KRAS2 have been de-
MYB, AKT2, NCOA3 (AIB1) 6q, 19q, 20q Amplification a
10–20%
tected in stool, pancreatic juice, cytology
ERBB2 17q Overexpression 70% and/or blood samples from patients with
proven ductal adenocarcinoma of the
Tumour-suppressor genes
pancreas {399, 1643, 3102, 3153}, but the
CDKN2A (p16) 9p Homozygous deletion 40% diagnostic value of these mutations in
LOH and intragenic mutation 40% daily clinical practice is uncertain.
Promoter hypermethylation 15%
TP53 17p LOH and intragenic mutation 50–70% DNA mismatch repair
Microsatellite instability has been identi-
SMAD4 (DPC4) 18q Homozygous deletion 35%
fied in 4% of pancreatic carcinomas
LOH and intragenic mutation 20%
{1007}; these carcinomas are also char-
BRCA2 13q Inherited intragenic mutation and LOH 7% acterized by wild-type KRAS, frequent
BRAF gene mutations and a distinctive
MAP2K4 (MKK4) 17p Homozygous deletion 4%
LOH and intragenic mutation “medullary” histological appearance.
STK11 (LKB1) 19p LOH and intragenic mutation 5% Molecular pathology of precursor lesions
Homozygous deletion The histological progression of PanIN
TGFBR1 (ALK5) and TGFBR2 9q, 3p Homozygous deletion 4% lesions to invasive cancer is usually mir-
rored by genetic and epigenetic progres-
DNA mismatch-repair genes
sion, with the frequency of individual
MSH2, MLH1, others 2p, 3p, others Unknown < 5% molecular aberrations being higher in
a
higher-grade precursors {922, 2821}. For
LOH, loss of heterozygosity. In cases of amplification, it is generally not possible to unambiguously identify the key
example, mutations of the KRAS gene are
oncogene due to the participation of multiple genes in an amplicon.
found in 36%, 44%, and 87% of PanIN-
1A, PanIN-1B and PanIN-2/3 lesions, re-
are “passenger mutations” accumulated nostic aid in the histopathological evalua- spectively {1886}. Although the precise
before or during tumorigenesis and that tion of pancreatic biopsies {3511}. The sequence of alterations is not well-de-
they play no direct role in the disease it- BRCA2 gene is involved in DNA repair as fined, and not every mutation is found in
self. an effector in the FANC anaemia signal- all PanIN lesions, certain genetic abnor-
transduction pathway {1264}. BRCA2 is malities, such as activating mutations of
Tumour suppressor genes inactivated in about 7% of pancreatic car- KRAS and telomere shortening, are
Sequencing has also identified a number cinomas {1008, 2426, 2859}; remarkably, “early” changes that are likely to con-
of recurrent genetic abnormalities, “driver in almost all these cases one allele of tribute to disease initiation. Mutations of
mutations” that play critical roles in the BRCA2 has been inactivated by a CDKN2A occur in intermediate-grade
development of pancreatic neoplasia. germline mutation {1008}. (PanIN-2) lesions, while inactivating mu-
These include CDKN2A, TP53, and Other tumour-suppressor genes that have tations of TP53, BRCA2 and SMAD4
SMAD4 {1444, 2888}. The CDKN2A gene been shown to be occasionally inacti- (DPC4) are typically observed in higher-
is inactivated by homozygous deletion in vated in pancreatic carcinoma include grade lesions (most often, PanIN-3) or
40% of pancreatic carcinomas, by loss of MKK4, STK11, transforming growth factor invasive cancers, suggesting an associ-
one allele coupled with an intragenic mu- β receptors I and II, and the FANC path- ation between these “late” changes and
tation in the second allele in a further way genes FANCC, FANCG, and FANCN disease progression.
40%, and by promoter methylation in an {1009, 1443, 3104, 3105, 3359}. It is PanINs differ genetically from IPMNs in
additional 15% {398, 2860, 3509}. TP53 is thought that inactivation of the FANC that they express the apomucin MUC1,
inactivated by loss of one allele coupled pathway increases sensitivity to treatment but not MUC2, while the reverse is true for
with an intragenic mutation in the second by DNA-crosslinking agents or poly- intestinal-type IPMNs {1813}. Certain ge-
allele in 75% of pancreatic carcinomas (ADP-ribose) polymerase (PARP) en- netic alterations, such as activating muta-
{2651, 2740}. The SMAD4 gene is inacti- zyme-inhibiting drugs {878, 3358}. tions of the PIK3CA gene, which encodes
vated in 55% of pancreatic carcinomas a protein in the oncogenic AKT signalling
(by homozygous deletion in 35% of cases Oncogenes pathway, appear to be restricted to IPMNs
and by loss of one allele coupled with an Oncogenes that have been shown to be {2853}. In conjunction with the finding that
intragenic mutation in the second allele in activated in ductal adenocarcinomas of a subset of IPMN-associated invasive
20% of cases) {1100}. The consequent the pancreas include KRAS on chromo- carcinomas tends to have an overall bet-
loss of SMAD4 protein is essentially can- some 12p, which is activated by point ter prognosis than adenocarcinomas aris-
cer-specific and thus serves as a diag- mutations in > 90% of these carcinomas, ing in the setting of PanINs, an emerging

consensus suggests that there are two within 2 years after curative resection to the total number of nodes examined, is
major avenues to invasive carcinoma in {208, 3357}, often local-regionally and in one of the most powerful predictors of
the pancreas: one that is more “aggres- the liver. The peritoneal cavity or lymph postoperative survival {2505}.
sive” (via PanIN and pancreatobiliary- nodes are also common sites of recur- Histological features are less significant
type IPMN precursors) and a second that rence {208, 3357}. Adjuvant chemother- prognostic factors than stage, but tumour
is more “indolent” (via intestinal-type apy with gemcitabine or 5-fluorouracil grade, mitotic index, and severity of cel-
IPMN precursors) {1266}, although prolongs survival time only slightly {2266, lular atypia have been correlated with
PanINs and IPMNs can be found in the 2268, 2357}. postoperative survival {1612, 1921}. Major
same pancreas. Survival is longer in patients with carcino- vessel involvement {2239}, vascular inva-
mas that are confined to the pancreas sion and perineural invasion {2098, 2240,
Prognosis and predictive factors and < 30 mm in diameter than it is in pa- 2422} are also prognostic indicators.
Ductal adenocarcinoma is fatal in almost tients with tumours that extend beyond
all cases {1413}. The mean survival time the gland and are > 30 mm {1175, 1853, Molecular prognostic factors
for untreated patients is 3–5 months, while 2941, 3007, 3634}. None of the many molecular prognostic
the mean survival after surgical resection Patients with no residual tumour after re- indicators reported has yet become es-
ranges from 10 to 20 months {589, 1168, section (R0) have the most favourable tablished in routine clinical practice. Loss
1347, 1360, 1674, 2267}. Only 10–20% of prognosis of those who are treated surgi- of SMAD4 expression and SMAD4 muta-
patients or fewer have surgically re- cally {1175, 2267, 3514, 3525}. This im- tions have been correlated with poor sur-
sectable carcinomas at the time of diag- plies that local spread to peripancreatic vival after surgery {273, 3203, 3699}, and
nosis {589, 590, 2876, 3041}. Carcinomas tissues, i.e. the retroperitoneal resection an autopsy study reported that pancreatic
of the body or tail of the pancreas tend to margin, is of critical importance in terms cancers with loss of SMAD4 expression
present at a more advanced stage than of prognosis {1923}. The presence of were more likely to have widespread
those of the head {937, 2939, 3290, 3308, lymph-node metastases significantly metastases than those with intact expres-
3316}. worsens prognosis {1202, 1252, 1853, sion {1300}. Down-regulation of E-cad-
Resectability is the most important deter- 2849, 3007, 3290, 3634}. The status of the herin and up-regulation of dysadherin
minant of prognosis. The overall 5-year lymph nodes correlates with both short- have been reported to be significantly as-
survival rate is 3–5% {1413}, while that for term (< 5 years) and long-term survival sociated with poorer survival and to be in-
patients treated by curative resection is (≥ 5 years) after surgical resection {2849}. dependent prognostic indicators {2943,
15–25% {848, 1252, 1675, 3525}. Unfor- The lymph-node ratio, i.e. the ratio of the 3527}.
tunately, most (70–90%) carcinomas recur number of nodes harbouring a metastasis

Ductal adenocarcinoma variants and N. Fukushima

R.H. Hruban
mixed neoplasms of the pancreas Y. Kato
D.S. Klimstra
G. Klöppel
M. Shimizu
B. Terris
This category includes mixed neoplasms Histopathology Carcinomas with mixed differentiation
and histological variants of ductal adeno- Histologically, the adenocarcinoma com-
carcinoma of the pancreas that have dis- ponent forms ductal or glandular struc- Carcinomas with mixed differentiation are
tinct clinical or prognostic significance. tures with focal to abundant intra- malignant epithelial neoplasms of the
and/or extracellular mucin. Squamous pancreas with significant components of
ICD-O codes differentiation is characterized by an in- more than one distinct direction of dif-
Adenosquamous carcinoma 8560/3 filtrating sheet-like arrangement of polyg- ferentiation {1235, 1238, 2857, 3340}.
Colloid carcinoma onal cells with distinct cellular borders, “Collision tumours” composed of two
(mucinous noncystic carcinoma) 8480/3 prominent intracellular junctions, hard topographically separate neoplasms are
Hepatoid carcinoma 8576/3 eosinophilic cytoplasm and varying de- not included in the mixed differentiation.
Medullary carcinoma 8510/3 grees of keratinization. Rare acinar neoplasms have a substan-
Mixed acinar-ductal carcinoma 8552/3 tial proportion (> 30%) of more than one
Mixed acinar-neuroendocrine carcinoma Molecular pathology cell type {1270, 1710, 2313, 2369, 3405}.
8154/3 Most cases harbour KRAS2 mutations at Of these, the best characterized is mixed
Mixed acinar-neuroendocrine-ductal codon 12, and immunohistochemically acinar-neuroendocrine carcinoma {1710}.
carcinoma 8154/3 show loss of CDKN2A (p16) protein ex- This carcinoma has also been referred to
Mixed ductal-neuroendocrine carcinoma pression, loss of SMAD4 (DPC4) protein as mixed carcinoid-adenocarcinoma, mu-
8154/3 and strong nuclear p53 immunoreactivity, cinous carcinoid tumour, or simply mixed
Signet ring cell carcinoma 8490/3 similar to the molecular signature found in exocrine-endocrine tumour {1106}. Pa-
Undifferentiated carcinoma 8020/3 pancreatic ductal adenocarcinomas {337, tients with mixed ductal-neuroendocrine
Undifferentiated carcinoma with 1482}. The squamous component often carcinoma are usually older adults and
osteoclast-like giant cells 8035/3 expresses p63 {337}. present with nonspecific symptoms. This
neoplasm is characterized by an intimate
Prognosis and predictive factors admixture of neoplastic ductal and neo-
Adenosquamous carcinoma Patients with resected adenosquamous plastic neuroendocrine cells in the pri-
carcinoma have a poorer prognosis (me- mary neoplasm as well as in its
Adenosquamous carcinoma is a malignant dian survival, 7–11 months) than do those metastases. Two patterns can be distin-
epithelial neoplasm of the pancreas that with pure adenocarcinoma {1482, 2383, guished, one consisting of intermingled
has both significant ductal and significant 3419}. The presence of any squamous neoplastic ductal and neuroendocrine
squamous differentiation. The squamous component in the neoplasm appears to cells forming glandular (occasionally also
component should account for at least portend a worse prognosis {3419}. squamoid) and solid structures, and an-
30% of the neoplasm. Neoplasms with other consisting of moderately differentiated
these features were previously designated
adenoacanthoma, mixed squamous and
adenocarcinoma, and mucoepidermoid
carcinoma. Adenosquamous carcinomas
account for only 1–4% of exocrine pancre-
atic malignancies {1273, 1945}. Pure squa-
mous carcinoma of the pancreas is very
rare, and a metastasis from another site
(e.g. lung) should be excluded if a neo-
plasm has purely squamous differentiation.
Even focal glandular differentiation in a
carcinoma with predominant squamous
differentiation warrants a diagnosis of
adenosquamous carcinoma.
Macroscopy
Macroscopically, most adenosquamous
carcinomas are infiltrative yellow-white to
grey firm masses; however, some are
multinodular and others are cystic {1482}. Fig. 12.15 Adenosquamous carcinoma. Both glandular and squamous differentiation are present.

neoplastic ductal structures embedded in acinar elements. There may be nests of

a solid neuroendocrine cell compartment acinar cells floating in colloid-like pools of
{1270, 2368}. By definition, each compo- mucin, or the neoplastic elements may
nent should comprise at least one third of have a combination of typical acinar ele-
the neoplastic tissue. Ductal differentia- ments mixed with columnar or signet ring-
tion is defined by mucin production and like cells with cytoplasmic mucin. Mucin
the expression of ductal markers such as staining (mucicarmine or Alcian blue) is
carcinoembryonic antigen (CEA) or MUC1. positive, as is immunohistochemical la-
The neoplastic neuroendocrine cells are belling for trypsin and chymotrypsin. Indi-
typically of high grade on the basis of mi- vidual cells can have multiple directions A
totic rate and express neuroendocrine of differentiation. Other mixed acinar-duc-
markers such as synaptophysin, chromo- tal carcinomas have an individual gland
granin A, and pancreatic hormones. pattern of infiltration with an associated
As defined above, these neoplasms are desmoplastic stromal response, reminis-
exceptionally rare in the pancreas {2368, cent of infiltrating ductal adenocarci-
2884, 3012}. It is much more common to noma, but nonetheless show significant
find a neuroendocrine neoplasm that has acinar differentiation by immunohisto-
entrapped non-neoplastic ductal cells chemistry.
{2318, 3261, 3361}. The trapped ductal
cells are cytologically benign and limited Mixed acinar-neuroendocrine-ductal
by the well-demarcated edges of the carcinoma
underlying neuroendocrine neoplasm. These are extremely rare and poorly
The latter behave like pure neuroendocrine documented, but show mixed morphology,
neoplasms, while true mixed ductal-neuro- with acinar patterns, cells with neuro-
endocrine carcinomas behave like the endocrine differentiation and areas
usual ductal adenocarcinoma. simulating infiltrating ductal adenocarci-
Mixed ductal-neuroendocrine carcino- noma {3073}. Immunohistochemistry is
mas should also be distinguished from positive for acinar, neuroendocrine, and
ductal adenocarcinomas with reactive ductal markers, and mucin production is
non-neoplastic neuroendocrine cells also evident. One of the reported cases
{2368}. Scattered non-neoplastic neuro- arose in association with high-grade
endocrine cells are found in 40–80% of pancreatic intraepithelial neoplasia B
ductal adenocarcinomas and seem to (PanIN) {1270}.
be particularly frequent in well-differenti- There is an insufficient number of Fig 12.16 Colloid carcinoma. A Arising in association
with an intraductal papillary mucinous neoplasm (IPMN).
ated adenocarcinomas, where they tend recorded cases to define the biological
B Note the neoplastic cells “floating” in large stromal pools
to either line up along the base of the behaviour of mixed acinar carcinomas, of mucin.
neoplastic ductal structures or lie be- but, like pure acinar cell carcinomas,
tween the neoplastic columnar cells they appear to be aggressive {2369}.
{504, 2368}. signet-ring type. The neoplastic cells of
colloid carcinoma show intestinal differ-
Mixed acinar-neuroendocrine carcinoma Colloid carcinoma entiation; there is strong expression of
In many of these neoplasms, the only ev- CDX2 and MUC2, which are not signifi-
idence for divergent differentiation is pro- Synonym cantly expressed in conventional ductal
vided by immunohistochemical labelling. Mucinous noncystic adenocarcinoma adenocarcinoma.
Although different regions of the neo- Two features help to distinguish benign
plasm may suggest acinar or neuro- Colloid carcinoma is an infiltrating ductal spillage of mucin into the extraductal
endocrine differentiation morphologically, epithelial neoplasm of the pancreas char- stroma caused by rupture of the dilated
many areas have intermediate features, acterized by the presence, in at least 80% pancreatic duct occupied by an IPMN
and immunohistochemistry generally of the neoplasm, of large extracellular from true tissue invasion by a colloid
shows a mixture of cells expressing aci- stromal mucin pools containing sus- carcinoma. Neoplastic cells “floating” in
nar or neuroendocrine markers (or both). pended neoplastic cells {37}. Colloid car- pools of stromal mucin, and neoplastic
Most reported acinar-neuroendocrine carcinomas tend to be large and cells in an abnormal location, such as in
cinomas have been composed predomi- well-demarcated and almost always arise the perineurium, help identify the lesion
nantly of acinar elements {1710}. in association with an intestinal-type as a colloid carcinoma. In contrast, be-
intraductal papillary mucinous neoplasm nign mucin spillage will consist of
Mixed acinar-ductal carcinoma (IPMN) {2868}. The large pools of mucin mucus lakes adjacent to a pancreatic
These neoplasms have one of two differ- are partially lined by well-differentiated branch duct without “floating” neoplas-
ent patterns {1270, 3070, 3073}. Some cuboidal to columnar neoplastic cells and tic cells.
exhibit extensive intra- or extracellular contain clumps or strands of neoplastic Pseudomyxoma peritonei can be a rare
mucin accumulation in association with cells. Some floating cells may be of the complication of this carcinoma. Colloid
Ductal adenocarcinoma variants and mixed neoplasms 293

carcinomas seem to have a more Medullary carcinoma 1007, 1165, 1193, 3103, 3591}. A
favourable prognosis than conventional medullary carcinoma with Epstein-Barr
ductal adenocarcinomas {2575B}. Medullary carcinoma is a malignant ep- virus (EBV) infection of the neoplastic
ithelial neoplasm characterized by poor cells has been reported {3510}.
differentiation, limited gland formation, Despite poor differentiation, the progno-
Hepatoid carcinoma pushing borders at the interface between sis for patients with medullary carcinomas
the neoplasm and non-neoplastic tissues is better than for those with ductal adeno-
Hepatoid carcinoma of the pancreas is an and a prominent syncytial growth pattern carcinomas {2243, 2244, 3510, 3591}. On
extremely rare malignant epithelial neo- {1007, 3510}. Increased numbers of tu- the basis of extensive experience with
plasm with a significant component of he- mour-infiltrating leukocytes (CD3+) are MSI+ colorectal carcinomas, it is likely
patocellular differentiation. Hepatoid present in some cases {2244}. Because of that medullary carcinomas of the pan-
differentiation can occur in a pure form, or the histological overlap with acinar cell creas will not respond to 5-fluorouracil
in association with a ductal adenocarci- carcinoma, acinar differentiation should therapy {698}.
noma, an acinar or a neuroendocrine neo- be excluded by immunolabelling for
plasm {1285, 2443, 3200, 3618}. trypsin or chymotrypsin. Medullary carci-
Hepatoid carcinomas are composed of nomas express keratin, and immunohisto- Signet ring cell carcinoma
large polygonal cells with abundant chemistry will often demonstrate the loss
eosinophilic cytoplasm. Most express α- of expression of one of the DNA mismatch The extremely rare signet-ring cell carci-
fetoprotein (AFP); however, AFP secretion repair genes {190, 1640, 2243, 3510}. noma is an adenocarcinoma composed
can also be observed in pancreatoblas- Medullary carcinomas may arise sporad- almost exclusively of poorly cohesive
tomas and in acinar, neuroendocrine, and ically or in patients with Lynch syndrome neoplastic epithelial cells containing in-
ductal neoplasms without hepatoid fea- {190, 3591}. It has been reported that pa- tracytoplasmic mucin that displaces the
tures {564, 1505}. The expression of tients with medullary carcinoma of the nuclei towards the periphery, infiltrating in
hepatocyte-specific antigen (hepatocyte pancreas are more likely to have a family an individual cell pattern {813, 3284}. A
paraffin-1) is more specific for hepatocel- history of cancer than are patients with variable amount of extracellular mucin is
lular differentiation. A canalicular pattern ductal adenocarcinoma of the pancreas usually present. The prognosis is ex-
of labelling with antibodies to polyclonal {3510}. The age and sex distributions are tremely poor. A gastric or breast primary
CEA and CD10 can help establish the similar to those for ductal adenocarci- should always be excluded before mak-
diagnosis in some cases {630, 1103}. noma {2244, 3510}. ing this diagnosis.
Hepatocellular carcinoma arising from Medullary carcinomas in patients with
ectopic liver tissue should not be Lynch syndrome harbour biallelic muta-
included in this category. Pancreatic tions (one germline, the second somatic) Undifferentiated (anaplastic)
metastases from an occult hepatocellular in one of the DNA mismatch repair genes carcinoma
carcinoma are probably much more com- (i.e. MLH1 and MSH2 {190}). Most
mon than are primary hepatoid carcino- medullary carcinomas are microsatellite- Synonyms
mas of the pancreas, and a metastasis to unstable (MSI+) {3510} and, as one would Anaplastic carcinoma, pleomorphic carci-
the pancreas needs to be excluded, usu- expect in an MSI+ neoplasm, most are noma, pleomorphic large cell carcinoma,
ally on clinical grounds, before establish- wild-type for the KRAS2 gene, and diploid pleomorphic giant cell carcinoma, spin-
ing the diagnosis of a hepatoid carcinoma (no loss of heterozygosity) {1007, 3510}. dle cell carcinoma, sarcomatoid carci-
primary to the pancreas. Data on the Medullary carcinomas also can harbour noma and carcinosarcoma.
prognosis of hepatoid carcinomas are BRAF mutations, FHIT homozygous dele- Undifferentiated carcinoma is a malignant
minimal. tions, and biallelic inactivating mutations epithelial neoplasm in which a significant
of the ACVR2 and TGFBR2 genes {400, component of the neoplasm does not
A B
Fig. 12.17 A Medullary carcinoma characterized by poor differentiation, a syncytial growth pattern, pushing borders, and tumour-infiltrating lymphocytes. B Undifferentiated carcinoma
with spindle cells, pleomorphic nuclei, and mitoses.

show a definitive direction of differentia-

tion. These neoplasms usually occur in
elderly people, and males and females
are equally affected.
Three histological variants have been de-
scribed. Anaplastic giant cell carcinomas
are composed of pleomorphic mononu-
clear cells admixed with bizarre-appear-
ing giant cells with eosinophilic
cytoplasm. Cells with spindle-cell mor-
phology predominate in the sarcomatoid
carcinoma, and carcinosarcomas have
cells recognizable as adenocarcinoma as
well as a high-grade spindle-cell compo-
nent. In contrast to ductal adenocarci-
noma, undifferentiated carcinomas are
poorly cohesive, cellular and often have
only scant stroma {628, 1604, 3299}. Nu-
clear pleomorphism, mitoses as well as
perineural, lymphatic, and vascular inva-
sion are easily identified. Immunohisto- Fig. 12.18 Undifferentiated carcinoma with osteoclast-like giant cells. A component of ductal adenocarcinoma is also seen
chemically, most of these carcinomas (right).
express keratin and vimentin but not E-
cadherin {1236, 2428, 3527}. Electron mi- hand, osteoclast-like giant cells, and a {2452, 3012}, non-mucinous, glycogen-
croscopy reveals epithelial differentiation, subset of the mononuclear cells, express poor cystadenocarcinoma {896}, chorio-
microvilli and occasional mucin in some CD68, vimentin, and leukocyte common carcinoma {3012, 3668}, clear cell
cases {628}. The prognosis is extremely antigen, but are negative for keratin and carcinoma {628, 1470, 1556, 1604, 1896,
poor, and average survival is just 5 do not label with antibodies to p53 {1236, 1922, 3012, 3212}, ciliated cell adenocar-
months {1236, 2428, 3299}. 1912, 2124, 3493}. These immunola- cinoma {2154} and microadenocarcinoma
belling studies, when combined with mo- {628, 1604}. Although most of these neo-
Undifferentiated carcinoma with lecular analyses, have shown that the plasms are reported to have a distinctive
osteoclast-like giant cells pleomorphic mononuclear cells are the histological appearance, their clinical/bio-
This is a rare neoplasm composed of neoplastic cells, while the osteoclast-like logical significance is not well defined, and
round to spindle-shaped, highly pleomor- giant cells are reactive non-neoplastic they are therefore not considered as sep-
phic neoplastic mononuclear cells and cells {3493}. arate entities at this time. Some have been
large, non-neoplastic multinucleated, his- The mean age of patients with an undif- reclassified immunohistochemically as
tiocytic giant cells. The latter usually con- ferentiated carcinoma with osteoclast-like adenocarcinoma, acinar cell carcinomas
tain > 20 uniform and small nuclei, and giant cells is 62 years, but there is a wide and neuroendocrine carcinoma, and oth-
are often found in areas adjacent to range (32–93 years) {1270, 2314}. Recent ers are regarded as patterns of growth
haemorrhage or necrosis. In most cases studies have shown that the prognosis is rather than distinctive entities.
there is an associated in situ or invasive poor and mean survival is only 12 months
adenocarcinoma or an associated muci- {628, 1270}. Interestingly, in situ as well as
nous cystic neoplasm (MCN) {2124, early-stage undifferentiated carcinomas
3493, 3673}. The osteoclast-like giant with osteoclast-like giant cells have also
cells can be phagocytically active and been reported {237, 3225}.
may contain haemosiderin. Some of the
mononuclear cells are atypical, while oth- Other entities
ers can be histiocyte-like {2778}.
Immunohistochemically, most of the neo- A number of rare entities of uncertain clin-
plastic mononuclear cells express vi- ical significance have been reported.
mentin, some express keratin, and some Those carcinomas of probable ductal phe-
label with antibodies to p53. On the other notype include oncocytic carcinoma
Ductal adenocarcinoma variants and mixed neoplasms 295

Serous neoplasms of the pancreas B. Terris

N. Fukushima
R.H. Hruban
Serous cystic neoplasms are usually cys- women (67–80%) {584, 585, 934, 1655,
tic epithelial neoplasms composed of 3647}. As many as 90% of patients with
cuboidal, glycogen-rich, epithelial cells the von Hippel-Lindau (VHL) syndrome
that produce a watery fluid similar to develop serous cystic neoplasms {585,
serum. Most are benign (serous cystade- 1109, 2123, 3421}.
nomas), and only rare cases metastasize
(serous cystadenocarcinoma). In addition Localization
to the most common microcystic type, These neoplasms occur most frequently
four variants of serous cystic neoplasm (50–75%) in the body or tail of the pan-
have been described: macrocystic creas; the remaining tumours involve the
serous cystic neoplasm, solid serous neo- pancreatic head {584, 585, 934, 1655,
Fig. 12.19 Gross appearance of microcystic serous
plasm, von Hippel-Lindau (VHL)-associ- 3647}. They are only rarely multifocal, cystadenoma. Note the central stellate scar and sponge-
ated serous cystic neoplasm, and mixed large, or involve almost the full length of like appearance.
serous-neuroendocrine neoplasm. the pancreas.
Clinical features 6 cm) {585, 934, 1655}. On cross-section,

Serous adenoma Approximately 40% of resected serous serous cystadenomas are sponge-like and
neoplasms present as an incidental find- composed of numerous tiny cysts (usually
Definition ing at routine physical examination {584, < 2 mm to 10 mm) filled with serous (clear
A benign neoplasm composed of uniform 934, 3647}. Other patients exhibit symp- watery) fluid. The cysts do not communi-
glycogen-rich cuboidal epithelial cells toms related to local mass effects, includ- cate with the larger pancreatic ducts, and
that usually form cysts containing serous ing abdominal pain, palpable mass, often are arranged around a central, dense
fluid. The term “serous cystadenoma” nausea and vomiting, and weight loss fibronodular scar from which thin fibrous
refers to the microcystic form of the neo- {584, 934, 3647}. Jaundice caused by ob- septa radiate to the periphery. The cysts at
plasm unless otherwise specified. struction of the common bile duct is un- the periphery are often larger than those
usual, even in neoplasms originating in near the centre of the tumour. The central
ICD-O code the head of the pancreas. scar may be calcified.
Serous cystadenoma 8441/0
Serous cystadenocarcinoma 8441/3 Imaging Histopathology
Serum tumour markers are generally nor- The cysts are lined by a single layer of
Epidemiology mal. Endoscopic ultrasonography (EUS) cuboidal or flattened epithelial cells. Their
This is a relatively uncommon neoplasm, and computed tomography (CT) reveal a cytoplasm is almost always clear, but can
accounting for 1–2% of all pancreatic well-circumscribed, multilocular mass, oc- rarely be eosinophilic (oncocytic) and
neoplasms {1270, 1655}. The mean age casionally with evident prominent central granular. The nuclei are centrally located,
at presentation is 60 years (range, 26–91 stellate scar with a sunburst-type pattern round to oval, uniform, and have an in-
years), with a slight predominance in of calcification {944, 1551}. On magnetic conspicuous nucleolus. Owing to the
resonance imaging (MRI), serous cystic presence of abundant intracytoplasmic
neoplasms are predominantly hypointense glycogen, the periodic acid-Schiff (PAS)
in T1-weighted images and hyperintense stain without diastase digestion is posi-
in T2-weighted images, a manifestation of tive, whereas PAS-diastase and Alcian
of the fluid content of the small cysts blue stains are negative. Nuclear atypia
{3708}. Any areas of haemorrhage are hy- and mitoses are practically absent. Oc-
perintense on T1-weighted sequences casionally, the neoplastic cells form intra-
{3708}. Angiographically, these neoplasms cystic papillary projections, usually
are usually hypervascular. The cysts do not without a fibrovascular stalk. The central
communicate with the pancreatic duct sys- fibrous stellate core is composed of rela-
tem. tively acellular hyalinized tissue admixed
with a few clusters of tiny cysts.
Macroscopy
Serous cystadenomas are usually single, Immunohistochemistry
Fig. 12.20 Axial CT scan of a serous cystadenoma in the well-circumscribed, slightly bosselated, Serous cystadenoma and its variants
tail of the pancreas (arrow). Note the central calcified scar. round lesions 1–25 cm in diameter (mean, have a similar immunoprofile. The epithe-

lial nature of these neoplasms is reflected cells {3607}. The apical surfaces have broad septa, and lie within a fibrous
in their immunoreactivity with antibodies poorly developed or no microvilli. The cy- stroma that lacks a central stellate scar.
to epithelial membrane antigen and ker- toplasm contains numerous glycogen The cysts and the supporting fibrous tis-
atins 7, 8, 18, and 19. In addition, the neo- granules. Zymogen granules and neu- sue may extend into the adjoining pan-
plastic cells express neuron-specific rosecretory granules are absent. creatic tissue so that the neoplasms
enolase, but immunolabelling for antigens are poorly demarcated. Microscopically,
that are more specific for neuroendocrine Histological variants macrocystic variants are composed
differentiation (e.g. chromogranin or Four variants of serous adenoma have of the same glycogen-rich cells as
synaptophysin) is uniformly negative been characterized. The serous epithelial are serous cystadenomas. Occasionally,
{1657}. α-Inhibin, MUC6 and MUC1 are component of these variants is cytologi- however, the lining epithelium may
expressed in 82%, 70% and 34% of cally identical to the epithelial component be more cuboidal and less flattened, and
serous cystadenomas, respectively. This of serous cystadenomas. the nuclei are generally larger. The
mucin expression profile supports a cen- cytoplasm is usually clear, owing to the
troacinar differentiation. Serous cystic Macrocystic serous cystadenoma presence of glycogen, but may be
neoplasms occurring sporadically or in This category includes entities previously eosinophilic. Smaller microscopic cysts
association with VHL disease show a dys- classified as serous oligocystic and ill- may be present in the wall of unilocular
regulation of VHL/hypoxia-inducible fac- demarcated serous adenoma {766, 1655, lesions. The stromal framework is well de-
tor (HIF) pathway with the expression of 1657}. These benign neoplasms are veloped and often hyalinized. The tumour
HIF-1α and carbonic anhydrase 9 (CA9) composed of a few large cysts and may border is not well defined and small cysts
{2524}. even be unilocular. Macrocystic serous often extend into the adjoining pancreatic
cystadenomas are much less common tissue. The immunohistochemical and ul-
Cytopathology than serous cystadenomas and occur trastructural features are the same as for
Fine-needle aspiration (FNA) biopsy is more frequently in males {1655}. Most pa- serous cystadenoma {1657}. These le-
usually paucicellular. The neoplastic tients are > 60 years of age (age range, sions are entirely benign.
epithelial cells are rarely identified on CT 28–85 years; mean, 65 years); however,
or EUS-guided FNA biopsy. Any cells these neoplasms have also been de- Solid serous adenoma
observed form sheets or small clusters. scribed in infants as young as 2–16 These well-circumscribed neoplasms
They have moderate to scant cytoplasm months of age {2131}. Most macrocystic have a solid gross appearance, similar to
and round uniform nuclei {229, 1728}. serous cystadenomas are located in the well-differentiated pancreatic neuroen-
Nuclei without associated cytoplasm head of the pancreas {1655} where they docrine neoplasms, and are usually
(naked nuclei) are occasionally present. may obstruct the periampullary portion of smaller than serous cystadenomas,
The stroma is relatively acellular, and cal- the common bile duct. Grossly, these le- measuring 2–4 cm {449}. The cells are
cifications can be seen in some cases sions appear as a cystic mass with a di- arranged in small acini with no or minute
{229}. ameter of 2–14 cm (mean, 7.2 cm) central lumina, resembling a solid tumour.
{1655}. They are composed of few or only These neoplasms otherwise share the cy-
Ultrastructure one macroscopically visible cyst(s) filled tological and immunohistological features
Electron microscopy shows a single row with watery clear or light-brown fluid. The of serous cystadenoma.
of uniform epithelial cells lining the cysts cysts usually vary between 1 and 3 cm in
and resting on a basal lamina {99, 2799}. diameter, but cysts as large as 8 cm have VHL-associated serous cystic neoplasm
Many small blood vessels are intimately been reported {1820}. They are irregu- Multiple serous cystadenomas and
associated with the neoplastic epithelial larly arranged, sometimes separated by macrocystic variants are the most common
Fig. 12.21 Microcystic serous cystadenoma. Characteristic cuboidal epithelium focally Fig. 12.22 Microcystic serous cystadenoma: the cysts are lined by a single layer of clear
forming intracystic papillary structures. cuboidal epithelial cells with round, hyperchromatic, uniform nuclei.
Serous neoplasms 297

Fig. 12.23 Microcystic serous cystadenoma. The cytoplasm shows granular periodic acid-Schiff (PAS) positivity. Fig. 12.24 Macrocystic (oligocystic) serous cystadenoma.
pancreatic lesions in VHL patients, docrine neoplasms and 70% have neu- Genetic susceptibility
occurring in 35–90% of patients {1109, roendocrine microadenomatosis {1109, Pancreatic serous cystadenomas and
1249}. Microscopically, these cysts are 1909, 2524}. In a few cases, however, no macrocystic variants are observed in 35–
virtually indistinguishable from those oc- genetic syndrome is found {279}. 90% of patients with VHL syndrome
curring sporadically. In VHL patients, {1109, 1249}. Pancreatic involvement is
however, serous cystic neoplasms typi- Differential diagnosis the first manifestation of this syndrome in
cally involve the pancreas diffusely or in Serous cystadenomas are usually so char- 8% of patients with VHL.
a patchy fashion rather than forming a acteristic that they do not present a signif-
distinct, well-demarcated tumour. The le- icant diagnostic challenge. When the Molecular pathology
sions vary from single and minute cystic lesion is not a classic example, the main Loss of heterozygosity at the VHL gene
dilatations of the centroacinar lumen to in- entities to consider in the differential diag- locus, mapped to chromosome 3p25, has
volvement of the entire pancreatic gland. nosis are lymphangioma, haemangioma been reported in two of two serous cys-
and metastatic renal cell carcinoma. tadenomas associated with VHL disease
Mixed serous neuroendocrine neoplasm Immunostains for epithelial and vascular and in 40–70% of sporadic cases {2123,
In rare cases, serous cystadenomas are markers can help to distinguish serous 2142}. Somatic inactivating mutations in
associated with pancreatic neuroen- cystic neoplasms from vascular tumours, the VHL gene have been reported in a mi-
docrine neoplasms. The neuroendocrine and immunolabelling for PAX8 and a nority (22%) of sporadic cases. In con-
proliferation can be independent or inter- good clinical history can identify renal trast to ductal adenocarcinomas, no
mingled with the cysts. Such an associa- metastases. In contrast, variant forms can mutations in KRAS or TP53 have been re-
tion is highly suggestive of VHL be more challenging and have a broader ported in serous cystadenomas {2142}.
syndrome; 10–17% of patients with VHL differential diagnosis.
have been reported to have neuroen- Macrocystic variants closely mimic muci- Prognosis and predictive factors
nous cystic neoplasms (MCN) and The prognosis for patients with serous
pseudocysts both radiologically and cystadenoma is excellent. These neo-
macroscopically. This may also be the plasms grow slowly, and there is minimal
case on microscopic examination, as ep- risk of malignant transformation. In a
ithelial denudation occurs frequently both study in which 24 patients were followed
in serous and in mucinous cysts. Identifi- with serial radiographic imaging, the an-
cation of small conserved microscopic nual median growth rate was only 0.6 cm,
cysts within the wall of the macrocystic and none of the neoplasms metastasized
variant can be used to establish the diag- {3300}. Because serous cystic neoplasms
nosis {495}. grow and because complete surgical re-
Solid serous adenoma can be difficult to section is curative, most institutions rec-
A distinguish from pancreatic neuroen- ommend the removal of these neoplasms
docrine neoplasms, metastatic renal cell {3300}. However, conservative manage-
carcinoma and clear cell sugar tumour. ment has been proposed when serous
The use of immunohistochemistry helps cystadenomas are small, not clinically
to differentiate these different entities. It complicated and show typical morpho-
can be particularly difficult to distinguish logical characteristics on radiological ex-
between a VHL-associated serous cystic amination. This course of action is
neoplasm and a well-differentiated neu- supported by the benign nature of the
roendocrine neoplasm in patients with vast majority of serous cystadenomas
VHL, as the syndrome predisposes to and by the potentially significant postop-
both entities and well-differentiated neu- erative morbidity and mortality, particu-
B roendocrine neoplasms in patients with larly in elderly patients.
Fig. 12.25 Solid serous adenoma. A Whole mount. VHL are often composed of cells with Although not technically classified as ma-
B Microscopic pattern. clear cytoplasm {1909}. lignant, serous cystic neoplasms with lo-

cally aggressive features, such as direct

extension into adjacent structures, can
rarely recur or even metastasize {934};
clinical postoperative follow-up of patients
with such neoplasms is therefore war-
ranted {934}.
Serous cystadenocarcinoma
Definition
A malignant neoplasm composed of uni-
form glycogen-rich cuboidal epithelial
cells that usually form cysts containing
serous fluid. Malignancy is defined by the
presence of distant metastases.
Epidemiology
Some 1–3% of serous cystic neoplasms
are malignant, and only about 25 cases
have been reported {934, 1571}. These
patients were between 52 and 81 years of
age; two thirds were women and one third Fig. 12.26 Serous cystadenocarcinoma metastatic to the colonic mucosa. Note the bland cytological features, virtually
indistinguishable from an ordinary serous cystadenoma.
were men {1571}.
Localization Serum CEA and CA19-9 levels are usually Differential diagnosis
Serous cystadenocarcinomas usually normal or only slightly increased. Benign serous cystadenoma is the pri-
arise in the tail of the gland. mary differential diagnosis. Clinical be-
Macroscopy haviour is the only established way to
Clinical features These neoplasms are grossly similar to distinguish the two entities. By definition,
Presenting signs and symptoms include benign serous cystic neoplasms, except distant metastases need to be present to
abdominal pain, upper gastrointestinal that they tend to be larger (mean diame- establish the diagnosis of serous cys-
bleeding, jaundice, weight loss and a pal- ter, 10 cm), and some, but not all, are lo- tadenocarcinoma.
pable upper abdominal mass. Imaging cally aggressive {1571}. Direct invasion
typically reveals a large cystic mass. into lymph nodes, the spleen, stomach, Prognosis and predictive factors
small intestines and adrenal gland has Serous cystadenocarcinomas are slowly
been observed {934, 1571, 3557}. growing neoplasms and palliative resec-
tion may be helpful even at an advanced
Histopathology stage. With a mean follow-up of
The histological features of the primary as 36 months, most patients were still alive
well as the metastases are remarkably at the time their cases were reported
similar to those of benign serous neo- {1571}.
plasms. The neoplastic cells are uniform
and most serous cystadenocarcinomas
do not have an increased mitotic rate.
Vascular and perivascular invasion have
been reported. As is true for their benign
Fig. 12.27 Mixed serous neuroendocrine neoplasm. counterparts, serous cystadenocarcino-
The serous cystadenoma is juxtaposed with a mas express keratins (keratins 7,8,18 and
pancreatic neuroendocrine neoplasm in this patient with 19), α-inhibin, MUC6, and neuron-specific
von Hippel-Lindau (VHL) syndrome. enolase {1657}.
Serous neoplasms 299

Mucinous cystic neoplasms G. Zamboni

N. Fukushima
of the pancreas R.H. Hruban
G. Klöppel
Definition rise in the incidence of these lesions is cluding carcinoembryonic antigen (CEA),
A cyst-forming epithelial neoplasm that most likely attributable to advances in im- and CA19-9, are useful but imperfect
usually does not communicate with the aging and other diagnostic techniques. markers for distinguishing mucinous from
pancreatic ductal system, and is com- The vast majority of MCNs occur in non-mucinous cystic lesions and for pre-
posed of columnar, mucin-producing ep- women, with a female-to-male ratio of dicting the presence of a malignant com-
ithelium associated with ovarian-type 20 : 1 {618, 2809}. The mean age at diag- ponent (since they are not sufficiently
subepithelial stroma {1106, 1270}. This nosis is between 40 and 50 years in most reliable in individual cases). The highest
neoplasm occurs almost exclusively in series, with a range of 14–95 years {618, levels of tumour markers are seen in
women. 1010, 1270}. Patients with MCNs with an MCNs with an associated invasive carci-
Noninvasive mucinous cystic neoplasms associated invasive carcinoma are 5–10 noma {1821, 3042}. Cyst-fluid amylase
(MCN) are categorized as MCN with low- years older, on average, than are patients activity is usually low as the cysts of
grade, intermediate-grade or high-grade with noninvasive MCNs, suggesting that MCNs do not communicate with the
dysplasia. If there is a component of in- progression from a noninvasive curable larger pancreatic ducts. Recent studies
vasive carcinoma, the lesions are desig- neoplasm to an invasive cancer occurs have shown that exopeptidases may
nated as MCN with an associated over a period of years {1655}. hamper the proteomic analysis of pan-
invasive carcinoma. The incidence of MCNs does not vary ac- creatic cystic fluids {1510}.
cording to ethnic group. An MCN should be suspected whenever
ICD-O codes a cystic lesion is seen by endoscopic ul-
MCN with low- or intermediate-grade Localization trasonography (EUS), computed tomog-
dysplasia 8470/0 Most cases (> 95%) occur in the body raphy (CT) or magnetic resonance
MCN with high-grade dysplasia 8470/2 and tail of the pancreas {3239, 3578, imaging (MRI) in the pancreatic body–tail
MCN with an associated invasive 3673}. The head is only rarely involved of a young or middle-aged woman, espe-
carcinoma 8470/3 {618, 1010, 3239, 3673}. cially in the absence of a history of pan-
creatitis. The morphological features
Synonyms Clinical features revealed by radiography and EUS include
Terms that are no longer to be used: Clinical presentation depends on the size a sharply demarcated lesion with one or
mucinous cystadenoma, not otherwise of the tumour. Small tumours (< 3 cm) are more thick-walled large loculations
specified (NOS); mucinous cystadeno- usually found incidentally. Larger tumours {2366}. The cysts do not communicate
carcinoma, noninvasive; mucinous cys- may produce symptoms that are usually with the main pancreatic duct {2366}.
tadenocarcinoma, NOS. secondary to compression of adjacent Features suggestive of an associated in-
structures, and are often accompanied by vasive carcinoma include large size, an
Epidemiology a palpable abdominal mass. In rare irregular thickening of the cyst wall, mural
MCNs are relatively rare, accounting for cases, patients present with symptoms nodules and/or papillary excrescences
about 8% of surgically resected cystic le- related to cancerous invasion of the bile projecting into the cyst {362, 3458}.
sions of the pancreas {1655}. Poorly de- duct, stomach, colon, peritoneal cavity or
fined diagnostic criteria may have led to liver metastasis. Some patients present Macroscopy
over-representation of MCNs in older with new-onset diabetes mellitus {3012}. MCNs typically present as a single spher-
histopathology series, while the recent Serum tumour and cyst-fluid markers, in- ical mass with a smooth surface and a
fibrous pseudocapsule of variable thick-
ness and occasional calcifications. The
size of the tumour ranges from 2 to 35 cm
in diameter (average, 6–10 cm). On the
cut surface, the tumours are either uniloc-
ular or multilocular, with cysts ranging
from a few millimetres to several centime-
tres in diameter. The cysts contain either
thick mucin or a mixture of mucin and
haemorrhagic-necrotic material. The in-
ternal surface of unilocular tumours is
usually smooth and glistening, whereas
Fig. 12.28 MRI of a mucinous cystic neoplasm. Note the Fig. 12.29 CT of a mucinous cystic neoplasm in the tail higher-grade neoplasms often have pap-
large septated and fluid-filled mass. of the pancreas. illary projections.

Fig. 12.30 Mucinous cystic neoplasm. Gross appearance, with glistening mucin. Fig. 12.31 Mucinous cystic neoplasm with an associated invasive carcinoma (upper right).
Note that the neoplasm does not involve the pancreatic duct (arrow).
MCNs with an associated invasive carci- with a slight increase in the size of the diagnosis {3185}. It can be particularly
noma are usually large and multilocular, basally located nuclei; mitoses are absent. useful in cases in which the epithelial lin-
and the locules often contain papillary MCNs with intermediate-grade dysplasia ing is extensively denuded. In such
projections and/or mural nodules {3673}. have mild-to-moderate architectural and cases, histological examination of the en-
Associated infiltrating carcinomas may cytological atypia with papillary projec- tire lesion and scrutiny of the epithelial lin-
also infiltrate the adjacent organs. Unless tions or crypt-like invaginations, cellular ing in the smaller cysts will usually lead to
there is fistula formation, there is no com- pseudostratification caused by crowding the correct diagnosis. The stroma fre-
munication between the locules of MCNs of slightly enlarged nuclei, and occasional quently displays a variable degree of
and the pancreatic duct system {211}. mitoses. MCNs with high-grade dysplasia luteinization, characterized by the pres-
are characterized by significant architec- ence of single or clusters of epithelioid
Tumour spread and staging tural and cytological atypia, with the for- cells with round to oval nuclei and abun-
MCNs with an associated invasive ade- mation of papillae with irregular branching
nocarcinoma follow the same pathways of and budding, nuclear stratification with
local spread as invasive ductal adeno- loss of polarity, pleomorphism and promi-
carcinoma. The first metastases are typi- nent nucleoli. Mitoses are frequent and
cally found in the regional peripancreatic can be atypical.
lymph nodes and the liver. Staging follows Up to one third of MCNs have an associ-
the protocol for ductal adenocarcinoma. ated invasive carcinoma. The invasive
component can be focal, and MCNs
Histopathology therefore require careful and extensive
MCNs have two distinct components – an histological examination. The presence of
epithelial lining and an underlying ovarian- a stromal desmoplastic reaction can be
type stromal component. The cysts are useful in the differential diagnosis be-
lined by tall, columnar, mucin-producing tween invasive carcinoma and trapped
cells that stain with diastase-resistant pe- non-neoplastic glands {1270}. The inva-
riodic acid-Schiff (PAS) and Alcian blue. sive component usually resembles the A
Pseudopyloric, gastric foveolar, small- and common infiltrating ductal adenocarci-
large-intestinal, and rarely even squamous noma, forming tubular and duct-like struc-
differentiation can also be found. Atypia tures. However, other rare variants of
exhibited by the columnar cells in a single invasive carcinoma have been described,
neoplasm may vary widely from uniform including adenosquamous carcinoma,
benign-appearing to severely atypical. On undifferentiated carcinoma and undiffer-
the basis of the highest degree of archi- entiated carcinoma with osteoclast-like
tectural and cytological atypia (dysplasia), giant cells {283, 945, 2581, 3668}.
noninvasive MCNs are categorized as The distinctive ovarian-type stroma un-
MCN with low-grade dysplasia, intermedi- derlying the epithelium consists of B
ate-grade dysplasia, or high-grade dys- densely packed spindle-shaped cells Fig. 12.32 Mucinous cystic neoplasm. A Whole-mount
plasia {1270}. with round or elongated nuclei and section. Note that the cysts do not communicate with the
In MCN with low-grade dysplasia, the sparse cytoplasm. This type of stroma is pancreatic duct (arrow). B The columnar, mucin-containing
columnar epithelium has only minimal to an entity-defining feature of MCNs, and its epithelium displays low-grade dysplasia and ovarian-type
mild architectural and cytological atypia presence has become a requirement for subepithelial stroma.

SMAD4 and express MUC1 {1302, 1918,

1918}.
The subepithelial ovarian-type stroma ex-
presses smooth muscle actin (SMA),
progesterone receptors (60–90%) and es-
trogen receptors (30%) {919, 3673}.
Luteinized cells label with antibodies
to tyrosine hydroxylase, calretinin and
α-inhibin {3673, 3707}. In addition,
steroidogenic acute regulatory (STAR)
protein, 3-β-hydroxysteroid dehydroge-
nase (3βHSD) and 17-α-hydroxylase
(17αH) are occasionally expressed in
luteinized cells of the MCN, suggesting
that such cells are capable of steroidoge-
nesis {921, 1355}.
Cytopathology
Fig. 12.33 Mucinous cystic neoplasm. Note the abrupt transition from low-grade (lower left) to high-grade (upper right)
Aspirates contain varying amounts of
dysplasia.
mucin and often only few epithelial cells.
The epithelium is mucin-producing and
can have varying degrees of architectural
and cytological atypia {1270, 1756, 2648,
2948}. The neoplastic cells form sheets
and small clusters, the nuclei are usually
basally located and the cytoplasm con-
tains mucin. The degree of dysplasia in
cytological samples often underestimates
that observed histologically when the le-
sion is resected {1270}. The ovarian-type
stroma is often not present in aspirates
and, in such cases, only the nonspecific
diagnosis of mucin-producing cystic neo-
plasm can be made {1270, 2648}.
Ultrastructure
Electron microscopy reveals columnar
epithelial cells resting on a thin basement
Fig. 12.34 Mucinous cystic neoplasm with an associated invasive, tubular-type adenocarcinoma (centre).
membrane. The cells may have well-de-
veloped microvilli and mucin granules
dant clear or eosinophilic cytoplasm. Oc- {3239, 3673}, epithelial membrane anti- {65}. The ovarian-type stroma has a my-
casionally, these cells, resembling ovar- gen (EMA), CEA, and express the gastric- ofibroblastic differentiation {2952}.
ian hilar cells, can be found associated type mucin marker MUC5AC {919, 2884}
with (or present in) nerve trunks. The fre- and the pancreatic-type mucin markers Differential diagnosis
quency of stromal luteinization decreases DUPAN-2 and CA19-9. Scattered goblet- The differential diagnosis of MCN in-
as the degree of dysplasia increases like cells express the intestinal mucin cludes other cystic neoplasms of the pan-
{3668}. In large MCNs, the stroma may marker MUC2 {919, 1270, 2884}, and creas and pseudocysts. The best
become fibrotic and hypocellular, and scattered intraepithelial chromogranin A- approach to obtaining an accurate diag-
some foci have the appearance of cor- positive neuroendocrine cells express nosis is the combined evaluation of all
pora albicantia. Uncommonly, the ovar- serotonin followed by somatostatin, pan- available clinical, serological, radiological
ian-type stroma predominates over the creatic polypeptide and gastrin {1918, and morphological findings.
epithelial component, creating a solid 3239, 3673}. With increasing epithelial It is usually easy to distinguish MCNs from
mass {1117, 1792}. The adjoining pan- atypia, the mucin that is produced entities that do not have a mucin-produc-
creatic tissue may show fibrous atrophy changes from sulfated to sialated or neu- ing epithelium, i.e. serous cystic neo-
owing to obstruction of the main pancre- tral {3239} and nuclear p53 protein im- plasms, acinar cell cystadenocarcinoma,
atic duct by the tumour. munoreactivity occurs {1918, 3673}. While solid-pseudopapillary neoplasm and cys-
most noninvasive MCNs express SMAD4 tic neuroendocrine neoplasms.
Immunohistochemistry (DPC4) protein, but not MUC1, MCNs with The differential diagnosis also includes
The neoplastic epithelial cells are im- an invasive ductal adenocarcinoma com- mucinous non-neoplastic cysts, charac-
munoreactive with keratins 7, 8, 18 and 19 ponent may lose the expression of terized by the presence of mucin-produc-

ing cells without atypia. The correct diag- become activated in the setting of a hor-
nosis is established considering the equal monal imbalance, releasing hormones
prevalence in males and females, the and growth factors causing nearby ep-
more common involvement of the head of ithelium to proliferate and form cystic
the pancreas, and microscopically by the neoplasms {800, 1374, 3673}. This hypo-
lack of the ovarian-type stroma {1652, thesis could explain the predilection of
1655}. pancreatic MCNs for the body–tail region
Differentiating a pseudocyst from an MCN (which is in close proximity to the left pri-
may not only be a clinical problem but mordial gonads) {800, 3317, 3673}. Of
also a morphological one, since some course, this hypothesis cannot account A
MCNs can have significant degenerative for MCNs in males. Another possibility is
changes, including denuded epithelium that the ovarian-type stroma represents a
and haemorrhagic cyst contents. Exten- fetal primitive mesenchyme, which re-
sive sampling to identify one of the two sponds and proliferates in response to
morphological diagnostic features of an hormonal stimulation {1270}.
MCN (the mucin-producing epithelial lin-
ing or the ovarian-type stroma) is often Molecular pathology
needed {1270}. Activating point mutations in codon 12 of
The differential diagnosis with intraductal the KRAS gene have been observed in
papillary mucinous neoplasms (IPMNs) both noninvasive and invasive MCNs,
can be relatively straightforward for main with the prevalence of mutations increas- B
duct-type IPMNs, but may be difficult for ing with increasing degree of dysplasia Fig. 12.35 Mucinous cystic neoplasm, with
“branch duct-type” IPMNs. Two features {206, 1430, 1558}. Alterations of TP53, immunolabelling for progesterone receptors (A) and
distinguish these entities: MCNs do not CDKN2A (p16) and SMAD4 (DPC4) tu- α-inhibin (B).
grow significantly within the pancreatic mour-suppressor genes are more fre-
duct system and contain, by definition, an quent in cases with an associated
ovarian-type stroma {1106, 3185}. invasive component {206, 968}. Aberrant tients with an MCN with an associated in-
hypermethylation of the CDKN2A gene vasive carcinoma depends on the extent
Pathogenesis has been reported in about 15% of MCNs (depth) of the invasive component, tu-
Pancreatic MCNs share many clinico- with low- to intermediate-grade dysplasia mour stage (lymph-node and distant
pathological features with their counter- {1558}. metastasis), and resectability {3673}. The
parts in the ovary, hepatobiliary tree, Rare examples of MCNs with a sarcoma- 2-year survival rate for patients with a sur-
mesentery, retroperitoneum and with the tous stroma have been reported and mo- gically resected MCN with an associated
mixed epithelial stromal (MEST) tumour of lecular genetic analyses of these cases invasive carcinoma is about 67%, and the
the kidney {367, 2002, 2053, 2952, 3227, have revealed that the epithelial and “sar- 5-year survival rate is about 50% {618,
3320, 3673, 3711}. The possibility that the comatous” components have a clonal ori- 1270, 1771, 3508}. Recurrence of the car-
stromal component of MCNs is derived gin {3355}. These lesions are therefore cinoma and poor outcome correlate with
from ovarian primordium is supported by best categorized as undifferentiated car- invasion of the carcinoma beyond the tu-
morphology, tendency to undergo luteiniza- cinomas arising in association with MCNs mour wall and into peritumoral tissue. Pa-
tion, presence of hilar-like cells, and {3355}. tients aged > 50 years appear to have a
immunophenotypic sex cord–stromal differ- lower survival rate {3673}.
entiation. It is conceivable that ectopic Prognosis and predictive factors
ovarian stroma incorporated during em- Surgical resection is curative for almost all
bryogenesis in the pancreas, hepatobil- patients with a noninvasive MCN {618,
iary tree, retroperitoneum or kidney, may 2809, 3508, 3673}. The prognosis for pa-

Intraductal neoplasms of the pancreas N.V. Adsay

N. Fukushima
G. Klöppel
G.J.A. Offerhaus
T. Furukawa M.B. Pitman
R.H. Hruban M. Shimizu
D.S. Klimstra G. Zamboni
Introduction commonly assoicated with significant lu- The neoplastic epithelium is usually pap-
The intraductal neoplasms discussed in minal accumulation of mucin, whereas illary, and the degrees of mucin secretion,
the following section, intraductal papillary ITPNs have minimal luminal mucin and duct dilatation (cyst formation), and dys-
mucinous neoplasms (IPMNs) and intra- also commonly lack obvious intracellular plasia are variable. Noninvasive IPMNs
ductal tubulopapillary neoplasms (ITPNs; mucin; (2) most IPMNs have a predomi- are classified into three categories on
previously designated as intraductal tubu- nantly papillary histological growth pat- the basis of the highest degree of cyto-
lar neoplasms), are defined as macro- terns, whereas ITPNs are predominantly architectural atypia: low-grade dysplasia,
scopic (cystic or mass-forming) epithelial tubular in architecture; (3) grossly or his- intermediate-grade dysplasia and high-
neoplasms with ductal differentiation that tologically evident necrosis, often with a grade dysplasia {1270}. The presence of
characteristically grow primarily within the comedo-like pattern, may be found in a component of invasive carcinoma leads
ductal system of the pancreas {211, 1270, ITPNs and is not typical of IPMNs; and (4) to the designation “IPMN with an associ-
3156, 3185, 3580}. These lesions are dis- immunolabelling of MUC5AC is common ated invasive carcinoma.”
tinct from pancreatic intraepithelial neo- in IPMNs, but negative in the vast major-
plasia (PanIN), which is a microscopic ity of ITPNs {3156, 3580}. Synonyms
lesion that is not usually macroscopically An arbitrary minimal size criterion of 1 cm Before they were unified under the head-
detectable. Intraductal growth of neo- has been suggested to define this family, ing of “intraductal papillary mucinous
plasms with non-ductal directions of differ- underlining the mass-forming nature (gross neoplasms,” these neoplasms were vari-
entiation, such as acinar cell carcinomas, and radiographic detectability) of the intra- ably designated as “mucin-producing tu-
are not included in this category {1271}. ductal neoplasms and distinguishing them mour” {3578, 3588}, “mucinous duct
Both IPMNs and ITPNs form intraductal from the smaller PanINs {1271}. ectasia”, “ductectatic mucinous cystade-
masses that are radiographically and noma/cystadenocarcinoma” {3611}, “vil-
grossly detectable. These neoplasms, ICD-O codes lous adenoma” {2506} or “papillary
due to their relatively slow-growing nature, IPMN with low- or intermediate- adenoma/carcinoma” {2160} of pancre-
often achieve fairly large sizes before they grade dysplasia 8453/0 atic ducts, each term reflecting a differ-
come to clinical attention, and both IPMN with high-grade dysplasia 8453/2 ent but important facet of this entity.
IPMNs and ITPNs may be associated with IPMN with an associated invasive These designations are no longer em-
(or progress to) invasive carcinoma. While carcinoma 8453/3 ployed.
some invasive carcinomas arising within Intraductal tubulopapillary neoplasm The names given to three of the four cat-
these neoplasms are morphologically in- 8503/2 egories of IPMN have been updated
distinguishable from conventional ductal such that the nomenclature presented
adenocarcinomas, many are distinctive Intraductal papillary mucinous here parallels that used in other organs
enough to be classified as separate vari- neoplasm (IPMN) and in the fourth series of the Armed
ants of adenocarcinoma, including colloid Forces Institutes of Pathology Atlas of
carcinoma {37}. Definition Tumor Pathology {1270}. The entity previ-
Both IPMNs and ITPNs can form tubules An intraductal grossly-visible (typically ously classified as “intraductal papillary
and papillary growths. The major features ≥ 1.0 cm) epithelial neoplasm of mucin- mucinous adenoma” is now designated
that distinguish these two groups of in- producing cells, arising in the main pan- “intraductal papillary mucinous neoplasm
traductal neoplasms are: (1) IPMNs are creatic duct or its branches {1271, 3185}. with low-grade dysplasia.” “Intraductal
papillary mucinous neoplasm with mod-
erate dysplasia” has been changed to
“intraductal papillary mucinous neoplasm
with intermediate-grade dysplasia;” the
old term “borderline” used synonymously
for this group has been eliminated. “In-
traductal papillary mucinous carcinoma,
noninvasive” is now designated “intra-
ductal papillary mucinous neoplasm with
high-grade dysplasia,” and “intraductal
papillary mucinous carcinoma, invasive”
A B is now designated "intraductal papillary
Fig. 12.36 Imaging of IPMNs. A Axial CT: note the dilatation of the pancreatic duct. B Magnetic resonance mucinous neoplasm with an associated
cholangiopancreatography (MRCP): numerous branch-duct type IPMNs are highlighted. invasive carcinoma.”

Epidemiology gland are associated with obstructive di-

The incidence of IPMNs in the general latation of the entire length of the pancre-
population is poorly defined because atic duct, although not all of the dilated
most are asymptomatic. The apparent ducts are involved by the neoplasm.
rise in the reported incidence of IPMNs is IPMNs may extend to the ampulla of
mostly attributable to increased recogni- Vater, and some IPMNs extend into the
tion secondary to better characterization common bile duct {3012}.
of this entity {3255}. Another established
factor is the advancement and wide- Clinical features
spread use of imaging modalities with IPMNs are found at a broad age range
which small IPMNs are detected inciden- (30–94 years); however, they are signifi-
Fig. 12.37 IPMN involving the main pancreatic duct.
tally during the evaluation of patients for cantly more common in the elderly, with a
other conditions {3526}. median age at diagnosis of about
IPMNs are fairly common, particularly in 66 years {32, 931, 2429, 2848, 3578}. The
the elderly. Asymptomatic cysts, most of mean age of patients with IPMNs without
which were presumably small IPMNS, an associated invasive carcinoma is 3–
were identified in 2.8% of 2832 consecu- 5 years younger than the mean age of pa-
tive CT scans performed in 1 year at a tients with IPMNs with an associated
single institution {1717}. This rose to 8.7% invasive carcinoma, suggesting that pro-
in individuals of > 80 years {1717}. IPMNs gression from a noninvasive curable neo-
are currently estimated to account for 1– plasm to an invasive cancer occurs over
3% of exocrine pancreatic neoplasms, a period of years {2787, 3005}. IPMNs
and for 20% of all cystic neoplasms of the occur slightly more frequently in males
pancreas {211}, but these figures repre- than in females {1946, 2787, 3005, 3578}.
sent older surgical data, and both num- Clinical symptoms include epigastric
bers are increasing {1894, 2159, 3185}. pain, chronic pancreatitis, weight loss, di-
Two studies provide some evidence that abetes mellitus, and jaundice {1605,
the incidence may be higher among 2787, 3005, 3287, 3626}. Many cases are Fig. 12.38 IPMN, branch-duct type (arrow) involving
Asians than among whites, but issues of detected incidentally during clinical evalu- uncinate process. The probe is in the main pancreatic duct.
consistency of classification require that ation for other conditions {1717}. The inci-
these associations be further evaluated dence of synchronous and metachronous
{1604, 1894}. neoplasms of other organs appear to be
high {216, 768, 1468, 2655, 3122}. Some
Etiology patients have a history of many years of
There are no well established environ- chronic pancreatitis, suggesting that
mental etiological factors. In one series, IPMNs can be present for years before
most patients with IPMNs were cigarette they are diagnosed. Serum amylase and
smokers {920}. IPMNs have been re- lipase levels are commonly elevated.
ported in patients with Peutz-Jeghers syn- Serum tumour markers such as CEA and
drome and in patients with familial CA19-9 are generally not of value, but are
adenomatous polyposis (FAP) {1955, often elevated in patients with an associ- Fig. 12.39 Multifocal branch-duct type IPMN. Note that
3105}. Some studies have suggested that ated invasive carcinoma {3287, 3578}. the main pancreatic duct is not involved.
IPMNs may be particularly common CT, MRI and EUS are commonly used to
among the neoplasms arising in patients visualize IPMNs. IPMNs typically appear the main pancreatic duct, sometimes also
with a family history of pancreatic carci- as cystic lesions communicating with the with dilated secondary branches.
noma {407, 2571, 2930}. pancreatic duct system. By imaging, two More advanced IPMNs are more complex
distinct types of IPMN can be discerned and can have mural nodules and irregu-
Localization {1506, 1630}. Most of those detected in- larities in the duct contours, mostly re-
Although IPMNs can occur throughout the cidentally are branch-duct type IPMNs, flecting the papillary component of the
pancreas, most are located in the head of which are cystic lesions that do not affect neoplasm, and in some cases, corre-
the gland {169, 211, 588, 3012}. Branch- the main pancreatic duct, but instead in- sponding to an invasive component {930,
duct type IPMNs usually form a cystic volve the smaller, secondary pancreatic 1631}. Endoscopically, mucin extrusion
mass in the uncinate process {3611}. ducts {2512, 2787, 2848, 3005}. Branch- from the ampulla of Vater (or even the
Main-duct type IPMNs can be diffuse, in- duct type IPMNs typically arise in the minor papilla, in rare cases) is character-
volving the entire length of the main pan- head of the pancreas, in particular, in the istic, but not always present {3588}.
creatic duct {1893, 2957, 3287}. uncinate region. In contrast, symptomatic
Multicentricity, depending upon the defi- patients often have a main-duct type Macroscopy
nition thereof, is observed in up to 40% of IPMN {2787, 3123, 3185}, which are char- Proper macroscopic examination and
cases {1883, 2512, 3006}. Some main- acterized by primary involvement of the sampling is important; bisecting resected
duct IPMNs limited to the head of the main pancreatic duct with distention of pancreata along a plane created by
Intraductal neoplasms 305

Main-duct type IPMNs Small invasive carcinomas may be

In this type, the main pancreatic duct is macroscopically undetectable, and thor-
typically diffusely dilated. The duct is ough histological sampling is needed to
often filled with mucin, and is tortuous and rule out invasion.
irregular. Main duct IPMNs usually arise in Large advanced IPMNs can fistulize into
the head of the gland and progress along adjacent organs (duodenum, bile duct,
the main duct. In some cases, the entire and stomach), and neoplastic papillae
pancreas is involved. The neoplasm may may develop in these secondary sites.
even extend to involve the major and/or Whether fistuli are sufficient evidence to
minor papillae, leading in some cases to diagnose invasive carcinoma is contro-
mucin extrusion from a patulous am- versial {2252, 3072}.
pullary orifice into the duodenum {3588}.
The documentation of involvement of the Tumour spread and staging
main pancreatic duct has clinical signifi- Intraductal components of IPMNs can ex-
cance because this type is associated tend along the ductal system into the ad-
with a higher risk of high-grade dysplasia jacent pancreas, as well as into the
and invasive carcinoma. In main duct- ampulla. Occasionally, an IPMN may be
type IPMNs, the uninvolved pancreas is associated with fistulas, and the neoplas-
often pale and firm, reflecting changes of tic cells may spread along these fistula
extensive chronic obstructive pancreatitis tracks {2252, 3072}.
{1883}. IPMN with high-grade dysplasia is staged
as Tis. Since invasive carcinoma can be
Branch-duct type IPMNs small and occult, careful evaluation is
Fig. 12.40 IPMN (arrow) with an associated invasive
IPMNs of this type arise most often in the necessary before classifying a case as
carcinoma.
uncinate process {3611}. Branch-duct Tis. The adverse outcome reported in
IPMNs form multicystic, grape-like struc- some cases classified as Tis have been
placing a probe in the main pancreatic tures. The cystically dilated ducts, range at least partially attributed to sampling or
duct is the best way to define the pattern from 1 to 8–10 cm, and are filled with evaluation errors.
of ductal involvement. tenacious mucin. The cyst walls are usu- The pattern of spread of invasive carcino-
The subtypes of IPMNs recognized by im- ally thin, and they can have either a flat or mas arising in association with IPMNs is
aging studies, namely the branch-duct; papillary lining. The individual cysts may similar to that of ductal adenocarcinoma.
and main-duct types, are also identifiable be separated by intervening normal pan- Regardless of type, whether colloid or
by macroscopic examination; however, creatic parenchyma, giving the impres- ductal, invasive carcinomas arising in as-
many IPMNs involve both the main and sion of separate individual cysts on cut sociation with IPMNs often show per-
branch ducts {2512, 2787, 2848, 3005, sections. The number and size of papillae ineural invasion. The lymph nodes are the
3123, 3185}. When both are significantly vary from case to case and region to re-
involved, the neoplasms are designated gion, but grossly visible papillae are pres-
“combined” type. Since the clinical be- ent in most resected branch-duct type
haviour of combined-type IPMNs mirrors IPMNs if inspected carefully. The adjacent
that of main-duct type IPMNs, it would be pancreas is generally normal in branch-
reasonable to consider them in the pre- duct type IPMNs.
dominantly main-duct type category.
Oncocytic-type IPMNs
IPMNs with predominantly oncocytic mor-
phology, also known as intraductal onco-
cytic papillary neoplasms (IOPNs), can
have a distinctive gross appearance.
A
They typically form large (5–6 cm), tan-
brown friable nodular papillary growths in
the larger pancreatic ducts {27, 28}.
Invasive carcinoma
If present, invasive carcinoma produces
irregular, heterogeneous thickening of the
cyst walls, fibrotic foci in endoluminal
papillary-nodular vegetations, or gelati-
nous stromal masses. The latter appear- B
ance is characteristic of colloid Fig. 12.42 Gastric-type IPMN. A With low-grade dysplasia.
Fig. 12.41 IPMN within the dilated main pancreatic duct carcinoma (see Ductal adenocarcinoma B The epithelium is reminiscent of gastric foveolar
and branch ducts. variants and mixed neoplasms) {37}. epithelium.

A B
Fig. 12.43 Intestinal-type IPMN. A Pseudostratified tall columnar cells line papillae. B Note the goblet cells.
most common site of metastases and are 184, 929}. On the basis of the predomi- and is less well-characterized. Pancre-
seen in 30% of resected IPMNs with inva- nant architectural and cell differentiation atobiliary-type IPMNs typically involve the
sive carcinoma, in contrast to 75% pattern, IPMNs can be subclassified into main pancreatic duct, and form thin,
in resected conventional ductal adeno- four types: gastric, intestinal, pancreato- branching papillae with high-grade dys-
carcinomas of the pancreas without an biliary and oncocytic {28, 36, 184, 562, plasia. The neoplastic cells are cuboidal,
accompanying IPMN {492}. The liver is 929, 1270}. with round, hyperchromatic nuclei, promi-
the main site of distant metastasis. IPMNs nent nucleoli, moderately amphophilic cy-
associated with an invasive carcinoma Gastric-type IPMN toplasm, and have a less mucinous
are staged on the basis of the character- The gastric type is characteristically appearance. Some cases have overlap-
istics of the invasive component only, and found in the branch-duct IPMNs. The ep- ping features with intraductal oncocytic
the conventional staging system for duc- ithelium lining gastric IPMNs is composed papillary neoplasms, and some with in-
tal adenocarcoma is employed. of innocuous, tall columnar cells with traductal tubulopapillary neoplasms.
basally oriented nuclei and abundant
Histopathology pale mucinous cytoplasm, reminiscent of Oncocytic-type IPMN
IPMNs are characterized by the intraduc- gastric foveolar epithelium. The periph- The oncocytic type of IPMN usually has
tal proliferation of columnar mucin-pro- eral portions of the lesion often form py- complex and arborizing papillae with del-
ducing cells. The intraductal nature of loric-like glands {184}. This latter finding icate stroma. The papillae are lined by
these neoplasms can be appreciated by may be prominent in some cases and has two to five layers of cuboidal to columnar
their involvement of the branching duct been designated as “pyloric gland ade- cells with abundant eosinophilic granular
system. IPMNs lack the “ovarian-type” hy- noma” by some authors {79, 522, 2246}. cytoplasm. The nuclei are round, large,
percellular periductal stroma that charac- Generally, the gastric-type IPMN proves and fairly uniform and typically contain
terizes mucinous cystic neoplasms to have only low- or intermediate-grade single, prominent, eccentrically located
(MCNs) {3185}. dysplasia. Scattered goblet cells can be nucleoli. Goblet cells may be inter-
Architecturally, the epithelium of IPMNs seen. spersed among the oncocytic cells. The
can be flat or form papillae with fibrovas- neoplastic cells often form intraepithelial
cular cores. The papillae range from mi- Intestinal-type IPMN lumina, which are spaces about one quar-
croscopic folds of neoplastic epithelium This type is characterized by main-duct ter the size of the cells, but which merge
to grossly visible finger-like projections involvement, the formation of tall papillae to form multicell-sized punched-out
that measure up to several centimetres. lined by columnar cells with pseudostrat- spaces within the epithelium. In some
The papillae may be simple and villous- ified, cigar-shaped nuclei, and basophilic cases, these intraepithelial lumina pro-
like, or complex and branching. The le- cytoplasm with variable amount of apical duce a cribriform pattern, and in others
sion can be focal (localized), multifocal (in mucin. The overall picture is highly remi- the epithelium of adjacent papillae may
up to 40% of cases {2512}), or diffuse. In niscent of colonic villous adenomas {36}. fuse, producing a solid growth pattern
general, the leading edges of IPMNs tend Some examples are composed predomi- punctuated by small vessels. The intra-
to be relatively ill-defined, and IPMNs nantly of goblet-like cells with micropapil- ductal nature of oncocytic-type IPMNs
often extend microscopically beyond the lary features {929}. The epithelial cells in with extensive solid areas may be difficult
grossly visible mass lesion. The neoplas- intestinal-type IPMNs usually have inter- to recognize. Most oncocytic-type IPMNs
tic epithelium can extend into the smaller mediate- or high-grade dysplasia. have sufficient cytoarchitectural atypia to
pancreatic ducts, mimicking pancreatic be calssified as having high-grade dys-
intraepithelial neoplasia. Pancreatobiliary-type IPMN plasia.
The neoplastic epithelium can show a va- The pancreatobiliary type of IPMN {36} Several directions of differentiation can be
riety of directions of differentiation {36, occurs less frequently than the others, seen in an individual IPMN. In particular,

Table 12.05 Differential immunolabelling of intraductal neoplasms of the exocrine pancreas. intestinal-type IPMNs. Invasive carcino-
Histopathological type MUC1 MUC2 MUC5AC MUC6 CDX2
mas occurring in IOPNs are typically of
the tubular type, closely resembling con-
Intestinal – ++ ++ – ++ ventional ductal adenocarcinomas, but
Pancreatobiliary ++ – ++ + – displaying more oncocytic features.
IPMN The pathology report of IPMNs with an as-
Gastric – – ++ – –
sociated invasive carcinoma should
Oncocytic + – + ++ – specify the type, grade, size and stage of
ITPN + – – ++ – the invasive component {211, 1493}. All
other parameters typically documented
IPMN, intraductal papillary mucinous neoplasm; ITPN, intraductal tubulopapillary neoplasm. for invasive carcinomas, such as vascu-
– no labelling; +, may be positive; ++, usually positive lar and perineural invasion, should also
be documented.
the gastric type of epithelium can be seen by severe architectural and cytological Immunohistochemistry
in the less papillary regions of all IPMNs atypia, with the formation of irregular Ductal markers including keratins 7 and
{36}. In fact, some authors believe that the branching papillae and sometimes cribri- 19, CA19-9, B72.3, and CEA are strongly
pancreatobiliary type of IPMNs is a high- form growth. The epithelial cells lack po- expressed in most IPMNs {3214, 3215}.
grade transformation of the gastric type larity, and the nuclei are stratified, The expression of mucin glycoproteins
{184}. However, it is uncommon to find hyperchromatic, and pleomorphic. Mi- (MUCs) is useful for distinguishing the
both intestinal and pancreatobiliary ep- toses are frequently found, and can even morphological subtypes {28, 35, 36, 929,
ithelium within the same IPMN {929, be found near the luminal surface. 3645, 3646}. Gastric-type IPMNs label for
1270}. MUC5AC, but not MUC1 or MUC2 (with
Associated invasive carcinoma the exception of scattered goblet cells
Degree of dysplasia Approximately 30% of resected IPMNs highlighted by MUC2). The intestinal-type
Noninvasive IPMNs are classified as hav- have an associated invasive carcinoma, IPMNs consistently label diffusely and
ing low-grade, intermediate-grade, or which can be unifocal or multifocal. This strongly for intestinal-differentiation mark-
high-grade dysplasia on the basis of the figure is decreasing with the increased di- ers, MUC2 and CDX2 {36}, in addition to
highest degree of architectural and cyto- agnosis of earlier, incidental lesions. Most MUC5AC, but not MUC1. In contrast, the
logical atypia (dysplasia) identified invasive carcinomas arise in association pancreatobiliary-type IPMNs express
{1270}. IPMNs with low-grade dysplasia with main-duct type IPMNs with high- MUC5AC and MUC1 but not MUC2 or
are characterized by a single layer of grade dysplasia {2786, 2787, 3123, 3199, CDX2 {36, 184, 929, 1352, 2212}. IPMNs
well-polarized cells, small and uniform nu- 3222}. Two distinct types of invasive car- with oncocytic differentiation diffusely
clei with only mild pleomorphism, and cinoma can be seen. Invasive colloid car- label with antibodies to mitochondrial el-
rare mitoses. IPMNs with intermediate- cinoma usually arises in association with ements, such as 111.3, and express
grade dysplasia have nuclear stratifica- intestinal-type IPMNs {37, 2868}. Tubular MUC6 and MUC5AC (focal) {28}. Most
tion, crowding, and loss of polarity. The (conventional ductal) adenocarcinoma, IPMNs with onocytic differentiation are
nuclei are enlarged and moderately hy- which is morphologically similar to usual negative for MUC2 and CDX2. MUC6, the
perchromatic. The papillae maintain iden- ductal adenocarcinoma not arising in as- pyloric-type mucin, is consistently ex-
tifiable stromal cores. IPMNs with sociation with an IPMN, arises in associa- pressed in the pyloric-type glands that
high-grade dysplasia are characterized tion with either pancreatobiliary-type or can occur in low-grade dysplasia and
Fig. 12.44 Intestinal-type IPMN, with progression of intermediate-grade dysplasia (left) to Fig. 12.45 Pancreatobiliary-type IPMN, with high-grade dysplasia.
high-grade dysplasia (centre right).

cystic components of any subtype of with oncocytic differentiation is reflected

IPMNs; however, it is mostly confined to in the cytoplasm of the aspirated cells.
pancreatobiliary-type IPMNs, and is not The presence of small clusters of atypical
detected in intestinal or gastric types epithelial cells with irregular nuclei and a
{212}. high nucleus-to-cytoplasm ratio, with or
Epidermal growth factor receptor (EGFR) without visible cytoplasmic mucin, corre-
is expressed relatively frequently in lates with an increased risk of malignancy,
IPMNs, especially in those with high- even when these clusters are very few in
grade dysplasia {3631}. ERBB2 is com- number {2060, 2558, 2917}. A diagnosis
monly overexpressed in IPMNs {665, of malignancy is rendered with sufficient
2827, 2886}. The Ki67 labelling index is quality and quantity of an atypical epithe-
associated with grade of dysplasia in lial component, generally composed of Fig. 12.46 Oncocytic-type IPMN, with high-grade dysplasia.
IPMNs, being higher in IPMNs with a more crowded groups of cells with parachro-
significant degree of dysplasia {1363, matin clearing, irregular nuclear mem-
1432, 3214}. Loss of expression of branes and nucleoli {1859, 2060, 2700}. MCNs are located in the tail or body of the
CDKN2A increases in frequency from Whether the malignant cells represent pancreas. The vast majority of MCNs do
IPMNs with low-grade dysplasia to those high-grade dysplasia or invasive carci- not communicate with the pancreatic duct
with high-grade dysplasia {254, 928}. Ab- noma is often difficult to determine. The system. MCNs contain a cellular “ovarian-
normal labelling with antibodies to p53 association of such cells with abundant type” stroma that expresses hormone re-
has been observed in a small fraction (5– acute inflammation or necrosis suggests ceptors by immunohistochemistry. In
19%) of IPMNs with high-grade dysplasia, an associated invasive carcinoma {2060}. contrast, IPMNs occur in men slightly
but not in those with low-grade dysplasia more often than women, in a slightly older
{928, 1503}. Expression of SMAD4 Ultrastructure age group, involving the head of the
(DPC4) is preserved in most IPMNs with IPMN has no specific ultrastructural fea- gland more frequently than the tail, always
any grade of dysplasia; this contrasts with tures {2160}. The neoplastic cells lie on a communicating with the duct system, and
the high frequency of loss of expression basement membrane and have numerous do not have ovarian-type stroma.
in high-grade pancreatic intraepithelial microvilli on the apical surface, a number Macrocystic serous cystadenomas. Macro
neoplasia and in infiltrating ductal adeno- of mitochondria, a well-developed rough (oligocystic) serous cystic neoplasms
carcinoma {254, 928, 1301}. endoplasmic reticulum and Golgi appa- {211} form larger and less defined cysts
ratus. Mucin droplets of variable size and than the more common microcystic
Cytopathology electron density are present {2160}. On- serous cystic neoplasms; they may thus
On cytological preparations, the findings cocytic-type IPMNs contain numerous mi- resemble branch-duct IPMNs. However,
for IPMNs and MCNs are nearly identical, tochondria that exclude other organelles. the epithelial cells of macrocystic serous
and the generic cytological diagnosis of cystic neoplasms are cuboidal and have
“mucinous cyst” is often used to refer to Differential diagnosis glycogen-rich clear cytoplasm, with no
cytological findings consistent with either The differential diagnosis for larger IPMNs mucin and no significant nuclear atypia.
of these neoplasms. Cyst fluid aspirated includes other macrocystic (oligocystic) PanIN. PanINs should be distinguished
from an IPMN can contain highly variable lesions, in particular, MCNs and macro- from small IPMNs. Most PanINs are
amounts of extracellular mucin and neo- cystic serous cystadenomas {211}. The < 0.5 cm in greatest ductal diameter,
plastic epithelium {197, 788, 906, 1769, differential for small IPMNs primarily in- whereas IPMNs are defined to be grossly
2060, 2558, 2648, 3015, 3074}. In many cludes PanIN and retention cysts {35, detectable cystic lesions that typically
cases, the aspirate is composed only of 1271}. measure ≥ 1.0 cm {1271}. Lesions meas-
mucinous material, without a cellular com- MCN. MCNs can closely mimic branch- uring 0.5–1.0 cm with mucinous epithe-
ponent. Thus, if gastrointestinal contami- duct type IPMNs {211, 3185}. MCNs typ- lium are intermediate-grade lesions.
nation can be ruled out, the presence of ically occur in women with a median age PanINs tend to have short stubby papil-
mucin may be the only manifestation that in the fifth decade of life, and almost all lae, while IPMNs often have long finger-
the lesion is in fact a “mucinous cyst.” In
such cases, the imaging findings, stains
for mucin, and elevated levels of CEA in
the cyst fluid {1204}, with or without ele-
vated levels of exocrine enzymes, may be
needed to verify the diagnosis of IPMN.
As IPMNs connect with the duct system, it
has been suggested that cytology of the
pancreatic juice may also be useful
{1186}.
Owing to sampling phenomena, cytology
tends to underestimate the highest histo- Fig. 12.47 A Intestinal-type IPMN, with an invasive colloid carcinoma. Immunolabelling for MUC2 labels both components.
logical grade of dysplasia {211, 2060, B Pancreatobiliary-type IPMN, with high-grade dysplasia. Immunolabelling for MUC1 reveals a cell-surface pattern of
2558}. The oncocytic nature of IPMNs expression.

Molecular pathology
Activating point mutations in codon 12 of
the KRAS oncogene have been reported
in 30–80% of IPMNs, and the prevalence
of these mutations increases with in-
creasing degree of dysplasia {2852,
3333}. Heterogeneous mutations in KRAS
have been identified in multicentric
IPMNs, helping to establish these lesions
as polyclonal {353, 1580}. KRAS muta-
tions have not been reported in IPMNs
Fig. 12.48 Fine-needle aspiration cytology of IPMN (Papanicolaou stain). A Thick extracellular mucin is typical. B The
presence of parachromatin clearing, irregular nuclear membranes and nucelar-size variation correlates with high-grade with oncocytic differentiation {562}.
dysplasia. PIK3CA gene mutations occur in about
10% of IPMNs, which is in contrast to pan-
creatic ductal adenocarcinoma, in which
like papillae. The presence of abundant mucin spillage into the stroma that pre- no mutations in PIK3CA have so far been
luminal mucin and the expression of sumably occurs owing to rupture of in- found {1818, 2853}. Mutations in the
MUC2 suggests a diagnosis of IPMN {35, volved distended duct can mimic an BRAF gene are found in a small fraction
1271}. However, there is histological over- invasive colloid carcinoma. Mucin of IPMNs {2852}. Allelic losses involving
lap, and the distinction between these two spillage is characterized by stromal dis- loci of tumour-suppressor genes, includ-
lesions can be nearly impossible in cases section by acellular mucin and is usually ing CDKN2A, TP53, and SMAD4, are
measuring between 0.5 and 1.0 cm. associated with a brisk inflammatory re- found in up to 40% of IPMNs, and these
Retention cysts. These are usually uniloc- action. In contrast, the stromal mucin of losses increase with increasing degree of
ular and are lined by a flat single layer of invasive carcinoma contains neoplastic dysplasia {4, 908, 3424}. Although muta-
ductal epithelium without nuclear atypia. cells and is usually not associated with in- tions in CDKN2A are not common,
Mucinous cytoplasm is typically lacking, tense inflammation; however, any mucin methylation of the CDKN2A promoter, re-
although retention cysts can be focally in- in the stroma should be evaluated care- sulting in loss of expression, is more fre-
volved by PanIN {1652}. fully as being suspicious for invasion. quently found in IPMNs {2176, 2823}.
ITPN. ITPNs may resemble IPMNs of the Similarly, IPMN extending along branch TP53 gene mutations have been reported
pancreatobiliary type {1646, 3157, 3580}. ducts or tributary ductules may create the in IPMNs with high-grade dysplasia {465,
IPMNs are distinguished by more com- impression of early invasion. The lobular 2176}. Despite the high frequency of al-
plex papillary architecture, fewer tubular architecture, smooth contours of the units, lelic loss involving the SMAD4 locus, mu-
structures, and evident intracellular and morphological similarity to the larger tations in the SMAD4 gene are rare, and
mucin. The similarities between pancre- lesion are the main features that help dis- expression of the SMAD4/DPC4 protein
atobiliary variant of IPMN and intraductal tinguish this pattern of growth from inva- is preserved in most noninvasive IPMNs
tubulopapillary neoplasms include ex- sive carcinoma. {1301, 1330}.
pression of MUC6 {212}.
Acinar cell carcinoma. Some acinar cell Genetic susceptibility Prognosis and predictive factors
carcinomas have a prominent intraductal Some patients with a strong family history It is generally agreed that all main-duct
pattern of growth and contain papilla, and of pancreatic cancer develop an IPMN, IPMNs should be surgically resected be-
can resemble IPMNs {213}. The cells of suggesting that IPMNs may be part of a cause of the significant risk of high-grade
these carcinomas contain abundant api- genetic susceptibility syndrome {4, 407}. dysplasia or an invasive carcinoma {2786,
cal, acidophilic zymogen granules, and Although the gene in most cases is not 2787, 3123, 3185, 3199, 3222}. Branch-
immunolabelling reveals the expression of known, IPMNs have been reported in in- duct IPMNs are less likely to harbour
pancreatic exocrine enzymes {213, dividuals with the Peutz-Jeghers syn- high-grade dysplasia or an associated in-
3254}. drome, and genetic analyses have vasive carcinoma {2512, 2786, 2787,
Oncocytic variants. The differential diag- revealed biallelic inactivation of the 2848, 3005, 3123, 3199, 3222}. Interna-
nosis of rare solid examples of oncocytic- STK11 gene in these neoplasms, sug- tional consensus guidelines defining the
type IPMN include occasional oncocytic gesting a causal link between Peutz- indications for the surgical resection of
variants of pancreatic neoplasms, such Jeghers and IPMNs {2822}. Also, branch-duct IPMNs were published by
as oncocytic neuroendocrine neoplasms, excessive rates of synchronous and the International Association of Pancre-
and rare oncocytic solid-pseudopapillary metachronous gastric and colonic ep- atology {3185}. These guidelines recom-
neoplasms; however, careful sampling al- ithelial neoplasms have been reported in mend that patients with symptoms related
lows for the recognition of the character- patients with IPMNs {216, 768, 1468, to their IPMN, those with main-duct di-
istic features of the respective entities in 2655, 3122}. This finding suggests the latation, and those with a branch-duct
each case. possibility of genetic predisposition, but IPMNs of > 30 mm or with a mural nodule
Pseudoinvasion. The distinction between no specific hereditary syndrome linking should undergo resection. Smaller
an invasive carcinoma arising in associa- IPMNs with other cancers has been es- branch-duct IPMNs without these features
tion with an IPMN and pseudoinvasion is tablished. can be followed using imaging such as
critically important. In particular, benign CT and MRI {3185}. These criteria have

A B
Fig. 12.49 Intestinal-type IPMN with associated invasive colloid carcinoma. A The IPMN is indicated by an arrow. B The IPMN contains high-grade dysplasia (top left) adjacent to the
invasive colloid carcinoma (bottom right).
recently been validated in several retro- gest that careful clinical follow-up is war- are designated “intraductal tubulopapil-
spective and prospective studies {1779, ranted following the surgical resection of lary neoplasm with an associated invasive
2512, 2704, 2771, 2848, 3124, 3185, a noninvasive IPMN, even if the margins carcinoma”.
3199}. That most IPMNs occur in older are not involved {3497}. It should be kept
age groups with several comorbities is a in mind that invasive carcinoma may de- Epidemiology
major confounding factor in the manage- velop in parts of the pancreas grossly Intraductal tubulopapillary neoplasms
ment of these patients. separate from the main IPMN {3587}. (ITPNs) are rare neoplasms accounting for
Another subclassification of IPMNs with The prognosis for IPMNs with an associ- < 1% of all pancreatic exocrine neoplasms
some predictive value for clinical outcome ated invasive carcinoma is significantly and only 3% of intraductal neoplasms of
is based on the phenotype of the neo- worse than for noninvasive IPMNs; the 5- the pancreas {3580}. Although data on this
plastic cells {36, 1352}. Gastric-type year survival rates for IPMNs with an as- entity are still limited, ITPNs occur equally
IPMNs are often noninvasive lesions, and sociated invasive carcinoma are reported frequently in males and females. The age
most reveal low-grade dysplasia. Most to be between 27% and 60%, depending range of reported cases has been be-
branch-duct IPMNs are of this type. In upon the extent and histological type of tween 35 and 84 years, with a mean age of
contrast, intestinal-type IPMNs tend to be the invasive component {492, 816, 1579, 56 years.
large, often of the main-duct type, and 1723, 2787, 2848, 2940, 3005, 3497}. Pa-
commonly harbour high-grade dysplastic tients with a colloid (mucinous noncystic) Clinical features
changes. Invasive carcinomas arising type of invasive carcinoma have a better Patients present with nonspecific symp-
from this type are more commonly colloid prognosis than do those with a ductal toms including abdominal pain, vomiting,
carcinomas. Pancreatobiliary-type IPMN, (tubular) type of invasive cancer {36, weight loss, steatorrhea, and diabetes
the least common type, tends to have 2575B}. Those with invasion of < 5 mm mellitus. Obstructive jaundice is uncom-
high-grade dysplasia, and invasive carci- have an excellent prognosis {2252}, mon. Some patients are asymptomatic,
nomas associated with this phenotype whereas the prognosis for advanced- and their neoplasms are detected inci-
are usually of tubular type. stage invasive carcinomas arising in as- dentally during the clinical evaluation for
The main determinant of outcome for sur- sociation with IPMNs (i.e. with metastasis other conditions. Laboratory tests, in-
gically resected IPMNs is the presence or to the lymph nodes or other sites) is as cluding those for cancer antigens in the
absence of an associated invasive carci- poor as for invasive ductal adenocarci- blood, are nonspecific. Imaging studies,
noma. IPMNs without an associated inva- noma {2252, 2848, 2757B}.
sive component are often curable; the
5-year survival rate for patients with re-
sected noninvasive IPMNs is 90–95% Intraductal tubulopapillary
{492, 3005}. While some of the mortality neoplasm (ITPN)
in this group represents deaths from other
causes and the presence of residual neo- Definition
plasm at a margin {3287, 3497}, the ob- An intraductal, grossly visible, tubule-
servation that patients with noninvasive forming epithelial neoplasm with high-
IPMNs who undergo a total pancreatec- grade dysplasia and ductal differentiation
tomy have a nearly 100% survival rate without overt production of mucin {1597,
suggests that metachronous multifocal 3112, 3156, 3580}. Focal tubulopapillary
disease remains a significant risk for growth may be seen. If there is a compo- Fig. 12.50 ITPN, gross appearance. Note the polypoid
these patients. Certainly, these data sug- nent of invasive carcinoma, the lesions component within the main pancreatic duct (arrow).

A B
Fig. 12.51 ITPN with high-grade dysplasia. A The duct is completely filled by the tubule-forming neoplasm. B Note the back-to-back glands.
particularly CT, endoscopic ultrasonogra- high-grade dysplasia. Each neoplastic Immunohistochemistry

phy and endoscopic retrograde cholan- nodule consists of tightly packed small The immunohistochemical labelling pro-
giopancreatography (ERCP), may be acinar glands lined by predominantly file of ITPNs confirms their ductal nature.
helpful in demonstrating the intraductal lo- cuboidal cells with modest amounts of The neoplastic cells commonly label for
cation of the lesion. Preoperatively, most eosinophilic to amphophilic cytoplasm. In keratins 7 and 19, in addition to display-
ITPNs are indistinguishable from IPMNs. some cases, apocrine snout-like forma- ing consistent positivity for pankeratins.
About half of ITPNs occur in the head of tions are noted in the apical surface of the Labelling for the acinar marker, trypsin,
the pancreas; a third diffusely involve the cells. Intraluminal secretions may be and endocrine markers chromogranin
gland, and 15% are localized to the tail. seen. Cases with more papillary growth and synaptophysin, is negative. Mucin-
also tend to be complex {1646, 3580}. related glycoproteins are typically ex-
Macroscopy The nuclei are round to oval and moder- pressed at lower levels than in mucinous
Grossly, ITPNs form solid, nodular ately to markedly atypical. Mitotic figures ductal neoplasms: CA19-9 is commonly
masses within dilated pancreatic ducts are often readily identifiable (range, 0–9 detected but only as a focal finding.
{1209, 1597, 3112, 3580}. The nodules per 10 high power fields) {3580}. Some B72.3, CEA and CA125/MUC16 are de-
are large (up to 9 cm), dense and fleshy cases contain foci of necrosis or desmo- tected in less than half of cases and typ-
to rubbery. Cyst formation is often less ev- plastic stroma within the intraductal, poly- ically as a very focal finding. Neither
ident than in IPMNs. Mucinous secretions poid neoplastic nodules. Occasionally, a MUC5AC, which is a consistent marker
are not present in the dilated ducts of comedocarcinoma-like pattern is noted. of IPMNs regardless of type, nor MUC2,
ITPNs. The intraductal location of the tu- In general, cyst formation is less promi- which is expressed in intestinal-type
mour can usually be confirmed by a care- nent than in IPMNs. IPMNs, are expressed in ITPNs. MUC1 is
ful dissection of the ductal system. The ITPNs typically have a relatively homoge- expressed in 90% and MUC6 in 60% of
average ITPN is 6 cm in diameter (range, neous appearance, and there are no tran- ITPNs. The expression of SMAD4/DPC4
0.8–15.0 cm). The surrounding pancreatic sitions to areas with less marked is retained in most cases. Immunohisto-
tissue is usually densely sclerotic. cytoarchitectural atypia, or to IPMNs chemical expression of p53 and
{3156, 3157, 3580}. CDKN2A/p16 are detected in 20% and
Histopathology Invasive carcinoma is found in associa- 54% of cases, respectively. The Ki67 la-
ITPNs form nodules of back-to-back tu- tion with about 40% of cases and the in- belling index varies from case to case
bular glands with occasional papillary el- vasive component is usually limited in (range, 6–43%). β-Catenin nuclear ex-
ements, resulting in large cribriformed extent {1597, 3112, 3580}. Because pression and loss of E-cadherin expres-
structures within dilated pancreatic ducts many of the individual neoplastic nodules sion are reported in < 10% of ITPNs.
{1597, 3156, 3580}. Mucin is typically not lack a peripheral rim of non-neoplastic
detectable, or, is minimal at most. While ductal epithelium, it can be difficult Cytopathology
most ITPNs are predominantly or exclu- to recognize invasive carcinoma. Thin There have been no systematic analyses
sively tubular, papillae may be present in strands of cells extending into the stroma of cyst fluid in patients with ITPN. In a
some {3580}. Solid areas with abortive surrounding the circumscribed neoplas- case report {155}, prominent tubular
glandular arrangements may also be tic nodules represent invasive carcinoma. growth was documented in cytological
seen. Some of the neoplastic nodules The cytological appearance of the inva- smears from an endoscopic ultrasound-
obliterate the ductal lumen, appearing as sive elements is similar to that of the in- guided biopsy of an ITPN.
sharply circumscribed nests of cells sur- traductal portion, and typically exhibits a
rounded by fibrotic stroma. ITPNs are ar- tubular pattern.
chitecturally complex and typically have

Differential diagnosis It has been suggested that some ITPNs beyond 5 years is noted in more than a
On clinical grounds, the main differential have a predominantly papillary growth third of the patients reported {1597}. Re-
diagnosis of ITPNs is with IPMNs. Both pattern, an area that deserves further currence and metastasis to lymph nodes
may present with intraductal lesions study {3580}. or to the liver are reported in about a third
showing solid and cystic areas. ITPNs ap- On histological sections, more tubular ex- of cases, and even these patients some-
pear to occur in younger patients (aver- amples of ITPN can be difficult to distin- times experience a protracted clinical
age age is a decade younger than that of guish from acinar cell carcinomas, which course over > 2 years, which would be
patients with IPMNs). The presence of co- may also grow intraductally {213}. In con- unusual for conventional ductal adeno-
pious mucin is characteristic of IPMN, trast with ITPNs, acinar cell carcinomas carcinoma. In one study {1597}, no sig-
and prominent cystic change is also more often have apical acidophilic granules, nificant correlation between invasion and
common in IPMNs. On microscopic ex- which can be highlighted by PAS stain, survival was identified, which was attrib-
amination, IPMNs of gastric and intestinal and occasionally display intraluminal uted to the microscopic nature of the in-
types are easy to distinguish from ITPNs crystals (enzymatic concretions). Im- vasion detected in most cases, and also
by their mucinous nature in parallel with munohistochemical labelling for markers partly to the fact that inadequate sam-
their MUC-immunolabelling profile show- of pancreatic exocrine enzymes, such as pling may have missed small foci of inva-
ing MUC5AC and MUC2 expression, re- chymotrypsin, may be crucial in this dif- sion in the neoplasms classified as
spectively, as well as the presence of a ferential diagnosis. noninvasive. We recommend that the in-
spectrum of neoplastic changes that con- vasive carcinomas associated with these
trast with the more uniform appearance of Prognosis and predictive factors neoplasms be reported and staged sep-
ITPNs. Some pancreatobiliary-type The limited data in the literature regarding arately, as is done for IPMNs.
IPMNs may be difficult to distinguish from the prognosis for patients with ITPNs sug-
ITPNs. Significant amounts of mucin, the gest that these neoplasms are relatively
presence of a component with low-grade indolent neoplasms, with a prognosis that
dysplasia, and the expression of is significantly better than that of infiltrat-
MUC5AC would all favour a diagnosis of ing ductal adenocarcinoma of the pan-
pancreatobiliary-type IPMN. creas {1597, 3112, 3156, 3580}. Survival

D.S. Klimstra
Acinar cell neoplasms of the pancreas R.H. Hruban
G. Klöppel
T. Morohoshi
N. Ohike
Introduction diographic imaging in asymptomatic pa-

Acinar cell neoplasms are epithelial neo- tients {3674}. Incidental cases are identi-
plasms defined by their morphological re- fied only microscopically in pancreata
semblance to acinar cells and the removed for other reasons.
production of pancreatic exocrine en-
zymes. Most are solid malignant neo- Macroscopy
plasms (acinar cell carcinoma). A rare Clinically recognized acinar cell cystade-
benign cystic lesion (acinar cell cystadenomas range from 1.5 to 10.0 cm in diam-
noma) and rare malignant cystic (acinar eter (mean, 6 cm) and form unilocular or
cell cystadenocarcinoma) and mixed car- multilocular cystic masses that are usually
cinomas (mixed acinar-neuroendocrine grossly circumscribed {64, 496, 3674}. In-
Fig. 12.52 CT scan of an acinar cell cystadenoma.
carcinoma, mixed acinar-ductal carci- dividual cysts range from 1 mm to several
noma, and mixed acinar-neuroendocrine- cm. The cysts contain watery fluid and
ductal carcinoma) also exist. have a smooth lining. Communication with
the ductal system of the pancreas is rare.
ICD-O codes Some cases are multicentric and others dif-
Acinar cell cystadenoma 8551/0 fusely involve the entire gland, with islands
Acinar cell carcinoma 8550/3 of parenchyma between the cysts. Inci-
Acinar cell cystadenocarcinoma 8551/3 dentally detected acinar cell cystadeno-
Mixed acinar-neuroendocrine mas are usually < 1.0 cm and unilocular,
carcinoma 8154/3 and some are not apparent grossly.
Mixed acinar-neuroendocrine-ductal
carcinoma 8154/3 Histopathology
Mixed acinar-ductal carcinoma 8552/3 Acinar cell cystadenomas produce vari- Fig. 12.53 Acinar cell cystadenoma involving the entire
ably sized cysts; some are little more than length of the pancreas.
slightly dilated acinar-like spaces, whereas
Acinar cell cystadenoma others are more substantial. Most of the
cysts are lined by well-differentiated cells
Definition with acinar differentiation, either in a sin-
Acinar cell cystadenoma is a benign cys- gle layer or forming small clusters of cells
tic epithelial lesion lined by cells with mor- surrounding the lumen {64, 496, 3674}.
phological resemblance to acinar cells Residual pancreatic elements are present
and with evidence of pancreatic exocrine between the larger cysts, and some of the
enzyme production. adjacent acini may be dilated. The le-
sional cells have basally situated, uniform
Epidemiology nuclei, apical granular eosinophilic cyto-
The lesion is too rare to establish plasm, and basal cytoplasmic basophilia,
epidemiological associations. resembling non-neoplastic acinar cells. In
some cases, the cysts are partially lined Fig. 12.54 Acinar cell cystadenoma. In contrast to Fig.
Localization by cuboidal cells that lack cytoplasmic 12.50, this lesion is localized.
Acinar cell cystadenomas may involve granules and that instead resemble nor-
any portion of the pancreas, but are more mal ductal epithelium. Incidental micro- cells stain with periodic acid–Schiff and
common in the head, and some involve scopic cases may consist of a single cyst are resistant to diastase. Staining for
the entire gland {3674}. lined by cells with acinar differentiation. mucins is negative.
Transitions to ductal epithelium including
Clinical features cells with columnar, mucinous cytoplasm Immunohistochemistry
Cases are divided into two categories: (low-grade pancreatic intraepithelial Acinar cell cystadenomas express pan-
clinically recognized macroscopic lesions neoplasia, PanIN) may be found. The creatic exocrine enzymes, including
and incidental microscopic findings. Clin- cyst lumina may contain inspissated trypsin, chymotrypsin, and lipase {64,
ically recognized cases may present with eosinophilic enzymatic secretions. The 496, 3674}. Most cases show diffuse la-
abdominal pain or, in one case, poly- surrounding pancreatic parenchyma is belling of the lesional cells and the luminal
arthralgia, or they may be detected by ra- typically fibrotic and atrophic. The lining secretions, although some with a greater

A B C
Fig. 12.55 Acinar cell cystadenoma. A Small acinar cell cystadenoma. B Cystic structures are lined by acinar cells. C The lesion displays granular labelling for trypsin.
proportion of duct-like cells only label fo- acinar-neuroendocrine carcinoma, mixed including subcutaneous fat necrosis
cally. Keratins (e.g. keratin 8 and 18) are acinar-ductal carcinoma, or mixed acinar- and polyarthralgia. Peripheral blood
also expressed {3674}. neuroendocrine-ductal carcinoma) {1270, eosinophilia may also be noted. In some
3070, 3073}. Rare cases with macro- patients, lipase hypersecretion syndrome
Differential diagnosis scopic, nondegenerative cyst formation is the first presenting sign of the carci-
Small, incidental acinar cell cystadeno- have been reported as acinar cell cys- noma, while in others it develops after tu-
mas can resemble PanINs. Recognition of tadenocarcinoma {408, 583, 1235, 1376, mour recurrence. Successful surgical
the granular eosinophilic cytoplasm and 3054}. removal of the neoplasm may result in the
the absence of mucin help confirm the di- normalization of the serum lipase levels
agnosis of acinar cell cystadenoma. Epidemiology and resolution of the symptoms. Other
Larger acinar cell cystadenomas can be Acinar cell carcinomas represent 1–2% of than an elevation of serum lipase levels
confused with serous cystic neoplasms, all exocrine pancreatic neoplasms in associated with the lipase hypersecretion
squamoid cyst of pancreatic ducts, or adults {1235, 1598} and 15% of those in syndrome, there are no specific labora-
mucinous cystic neoplasms (MCNs). children {1227, 1235, 1598}. Most occur tory abnormalities in patients with acinar
Again, recognition of acinar differentiation in late adulthood, with a mean age of 58 cell carcinoma. Serum α-fetoprotein lev-
is very helpful. Acinar cell cystadenomas years (range, 10–87 years) {1376, 1682, els are elevated in some patients {1365,
lack the clear cells of serous cystic neo- 3474}. Paediatric cases account for only 2313, 2403, 2949}.
plasms, the squamous differentiation of 6% of acinar cell carcinomas, usually in
squamoid cysts, and the mucinous cells patients of 8–15 years of age {1682, Imaging
and ovarian-type stroma of MCNs {2414}. 2161}. Males are affected more frequently Radiographically, acinar cell carcinomas
than females, with a male-to-female ratio are generally bulky, with a mean size of
Prognosis and predictive factors of 3.6 : 1 {1235, 1598}. There are no 11 cm, and cases of < 2 cm are rare
All acinar cell cystadenomas reported to known racial associations. {1682}. On abdominal computed tomog-
date have been clinically benign, and raphy (CT) scans, they are circumscribed
there is no evidence of malignant transfor- Localization and enhance homogeneously, although
mation or association with acinar cell car- Acinar cell carcinomas may arise in any less than the surrounding pancreas
cinoma {64, 496, 3674}. In fact, some portion of the pancreas, but are some- {3205}. Cystic change attributable to
authorities have questioned the neoplastic what more common in the head. necrosis can occur. Owing to their larger
nature of acinar cell cystadenoma, espe- size and relatively sharp circumscription,
cially of the incidental microscopic exam- Clinical features acinar cell carcinomas can generally be
ples. Cases involving the entire pancreas Most acinar cell carcinomas present with distinguished from ductal adenocarcino-
present a management dilemma, given the nonspecific symptoms including abdom- mas radiographically.
radical nature of the operation necessary inal or back pain, weight loss, nausea, or
to completely remove the lesion. diarrhoea {1235, 1598, 1682, 2001, Macroscopy
3474}. Since they generally compress Acinar cell carcinomas are generally
rather than infiltrate into adjacent struc- softer and more circumscribed than duc-
Acinar cell carcinoma tures, biliary obstruction and jaundice are tal adenocarcinomas. They may be
infrequent presenting complaints. multinodular {1235, 1598}. Individual nod-
Definition ules are soft and vary from yellow to
Acinar cell carcinoma is a malignant ep- Hypersecretion syndrome brown. Areas of necrosis and cystic de-
ithelial neoplasm composed of cells with The lipase hypersecretion syndrome oc- generation may be present. Extension into
morphological resemblance to acinar curs in 10–15% of patients {377, 1598, adjacent structures, such as duodenum,
cells and with evidence of pancreatic ex- 1673, 3012}. It is more commonly en- spleen, or major vessels may occur.
ocrine enzyme production. Cases with countered in patients with hepatic metas- Some acinar cell carcinomas grossly in-
significant endocrine or ductal compo- tases and is caused by the release into volve the ductal system, with polypoid
nents (i.e. > 25% of the neoplasm) are re- the serum of excessive amounts of lipase nodules projecting into dilated pancreatic
garded as mixed carcinomas (mixed by the neoplasm, with clinical symptoms ducts {213, 810, 3254}.
Acinar cell neoplasms 315

mina. The cytoplasm varies from am-

phophilic to eosinophilic and is charac-
teristically finely granular, reflecting the
presence of zymogen granules (although
only minimal cytoplasmic granularity may
be detectable in many cases). The nuclei
are generally round to oval and relatively
uniform, with marked nuclear pleomor-
phism being exceptional {1595, 2518}. A
A B single, prominent, central nucleolus is
characteristic but not invariably present.
Fig. 12.56 Acinar cell carcinoma. A CT of an acinar cell carcinoma in the head of the pancreas. B Acinar cell carcinoma
in the tail of the pancreas. The mitotic rate ranges from 0 to more
than 50 per 10 high power fields (mean,
14 per 10 high power fields).
Tumour spread and staging Within these nests, cellular polarization is Zymogen granules are weakly positive
Metastases are found in half of patients at generally not evident, but there may be an with PAS staining, and resistant to dia-
presentation and another 25% develop accentuation of polarization at the inter- stase. Mucin production is generally not
them following surgical resection of the face with the vessels, resulting in basal detectable with mucicarmine or Alcian
primary carcinoma {1598}. Most com- nuclear localization in these regions and a blue stains and, if present, is limited to the
monly metastases involve regional lymph palisading of nuclei along the microvas- luminal membrane in acinar or glandular
nodes and the liver, although metastatic culature. In rare instances, a trabecular formations. Owing to the scarcity of zy-
spread to other organs occurs occasion- arrangement of neoplastic cells may be mogen granules in many examples of aci-
ally, and some patients present with dis- present, with exceptional cases also nar cell carcinoma, histochemical stains
tant metastases as the first manifestation showing a gyriform appearance {1598}. are relatively insensitive for documenting
of the disease {3348}. Acinar cell carci- Recently, intraductal and papillary vari- acinar differentiation, and very focal stain-
nomas are staged using the same proto- ants of acinar cell carcinoma have been ing may be difficult to interpret.
col as ductal adenocarcinomas. reported {213, 810, 3254}. These neo-
plasms are composed of polypoid Immunohistochemistry
Histopathology growths of neoplastic cells histologically Immunohistochemical detection of the
Acinar cell carcinomas are highly cellular, similar to conventional acinar cell carci- production of pancreatic exocrine en-
with a high neoplastic-cell-to-stroma ratio. noma projecting into dilated ducts, some zymes (e.g. trypsin, chymotrypsin, lipase,
These neoplasms are composed of large of which retain a layer of normal ductal and elastase) is helpful in confirming the
circumscribed nodules of neoplastic cells epithelium surrounding the carcinoma- diagnosis of acinar cell carcinoma {1235,
separated by hypocellular fibrous bands tous polyp. In rare cases, true papillae 1356, 1598, 2161}. Both trypsin and chy-
{1235, 1598}. The desmoplastic stroma may be found, with fibrovascular cores motrypsin are detectable in > 95% of
characteristic of ductal adenocarcinomas lined by neoplastic cells with acinar dif- cases; lipase is less commonly identified
is generally absent. Tumour necrosis may ferentiation. Most such cases have areas (approximately 70% of cases) {1598}. In
occur and is generally infarct-like in ap- with conventional histological features solid areas, immunohistochemical la-
pearance. Numerous small vessels sur- elsewhere in the neoplasm. belling for these enzymes may show dif-
round the nests of neoplastic cells. fuse cytoplasmic positivity, whereas the
High magnification reaction product is restricted to the apical
Architectural patterns At high magnification, the neoplastic cells cytoplasm in acinar areas. Pancreatic
Of the several architectural patterns de- of acinar cell carcinoma contain minimal stone protein, pancreatic secretory
scribed {1598}, the most characteristic is to moderate amounts of cytoplasm that trypsin inhibitor, phospholipase A2, and
the acinar pattern, with neoplastic cells may be more abundant in cells lining lu- BCL10 are also commonly expressed
arranged in small acinar units; there are
numerous small lumina within each island
of cells, producing a cribriform appear-
ance. In some instances, the lumina are
more dilated, resulting in the glandular
pattern, although individual glandular
units, each surrounded by stroma, are not
commonly encountered. A number of the
microglandular carcinomas previously re-
ported as “microadenocarcinoma” were
more recently shown to have been acinar
cell carcinomas {1890}. The second most A B
common pattern is the solid pattern: solid Fig. 12.57 Architectural patterns in acinar cell carcinoma. A Acinar pattern. Note the granular, eosinophilic cytoplasm
nests of neoplastic cells lacking luminal and single, prominent nucleoli. B Solid pattern. Note the single prominent nucleoli, obvious mitotic figures, and
formations separated by small vessels. cytoplasmic basophilia.

{1235, 1682, 1704, 3012}. Acinar cell car-

cinomas express keratins 8 and 18, but
usually do not label with antibodies to ker-
atins 7, 19, or 20 {2406}.
Scattered individual cells labelling for
chromogranin A or synaptophysin are
found in more than one third of acinar cell
carcinomas. More than half focally ex-
press carcinoembryonic antigen (CEA)
and B72.3 {1235, 1598}. Uncommonly,
there is immunohistochemical positivity
for α-fetoprotein, mostly in younger pa-
tients and in cases associated with ele-
vations in serum α-fetoprotein {564,
1365}.
Reflecting abnormalities in the APC/β-
catenin pathway, some acinar cell carci-
nomas show nuclear immunolabelling for
β-catenin that can be patchy or diffuse
{586}. There is also strong membranous Fig. 12.58 Acinar cell cystadenocarcinoma.
expression of claudin 7 and absence of
claudin 5 {586}.
Cytopathology
Fine-needle aspirates are usually highly
cellular {1356, 1710, 2791, 3070, 3405}.
The neoplastic cells are arranged in irreg-
ular solid sheets, small glandular clusters,
and individually. The cytological appear-
ance of acinar cell carcinoma closely
mimics that of pancreatic neuroendocrine
neoplasm, although smears from the lat-
ter are more likely to contain uniform plas-
macytoid cells and speckled chromatin.
Coarsely clumped chromatin and promi-
nent nucleoli are typical of acinar cell car-
cinoma. Immunohistochemistry may be
used on cytological specimens to confirm
acinar differentiation {1710}.
Fig. 12.59 Mixed acinar-ductal carcinoma. Ductal differentiation is seen on the right, acinar differentiation on the left.
Ultrastructure
Exocrine secretory features are consis-
tently found, with abundant rough endo- that are often < 1 cm in diameter. The acinar carcinomas are described in
plasmic reticulum arranged in parallel cysts are lined by layers of neoplastic greater detail in Ductal adenocarcinoma
arrays and relatively abundant mitochon- cells with acinar morphology that im- variants and mixed neoplasms.
dria {716, 1132, 1598, 3318}. Most acinar munolabel for pancreatic exocrine en-
cell carcinomas contain electron-dense zymes. The clinical behaviour of these Differential diagnosis
zymogen granules ranging in size from neoplasms is not different from that of Other pancreatic neoplasms with a solid,
125 to 1000 nm. A second granule type, conventional acinar cell carcinoma. cellular appearance should be consid-
the irregular fibrillary granule, is detected ered in the differential diagnosis with aci-
ultrastructurally in many cases {538, Mixed acinar carcinomas nar cell carcinoma. These include
1598, 1601, 2496}. Rare neoplasms have shown a substan- pancreatic neuroendocrine tumours
tial (> 30%) proportion of more than one (NETs), pancreatoblastoma, and solid-
Histological variants cell type. These “mixed acinar carcino- pseudopapillary neoplasm {1594, 1600}.
Acinar cell cystadenocarcinoma mas” have been designated, depending Pancreatic neuroendocrine tumours
Acinar cell cystadenocarcinomas are upon the cell types identified, as “mixed (NETs). These neoplasms are commonly
rare, grossly cystic neoplasms with acinar acinar-neuroendocrine carcinoma”, “mixed confused with acinar cell carcinomas
differentiation {408, 583, 1235, 1376, acinar-ductal carcinoma”, or “mixed acinar- because they share certain architectural
3054}. Most cases are large tumours neuroendocrine-ductal carcinoma” {1270, patterns (nesting, trabecular) and
(mean, 24 cm) with variably sized cysts 1710, 2313, 2369, 3405}. These mixed cytological features (uniform nuclei,
Acinar cell neoplasms 317

A B
Fig. 12.60 A Acinar cell carcinoma with immunohistochemical labelling for trypsin. B Mixed acinar-neuroendocrine carcinoma showing immunoreactivity for chromogranin.
eosinophilic to amphophilic cytoplasm) and are composed of uniform, poorly co- Prognosis and predictive factors
and because acinar cell carcinomas may hesive polygonal cells arranged in solid Acinar cell carcinomas are aggressive;
have focal or (in the case of mixed acinar- sheets and degenerative pseudopapillae however, outcome is better than that for
neuroendocrine carcinomas) widespread supplied by an abundant network of small stage-matched infiltrating ductal adeno-
labelling for chromogranin and synapto- delicate vessels {1603}. True glands or carcinomas, with 5-year survival figures of
physin. Features that favour a diagnosis acini are not present. Solid-pseudopapil- 25–50% depending on stage at diagnosis
of acinar cell carcinoma include single lary neoplasms usually contain aggre- {1576, 2001, 2844, 3528}. There are re-
prominent nucleoli, granular eosinophilic gates of large eosinophilic hyaline ports of survival for several years in the
cytoplasm, basal nuclear polarization, globules, foamy histiocytes and choles- presence of metastatic disease, and re-
abundant acinar formations, absolutely terol clefts. The mitotic rate is usually very sponses to chemotherapy have been
no fibrotic stroma within neoplastic nod- low. Immunohistochemically, solid- noted {1598}. Thus, the prognosis for aci-
ules, an elevated mitotic rate, and limited pseudopapillary neoplasms do not ex- nar cell carcinoma is somewhat less poor
labelling for neuroendocrine markers press trypsin, chymotrypsin, lipase, or than that of ductal adenocarcinoma.
{1270}. If the diagnosis of acinar cell car- chromogranin, although synaptophysin The most important prognostic factor is
cinoma is considered, immunohisto- and CD56 (NCAM1) may be positive. stage, with patients lacking lymph-node
chemical labelling for trypsin and Solid-pseudopapillary neoplasms will also or distant metastases surviving longer
chymotrypsin are usually sufficient to es- express vimentin, CD10, α-1-antitrypsin, than patients with metastases {1598}.
tablish the diagnosis, although it should and β-catenin (nuclear){8}. Being < 65 years of age and negative sur-
be noted that scattered trypsin-express- gical resection margins also predict a bet-
ing cells can be found in pancreatic NETs Molecular pathology ter outcome {2844}. Patients with the
{3622}. In contrast to ductal adenocarcinomas, lipase hypersecretion syndrome have a
Pancreatoblastomas. Pancreatoblas- acinar cell carcinomas very rarely have particularly short survival because most
tomas share with acinar cell carcinomas KRAS gene mutations, p53 immunoreac- of these patients have hepatic metas-
the consistent presence of acinar differ- tivity, loss of SMAD4 (DPC4) expression, tases. No specific grading system for aci-
entiation, both at the histological and im- or CDKN2A (p16) abnormalities {18, nar cell carcinomas has been proposed.
munohistochemical levels {2980}. 1235, 2141, 2513, 3218, 3219}. Half of In particular, no association between the
Pancreatoblastomas most commonly af- acinar cell carcinomas have losses of het- extent of acinus formation and prognosis
fect children < 10 years of age, although erozygosity (LOH) on chromosome arm has been observed.
cases in adulthood have been reported 11p and 25% have abnormalities in the There is an insufficient number of paedi-
{1602}. The characteristic feature of pan- APC/β-catenin pathway, either activating atric acinar cell carcinomas to allow an
creatoblastoma is the squamoid nests. mutations in the β-catenin gene, accurate assessment of the biological be-
Squamoid nests are circumscribed is- CTNNB1, or truncating mutations in the haviour of this neoplasm in children, but
lands of larger, spindled cells that may APC gene {18}. Immunolabelling for the available data suggest that acinar cell
show keratinization. There is also more β-catenin protein can show a normal carcinomas occurring in patients < 20
pronounced lobulation in pancreatoblas- membranous pattern of labelling, diffuse years of age may be less aggressive than
tomas, and the stromal bands separating abnormal nuclear labelling, or a peculiar their adult counterparts {1598, 2436,
the lobules are hypercellular. mosiac pattern with some cells showing 2958}.
Solid-pseudopapillary neoplasms. These nuclear labelling and others showing
neoplasms typically affect young females membranous labelling.

Pancreatoblastoma T. Morohoshi
R.H. Hruban
D.S. Klimstra
N. Ohike
B. Terris
Definition ing and bowel obstruction. An abdominal later in the course of their disease {711}.
An uncommon malignant epithelial neo- mass is often palpable on physical exam- The liver is the most common site of
plasm characterized by neoplastic cells ination, especially in children. Isolated metastases, followed by the lymph nodes
with acinar differentiation and distinctive case reports have described patients with and lung. Bone metastases are rare.
squamoid nests. Endocrine and ductal Cushing syndrome secondary to the in-
differentiation also occur but are typically appropriate secretion of adrenocorti- Histopathology
less extensive. These neoplasms rarely cotropic hormone by the tumour {1590}. The epithelial elements of pancreatoblas-
contain a discrete mesenchymal compo- Radiologically, pancreatoblastomas are tomas are highly cellular and are
nent. Pancreatoblastoma usually occurs large, well-defined, heterogeneous masses arranged in well-defined islands sepa-
in childhood. that may contain calcifications {2130, rated by stromal bands, producing a ge-
2709}. ographic low power appearance. By
ICD-O code 8971/3 A quarter of all patients have elevated definition, these neoplasms have both
serum α-fetoprotein levels, a marker that, acinar differentiation and squamoid nests
Epidemiology when present, can be used to monitor the (corpusels). Solid, hypercellular nests of
Although pancreatoblastoma is a rare effectiveness of therapy. polygonal-shaped cells alternate with re-
neoplasm, with < 200 cases reported, it is gions showing more obvious acinar dif-
one of the most frequent pancreatic neo- Macroscopy ferentiation. The cells with acinar
plasms in childhood, accounting for ap- Pancreatoblastomas are usually large at differentiation are polarized around small
proximately 25% of pancreatic neoplasms presentation; reported cases have meas- lumina and have nuclei with single promi-
occurring in the first decade of life {2958}. ured 1.5–20 cm and the mean size is nent nucleoli. Nuclear atypia is generally
The great majority of pancreatoblastomas 11 cm. Most are solitary, circumscribed, modest.
occur in children, mostly < 10 years of solid neoplasms composed of well-de- A characteristic feature of pancreatoblas-
age. The median age of paediatric pa- fined lobules of soft, fleshy tissue sepa- toma is the squamoid nest. These enig-
tients is approximately 4 years. Rare rated by fibrous bands. Areas of necrosis matic structures vary from large islands of
cases have been reported in association may be prominent. Uncommonly the tu- plump, epithelioid cells to whorled nests
with Beckwith-Wiedemann syndrome mours are grossly cystic, a phenomenon of spindled cells to frankly keratinizing
{2177}. reported in all cases arising in patients squamous islands. The nuclei of the
Exceptionally, pancreatoblastomas can with the Beckwith-Wiedeman syndrome squamoid nests are larger and more oval
be encountered in adults. More than {741}. than those of the surrounding cells. The
twenty cases have been reported in pa- nuclei in the squamoid nests may be
tients of between 18 and 78 years of age Tumour spread and staging clear owing to the intranuclear accumula-
{458}. There is a slight male predomi- These are fully malignant neoplasms and tion of biotin {1130, 3188}. The prominent
nance, with a male-to-female ratio of should be staged as one would stage a nucleoli of the solid and acinar regions
1.3 :1. Approximately half of the cases re- ductal adenocarcinoma. Pancreatoblas- are not seen in the cells of the squamoid
ported to date have been in Asians tomas can invade adjacent structures. nests. The density and composition of the
{1270}. Metastases are present in 17–35% of pa- squamoid nests varies in different regions
tients at the time of diagnosis, and addi- of the neoplasm and among different
Localization tional patients will develop metastases cases, but these structures are regarded as
Pancreatoblastomas do not preferentially
localize to any particular part of the pan-
creas {1238}. The cases reported to date
are almost evenly distributed between the
head and the body–tail of the gland.
Clinical features
The presenting features of pancreato-
blastoma are nonspecific and many
cases are discovered incidentally. Com-
mon symptoms typically include abdomi-
nal pain, weight loss, nausea and
diarrhoea. Less common presentations Fig. 12.61 Pancreatoblastoma seen on a CT scan. Fig. 12.62 Pancreatoblastoma. The cut section of the
include jaundice, gastrointestinal bleed- neoplasm reveals the lobulated surface.
Pancreatoblastoma 319
B72.3 can also be seen in more than half

of cases. In most cases, the proportion of
cells expressing acinar markers outnum-
bers the proportion expressing endocrine
or ductal markers. Immunohistochemical
positivity for α-fetoprotein is found in 20%
of pancreatoblastomas, especially cases
associated with elevations in the serum
levels of α-fetoprotein {1348}. Immuno-
histochemical evaluation of the squamoid
nests has failed to define a reproducible
direction of differentiation for this compo-
nent, {1602, 2303}. The nuclei of the cells
in the squamoid nests contain abundant
biotin, and can nonspecifically label with
a number of antibodies, a feature that can
help highlight these nests in some cases.
Loss of expression of SMAD4 (DPC4) is
found in up to 22% of pancreatoblas-
tomas and p53 is usually not expressed
Fig. 12.63 Pancreatoblastoma. Note the prominent squamoid nests. at immunohistochemically detectable lev-
els {19}. Consistent with the involvement
a defining component of pancreatoblas- may be less abundant and the stroma can of the WNT pathway in tumorigenesis,
toma and serve to distinguish it from acinar be less cellular than in paediatric cases. pancreatoblastomas may show nuclear
cell carcinoma and other related entities. immunolabelling for β-catenin, although in
In addition to cells with acinar differentia- Immunohistochemistry some cases the nuclear labelling is
tion and the squamoid nests, cells in the Pancreatoblastomas express keratins by patchy or limited to the squamoid nests
solid areas may have nuclear features immunohistochemistry, including keratins {19, 586, 3070, 3190}. The downstream
suggestive of endocrine differentiation, al- 7,8,18, and 19. They also exhibit evi- target of β-catenin, cyclin D1, is also over-
though the morphological features do not dence of acinar differentiation in the form expressed in the squamoid nests {3190}.
strongly correlate with immunohistochem- of periodic acid–Schiff (PAS)-positive, di- Pancreatoblastomas have diffuse mem-
ical labelling. A more primitive-appearing astase-resistant cytoplasmic granules branous immunoexpression of claudin 7
small-cell component may also occur, and and immunohistochemical labelling for but lack claudin 5, in contrast to solid-
in rare neoplasms, glandular spaces lined pancreatic enzymes, including trypsin, pseudopapillary neoplasms, which have
by mucin-containing cells may be seen. chymotrypsin, and lipase. The labelling the opposite profile for these markers
The stroma of pancreatoblastomas is may be focal, sometimes limited to areas {586}.
often hypercellular, in some instances of the neoplasm with acinar formations. At
achieving a neoplastic appearance. least focal immunoreactivity for markers Cytopathology
Rarely, heterologous stromal elements, in- of endocrine differentiation (chromogranin Fine-needle aspiration biopsy has been
cluding neoplastic bone and cartilage, or synaptophysin) is found in more than performed for only a few cases. Aspira-
have been reported {233}. two thirds of cases, usually in scattered tion smears show both a noncohesive
Pancreatoblastomas in adults have simi- clusters of cells. Specific peptide hor- and a clustered cellular pattern. Most of
lar histological features to those in chil- mones are not usually expressed. Ex- the neoplastic cells are polygonal with
dren, including the presence of squamoid pression of markers of ductal round to oval nuclei, one or more small
nests {458}; however, the stromal bands differentiation such as CEA, DUPAN-2, or nucleoli, and granular, amphophilic or
eosinophilic cytoplasm {1130, 2776,
2968, 3716}. These nuclear features are
similar to those of acinar cell carcinoma.
The squamoid nests are usually more dif-
ficult to appreciate, and are best seen in
cell-block preparations {1167, 2557}. Op-
tically clear nuclei may be recognized in
some of the neoplastic cells forming the
squamoid nests {1130}.
Ultrastructure
Pancreatoblastomas have only rarely
Fig. 12.64 Pancreatoblastoma. A Squamoid nest with biotin-rich, optically clear nuclei. This biotin may cause been examined ultrastructurally {357,
nonspecific nuclear immunolabelling. B Close-up of a squamoid nest. Note the clearing of some of the nuclei 752, 1504, 2303, 2920}. The predominant
secondary to the accumulation of biotin. cells have acinar differentiation, with well-

developed organelles, including promi-

nent rough endoplasmic reticulum, and
numerous zymogen granules (400–
800 nm in size). Additionally, the large ir-
regular fibrillary granules characteristic of
acinar cell carcinoma may be recognized.
Cells with small dense-core endocrine
granules (125–250 nm in size) are often
present, as are glandular cells with rela-
tively large mucinous granules (500– A B
900 nm in size). The cells of the squamoid
nests contain numerous desmosomes but
only focally well-developed desmosome-
tonofilament complexes {2303}. These
cells have no other features to suggest a
direction of differentiation.
The differential diagnosis should include
acinar cell carcinoma (including mixed
acinar-neuroendocrine carcinoma), pan- C D
creatic NET, ductal adenocarcinoma in Fig. 12.65 Pancreatoblastoma. A Immunolabelling for chromogranin. B Immunolabelling for β-catenin. Note the
childhood, and solid-pseudopapillary mosaic pattern of membranous and nuclear labelling. C Immunolabelling for trypsin. D Nonspecific nuclear labelling
neoplasm. Although extremely rare, of the biotin-rich nuclei in a squamoid nest.
metastases to the pancreas, such as neu-
roblastoma, Wilms tumour, hepatoblas- the maternal allele {1523}. These findings nous metastases. Factors associated with
toma, should also be considered if are identified in other embryonal neo- a worse prognosis are metastases and
clinically indicated. The clinical and mor- plasms that arise in association with the non-resectable disease {711}. The out-
phological features of pancreatoblastoma Beckwith-Wiedemann syndrome, includ- come in children may be more favourable
extensively overlap with those of acinar ing Wilms tumour and hepatoblastoma. than in adults {711}. One of the reasons
cell carcinoma {1598, 2162}. Both neo- Alterations in the β-catenin/APC pathway appears to be that children often present
plasms are often associated with eleva- have been reported in 50–80% of pan- with non-metastatic and well-encapsu-
tion of serum α-fetoprotein levels {564}, creatoblastomas {19, 3190}. Most often lated neoplasms with an indolent course.
and they both are composed of cells with these involve mutation of the β-catenin Even adults can achieve long-term dis-
predominantly acinar differentiation. gene (CTNNB1), which results in abnor- ease-free survival when these features
Squamoid nests are the most useful fea- mal nuclear accumulation of the β-catenin are present {458, 1234, 2370}.
ture for distinguishing these two entities. protein. Biallelic inactivation of the APC Chemotherapy and radiotherapy may
gene was identified in the pancreatoblas- have a role in the treatment of recurrent,
Genetic susceptibility toma reported in an FAP patient {19}. Mu- residual, unresectable and metastatic
Pancreatoblastoma has been reported in tations in KRAS2 and accumulation of p53 disease.
infants with Beckwith-Wiedemann syn- protein, typically found in ductal adeno-
drome {1523}, which is characterized by carcinoma of the pancreas, are not de-
hemihypertrophy, macroglossia, macro- tected {19, 1234}.
somia, midline abdominal-wall defects,
neonatal hypoglycaemia, abnormalities of Prognosis and predictive factors
chromosome 11p15.5, and an increased Overall survival is approximately 50% in
risk of developing embryonal neoplasms. patients with pancreatoblastoma. Postop-
A pancreatoblastoma has also been re- erative prognosis in patients with local-
ported in an adult patient with familial ized surgically resectable disease is
adenomatosis polyposis (FAP) {19}. favourable, with a 5-year survival of 65%,
while patients with non-resectable dis-
Molecular pathology ease usually do not survive beyond 5
The most common genetic alteration years {711}. After complete resection,
identified to date is loss of heterozygosity 18% of patients with pancreatoblastoma
(LOH) of the short arm of chromosome develop local recurrence at a median of
11p {19, 1523}. The allele lost is typically 20 months, and 26% develop metachro-
Pancreatoblastoma 321
Neuroendocrine neoplasms D.S. Klimstra

R. Arnold
P. Komminoth
E. Solcia
of the pancreas C. Capella
R.H. Hruban
G. Rindi
G. Klöppel
Definition Classification
A neoplasm arising in the pancreas that Pancreatic NETs and NECs are classified
has predominantly neuroendocrine differ- on the basis of criteria similar to those for
entiation. This includes well-differentiated other neuroendocrine neoplasms of the
(low- to intermediate-grade) neuroen- gastrointestinal tract (Chapter 1). Pancre-
docrine tumours (NETs) and poorly differ- atic NETs can be associated with charac-
entiated (high-grade) neuroendocrine teristic clinical syndromes owing to
carcinomas (NECs); NECs, defined by hormone hypersecretion (“functioning
the presence of > 20 mitoses per 10 high NETs” or “syndromic NETs”) or they can
power fields, are divided into large cell be nonfunctioning (“nonsyndromic NETs”.
NEC and small cell NEC. Mixed ade- Although routine immunohistochemical
Fig. 12.66 CT scan of a pancreatic NET.
noneuroendocrine carcinoma (MANEC) staining for peptide hormones is not sug-
has both an exocrine and a neuroen- gested for clinically nonfunctional pan-
docrine component, with each compo- creatic NETs, for cases in which the creatic neuroendocrine microadenomas
nent exceeding 30%, and include mixed production of a specific hormone has are usually clinically unrecognized and
acinar-neuroendocrine carcinoma, mixed been demonstrated in the majority of the asymptomatic and have been found in
ductal-neuroendocrine carcinoma, and neoplastic cells, it is acceptable to sup- 0.4–1.5% of unselected autopsies {1068,
mixed acinar-neuroendocrine-ductal car- plement the diagnosis of pancreatic NET 1567, 1660, 1907, 2735, 3013}.
cinoma. Nonfunctional (nonsyndromic) to reflect the corresponding cell type (e.g. High-grade pancreatic NECs are rare tu-
pancreatic NETs measuring < 0.5 cm are “α cell/glucagon-producing NET,” “β mours accounting for < 1% of pancreatic
termed pancreatic neuroendocrine mi- cell/insulin-producing NET,” “G cell/gas- carcinomas {2159, 2338} and no more
croadenomas. trin-producing NET”), but specific func- than 2–3% of all pancreatic NETs {3012}.
tional terms (e.g. “glucagonoma,” An association with cigarette smoking has
ICD-O codes “insulinoma,” “gastrinoma”) should not be been reported for high-grade pancreatic
Pancreatic neuroendocrine used in the absence of a hormonal syn- NECs {521}.
microadenoma 8150/0 drome. Changes to the classification of
Neuroendocrine tumour (NET) pancreatic neuroendocrine neoplasms Age and sex distribution
NET G1 8240/3 since the third edition of the WHO Classi- Pancreatic NETs may occur at any age,
NET G2 8249/3 fication of Tumours include the use of but are rare in childhood {2958}. The peak
Nonfunctional pancreatic NET, “neuroendocrine” rather than “endocrine” incidence is between 30 and 60 years
G1, G2 8150/3 (to parallel the terminology of the remain- and the mean age at presentation is 50
Neuroendocrine carcinoma (NEC) 8246/3 der of the gastrointestinal tract) and the years {719, 759, 1522, 1874, 3390}. Pan-
Large cell NEC 8013/3 replacement of the hybrid grade- and creatic NETs in patients with specific ge-
Small cell NEC 8041/3 stage-based classification system with a netic backgrounds (multiple endocrine
EC cell, serotonin-producing NET purely grade-based system determined neoplasia type 1 [MEN1], and von Hippel
(carcinoid) 8241/3 by proliferative rate. Pancreatic NETs Lindau [VHL]) occur at a younger age.
Gastrinoma 8153/3 should also now be staged, since stage Both sexes are equally affected (the male-
Glucagonoma 8152/3 is an independent prognostic indicator. to-female ratio is 1 : 1.15).
Insulinoma 8151/3 High-grade pancreatic NECs usually
Somatostatinoma 8156/3 Epidemiology arise in older patients, mostly males of
VIPoma 8155/3 Incidence > 40 years of age {2665}.
Pancreatic NETs are uncommon and rep-
Synonyms resent 1–2% of all pancreatic neoplasms. Localization
Synonyms for pancreatic NETs include Their prevalence has been estimated to Pancreatic NETs can occur anywhere in
“islet cell tumour,” “APUDoma” (obsolete), be 0.2–2 per million persons per year the pancreas, and some functional types
well-differentiated pancreatic endocrine {3012}. Based on surgical series, 30–40% are slightly more common in the head
neoplasm, neuroendocrine neoplasm and of all pancreatic NETs are nonfunctioning (e.g. gastrinoma) or tail (e.g. VIPoma)
well-differentiated pancreatic endocrine {346, 1522, 1609, 3012}, although the in- {691}. Approximately two thirds of surgi-
carcinoma. Synonyms for NEC include creasing detection of incidental nonfunc- cally resected nonfunctioning pancreatic
high-grade neuroendocrine carcinoma tioning NETs during imaging procedures NETs arise in the head of the pancreas
and poorly differentiated endocrine is expected to increase their numbers rel- {719, 759, 1522, 1874, 3390}; because
carcinoma. ative to functioning pancreatic NETs. Pan- these neoplasms are hormonally silent,

those lesions that cause local symptoms drome {605}, carcinoid syndrome {1033}
(i.e. those in the head of the gland) are and hypercalcaemia {1218}.
most commonly detected. Pancreatic
high-grade NECs are also more common Macroscopy
in the head of the gland {2665}. NETs
Most pancreatic NETs are well-demar-
Clinical features cated, solitary, and white-yellow or pink-
NETs brown. They can be soft and fleshy or
Functioning pancreatic NETs are associ- densely fibrotic. Areas of haemorrhage or
ated with clinical syndromes caused by necrosis can occur, usually in larger neo- A
hypersecretion of hormones either appro- plasms. Rarely, pancreatic NETs are cystic
priate to the endocrine pancreas (insulin, {1850}. Among the functioning neo-
glucagon, and somatostatin) or inappro- plasms, insulinomas are usually smaller
priate (e.g. gastrin, vasoactive intestinal (< 2 cm in diameter) than glucagonomas,
peptide [VIP], growth hormone-releasing somatostatinomas, gastrinomas or VIPo-
factor, adrenocorticotropic hormone mas, but the size of the tumours is not re-
[ACTH]). Within this group are insulino- lated to the severity of the hormonally
mas, glucagonomas, somatostatinomas, induced symptoms. Nonfunctioning NETs
gastrinomas, VIPomas, and other less are generally > 2 cm in diameter (often
common pancreatic NETs. These desig- 5 cm or more); in part, their larger size can
nations should only be used when the be attributed to later detection. B
hormone production produces a clinical NECs Fig. 12.67 Macroscopy of well-differentiated pancreatic
syndrome (“syndromic” or “functional”). Pancreatic NECs have an average diam- neuroendocrine tumours (NETs). A This large soft fleshy
The clinical and pathological features of eter of approximately 4 cm {2665}. They tumour has areas of degeneration and haemorrhage. The
the specific functioning pancreatic NETs are firm, white-grey masses with ill-de- normal pancreas is in the upper left. B Invasion of a large
are described elsewhere {691}. Pancre- fined borders, often showing areas of vessel (arrow) in a well-differentiated NET.
atic neuroendocrine microadenomas are, necrosis and haemorrhage.
by definition, nonfunctioning. toses are nearly undetectable. The mitotic
By definition, nonfunctioning (or inactive, Histopathology rate is a critical component of grading.
clinically silent, nonsyndromic) tumours NETs The amount of stroma and degree of fi-
are not associated with a distinct clinical Pancreatic NETs are well-differentiated by brosis vary. Necrosis is usually limited
hormonal syndrome, but may still be as- definition and show various “organoid” and may be comedo-like. In general, the
sociated with elevated hormone levels in histological patterns, characterized by a histological pattern of a neoplasm does
the blood and hormone immunoreactivity nesting, trabecular, glandular, gyriform, not indicate its functional state or type of
in tissue sections. Neoplasms in which tubuloacinar or pseudorosette arrange- hormone produced. There are two ex-
the majority of cells express (and often ments of their cells. The cells are relatively ceptions to this rule: amyloid deposits are
secrete) pancreatic polypeptide (PP) or uniform, show finely granular amphophilic more typical of insulinomas, and glan-
neurotensin are included in the group of to eosinophilic cytoplasm and a centrally dular structures containing psammoma
nonfunctioning neoplasms (as are many located round to oval nucleus that may bodies are commonly observed in so-
delta [D] cell or somatostatin-producing display a distinct nucleolus. The chro- matostatin cell tumours, usually not pri-
cell tumours and the rare ghrelin cell tu- matin pattern is characteristically coarsely mary in the pancreas but rather in the
mours), because they do not cause a dis- clumped (“salt and pepper”). Occasion- periampullary duodenum.
tinct hormonal syndrome. Nonfunctioning ally, clear cells, vacuolated lipid-rich cells,
tumours only become clinically apparent oncocytes, or “rhabdoid” features {443, NECs
when they become large and invade ad- 1040, 1214, 2523, 2614} may be ob- Pancreatic high-grade NECs commonly
jacent organs, or when they metastasize. served. Pancreatic NETs with marked nu- consist of tightly packed nests or diffuse,
They rarely present with acute pancreati- clear enlargement and irregularities have irregular sheets of cells, often, with exten-
tis. Increasingly, they are detected on im- been termed “pleomorphic” pancreatic sive necrosis. NECs are classified as
aging tests as incidental findings. NETs {3686}. small cell NEC or large cell NEC depend-
Non-neoplastic ductules may be trapped ing upon the size of the neoplastic cells,
NECs in the tumour, and the neoplastic cells the prominence of nucleoli and the
High-grade pancreatic NECs may pres- may even form glands, but these features amount of cytoplasm, using similar crite-
ent with symptoms similar to those of the do not indicate a diagnosis of mixed duc- ria to those used for NECs of the lung
exocrine pancreatic neoplasms {682, tal-neuroendocrine carcinoma unless a {2665, 3012, 3288}. In the pancreas, large
1419, 1522}. Presentation with wide- separate component of histologically typ- cell NECs are more common than small
spread metastases may occur. Lesions in ical infiltrating ductal adenocarcinoma is cell NECs. By definition, mitoses are
the pancreatic head may induce back present. abundant (> 20 per 10 HPF). Most cases
pain and jaundice owing to obstruction of By definition, pancreatic NETs have < 20 have > 40–50 per 10 HPF and necrosis is
the common bile duct. Individual cases mitoses per 10 HPF; most cases have frequent and often geographic. Neo-
have been associated with Cushing syn- < 10 per 10 HPF, and in many cases mi- plasms with an organized pattern of

growth, uniform nuclei with salt-and- produce hormones other than those not express neuroendocrine markers and,
pepper chromatin, and with > 20 mitoses found in the primary {1219, 1747, 3012, following the definition used in the lung,
per HPF are currently classified as NEC 3013}. Clinically nonfunctioning NETs with this does not preclude the diagnosis so
based solely on the mitotic count. Further immunolabelling for pancreatic polypep- long as alternative diagnostic considera-
studies are necessary, however, to estab- tide (PP) in the majority of cells have been tions are excluded. As a rule, no reactiv-
lish the clinical behaviour of such neo- designated as “PPomas” {1748, 3262, ity for peptide hormones is found in
plasms. 3263}. Microadenomas are more likely to pancreatic NECs. Abnormal nuclear ac-
show diffuse expression of a single pep- cumulation of p53, a feature virtually ab-
Immunohistochemistry tide, most often glucagon or PP {3012}. sent in NETs, is commonly although not
NETs Many pancreatic NETs also express gly- invariably found in NECs. The Ki67-MIB1
Pancreatic NETs can be identified by coproteins including carcinoembryonic labelling index is consistently > 20% and
using antibodies against chromogranin A antigen(CEA) and CA19-9 {1219, 1467}. often exceeds 50%.
and synaptophysin, which are strongly Neoplasms with gland formation are par-
expressed in the vast majority of cases ticularly likely to stain for glycoproteins. Cytopathology
{2735, 3013}. Synaptophysin expression Focal acinar differentiation may also be Fine-needle aspiration (FNA) is a useful
is often more diffuse than chromogranin detected, generally in single widely scat- method for diagnosing pancreatic NETs
A, which can be focal or patchy. Also ex- tered cells (less than one third) that stain and their metastases. Smears are usually
pressed are protein gene product (PGP) for trypsin or chymotrypsin {1467}. Ex- uniformly cellular and composed of a rel-
9.5 and neural cell adhesion molecule pression of progesterone receptors and atively monotonous population of cells
(NCAM1/CD56), but these are considered CD99 is found in a subset of normal islet predominantly arranged singly, but also in
less specific {1156, 1876, 2178}. Pancre- cells and also in some pancreatic NETs. loose clusters or pseudorosettes {59, 226,
atic NETs also contain keratins 8 and 18, Immunohistochemical labelling for Ki67 581, 2992}. The round to ovoid, smoothly
and keratin 19 may also be expressed, with MIB1 antibody may be used to de- contoured nuclei demonstrate a salt-and-
especially in more aggressive cases. termine the proliferative rate of pancre- pepper chromatin pattern. The cytoplasm
Lineage markers including PDX1 and Isl1 atic NETs. Most have a low proliferative is amphophilic and varies in quantity and
may be expressed and can indicate a rate, with a labelling index of 1–5%, but density. Some cells may be stripped of
pancreatic origin for NETs of unknown pri- values of up to 20% are acceptable, al- their cytoplasm whereas others may have
mary {832, 2846, 3052}. CDX2 expression though rarely observed {3012}. A greater abundant cytoplasm, and a plasmacytoid
can also occur, but is not specific for pan- percentage of immunoreactivity for MIB1 appearance is highly characteristic. Im-
creatic origin {2801, 3052}. indicates a diagnosis of high-grade munocytochemical techniques may
Peptide hormones (e.g. insulin, glucagon) NEC. effectively be applied to cytology sam-
are generally detectable in the corre- ples.
sponding functioning pancreatic NETs. It NECs
is important to recognize that functioning It is necessary to demonstrate immunola- Differential diagnosis
NETs are defined on the basis of clinical belling for general neuroendocrine mark- NETs
symptoms rather than immunohistochem- ers (chromogranin A and synaptophysin) Most pancreatic NETs are recognizable
ical findings, and the immunohistochemi- to establish a diagnosis of large cell NEC without much difficulty. The use of im-
cal detection of peptide hormones in of the pancreas, and therefore a variable munohistochemical markers of the neu-
nonfunctioning pancreatic NETs has no proportion of the neoplastic cells label in roendocrine phenotype can often
clinical significance. The expression of all cases, usually with less intensity than establish the diagnosis. Primary pancre-
different hormones by distinct cells within in well-differentiated NETs {1110}. atic neoplasms that must be distin-
a NET can occur, and metastases may Cytologically, classic small cell NECs may guished from NETs include solid-
A B
Fig. 12.68 Well-differentiated pancreatic neuroendocrine tumour (NET). A Trabecular and nesting growth. B Note the “salt and pepper” nuclei.

pseudopapillary neoplasm, acinar cell

carcinoma and pancreatoblastoma, prim-
itive neuroectodermal tumour, and ductal
adenocarcinoma.
Solid-pseudopapillary neoplasms can
morphologically resemble NETs, and both
neoplasms can immunolabel for CD56
(NCAM1), neuron-specific enolase (NSE)
and synaptophysin. Findings that favour
a diagnosis of solid-pseudopapillary neo-
plasm include poorly cohesive cells with
degenerative pseudopapilla formation, lon-
gitudinal nuclear grooves, and aggre-
gates of PAS-positive, diastase-resistant
hyaline globules. Immunoreactivity for vi-
mentin, CD10, α-1-antitrypsin, and β-
catenin (nuclear) are also features of
solid-pseudopapillary neoplasm.
Immunolabelling for trypsin and chy-
motrypsin can be used to distinguish aci-
nar cell carcinomas from pancreatic Fig. 12.69 Pancreatic neuroendocrine carcinoma (NEC). Note the very high mitotic rate.
NETs. The same is true for pancreato-
blastomas, which have the additional
distinguishing histological feature of Expression of neuroendocrine markers is patients with MEN1, and most affected
squamoid nests. Both neoplasms may needed to distinguish NECs from poorly patients have at least one functioning
contain scattered neuroendocrine cells. differentiated ductal adenocarcinomas. pancreatic NET. Gastrinomas, almost ex-
True mixed acinar-neuroendocrine carci- Acinar cell carcinomas share with NECs clusively of the duodenum, are the most
nomas are very rare. In these carcinomas, a relatively high mitotic rate, and since frequent functioning gastroenteropancre-
the neuroendocrine-cell component they are much more frequent pancreatic atic tumour in MEN1 patients; pancreatic
should account for at least one third of the primaries, they should be ruled out using insulinomas are the next most frequent
entire cell population. immunolabelling for trypsin and chy- {1049, 1660, 1770, 2807, 2883}. Pancre-
Poorly differentiated ductal adenocarci- motrypsin in all cases. The possibility of a atic NETs in MEN1 patients usually arise
nomas may have a solid growth pattern, metastasis from an extrapancreatic NEC in a background of multiple neuroen-
resembling a NET, but they have more should always be excluded, especially in docrine microadenomas and other ab-
pleomorphism and mitotic activity and the case of small cell carcinoma. Im- normalities of the islets (hypertrophy or
usually demonstrate focal production of munolabelling for TTF1 may not be help- hyperplasia). Between 12% and 17% of
mucin; immunolabelling for neuroen- ful, since the expression of this marker is patients with VHL develop pancreatic
docrine markers is not found. The occa- well described in extrapulmonary small NETs, most of which are nonfunctioning
sional nuclear pleomorphism that can cell carcinomas as well as in lung primar- {1909}. Background abnormalities in the
occur in pancreatic NETs may lead to ies. islets have only recently been reported in
confusion with poorly differentiated ade- VHL patients {2524}.
nocarcinoma. Genetic susceptibility In contrast to well-differentiated pancre-
Primary primitive neuroectodermal tu- Pancreatic NETs are a major component atic NETs, high-grade NECs are very in-
mours are rare in the pancreas {1920, of the multiple endocrine neoplasia type frequently associated with MEN1 {2334}.
2170}. Since reported cases in this loca- 1 (MEN1) syndrome and NETs are also
tion may strongly express keratin and be- found in patients with von Hippel Lindau Molecular pathology
cause pancreatic NETs often express (VHL) syndrome. The underlying germline Whereas the molecular basis of familial
CD99, these entities can be confused. genetic abnormalities of these syndromes pancreatic NETs associated with MEN1
Molecular or cytogenetic evidence of the (in the MEN1 and VHL genes, respec- and VHL syndromes has been estab-
characteristic 11;22 chromosomal translo- tively) are known to play a role in the de- lished {477, 1753}, little is known about
cation is helpful in the diagnosis of primi- velopment of pancreatic NETs in these the molecular basis for sporadic tumours.
tive neuroectodermal tumour. patients. A few cases have been associ- It appears that activation of oncogenes is
ated with tuberous sclerosis, especially in not a common event in pancreatic NETs
NECs children {885, 3395}. The somatostatino- {1224, 1369, 1885}. In particular, the com-
Prominent cytological atypia, extensive mas associated with neurofibromatosis mon genetic mutations identified in pan-
necrosis, a Ki67 index of > 20% and (NF) are almost exclusively duodenal. creatic ductal adenocarcinomas (e.g.
diffuse nuclear expression of p53 (when Rare examples of insulinomas have also TP53, KRAS, CDKN2A/p16, SMAD4/DPC4)
present) are useful in differentiating high- been described in patients suffering from are not found with any significant fre-
grade NECs with intermediate-sized cells NF1 {923}. quency in pancreatic NETs {560, 1036,
from well-differentiated pancreatic NETs. Pancreatic NETs are found in 60–70% of 1267, 2141, 2530, 2881}. Somatic MEN1

mutations are present in about 20% of nomas are very small (often < 1.0 cm) at count or Ki67 index has been shown to be
sporadic pancreatic NETs, and 68% har- diagnosis, and probably for this reason prognostically relevant in many studies
bour losses of 11q13 or more distal parts they pursue a benign clinical course, {570, 2514, 3412}. The most widely used
of the long arm of chromosome 11, indi- even when treated by enucleation. The proliferative rate-based grading system
cating that another yet unknown tumour percentage of insulinomas with malignant is that of ENETS, which separates pan-
suppressor gene might be involved {633, behaviour ranges from 2.4% to 17.9% creatic NETs into low-grade (G1) and in-
641, 1036, 1181, 1182, 2140, 2529, 2676, with an average of 8.4% {935, 986, 998, termediate-grade (G2) categories based
2900, 3442, 3718}. Point mutations in the 1772, 2882, 3002, 3065, 3366}. Most on mitoses (0–1 vs 2–20 per 10 HPF) and
VHL gene appear to be extremely rare in other functioning and nonfunctioning pan- Ki67 labelling rate (0–2% versus 3–20%).
sporadic pancreatic NETs (1–3%) {560, creatic NETs are relatively aggressive This system strongly correlates with out-
1036, 2141, 2530, 2881}. neoplasms. come {772, 868, 1705, 2449}.
Approximately 65–80% of cases are as- In nonfunctioning pancreatic NETs, pro-
Staging, prognosis and predictive factors sociated with clear-cut evidence of ma- duction of specific peptides has no im-
NETs and NECs should be staged using lignant behaviour (gross invasive growth pact on survival {1219}. Some studies
the TNM (tumour, node, metastasis) sys- or metastasis), and tumour recurrence fol- have demonstrated a correlation between
tem for ductal adenocarcinoma of the lowing resection is common {719, 759, overall nuclear grade and prognosis
pancreas. The issue of TNM/staging clas- 1190, 1522, 2591, 2762, 3012, 3390}. {1219}. Other factors reportedly predic-
sification for NETs is controversial. The Once distant metastases occur, cure is tive of more aggressive behaviour include
classification presented in this book fol- highly unlikely, although the rate of tumour necrosis, loss of progesterone-receptor
lows that of the American Joint Commit- progression may be slow. Following sur- expression {2514, 3401}, aneuploidy
tee on Cancer/ Internation Union Against gical resection, the 5-year survival for pa- {1521}, increased fractional allelic loss
Cancer (AJCC/UICC) and is the same for tients with pancreatic NETs other than {2676}, upregulated expression of CD44
adenocarcinoma and NETs, including insulinomas is reportedly 65%, and 10- isoforms {1322}, and immunohistochemi-
“carcinoids,” i.e. well-differentiated le- year survival is only 45% {1219}. A size- cal expression of keratin 19 {701}.
sions only {762, 2996}. Conversely, the able proportion of patients with nonfunc-
classification proposed by the European tioning pancreatic NETs initially present NECs
Neuroendocrine Tumor Society (ENETS) with distant metastases, perhaps be- The highly aggressive behaviour of high-
is also meant for high-grade neuroen- cause there is no hormonal syndrome to grade pancreatic NECs and the usually
docrine neoplasms, has different T (tu- draw clinical attention to the neoplasm advanced and unresectable stage at the
mour) definitions and stage groupings early in its course. time of diagnosis make mortality from
{2684, 2685, 2832A}. A variety of prognostic factors can be these tumours virtually 100%. Invasion of
used to stratify pancreatic NETs into dif- the adjacent duodenum or of other peri-
NETs ferent risk groups, but stage (extent of pancreatic tissues is frequent. Extensive,
Other than neuroendocrine microadeno- disease) and grade (based on prolifera- widespread metastases are the rule, in-
mas, which are benign neoplasms {3012} tive rate) have emerged as the most po- volving regional and distant lymph nodes,
(there being no evidence for progression tent predictive features in most studies as well as intra- and extra-abdominal or-
to clinically relevant malignant NETs out- {772, 850, 868, 1219, 1705, 2449, 2845}. gans such as liver and lung {2665, 3012}.
side the setting of MEN1), all pancreatic Staging and grading information should Survival ranges from 1 month to 1 year,
NETs are regarded to have malignant po- therefore be provided separately. despite some initial favourable responses
tential. Most clinically functioning insuli- The proliferative rate based on mitotic to chemotherapy {2146, 2338}.

Solid-pseudopapillary neoplasm G. Klöppel

R.H. Hruban
K. Notohara
M. Shimizu
of the pancreas D.S. Klimstra
A. Maitra
B. Terris
T. Morohoshi
Definition of age {3012}. There is no apparent ethnic

A low-grade malignant neoplasm com- predilection {1680, 2356} or any estab-
posed of poorly cohesive monomorphic lished association with recognized clini-
epithelial cells forming solid and cal or genetic syndromes, although very
pseudopapillary structures. These neo- rare cases have been reported in the set-
plasms frequently undergo haemor- ting of familial adenomatous polyposis
rhagic-cystic degeneration, and occur (FAP) {2758}.
predominantly in young women.
Localization
Synonyms There is no preferential localization within
Synonyms that should no longer be used the pancreas {1270, 1656, 2297}. Origin
Fig. 12.70 Solid-pseudopapillary neoplasm with
include solid-pseudopapillary tumour, outside of the pancreas is uncommon, but
lobulated, fleshy surface showing marked haemorrhage
solid-cystic tumour {1615}, papillary-cys- solid-pseudopapillary neoplasms have and degenerative changes.
tic tumour {301}, solid and papillary ep- been reported in the retropancreatic tis-
ithelial neoplasm {1845}, and Frantz sue and in the mesocolon {1270, 1359,
tumour {313}. 1564, 1614}. Invasion of adjacent organs sulated. Multiple tumours are exceptional
or the portal vein is rare {2864}. {2407}. The cut section reveals lobulated,
ICD-O code 8452/3 light brown to yellow solid areas and
Clinical features zones of haemorrhage, necrosis, and
Epidemiology Solid-pseudopapillary neoplasms are cystic degeneration filled with necrotic
Solid-pseudopapillary neoplasms are usually found incidentally on routine phys- debris. The contribution of each compo-
rare, accounting for 0.9–2.7% of all ex- ical examination or imaging for another in- nent varies greatly. Small tumours tend to
ocrine pancreatic neoplasms and only dication. If symptomatic, they cause be more solid than larger examples.
5% of cystic neoplasms {1270, 1654}. abdominal discomfort, early satiety, nau- Solid-pseudopapillary neoplasms are
They occur predominantly in adolescent sea, vomiting and pain {2297}. Intratu- usually very soft, although some cases
girls and young women (female, 90%; moral haemorrhage following abdominal are firm and sclerotic. Occasionally, the
mean, 28 years; range, 7–79 years) trauma can produce an acute abdomen haemorrhagic-cystic changes may be so
{3012} and are rare in men (mean, 35 {1614}. Jaundice is rare even in cases extensive as to mimic a pseudocyst. The
years; range, 25–72 years) {1270, 1614, that originate in the head of the pancreas. wall of the neoplasm may contain calcifi-
1656, 2009, 3315}. It should therefore not Blood tumour markers are normal and the cations {2297}.
be surprising that solid-pseudopapillary neoplasms have not been associated with
neoplasms account for 30% of all pan- a functional endocrine syndrome. Tumour spread and staging
creatic neoplasms in patients < 40 years Endoscopic ultrasonography (EUS) and Rarely, these neoplasms may directly ex-
computed tomography (CT) reveal a tend into the stomach, duodenum and
sharply demarcated, heterogeneous (i.e. spleen. Metastases occur in 5–15% of
variably solid and cystic) mass without cases, usually to the peritoneum and liver.
internal septations {533}. The tumour Lymph nodes and skin are exceptionally
margin may contain calcifications. Ad- rare sites of metastatic disease {533,
ministration of contrast medium results in 1185, 2297, 3721}. Staging follows that for
enhancement of the solid components. other carcinomas of the exocrine pan-
On angiography, solid-pseudopapillary creas.
neoplasms are usually hypovascular or
mildly hypervascular lesions that displace Histopathology
surrounding vessels {3585}. Solid-pseudopapillary neoplasms have a
distinctive microscopic appearance. The
Macroscopy growth pattern is heterogeneous, with a
Solid-pseudopapillary neoplasms usually combination of solid, pseudopapillary
form large, round, solitary masses (aver- and haemorrhagic-necrotic, pseudocys-
age size, 8–10 cm; range, 0.5–25.0 cm) tic structures in various proportions. The
{1270}, and are often fluctuant. They are solid areas, which in large haemorrhagic-
Fig. 12.71 Coronal CT scan revealing a solid- well-demarcated from the surrounding cystic neoplasms are only found at the
pseudopapillary neoplasm in the head of the pancreas. pancreas and may appear to be encap- periphery of the tumour, are composed of
Solid-pseudopapillary neoplasm 327

in contrast, is usually diffuse. Labelling

using antibodies to the extracellular do-
main of E-cadherin shows complete loss
of expression, while labelling with anti-
bodies to the intracellular domain of the
protein produces an abnormal cytoplas-
mic/nuclear pattern of labelling {2880}.
Inconsistent results have been reported
for epithelial markers, synaptophysin, and
other antigens such as CEA or CA19-9.
Antibodies to chromogranin A, exocrine
enzymes (trypsin, chymotrypsin, and li-
pase), pancreatic hormones, estrogen re-
ceptors α, and α-fetoprotein do not label
A B the neoplastic cells. Keratin is detected in
30–70% of cases {1615, 1656, 3669}, de-
Fig. 12.72 Solid-pseudopapillary neoplasm. A Note the delicate vessels surrounded by loosely cohesive cells.
B Delicate pseudopapillae and uniform loosely cohesive cells.
pending on the method of antigen re-
trieval applied. Usually, labelling for
keratins (7, 8, 18 and 19) is focal and
poorly cohesive monomorphic cells that in large amounts. Glycogen is not promi- faint.
are admixed with hyalinized to myxoid nent and mucin is absent. The round to As solid-pseudopapillary neoplasms ex-
stromal bands containing thin-walled oval nuclei of the neoplastic cells have press so many diverse antigens, a core
blood vessels. Pseudopapillae are finely dispersed chromatin and the nuclei panel of markers that includes β-catenin,
formed when the poorly cohesive neo- are often grooved or indented. Bizarre, CD10, chromogranin and vimentin is rec-
plastic cells drop away, leaving variable presumably degenerative, nuclei may oc- ommended for establishing the diagno-
aggregates of loosely cohesive cells be- casionally occur. Mitoses are usually rare, sis.
tween the fibrovascular stalks. Touch but in a few instances prominent mitotic
preparations at the time of intraoperative activity has been observed {2297}. If Ultrastructure
frozen section can highlight the pattern of there are metastases, they have largely The neoplastic cells contain abundant cy-
delicate branching vessels and loosely the same morphological appearance as toplasm, which is rich in mitochondria. Zy-
cohesive cells. Sometimes the neoplastic the primary neoplasm, but the cells may mogen-like granules of variable sizes
cells are arranged radially around the be more pleomorphic and show more mi- (500–3000 nm) are conspicuous, probably
minute fibrovascular stalks thereby re- toses. representing deposits of α-1-antitrypsin.
sembling “ependymal” rosettes. True Perineural invasion, angioinvasion, or The contents of these granules commonly
gland formation is not seen. The solid deep infiltration of the surrounding acinar disintegrate, forming multilamellated vesi-
parts may contain aggregates of neo- tissue do not indicate an accelerated ma- cles and lipid droplets {1615, 1775, 2071,
plastic cells with foamy cytoplasm and lignant behaviour, because solid- 3586}. Neurosecretory-like granules have
often include cholesterol crystals sur- pseudopapillary neoplasms in which the been described in a few neoplasms
rounded by foreign-body giant cells. The above-mentioned histological criteria of {1448, 1466, 2843, 3522, 3575}. Interme-
pseudopapillary areas are usually associ- agressive behaviour are not detected diate cell junctions are rarely observed
ated with blood lakes. Foci of calcification may also metastasize. Consequently, all and microvilli are lacking, but small inter-
and even ossification may be seen in the solid-pseudopapillary neoplasms are cur- cellular spaces are frequent.
hyalinized connective tissue {2009}. Al- rently classified as low-grade malignant
though the tumour is in most cases neoplasms. Cytopathology
grossly well-demarcated from the normal Fine-needle aspiration cytology usually
pancreas, often by a fibrous capsule, mi- Immunohistochemistry shows small monomorphic cells loosely
croscopically the neoplastic cells deli- Almost all solid-pseudopapillary neo- adherent to thin branching vessels {417,
cately infiltrate into the surrounding plasms express α-1-antitrypsin, α-1- 1270, 3522, 3552}. Poorly cohesive neo-
pancreatic tissue, entrapping acinar cells antichymotrypsin, NSE, vimentin, plastic cells fill the spaces between the
and islets {2009, 2297}. Vascular and per- progesterone receptors, CD10, CD56, vessels, and naked nuclei stripped of cy-
ineural invasion are rare {3552}. claudins 5 and 7, galectin 3, cyclin D1, toplasm are usually abundant. The back-
The neoplastic cells have either and nuclear/cytoplasmic β-catenin {541, ground often contains haemorrhagic
eosinophilic or clear vacuolated cyto- 586, 775, 956, 1614, 1656, 2071, 2161, debris, foamy histiocytes and multinucle-
plasm. A few neoplasms are almost en- 2324, 3247}. Immunoreactivity for α-1- ated giant cells. The neoplastic cells have
tirely composed of either eosinophilic antitrypsin and α-1-antichymotrypsin is al- round nuclei with indented or grooved nu-
cells or multivacuolated clear cells {82, ways intense, but only involves small cell clear membranes and eosinophilic or
1018}. Some of the neoplastic cells con- clusters or single cells, a finding that is foamy cytoplasm. The presence of intra-
tain eosinophilic, diastase-resistant PAS- characteristic of this neoplasm, and the cytoplasmic hyaline globules can aid the
positive globules of varying size, which distribution parallels that of the hyaline diagnosis.
may also occur extracellularly, sometimes globules. Staining for NSE and vimentin,

Histological variants
Solid-pseudopapillary neoplasms with
apparent high-grade malignant transfor-
mation have been reported. In addition to
areas with the appearance of a conven-
tional solid-pseudopapillary neoplasm,
these neoplasms contained foci with a dif-
fuse solid growth pattern, increased nu-
clear atypia, and relatively abundant
mitoses. One case contained a focus of
sarcomatoid (spindle cell) carcinoma
{3191}. These neoplasms were clinically
extremely aggressive.
Macroscopically, solid-pseudopapillary
neoplasms may be mistaken for pseudo-
cysts. They can be clearly separated from
other cystic neoplasms of the pancreas Fig. 12.73 Solid-pseudopapillary neoplasm showing numerous hyaline globules (haematoxylin phloxine saffron stain).
by the yellow to haemorrhagic appear-
ance of their cut surface. Microscopically
the main differential diagnosis is with well- be hard to identify on cursory examina- β-catenin, and negativity for chromo-
differentiated pancreatic neuroendocrine tion. Occasionally, “ghosts” of necrotic granin A and exocrine enzymes (trypsin
neoplasms and acinar cell carcinomas. pseudopapillary structures may be visible and chymotrypsin in particular) may be
Pseudocysts occur in males and females, in the periphery of such lesions. helpful in establishing the diagnosis of a
usually with a history of pancreatitis and Solid-pseudopapillary neoplasms may solid-pseudopapillary neoplasm.
pain. In contrast, solid-pseudopapillary be confused with well-differentiated
neoplasms are often found incidentally pancreatic neuroendocrine neoplasms or Molecular pathology
and occur predominantly in young with acinar cell carcinomas, particularly if Almost all solid-pseudopapillary neo-
women. the solid-pseudopapillary neoplasm plasms harbour somatic point mutations
Histologically, pseudocysts are easily dis- displays a predominantly solid growth in exon 3 of CTNNB1, the gene encoding
tinguished from solid-pseudopapillary pattern and lacks pseudopapillary struc- β-catenin {8, 3189}. This mutation leads to
neoplasms by the absence of epithelial tures, eosinophilic globules, foam cells a β-catenin protein that escapes intracy-
lining of the inner cyst surface, but it and hyalinized fibrovascular stalks. In toplasmic phosphorylation and subse-
should be noted that some solid- these cases, immunohistochemical ex- quent degradation and that therefore
pseudopapillary neoplasms are exten- pression of CD10 and vimentin, abnormal binds to the T-cell transcription factor
sively necrotic and viable epithelium can nuclear labelling with antibodies to (Tcf)/lymphoid enhancer-binding factor
(Lef). The β-catenin-Tcf/Lef complex is
then abnormally translocated to the nu-
cleus, as indicated by nuclear expression
of β-catenin on immunohistochemistry {8,
3189}. In the nucleus, the β-catenin-
Tcf/Lef complex activates the transcrip-
tion of several oncogenic genes, among
them MYC and cyclin D1 {2181}. This
leads to activation of the Wnt/β-catenin
signalling pathway. Although this activa-
tion increases proliferation in other
neoplasms, in solid-pseudopapillary neo-
plasms the signalling cascade may be in-
terrupted by an as yet unexplained
overexpression of p21 and p27 {3247}, re-
sulting in a very low proliferation rate.
Alterations in the KRAS, CDKN2A/p16,
TP53 and SMAD4/DPC4 genes, fre-
quently found in ductal adenocarcino-
mas, have not been reported in
solid-pseudopapillary neoplasms. A study
Fig. 12.74 Solid-pseudopapillary neoplasm with giant-cell reaction to cholesterol crystals and scattered foamy histiocytes using fluorescent in situ hybridization
in the background. (FISH) and comparative genomic
Solid-pseudopapillary neoplasm 329

A B
Fig. 12.75 Solid-pseudopapillary neoplasm. A Cytological preparation: note the delicate branching vessels and poorly cohesive uniform cells. B The neoplastic cells show
nuclear immunolabelling for β-catenin: note the normal membranous labelling of the non-neoplastic acinar cells (bottom).
hybridization detected neither EWS/FLI1 ation with endocrine disturbances, in- have died of a metastastic solid-
translocations nor any gross chromoso- cluding overproduction of estrogen or pseudopapillary neoplasm, mostly those
mal gains or losses {3248}. Although up progesterone. Moreover, only very few patients whose tumours harboured an un-
to 50% of solid-pseudopapillary neo- women develop a solid-pseudopapillary differentiated component {2007, 2356,
plasms diffusely express the KIT (CD117) neoplasm after long-term use of hormonal 2649, 3191}. There are no proven biolog-
antigen on immunohistochemistry, this contraceptives {744}. ical or morphological predictors of out-
finding is not associated with underlying come, although it has been suggested
mutations of the KIT gene {409}. A study Prognosis and predictive factors that older patients do worse than younger
of global gene expression revealed a After complete surgical resection, 85– patients, that patients with neoplasms
gene expression profile that is distinct 95% of patients are cured. Local spread with an aneuploid DNA content do worse
from that of ductal adenocarcinomas and or dissemination to the peritoneal cavity than those with diploid tumours, and that
from neuroendocrine neoplasms, and has been reported in the context of ab- an elevated mitotic rate and certain nu-
demonstrated the involvement of the dominal trauma and rupture of the tumour clear features of the neoplastic cells, such
Wnt/β-catenin and the Notch signalling {1819}. Even in patients who had local as mean nuclear diameter and size, are
pathways {459}. spread, recurrences, or metastases, long associated with the presence of metas-
The striking sex and age distribution sug- disease-free periods have been recorded tases {2297, 3191}.
gest genetic and hormonal factors, but after initial diagnosis and resection {1713,
there are no reports indicating an associ- 2007, 2649, 2760}. Only a few patients

Mesenchymal tumours of the pancreas M. Miettinen

C.D.M. Fletcher
L.-G. Kindblom
W.M.S. Tsui
Introduction 18 and 19, while lymphangiomas express cell tumours have rearrangement of the
Although some mesenchymal tumours CD31. EWSR1 gene, usually a EWSR1-FLI1 fu-
occur primarily in the pancreas, most are Lipomas. Lipomas of the pancreas have sion with t(11;22) translocation, and are
extrapancreatic lesions that have invaded been reported, and should be distin- strongly immunoreactive for CD99. They
the pancreas. guished from non-neoplastic fat accumu- often express synaptophysin, and occa-
lation. These lesions are particularly sionally keratins. Before making a diag-
Extrapancreatic mesenchymal tumours problematic because their low attenuation nosis of Ewing sarcoma, other small
Such tumours can involve the pancreas. on computed tomography (CT) imaging round blue cell tumours and pancreatic
For example, gastrointestinal stromal tu- can mimic a pancreatic cancer {1507}. In neuroendocrine neoplasms must be ex-
mours (GISTs) of the second part of the most cases, magnetic resonance imaging cluded {1270}.
duodenum can infiltrate the pancreatic (MRI) can detect the lipomatous nature of Desmoplastic small round cell tumours.
head, and gastric GISTs can extend into these lesions. These are small round blue cell tumours
the pancreatic body and tail. The same is Solitary fibrous tumour. This neoplasm, characterized by a distinctive desmo-
true for retroperitoneal and gastrointesti- more commonly seen on the serosal sur- plastic stroma {1270, 2764} and can
nal leiomyosarcomas, liposarcomas, and faces of the peritoneum, has been de- occur adjacent to the pancreas. They
intra-abdominal desmoids. Whenever an scribed as an intrapancreatic mass have divergent differentiation, and ex-
intrapancreatic sarcoma (GIST, leiomyosar- {1919}. It is composed of bland spindle press keratins, desmin, and neuron-spe-
coma) is encountered, a search for an ex- cells in a variably collagenous to focally cific enolase (NSE) {1270}. Unlike PNETs,
trapancreatic primary is necessary. myxoid background, and a haeman- desmoplastic small round cell tumours do
giopericytoma-like vascular pattern is a not strongly express CD99. These tu-
Primary mesenchymal neoplasms usual finding. The neoplastic cells are mours typically harbour the EWSR1-WT1
The mesenchymal neoplasms that occur positive for CD34 and negative for KIT gene fusion.
primarily in the pancreas include most of and desmin. Others. Cystic schwannomas can clini-
the entities occurring primarily in soft tis- Perivascular epithelioid cell neoplasms cally mimic cystic epithelial neoplasms of
sues, but several deserve special note (PEComas). PEComas have been re- the pancreas {1087}. Both cystic and
{2184}. ported in the pancreas {1197, 2629, solid hamartomas have been reported in
Lymphangiomas. A small number of lym- 3672}. These well-vascularized neo- the pancreas {1270, 2209, 2503}. These
phangiomas of the pancreas have been plasms are composed of large, clear, ep- well-circumscribed lesions, composed of
reported, most commonly centred in the ithelioid smooth-muscle cells. They cystically dilated ducts, acini and fibrob-
peripancreatic tissues. These neoplasms variably express HMB45 and smooth lastic stroma, are important to recognize
often occur in young adults and tend to muscle actin, but not keratins. because they can mimic mesenchymal
be cystic {1307, 3129}. Lymphangiomas Ewing sarcoma. Tumours of this family and epithelial neoplasms of the pancreas
should be distinguished from serous cys- (peripheral primitive neuroectodermal tu- {1270, 2209, 2503}.
tadenomas of the pancreas. Serous cys- mours [PNETs]) have been reported in the
tic neoplasms will express keratins 7, 8, pancreas {2170}. These small round blue
A B
Fig. 12.76 Perivascular epithelioid cell neoplasm (PEComa). A PEComa involving the pancreas. B. Immunolabelling for HMB45.

Lymphoma of the pancreas E.S. Jaffe

J. Delabie
Y.H. Ko
S. Nakamura
Definition
Primary lymphoma of the pancreas is an
extranodal lymphoma arising in the pan-
creas, with the bulk of the disease local-
ized to this site. Contiguous lymph-node
involvement and distant spread may be
seen, but the primary clinical presentation
is in the pancreas.
Epidemiology
Primary lymphoma of the pancreas is very
rare, accounting for < 0.5% of pancreatic
tumours. As with primary lymphomas oc-
curring elsewhere in the digestive tract,
patients are more frequently elderly
{1341}.
Etiology
Pancreatic lymphomas may be associ-
ated with immunodeficiency; they may be
iatrogenic following solid-organ trans- Fig. 12.77 Diffuse large B-cell lymphoma involving the parenchyma of the pancreas.
plantation {423}, and they can arise in the
setting of infection with human immunod-
eficiency virus (HIV) {1445}. Pancreatic {3234}, and diffuse large B-cell lymphoma Prognosis
lymphoma has also been described in a (DLBCL) {1382, 2579}. Only extremely The distinction between lymphoma and
patient with short-bowel syndrome {1527}. rare cases of T-cell lymphomas present- carcinoma is important, as pancreatic
ing with pancreatic involvement have lymphomas are associated with better
Clinical features been reported {1996, 2374}. The histol- prognosis and may be curable even at an
The presentation of primary pancreatic ogy of these cases varies little from that advanced stage. Surgical resection does
lymphoma may mimic that of an epithelial seen elsewhere in the body. not play a role in clinical management of
neoplasm or pancreatitis {423}. Pain-free lymphoma of the pancreas. Therefore, di-
jaundice can occur {2260}. Ultrasonogra- Differential diagnosis agnosis before pancreatic resection is im-
phy may show an echo-poor lesion Autoimmune pancreatitis should be con- portant. Fine-needle aspiration or biopsy
{2260}. sidered in the differential diagnosis of with ancillary studies of immunopheno-
MALT lymphoma {2617}. Autoimmune type and molecular genetics can often
Histopathology pancreatitis is associated with increased lead to accurate diagnosis.
Primary pancreatic lymphomas are usu- levels of IgG4 in the serum. Histologically,
ally of B phenotype. Lymphomas of vari- autoimmune pancreatitis is characterized
ous types have been described, by a duct-centric mixed inflammatory cell
including follicular lymphoma {2091, infiltrate and venulitis. Large numbers of
2260, 2816}, lymphoma of mucosa-asso- the infiltrating plasma cells in autoimmune
ciated lymphoid tissue (MALT lymphoma) pancreatitis often express IgG4.

Secondary tumours of the pancreas C. Iacobuzio-Donahue

N. Fukushima
Definition
Neoplasms that have spread to the pan-
creas from an extra-pancreatic primary.
Origin
Both epithelial and nonepithelial neo-
plasms can metastasize to the pancreas.
The pancreas may be involved by direct
extension, or by lymphatic or haematoge-
nous spread from distant sites. Cancers
of the ampulla of Vater, duodenum and
Fig. 12.78 Renal cell carcinoma metastatic to the Fig. 12.79 Renal cell carcinoma (left) metastatic to the
distal common bile duct often involve the
pancreas. pancreas. A residual islet of Langerhans can be seen (right)
pancreas by direct extension. The most
common more distant malignancies that
metastasize to the pancreas are renal cell Macroscopy tasis, even after a previously negative or
carcinomas, melanomas, colorectal car- Metastases to the pancreas are most often inconclusive imaging study {709, 3409}.
cinomas, breast carcinomas and sarco- seen as circumscribed masses that may Lesions with the impression of having
mas {2650}. Occasionally, neoplasms have extensive haemorrhage and/or a cys- well-defined borders by EUS are more
may metastasize to the pancreas many tic component {29}. Pigmented melanomas likely to be a secondary tumour {709}.
years after diagnosis of the primary neo- can form discrete black or brown masses
plasm {53, 1120}. surrounded by normal pancreatic Differential diagnosis
parenchyma; renal cell carcinomas often The most problematic secondary neo-
Epidemiology have a yellow-orange cut surface. plasms to differentiate from a primary
Secondary neoplasms of the pancreas pancreatic neoplasm are metastases
account for 4–15% of all malignancies in Histopathology from the gastrointestinal tract, renal cell
the pancreas found at autopsy {29, 617, The diagnosis of a secondary neoplasm carcinomas and melanomas. Renal cell
2213}. Secondary neoplasms affect of the pancreas is often straightforward as carcinomas can be difficult to distinguish
males and females equally. As is true most patients will have a known history of from well-differentiated pancreatic neu-
for metastases in general, the highest an extra-pancreatic primary malignancy. roendocrine neoplasms, especially in pa-
incidence is in the sixth and seventh Metastases to the pancreas are histolog- tients with von Hippel-Lindau syndrome
decades of life. ically similar to their primary tumour of ori- {584, 1214}. Melanomas may mimic solid
gin. Multiple tumour foci with an abrupt pancreatic neoplasms with brisk mitotic
Localization transition from normal pancreas to the activity and nuclei with single prominent
Any anatomical region of the pancreas neoplastic tissue without signs of nucleoli, such as acinar cell carcinomas
may be involved and there is no site chronic pancreatitis in the surrounding or medullary carcinomas of the pancreas
predilection {1589}. Although usually multi- parenchyma support metastatic origin {29}. Breast cancer metastatic to the pan-
ple, metastases to the pancreas can also {29}. As expected, renal cell carcinomas creas is important to recognize because
be solitary, or they may diffusely involve the metastatic to the pancreas often have of the specific therapies available to treat
gland {1589}. clear cytoplasm, while the cells of some metastatic breast cancers. The
metastatic melanoma may produce patient's history and immunolabelling
Clinical features melanin and have prominent nucleoli. studies can help establish the correct
Similar to primary pancreatic neoplasms, diagnosis.
the early signs and symptoms of isolated Immunohistochemistry
pancreatic metastases are often nonspe- A panel of immunohistochemical markers Prognosis and predictive factors
cific and subtle. The most common can be employed to narrow possible or- Since in most cases pancreatic metas-
symptoms are abdominal pain, jaundice gans of origin in problematic cases or to tases indicate an advanced stage of dis-
and gastrointestinal bleeding {2650}. validate a clinical impression. ease, the prognosis is generally poor.
Many lesions are asymptomatic and de- Surgical resection may be beneficial in
tected on imaging studies performed to Cytopathology selected patients {2650}.
follow-up the patient's original primary Endoscopic ultrasound (EUS)-guided
neoplasm. fine-needle aspirations have a high sen-
sitivity in diagnosing a pancreatic metas-

Diagnostic algorithms for tumours D.S. Klimstra

N. Fukushima
of the pancreas R.H. Hruban
G. Klöppel
Introduction {1596}. The differentiation present in a Table 12.07 Frequency of selected pancreatic epithelial
A simple diagnostic algorithm that inte- pancreatic neoplasm may be obvious his- neoplasms.
grates gross and radiographic features tologically, but additional studies such as Entity Frequency
with histological and immunohistochemi- immunohistochemistry are needed in
cal findings can help classify neoplasms some cases (Table 12.09). Ductal adenocarcinoma 85%
of the pancreas {1600}. Most pancreatic Intraductal papillary mucinous neoplasm 3–5%
neoplasms can be accurately diagnosed Gross appearance
Pancreatic neuroendocrine neoplasm 3–4%
using the process detailed below, al- Most pancreatic neoplasms (ductal ade-
though some exceptions occur because nocarcinoma, pancreatic neuroendocrine Serous cystadenoma 1–2%
rare, and occasionally also some com- neoplasm, acinar cell carcinoma, pancre- Mucinous cystic neoplasm 1–2%
mon neoplasms, may demonstrate un- atoblastoma) typically form a solid mass.
usual features. Cystic neoplasms are less common, but Acinar cell carcinoma 1–2%
are increasingly recognized owing to the Solid-pseudopapillary neoplasm 1–2%
The basis for classifying pancreatic use of sensitive imaging techniques {34,
Pancreatoblastoma < 1%
neoplasms 1655, 1717}.
The classification of pancreatic epithelial Cystic change can occur via several
neoplasms appears to be long and com- mechanisms {1270}. The cysts of “true”
plex. However, it can be distilled into a cystic neoplasms are lined by a continu- nectivity between the native duct system
much shorter list if only the commonly en- ous layer of neoplastic epithelium. Other and a cystic lesion.
countered entities that encompass > 98% neoplasms develop secondary cystic
of all pancreatic neoplasms are consid- changes because of degeneration or Line of differentiation
ered (Table 12.07). Most pancreatic necrosis; this type of cystic change is The most common cellular differentiation in
neoplasms are infiltrating ductal adeno- characteristic in certain entities (solid- pancreatic neoplasms is ductal {1592}.
carcinomas {1270}. Each of the other pseudopapillary neoplasm) but uncom- Mucin can be demonstrated histochemi-
more commonly encountered entities monly may also affect most typically solid cally (periodic-acid-Schiff, or mucicarmine),
makes up only 1–5% of pancreatic neo- neoplasms. Intraductal neoplasms can and with immunohistochemical markers,
plasms, but these entities include some appear cystic due to dilatation of the na- which detect mucin-related antigens in-
of the most treatable pancreatic neo- tive pancreatic ducts {34, 929}. cluding CA19-9, carcinoembryonic antigen
plasms, so their proper recognition is very When present, the intraductal nature of a (CEA), and MUC1 {1600, 2126}. Finally,
important. cystic neoplasm is important to recog- expression of keratins 7 and 19 are most
The classification of pancreatic neo- nize. Careful gross evaluation and radi- typical of ductal differentiation {1785}, al-
plasms is based on: (1) the gross ap- ographic images can help define the though these keratins, particularly 19, are
pearance of the tumour (solid, cystic, or relationship between the duct system and also found in a subset of pancreatic neu-
intraductal) (Table 12.06); and (2) the the neoplastic cysts. By probing the roendocrine neoplasms {90}.
line(s) of cellular differentiation of the neo- larger pancreatic ducts, one can deter- Neuroendocrine differentiation is usually
plastic cells (ductal, acinar, or endocrine) mine the presence or absence of con- suggested by an organoid growth pattern
(nests and trabeculae) and typical nuclear
features (“salt and pepper” chromatin). En-
Table 12.06 Gross configuration of common pancreatic neoplasms. docrine differentiation can be demon-
strated by immunohistochemical labelling
Gross configuration Type Neoplasm with antibodies against the general neu-
roendocrine markers chromogranin A and
Ductal adenocarcinoma, acinar cell carcinoma, pancreatoblastoma,
Solid — synaptophysin {1876}. Acinar differentia-
pancreatic neuroendocrine neoplasm (solid-pseudopapillary neoplasm)a
tion may be suspected from the growth
True cysts Serous cystadenoma, mucinous cystic neoplasm pattern (formation of acini) and nuclear
features (single prominent nucleoli), but
Cystic
Intraductal Intraductal papillary mucinous neoplasm immunohistochemical labelling using anti-
bodies against the enzymes trypsin and
Solid-pseudopapillary neoplasm (ductal adenocarcinoma, acinar cell
Degenerative chymotrypsin is the most sensitive and
carcinoma, pancreatic neuroendocrine neoplasm)a
specific tool {1598, 1601}.
a
Entities in parentheses also uncommonly exhibit this gross configuration.

Diagnostic clues from the clinical Table 12.08 Sex ratio and location of common pancreatic neoplasms.
presentation Entity Males : Females Location
Clinical findings that can aid in the diag-
nosis of pancreatic neoplasms are age Ductal adenocarcinoma 1.3 : 1.0 Head > tail
and sex of the patient, location of the neo- Intraductal papillary mucinous neoplasm 1.5 : 1.0 Head > tail
plasm within the pancreas (head or tail),
Pancreatic neuroendocrine neoplasm 1.0 : 1.0 Head = tail
and presenting symptoms. For example,
a young woman with a cystic neoplasm in Serous cystadenoma 1.0 : 2.3 Head = tail
the tail of the pancreas is likely to have ei- Mucinous cystic neoplasm 1.0 : 20.0 Tail >>> head
ther a mucinous cystic neoplasm or a
Acinar cell carcinoma 3.6 : 1.0 Head = tail
solid-pseudopapillary neoplasm. An older
individual with a cystic lesion in the head Solid-pseudopapillary neoplasm 1.0 : 9.0 Head = tail
of the gland is more likely to have a
Pancreatoblastoma 1.7 : 1.0 Head = tail
serous cystic neoplasm or an intraductal
papillary mucinous neoplasm. Older
adults with solid neoplasms in the head of evaluation of a pancreatic neoplasm is to pancreatitis {1606}. The presence of hap-
the pancreas associated with jaundice, determine whether the lesion is solid or hazardly arranged glands in abnormal lo-
back pain, and weight loss have infiltrat- cystic. The entities included in the cystic cations (within the perineurium or
ing ductal adenocarcinomas until proven category should have a predominantly vascular spaces, or adjacent to muscular
otherwise. Pancreatic neoplasms pre- cystic appearance that is obvious on vessels or adipocytes,) and cytological
senting in the first decade of life are most gross examination or radiographic im- atypia (nuclear enlargement, loss of po-
commonly pancreatoblastomas, whereas ages, since some solid neoplasms can larity, and variation in size and shape of
teenagers usually develop solid-pseudo- contain small cysts caused by necrosis or nuclei among cells within a gland) all
papillary neoplasms or pancreatic neu- dilated, obstructed ducts. point to a diagnosis of carcinoma.
roendocrine neoplasms {2958}. When If the solid neoplasm is composed pre-
there is a pancreatic mass associated Solid neoplasms dominantly of neoplastic elements with lit-
with endocrine paraneoplastic syn- For solid neoplasms, the next step is to tle stroma, it will have a more cellular low
dromes, such as hyperinsulinaemic hypo- determine the density of the neoplastic power appearance, and the differential di-
glycaemia or Zollinger-Ellison syndrome, cells relative to the stroma, and the char- agnosis of these “solid, cellular pancre-
a well-differentiated pancreatic neuroen- acter of the stromal component. Is the atic neoplasms” includes pancreatic
docrine neoplasm is usually the diagno- neoplasm composed of relatively few neuroendocrine neoplasm, acinar cell
sis, whereas subcutaneous fat necrosis neoplastic elements associated with carcinoma, pancreatoblastoma, and
and polyarthralgia occur in association abundant stroma, or is it predominantly solid-pseudopapillary neoplasm {1592}.
with acinar cell carcinoma {1598}. neoplastic cells with little stroma? If the These four neoplasms are distinguished
Trousseau syndrome is a classic presen- neoplasm is composed of individually by their direction of differentiation. The
tation of ductal adenocarcinoma {1253}. arranged mucin-producing glands with a next step in the algorithm is therefore to
prominent desmoplastic stroma, it is likely determine the line(s) of differentiation for
The diagnostic algorithm to be an infiltrating ductal adenocarci- the solid cellular neoplasm. Neoplasms with
A simple diagnostic algorithm is illus- noma. The most important differential di- neuroendocrine differentiation, expressing
trated here {1270}. The first step in the agnosis in this case is chronic chromogranin A and synaptophysin,
Table 12.09 Immunohistochemical labelling of common pancreatic neoplasms.

Label Pancreatic neuroendocrine Acinar cell carcinoma Pancreatoblastoma Solid-pseudopapillary Ductal neoplasmsb
neoplasms neoplasms
Keratins 8/18 ++ ++ ++ F ++
Keratin 19 + – + – ++
Vimentin – – – + –
Trypsin/chymotrypsin – ++ ++ – –
Chromogranin ++ F + – F
Synaptophysin ++ F + + F
CD10 – – – ++ +
β-Catenin a
– + + ++ –
++, usually positive; +, may be positive; F, may be focally positive; –, usually negative.
a
Nuclear labelling.
b
Ductal neoplasms include infiltrating ductal adenocarcinoma, mucinous cystic neoplasm, intraductal papillary mucinous neoplasm and serous cystic neoplasms.

336
Gross configuration
Solid neoplasm Cystic neoplasm
Nature of epithelium and stroma Cyst structure
Tumours of the pancreas

Degenerative Epithelium-lined
Individual glands
Solid, cellular epithelium
Desmoplastic stroma
Minimal or hyalinized stroma
Mucin production
Ductal adenocarcinoma Predominant cellular differentiation
Acinar Neuroendocrine Undefined Serous Mucinous

(trypsin, chymotrypsin (chromogranin, synaptophysin (Vimentin, CD10, CD56, (cuboidal, clear cells) (columnar, mucin-filled cells)
immunolabelling) immunolabelling)
β-catenin [nuclear]
immunolabelling)
Ovarian-type stroma and
Separate from ducts
Squamoid nests?
Yes No Yes No
Pancreatic neuroendocrine Solid-pseudopapillary Mucinous cystic Intraductal papillary

Pancreatoblastoma Acinar cell carcinoma Serous cystic neoplasm
tumour (NET) neoplasm neoplasm mucinous neoplasm
Fig 12.80 Simple algorithm for the diagnostic evaluation of pancreatic neoplasms {1270}.
are usually well-differentiated pancreatic If the cysts are lined by neoplastic ep- the hypercellular ovarian-type subepithe-
neuroendocrine neoplasms. Neoplasms ithelium, then the nature of the neoplastic lial stroma of mucinous cystic neoplasms
with acinar differentiation are usually cells should be determined. Serous, is not found in IPMNs.
acinar cell carcinomas or pancreato- cuboidal, clear cells with uniform, round
blastomas {1598, 1602} and consistently hyperchromatic nuclei indicate either a Exceptions to the rules
express trypsin and chymotrypsin {1235, microcystic or macrocystic serous cys- Rare neoplasms are not included in the al-
1598}. Although most pancreatoblas- tadenoma {1610}. Mucin stains are nega- gorithm to prevent it from becoming un-
tomas arise in young children and acinar tive in serous cystadenomas, and wieldy. Also, some of the neoplasms in the
cell carcinoma affect adults, exceptions periodic acid-Schiff (PAS) stain will reveal algorithm have uncommon variants with fun-
occur, and the histological and immuno- intracellular glycogen, which is sensitive damentally different features that would
histochemical features of acinar cell car- to digestion with diastase. If mucinous place them elsewhere in the algorithm. For
cinoma and pancreatoblastoma overlap cells are present, then the next step is to example, acinar cell cystadenocarcinoma
extensively. determine whether the lesion is a true {408} is an inherently cystic neoplasm with
The single histological feature that most cystic neoplasm or an intraductal neo- acinar differentiation. Similarly, an intraductal
distinguishes pancreatoblastoma is the plasm {1270}. True cystic neoplasms that growth pattern can also occur rarely in
squamoid nest (corpuscle), which can be are separate from the ductal system and acinar cell carcinomas {213} as well as in
composed of vaguely whorled nests of also have cellular, ovarian-type subep- pancreatic neuroendocrine neoplasms.
cells with elongate nuclei and more cyto- ithelial stroma are mucinous cystic Pathologists need to keep these rarer le-
plasm than the surrounding acinar ele- neoplasms {3673}. Immunohistochemical sions in mind, especially when dealing with
ments, or of spindled cells with labelling for estrogen and progesterone a neoplasm that does not fit cleanly into one
keratinization {1602}. receptors can be used to demonstrate of the more common categories covered in
Cellular neoplasms composed of poorly this stroma, which is considered a requi- the algorithm.
cohesive cells lacking a clearly definable site feature for the diagnosis of mucinous As previously mentioned, rare pancreatic
line of differentiation and expressing cystic neoplasm {3239, 3673}. These neo- neoplasms have significant components
CD10, CD56 (NCAM1), α-1-antitrypsin, plasms occur almost exclusively in fe- of more than one cell type. For example,
and β-catenin (nuclear) are likely to be males (female to male ratio, at least 20 : 1) although they are predominantly acinar,
solid-pseudopapillary neoplasms {8, and nearly always arise in the tail of the pancreatoblastomas often have en-
1603, 2324}. Other histological features of pancreas. docrine and ductal differentiation. Rare
solid-pseudopapillary neoplasms include Neoplastic mucinous epithelium involving carcinomas have been described with all
degenerative pseudopapillae, loosely co- the duct system without associated ovar- different combinations of differentiation
hesive cells with grooved nuclei, aggre- ian-type stroma is characteristic of an in- (acinar-neuroendocrine, ductal-neuroen-
gates of large hyaline globules, and a traductal papillary mucinous neoplasm docrine, acinar-ductal, and acinar-neu-
giant-cell reaction to cholesterol crystals. (IPMN) {1106, 1271}. When an IPMN in- roendocrine-ductal) {182, 691, 1270,
volves one of the major pancreatic ducts, 2369}. These are not included in the al-
Cystic neoplasms it is relatively easy to confirm that the neo- gorithm. A final note is that metastases to
If a pancreatic neoplasm is cystic, the first plasm is intraductal. For branch-duct the pancreas from other organs (lung,
step is to determine whether the cystic IPMNs {3222}, it can be more difficult to ovary, breast, melanoma and kidney in
change is degenerative in nature or recognize grossly that the cystic struc- particular) do occur, although usually in
whether the cysts are lined by continuous tures represent dilated ducts, but micro- the context of widespread disease {29}.
epithelium (truly cystic or intraductal). If scopically there are periductal glands Some metastatic carcinomas have over-
the cystic change is degenerative, the surrounding the cysts, and the cysts are lapping features with primary pancreatic
noncystic regions of the neoplasm should separated by other pancreatic elements neoplasms, and in the case of infiltrating
be evaluated as though the tumour were (islets, non-neoplastic ducts, or acinar ductal adenocarcinoma, there is no pan-
solid. Degenerative cystic change is usu- cells). IPMNs appear as multiple separate creas-specific immunohistochemical
ally extensive in solid-pseudopapillary cysts on cross section, whereas muci- marker to allow easy distinction from a
neoplasm, and this is the solid neoplasm nous cystic neoplasms are single, multi- metastatic adenocarcinoma.
that would most often be placed (initially) locular cysts usually surrounded by a
on the cystic arm of the algorithm. fibrous pseudocapsule. Most importantly,

Contributors
Dr N. Volkan ADSAY* Dr Charles BALABAUD Dr Randall W. BURT

Department of Pathology Department of Hepatology Huntsman Cancer Institute
Emory University Hospital Hôpital Saint André University of Utah
1364 Clifton Road, NE, Room H180-B INSERM U889, Université Bordeaux 2 Salt Lake City, UT 84112
Atlanta, GA 30322 Place Amélie-Raba-Léon USA
USA 33076 Bordeaux Cedex Tel. +1 801 585 3281
Tel. +1 404 712 4179 FRANCE Fax. +1 801 581 3389
Fax. +1 404 727 2519 Tel. +33 5 57 57 17 71 (ext 76769) randall.burt@hci.utah.edu
volkan.adsay@emory.edu Fax. +33 5 56 51 40 77
charles.balabaud@chu-bordeaux.fr
Dr Dennis J. AHNEN Dr Marc BILLAUD Dr Carlo CAPELLA

Department of Medicine Laboratoire Génétique Moléculaire Department of Pathology
Denver Dept of Veterans Affairs Medical Center Signalisation et Cancer, CNRS UMR5201 Ospedale di Circolo
and University of Colorado School of Medicine Centre Léon Bérard, Bâtiment Cheney D Viale Borri 57
Denver, CO 80220 28, rue Laënnec, 69008 Lyon 21100 Varese
USA FRANCE ITALY
Tel. +1 303 399 8020 Tel: +33 4 69 16 66 56 Tel. +39 0332 270 601
Fax. +1 303 393 4168 Fax: +33 4 69 16 66 60 Fax. +39 0332 270 600
dennis.ahnen@ucdenver.edu billaud@lyon.fnclcc.fr carlo.capella@ospedale.varese.it
Dr Jorge ALBORES-SAAVEDRA* Dr Paulette BIOULAC-SAGE* Dr Fátima CARNEIRO*

Department of Pathology Department of Pathology, Hopital Pellegrin Institute of Molecular Pathology and Immunology
Instituto Nacional de Ciencias Medicas Centre Hospitalier Universitaire Bordeaux of the University of Porto (IPATIMUP)
y Nutricion Salvador Zubiran INSERM U889, Université Bordeaux 2 and University Hospital S.João/Faculty
Vasco de Quiroga 15, Col. Seccion XVI Place Amélie-Raba-Léon of Medicine of the University of Porto,
Talpan 14000, CP 14400 Mexico D.F. 33076 Bordeaux Cedex Rua Dr Roberto Frias s/n, 4200-465 Porto
MEXICO FRANCE PORTUGAL
Tel. +52 55 548 70900 Tel. +33 5 56 79 56 02 Tel. +351 225 570 700
Fax. +52 55 548 53489 Fax. +33 5 56 79 60 88 Fax. +351 225 570 799
alboresjorge@yahoo.com paulette.bioulac-sage@chu-bordeaux.fr fcarneiro@ipatimup.pt
Dr Stefan ARETZ Dr Paolo BOFFETTA Dr Norman J. CARR

Institute of Human Genetics Section of Environment School of Medicine
Biomedical Center, University Hospital Bonn International Agency for Research University of Southampton
Sigmund-Freud Strasse 25 on Cancer (IARC) Mailpoint 801, Southampton General Hospital
53127 Bonn 150 cours Albert Thomas Tremona Road,
GERMANY 69372 Lyon cedex 08 Southampton S016 6YD
Tel. +49 228 287 51009 FRANCE UK
Fax. +49 228 287 51011 paolo.boffetta@mssm.edu Tel. +44 23 8079 5107
Stefan.Aretz@uni-bonn.de Fax. +44 23 8079 4760
carrnj@doctors.org.uk
Dr Rudolf ARNOLD Dr Fredrik T. BOSMAN* Dr Parakrama CHANDRASOMA

Wittelsbacherstrasse 6 University Institute of Pathology Keck School of Medicine
80469 Munich Rue du Bugnon 25 University of Southern California
GERMANY 1011 Lausanne LAC-USC Medical Center CT-7A-121
Tel. + 49 892 016 359 SWITZERLAND 1100 N State Street, Los Angeles, CA 90033
Fax. + 49 892 020 5564 Tel. +41 21 314 7202 USA
arnoldr@mailer.uni-marburg.de Fax. +41 21 314 7205 Tel. +1 323 409 4600
fred.bosman@chuv.ch Fax. +1 323 441 8183
ptchandr@usc.edu
*The asterisk indicates participation in the

Working Group Meeting on the Classification
of Tumours of the Digestive System that was
held in Lyon, France, December 10–12, 2009
338 Contributors
Dr Amanda CHARLTON Dr Charis ENG Dr Noriyoshi FUKUSHIMA*

Dept of Molecular Medicine and Pathology Genomic Medicine Institute Department of Pathology
Faculty of Medical and Health Sciences Cleveland Clinic Jichi Medical University
University of Auckland 9500 Euclid Avenue, NE-50 3311-1 Yakushiji, Shimotsuke-shi
Private Bag 92019 Cleveland, OH 44195 329-0498 Tochigi
Auckland USA JAPAN
NEW ZEALAND Tel. +1 216 444 3440 Tel. +81 285 58 7330
Tel. +64 9 373 7599 Fax. +1 216 636 0655 Fax. +81 285 44 8467
a.charlton@auckland.ac.nz engc@ccf.org nfukushima@jichi.ac.jp
Dr James M. CRAWFORD Dr Linda FERRELL Dr Toru FURUKAWA

Dept of Pathology and Laboratory Medicine Department of Anatomic Pathology Institute for Integrated Medical Sciences
North Shore-LIJ Health System University of California, San Francisco Tokyo Women’s Medical University
North Shore-LIJ Core Laboratory 505 Parnassus Avenue, M-590, Box 0102 8-1 Kawada-cho, Shinjuku-ku
10 Nevada Drive, San Francisco, CA 94143 162-8666 Tokyo
Lake Success, NY 11042-1114 USA JAPAN
USA Tel. +1 415 353 1090 Tel. +81 3 3353 8111 Ext 29675
Tel. +1 516 719 1060 Fax. +1 415 353 1200 Fax. +81 3 3352 3088
Fax. +1 516 719 1061 linda.ferrell@ucsf.edu toru.furukawa@twmu.ac.jp
jcrawford1@nshs.edu
Dr Maria-Paula CURADO Dr John K. FIELD Dr Karel GEBOES

Section of Cancer Information Roy Castle Lung Cancer Research Programme Department of Pathology
International Agency for Research University of Liverpool, Cancer Research Centre University Hospital, K.U. Leuven
on Cancer (IARC) Roy Castle Building Minderbroedersstraat 12
150 cours Albert Thomas 200 London Road 3000 Leuven
69372 Lyon cedex 08 Liverpool, L3 9TA BELGIUM
FRANCE UK Tel. + 32 16 33 65 84
Tel. + 44 151 794 8901/8900 Fax. + 32 16 33 65 48
Fax. + 44 151 794 8989 karel.geboes@uz.kuleuven.ac.be
j.k.field@liv.ac.uk
Dr Yataro DAIGO Dr Jean-François FLÉJOU* Dr Robert M. GENTA

Laboratory of Molecular Medicine Service d’Anatomie Pathologique Department of Pathology
Human Genome Center Hôpital Saint-Antoine Dallas Veterans Affairs Medical Center
Institute of Medical Science, University of Tokyo Faculté de Médecine Pierre et Marie Curie University of Texas Southwestern Medical School
4-6-1 Shirokanedai Minato-ku 184, rue du Faubourg Saint-Antoine 5323 Harry Hines Blvd
108-8639 Tokyo 75571 Paris Cedex 12 Dallas, TX 75390-9072
JAPAN FRANCE USA
Tel. +81 3 5449 5457 Tel. + 33 1 49 28 30 12 Tel. +1 214 596 7440
Fax. +81 3 5449 5406 Fax. + 33 1 49 28 28 78 Fax. +1 214 596 2297
ydaigo@ims.u-tokyo.ac.jp jean-francois.flejou@sat.aphp.fr robert.genta@utsouthwestern.edu
Dr Jan DELABIE Dr Christopher D.M. FLETCHER Dr Francis M. GIARDIELLO

Department of Pathology Department of Pathology The Johns Hopkins Hospital
The Norwegian Radium Hospital Brigham and Women’s Hospital 1830 E Monument Street
University of Oslo and Harvard Medical School Baltimore, MD 21205
0310 Oslo 75 Francis Street USA
NORWAY Boston, MA 02115 Tel. +1 410 955 2635
Tel. +47 22934879 USA Fax. +1 410 614 8337
Fax. +47 22730164 Tel. +1 617 732 8558
jan.delabie@labmed.uio.no Fax. +1 617 566 3897
cfletcher@partners.org
Dr Cathy ENG Dr Silvia FRANCESCHI Dr Gregory GORES

Dept of Gastrointestinal Medical Oncology Section of Infections Division of Gastroenterology and Hepatology
University of Texas MD Anderson Cancer Center International Agency for Research on Cancer Mayo Clinic College of Medicine
1515 Holcombe Blvd, Unit 426 (IARC) 200 1st Street SW
Houston, TX 77030 150 cours Albert Thomas Rochester, MN 55905
USA 69372 Lyon cedex 08 USA
Tel. +1 713 792 2828 FRANCE Tel. +1 507 284 0686
Fax. +1 713 794 1873 Tel. +33 4 72 73 84 02 Fax. + 1 507 284 0762
ceng@mdanderson.org Fax.+33 4 72 73 83 45 gores.gregory@mayo.edu
franceschi@iarc.fr
Contributors 339
Dr David Y. GRAHAM Dr Heinz HÖFLER Dr Mohammad ILYAS

Dept of Medicine/Gastroenterology Department of Pathology School of Molecular Medical Sciences
Michael E DeBakey VA Medical Center Technical University of Munich Faculty of Medicine & Health Sciences
and Baylor College of Medicine Ismaningerstrasse 22 University of Nottingham
Rm 3A-320 (111D) 2002 Holcombe Blvd 81675 Munich Level A, West Block, Queens Medical Centre
Houston, TX 77030 GERMANY Nottingham NG7 2UH
USA Tel. +49 89 4140 4160 UK
Tel. +1 713 794 7280 Fax. +49 89 4140 4865 Tel. +44 115 8230735
Fax. +1 713 795 4471 hoefler@lrz.tum.de Fax. +44 115 823 0759
dgraham@bcm.tmc.edu mohammad.ilyas@nottingham.ac.uk
Dr Gabriel M. GROISMAN Dr James R. HOWE Dr Elaine S. JAFFE

Department of Pathology Department of Surgery Hematopathology Section, Laboratory
Hillel Yaffe Medical Center University of Iowa College of Medicine of Pathology, Center for Cancer Research
Hadera 38100 Iowa City, IA 52242-1086 National Cancer Institute
ISRAEL USA 10 Center Drive MSC 1500
Tel. +972 4 630 4627 Tel. +1 319 356 1727 Bethesda, MD 20892
Fax. +972 4 630 4630 Fax. +1 319 353 8940 USA
groisman@hy.health.gov.il james-howe@uiowa.edu Tel. +1 301 496 0183
Fax. +1 301 402 2415
elainejaffe@nih.gov
Dr Stephen B. GRUBER Dr Ralph H. HRUBAN* Dr Heikki J. JÄRVINEN

Division of Molecular Medicine and Genetics Department of Pathology Department of Surgery
University of Michigan The Sol Goldman Pancreatic Cancer Research Helsinki University Central Hospital
4301 MSRB III Center, Johns Hopkins Medical Institutions Haartmaninkatu 4, PO Box 340
Ann Arbor, MI 48109-0652 401 N. Broadway, Weinberg 2242 00029 HUS Helsinki
USA Baltimore, MD 21231-2410 FINLAND
Tel. +1 734 615 9712 USA Tel. +358 947173852
Fax. +1 734 647 7950 Tel. +1 410 955 9132 Fax. +358 947174675
sgruber@umich.edu Fax. +1 410 955 0115 heikki.jarvinen@hus.fi
rhruban@jhmi.edu
Dr Stanley R. HAMILTON* Dr David G. HUNTSMAN Dr Yo KATO

Division of Pathology and Laboratory Medicine Department of Pathology Department of Pathology
University of Texas MD Anderson Cancer Center British Columbia Cancer Agency - CTAG Lab Cancer Institute, JFCR
1515 Holcombe Blvd, Unit 85 3427-600 West 10th Avenue 3-10-6 Ariake, Koto-ku
Houston,TX 77030 Vancouver, BC V5Z 4E6 135-8550 Tokyo
USA CANADA JAPAN
Tel. + 1 713 792 2040 Tel. +1 604 877 6000 Ext 2148 Tel. +81 3 3520 0111
Fax. +1 713 792 4094 Fax. +1 604 877 6089 Fax. +81 3 3570 0558 / +81 3 5879 8846
shamilto@mdanderson.org dhuntsma@bccancer.bc.ca kato@jfcr.or.jp
Dr Takanori HATTORI Dr Prodromos HYTIROGLOU* Dr Scott E. KERN

Shiga University of Medical Science Department of Pathology Department of Oncology
Seta Tsukinowa-Cho, Ohtsu Aristotle University Medical School Johns Hopkins University
520-2192 Shiga 54006 Thessaloniki 1650 N. Orleans Street, CRB 451
JAPAN GREECE Baltimore, MD 21231
Tel. +81 77 548 2002 Tel. +302 310 999 218 USA
Fax. +81 77 543 9880 Fax. +302 310 999 229 Tel. +1 410 614 3314
hattori@belle.shiga-med.ac.jp phitir@med.auth.gr Fax. +1 443 287 4653
skern1@jhmi.edu
Dr Nobuyoshi HIRAOKA Dr Christine IACOBUZIO-DONAHUE Dr Lars-Gunnar KINDBLOM

Pathology Division Department of Pathology Department of Musculoskeletal Pathology
National Cancer Center Research Institute The Sol Goldman Pancreatic Cancer Research Royal Orthopaedic Hospital NHS Trust
5-1-1 Tsukiji, Chuo-ku Center, Johns Hopkins Medical Institutions University of Birmingham Medical School
104-0045 Tokyo 1550 Orleans Street, CRB II Room 343 Bristol Road South, Northfield
JAPAN Baltimore, MD 21231 Birmingham B31 2AP
Tel. +81 3 3542 2511 USA UK
Fax. +81 3 3248 2463 Tel. +1 410 955 3511 Tel. + 44 12 1414 7643
nhiraoka@gan2.res.ncc.go.jp Fax. +1 410 614 0671 Fax. + 44 12 1414 7640
ciacobu@jhmi.edu lars.kindblom@roh.nhs.uk
340 Contributors
Dr David S. KLIMSTRA* Dr René LAMBERT Dr Hans MORREAU*

Department of Pathology Section of Early Detection and Prevention Department of Pathology
Memorial Sloan-Kettering Cancer Center International Agency for Research on Cancer Leiden University Medical Center
1275 York Avenue (IARC) Albinusdreef 2,
New York, NY 10065 150 cours Albert Thomas PO Box 9600
USA 69372 Lyon cedex 08 2333 ZA Leiden
Tel. +1 212 639 2410 FRANCE THE NETHERLANDS
Fax. +1 646 422 2016 Tel. +33 4 72 73 84 99 Tel. +31 71 526 6630
klimstrd@mskcc.org Fax: + 33 4 72 73 85 18 Fax. +31 71 526 6952
lambert@iarc.fr j.morreau@lumc.nl
Dr Günter KLÖPPEL* Dr Gregory Y. LAUWERS* Dr Hans Konrad MÜLLER-HERMELINK

Department of Pathology Department of Pathology Institute of Pathology
TU-Munich Massachusetts General Hospital University of Würzburg
Ismaningerstrasse 22 and Harvard Medical School Josef Schneider Srt. 2
81675 Munich 55 Fruit Street 97080 Würzburg
GERMANY Boston, MA 02114-2696 GERMANY
Tel. +49 89 4140 6158 USA Tel. +49 931 2014 7776/+49 931 2014 7427
Fax. +49 89 4140 4865 Tel. +1 617-726-0931 Fax. +49 931 2014 7440
Guenter.Kloeppel@lrz.tu-muenchen.de Fax. +1 617-726-0982 Konrad.mh@mail.uni-wuerzburg.de
glauwers@partners.org
Dr Young Hyeh KO Dr Anirban MAITRA Dr Shin-ichi NAKAMURA*

Department of Pathology Department of Pathology Diagnostic Pathology Research Co., Ltd
Samsung Medical Center The Sol Goldman Pancreatic Cancer Research 10-53 Mitake 4
Sungkyunkwan University Center, Johns Hopkins Medical Institutions 020-0122 Morioka
Gangnam-gu, Irwondong 50 1550 Orleans Street, CRB II, Room 345 JAPAN
135-710 Seoul Baltimore, MD 21231 Tel. +81 19 648 1432
REPUBLIC OF KOREA USA Fax. +81 19 648 1386
Tel. +82 02 3410 2762 Tel. +1 410 955 3511 nakamurashin@grace.ocn.ne.jp
Fax. +82 02 3410 0025 Fax. +1 410 614 0671
yhko310@skku.edu amaitra1@jhmi.edu
Dr Paul KOMMINOTH Dr Markku MIETTINEN Dr Shigeo NAKAMURA

Institute of Pathology, Stadtspital Triemli Department of Soft Tissue Department of Pathology
Birmendorferstrasse 497 and Orthopedic Pathology and Laboratory Medicine
CH-8063 Zurich Armed Forces Institute of Pathology Nagoya University Hospital
SWITZERLAND 6825 16th Street NW Bldg 54 65 Tsurumai-cho, Showa-ku
Tel. +41 444 662122 Washington, DC 20306-6000 466-8550 Nagoya
Fax. +41 444 662138 USA JAPAN
paul.komminoth@triemli.stzh.ch Tel. +1 202 782 1575 Tel. +81 52 744 2896
Fax. +1 202 782 9182 Fax. +81 52 744 2897
Markku.Miettinen@us.army.mil snakamur@med.nagoya-u.ac.jp
Dr Masatoshi KUDO Dr Elizabeth MONTGOMERY* Dr Yasuni NAKANUMA

Department of Gastroenterology and Hepatology Department of Pathology Department of Human Pathology
Kinki University School of Medicine Johns Hopkins Medical Institutions Kanazawa University
377-2, Ohno-Higashi 401 N Broadway, Weinberg 2242 Graduate School of Medicine
Osaka-Sayama Baltimore, MD 21231-2410 Takaramachi 13-1
589-8511 Osaka USA 920-8640 Kanazawa
JAPAN Tel. +1 410 614 2308 JAPAN
Tel. +81 72 366 0221 Fax. +1 443 287 3818 Tel. +81 076 265 2195
Fax. +81 72 367 2880 emontgom@jhmi.edu Fax. +81 076 234 4229
m-kudo@med.kindai.ac.jp pbcpsc@kenroku.kanazawa-u.ac.jp
Dr Sunil R. LAKHANI* Dr Toshio MOROHOSHI Dr Osamu NAKASHIMA

Molecular and Cellular Pathology First Department of Pathology Department of Pathology
The University of Queensland Centre for Showa University School of Medicine Kurume University School of Medicine
Clinical Research and School of Medicine 1-5-8 Hatanodai, Shinagawa-ku 67 Asahi-machi
The Royal Brisbane & Women’s Hospital 142-8555 Tokyo 830-0011 Kurume-shi
Herston, 4029, Brisbane QLD JAPAN JAPAN
AUSTRALIA Tel. +81 3 3784 8118 Tel. +81 942 31 7546
Tel. +61 7 3346 6052 Fax. +81 3 3784 8249 Fax. +81 942 32 0905
Fax. +61 7 3346 5596 moro@med.showa-u.ac.jp osamu31@med.kurume-u.ac.jp
s.lakhani@uq.edu.au
Contributors 341
Dr Amy E. NOFFSINGER Dr Valérie PARADIS Dr Robert H. RIDDELL*

Department of Pathology Service d’Anatomie Pathologique Department of Pathology
and Laboratory Medicine Hôpital Beaujon and Laboratory Medicine, Mount Sinai Hospital
University of Cincinnati 100 Boulevard Général Leclerc Joseph & Wolf Lebovic Health Complex
234 Goodman Ave ML 0533 92118 Clichy 600 University Ave
Cincinnati, OH 45219 FRANCE Ontario, M5G 1X5 Toronto
USA Tel. +33 1 40 87 54 63 CANADA
Tel. +1 513 584 3837 Fax. +33 1 40 87 00 77 Tel. +1 416 586 4768
Fax. +1 513 584 3892 vparadis@teaser.fr Fax. +1 416 586 8481
amy.noffsinger@uc.edu RRiddell@mtsinai.on.ca
Dr Kenji NOTOHARA Dr Young Nyun PARK Dr Guido RINDI*

Department of Pathology Department of Pathology and Severance Institute of Anatomic Pathology
Kurashiki Central Hospital Medical Research Institute Catholic University Sacro Cuore
1-1-1 Miwa, Kurashiki Yonsei University College of Medicine Policlinico A. Gemelli
710-8602 Okayama CPO Box 8044 Seoul Largo A. Gemelli, 8
JAPAN REPUBLIC OF KOREA 00168 Rome
Tel. +81 86 422 0210 Tel. +82 2 2228 1768 ITALY
Fax. +81 86 421 3424 Fax. +82 2 362 0860 Tel. +39 06 3015 5883
notohara@kchnet.or.jp young0608@yuhs.ac Fax. +39 06 3015 7008
guido.rindi@rm.unicatt.it
Dr Robert D. ODZE* Dr Paivi PELTOMAKI Dr Massimo RUGGE

Pathology Department Department of Medical Genetics Department of Pathology
Brigham and Women’s Hospital Haartman Institute University of Padova
Harvard Medical School P.O. Box 63, Haartmaninkatu 8 Via Aristide Gabelli, 61
75 Francis Street FI-00014 University of Helsinki 35100 Padova
Boston, MA 02115 FINLAND ITALY
USA Tel. +358 9 1912 5092 Tel. + 39 049 827 2248
Tel. +1 617 732 7549 Fax. +358 9 1912 5105 Fax. + 39 049 827 2277
Fax. +1 617 278 6950 paivi.peltomaki@helsinki.fi massimo.rugge@unipd.it
rodze@partners.org
Dr G. Johan A. OFFERHAUS* Dr Martha Bishop PITMAN Dr Michiie SAKAMOTO*

Department of Pathology Department of Pathology Department of Pathology
University Medical Center Utrecht Harvard Medical School Keio University School of Medicine
PB 85500 Massachusetts General Hospital 35 Shinanomachi, Shinjuku-ku
3508 GA Utrecht 55 Fruit Street, WRN 2 160-8582 Tokyo
THE NETHERLANDS Boston MA 02114 JAPAN
Tel. +31 88 7556561 USA Tel. +81 3 5363 3762
Fax. +31 30 2544990 Tel. +1 617 726 3185 Fax. +81 3 3353 3290
g.j.a.offerhaus@umcutrecht.nl Fax. +1 617 724 6564/+1 617 726 7474 msakamot@sc.itc.keio.ac.jp
mpitman@partners.org
Dr Hiroko OHGAKI* Dr Phil QUIRKE Dr Romil SAXENA*

Section of Molecular Pathology Wellcome Trust Brenner Building Clarian Pathology Laboratory
International Agency for Research on Cancer Leeds Institute of Molecular Medicine Indiana University
(IARC) University of Leeds St James’s University Hospital 350 West 11th Street, Room 4056
150 cours Albert Thomas Beckett Street Indianapolis, IN 46202-4108
69372 Lyon cedex 08 Leeds, LS9 USA
FRANCE UK Tel. +1 317 491 6487
Tel. +33 4 72 73 85 34 Tel. +44 113 343 8407 Fax. +1 317 491 6419
Fax. +33 4 72 73 86 98 Fax. +44 113 34 38 431 rsaxena@iupui.edu
ohgaki@iarc.fr P.Quirke@leeds.ac.uk
Dr Nobuyuki OHIKE Dr Elio RIBOLI Dr Neil A. SHEPHERD

First Department of Pathology Dept of Epidemiology and Public Health Gloucestershire Cellular Pathology Laboratory
Showa University School of Medicine Imperial College, St Mary’s Campus Cheltenham General Hospital
1-5-8 Hatanodai, Shinagawa-ku Norfolk Place Sandford Road
142-8555 Tokyo Paddington Cheltenham
JAPAN London W2 1PG Gloucestershire GL53 7AN
Tel. + 81 3 3784 8118 UK UK
Fax. +81 3 3784 8249 Tel. +44 20 7594 1913 Tel. +44 8454 223304
ohike@med.showa-u.ac.jp Fax. +44 20 7262 1034 Fax. +44 8454 223318
e.riboli@imperial.ac.uk neil.shepherd@glos.nhs.uk
342 Contributors
Dr Michio SHIMIZU Dr Banchob SRIPA Dr J. Han VAN KRIEKEN

Department of Pathology Department of Pathology Department of Pathology, 824 PA
Saitama International Medical Center Faculty of Medicine Radboud University Nijmegen Medical Centre
1397-1 Yamane Hidaka-shi Khon Kaen University PO Box 9101
Saitama 123 Mitraparp Road NL-6500HB Nijmegen
JAPAN 40002 Khon Kaen THE NETHERLANDS
Tel. +81 42 984 4625 THAILAND Tel. +31 24 361 4352
Fax. +81 42 984 0609 Tel. +66 43 363113 Fax. +31 24 366 8750
shimizu@saitama-med.ac.jp Fax. +66 43 202024 J.vanKrieken@pathol.umcn.nl
banchob@kku.ac.th
Dr Tadakazu SHIMODA* Dr Masae TATEMATSU Dr Hans F.A. VASEN

Cancer Control and Information Services Division of Oncological Pathology The Netherlands Foundation for the Detection
National Cancer Center Aichi Cancer Center Research Institute of Hereditary Tumours & Department
5-1-1 Tsukiji Chuo Ku 1-1 Kanokoden, Chikusa-ku of Gastroenterology and Hepatology
104-0045 Tokyo 464-8681 Nagoya Leiden University Medical Center
JAPAN JAPAN 2300 RC Leiden
Tel. +813 3542 2511 Tel. +81 052 802 8600 THE NETHERLANDS
Fax. +813 3457 5013 Fax. +81 052 802 8700 Tel. +31 71 52 62 687
tshimoda@ncc.go.jp mtate821@dream.ocn.ne.j Fax.+ 31 71 52 12 137
hfavasen@stoet.nl
Dr Dale C. SNOVER* Dr Benoit TERRIS* Dr Michael VIETH

Department of Pathology Service d’Anatomie Pathologique Institute of Pathology, Klinikum Bayreuth
Fairview Southdale Hospital Hôpital Cochin Preuschwitzer Strasse 101
6401 France Ave S 27 rue du Faubourg Saint-Jacques 95445 Bayreuth
Minneapolis, MN 55435 75679 Paris cedex 14 GERMANY
USA FRANCE Tel. +49 921 400 502
Tel. +1 952 924 5152 Tel. +33 1 58 41 14 79 Fax. +49 921 400 5609
Fax. +1 952 924 5256 Fax. +33 1 58 41 14 80 vieth.lkpathol@uni-bayreuth.de
snoverd@umn.edu benoit.terris@cch.ap-hop-paris.fr
Dr Leslie H. SOBIN* Dr Neil D. THEISE* Dr Ian WANLESS

Division of Gastrointestinal Pathology Division of Digestive Diseases MacKenzie Building, 7th floor
Armed Forces Institute of Pathology Beth Israel Medical Center QEII HSC, Anatomic Pathology
Washington, DC 20306 First Avenue at 16th Street 740-5788 University Avenue
USA New York, NY 10003 Halifax, Nova Scotia, B3H 1V8
Tel. +1 202 364 8358 USA CANADA
sobin@uicc.org Tel. +1 212 420 2211/+1 212 420 4246 Tel. +1 902 473 7713/+1 902 473 5236
Fax. +1 212 420 4373 Fax. +1 902 473 1049
ntheise@chpnet.org ian.wanless@cdha.nshealth.ca
Dr Enrico SOLCIA Dr Michael TORBENSON Dr Bryan F. WARREN

Department of Human Pathology and Genetics Department of Pathology Cellular Pathology
University of Pavia and IRCCS The Johns Hopkins University School John Radcliffe Hospital
Policlinico San Matteo of Medicine Oxford OX3 9DU
Via Forlanini 16 1503E Jefferson (Bond Street Building) UK
27100 Pavia Baltimore, MD 21231 Tel. +44 1865 220499
ITALY USA Fax.+44 1865 220519
Tel. +39 0382 528 474-5-6-7 Tel. +1 443 287 4730 wbf7warren@aol.com
Fax. +39 0382 525 866 Fax. +1 410 502 5158
solciae@smatteo.pv.it mtorben@jhmi.edu
Dr Stuart Jon SPECHLER Dr Wilson M.S. TSUI Dr Aileen WEE

Division of Gastroenterology Departement of Pathology Department of Pathology
UT Southwestern Medical Center at Dallas Caritas Medical Centre Yong Loo Lin School of Medicine
4500 South Lancaster Road Wing Hong Street, Shamshuipo National University of Singapore
Dallas, TX 75216 Kowloon National University Hospital
USA Hong Kong SAR Main Building, Level 3, Singapore 119074
Tel. +1 214 374 7799 CHINA SINGAPORE
Fax. +1 214 857 1571 Tel. +852 3408 7961 Tel. +65 6772 4305
sjspechler@aol.com Fax. +852 2745 1804 Fax. +65 6778 0671
mstsui@ha.org.hk aileen_wee@nuhs.edu.sg
Contributors 343
Dr Mark Lane WELTON Dr Giuseppe ZAMBONI* Dr Arthur ZIMMERMANN

Department of Surgery Department of Pathology Institute of Pathology of the University
Stanford University School of Medicine University of Verona Murtenstrasse 31
875 Blake Wilbur Drive, Rm CC2213 Ospedale Sacro Cuore-Don Calabria P.O. Box 62
Stanford, CA 94305-5820 Via don Sempreboni 5 CH – 3010 Bern
USA 37024 Negrar-Verona SWITZERLAND
Tel. +1 650 721 1792 ITALY Tel. +41 31 632 32 22 / 632 99 50
Fax. +1 650 736 8136 Tel. +39 045 6013 415 Fax. +41 31 632 49 95
MWelton@Stanfordmed.org Fax. +39 045 7500 480 zimmerma@patho.unibe.ch
giuseppe.zamboni@sacrocuore.it
IARC/WHO Committee for the International Classification

of Diseases for Oncology (ICD-O)
Dr Jean FAIVRE Dr Robert JAKOB Dr Kanagaratnam SHANMUGARATNAM

Registre Bourguignon des Cancers Digestifs Classifications and Terminologies Department of Pathology
Faculté de Médecine Evidence and Information for Policy National University Hospital
7 boulevard Jeanne d’Arc World Health Organization (WHO) 5 Lower Kent Ridge Road
21079 Dijon cedex 20 Avenue Appia Singapore 119074
FRANCE 1211 Geneva 27 SINGAPORE
Tel. +33 3 80 39 33 40 SWITZERLAND Tel. +65 67724312
Fax +33 3 80 66 82 51 Tel. +41 22 791 58 77 Fax +65 6773 6021
jean.faivre@u-bourgogne.fr Fax +41 22 791 48 94 k_shanmugaratnam@nuhs.edu.sg
jakobr@who.int
Dr David FORMAN Dr Paul KLEIHUES Dr Leslie H. SOBIN

Section of Cancer Information Department of Pathology Division of Gastrointestinal Pathology
International Agency for Research on Cancer University Hospital Zurich Armed Forces Institute of Pathology
(IARC) Schmelzbergstrasse 12 Washington, DC 20306
150 cours Albert Thomas 8091 Zurich USA
69372 Lyon cedex 08 SWITZERLAND Tel. +1 202 364 8358
FRANCE Tel. +41 44 255 2502 sobin@uicc.org
Tel. +33 4 72 73 80 56 Fax +41 44 255 2525
Fax +33 4 72 73 86 96 paul.kleihues@usz.ch
formand@iarc.fr
Mrs April FRITZ Dr Hiroko OHGAKI

April Fritz and Associates, LLC Section of Molecular Pathology
21361 Crestview Road International Agency for Research on Cancer
Reno, NV 89521 (IARC)
USA 150 Cours Albert Thomas
Tel. +1 775 636 7243 69372 Lyon cedex 08
Fax +1 888 891 3012 FRANCE
april@afritz.org Tel. +33 4 72 73 85 34
Fax +33 4 72 73 86 98
ohgaki@iarc.fr
Dr Elaine S. JAFFE Dr D. Maxwell PARKIN

Hematopathology Section Clinical Trials Service and Epidemiology
Laboratory of Pathology Studies Unit
Center for Cancer Research University of Oxford
National Cancer Institute Richard Doll Building, Old Road Campus
10 Center Drive MSC 1500 Roosevelt Drive, Headington
Bethesda, Maryland 20892 Oxford OX3 7LF
USA UK
Tel. +1 301 496 01 83 Tel. +44 1865 743663
Fax +1 301 402 24 15 Fax +44 1865 743985
elainejaffe@nih.gov ctsu0138@herald.ox.ac.uk
344 Contributors
Source of charts and photographs
2.01 A IARC {842A} 4.08 A,B Lauwers G.Y. 5.10 A,B Albores-Saavedra J.
2.01 B IARC {842} 4.09 Fenoglio-Preiser C. 5.11 A,B Albores-Saavedra J.
2.02 Japanese Esophageal Cancer 4.10 Lauwers G.Y. 5.12 Albores-Saavedra J.
Society {1388} 4.11 A,B Lauwers G.Y. 5.13 A,B Albores-Saavedra J.
2.03 A,B Shimoda T. 4.12 Lauwers G.Y 5.14 Klöppel G.
2.04 A-C Shimoda T. 4.13 A-D Hattori T. 5.15 A,B Klöppel G.
2.05 A Shimizu M. 4.14 A,B Lauwers G.Y. 5.16 Klöppel G.
2.05 B Gabbert H.E. 4.15 Lauwers G.Y. 5.17 A,B Klöppel G.
Institute of Pathology, 4.16 Lauwers G.Y. 5.18 Albores-Saavedra J.
Heinrich Heine University, 4.17 A,B Shimoda T. 5.19 Albores-Saavedra J.
Dusseldorf, Germany 4.18 A Charlton A. {493}
2.06 Montgomery E. 4.18 B Charlton A.
2.07 A,B Shimoda T. 4.19 A Shaw D. {2910} 6.01 Fenoglio-Preiser C.
2.08 A-C Shimizu M. 4.19 B Charlton A. 6.02 Shepherd N.A.
2.09 A,B Shimoda T. 4.20 Charlton A. 6.03 Shepherd N.A.
2.10 A-C Dunbar K.B. 4.21 Carneiro F. 6.04 A Sobin L.H.
Johns Hopkins School of 4.22 Carneiro F. 6.04 B Carr N.J.
Medicine, Baltimore, MD, USA 4.23 Carneiro F. 6.05 A,B Carr N.J.
2.11 A,B Fléjou J.-F. 4.24 Carneiro F. 6.06 A Sobin L.H.
2.12 A Odze R. 4.25 Charlton A. 6.06 B Carr N.J.
2.12 B Montgomery E. 4.26 A,B Carneiro F. 6.07 Klöppel G.
2.13 A,B Fléjou J.-F. 4.27 Olivera C. & Seruca R. 6.08 A,B Capella C. & La Rosa S.
2.14 Fenoglio-Preiser C.M. IPATIMUT, Porto, Portugal 6.09 Capella C. & La Rosa S.
Gastrointestinal Pathology 4.28 Capella C. 6.10 Vogt P.
University of Cincinnati, OH, 4.29 A Hamilton S.R. Dept of Pathology,
USA 4.29 B Capella C. University Hospital Zurich,
2.15 A,B Montgomery E. 4.30 A Jass J.R. Switzerland
2.16 Anthony P.P. 4.30 B Capella C. 6.11 A,B Capella C. & La Rosa S.
Histopathology Dept, Royal 4.31 Capella C. 6.12 Capella C. & La Rosa S.
Devon and Exeter Hospital, 4.32 A,B Nakamura S. 6.13 Capella C. & La Rosa S.
UK 4.33 A,B Nakamura S. 6.14 Oda Y.
2.17 Klöppel G. 4.34 Nakamura S. Kyushu University, Japan
2.18 Klöppel G. 4.35 Nakamura S. 6.15 Sobin L.H.
2.19 Miettinen M. 4.36 A,B Nakamura S. 6.16 Nakamura S.
2.20 A,B Miettinen M. 4.37 A-D Nakamura S. 6.17 A,B Nakamura Sh.
2.21 A,B Miettinen M. 4.38 Nakamura S. Dept of Gastroenterology,
2.22 A,B Miettinen M. 4.39 A,B Nakamura S. Kyushu University Hospital,
2.23 Fenger C. 4.40 Nakamura S. Japan
University Hospital Odense, 4.41 A,B Miettinen M. 6.18 Sobin L.H.
Denmark 4.42 A-D Miettinen M. 6.19 Futamura S.
2.24 Carr N.J. 4.43 A-D Miettinen M. Fukuoka University, Japan
4.44 A-F Miettinen M. 6.20 Nakamura S.
4.45 Lasota J. 6.21 Jass J.R.
3.01 Spechler S.J. {3033} AFIP, Washington, DC, USA 6.22 Muller-Hermelink H.K.
3.02 Lambert R. 4.46 Miettinen M. 6.23 A-D Isaacson P.G.
3.03 Odze R. 4.47 A,B Miettinen M. Dept of Histopathology,
3.04 Rubio C.A., 4.48 A,B Miettinen M. University College Medical
Dept of Pathology, 4.49 A,B Miettinen M. School, London, UK
Karolinska Institute, 4.50 Miettinen M. 6.23 B Brunning R.D.
Stockholm, Sweden 4.51 Sobin L.H. 6.24 A-D Muller-Hermelink H.K.
3.05 A,B Odze R. 4.52 Ishak K. 6.25 Muller-Hermelink H.K.
AFIP, Washington, DC, USA 6.26 A-D Muller-Hermelink H.K.
4.53 A,B Iacobuzio-Donahue C. 6.27 A-C Miettinen M.
4.01 Graham D.Y. 6.28 A,B Miettinen M.
4.02 A,B IARC {842A} 6.29 A,B Miettinen M.
4.03 A,B Kato M. 5.01 Klimstra D.S. 6.30 Miettinen M.
Division of Endoscopy, 5.02 Klimstra D.S. 6.31 Miettinen M.
Hokkaido University Hospital, 5.03 A,B Klimstra D.S. 6.32 Hruban R.H.
Sapporo, Japan 5.04 A,B Albores-Saavedra J. 6.33 Iacobuzio-Donahue C.
4.04 A,B Shimoda T. 5.05 A,B Klimstra D.S. 6.34 Iacobuzio-Donahue C. {735}
4.05 Lauwers G.Y. 5.06 Klimstra D.S. 6.35 A Talbot I.C.
4.06 A-C Shimoda T. 5.07 Albores-Saavedra J. 6.35 B Sobin L.H.
4.07 A Lauwers G.Y. 5.08 A,B Albores-Saavedra J. 6.36 A,B Fenoglio-Preiser C.
4.07 B Carneiro F. 5.09 Albores-Saavedra J. 6.37 Sobin L.H.
Source of charts and photographs 345

6.38 Niederau C., 8.28 A Talbot I.C. 9.01 Fenger C. Reproduced with
Dept of Medicine, St Joseph 8.28 B Fenger C. permission from {835}.
Hospital, Oberhausen, 8.29 Talbot I.C. 9.02 Fenger C.
Germany. 8.30 Offerhaus J.G.A. 9.03 Fenger C.
8.31 Talbot I.C. 9.04 Fenger C.
8.32 Jarvinen H., 9.05 A,B Fenger C.
7.01 Carr N.J. Dept of Surgery, Helsinki 9.06 Sobin L.H.
7.02 A,B Carr N.J. University Central Hospital, 9.07 Talbot I.C.
7.03 Carr N.J. Finland 9.08 Fenger C.
7.04 Carr N.J. 8.33 Giardiello F.M. 9.09 Jass J.R.
7.05 A Sobin L.H. 8.34 Jass J.R. 9.10 Sobin L.H.
7.05 B Jass J.R. 8.35 A,B Jass J.R. 9.11 Talbot I.C.
7.05 C Sobin L.H. 8.36 A,B Jass J.R. 9.12 A,B Talbot I.C.
7.06 Carr N.J. 8.37 Sampson J.R & Jones N. 9.13 Sobin L.H.
7.07 Sobin L.H. {2790}
7.08 Jass J.R. 8.38 Ponti et al. {2575A}
7.09 Fenger C. 8.39 A Nielsen et al. {2283} 10.01A-C Bioulac-Sage P.
7.10 Komminoth P. 8.39 B Morreau H. & Nielsen M. 10.02 Bioulac-Sage P.
7.11A Komminoth P. 8.40 Cheadle J.P. & Sampson N. 10.03 Bioulac-Sage P.
7.11 B Tang L. {499A} 10.04 Bioulac-Sage P.
Memorial Sloan Kettering, 8.41 Burt R.W. 10.05 Bioulac-Sage P.
New York, NY, USA 8.42 A,B Snover D.C. 10.06 A,B Bioulac-Sage P.
7.12 A Rindi G. 8.43 A-C Snover D.C. 10.07 A,B Bioulac-Sage P.
7.12 B Carr N.J. 8.44 A,B Snover D.C. 10.08 A-C Bioulac-Sage P.
7.13 A,B Nakamura S.-I. 8.45 A,B Snover D.C. 10.09 Bioulac-Sage P.
7.14 Carr N.J. 8.46 A-C Snover D.C. 10.10 Bioulac-Sage P.
7.15 Snover D.C. 8.47 A-D Snover D.C. 10.11 Bioulac-Sage P.
8.48 Jass J.R. 10.12 Bioulac-Sage P.
8.01 A IARC {842A} 8.49 Snover D.C. 10.13 Bioulac-Sage P.
8.01 B IARC {842} 8.50 Jass J.R. 10.14 Bioulac-Sage P.
8.02 A,B Kudo S., 8.51 A Sobin L.H. 10.15 Bioulac-Sage P.
Showa University & Northern 8.51 B Talbot I.C. 10.16 Bioulac-Sage P.
Yokohama Hospital, Japan. 8.52 Talbot I.C. 10.17 Bioulac-Sage P.
8.02 C Gabbert H.E. 8.53 Talbot I.C. 10.18 IARC {842A}
8.03 A,B Hamilton S.R. 8.54 A Offerhaus G.J.A. 10.19 IARC {842A}
8.04 A Fogt F., 8.54 B Sobin L.H. 10.2 A Kadar A.
Dept of Pathology, Medical 8.55 A,B Sobin L.H. 10.2 B, C Hirohashi S.
Center, University of 8.56 Sobin L.H. 10.20 D Sakamoto M.
Pennsylvania, Philadelphia, 8.57 A,B Snover D.C. 10.21 Sakamoto M.
PA, USA 8.58 A,B Snover D.C. 10.22 Wee A.
8.04 B,C Jass J.R. 8.59 A Jass J.R. 10.23 Wee A.
8.05 Talbot I.C. 8.59 B Talbot I.C. 10.24 Wee A.
8.06 Fenoglio-Preiser C. 8.60 Reprinted by permission from 10.25 Wee A.
8.07 Hamilton S.R. Macmillan Publishers Ltd: 10.26 A,B Hirohashi S.
8.08 A-C Hamilton S.R. European Journal of Human 10.27 A,B Hirohashi S.
8.09 Nakamura S.-I. Genetics, Blumenthal GM et al. 10.28 A Hirohashi S.
8.10 A,B Kudo S. {287A}, Copyright 2008. 10.28 B Fischer H.P.
8.11 A,B Rubio C.A. 8.61 Rindi G. 10.29 A,B Hirohashi S.
8.12 A,B Kudo S. 8.62 Tang L. 10.30 Wee A.
8.13 Hamilton S.R. 8.63 Sobin L.H. 10.31 Ishak K.
8.14 A Talbot I.C. 8.64 Snover D.C. 10.32 A,B Torbenson M.
8.14 B Sobin L.H. 8.65 A Sobin L.H. 10.33 Torbenson M.
8.15 Rubio C.A. 8.65 B Fenoglio-Preiser C. 10.34 Park Y.N.
8.16 A Jass J.R. 8.66 Rindi G. 10.35 Park Y.N.
8.16 B Rubio C.A. 8.67 Talbot I.C. 10.36 Park Y.N.
8.17 Kudo S. 8.68 Sobin L.H. 10.37 Park Y.N.
8.18 A Jass J.R. 8.69 Talbot I.C. 10.38 A Park Y.N.
8.18 B Rubio C.A. 8.70 Wotherspoon A. 10.38 B Hirohashi S.
8.18 C Sobin L.H. Histopathology Dept, Royal 10.38 Hytiroglou P.
8.19 A Talbot I.C. Marsden Hospital, London, 10.39 Kudo M.
8.19 B Jass J.R. UK 10.40 A,B Sakamoto M.
8.20 A,B Nakamura S.-I. 8.71 Jass J.R. 10.41 Hytiroglou P.
8.21 Talbot I.C. 8.72 A,B Miettinen M. 10.42 Hytiroglou P.
8.22 Talbot I.C. 8.73 Miettinen M. 10.43 A,B Sakamoto M.
8.23 Talbot I.C. 8.74 Miettinen M. 10.43 C Hirohashi S.
8.24 Fenoglio-Preiser C. 8.75 Fletcher C.D.M. 10.44 A-C Nakanuma Y.
8.25 Sobin L.H. 8.76 A,B Miettinen M. 10.45 A-D Nakanuma Y.
8.26 Rubio C.A. 8.77 Fenger C. 10.46 Nakanuma Y.
8.27 A,B Nakamura S.-I. 8.78 Sobin L.H. 10.47 A-D Nakanuma Y.
346 Source of charts and photographs

10.48 A-D Nakanuma Y. 11.06 Albores-Saavedra J. 12.41 B Klimstra D.S.

10.49 A-D Nakanuma Y. 11.07 Albores-Saavedra J. 12.42 A,B Klimstra D.S.
10.50 A,B Nakanuma Y. 11.08 Albores-Saavedra J. 12.43 A Adsay N.V.
10.51 A,B Nakanuma Y. 11.09 Albores-Saavedra J. 12.43 B Zamboni G.
10.52 A-H Nakanuma Y. 11.10 Albores-Saavedra J. 12.44 Adsay N.V.
10.53 Nakanuma Y. 11.11 Albores-Saavedra J. 12.45 Zamboni G.
10.54 A-D Nakanuma Y. 11.12 A,B Albores-Saavedra J. 12.46 Adsay N.V.
10.55 A,B Nakanuma Y. 11.13 Albores-Saavedra J. 12.47 A Adsay N.V.
10.56 A,B Ishak K. 11.14 Albores-Saavedra J. 12.47 B Zamboni G.
10.57 Theise N. 11.15 Albores-Saavedra J. 12.48 A,B Bishop Pitman M.
10.58 A-D Nakanuma Y. 11.16 A,B Albores-Saavedra J. 12.49 A Klimstra D.S.
10.59 A-D Park Y.N. 11.17 Albores-Saavedra J. 12.49 B Klöppel G.
10.60 A-I Nakashima O. 11.18 Albores-Saavedra J. 12.50 Klöppel G.
10.61 Stocker J.T. 11.19 Albores-Saavedra J. 12.51 A,B Adsay N.V.
10.62 A,B Stocker J.T. 11.20 A-C Fischer H.P. 12.52 Ohike N.
10.63 Stocker J.T. 11.21 A-C Albores-Saavedra J. 12.53 Klimstra D.S.
10.64 Zimmermann A. 11.22 Albores-Saavedra J. 12.54 Hruban R.H.
10.65 Ishak K. 11.23 A,B Miettinen M. 12.55 A Klöppel G.
10.66 Stocker J.T. 11.24 A,B Miettinen M. 12.55 B Terris B.
10.67 A,B Zimmermann A. 12.55 C Zamboni G.
10.68 A Stocker J.T. 12.56 A Tang L.
10.68 B Zimmermann A. 12.01 IARC {842A} 12.56 B Hruban R.H.
10.69 A-C Zimmermann A. 12.02 A Zamboni G. 12.57 A Adsay N.V.
10.70 A,B Zimmermann A. 12.02 B Kawamoto S. 12.57 B Klimstra D.S.
10.71 Zimmermann A. 12.03 Klöppel G. 12.58 Klimstra D.S.
10.72 Zimmermann A. 12.04 Terris B. 12.59 Klimstra D.S.
10.73 A-C Zimmermann A. 12.05 Hruban R.H. 12.60 A Klimstra D.S.
10.74 A-C Zimmermann A. 12.06 A,B Klöppel G. 12.60 B Zamboni G.
10.75 Tsui W.M.S. 12.07 Klöppel G. 12.61 Klimstra D.S.
10.76 Tsui W.M.S. 12.08 Hruban R.H. 12.62 Zamboni G.
10.77 A-D Tsui W.M.S. 12.09 Hruban R.H. 12.63 Klimstra D.S.
10.78 A,B Tsui W.M.S. 12.10 Hruban R.H. 12.64 A Ohike N.
10.79 A-C Tsui W.M.S. 12.11 Pathology AMC 12.64 B Hruban R.H.
10.80 A,B Tsui W.M.S. 12.12 A,B Bishop Pitman M. 12.65 A,C Klimstra D.S.
10.81 A,B Nakanuma Y. 12.13 Maitra A. 12.65 B Ohike N.
10.82 Tsui W.M.S. 12.14 Klimstra D.S. 12.65 D Hruban R.H.
10.83 A,B Jaffe E.S. 12.15 Fukushima N. 12.66 Tang L.
10.84 Jaffe E.S. 12.16 A Klimstra D.S. 12.67 A Klimstra D.S.
10.85 A,B Jaffe E.S. 12.16 B Zamboni G. 12.67 B Hruban R.H.
10.86 A Stocker J.T. 12.17 A Hruban R.H. 12.68 A,B Klimstra D.S.
10.86 B-D Ishak K. 12.17 B Shimizu M. 12.69 Klimstra D.S.
10.87 A,B Ishak K. 12.18 Shimizu M. 12.70 Klöppel G.
10.88 A,B Ishak K. 12.19 Terris B. 12.71 Kawamoto S., Johns
10.89 A Tsui W.M.S. 12.20 Kawamoto S., Johns Hopkins, USA
10.89 B,C Ishak K. Hopkins, USA 12.72 A Klimstra D.S.
10.90 Anthony P. 12.21 Klöppel G. 12.72 B Klöppel G.
10.91 Ishak K. 12.22 Terris B. 12.73 Terris B.
10.92 A-H Tsui W.M.S. 12.23 Fukushima N. 12.74 Hruban R.H.
10.93 A,B Tsui W.M.S. 12.24 Zamboni G. 12.75 A Hruban R.H.
10.94 A-D Tsui W.M.S. 12.25 A Zamboni G. 12.75 B Klöppel G.
10.95 A-D Miettinen M. 12.25 B Terris B. 12.76 A Zamboni G.
10.96 A,B Ishak K. 12.26 Adsay N.V. 12.76 B Zamboni G.
10.97 Miettinen M. 12.27 Adsay N.V. 12.77 Hruban R.H.
10.98 Miettinen M. 12.28 Klimstra D.S. 12.78 Iacobuzio-Donahue C.
10.99 A,B Zimmermann A. 12.29 Klöppel G. 12.79 Hruban R.H.
10.100 A-D Zimmermann A. 12.30 Zamboni G. 12.80 Hruban R.H. {1270}
10.101 DiSibio G et al. {725} 12.31 A,B Zamboni G.
10.102 A,B,D Anthony P.P. 12.32 Zamboni G.
10.103 C Fenoglio-Preiser C. 12.33 Zamboni G.
10.103 Anthony P. 12.34 A,B Zamboni G.
10.104 Saxena R. 12.35 A Kawamoto S., Johns
10.105 Saxena R. Hopkins, USA
12.35 B Zamboni G.
12.36 Terris B.
11.01 Albores-Saavedra J. 12.37 Klöppel G.
11.02 Albores-Saavedra J. 12.38 Hruban R.H.
11.03 A,B Albores-Saavedra J. 12.39 Klöppel G.
11.04 Albores-Saavedra J. 12.40 Zamboni G.
11.05 Albores-Saavedra J. 12.41 A Klöppel G.
Source of charts and photographs 347

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402 References
Subject index
14-3-3σ, 287 Adenocarcinoma of the oesophagogastric α-1-Antichymotrypsin, 247, 328

111.3, 308 junction (OGJ), 27, 39–44 α-1-Antitrypsin, 206, 210, 247, 253,
3-β-Hydroxysteroid dehydrogenase Adenocarcinoma of the small intestine, α Cell/glucagon-producing NET, 322
(3βHSD), 302 98–101, 108,
α Cell/insulin-producing NET, 322
5-Fluorouracil (5FU), 31, 44, 144–146, Adenocarcinoma, pancreatobiliary type,
82 α-Fetoprotein (AFP), 53, 89, 208, 209,
291, 294 215, 216, 225, 226, 228–231, 233,
5-Hydroxytryptophan (5HT), 65 Adenoid cystic carcinoma, 16, 22, 25, 30 235, 242, 247, 249, 252–254, 256,
8-OxoG repair system, 158, 159 Adenoma, 10, 11, 46, 48, 96, 120, 132, 257, 260, 261, 268, 269, 294, 315,
264, 269 317, 319–321, 328
17-α-Hydroxylase (17αH), 302
Adenoma, intestinal type, 82–84, 270 α Heavy chain disease (αHCD), see
Adenomatous polyposis coli, 147 IPSID
Adenomatous polyps, 56, 143 α-hCG (α-human chorionic

A gonadotrophin), 66, 103
Adenosquamous carcinoma, 16, 25, 30,
ABCB1, 209 42, 46, 48, 53, 82, 87, 89, 90, 96, 100, α-Inhibin, 237, 277, 297, 299, 302
Aberrant crypt foci (ACF), 101, 138, 139, 132, 134, 138, 144, 220, 264, 266, α-Smooth muscle actin, see Smooth
148 267–269, 273, 280, 286, 292, 301 muscle actin
ABO blood group, 289 Adrenocortical carcinoma, 253, 255 AMACR, 31, 99
Acardia syndrome, 234 Adrenocorticotropic hormone (ACTH), American College of Gastroenterology, 28
33, 64, 65, 93, 275, 319, 323 American Joint Committee on Cancer,
ACF, see Aberrant crypt foci
AE1, 91, 192, 254, 275 see AJCC
Achalasia, 19, 22, 32, 37
AE3, 91, 275 AMPK family, 170
Achlorhydria, 32, 50, 64, 65, 92, 103
aFGF (acidic fibroblast growth factor), Ampullary adenoma, 11, 85, 86, 90
ACIN, see Anal canal intraepithelial 104, 107
neoplasia Amylase, 300, 305
Aflatoxin (AFB), 205–208, 215 Anaemia, 37, 65, 74, 79, 92, 98, 103,
Acinar cell carcinoma, 280, 285, 286,
293–295, 304, 310, 313, 314–318, AIB1, see NCOA3 135, 166–168, 178, 203, 228, 289
320, 321, 325, 333–337 AIDS, 36, 78, 108, 186, 192, 193, 247, 250 Anal canal intraepithelial neoplasia
Acinar cell cystadenocarcinoma, 280, AIN, see Anal intraepithelial neoplasia (ACIN), 11
302, 314–317, 337 Anal intraepithelial neoplasia (AIN), 184,
AJCC (American Joint Committee on
Acinar cell cystadenoma, 280, 314, 315 Cancer), 20, 21, 23, 24, 31, 52, 68, 91, 186, 187, 190
ACTH, see Adrenocorticotropic hormone 104, 128, 190, 326 Anal squamous intraepithelial neoplasia,
AKAP9, 144 190
ACVR2, 294
AKT/PKB, 172, 173, 215, 290 Anal tag, 193
ACVRL1, 143, 167
Albumin, 252, 253 Anaplastic carcinoma, 294
ADAM9, 286
Alcian blue, 209, 211, 221, 283, 293, Anaplastic giant cell carcinoma, 295
Adenoacanthoma, 292
296, 301, 316 Anaplastic lymphoma kinase (ALK), 73, 77
Adenocarcinoma, biliary type, 264, 267,
273 Alcohol, 18, 23, 26, 41, 98, 134, 144, Androgen receptor, 199
205–207, 251, 281 Angiolipoma, 245
Adenocarcinoma, cribriform comedo-type,
132 Alcoholic cirrhosis, 223 Angiomyolipoma, 182, 196, 201, 232,
Adenocarcinoma, gastric foveolar type, Aldehyde dehydrogenase, 23, 144 241, 244–246, 254, 255, 261, 331
264, 267, 273 ALK5, see TGFBR1 Angiomyxoma, 193
Adenocarcinoma, intestinal type, 264, 267 Alkaline phosphatase, 83, 87, 239, 252, Angiopoietin, 199
Adenocarcinoma, invasive intestinal 290 Angiosarcoma, 96, 115, 116, 132, 181,
type, 82 Allografts, 250 182, 196, 241, 243, 248, 249, 254, 277
Adenocarcinoma of the appendix, 122– Alport syndrome, 35 ANGPT1, 199
125
Subject index 403

ANGPT2, 199 Ber-EP4b, 189 Bussey-Gardner polyposis, 147

Ann Arbor staging system, 73 β-Carotene, 49
Annexin A8, 286 β-Catenin (CTNNB1), 43, 50, 56, 57, 86,
Anoctamin-1 (ANO1), see DOG1 91, 101, 104, 107, 125, 143, 150, 157, C
199, 200, 202–204, 215, 216, 224,
APC, 31, 43, 44, 56, 57, 86, 91, 101, 229–231, 233–256, 272, 312, 317, CA9, see Carbonic anhydrase 9
104, 107, 125, 141–144, 147–151, 318, 320, 321, 325, 328–330, 335 CA19-9, 85, 88, 236, 238, 260, 270, 282,
156, 158, 162, 190, 234, 317, 318, 321
β-Catenin-activated hepatocellular 285, 299, 300, 302, 305, 308, 312,
APUDoma, 322 adenoma, 202–204 324, 328, 334
Argyrophylic granules, 33 β-Endorphin, 175 CA125, 285, 287, 312
Armed Forces Institute of Pathology β-Thalassemia, 201 Caenorhabditis elegans, 170
(AFIP), 75, 267, 304 CagA type, 26, 49
Bile duct adenoma, 196, 221, 224, 253,
Ascites, 51, 98, 122, 123, 208, 218, 242, 254, 257, 258, 260 Calcifying nested epithelial stromal
248, 251, 275, 282 tumour, 196, 232, 233, 261
Bile duct microhamartoma, 222, 260
Aspergillus parasiticus, 207 Calcitonin, 33, 93
Biliary adenofibroma, 196, 222, 236,
ATIC (5-aminoimidazole-4-carboxamide 238, 260 Calcium-channel blockers, 26
ribonucleotide formyltransferase), 77
Biliary cystadenocarcinoma, see Mucinous Calretinin, 302
Atypical carcinoid, 33, 65 cystic neoplasms of the liver
Cam5.2, 175
Autoimmune pancreatitis, 240, 286, 332 Biliary cystadenoma, see Mucinous
cystic neoplasms of the liver Carbamoyl phosphate synthetase-1,
Auxilin, 172 see HepPar1
AXIN, 150, 199 Biliary intraepithelial neoplasia, see BilIN
Carbonic anhydrase 9 (CA9), 297
AXIN1, 199, 215, 234 Biliary microhamartoma, 222, 260
Carcinoembryonic antigen (CEA), 67,
AXIN2, 234 Biliary rosettes, 254 85, 88–90, 106, 124, 127, 128, 189,
BilIN (biliary intraepithelial neoplasia), 11, 192, 209, 221, 225, 226, 236, 237–
196, 217, 222, 223, 264, 267, 270–273 238, 252, 254, 255, 258, 260, 267–
269, 275, 282, 285, 287, 288, 293,
B Bilirubin, 83, 87 294, 297, 299, 300, 302, 305, 308,
Biotin, 319, 320 309, 312, 317, 320, 324, 328, 334
B3GAT1, 33
BIRC3-MALT1, 69, 71–73, 111, 278 Carcinoid (see NET G1), 13, 14, 32–34,
B72.3, 260, 285, 287, 288, 308, 312, 46, 47, 64, 65, 67, 68, 90, 92–94, 97,
317, 320 BIRC5, 215
102–107, 118, 121–123, 125–128,
BAF47 antibody, 250 Birt-Hogg-Dube syndrome, 143 133, 174–177, 251–253, 274, 322,
Blue cell tumour, 331 323, 326
Bannayan-Riley-Ruvalcaba syndrome,
143, 173 Bmi, 144 Carcinoma in situ, 11, 16, 17, 21, 22, 27,
30, 46, 60–62, 82, 84, 96, 97, 120,
Barrett adenocarcinoma, 29 BMP, 167 121, 132, 133, 184, 190, 196, 197,
Barrett oesophagus, 10, 11, 25–35, 40–43 BMP4, 144 264, 265, 280
Basal cell carcinoma, 183, 189, 191, 192 BMPR1A, 143, 167, 172, 173 Carcinoma of the extrahepatic bile
Basal cell hyperplasia, 23 ducts, 272–273, 314, 322
BMPR1B, 167
Basaloid squamous cell carcinoma, 16, Carcinoma of the gallbladder, 266–272,
BMPR2, 143, 167
18, 22, 30 312, 314, 316, 321
Bowen disease, 10, 184, 189, 190
Basic fibroblast growth factor (bFGF), Carcinoma of the small intestine, 108–110
64, 104, 107 BRAF, 86, 125, 138, 143–145, 154, 161,
Carcinoma with lymphoid stroma, 46, 48,
163, 165, 290, 294, 310
BAT25, 143 52, 53
Brain tumour, 143, 147, 152
BAT26, 143 Carcinoma with mesenchymal stroma, 22
Branch-duct type IPMNs, 305–307,
BAX, 143 Carcinomatous cirrhosis, 251
309–311, 337
B-cell lymphoma, 70, 95, 108, 111, 131, Carcinosarcoma, 22, 53, 90, 196, 241,
BRCA1, 142, 144, 169, 289
178, 179, 239 249, 268, 273, 294
BRCA2, 169, 289, 290
B-cell lymphoma, unclassifiable, 96, 178 CARD15, 142, 144
Breast cancer, 60, 79, 80, 118, 129, 171,
BCL2, 57, 71–73, 110, 111, 179, 180 Carney triad, 74–76
172, 252, 269, 333
BCL6, 72, 73, 110, 111, 179, 180 Carney-Stratakis syndrome, 74–76
BUB1, 143
BCL10, 71, 111, 180, 316 Caroli disease, 217, 218
Budd-Chiari syndrome, 198, 241, 248
Beckwith-Wiedemann syndrome, 234, CASP5, 143
Burkitt lymphoma, 73, 96, 108–111, 132,
319, 321 178–180, 239 CaSR, 144
404 Subject index

Cavernous haemangioma, 196, 241, CDX2, 44, 53, 56, 80, 85, 88–90, 103, COG (Children’s Oncology Group)
243, 254 106, 118, 124, 127, 137, 167, 176, system, 233, 234, 249
CCND1, see Cyclin D 253, 255, 260, 261, 267, 283, 288, COL4A5, 35
293, 308, 324
CCR4, 73 COL4A6, 35
CEA, see Carcinoembryonic antigen
CD3, 112–114, 154, 294 Collision tumour, 225
Cerebellar dysplastic gangliocytoma, 172
CD4, 73, 113, 114, 186 Colloid (adeno)carcinoma, 280, 286,
CEUS, see Contrast-enhanced 292, 293, 304, 306, 308, 310
CD5, 71, 72, 110, 111, 113, 179 ultrasonography
CD7, 113 Colorectal cancer (CRC), 99, 134–138,
CHEK2, 143, 144 141, 142, 144–148, 152–159, 164, 167
CD8, 112–114, 154 Cholangiocarcinoma, 197, 211, 216, Combined hepatocellular-cholangio-
CD10 (MME), 53, 56, 71–73, 78, 90, 217, 222, 224–227, 249, 253, 254, carcinoma, 195, 196, 225–227, 258
110, 111, 179, 209, 225, 247, 254, 257, 260, 261
258, 260, 261, 294, 318, 325, 328, Combined hepatocellular-cholangio-
Cholecystitis, 266, 270, 271, 278 carcinoma with stem-cell features,
329, 335, 337
Cholecystokinin, 103 226, 227
CD11c (ITGAX), 71, 110, 179
Choledocholithiasis, 83, 272 Combined juvenile polyposis/hereditary
CD19, 72, 110, 111 haemorrhagic telangiectasia
Cholelithiasis, 83, 266, 268–270
CD20, 71–73, 110, 111, 179, 239 syndrome, 166
Cholestasis, 213, 218, 219, 257
CD21 (CR2), 71, 110, 179 Comparative genomic hybridization
Choriocarcinoma, 53, 54, 138, 252, 295 (CGH), 106, 247
CD22, 72, 111
Chromoendoscopy, 19, 29, 49, 50, 55, Confocal laser endomicroscopy, 25, 29
CD23 (FCER2), 71, 110, 111, 179 60, 69, 70, 109, 135, 138, 139, 160
Congenital hypertrophy of the retinal
CD24, 144 Chromogranin, 14, 33, 65, 66, 85, 92, pigment epithelium, see CHRPE
CD25 (IL2RA), 73 93, 103, 106, 124, 127, 175–177, 189,
237, 253, 255, 275–277, 285, 287, Contrast-enhanced ultrasonography
CD30, 113 293, 297, 302, 312, 317, 318, 320, (CEUS), 199, 200
CD31 (PCAM1), 79, 116, 243, 248, 260, 324, 328, 329, 334, 335 Cornelia de Lange syndrome, 243
331 Chronic atrophic gastritis, 40, 43, 64 Corpora albicantia, 302
CD34, 76, 77, 79, 115, 116, 181, 199, Chronic gastritis, 10, 12, 49, 54, 61, 64, 69 Courvoisier sign, 87
201, 209, 229, 243, 246, 248, 253,
260, 331 Chronic lymphocytic leukaemia, 239 Cowden syndrome, 131, 143, 167,
Chronic pancreatitis, 281, 283, 285–287, 171–173
CD35 (CR1), 71, 110
305, 333, 335 Cowden-associated polyp, 132
CD43 (SPN), 71, 110, 179
CHRPE (congenital hypertrophy of the COX2 (PTGS2), 30, 31, 44, 106
CD44, 326 retinal pigment epithelium), 148, 149, CRABP1 (cellular retinoic acid binding
CD44v6, 286 151 protein 1), 24
CD56, see NCAM Chymotrypsin, 285, 293, 294, 313, 314, CRAC1, 143, 144
316, 318, 320, 324, 325, 328, 329,
CD68, 90, 247, 269, 295 334, 335, 337 C-reactive protein (CRP), 202–204, 256
CD79a, 71, 72, 111, 179 Cigarette smoking, see Tobacco Cribriform carcinoma, 268
CD99, 230, 246, 324, 325, 331 Ciliated cell adenocarcinoma, 295 Cribriform comedo-type adenocarcinoma,
CD103 (ITGAE), 73, 113 132, 134, 138
CIMP, 104, 143, 144, 161, 163
CD105, see ENG Crohn disease, 10, 98, 99, 101, 108,
Claudin 4, 286, 287 135, 141, 142, 174, 178, 187, 191,
CD117, see KIT Claudin 5, 317, 320, 328 193, 239
CD133, 144, 145 Claudin 7, 317, 320, 328 Cronkhite-Canada syndrome, 57
CD163, 269 Claudin18, 286 CRP, see C-reactive protein
CD166, 144 Clear cell adenocarcinoma, 264, 266, 268 CTGF, 107
CDH1, see E-cadherin Clear cell carcinoma, 82, 87, 89, 90, CTNNB1, see β-Catenin
CDK6, 43 138, 220, 295 Cushing syndrome, 65, 68, 275, 319, 323
CDKN1A (p21/WAF1), 57, 215 Clear cell sugar tumour, 298 Cutaneous Merkel cell carcinomas, 176
CDKN1B (p27/KIP1), 50, 57, 93, 212, Clonorchis sinensis, 217, 218, 272 CXCL12, 145
234, 329 CLTC (clathrin heavy chain), 77 CXCR4, 251
CDKN2A (p16/INK4A), 11, 24, 31, 44, CNTN6, 107
57, 104, 111, 177, 190, 215, 224, 234, Cyclin A, 190, 215
250, 272, 276, 283, 288–290, 292, Coeliac disease, 19, 73, 99, 101, 108,
303, 309, 310, 312, 318, 325, 329 109, 112–114
Subject index 405

Cyclin D1 (CCND1), 24, 30, 50, 71, 72, DPC4, see SMAD4 EGFR (epidermal growth factor receptor),
104, 110, 111, 150, 173, 179, 180, Ductal adenocarcinoma, 85, 237, 279– 24, 31, 43, 104, 145, 224, 309
215, 250, 320, 328, 329 291, 292–294, 298, 304, 307, 308, EHE, see Epithelioid
Cyclin E, 57 315, 316, 318, 325, 329, 330, 334, 335 haemangioendothelioma
Cyclooxygenase 2 (PTGS2/COX2) gene, Ductal carcinoma in situ (DCIS), 172 Elastase, 316
30 Ductal plate tumour, 232 ElF3F, 144
CYP1B1, 202 Ductectatic mucinous cystadenoma/ EMA, see Epithelial membrane antigen
Cystadenocarcinoma, 236, 256, 314 cystadenocarcinoma, 304 Embryonal carcinoma, 53
Cystadenoma, 125, 223, 236–238, 256, DUPAN-2, 302, 320 Embryonal sarcoma, 196, 232, 241, 246,
314 Dutcher bodies, 72 254, 255, 261
Cytochrome P450 enzymes, 208 Dysadherin, 291 Endocytoscopy, 19
Cytoglobin (CYGB), 23 Dysphagia, 19, 22, 32, 34, 35, 37, 41 Endodermal sinus tumour, 53, 196
Dysplasia (intraepithelial neoplasia), Endometrial carcinoma, 152, 172
10–12, 22, 25, 27, 28, 31, 42, 47, 49, Endoscopic retrograde
D 51, 53, 55, 56, 62, 64, 65, 67, 68, cholangiopancreatography (ERCP), 87,
83–86, 91, 101, 123, 124, 139, 141, 272, 282, 312
DCAM kinase-like II, 144 149, 161, 162–165, 167, 169, 190,
DCC, 31, 43, 57, 67, 177, 190 212, 213, 218, 234, 237, 242, 266, Endoscopic ultrasonography (EUS), 19,
301–304, 308–310 29, 282, 286, 288, 296, 300, 305, 327,
DEC1 (deleted in esophageal cancer-1), 333
24 Dysplasia (intraepithelial neoplasia),
high grade, 16, 25, 96, 120, 132 ENETS, 13, 68, 104, 128, 177, 326
Dermatomyositis, 267
Dysplasia (intraepithelial neoplasia), low ENG (endoglin), 143, 167
Desmin, 35, 36, 76, 77, 181, 237, 245, grade, 16, 25, 96, 120, 132
247, 249, 250, 253, 277, 331 Enkephalin, 175
Dysplasia, foveolar, 28 Enterochromaffin, see EC
Desmoid fibromatosis, 79
Dysplastic gangliocytoma of the Enteroglucagon, 124, 127
Desmoid tumour, 147–151 cerebellum (Lhermitte-Duclos disease),
Desmoplasia, 11, 28, 52–54, 56, 107, 171 Enteropathy-associated T-cell lymphoma
124, 146, 220, 221, 226, 233, 261, (EATL), 73, 112–114
Dysplastic nodules, 11, 196, 208, 212–
267, 273, 284, 287 214, 254, 257, 260 Eosinophilic globules, 53, 254, 329
Desmoplastic small round cell tumour, 331 Eosinophilic granuloma, 193, 261
Diabetes mellitus, 92, 103, 206, 217, Epithelial cell adhesion molecule
245, 281, 282, 300, 305, 311 E (EpCAM/TACSTD1), 143, 152, 153,
Diarrhoea, 32, 65, 92, 103, 105, 107, 225, 226
109, 117, 148, 167, 178, 315, 319 E2F4, 143 Ependymoma, 193
Dietary factors, 19, 26, 41, 49, 134, 281 EATL, see Enteropathy-associated T-cell Epidermal growth factor (EGF), 30, 224,
lymphoma 286
Diffuse large B-cell lymphoma (DLBCL),
16, 34, 46, 69, 70, 72, 73, 96, EBER (EBV-encoded mRNA), 72, 240 Epidermal growth factor receptor-2
108–111, 132, 178, 179, 239, 240, EBV, 53, 70–73, 108, 114, 178, 179, 211, (EGFR2), 224
278, 332 218, 220, 239, 240, 246, 250, 277, 294 Epidermoid cyst, 147, 148
Dihydropyrimidine dehydrogenase, 146 EC (enterochromaffin), 64, 82, 120, 132, Epithelial atypia, 12
Disseminated peritoneal adenomucinosis 175, 280
Epithelial membrane antigen (EMA), 36,
(DPAM), 123 E-cadherin (CDH1), 24, 31, 53, 57, 59, 78, 182, 192, 209, 221, 231, 233, 237,
DLBCL, see Diffuse large B-cell lymphoma 60–63, 101, 107, 144, 150, 215, 224, 250, 254, 255, 260, 275, 297, 302
286, 291, 295, 312, 328
DLEC1 (deleted in lung and esophageal Epithelioid haemangioendothelioma
cancer-1), 24 EC cell NET, 127 (EHE), 196, 241, 248, 254, 257
DLK1, 234 EC cell serotonin-producing NET Epstein-Barr virus, see EBV
(carcinoid), 46, 64–66, 82, 92, 96, 102,
DNA mismatch repair (MMR), 57, 58, 86, 105–107, 120, 126, 132, 174, 175, ERBB2 (human epidermal growth factor
142, 143, 146, 152–155, 157, 159, 280, 322 receptor-2, HER2), 24, 31, 43, 44, 57,
163, 177, 180, 289, 290, 294 91, 224, 272, 286, 290, 309
ECL-cell hyperplasia, 64, 65
DNA ploidy, 24, 31, 190 ERBB3 (human epidermal growth factor
ECL cell NET, 64–68, 128 receptor-3, HER3), 91
DNA replication errors, 143
Echinococcosis, 247 ERCP, see Endoscopic retrograde
DOG1 (ANO1), 35, 75–78, 115, 116, 181
EGF (epidermal growth factor), 30, 91 cholangiopancreatography
Double-duct sign, 282
406 Subject index

Estrogen receptor, 80, 253, 271, 302, Fibrocystic disease of the breast, 171, GANT, see Gastrointestinal autonomic
328, 337 172 nerve tumour
European Neuroendocrine Tumor Society, Fibroepithelial polyp, 193 Gardner syndrome, 83, 86, 87, 116, 147,
see ENETS Fibrolamellar carcinoma (FLC), 210, 270
EUS, see Endoscopic ultrasonography 211, 257, 260, 261 Gastric epithelial dysplasia, 55
Ewing sarcoma (EWS), 330, 331 Fibrolamellar hepatocellular carcinoma, Gastric yolk sac tumour, 53
EWSR1-FLI1, 330, 331 256 Gastric-type IPMN, 306–309
EWSR1-CREB1, 116 Fibroma, 172 Gastrin, 14, 64–68, 93, 102–104, 253,
EWSR1-WT1, 331 Fibromatosis, 149, 182 275, 276, 302, 323
Extramedullary haematopoiesis, 229, Fibrosarcoma, 193, 221 Gastrin-cell hyperplasia, 64

243, 256 Fibrous polyp, 193 Gastrinoma (gastrin-producing NET),
Extranodal natural killer/T-cell lymphoma Fibrous stroma, 193, 219, 222, 225, 226, 14, 46, 64–68, 92, 96, 102–105, 275,
(NK/T-cell lymphoma), 73, 240 243, 254, 260, 297 280, 322, 323, 325
EZH2, 224 Filiform serrated adenoma, 161 Gastrin-producing NET, see Gastrinoma
FISH, see Fluorescent in situ Gastritis, 10, 54

hybridization Gastrointestinal autonomic nerve tumour
(GANT), 74
F Flat intraepithelial neoplasia (dysplasia),
11, 82–85 Gastrointestinal clear cell sarcoma, 79,
FABP1, 202 116
FLC, see Fibrolamellar carcinoma
Factor-VIII-related antigen, 209 Gastrointestinal hamartoma, 171, 172
FLCN (folliculin), 143
FAK, see PTK2B Gastrointestinal stromal tumour (GIST),
Fluorescent in situ hybridization (FISH),
Familial adenomatous polyposis (FAP), 77, 111, 180, 221, 329 16, 35, 46, 47, 74–76, 77–78, 94, 96,
56, 57, 79, 83–87, 91, 98, 101, 125, 115, 116, 120, 129, 132, 138, 181,
131, 139, 141, 143, 147–151, 152, Focal nodular hyperplasia (FNH), 195, 182, 253, 277, 331
153, 156–159, 166–168, 234, 266, 196, 198–201, 204, 210, 214, 232,
254, 256–258, 260, 261 Gastro-oesophageal reflux disease
270, 305, 321, 327 (GORD), 22, 25–28, 32, 40, 41
Familial adenomatous polyposis coli, Focal non-epidermolytic palmoplantar
keratoderma, 23 GCDFP, see Gross cystic disease fluid
147 protein
Familial atypical multiple mole Follicular carcinoma, 255
GCHP, 160, 161
melanoma (FAMMM), 288, 289 Follicular lymphoma, 71, 109–111, 178,
179, 239, 278, 332 Generalized juvenile polyposis, 166
Familial colorectal cancer (type X), 153
Forbes disease, 201 Genitourinary tumour, 172
Familial diffuse gastric cancer (FDGC),
59 Foveolar dysplasia, 28 Genome-wide association studies
(GWAS), 142, 144
Familial intestinal gastric cancer (FIGC), FOXP1, 71–73
59 Germ cell tumour, 196
Fragile histidine triad, see FHIT
Familial juvenile polyposis, 166 GFAP, see Glial fibrillary acidic protein
Frantz tumour, 327
Familial multiple polyposis, 147 Ghrelin, 64–66
Frizzle receptor, 215
Familial polyposis coli, 201 Ghrelin cell tumour, 323
Functioning NET, 322–324
FAMMM, see Familial atypical multiple Giant hyperplastic polyposis, 161
mole melanoma GIST, see Gastrointestinal stromal tumour
Fanconi anaemia (FANC), 201, 289, 290 Glial fibrillary acidic protein (GFAP), 77,
G 182, 277
FAP, see Familial adenomatous
polyposis G cell NET, see Gastrinoma Glicentin, 127, 175
Fatty change, 210, 211, 214, 231, 245 G1 NET, see NET G1 Glioblastoma, 153
FBXW7/CDC4, 143 G2 NET, see NET G2 Glomus tumour, 36, 46, 74, 76, 78
FDG-PET (18-fluoro-2-deoxyglucose- Galactosaemia, 201 GLP-1, 175
positron emission tomography), 20, Galectin, 106, 328 GLP-2, 175
44, 70
Gallstones, 92, 103, 266, 271, 274 Glucagon, 105, 106, 120, 126–128, 253,
FGF (fibroblast growth factor), 24, 104 323, 324
Gangliocytic paraganglioma, 82, 92–94,
FHIT (fragile histidine triad gene), 24, 96, 102, 103, 105, 129 Glucagon-like peptide-producing NET,
31, 67, 177, 294 96, 102, 120, 126, 132, 174, 175, 322
Ganglioneuroma, 129, 171, 182
Fibrinogen, 209, 210, 253 Glucagonoma, 280, 322, 323
Ganglioneuromatosis, 174, 182, 277
Subject index 407

GLUL, see Glutamine synthetase Hamartomatous polyps, 57, 166, 171 Hereditary diffuse gastric carcinoma
Glutamic oxaloacetic transaminase, 83, 87 HBsAg, 206, 210, 255 (HDGC), 11, 45, 46, 59, 60–63
Glutamic pyruvic transaminase, 83, 87 HBV, 205–208, 215, 216, 218, 239, 255 Hereditary haemorrhagic telangiectasia
(HHT), 143, 166, 167, 198, 244
Glutamine synthetase, 199–203, 216, HCA, see Hepatocellular adenoma
235, 256, 257 Hereditary mixed polyposis syndrome
HCC, see Hepatocellular carcinoma (HMPS), 143, 144
Glutathione S-transferase (GST), 30, 57, HCV, 205–207, 216–218, 239
144 Hereditary nonpolyposis colorectal
HDGC, see Hereditary diffuse gastric cancer (HNPCC), 142, 152, 153, 156
Glycogen synthase kinase 3β (GSK3β), carcinoma
150, 151 Hereditary pancreatitis, 281
HDLG, 150, 151 HGDN, 213, 214, 257
Glycogenic acanthosis, 171
HDV, see Hepatitis D virus HGIEN, see High-grade intraepithelial
Glycogenosis type 1, 201
Heat shock protein, see HSP neoplasia
Glypican-3 (GPC3), 216, 253, 255–257
Helicobacter pylori, 26, 41, 43, 49, 50, HHV-8 (human herpesvirus 8), 79, 248
Goblet cell carcinoid, 120, 122, 124– 54, 57, 61, 64, 69, 71, 73, 102
126, 128, 264, 274 HHT, see Hereditary haemorrhagic
Hemihypertrophy, 234, 243, 321 telangiectasia syndrome
Goblet-cell rich hyperplastic polyps
(GCHP), 160, 161 Hepatitis B, 205, 206, 213, 215, 239, Hibernoma, 245
255, 257 HIC1, 104
Goldenhar syndrome, 234
GORD, see Gastro-oesophageal reflux
Hepatitis B surface antigen, see HBsAg HIF-1 α, see Hypoxia-inducible factor α
disease Hepatitis B virus, see HBV High-grade anal intraepithelial neoplasia,
Goseki classification, 58 Hepatitis C, 205, 213, 217, 239 186
gp130, 203 Hepatitis C virus, see HCV High-grade dysplasia, 11, 12, 17, 21,
27–29, 31, 46, 55, 56, 82–86, 88, 123,
GPC3, see Glypican-3 Hepatitis D virus (HDV), 207 124, 137, 139, 304, 306–311
Granular cell tumour, 16, 35, 46, 74, 182, Hepatobiliary rhabdomyosarcoma, 249 High-grade dysplastic nodule, 257
193, 264, 277 Hepatoblastoma, 149, 150, 195, 228– High-grade intraepithelial neoplasia
Granuloma, 193 235, 242, 246, 247, 250, 254–256, (dysplasia), 21, 22, 55, 83, 139, 154,
258, 260, 261, 321 217, 253, 269, 270, 271
Granzyme B, 73, 113
Hepatoblastoma, epithelial variants, 196 High-grade MALT lymphoma, 70, 72
Gross cystic disease fluid protein
(GCDFP), 80, 189, 192 Hepatoblastoma, mixed epithelial- High-grade neuroendocrine carcinoma
mesenchymal, 196 (NEC), 32, 64, 92, 102, 126, 174, 176,
GSK3β, see Glycogen synthase kinase 3β
Hepatocellular adenoma (HCA), 195, 177, 274, 322–326
GST, see Glutathione S-transferase 196, 198, 200–204, 215, 254, 256, 260 High-grade squamous intraepithelial
Guillain-Barré syndrome, 267 Hepatocellular carcinoma (HCC), 195– lesion (HSIL), 184, 186, 190
GWAS, see Genome-wide association 197, 200, 201–204, 205–216, Highly-active antiretroviral therapy
studies 217–219, 225–228, 230, 233, 245, (HAART), 178, 179
247, 251–258, 260, 261, 269, 294
Hilar cholangiocarcinoma, see
Hepatocellular carcinoma, fibrolamellar Intrahepatic cholangiocarcinoma
variant, 196, 205
H Histamine, 65, 66
Hepatocyte nuclear factor 1 α (HNF1α),
H. pylori, see Helicobacter pylori 201, 202, 204, 245, 256 HIV, 34, 36, 70, 78, 108, 111, 178, 179,
186, 187, 193, 217, 239, 250, 332
H2-receptor antagonist, 26 Hepatocyte-paraffin-1 antibody (Hep-
Par1), 80, 89, 118, 209, 225, 226, HLA (human leukocyte antigen), 112,
H3, 57 114, 159, 190, 271
253–255, 258, 269, 294
H4, 57 HLA-DQ2, 112, 114
Hepatocyte-specific antigen, see HSA
HAART, see Highly-active antiretroviral HLA-DQ8, 112, 114
therapy Hepatoid adenocarcinoma, 46, 48, 53,
82, 87, 89, 269 HLA-DQB1, 114
Haemangioma, 16, 35, 36, 79, 182, 193,
198, 242–244, 253–255, 261, 277, 298 Hepatoid carcinoma, 280, 286, 292, 294 HMB45, 37, 91, 116, 182, 189, 190, 245,
Hepatolithiasis, 217, 218 253, 255, 331
Haemangiopericytoma, 193, 246, 247, 331
Hepatomegaly, 208, 239, 241, 251 HMPS, see Hereditary mixed polyposis
Haematemesis, 32, 37 syndrome
Haematochezia, 135 HepPar1, see Hepatocyte-paraffin-1
antibody HNF1A (HNF1α), see 201, 202, 204,
HAM56, 269 245, 256
HER2, see ERBB2
Hamartoma, 10, 96, 132, 167, 171, 331 HNF1α-inactivated HCA, 201–204, 256
HER3, see ERBB3
408 Subject index

HNPCC, see Hereditary nonpolyposis ICUD (intermediate cell undifferentiated) International Childhood Liver Tumor
colorectal cancer hepatoblastoma, 230 Strategy Group, see SIOPEL
Hodgkin disease, see Hodgkin lymphoma IFP, see Inflammatory fibroid polyp International Classification of Disease
Hodgkin lymphoma, 34, 73, 108, 178, 253 IgA, 71, 109 Oncology, see ICD-O
HP, see Hyperplastic polyp IgD, 71, 110, 179 International Gastric Cancer Linkage
Consortium, see IGCLC
HPV (human papilloma virus), 10, 19, IgG, 71
185–187, 189–192 International Union against Cancer, see
IgG4, 239, 245, 246, 286, 332 UICC
HPV6, 189 IgM, 71, 110, 111, 179 Intestinal metaplasia, 25–27, 41–43, 49,
HPV11, 189 IGCLC (International Gastric Cancer 54, 55, 64, 270
HPV16, 186 Linkage Consortium), 59–61 Intestinal-type adenoma, 82–84, 270
HPV18, 186 IGF, see Insulin-like growth factor Intestinal-type IPMN, 191, 290, 307–309,
HRAS1, 144 IGH@ (immunoglobulin heavy-chain 311, 312
HSA (hepatocyte-specific antigen), 255, gene locus), 72, 73, 111 Intracystic papillary neoplasm, 266, 267,
258 IGHα, 240 270–272
HSIL, see High-grade squamous IGHJ@, 111, 180 Intracystic papillary neoplasm with an
intraepithelial lesion associated invasive carcinoma, 264
IKH4, 192
HSP (heat shock protein), 24, 215, 216, Intracystic papillary neoplasm with
IL (interleukin), 50, 224 high-grade intraepithelial neoplasia,
257
Immunoproliferative small-intestinal 264
HSP70, 215, 216 disease, see IPSID Intracystic papillary neoplasm with
HST1, 24 IMP3 (insulin-like growth factor II mRNA intermediate-grade intraepithelial
HST2, 24 binding protein), 31 neoplasia, 264
HTLV-1, 73 Imprinting, 234 Intracystic papillary neoplasm with
low-grade intraepithelial neoplasia,
Human androgen receptor (HUMARA), Indefinite for dysplasia, 28 264
199 Infantile haemangioendothelioma, 228, Intraductal papillary neoplasm with an
Human herpesvirus 8, see HHV-8 232, 242, 243 associated invasive carcinoma, 264
Human leukocyte antigen, see HLA Infantile haemangioma, 196, 241, 242, Intraductal papillary neoplasm with
Human papilloma virus, see HPV 254, 261 high-grade intraepithelial neoplasia,
HUMARA, see Human androgen receptor Infiltrating duct carcinoma, not otherwise 264
specified, 281 Intraductal papillary neoplasm with
Hyaline bodies, 210, 211
Inflammatory bowel disease (IBD), 10, intermediate-grade intraepithelial
Hyaline globules, 246, 329 11, 27, 178 neoplasia, 264
Hydatid cyst, 259, 300, 306 Inflammatory bowel disease dysplasia- Intraductal papillary neoplasm with
Hypercalcaemia, 208, 211, 282, 323 grading system, 10 low-grade intraepithelial neoplasia,
Inflammatory clocagenic polyp, 193 264
Hypergastrinaemia, 64, 65, 68, 103
Inflammatory fibroid polyp, 116 Intraductal neoplasms, 304, 308, 311
Hyperplastic polyp (HP), 57, 120, 125,
132, 139, 143, 156–158, 160–162, Inflammatory fibrosarcoma, 246 Intraductal oncocytic papillary
164, 166 neoplasm, see IOPN
Inflammatory hepatocellular adenoma,
Hyperplastic polyposis syndrome, 143 202–204 Intraductal papillary biliary neoplasm,
see IPBN
Hypoglycaemia, 208, 245, 282, 321, 335 Inflammatory myofibroblastic tumour, 46,
74, 77, 78, 246 Intraductal papillary mucinous
Hypohydria, 92 neoplasm, see IPMN
Hypokalaemia-achlorhydria syndrome, Inflammatory pseudotumour, 196, 241, 246
Intraductal papillary neoplasm, see IPN
32 Inhibin, 253, 255, 275, 277
Intraductal papillary-mucinous carcinoma,
Hypomethylation, 215 INI1, see SMARCB1 invasive, 304
Hypoxia-inducible factor α (HIFα), 297 Insulin, 31, 103, 146, 175, 234, 235, 253, Intraductal papillary-mucinous carcinoma,
323, 324 noninvasive, 304
Insulin-like growth factor (IGF), 31, 143, Intraductal tubulopapillary neoplasm,
I 146, 215, 234, 245, 251 see ITPN
Insulinoma, 280, 322, 323, 325, 326 Intraepithelial neoplasia (dysplasia), 10–
IBD, see Inflammatory bowel disease
Integrin αb6, 251 12, 16, 18, 21–23, 27, 31, 46, 48, 51,
ICC, see Intrahepatic cholangiocarcinoma 55, 56, 82–85, 91, 96, 98, 101, 120,
International Association of Pancreatology, 132, 141, 169, 184, 186, 189, 190,
310 196, 222, 236, 261, 264, 273, 280, 287
Subject index 409

Intraepithelial neoplasia (dysplasia), IPN with low-grade intraepithelial Keratin 8, 93, 127, 175, 189, 209, 231,
high grade, 16, 18, 46 neoplasia, 217 233, 237, 250, 255, 285, 297, 299,
Intraepithelial neoplasia (dysplasia), IPN with intermediate-grade intraepithelial 302, 315, 317, 320, 324, 328, 331, 335
low grade, 16, 18, 22, 46 neoplasia, 217 Keratin 13, 189, 192
Intrahepatic cholangiocarcinoma (ICC), IPSID (immunoproliferative small-intestinal Keratin 14, 189
195–197, 205, 217–224, 237, 254, disease), 96, 108, 109, 111 Keratin 15, 192
255, 260, 261 IRF4/MUM1, 72 Keratin 18, 76, 93, 189, 209, 237, 248,
Intrahepatic cholangiocarcinoma, perihilar, Irinotecan, 144–146 250, 255, 285, 297, 299, 302, 315,
217, 219 317, 320, 324, 328, 331, 335
Iron-free foci, 212, 213
Intrahepatic cholangiocarcinoma, Keratin 19, 124, 127, 189, 192, 199, 209,
peripheral, 217 Ischaemic necrosis, 169
214, 216, 221, 225, 226, 232, 233,
Intrahepatic cholangiocarcinoma, Isl1, 324 237, 253, 255, 256, 260, 285, 288,
sarcomatous, 220 Islet cell tumour, 253, 322 297, 299, 302, 308, 312, 317, 320,
Intramucosal adenocarcinoma, 11, 12, 324, 326, 328, 331, 334, 335
ITPN (intraductal tubulopapillary
28, 137 neoplasm), 280, 304, 307, 308, 310– Keratin 20, 80, 85, 88, 90, 99, 100, 118,
Intramucosal carcinoma, 11, 20, 21, 55, 313 124, 127, 137, 176, 189, 192, 209,
56, 61, 137 221, 253, 255, 260, 261, 267, 283,
ITPN with an associated invasive 285, 288, 317
Intussusception, 109, 116, 117, 166, carcinoma, 311
168–170 Keratin 22, 192
ITPN with high-grade dysplasia, 312
Invasive papillary adenocarcinoma, 82, Keratin pearls, 42
87, 89 Keratoacanthoma, 152, 192
Ionizing radiation, 19, 247 J Ki67, 13, 14, 24, 66, 73, 103, 106, 107,
IOPN (intraductal oncocytic papillary 111, 124, 127, 161, 162, 176, 177,
neoplasm), 306, 308 Japanese Esophageal Society, 20 179, 190, 230, 231, 276, 309, 312,
324–326, 328
IPBN (intraductal papillary biliary Japanese Pancreas Society, 283
neoplasm), 221 KIT (CD117), 35, 74–78, 115, 116, 181,
Japanese Society for Cancer of the 226, 227, 245, 253, 330, 331
IPMN (intraductal papillary mucinous Colon and Rectum, 137
neoplasm), 11, 85, 223, 273, 280, Klatskin tumour, 217, 219, 265
Jaundice, 83, 87, 92, 98, 99, 103, 208,
287–291, 293, 303–313, 334, 335, 337 236, 241, 243, 246, 248, 249, 251, KOC, 286
IPMN, branch-duct type, 305–307, 309– 271, 272, 275, 282, 299, 305, 311, KRAS, 31, 57, 86, 91, 101, 125, 139,
311, 337 315, 319, 323, 332, 333, 335 142–145, 150, 157, 158, 161, 163,
IPMN, gastric type, 306–309 Juvenile polyp, 57, 96, 132, 139, 141, 165, 215, 249, 272, 276, 290, 298,
167, 168, 182 303, 310, 318, 325, 329
IPMN, intestinal type, 191, 290, 307–
309, 311, 312 Juvenile polyposis, 57, 101, 131,139, KRAS2, 290, 292, 294, 321
143, 166, 167, 172, 173 Krukenberg tumour, 52, 100
IPMN, main-duct type, 305, 306, 308, 310
Juvenile polyposis of infancy, 166, 172,
IPMN, oncocytic type, 306–310 173
IPMN, pancreatobiliary type, 307–309, 313
L
IPMN with dysplasia, 11
IPMN with an associated invasive K L cell NET, 127, 128, 175
carcinoma, 280, 304 L cell, Glucagon-like peptide-producing
Kaposi sarcoma, 16, 35, 36, 46, 74, 78, and PP/PYY-producing NETs, 96, 102,
IPMN with high-grade dysplasia, 280, 79, 96, 115, 120, 129, 132, 181, 182,
304, 306, 309, 310 120, 126, 132, 174, 175
192, 193, 196, 241, 247, 264, 277
IPMN with intermediate-grade dysplasia, Laminin, 76
Kassabach-Merritt syndrome, 255
304 LAMN, see Low-grade appendiceal
Keratin, 36, 71, 76, 78, 90, 138, 189, mucinous neoplasm
IPMN with low-grade dysplasia, 304, 313 190, 191, 210, 221, 239, 247, 250,
IPMN with moderate dysplasia, 304 254, 260, 269, 275, 277, 285, 294, Large cell change, 11, 196, 212, 213
295, 299, 331, 325 Large cell NEC, 16, 32, 33, 46, 64, 66,
IPN (intraductal papillary neoplasm),
196, 219–224, 236–238, 254, 260, Keratin 5, 33, 189, 191 82, 92, 93, 96, 102, 120, 126, 132,
261, 273 174, 176, 184, 264, 274, 275, 280,
Keratin 6, 33, 191 322–324
IPN with an associated invasive carcinoma, Keratin 7, 80, 85, 88, 93, 99, 100, 118,
196, 217 Large cell undifferentiated
124, 127, 137, 189, 191, 192, 199, hepatoblastoma, see LCUD
IPN with high-grade intraepithelial 200, 214, 237, 250, 255, 256, 260,
neoplasia, 196, 217 267, 275, 285, 297, 299, 302, 315, Larval granuloma, 253
320, 328, 331 Laurén classification, 29, 52, 53, 58
410 Subject index

LCUD (large cell undifferentiated) Lung carcinoma, 37, 41, 74, 75, 87, 88, Matrix proteinases, 24
hepatoblastoma, 230 102, 129–131, 136, 144, 193, 290, Mature teratoma, 280
Lef (lymphoid enhancer-binding factor), 292, 297, 326, 350, 393, 396, 411
MBD4, 143
150, 329 Lymphangioma, 36, 182, 193, 196, 241,
244, 277, 298, 331 MCC, 43
Leiomyoma, 16, 35, 46, 74, 77, 96, 115,
116, 120, 132, 171, 181, 193, 264, 277 Lymphangiomatosis, 196 MCN (mucinous cystic neoplasm), 11,
195, 221, 223, 236–238, 254, 256,
Leiomyomatosis, 35 Lymphoepithelioma-like carcinoma, 52, 261, 266, 271, 279, 287, 288, 295,
Leiomyosarcoma, 16, 35, 46, 74, 77, 96, 53, 211, 220 298, 300–303, 307, 309, 315, 334–337
115, 118, 120, 132, 181, 193, 196, Lynch syndrome, 57, 58, 62, 91, 101, MCN with an associated invasive
241, 250–253, 264, 277, 331 131, 141–143, 147, 149, 152–155, carcinoma, 196, 236, 238, 264, 271,
Leser-Trelat sign, 267 157, 163, 180, 289, 294 280, 300, 301, 303
Leu7, 33 MCN with dysplasia, 11
Leukaemia, 73, 172, 179, 193, 240, 278 MCN with high-grade dysplasia, 236,
M 280, 300, 301
L-FABP (liver fatty acid-binding protein),
201, 202, 256 Macrocephaly, 171–173 MCN with high-grade intraepithelial
LGDN, see Dysplastic nodules Macrocystic serous cystadenoma, 297, neoplasia, 196, 264
LGIEN, see Low-grade intraepithelial 298, 309, 337 MCN with intermediate-grade dysplasia,
neoplasia Macroglossia, 321 196, 236, 264, 280, 300, 301
LGR5, 144 Macrosomia, 321 MCN with low-grade dysplasia, 196,

236, 280, 300, 301
Lhermitte-Duclos disease, 171, 172 MAGE (melanoma antigen family), 57,
58, 128 MDR1, 209
Li-Fraumeni syndrome, 57, 142
MAGEA1, 58 Medullary carcinoma, 46, 48, 52, 53, 58,
Linitis plastica, 51, 59, 80, 136, 137, 269 96, 132, 134, 138, 280, 286, 292, 294,
Lipase, 285, 305, 314, 316, 318, 320, 328 MAGEA3, 58 333
Lipase hypersecretion syndrome, 315, 318 MAGED2, 128 Medulloblastoma, 147, 149, 150, 230
Lipoma, 16, 35, 36, 67, 79, 96, 115, 120, Main-duct type IPMNs, 305, 306, 308, 310 MEEC, see Mixed exocrine-endocrine
132, 172, 181, 182, 245, 277, 331 Malacoplakia, 193 carcinoma
Liposarcoma, 79, 116, 245, 277, 331 MALAT1 gene, 247 Megencephaly, 171, 172
Lithiasis, 85, 270, 286 Malignant extrarenal rhabdoid tumour, Melan A (MART1), 37, 80, 91, 116, 118,
230 245, 253, 255
Liver cirrhosis, 206, 207, 208
Malignant fibrous histiocytoma, 193, Melanoma, 15, 16, 35, 37, 79, 80, 91,
LKB1, 57, 143, 169, 170, 290 117, 118, 129, 132, 138, 179, 181,
221, 247, 277
LKB1L, 170 192, 251–253, 255, 263, 277, 278,
Malignant lymphoma, 189, 193 333, 337
LKB1S, 170
Malignant melanoma, 37, 189, 192 Melanoma antigen family, see MAGE
Lobular breast carcinoma, 60, 117
Malignant mesenchymoma of the liver, MEM hepatoblastoma, see Mixed
LOH (loss of heterozygosity), 23, 24, 31, 246 epithelial and mesenchymal type
43, 57, 63, 67, 103, 104, 106, 125,
128, 143, 144, 159, 190, 215, 272, Mallory-Denk bodies, 210, 214 MEN (multiple endocrine neoplasia)
290, 294, 318, 321 Mallory-Denk hyalin, 254 syndrome, 277
Low-grade appendiceal mucinous MALT lymphoma, 16, 34, 46, 69, 70–73, MEN1, 64–68, 94, 102–104, 106, 107,
neoplasms (LAMN), 120, 122, 124, 96, 108–111, 132, 178–180, 240, 278, 128, 149, 176, 177, 276, 277, 322,
125 332 325, 326
Low-grade dysplasia, 28, 31, 56, 82, 83, MALT1, 71, 73, 240 MEN1 syndrome, 65, 67, 104
84, 85, 86, 123, 124, 186, 304, 307, MANEC, see Mixed MEN2B, 149, 182, 277
308, 309, 311 adenoneuroendocrine carcinoma Mental retardation, 172
Low-grade intraepithelial neoplasia Mantle cell lymphoma, 46, 69, 71, 96,
(LGIEN), 22, 82, 83, 186, 270 Merkel cells, 192
108, 110, 111, 132, 178–180
Low-grade squamous intraepithelial Mesenchymal hamartoma (MH), 196,
MAP, see MUTYH-associated polyposis 228, 232, 238, 241, 242, 247, 254,
lesion (LSIL), 190
MAPK pathway, 101, 173, 215 255, 261
LRN, 257
Marginal zone lymphoma of mucosa- Mesenchymal–epithelial transition, 247
LRP1B (low density lipoprotein associated lymphoid tissue, see MALT
receptor-related protein 1B), 24 Mesothelin, 286, 287
lymphoma
Mesothelioma, 245
MART1, see Melan A
Matrix metalloprotein genes, 30
Subject index 411

MEST, see Mixed epithelial stromal Mixed serous neuroendocrine neoplasm, MUC5AC, 53, 54, 56, 80, 224, 270, 273,
tumour of the kidney 298, 299 285, 302, 304, 308, 312, 313
MET, 57, 146, 247 MKK4, 290 MUC6, 53, 54, 56, 270, 297, 299, 308,
Metallothionein, 24, 286 MLH1 (MutL homologue 1), 58, 101, 310, 312
Metaplastic carcinoma, 22 125, 143, 144, 152–155, 157, 161– Mucicarmine, 209, 211, 221, 225, 237,
163, 165, 289, 290, 294 293, 316, 334
Metaplastic polyp, 161
MLH3 (MutL homologue 3), 154, 155 Mucinous adenocarcinoma, 29, 46, 48,
Metastatic colorectal carcinoma, 98, 51, 52, 82, 84, 87, 89, 90, 96, 98, 100,
252, 253 MLP, 109, 110
120, 122–124, 132, 134, 137, 144,
MGMT, 31, 125, 163 MLPA, 62 152, 184, 264, 266, 268, 269, 273
MHLB1, 242, 247 MMAC1, 172 Mucinous carcinoid tumour, 292
MIB1, 110, 111, 324 MME, see CD10 Mucinous carcinoma, 51, 123, 220, 224,
MMP1, 31 269, 271
Microadenocarcinoma, 295, 316
MMR, see DNA mismatch repair Mucinous carcinoma peritonei, see
Microcystic adenoma, 196, 260, 261 Pseudomyxoma peritonei
Microcystic serous cystadenoma, MO25, 170
Mucinous cystadenocarcinoma, 123, 300
296–298, 337 MOC31, 254, 255
Mucinous cystadenoma, not otherwise
Microcystic serous cystic neoplasms, 309 Moderately differentiated specified, 300
Micropapillary carcinoma, 132, 134 (adeno)carcinomas, 54, 220, 284
Mucinous cystic neoplasm, see MCN
MicroRNAs, 144 Moderately differentiated hepatocellular
carcinoma, 211 Mucinous duct ectasia, 304
Microsatellite instability, see MSI Mucinous noncystic adenocarcinoma,
MODY3, 202
Microvesicular hyperplastic polyp 293, see Colloid adenocarcinoma
(MVHP), 160–164 Motilin, 175
Mucin-poor hyperplastic polyp, 161
Migratory thrombophlebitis, 282 MPHP, 161
Mucin-producing tumour, 304
Min mouse, 151 MPLA, 167
Mucocarcinoid, 13
Ming classification, 20, 53 MRCP, 219, 304
Mucoepidermoid carcinoma, 16, 25, 30,
Mismatch repair, see DNA mismatch MSH2, 57, 125, 143, 152–155, 289, 290, 33, 53, 220, 292,
repair 294
Mucosal Schwann cell hamartoma, 182
Mixed acinar carcinoma, 293, 317 MSH3, 143, 155
Muir-Torre syndrome, 143, 153, 157
Mixed acinar-ductal carcinoma, 280, MSH6, 125, 143, 153–155
Multicentric hepatocellular carcinoma, 208
292, 293, 314, 315, 317 MSI (microsatellite instability), 57, 58, 86,
91, 101, 104, 125, 135, 137, 138, 141, Multidrug resistance, 31
Mixed acinar-neuroendocrine
carcinoma, 280, 292, 293, 314, 315, 143–146, 152–155, 157, 161–165, Multinodular goitre, 172
317, 318, 321, 322, 325 234, 289, 290, 294
Multiple endocrine neoplasia syndrome,
Mixed acinar-neuroendocrine-ductal MSI-H (high microsatellite instability), see MEN syndrome
carcinoma, 280, 292, 293, 314, 315, 137, 138, 143–146, 153, 154, 163
Multiple endocrine neoplasia type 1,
317, 322 MSI-L (low microsatellite instability), 137, see MEN1
Mixed adenocarcinoma, 46, 48 143, 163
Multiple endocrine neoplasia syndrome
Mixed adenoneuroendocrine carcinoma MT-1, 230 type 2b, see MEN2b
(MANEC), 13, 14, 16, 32–34, 46, 64, MT-2, 230 Multiple hamartoma syndrome, 171
65, 67, 82, 92, 93, 96, 102, 103, 120, MTA1, 128
124, 126, 128, 132, 174, 176, 184, Multiple lymphomatous polyposis, 71,
264, 274, 276, 322 mTOR, 170, 173, 215 72, 108–111, 178, 179
Mixed carcinoid-adenocarcinoma, 292 MUC (mucin core) proteins, 100, 221, 313 Multiplex ligation-dependent probe
amplification (MLPA), 62, 167
Mixed ductal-neuroendocrine MUC1, 54, 85, 88, 90, 124, 138, 254,
carcinoma, 280, 292, 322, 323 267, 285, 290, 293, 297, 302, 308, Musashi-1, 144
312, 334 Muscle-specific actin, 253
Mixed epithelial and mesenchymal
(MEM) type hepatoblastoma, 231 MUC2, 53, 54, 56, 80, 85, 88–90, 124, MUTYH, 101, 131, 141, 143, 147,
224, 255, 260, 267, 285, 290, 293, 156–158, 165
Mixed epithelial stromal tumour (MEST) 302, 308, 310, 312, 313
of the kidney, 303 MUTYH-associated polyposis (MAP),
MUC3, 285 101, 131, 141, 143, 147, 156–159,
Mixed exocrine-endocrine carcinoma
(MEEC), 13 MUC4, 285 165, 173
Mixed exocrine-endocrine tumour, 292 MUC5A, 267 MVHP, see Microvesicular hyperplastic
polyp
Mixed hepatobiliary carcinoma, 261
412 Subject index

MYB, 290 Neurofibroma, 129, 193, 325 Ovarian cancer, 80, 117, 125, 142
MYC, 24, 31, 43, 57, 72, 73, 111, 114, Neurofibromatosis (NF), 325 Ovarian-type stroma, 223, 224, 236,
144, 150, 179, 180, 190, 215, 329 Neurofibromatosis type 1 (NF1), 75, 76, 237, 300–303, 309, 315, 337
Mycotoxins, 19 92, 94, 104, 115, 154, 182, 277, 325 Oxaliplatin, 145, 146
Myelolipoma, 245 Neuron-specific enolase (NSE), 33, 66, Oxyntomodulin, 127
Myeloma, 193 182, 253, 275, 276, 297, 299, 325, 331
MYH11, 170 Neurotensin, 103, 175, 323
Myoblastoma, 193 NFkB, 31 P

MYOD1, see Myogenin NK-cell lymphoma, 178 p16INK4a, see CDKN2A
Myogenin (MYOD), 36, 247, 249, 277 NLRP1, 125 p16-Leiden deletion, 289
Myxofibrosarcoma, 277 N-nitroso compounds, 19 p21/WAF1, see CDKN1A
NOD2, 142, 144 p27/KIP1, see CDKN1B
Nonfunctioning NETs, 102, 280, 322–326 p53, see TP53
N Non-Hodgkin lymphoma, 70, 109, 110, p63, 33, 191, 269, 292
178, 251, 253
N-acetyltransferase 1, 57 p73, 50
Noninvasive carcinoma, 12, 22, 27
NAP1L1, 128 Paget cells, 189, 190, 192
Noninvasive pancreaticobiliary papillary
NAT2, 144 neoplasm, 11 Paget disease, 183, 184, 191, 192
NCAM (CD56), 33, 66, 73, 92, 107, 112, Noninvasive pancreatobiliary papillary Paired box gene 8, see PAX8
114, 124, 126, 127, 175, 176, 225, neoplasm with high-grade dysplasia Pale bodies, 210, 211
226, 276, 318, 324, 325, 328, 337 (high-grade intraepithelial neoplasia),
82, 83 Pancreatic intraepithelial neoplasia, see
NCOA3 (AIB1), 290 PanIN
NEC (neuroendocrine carcinoma), 13, Noninvasive pancreatobiliary papillary
neoplasm with low-grade dysplasia Pancreatic neuroendocrine
14, 16, 23, 32–34, 46, 53, 64–68, 82, microadenoma, 280, 322–326
88, 89, 92–94, 96, 102–105, 120, 126, (low-grade intraepithelial neoplasia),
128, 132, 138, 174–177, 184, 251, 82, 83 Pancreatic polypeptide, 66, 93, 102,
255, 264, 274–276, 280, 293, 322–326 Noninvasive papillary carcinoma, 271 103, 105, 124, 275, 302, 323, 324
NF, see Neurofibromatosis Non-mucinous, glycogen-poor Pancreatic secretory trypsin inhibitor, 316
NEN, see Neuroendocrine neoplasms cystadenocarcinoma, 295 Pancreatic stone protein, 316
Neuroendocrine carcinoma, see NEC Non-steroidal anti-inflammatory drugs Pancreatobiliary-type IPMN, 307–309, 313
(NSAIDs), 27, 134, 135
NEPPK, 23 Pancreatoblastoma, 279, 280, 294, 317–
Nonsyndromic NETs, 322 321, 325, 334–337
NET (neuroendocrine tumour), 13, 14,
16, 32–34, 46, 47, 64–68, 82, 92–94, Notch signalling pathways, 330 Paneth cell carcinoma, 53
96, 97, 102–107, 120, 121, 126–128, NSE, see Neuron-specific enolase Paneth cell-rich papillary
132, 133, 174–177, 184, 189, 255, adenocarcinoma, 138
264, 274–276, 280, 317, 318, 321–326 Nuclear cell adhesion molecule, see
NCAM Paneth cells, 27, 29, 56, 84, 85, 88, 101,
NET G1, 13, 16, 32, 33, 46, 64, 82, 92, 124, 139, 267, 270, 276
96, 102, 120, 126, 132, 174, 184, 264,
274, 280, 322 PanIN (pancreatic intraepithelial
O neoplasia), 11, 280, 281, 284,
NET G2, 16, 32, 33, 46, 64, 82, 92, 96, 287–291, 293, 304, 307, 309, 310,
102, 120, 126, 132, 174, 184, 264, Oesophagitis, 19, 22 314, 315
274, 280, 322
Oligocystic serous cystic neoplasms, 309 PanIN-1, 287, 288, 290
Neurilemmoma, 193
Oncocytic adenocarcinoma, 53 PanIN-2, 287, 288, 290
Neuroblastoma, 115, 230, 321
Oncocytic carcinoma, 295 PanIN-3, 280, 281, 284, 287, 288, 290, 293
Neuroendocrine microadenoma, 280,
322, 323, 325, 326 Oncocytic solid-pseudopapillary Papillary adenocarcinoma, 46, 48, 52
neoplasms, 310 Papillary adenoma, 271, 304
Neuroendocrine microadenomatosis, 298
Oncocytic-type IPMN, 306–308, 310 Papillary carcinoma, 304
Neuroendocrine neoplasms (NEN), 9,
13, 14, 16, 32, 34, 46, 64–68, 82, 92, Opisthorchis viverrini, 205, 217, 272 Papillary hidradenoma, 192
94, 96, 102, 104–106, 120, 128, 132, Oral contraceptives, 198, 200
149, 174, 177, 184, 251, 252, 264, Papillary intraductal papillary neoplasm,
274, 276, 280, 285, 286, 293, 297, Osler-Weber-Rendu syndrome, 79, 166, see IPN
298, 302, 310, 322, 326, 330, 335 Osteoma, 147, 148 Papillary-cystic tumour, 327
Neuroendocrine tumour, see NET Osteopontin, 145 Paraganglioma, 75, 76, 97, 277
Subject index 413

Parietal cell carcinoma, 53 Pleomorphic giant cell carcinoma, 294 PSA (prostate specific antigen), 80, 118,
PARP (poly-[ADP-ribose] polymerase), 290 Pleomorphic large cell carcinoma, 294 189, 253
PAS (Periodic acid–Schiff), 53, 182, 189, Plexiform fibromyxoma, 46, 74, 77, 78 Psammoma bodies, 92, 93, 323
209, 210, 221, 225, 229, 247, 277, PLK1 (polo-like kinase-1), 234, 235 Psammomatous somatostatinoma, 93
283, 296, 301, 313, 314, 316, 320, PSAP (prostate-specific acid
325, 328, 334, 337 Plummer-Vinson syndrome, 19
phosphatase), 177, 189
PAX2 (paired box gene 2), 255 PMS2, 143, 153–155
PSC, see Primary sclerosing cholangitis
PAX8 (paired box gene 8), 80, 118, 253, PNET (primitive neuroectodermal tumour),
325, 331 Pseudocapsule, 208, 214, 228, 300, 337
268, 298
Podoplanin, 79 Pseudocyst, 252, 298, 302, 303, 327, 329
PCNA, 24, 229
Polo-kinase 1, see PLK1 Pseudoinvasion, 84, 140, 169, 214, 310
PDEC (poorly differentiated endocrine
carcinoma), 13, 14, 32, 64, 68, 92, Poly-(ADP-ribose) polymerase, see Pseudolipoma, 245
100, 102, 105, 126, 128, 174, 274, 322 PARP Pseudomyxoma peritonei, 121–125, 293
PDGF (platelet-derived growth factor), Polypoid carcinoma, 22 Pseudomyxoma retroperitonei, 122
107, 286
Polypoid mucinous adenocarcinoma, 87 Pseudosarcomatous squamous cell
PDGFRA, 74–76, 115, 116 carcinoma, 22
Poorly cohesive carcinoma, 46, 48, 52
PDX1, 324 Pseudotumour, inflammatory, 196
Poorly differentiated ductal
PEComa (perivascular epithelioid cell adenocarcinoma, 283, 284, 325 PTEN, 57, 143, 145, 167, 171–173, 215
neoplasm), 210, 224, 260, 269, 272,
359 Poorly differentiated endocrine PTEN hamartoma syndrome (PHTS),
carcinoma, see PDEC 143, 171, 173
Peliosis hepatis, 244
Poorly differentiated hepatocellular PTGS1, 144
Pepsinogen-1, 53 carcinoma, 212 PTGS2, 30, 31, 44
Peribiliary cysts, 238, 254, 273, Poorly differentiated neuroendocrine PTK2B, 173
Peribiliary gland hamartoma, 196, 222, 260 carcinomas, 33
Pulmonary chondroma, 75, 76
Perihilar intrahepatic cholangiocarcnoma, Poorly differentiated adenocarcinomas, 54
217, 219 Pyloric-gland adenoma, 56, 269, 270
Porcelain gallbladder, 266
Perineurioma, 182 Pylorocardiac carcinoma, 42
Positron emission tomography (PET), 51,
Periodic acid–Schiff, see PAS 70, 252, 282
Peripheral intrahepatic PP/PYY-producing NETs, 96, 102, 120,
cholangiocarcinoma, 217 126, 132, 174, 175 R
Peritoneal carcinomatosis, 136, 278 PPARA, 234 RAF, 101, 145
Perivascular epithelioid cell neoplasm, Prader Willi syndrome, 234 Ran-binding protein, see RANBP2
see PEComa PRAP1/UPA, 31 RANBP2 (Ran-binding protein), 77
Perivascular epithelioid cell tumour, 232 pRb, see Rb RARB, see Retinoic acid receptor β
Peutz-Jeghers polyp, 57, 96, 132, 140, PRETEXT (Pretreatment Extent of
168, 169 RAS, 44, 101, 145, 235
Disease staging system), 233–235
Peutz-Jeghers syndrome (PJS), 101, RASSF1A, 44, 104, 234, 235
Primary sclerosing cholangitis (PSC),
131, 140, 143, 168–170, 174, 270, 218, 223, 224 Rb, 24, 177, 190, 250, 275, 276
289, 305, 310 RB1, 57, 215
Progesterone receptor, 80, 118, 177,
Phospholipase A2, 316 237, 253, 261, 268, 271, 302, 324, RCC, see Renal cell carcinoma
Phosphtidylinositol-3,4,5-triphosphate, 326, 328, 337
RCD I, 113, 114
see PIP3 Prostate-specific antigen, see PSA
RCD II, 113, 114
PHTS, see PTEN hamartoma syndrome Prostate stem-cell antigen, 286
Redox defence-system components, 24
PI3K (PI3 kinase), 173, 215 Prostate-specific acid phosphatase, see
Reflux symptoms, 26, 30
PI3K/Akt/mTOR pathway, 173, 215 PSAP
Renal cell carcinoma (RCC), 89, 90,
PIK3CA, 143, 145, 290, 310 Prostatic carcinoma, 189
209, 251–253, 255, 260, 268, 298, 333
PIP3 (phosphtidylinositol-3,4,5- Protein phosphatase 2A, 150
RER, see DNA replication errors
triphosphate), 173 Proteus syndrome, 173
Retention cysts, 310
PJS, see Peutz-Jeghers syndrome Proton-pump inhibitor, 26, 56, 68
Reticular hyaline bodies, 210
PLAG1, 234 PRSS1, 289
Retinoic acid receptor ß (RARB), 57
Platelet-derived growth factor, see PDGF Pruritus, 187, 272, 282
Retinol, 19
Pleomorphic carcinoma, 294
414 Subject index

Rhabdoid tumour, 53, 196, 230, 241, Serous cystadenoma, 260, 280, 296– SNCG, see Synuclein-γ
247, 249, 250, 255, 261 299, 331, 334, 335, 337 Solid and papillary epithelial neoplasm,
Rhabdomyoma, 193 Serous oligocystic and ill-demarcated 327
Rhabdomyosarcoma (RMS), 16, 35, 36, serous adenoma, 297 Solid serous adenoma, 297, 298
79, 193, 196, 241, 247, 249, 255, 260, Serrated adenocarcinoma, 132, 134, 138 Solid-cystic tumour, 327
261, 264, 268, 277 Serrated adenoma, 161 Solid-pseudopapillary neoplasm, 280,
RHPN2, 144 Serrated lesions, 120, 132, 139 302, 317, 318, 321, 325, 327, 329,
Riboflavin, 19 Serrated polyposis, 131, 157, 160, 161, 330, 334, 335, 337
Rokitansky-Aschoff sinuses, 269, 270 164, 165 Solitary fibrous tumour, 196, 241, 245, 331
RT-PCR, 24 Serrated polyp, 131, 157, 160–164 Somatostatin, 14, 32, 66, 68, 92–94,
RUNX, 57 Serum amyloid A (SAA), 202–204, 256 102–105, 124, 128, 175, 253, 275,
302, 323
Sessile serrated adenoma (SSA), 160
Somatostatin cell tumour, 323
Sessile serrated adenoma/polyp
Somatostatin receptor 2A (SSTR2A),
S (SSA/P), 10, 11, 120, 125, 132, 139,
104, 106
157, 158, 160–165
S100 protein, 36, 37, 76, 77, 80, 93, 106, Somatostatin receptor, 103
115, 116, 118, 127–129, 181, 182, Siewert classification, 40
189, 190, 193, 245, 253, 270, 277 Signet ring cells, 11, 42, 48, 52, 59, 61, Somatostatinoma, 92, 280, 322, 323, 325
S100A4, 286, 287 88, 90, 267, 270 Somatostatin-producing NET, 82, 92, 94,
Signet ring cell carcinoma, 42, 46, 52, 96, 102, 103
S100A6, 286
54, 61–63, 82, 87, 90, 96, 98, 120, SOX11, 72, 110, 179
S100P, 286 122, 124, 132, 134, 137, 138, 220, Spasmolytic polypeptide-expressing
SAA, see Serum amyloid A 264, 266, 268, 269, 280, 286, 292, 294 metaplasia (SPEM), 54
Salt-and-pepper chromatin, 323, 324 SIOPEL (International Childhood Liver Spindle cell carcinoma, 16, 18, 22, 132,
Tumor Strategy Group), 234 134, 138, 294
Sarcomatoid carcinoma, 22, 90, 249,
277, 294, 295 SMA, see Smooth muscle actin Spindle cell lipoma, 193
Sarcomatous ICC, 220 SMAD1, 167 Spindle cell sarcoma, 221
SCC, see Squamous cell carcinoma SMAD2, 167 Spindle-cell component, 22, 90, 94, 295
Schistosoma mansoni, 135 SMAD3, 167 SPINK1, 289
Schwannoma, 36, 46, 74, 77, 78, 129, SMAD4, 31, 43, 67, 88, 91, 101, 125, Splenomegaly, 208
181, 331 143, 158, 167, 172, 177, 190, 272,
276, 283, 285, 287, 288, 290–292, Squamoid nest, 268, 318–321, 337
Schirrous hepatocellular carcinoma, 302, 303, 309, 310, 312, 318, 320,
210, 211 Squamous carcinoma, 30, 192, 220, 292
325, 329
Sclerosing cholangitis, 239, 257, 266, Squamous cell carcinoma (SCC), 16–24,
SMAD5, 167 28–30, 32–34, 37, 42, 46, 48, 53, 82,
270, 272
SMAD7, 144, 167 87, 90, 93, 96, 132, 134, 138, 141,
Sclerosing hepatic carcinoma, 211 176, 183–193, 221, 264, 266, 268,
Small cell and large cell endocrine 269, 273, 276
SCUD (small cell undifferentiated) carcinomas, 32, 64, 92, 102, 126, 174,
hepatoblastoma, 228, 230, 235 274 Squamous cell papilloma, 192
SDHB, 171–173 Small cell carcinoma, 13, 14, 42, 103, Squamous intraepithelial neoplasia, 10, 22
SDHD, 171–173 129, 144, 176, 189, 251, 252–253, SRC (c-src), 63
271, 275, 276, 325
Sebaceous gland tumour, 153, 157 SSA/P, see Sessile serrated
Small cell change, 11, 189, 196, 212, adenoma/polyp
Sebaceous gland adenoma, 152, 157 213, 214
SEER (Surveillance Epidemiology and STAR, see Steroidogenic acute regula-
Small cell NEC, 16, 32, 33, 46, 64, 82, tory protein
End Results), 74, 87, 89, 91, 98, 101, 92–94, 96, 102, 120, 126, 128, 132,
107, 122, 126, 186, 276 174, 176, 184, 255, 264, 274–276, Steatorrhoea, 92, 103, 109
Selenium, 19, 49 280, 322–324 Steroidogenic acute regulatory (STAR)
Serotonin, 46, 64, 65, 66, 102, 103, 106, Small cell undifferentiated hepatoblastoma, protein, 302
107, 124, 127, 128, 175, 177, 267, see SCUD STK11, 57, 143, 169, 170, 172, 289,
271, 275, 276, 302, 322 SMARCB1(INI1), 230, 250 290, 310
Serotonin-producing (EC) cell NETs, 106 Smoking, see Tobacco STRAD, 170
Serous adenoma, 296 Smooth muscle actin (SMA), 35, 76-78, Subendothelial laminin, 209
Serous cystadenocarcinoma, 280, 296, 115, 116, 181, 233, 247, 250, 255, Substance P, 127, 128, 175
299 302, 331
Subject index 415

Surveillance Epidemiology and End TMEFF2/HPP1, 31 Tumour necrosis factor, see TNF
Results, see SEER TNF (tumour necrosis factor), 142, 144, Tumour topoisomerase I, 146
SWI/SNF (SMARCA1/SMARCB1), 250 178, 251, 318, 325, 328 Turcot syndrome, 143, 147, 149, 153, 155
Synaptophysin, 14, 33, 65, 66, 76, 85, TNM classification, 14, 17, 20, 24, 29, Tylosis oesophageal cancer, 7, 23, 24
92, 93, 106, 124, 127, 175–177, 182, 31, 34, 42, 47, 50, 58, 76, 82, 91, 94,
189, 237, 253, 255, 275–277, 285, 97, 100, 104, 121–124, 128, 133, 136, Type IV collagen, 209
287, 293, 297, 312, 317, 318, 320, 137, 146, 177, 184, 188, 197, 219, Type-1a glycogen storage disease, 234
324, 325, 328, 331, 334, 335, 337 224, 237, 265, 267, 272, 276, 280,
283, 326 Type-I ECL cell NET, 65
Syndromic NETs, 322
Tobacco, 18, 23, 24, 26, 30, 32, 41, 49, Type-III sporadic ECL cell NET, 66
Synovial sarcoma, 16, 35, 36, 46, 74, 78,
80, 196, 241 57, 134, 186, 187, 205–207, 281, 282 Tyrosinaemia, 201
305, 322
Synuclein-γ (SNCG), 58 Tyrosine hydroxylase, 302
TOC, see Tylosis oesophageal cancer
Toker cells, 192
TP53, 11, 23, 24, 31, 43, 44, 57, 63, 66, U
T 67, 73, 86, 90, 91, 93, 101, 104, 107,
TACSTD1, see Epithelial cell adhesion 111, 124, 125, 128,141–144, 150, 157, UES, see Undifferentiated sarcoma
molecule 158, 177, 190, 207, 208, 215, 216, UICC (International Union against
222, 249, 267, 270, 272, 275, 276, Cancer), 21, 31, 52, 68, 91, 104, 128,
T-cell lymphoma, 34, 73, 95, 96, 112– 285, 287, 290, 292, 295, 298, 302,
114, 178, 179, 239, 240 326
303, 309, 310, 312, 318, 320, 321,
T-cell transcription factor (Tcf), 143, 144, 324, 325, 329 Ulcerative colitis (UC), 98, 122, 135,
150, 329 140–142, 174, 178, 191, 218, 266, 272
TP73, 50
TCF/LEF family, 150, 329 Ulex europaeus agglutinin 1 (UEA1), 192
TPM3 (tropomyosin 3), 77
TCF7L2, 143, 144 Ultrasound and magnetic resonance
TPM4 (tropomyosin 4), 77 cholangiography (MRCP), 219
TCRδγ, 114 Traditional serrated adenoma (TSA), Undifferentiated embryonal sarcoma
TCRβ, 113 120, 132, 160–164 (UES), see Undifferentiated sarcoma
Telomerase reverse transcriptase (TERT) Transforming growth factor α, see TGFα Undifferentiated carcinoma, 16, 18, 23,
gene, 215 Transforming growth factor β, see TGFβ 46, 48, 52, 53, 82, 87, 88, 90, 91, 96,
Telomere shortening, 212, 290 120, 122, 124, 132, 134, 138, 179,
Transforming growth factor β receptor,
184, 196, 205, 211, 212, 264, 266,
Tensin, 171, 172 see TGFBR1 and TGFBR2
269, 271–273, 280, 286, 292, 294,
TEP1, 172 Transitional liver cell tumour (TLCT), 232, 295, 301, 303
233, 235, 255, 261
Teratoma, 196 Undifferentiated carcinoma with
Trichilemmoma, 171, 172 osteoclast-like giant cells, 82, 87, 90,
TERT, see Telomerase reverse
transcriptase Tricyclic antidepressants, 26 286, 292, 295
TFF1 (thyroid transcription factor 1), 53 Tropomyosin 3, see TPM3 Undifferentiated sarcoma, 196, 228, 241,
242, 246, 274, 277
TGFα (transforming growth factor α), Tropomyosin 4, TPM4
215, 251, 286 Uterine fibroids, 172
Trousseau syndrome, 335
TGFβ (transforming growth factor β), 57, Uterine leiomyoma, 171
Trypsin, 285, 293, 294, 312, 314, 316,
64, 167, 215, 234, 286 318, 320, 324, 325, 328, 329, 334,
TGFBR1 (ALK5), 290 335, 337
TGFBR2, 143, 167, 290, 294 TSA, see Traditional serrated adenoma V
Thorotrast deposition, 223 TTF1 (thyroid transcription factor 1), 33, vacA, 49, 50
80, 93, 118, 127, 176, 253, 255, 288,
Thrombocytopenia, 239, 255 Vascular endothelial growth factor
325
Thrombocytosis, 228 (VEGF), 24, 31, 286
Tuberous sclerosis, 244, 325
Thymidine phosphorylase, 146 Vasoactive intestinal peptide, see VIP
Tubular adenocarcinoma, 46, 48, 51, 52,
Thymidylate synthase, 146 VEGF, see Vascular endothelial growth
281, 308
factor
Thyroglobulin, 255 Tubular adenoma, 82–84, 132, 140, 141,
Verrucous carcinoma, 16, 18, 21, 22,
Thyroid cancer, 150, 171, 172 269, 270
184, 188, 189
Thyroid transcription factor 1, see TTF1 Tubular carcinoid, 120, 126–128, 264,
Vesicular monoamine transporter 2,
274
TIA1, 73, 113 see VMAT2
Tubulovillous adenoma, 82, 83, 99, 132,
TLCT, see Transitional liver cell tumour VHL (von Hippel Lindau), 104, 275, 276,
140
296–298, 322, 325, 326, 333
416 Subject index

VHL-associated serous cystic neoplasm, Y

297, 298
Yolk sac tumour, 196
Vienna grading system, 10, 11, 27
Villous adenoma, 82–84, 86, 99, 132,
140, 304
Z
Vimentin, 189, 230, 231, 233, 237, 245,
247, 248, 250, 255, 285, 295, 318, Zinc, 19
325, 328, 329, 335 Zollinger-Ellison syndrome, 64, 102, 275,
VIP, 32, 93, 280, 323 335
VIPoma, 280, 322, 323
Vitamin A, 49
Vitamin C, 49
Vitamin D, 134
Vitamin E, 19, 49
VMAT2 (vesicular monoamine
transporter 2), 33, 65
Von Gierke disease, 201
Von Hippel-Lindau disease, see VHL
Von Meyenburg complex, 222, 260
Von Recklinghausen disease, 91, 92, 94,
104
W
Weibel-Palade bodies, 248
Well-differentiated endocrine carcinoma
(WDEC), 13; see NET G2
Well-differentiated endocrine tumour
(WDET), 13, 14, 32, 92, 102, 133, 274,
see NET G1
Well-differentiated endocrine tumour/
carcinoma, 64, 126
Well-differentiated hepatocellular
carcinoma, 211
WHO classification, 10–13, 16, 46, 52,
82, 96, 120, 180, 184, 189, 190, 264,
267, 273, 280, 322
Wilms tumour, 321
Wnt, 101, 104, 150, 158, 215, 234, 235,
320, 329, 330
WT1, 331
X
Xeroderma pigmentosum group C (XPC)
gene, 30
Xeroderma pigmentosum group D, 30
XRCC1 (X-ray repair
cross-complementing 1), 30
Subject index 417


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WHO Classification Tumours of the Digestive System

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WHO Classification of Tumours of the Digestive System

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© International Agency for Research on Cancer, 2010

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The copyright of figures and charts remains with the authors.

Second print run (10,000 copies)

Format for bibliographic citations:

IARC Library Cataloguing in Publication Data

(World Health Organization classification of tumours)

1. Digestive System Neoplasms − classification 2. Digestive System Neoplasms − genetics

ISBN 978-92-832-2432-7 (NLM Classification: WI 15)

1 Diagnostic terms revisited 9 9 Tumours of the anal canal 183

Diagnostic terms revisited

Premalignant lesions of the digestive system

Nomenclature and classification

Premalignant lesions R.D. Odze

10 Diagnostic terms revisited

Premalignant lesions of the digestive system 11

12 Diagnostic terms revisited

Nomenclature and classification G. Rindi

14 Diagnostic terms revisited

Tumours of the oesophagus

Squamous cell carcinoma

Secondary tumours and melanoma

WHO classificationa of tumours of the oesophagus

16 Tumours of the oesophagus

TNM classificationa of carcinoma of the oesophagus

Squamous cell carcinoma E. Montgomery

18 Tumours of the oesophagus

Squamous cell carcinoma 19

the ulcerative type described in the Ming

Tumour spread and staging

20 Tumours of the oesophagus

Squamous cell carcinoma 21

osseous, cartilaginous and skeletal-muscle

Basaloid squamous cell carcinoma

22 Tumours of the oesophagus

Basal cell hyperplasia Undifferentiated carcinoma. This lacks

Squamous cell carcinoma 23

24 Tumours of the oesophagus

Adenocarcinoma of the oesophagus J.-F. Fléjou

Definition In addition to increases in incidence, Barrett oesophagus and