Neck Swellings

Midline Neck
Swellings
Diagnostic and Therapeutic
Challenges
Mahmoud Sakr
123
Midline Neck Swellings
Mahmoud Sakr
Midline Neck Swellings

Diagnostic and Therapeutic Challenges
Mahmoud Sakr
Faculty of Medicine
Alexandria University
Alexandria, Egypt
ISBN 978-3-031-48564-0 ISBN 978-3-031-48565-7 (eBook)

https://doi.org/10.1007/978-3-031-48565-7
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To my dear students and colleagues
Preface
In this authored book, we aim at emphasizing established concepts, displaying the

ongoing arguments, controversies, challenges, and debates on diagnosis and treat-
ment of midline neck swellings with a view of clarifying some uncertainties, mak-
ing suggestions to resolve others, and establishing strategies to reach therapeutic
success.
This book, in 10 chapters with 76 images and 1683 references, will provide a
valuable source of knowledge and reference for all specialists and trainees entrusted
with the care of patients suffering from midline neck swellings. It addresses and
discusses the following topics: surgical anatomy of the neck with particular empha-
sis on midline cervical regions, classification and clinical approach for adequate
diagnosis and timely management, cervical lymphadenopathy, swellings of the sub-
mental region (submental lymph nodes, plunging sublingual dermoid cyst, hour-
glass ranula, abscesses related to the mandible, and submental ectopic thyroid
tissue), swellings of the hyoid bone region (sub-hyoid bursitis, chondroblastoma,
chondroma, osteoblastoma, osteoma, solitary plasmacytoma of bone, giant cell
tumor, aneurysmal bone cyst, and hyoid bone metastasis), swellings of the laryn-
geal/pharyngeal region (pre-laryngeal or Delphian lymph node, laryngeal tumors,
bursa in front of Adam’s apple, chondritis of thyroid cartilage, retropharyngeal
abscess, and laryngocele), swellings of the tracheal region (pre-tracheal lymph
nodes, tracheal adenoid cystic carcinoma, solid nodules as well as cystic and par-
tially cystic nodules in the isthmus of the thyroid gland), and swellings of the supra-
space of Burns (enlarged lymph nodes, lipoma, teratoma, thymoma, aneurysm of
the aorta or innominate artery, and high (cervical) aortic arch). In addition, this book
emphasizes, in the last chapter, the importance of scheduling regular follow-up as
well as patient counseling and education to obtain maximum patient safety and
optimum management outcome.
It is my collective hope that head and neck surgeons, maxillofacial surgeons,
orthopedic surgeons, endocrinologists, oncologists, pediatricians, and clinicians of
other specialties will find this book to be a useful and indispensable resource as they
face the most challenging of midline neck swellings to help provide individual
patients with the best possible outcome.
Alexandria, Egypt Mahmoud Sakr
vii
Acknowledgments
I would like to thank all those who helped and encouraged me during the writing,
editing, and revision of this book. I would like to express my appreciation and grati-
tude to my wife and children for their continuous support and unconditional love.
ix
Contents
1
Surgical Anatomy of the Neck�� 1
1.1 Triangles and Muscles of the Neck�� 1
1.2 Surgical Levels of the Neck�� 3
1.3 Anatomical Regions of the Central Neck �� 3
1.4 Lymph Nodes of the Central Neck�� 19
References�� 21
2
Midline Neck Swellings: Classification�� 25
2.1 Classification According to Anatomical Region �� 25
2.2 Classification According to the Structure of Origin�� 26
2.3 Classification According to Consistency�� 27
2.4 Classification According to Age�� 28
References�� 30
3
Midline Neck Swellings: Clinical Approach�� 31
3.1 Introduction to Clinical Approach�� 31
3.2 History-Taking�� 32
3.3 Physical Examination�� 33
3.4 Investigations�� 34
3.5 Differential Diagnosis �� 38
References�� 39
4
Midline Neck Swellings: Cervical Lymphadenopathy�� 41
4.1 Etiology of Cervical Lymphadenopathy (CLA) �� 41
4.2 Infections�� 42
4.3 Malignancy (Metastatic Lymphadenopathy)�� 45
4.4 Diagnostic Approach�� 49
References�� 54
5
Swellings of the Submental Region�� 61
5.1 Overview�� 61
5.2 Submental Lymphadenopathy�� 62
5.3 Cervical Dermoid Cyst �� 63
5.4 Plunging Ranula (Dumbbell-Shaped) �� 71
xi
xii Contents
5.5 Abscess in Relation to Odontogenic Infections�� 77

5.6 Submental Ectopic Thyroid Tissue �� 79
References�� 84
6
Swellings of the Hyoid Bone Region�� 89
6.1 Hyoid Bone Region Swellings�� 89
6.2 Thyroglossal Cyst �� 89
6.3 Median Ectopic Thyroid Tissue�� 101
6.4 Sub-hyoid Bursitis�� 107
6.5 Hyoid Bone Tumors�� 110
References�� 134
7
Swellings of the Laryngeal/Pharyngeal Region�� 147
7.2 Pre-laryngeal (Delphian) Lymph Node�� 148
7.3 Laryngeal Tumors �� 156
7.4 Prominence of Adam’s Apple �� 168
7.5 Chondritis of the Thyroid Cartilage�� 170
7.6 Retropharyngeal Abscess (RPA)�� 176
7.7 Laryngocele�� 184
8
Swellings of the Tracheal Region�� 199
8.2 Pre-tracheal Lymphadenopathy�� 199
8.3 Tracheal Adenoid Cystic Carcinoma�� 201
8.4 Solid Nodule in the Thyroid Isthmus�� 208
8.5 Cystic Nodule in the Thyroid Isthmus�� 248
9
Swellings of the Suprasternal Space of Burns �� 289
9.1 Introduction�� 289
9.2 Lymphadenopathy�� 290
9.3 Lipoma�� 293
9.4 Teratoma �� 297
9.5 Dermoid/Epidermoid Cyst�� 305
9.6 Thymic Lesions�� 307
9.7 Aneurysm of the Innominate Artery (IA) �� 334
9.8 Aortic Arch Aneurysm (AAA)�� 335
9.9 Cervical (High) Aortic Arch�� 342
10
Follow-Up and Patient Education�� 357
10.1 Follow-Up of Patient Not at Increased Risk �� 357
10.2 Education of Patient at Increased Risk �� 358
Surgical Anatomy of the Neck
1
Contents
1.1 Triangles and Muscles of the Neck 1
1.2 Surgical Levels of the Neck 3
1.3 Anatomical Regions of the Central Neck 3
1.4 Lymph Nodes of the Central Neck 19
References 21
1.1 Triangles and Muscles of the Neck
Triangles of the Neck
From a surgical perspective, the neck is usually divided into two triangles; the ante-
rior triangle, which consists of three and half triangles and the posterior triangle,
which consists of two triangles (Fig. 1.1). The sternocleidomastoid (SCM) muscle
is the key to understanding both of these triangles [1]. The neck also contains such
triangles as the suboccipital triangle in the posterior aspect of the neck, the triangle
of the vertebral artery and scalene triangle in the deep layer of the neck, as well as
other anatomical triangles that contain nerves, vessels, and other anatomical struc-
tures; these include the Lesser’s, Pirogov’s, Béclard’s, and Farabeuf’s triangles [2, 3].
Anterior Triangle
The anterior triangle of the neck is bounded by the anterior border of the sternoclei-
domastoid (SCM) muscle laterally, the inferior border of the mandible superiorly,
and the midline of the neck medially. In clinical practice, the structures deep to the
SCM muscle are considered to be inside the anterior triangle. The anterior triangle
© The Author(s), under exclusive license to Springer Nature 1

Switzerland AG 2024
M. Sakr, Midline Neck Swellings, https://doi.org/10.1007/978-3-031-48565-7_1
2 1 Surgical Anatomy of the Neck
Fig. 1.1 Triangles of the neck: Anterior triangle (submental, digastric, carotid, and muscular tri-
angles) and posterior triangle (occipital and subclavian triangles)
consists of three and half triangles, namely, digastric (submandibular) triangle,

carotid triangle, muscular triangle and half of the submental triangle. The midline of
the neck extends from the “symphysis menti” above to the “suprasternal notch”
below (Fig. 1.1).
Posterior Triangle
The posterior triangle of the neck is bounded by the posterior border of the sterno-
mastoid muscle anteriorly, the anterior edge of the trapezius muscle posteriorly, and
the middle one-third of the clavicle inferiorly. The union of the SCM and trapezius
muscles at their insertion on the superior nuchal line of the occipital bone forms the
apex of the triangle. As shown in Fig. 1.1, the posterior triangle consists of two tri-
angles: the occipital triangle and the subclavian (supraclavicular) triangle [1, 2].
Muscles of the Neck
The muscles of the anterior and posterior triangles of the neck may be classified into
four groups as follows [4]:
Superficial Group
The superficial group of muscles of the neck comprises the right and left platysma
muscles.
Anterolateral Group
The anterolateral group of neck muscles comprises the sternocleidomastoid (SCM)
muscles and trapezius muscles.
Anterior Group
The anterior group of muscles of the neck includes the following muscles:
–– Mylohyoid muscle
–– Anterior and posterior bellies of digastric (useful guides during surgery)
–– Stylohyoid muscle
–– Infrahyoid strap muscles (sternohyoid, sternothyroid, thyrohyoid, and omohy-
oid muscle)
Vertebral Group
The vertebral group of muscles of the neck is made up of two subgroups:
–– Anterior prevertebral muscles: These are exemplified by the longus colli and
longus capitis, which run longitudinally anterior to the cervical vertebral bodies
–– Lateral prevertebral muscles: These include the scalenus anterior, medius and
posterior, and levator scapulae. All of these muscles arise from the transverse
processes of cervical vertebrae and run infero-laterally to attach to the upper part
of the rib cage or upper border of the scapula. These muscles are not usually
encountered during head and neck surgery as they lie deep to the prevertebral
fascia, a relatively dense layer of tissue, which forms a useful barrier to deeper
dissection.
1.2 Surgical Levels of the Neck
Surface anatomy of the neck gives an approximate idea of the six surgical cervical
levels of regions [5]. These are summarized in Table 1.1.
1.3 Anatomical Regions of the Central Neck
The midline of the neck extends from the “symphysis menti” above to the “supra-
sternal notch” below. It, therefore, includes the following regions (Fig. 1.2):
1. Submental (suprahyoid) region

2. Hyoid bone region
3. Laryngeal/pharyngeal region
4. Tracheal region
5. Suprasternal space (SSS) of Burns
Table 1.1 Surgical levels of the neck [5]

Cervical Level Description
Level 1 This region (triangle) is bounded by the anterior belly of
the digastric muscles (both sides) and the hyoid bone
inferiorly
Level IA (submental region) This region (triangle) is bounded by the anterior and
Level IB (submandibular region) posterior bellies of digastric muscle inferiorly and the
body of the mandible superiorly
Level 1I The region anterior to the vertical plane of the spinal
accessory nerve (SAN), bounded by the digastric muscle
superiorly, and the inferior border of the hyoid bone
(clinical landmark) or the carotid bifurcation (surgical
landmark) inferiorly, down to the prevertebral fascia
Level IIA Posterior to the SAN and extending to the skull base
Level IIB superiorly
Level III This level extends from the inferior border of the hyoid
bone (or carotid bifurcation) superiorly to the inferior
border of the cricoid cartilage inferiorly
Level IV This level extends from the lower border of the cricoid
cartilage (or omohyoid muscle) superiorly to the clavicle
inferiorly
Level V (posterior triangle) The upper limit of this triangle is the convergence of the
trapezius and the SCM muscles while the lower boundary
is formed by the clavicle. Anteriorly, it is bounded by the
posterior border of SCM and posteriorly by the anterior
border of the trapezius muscle
Level VA This level lies above by an imaginary horizontal plane
marking the lower border of the cricoid cartilage
extending into the posterior triangle (or above the course
of the SAN as it crosses the posterior triangle)
Level VB This level lies below that imaginary horizontal plane of
the lower border of the cricoid cartilage (or the course of
the SAN)
Level VI (central compartment) This region extends from the hyoid bone superiorly to the
suprasternal notch inferiorly. On each side, the lateral
boundary is the medial border of the carotid sheath
SAN spinal accessory nerve, SCM sternocleidomastoid
Suprahyoid Region: Level 1A (Submental Triangle)
Boundaries
The submental triangle is bounded on either side by the anterior belly of digastric mus-
cle and inferiorly by the hyoid bone, which forms the base of the triangle, while the chin
forms the apex. The floor of the submental triangle is formed by the two mylohyoid
muscles while the roof is made by the investing layer of the deep cervical fascia
(Fig. 1.3). Since the anterior belly of the digastric muscle can have a variable anatomy
or even be absent, the submental triangle can consequently be distorted or absent [4, 6].
Contents
The submental triangle contains (1) submental lymph nodes (LNs) that receive lym-
phatic drainage from the mental region, apex of the tongue, lower lip, and incisor
Fig. 1.2 Front view of the

midline of the neck
showing the important
structures. STA superior
thyroid artery
Fig. 1.3 Boundaries and contents of the submental triangle. It is bounded by the anterior belly of
digastric muscle on either side and by the hyoid bone inferiorly (base)
teeth, and (2) small submental veins that anastomose in this triangle to form the
anterior jugular vein (AJV), which is a paired vessel that drains the anterior com-
partment of the neck (Fig. 1.3). It receives three sets of tributaries: laryngeal, small
thyroid, and inferior thyroid vein. It finally drains into the external jugular vein
(EJV). Less frequently, it may drain directly into the subclavian vein [4].
Clinical Significance
Above the hyoid bone, the paired mylohyoid muscles (also known as the “dia-
phragma oris”) interdigitate in the anterior midline at the mylohyoid raphe to form
a mobile muscular sheet extending between the inner aspects of the right and left
halves of the mandible. This mylohyoid “sheet” is an important “surgical landmark”
as it forms the floor of the mouth and thus demarcates the neck (cervical region)
below from the oral region above. It separates the submandibular space below from
the sublingual space above.
The mylohyoid muscle elevates the hyoid bone and the tongue, which is particu-
larly important during swallowing and speech. Alternatively, if other muscles are
used to keep the position of the hyoid bone fixed, then the mylohyoid muscle
depresses the mandible. It also reinforces the floor of the mouth. The source of
motor innervation of the mylohyoid muscle is via the “mylohyoid nerve,” which is
a branch of the inferior alveolar nerve, a branch of the third (mandibular) division
of the trigeminal nerve (CN-V). The mylohyoid nerve pierces the sphenomandibu-
lar ligaments and runs superficially on the mylohyoid itself. It also supplies the
anterior belly of digastric muscle and is sensory to the inferior part of the chin. This
nerve can sometimes be preserved during neck dissection.
Odontogenic infection from the lower central and lateral incisors can spread out
into the submental space and form a pyogenic abscess [7]. Swelling occurs around
the chin and the submental triangle. Occasionally, extraoral incisions are necessary
to adequately treat such abscesses.
ransfer of Submental Lymph Nodes

T
The submental lymph nodes (LNs) represent a reliable donor site for LN transfer
popularized by Cheng et al., who has reported outstanding outcomes in patients
receiving a submental LN transfer, for the management of both, upper extremity [8,
9] and lower extremity [10] lymphedema. The submental donor site reliably con-
tains an average of five LNs, and the anatomy of the flap is quite predicable [9, 11,
12]. The flap is based on the submental artery, which can serve as the pedicle for the
flap, but is limited by its size and length. If additional length and caliber are needed,
the facial vessels can be dissected and used as the pedicle to the flap. For distal
placement, a short pedicle can be sufficient, but for the axilla, a longer pedicle is
usually required; it is useful and will facilitate the microsurgical anastomosis [13].
In taking the LNs, skin can be included to add additional bulk if needed, but the
nodes can be harvested without a skin paddle in order to limit the bulk if distal
placement of the nodes is anticipated [14]. Patients should be cautioned regarding
the visible location of the scar following harvest of the submental nodes and the
potential risk of injury to the marginal mandibular nerve [15].
Hyoid Bone Region
Anatomical Features
The hyoid bone is a small U-shaped (horseshoe-shaped) solitary bone, situated ante-
riorly in the midline of the neck, at the base of the mandible and posteriorly at the
fourth cervical vertebra. Its anatomical position is just superior to the thyroid carti-
lage. It consists of a central part, the “body,” and two pairs of “horns,” the greater
and lesser horns [16].
The hyoid bone is suspended from the styloid processes by the stylohyoid liga-
ments and gives attachment to the suprahyoid and infrahyoid groups of muscles.
Blood is supplied to the hyoid bone via the lingual artery, a branch of the external
carotid artery (ECA). It runs down from the tongue to the greater horns of the bone.
The suprahyoid branch of the lingual artery runs along the upper border of the hyoid
bone and supplies blood to the attached muscles [16].
The primary role of the hyoid bone is to provide stability to adjacent structures via
the attached muscles. It also serves as a surgical landmark when approaching thyro-
glossal cysts and the tongue base. The hyoid bone is important for breathing, swal-
lowing, and speech. It is also thought to play a key role in keeping the upper airway
open during sleep [17] and as such the development and treatment of obstructive
sleep apnea (OSA) (characterized by repetitive collapse of the upper airway during
sleep). A more inferiorly positioned hyoid bone has been reported to be strongly
associated with the presence and severity of the disorder [18, 19]. Movement of the
hyoid bone is also thought to be important in modifying upper airway properties,
which was recently demonstrated in computer model simulations [20]. A surgical
procedure that aims to potentially increase and improve the airway is known as
“hyoid suspension.”
Due to its position, the hyoid bone is not easily susceptible to fracture. In a sus-
pected case of murder or physical abuse of an adult, a fractured hyoid strongly
indicates throttling or strangulation. In children and adolescents (in whom the hyoid
bone is still flexible because ossification is yet to be completed), fracture may not
occur even after serious trauma.
Laryngeal/Pharyngeal Region
Larynx
Location
The larynx is located in the midline of the anterior part of the neck at the level of the
cervical vertebrae C3–C6. It extends vertically from the tip of the epiglottis to the
inferior border of the cricoid cartilage (i.e., at the level of C6) where it is continuous
with the trachea, forming the laryngotracheal junction at the same horizontal level
as the pharyngoesophageal junction. The interior of the larynx can be divided into
supraglottis, glottis, and sub-glottis. Lying astride the anterior aspect of the upper
trachea is the thyroid isthmus, which on either side of the midline, is coextensive
with the corresponding thyroid lobe.
Structure
The laryngeal skeleton consists of nine cartilages: three single cartilages (epiglottis,
thyroid, and cricoid) and three paired (arytenoid, corniculate, and cuneiform) [21].
These cartilages are attached to one another, and to surrounding structures, by mus-
cles or by fibrous and elastic tissue components. Although the larynx is suspended
from the hyoid, the hyoid bone is not considered as part of the larynx.
The larynx is lined by a ciliated columnar epithelium except for the vocal folds.
The cavity of the larynx extends from its triangle-shaped inlet to the circular outlet
at the lower border of the cricoid cartilage, where it is continuous with the lumen of
the trachea. The mucous membrane lining the larynx forms two pairs of lateral folds
that project inward into its cavity. The upper folds are called the vestibular folds
(also known as the false vocal cords because they play no part in vocalization). The
lower pair of folds is known as the vocal cords, which control sound pitch and vol-
ume essential for phonation. The slit-like space between the left and right vocal
cords, called the rima glottidis, is the narrowest part of the larynx. The vocal cords
and the rima glottidis are together designated as the glottis.
The laryngeal cavity is divided into two parts by the projection of the vocal folds,
The portion of the cavity of the larynx above the vocal folds is called the laryngeal
vestibule. The very middle portion of the cavity between the vestibular folds and the
vocal cords is the ventricle of the larynx. The portion below the vocal folds is called
the infraglottic cavity. At its beginning, it has an elliptical form, but lower down it
widens out, assumes a circular form, and is continuous with the tube of the trachea.
Laryngeal Cartilages
There are nine cartilages, three unpaired (Fig. 1.4) and three paired (i.e., six carti-
lages), that support the larynx and form its skeleton [21].
Unpaired Cartilages
–– Thyroid cartilage: This cartilage forms the laryngeal prominence (also called
“Adam’s apple”), which is usually larger in males than in females. It is connected
to the hyoid bone by the thyrohyoid membrane (ligament). It supports the front
portion of the larynx.
–– Cricoid cartilage: A ring of hyaline cartilage that forms the inferior wall of the
larynx. It is attached to the top of the trachea below and is connected to the thy-
roid cartilage above by the median cricothyroid ligament.
–– Epiglottis: It is a large, spoon-shaped piece of elastic cartilage. During swallow-
ing, the pharynx and larynx rise. Elevation of the pharynx widens it to receive
food and drink; elevation of the larynx causes the epiglottis to move down and
form a lid over the glottis, closing it off.
Fig. 1.4 Anatomy of the

larynx (anterior view)
showing the thyrohyoid
membrane, thyroid
cartilage, cricoid cartilage,
and epiglottis
Paired Cartilages
–– Arytenoid cartilages: Of the paired cartilages, the arytenoid cartilages are the
most important because they influence the position and tension of the vocal
cords. These are triangular pieces of mostly hyaline cartilage located at the pos-
terosuperior border of the cricoid cartilage.
–– Corniculate cartilages: These are horn-shaped pieces of elastic cartilage located
at the apex of each arytenoid cartilage.
–– Cuneiform cartilages: These are club-shaped pieces of elastic cartilage located
anterior to the corniculate cartilages.
Laryngeal Muscles
The muscles of the larynx are divided into intrinsic and extrinsic muscles. The
intrinsic muscles are confined entirely within the larynx where they have their ori-
gin and insertion. The extrinsic muscles act on the region and pass between the
larynx and parts around it but have their origin elsewhere.
The intrinsic muscles are divided into respiratory and phonatory muscles. The
respiratory muscles move the vocal cords apart and serve breathing while the pho-
natory muscles move the vocal cords together and serve the production of voice.
The main respiratory muscles are the “posterior cricoarytenoid” muscles. The pho-
natory muscles are divided into adductors (lateral cricoarytenoid muscles, aryte-
noid muscles) and tensors (cricothyroid muscles, thyroarytenoid muscles).
Intrinsic Laryngeal Muscles

The intrinsic muscles of the larynx are responsible for controlling sound produc-
tion. Additionally, these muscles present a constitutive calcium-buffering profile
that predicts their better ability to handle calcium changes in comparison to other
muscles and allows them to function as very fast muscles with a well-developed
capacity for prolonged work [22]. Intrinsic laryngeal muscles and their action are
summarized in Table 1.2.
Extrinsic Laryngeal Muscles

Extrinsic laryngeal muscles support and position the larynx within the mid-cervical
cereal region. The extrinsic muscles, their action and innervation are summarized in
Table 1.3.
Nerve Supply
The larynx is innervated by branches of the vagus nerve (CN-X) on each side.
Sensory innervation to the glottis and laryngeal vestibule is by the internal branch
of the superior laryngeal nerve (SLN). The external branch of the superior laryngeal
nerve innervates the cricothyroid muscle. Motor innervation to all other muscles of
the larynx and sensory innervation to the sub-glottis is by the recurrent laryngeal
nerve (RLN).
Injury to the external branch of the SLN causes weakened phonation because the
vocal cords cannot be tightened. Injury to one of the RLNs produces hoarseness; if
both are injured the voice may or may not be preserved, but breathing becomes
difficult.
Function
The larynx is mainly involved in breathing, producing sound (manipulating pitch
and volume), and protecting the trachea against food aspiration (by coughing and
Table 1.2 Intrinsic muscles of the larynx

Intrinsic muscles Action
Cricothyroid Lengthens and tenses the vocal cords
Posterior cricoarytenoid Abducts and externally rotates the arytenoid cartilages, resulting in
abducted vocal cords. It is the only muscle capable of separating the
vocal cords for normal breathing. If it is incapacitated on both sides
due to bilateral injury to the recurrent laryngeal nerve (RLN), the
inability to abduct the vocal cords will cause dyspnea
Lateral cricoarytenoid Adducts and internally rotates the arytenoid cartilages and increases
medial compression
Transverse arytenoid Adducts the arytenoid cartilages, resulting in adduction of the vocal
cords [23]
Oblique arytenoid Narrows the laryngeal inlet by constricting the distance between the
arytenoid cartilages
Thyroarytenoid Narrows the laryngeal inlet, shortening the vocal cords, and
lowering voice pitch. The internal thyroarytenoid is the portion of
the thyroarytenoid that vibrates to produce sound
Table 1.3 Extrinsic muscles of the larynx

Intrinsic muscles Action Innervation
Sternothyroid Depresses the larynx Ansa cervicalis
Omohyoid Depresses the larynx Ansa cervicalis
Sternohyoid Depresses the larynx Ansa cervicalis
Inferior constrictor Used during breathing and speech. It Vagus nerve (CN-X)
helps to keep the pharynx open,
particularly during sleep
Thyrohyoid Elevates the larynx First cervical nerve (C1)
Digastric Elevates the larynx Trigeminal nerve (CN-V3),
facial nerve (CN-VII)
Stylohyoid Elevates the larynx Facial nerve (CN-VII)
Mylohyoid Elevates the larynx Trigeminal nerve (CN-V3)
Geniohyoid Elevates the larynx First cervical nerve (C1)
Hyoglossus Elevates the larynx Hypoglossal nerve
(CN-XII)
Genioglossus Elevates the larynx Hypoglossal nerve
(CN-XII)
other reflexive actions. A cough is initiated by a deep inhalation through the vocal
cords, followed by the elevation of the larynx and the tight adduction of the vocal
cords. The forced expiration that follows, assisted by tissue recoil and the muscles
of expiration, blows the vocal cords apart, and the high pressure expels the irritating
object out of the throat [24].
Another important role of the larynx is abdominal fixation, a kind of Valsalva’s
maneuver in which the lungs are filled with air in order to stiffen the thorax so that
forces applied for lifting can be translated down to the legs. This is achieved by a
deep inhalation followed by the adduction of the vocal cords. Grunting while lifting
heavy objects is the result of some air escaping through the adducted vocal cords
ready for phonation [24].
Abduction of the vocal cords is important during physical exertion. The vocal
cords are separated by about 8 mm (0.31 in) during normal respiration, but this
width is doubled during forced respiration [24].
During swallowing, elevation of the posterior portion of the tongue levers
(inverts) the epiglottis over the glottis’ opening to prevent swallowed material from
entering the larynx and provides a path for a food or liquid bolus to “slide” into the
esophagus; the hyo-laryngeal complex is also pulled upward to assist this process.
Stimulation of the larynx by aspirated food or liquid produces a strong cough reflex
to protect the lungs.
Pathological Disorders
There are several disorders that can cause laryngeal dysfunction (Table 1.4) [25].
Some resulting symptoms include hoarseness, loss of voice, pain in the throat or
ears, and breathing difficulties (dyspnea, stridor).
Table 1.4 Pathological disorders of the larynx [25]

Pathological disorders Description
Acute laryngitis Sudden inflammation and swelling of the larynx, usually caused by
the common cold or by excessive shouting
Chronic laryngitis Caused by smoking, dust, frequent yelling, or prolonged exposure
to polluted air
Presby larynx A condition in which age-related atrophy of the soft tissues of the
larynx results in weak voice and restricted vocal range and
stamina. Laryngoscopy shows bowing of the anterior portion of the
VCs
Ulcers May result from prolonged presence of an endotracheal tube
Polyps and VC nodules Caused by prolonged exposure to tobacco smoke and vocal misuse,
respectively
Cancer of the larynx Two types of laryngeal cancer, namely, squamous cell carcinoma
and verrucous carcinoma, are strongly associated with repeated
exposure to cigarette smoke and alcohol
VC paresis Weakness of one or both VCs; greatly impacts daily life
Laryngopharyngeal A condition in which gastric acid irritates and burns the larynx.
reflux Similar damage can occur with GERD [26, 27]
Laryngo-malacia A very common condition of infancy, in which the soft, immature
cartilage of the upper larynx collapses inward during inhalation,
causing airway obstruction
Laryngeal perichondritis Inflammation of the perichondrium of laryngeal cartilages, causing
airway obstruction
Laryngeal paralysis A condition in which the larynx no longer opens as wide as
required for the passage of air, which impedes respiration
Idiopathic laryngeal An uncommon disorder characterized by brief episodes of stridor,
spasm occurring at any time. Subsequent outpatient physical examination
is normal. These episodes cause considerable anxiety for both
patient and physician
VC vocal cord, GERD gastroesophageal reflux disease
Pharynx
Location
The centrally located visceral compartment of the neck comprises, most posteriorly,
the pharynx and its distal continuation the esophagus. The pharynx is a centrally
located posterior elongated chamber in the neck extending from the clivus superi-
orly to the pharyngoesophageal junction inferiorly, at the level of the lower border
of the cricoid cartilage (corresponding to the lower part of the body of the sixth
cervical vertebra [C6]). From above downward, the pharynx lies successively
behind the nasal cavity (nasopharynx), the oral cavity (oropharynx), and the larynx
(laryngopharynx).
Structure
Nasopharynx
The nasopharynx is the upper portion of the pharynx that extends from the base of
the skull to the upper surface of the soft palate; it lies above the oral cavity. The
adenoids (pharyngeal tonsils) are lymphoid tissue structures located in the posterior
wall of the nasopharynx. Waldeyer’s tonsillar ring is an annular arrangement of
lymphoid tissue in both the nasopharynx and oropharynx. The nasopharynx is lined
by respiratory epithelium that is pseudostratified, columnar, and ciliated.
Polyps or mucus can obstruct the nasopharynx, as can congestion due to an upper
respiratory infection. The auditory tube, which connects the middle ear to the phar-
ynx, opens into the nasopharynx. The opening and closing of the auditory tubes
serve to equalize the barometric pressure in the middle ear with that of the ambient
atmosphere [28].
Oropharynx
The oropharynx lies behind the oral cavity, extending from the uvula superiorly to
the level of the hyoid bone inferiorly. It opens anteriorly, through the isthmus fau-
cium, into the mouth, while in its lateral wall, between the palatoglossal arch and the
palatopharyngeal arch, is the palatine tonsil. The anterior wall consists of the base
of the tongue and the epiglottic vallecula; the lateral wall is made up of the tonsil,
tonsillar fossa, and tonsillar (faucial) pillars; and the superior wall consists of the
inferior surface of the soft palate and the uvula. Because both food and air pass
through the pharynx, a flap of connective tissue, the epiglottis closes over the glottis
when food is swallowed to prevent aspiration. The oropharynx is lined by non-
keratinized squamous stratified epithelium.
The HACEK organisms (Hemophylis, Actinobacillus actinomycetemcomitans,
Cardiobacterium hominis, Eikenella corrodens, Kingella) are part of the normal
oropharyngeal flora, which grow slowly, prefer a carbon dioxide-enriched atmo-
sphere, and share an enhanced capacity to produce endocardial infections, espe-
cially in young children [29]. Fusobacterium is a pathogen and not part of the
normal flora [30].
Laryngopharynx (Hypopharynx)
The laryngopharynx is the caudal part of the pharynx that connects to the esopha-
gus. It lies inferior to the epiglottis and extends to the location where this common
pathway diverges into the respiratory (laryngeal) and digestive (esophageal) path-
ways. Corresponding roughly to the area located between the fourth and sixth cervi-
cal vertebrae (C4–6), the superior boundary of the laryngopharynx is at the level of
the hyoid bone. The laryngopharynx includes three major parts: pyriform sinus,
post-cricoid area, and posterior pharyngeal wall. Similar to the oropharynx above it,
the laryngopharynx serves as a passageway for food and air and is lined with a
stratified squamous epithelium [31].
The vascular supply to the laryngopharynx includes branches from the ECA,
namely, the superior thyroid artery (STA), the lingual artery, and the ascending
pharyngeal artery. The primary neural supply is from both the vagus (CN-X) and
glossopharyngeal nerves (CN-IX) [32]. The vagus nerve provides an auricular
branch (Arnold’s nerve), which also supplies the external auditory canal; thus,
laryngopharyngeal cancer can result in referred ear pain. This nerve is also respon-
sible for the ear-cough reflex in which stimulation of the ear canal results in a person
coughing [33].
Function
The pharynx moves food from the mouth to the esophagus. It also moves air from
the nasal and oral cavities to the larynx. The pharynx is also used in human speech,
as pharyngeal consonants are articulated here, and it acts as a resonating during
phonation.
The pharynx may be the site of inflammation (pharyngitis) or pharyngeal cancer.
Studies have shown that 72–87% of pharyngeal cancers arise in the laryngopharynx
[34, 35]. The pyriform sinus has the highest proportion of these cancers (78.3%),
followed by the posterior pharyngeal wall (14%), and then the post-cricoid area
(8%) [34].
Waldeyer’s tonsillar ring is an anatomical term collectively describing the annu-
lar arrangement of lymphoid tissue in the pharynx. It circumscribes the naso- and
oropharynx, with some of its tonsillar tissue located above and some below the soft
palate (and to the back of the oral cavity). It is believed that Waldeyer’s ring pre-
vents the invasion of microorganisms to the air and food passages and thus helps in
the defense mechanism of the respiratory and alimentary systems [36].
Tracheal Region
Location
The trachea begins at the lower edge of the cricoid cartilage of the larynx [37] at the
level of sixth cervical vertebra (C6) [38] and ends at the carina, the point where the
trachea branches into left and right main bronchi [38], at the level of the fourth tho-
racic vertebra (T4) [38] although its position may change with breathing [37].
Although the trachea is a midline structure, it can be normally displaced to the right
by the aortic arch.
Structure
An adult’s trachea has an inner diameter of about 1.5–2 cm (0.59 to 0.79 in) and a
length of about 10–11 cm (3.9 to 4.3 in); wider in males than females [38]. The
trachea is formed of 16–20 incomplete and C-shaped rings of hyaline cartilage [38]
that are connected by ligaments [37]. The trachealis muscle connects the ends of the
incomplete rings and runs along the posterior wall of the trachea. It contracts during
coughing, reducing the size of the lumen of the trachea [37]. Adventitia, which is
the outermost layer of connective tissue that surrounds the hyaline cartilage,
contributes to the trachea’s ability to bend and stretch with movement. The tracheal
rings are generally highly elastic but, they may calcify with age.
Anatomical Relations
Anterior to the upper part of the trachea is the jugular arch, which joins the two
anterior jugular veins (AJVs). The sternohyoid and sternothyroid muscles stretch
along its length. The thyroid gland also stretches across the upper trachea, below the
cricoid cartilage, with the isthmus overlying the second to fourth rings, and the
lobes reaching to the level of the fifth or sixth cartilage [38]. The blood vessels of
the thyroid rest on the trachea next to the isthmus; the superior thyroid arteries
(STAs) join just above it, and the inferior thyroid veins below it [38]. Anterior to the
lower part of the trachea lies the manubrium of the sternum, the deep cardiac plexus,
lymph nodes (LNs), and the remnants of the thymus in adults [38]. Anteriorly and
to the left lie large blood vessels, namely, the aortic arch and its branches, the left
common carotid artery (CCA) and brachiocephalic trunk, as well as the left the
brachiocephalic vein. Posteriorly, the esophagus is situated along the whole length
of the trachea, followed by connective tissue and the vertebral column [38]. Lateral
to the trachea, run the carotid arteries and inferior thyroid arteries (ITAs); and to its
sides on its posterior surface run the recurrent laryngeal nerves (RLNs) in relation
to the upper part of the trachea, and the vagus nerves in relation to its lower part [38].
lood Supply and Lymphatic Drainage

B
The upper part of trachea is supplied by the inferior thyroid arteries (ITAs) [38] and
the lower by the bronchial arteries [37]. These vessels give small branches that sup-
ply the trachea from the sides, and as they approach the wall of the trachea, they
split to supply the anterior and posterior parts of the trachea [37]. The ITAs arise just
below the isthmus of the thyroid; they anastomose with ascending branches of the
bronchial arteries, which are direct branches from the aorta [38]. Lymphatic vessels
of the trachea drain into the pre-tracheal LNs that lie anterior to the trachea, and
para-tracheal LNs that lie lateral to it [38].
Microanatomy
The trachea is lined with a layer of interspersed layers of column-shaped cells with
cilia [37]. The epithelium contains goblet cells, which are glandular, column-shaped
cells that produce mucin, the main component of mucus, which helps to moisten
and protect the airways [39].
Function
The trachea is a part of the respiratory tree that functions as a conduit passage of air
to or from the alveoli of the lungs, to transmit oxygen to the body and remove car-
bon dioxide [37]. Mucus lines the ciliated cells of the trachea to trap inhaled foreign
particles, which are moved upward by the cilia toward the larynx and then the phar-
ynx where it can be either expelled as phlegm or swallowed into the stomach,
respectively. This self-clearing mechanism is termed “mucociliary clearance” [39].
Inflammation and Infection

Tracheitis is usually caused by viral infections [40], with bacterial infections occur-
ring almost entirely in children [41]. Most commonly, infections occur with inflam-
mation of other parts of the respiratory tract, such as the larynx and bronchi, known
as croup [40, 41]; however, bacterial infections may also affect the trachea alone
although they are often associated with a recent viral infection [40]. Viruses that
cause croup are generally the parainfluenza viruses 1–3, with influenza viruses A
and B also causing croup, but usually causing more serious infections; bacteria may
also cause croup and include Staphylococcus aureus, Haemophilus influenzae,
Streptococcus pneumoniae, and Moraxella catarrhalis [40]. Causes of bacterial
infection of the trachea are most commonly Staphylococcus aureus and Streptococcus
pneumoniae [42]. In hospitalized patients, additional bacteria that may cause tra-
cheitis include Escherichia coli, Klebsiella coli, Klebsiella pneumoniae, and
Pseudomonas aeruginosa [40].
Symptoms of tracheitis include cough, sore throat, or coryzal symptoms such as
a runny nose. Fever may develop and an affected child may develop dyspnea and
sepsis [40, 41]. Edema of the airway can cause its narrowing, leading to a hoarse
breathing sound (stridor), or even cause complete blockage [41]. Treatment of tra-
cheitis usually includes antibiotics [41]. Unfortunately, up to 80% of patients
affected by bacterial tracheitis require mechanical ventilation, and treatment may
include endoscopy for acquiring microbiological specimens for culture and sensi-
tivity, and removal of any necrotic tissue associated with the infection.
Tracheal Stenosis
The trachea may be narrowed or compressed, usually as a result of enlarged nearby
LNs, cancers of the trachea or nearby structures, large thyroid goiters, or rarely as a
result of other processes such as unusually dilated blood vessels [43]. Fibrosis scar-
ring from tracheobronchial injury or intubation, or inflammation associated with
granulomatosis with polyangiitis may also cause tracheal stenosis resulting in
obstruction and invariably stridor [43]. Management of obstruction depends on the
cause. Obstructions resulting from malignancy may be managed with surgery, che-
motherapy, or radiotherapy [43]. A stent may be inserted over the obstruction.
Benign lesions, such as narrowing resulting from fibrosis, are likely to be surgically
excised [43].
One cause of tracheal narrowing is tracheomalacia, which is the tendency for the
trachea to collapse when there is increased external pressure, such as when airflow
is increased during breathing in or out, due to decreased compliance [44]. Causes
may be congenital or acquired such as compression from nearby masses or trauma
[44]. Congenital tracheomalacia can occur alone or in association with other abnor-
malities such as broncho-malacia or laryngo-malacia, and tracheoesophageal fistula
[44]. Congenital tracheomalacia often improves without specific intervention; when
required, interventions may include beta-agonists and muscarinic antagonists,
which enhance the tone of the smooth muscle surrounding the trachea; positive
pressure ventilation (PPV), or surgery. A tracheal stenosis <5 cm in length can be

resected with end-to-end anastomosis. Longer tracheal lesions can be treated in a
palliative way by placement of a stent to secure airway lumen patency [44].
Intubation
Tracheal intubation is commonly performed by anesthetist during surgery in order
to ensure that the patient receives enough oxygen. In an emergency, or when tra-
cheal intubation is deemed impossible, a tracheostomy is often performed to insert
a tube for ventilation. Another procedure that can be carried, in an emergency situ-
ation, is cricothyrotomy [45].
Congenital Disorders
Tracheal agenesis [46] is a rare birth defect in which the trachea fails to develop.
The defect is usually fatal though sometimes surgical intervention has been
successful.
A tracheoesophageal fistula is a congenital defect in which the trachea and
esophagus are abnormally connected because of abnormalities in the separation
between the trachea and esophagus during development [47]. Other abnormalities
may be associated with this condition including cardiac abnormalities, or VACTERL
syndrome (Vertebral defects, Anal atresia, Cardiac defects, Tracheoesophageal fis-
tula, Renal anomalies, and Limb abnormalities) [47]. Congenital fistulas are often
treated by surgical repair [43]. In adults, fistulas may occur because of erosion into
the trachea from nearby malignant tumors, which erode into both the trachea and
the esophagus. Initially, these often result in coughing from swallowed contents of
the esophagus that are aspirated through the trachea, often progressing to fatal pneu-
monia; unfortunately, there is rarely a curative treatment [43].
Occasionally, as an anatomical variation, one or more of the tracheal rings are
formed as complete rings, rather than horseshoe-shaped rings. These O-shaped
rings are smaller than the normal C-shaped rings and can cause tracheal stenosis,
resulting in breathing difficulties. An operation called a slide tracheoplasty can
open up the rings and rejoin them as wider rings, shortening the length of the tra-
chea. Slide tracheoplasty is believed to be the best option for treating tracheal ste-
nosis [48].
Mounier-Kuhn syndrome is a rare congenital disorder of an abnormally enlarged
trachea, characterized by absent elastic fibers, smooth muscle thinning, and a ten-
dency to get recurrent respiratory tract infections [49].
Replacement/Transplantation
From 2008, operations have experimentally replaced tracheas, with those grown
from stem cells, or with synthetic substitutes; however, this is regarded as experi-
mental and there is no standardized method [50]. Difficulties with ensuring ade-
quate blood supply to the replaced trachea are considered a major challenge to any
replacement. Additionally, no evidence has been found to support the placement of
stem cells taken from bone marrow on the trachea as a method of stimulating tissue
regeneration, and such a method remains hypothetical [50].
Experience with tracheal allotransplantation has been anecdotal [51, 52] because
of the difficulties linked with restoration of the blood supply. The segmental blood
supply of the trachea originates from several tracheoesophageal branches that are
too small to allow for microvascular transfer of tracheal segments [53].
Recently, in 2019, Delaere et al. [54] reported that the trachea can be trans-
planted as a composite tissue with the cartilage structure as the critical functional
element of the graft. The technique holds promise for patients needing extensive
airway reconstruction because the chimeric trachea graft does not require ongoing
immunosuppression, a highly desired but elusive goal in the field of
allotransplantation.
More recently, in 2022, Dickerson and colleagues [55] reported a multidisci-
plinary effort that resulted in the first vascularized, single-stage, deceased donor
tracheal allograft transplantation in a 56-year-old woman with long-segment
(approximately, 8 cm) tracheal stenosis. The patient had a prolonged intubation of
nearly 3 weeks following a bronchial asthma attack in 2014. She subsequently
developed severe tracheal stenosis (i.e., >70%) and was left tracheostomy-dependent
for the ensuing 7 years. In that time period (before the allotransplant), she under-
went six tracheal procedures in order to address her stenosis, including endoscopic
dilatations, laser, and open resections. The tracheal allotransplant was successful; a
healthy, well-appearing graft was evident with serial bronchoscopy and the patient
became no more tracheostomy tube-dependent.
Suprasternal Space (SSS) of Burns
Boundaries
The suprasternal space (SSS) of Burns is a space of the inferior part of the front of
the neck that lies inferior to the hyoid bone. The superficial layer of the deep cervi-
cal fascia divides into anterior and posterior leaves to attach to the respective bor-
ders of the suprasternal (jugular) notch, forming this small space, approximately
2 cm, superior to the manubrium.
Anatomically, the SSS of Burns is anterior to the sternohyoid muscle, posterior
to the sternocleidomastoid (SCM) muscle, medial to the lateral border of the sterno-
hyoid muscle, and superior to the clavicle and sternum.
Contents
The SSS contains the following: (1) loose areolar tissue, (2) sternal head of SCM
muscle, (3) anterior jugular vein (AJV) anastomoses, (4) lymph nodes (LNs)—con-
sidered as part of level VI [56], and (5) interclavicular ligament.
A patient may present with a mass (swelling) in the space of Burns at the lower part
of the midline of the neck. Differentials include enlarged LNs, lipoma, teratoma,
thymoma, aneurysm of the aorta or innominate artery, and high (cervical) aortic
1.4 Lymph Nodes of the Central Neck 19
arch. Greater attention should be paid to the SSS as an area with the potential for LN
metastasis from papillary thyroid carcinoma (PTC) [57].
1.4 Lymph Nodes of the Central Neck
Introduction
Cervical lymphadenopathy (CLA) is a significant clinical finding associated with

acute infection, granulomatous disease, autoimmune disease, and malignancy. It
may represent a local neck disease, be a part of generalized disease such as lym-
phoma, or reflect a metastatic disease from a primary malignant tumor. Cervical
lymph nodes (LNs) represent the most common neck swelling. They are enlarged in
children mainly due to inflammation and in adults mainly due to neoplasms.
Suspicious features of LNs on ultrasonography (US) include round or globular
shape, irregular contour, internal necrosis, and lost echogenic hilum. Detection of
extracapsular invasion and accurate assessment of their relation to carotid sheath
vessels can be achieved by CT scan. Assessment of the patients with CLA is not
complete without FNAC.
Anatomical Considerations
The neck region contains approximately 300 LNs out of 800 LNs in the whole body.
The involvement of specific nodal groups is an indicator of pathologically affected
organs and tissues, which is critical for appropriate management. It is important
clinically to know the lymphatic drainage of the superficial and deep tissues of the
head and neck, and to fully understand the main lymphatic nodal levels of the neck,
their anatomical configuration and boundaries, patterns of drainage, and risk of
metastatic involvement in malignancy [58, 59].
On the left side, lymphatics drain either directly into the jugulo-subclavian
venous confluence or directly into the thoracic duct. On the right side, they flow
directly into the right lymphatic duct. Most structures drain ipsilaterally, except
those situated at the midline such as the nasopharynx, pharyngeal wall, base of the
tongue, soft palate, and larynx [58–62].
ymphatic Drainage of Superficial Tissues of the Head and Neck

L
Most of the superficial tissues are drained by vessels, which go first to regional LNs
that drain to the deep cervical LNs (DCLNs). However, some may pass directly to
DCLNs. Regional groups concerned with drainage of superficial tissues of neck are
shown in Table 1.5.
Table 1.5 Superficial cervical lymph nodes

Lymph node chain Description
A. Superficial circular chain – Submental
– Submandibular
– Facial (buccal)
– Parotid (preauricular)
– Retro-auricular (postauricular)
– Occipital
B. Superficial longitudinal chain Anterior cervical LNs along anterior jugular veins
1. Midline chain Superficial to the sternocleidomastoid (SCM) muscle
2. Lateral chain along the external jugular vein (EJV)
Table 1.6 Cervical lymph node (LN) level classification according to the American Academy of
Otolaryngology—Head and Neck Surgery (AAO-HNS)
Level Area Sublevels
I – Submental LNs IA
– Submandibular LNs IB
II Upper internal jugular LNs; lying between skull base and hyoid bone
– Anterior to the SAN vertical plane IIA
– Posterior to the SAN vertical plane IIB
III Middle internal jugular LNs; lying between hyoid bone and cricoid cartilage –
IV Lower internal jugular LNs; extending between cricoid cartilage and clavicle –
V Posterior triangle (spinal accessory chain) LNs
– Above an imaginary horizontal plane at the lower border of the cricoid VA
– Below an imaginary horizontal plane at the lower border of the cricoid VB
VI Central LNs (pre-tracheal + pre-laryngeal + para-tracheal LNs) –
VII Superior mediastinal LNs –
LNs lymph nodes, SAN spinal accessory nerve
ymphatic Drainage of Deeper Tissues of the Head and Neck

L
The American Academy of Otolaryngology—Head and Neck Surgery (AAO-HNS)
[63] developed the currently widely accepted levels classification of the cervical
LNs; levels I-VII. These are summarized in Table 1.6 [63].
Cervical Lymph Node Levels Involved in Midline Swellings
evel IA (Submental Region)

L
Anatomical boundaries: The submental group of LNs lies within the submental
triangle bounded by the anterior belly of the digastric muscles on both sides, the
symphysis menti superiorly, and the hyoid bone inferiorly. It is bounded anteriorly
by the platysma muscle, and posteriorly by the mylohyoid muscles.
Drainage: This group drains the skin of the chin, the mid-lower lip, the anterior
portion (apex) of the oral tongue, and the floor of the mouth. Their efferents pass
References 21
partly to the submandibular LNs (level IB) and partly to the upper jugular group of
LNs (level II).
Associated primary malignancies: These LNs may contain metastatic deposits,
most often from cancer of the floor of the mouth, anterior oral tongue, mandibular
alveolar ridge, and lower lip [64].
evel VI (Central or Anterior Compartment Group)

L
Anatomical boundaries: This level includes anterior jugular, pre-tracheal, para-
tracheal, pre-cricoid (Delphian), and peri-thyroidal LNs (including recurrent laryn-
geal LNs located along the recurrent laryngeal nerves). This region extends from the
hyoid bone superiorly (or the superior edge of the thyroid cartilage) to the superior
border of the manubrium sterni/suprasternal notch inferiorly. It is also bounded
anteriorly by the posterior margin of the infrahyoid muscles, and posteriorly by the
anterior larynx, thyroid gland, and trachea at the midline, the prevertebral muscles
on the right, and the esophagus on the left. Laterally, it is bounded by the common
carotid artery (CCA) and medially by the lateral aspects of the trachea and esopha-
gus [64]. The anatomical location of Level VII nodes, which are considered an
extension of the para-tracheal LN chain, is bounded by the suprasternal notch supe-
riorly, the aortic arch inferiorly, and by the carotid arteries laterally [64].
Drainage: The anterior (central) compartment group of LNs drains the efferent
lymphatics from the anterior floor of the mouth, tip of the oral tongue, lower lip,
thyroid gland, glottic and supraglottic larynx, hypopharynx, and cervical esophagus
[64]. Eventually, these LNs drain to the jugular trunk of their respective side, and
then to the right lymphatic trunk on the right side, or the thoracic duct on the
left side.
Associated primary malignancies: These nodes may contain metastatic deposits,
most often from malignancies of the lower lip, oral cavity (floor of the mouth and
anterior oral tongue), thyroid gland, glottic and sub-glottic larynx, the apex of the
pyriform sinus, and the cervical esophagus [65, 66]. Involvement of these central or
anterior LNs with metastatic cancer is the single most important prognostic factor
in head and neck squamous cell carcinoma (SCC) and is also a common feature of
papillary thyroid carcinoma (PTC) [67]. The number of these nodes and their size
are also correlated with the risk of distant metastases [68].
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Midline Neck Swellings: Classification
2
Contents
2.1 Classification According to Anatomical Region 25
2.2 Classification According to the Structure of Origin 26
2.3 Classification According to Consistency 27
2.4 Classification According to Age 28
References 30
2.1 Classification According to Anatomical Region
Swellings Superficial to the Cervical Deep Fascia
Swellings superficial to the cervical deep fascia (DF) arise from:
1. Skin: For example, sebaceous cyst (anywhere in midline of the neck, attached to
the skin, punctum may be seen, opaque, cystic, or doughy in consistency).
2. Subcutaneous tissues: For example, dermoid cyst (smooth, spherical, opaque,
fluctuant, clearly defined), hemorrhagic cyst (anywhere in midline of the neck,
history of trauma, or of associated blood disease, bluish in appearance, aspira-
tion is characteristic), lymphatic cyst, lipoma, and neurofibroma.
Swellings Deep to the Cervical Deep Fascia
Swellings deep to the DF are classified according to the anatomical region where
they present as follows (Table 2.1):

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26 2 Midline Neck Swellings: Classification
Table 2.1 Midline neck swellings according to anatomical location

Anatomical region Causes
A. Submental region 1. Submental LNs
2. Sublingual dermoid cyst
3. Hourglass ranula
4. Abscess related to the mandible (central incisors)
B. Hyoid bone region 1. Thyroglossal cyst
2. Median ectopic thyroid tissue
3. Subhyoid bursitis
4. Tumor of the hyoid bone
C. Laryngeal/pharyngeal region 1. Pre-laryngeal (Delphian) LNs
2. Laryngeal tumors
3. Bursa in front of Adam’s apple
4. Chondritis of thyroid cartilage
5. Retropharyngeal abscess (RPA)
6. Laryngocele
D. Tracheal region 1. Pre-tracheal LNs
2. Nodule in the isthmus of the thyroid gland
3. Cyst in the isthmus of the thyroid gland
E. Suprasternal space (Space of 1. Enlarged LNs
Burns) 2. Lipoma
3. Teratoma
4. Thymoma
5. Aneurysm of the aorta or innominate artery
6. High aortic arch
2.2 Classification According to the Structure of Origin
Midline neck masses have a relatively narrow differential, as few structures are
present in the midline. The causes of such masses, according to structure of origin
[1, 2], is summarized in Table 2.2.
2.3 Classification According to Consistency 27
Table 2.2 Midline neck swellings according to structure of origin

Structure of origin Causes
Lymph nodes – Inflammatory lymphadenopathy
– Malignancy
Thyroid gland – Thyroglossal duct cyst
– Thyroid cyst in the isthmus
– Thyroid nodule in the isthmus
– Median ectopic thyroid tissue
Parathyroid gland – Parathyroid adenoma (ectopic)
Hyoid bone – Sub-hyoid bursitis
– Tumor of the hyoid bone
Larynx/pharynx – Laryngocele
– Laryngeal tumor
– Bursa in front of Adam’s apple
– Chondritis of thyroid cartilage
– Retropharyngeal abscess (RPA)
Sublingual salivary gland – Plunging ranula (dumbbell-shaped)
Blood/lymph vessels – Hemangioma/vascular malformation
– Lymphangioma
– Aneurysm of the aorta or innominate artery
– High aortic arch
Thymus gland – Thymoma
Subcutaneous tissue – Dermoid/epidermoid cyst
– Lipoma
– Neurofibroma
2.3 Classification According to Consistency
Midline neck swellings can be classified according to consistency; solid versus cys-
tic/pseudocystic. These are listed in Table 2.3.
Table 2.3 Midline neck swellings according to consistency

Solid swellings Cystic/pseudocystic swellings
A. Superficial to the deep fascia
– Lipoma – Sebaceous cyst
– Neurofibroma – Dermoid/epidermoid cyst
– Hemorrhagic (blood) cyst
– Lymphatic cyst
B. Deep to the deep fascia
Lymph nodes (lymphadenopathy) 1. Mandibular abscess
1. Submental 2. Sublingual dermoid cyst
2. Pre-laryngeal 3. Ranula (hourglass)
3. Pre-tracheal 4. Thyroglossal cyst
4. Suprasternal 5. Sub-hyoid bursitis
Tumors 6. Bursa of Adam’s apple
1. Hyoid bone 7. Cold abscess (TB)
2. Larynx and pharynx 8. Retropharyngeal abscess
3. Thyroid gland 9. Laryngocele
4. Teratoma 10. Thyroid cystadenoma
5. Thymoma
Median ectopic thyroid tissue
Nodule in thyroid isthmus
TB tuberculosis, DF deep fascia
2.4 Classification According to Age
According to age, midline neck swellings can be classified into midline neck swell-
ings that occur in adults (Table 2.4) [3–5] and those that are seen in children [6]
(Table 2.5) as follows:
2.4 Classification According to Age 29
Table 2.4 Midline neck swellings in adults [3–5]

Malignant adult neck swellings
Lymph nodes (LNs) – Metastatic squamous cell carcinoma
– Lymphoma
Thyroid gland – Thyroid cancer (isthmus)
Larynx – Cancer of the larynx
Benign adult neck swellings
Specific infections – Soft tissue neck abscess
– Tuberculosis (LNs)
– Cat scratch disease
– Infectious mononucleosis
Lymphadenopathy – Lymphadenitis
Vascular lesions – Hemangioma
– Lymphangioma
Soft tissue masses – Paraganglioma
– Lipoma
– Neurofibroma
Thyroid swelling – Isthmic nodule
Salivary gland changes – Ranula
Congenital anomalies – Thyroglossal cyst
– Dermoid cyst
Miscellaneous conditions – Sarcoidosis
Table 2.5 Midline neck swellings in children [6]

Congenital neck swellings (55%)
1. Thyroglossal duct cyst
2. Dermoid cyst
3. Teratoma
4. Thymic cyst
5. Laryngocele
Acquired neck swellings (45%)
1. Inflammatory neck mass – Reactive lymphadenopathy
– Bacterial
– Granulomatous:
• Cat scratch disease
• Toxoplasmosis
• Sarcoidosis
• Histoplasmosis
• Actinomycosis
• Fungal infection
– Others
• AIDS
• Kawasaki disease
• Sialadenitis
(continued)
Table 2.5 (continued)

Congenital neck swellings (55%)
2. Neoplastic neck mass – Malignant
• HD
• NHL
• Thyroid cancer
• Neuroblastoma
• Fibrosarcoma
– Benign
• Lipoma
• Fibroma/neurofibroma
• Lipoblastoma
• Paraganglioma
• Goiter
• Benign salivary gland tumor
AIDS acquired immunodeficiency syndrome, HD Hodgkin disease, NHL non-Hodgkin lymphoma
References
1. Kraus R, Han BK, Babcock DS, Oestreich AE. Sonography of neck masses in children. AJR
Am J Roentgenol. 1986;146(3):609–13.
2. Tan E, Jaya J. An approach to neck masses in adults. AJGP. 2020;49(5):267–70.
3. Haynes J, Arnold KR, Aguirre-Oskins C, Chandra S. Evaluation of neck masses in adults. Am
Fam Physician. 2015;91(10):698–706.
4. McGuirt WF. The neck mass. Med Clin North Am. 1999;83:219–34.
5. Schwetschenau E, Kelley DJ. The adult neck mass. Am Fam Physician. 2002;66(5):831–8.
6. Meier JD, Grimmer JF. Evaluation and management of neck masses in children. Am Fam
Physician. 2014;89(5):353–8.
Midline Neck Swellings: Clinical
Approach 3
Contents
3.1 Introduction to Clinical Approach 31
3.2 History-Taking 32
3.3 Physical Examination 33
3.4 Investigations 34
3.5 Differential Diagnosis 38
References 39
3.1 Introduction to Clinical Approach
Swellings of the neck are generally categorized into two groups: midline and lateral
neck swellings. “Midline neck swellings” include those which clinically present in
the neck midline extending from the submental triangle just below the chin above to
the suprasternal notch below. Swellings which do not respect this anatomical imagi-
nary midline are termed “lateral neck swellings,”, whether presenting in the anterior
or posterior triangle. Midline and lateral neck swellings may be further classified as
solid versus cystic, congenital versus acquired, benign versus malignant, or accord-
ing to the anatomical subregion of presentation [1].
A complete history-taking with full head and neck examination are crucial to
reach a proper diagnosis of a cervical swelling. In children, most neck masses are
inflammatory or congenital. However, in adults, a neck mass more than 2 cm in
diameter has more than 80% probability of being malignant. Fine needle aspiration
(FNA), preferably guided by ultrasound (US) or computed tomography (CT), can
provide a valuable tool for diagnosis and early treatment planning that provides less
oncological disruption to a tissue mass than an open biopsy. The use of CT scan

Switzerland AG 2024
32 3 Midline Neck Swellings: Clinical Approach
and/or magnetic resonance imaging (MRI) is dictated by the patient’s presentation.

An open biopsy may be the last resort for reaching a proper diagnosis and plot a
therapeutic plan. Putting the skin incision for such a biopsy should take into consid-
eration the possibility of performing a future neck dissection, composite resection,
and/or a major reconstruction [2].
The proposed clinical approach herein involves an understanding of the anatomy
of the major structures of the neck and lymph nodes (LNs) and the possible pathol-
ogy that may arise in such structures (differential diagnosis).
3.2 History-Taking
A careful history-taking can provide important clues to the diagnosis of a neck mass
and can aid the clinician in identifying patients with a neck mass who are at increased
risk of malignancy. Symptoms, their onset, course and duration, and age of the
patient are of most importance in history-taking, and so are both, the past history
and family history (Table 3.1).
Table 3.1 History-taking of a patient presenting with a midline neck swelling

History Examples of suspected neck masses
Personal history (age) – Thyroglossal cyst
– Childhood – Lymphoma—Thyroid isthmic swelling
– Adults – Metastases
– Elderly
Associated symptoms – Acute inflammation of submental LNs
(lymphadenitis)—pyogenic abscess—sub-hyoid
bursitis
– Pain – Thyroid (isthmic) swelling
– Toxic or pressure symptoms – Metastases
– Dysphagia, hoarseness, dyspnea
Present history Submental lymphadenitis. Other causes are usually
discovered accidentally
Onset: Acute – Malignant swellings
Course (Progress) – Benign tumors
– Rapidly progressive – Inflammations such as Tuberculous adenitis
– Slowly progressive
– Remissions and relapses
Past history Tuberculosis—Primary focus
– Similar swelling Malignancy—Recurrent thyroid nodule
– Previous swellings Malignancy
– Irradiation Lymphadenopathy
– Animal contact
Family history – Malignancy
– Goiter
– Tuberculosis
TB tuberculosis, LNs lymph nodes
3.3 Physical Examination 33
Congenital neck masses are not always present since birth; a thyroglossal
cyst usually presents in young adults. Furthermore, rapid enlargement of a
small congenital mass may occur following an upper respiratory tract infec-
tion [1].
Inflammatory neck masses are usually acute in onset and resolve within a few
days or weeks. Cervical lymphadenitis is the most common cause of neck swell-
ings. A history of cough, fever, sore throat, recent travel, dental problems, and insect
bites or exposure to certain animals should be recorded [1–4]. An inflammatory
mass that persists despite adequate medical treatment should raise the suspicion of
malignancy.
Malignant neck masses tend to have a progressive course. The most common
origin of these metastases is squamous cell carcinoma (SCC) of the upper aerodi-
gestive tract. More than 80% of these tumors are associated with tobacco and
alcohol use in persons above the age of 40 years, and those with a past history of
head and neck malignancy. Further symptoms of malignancy, especially of the
thyroid gland, include change of voice, odynophagia, and dysphagia [5, 6].
Additional important information involve oral lesions, recent trauma, globus sen-
sation, referred ear pain, muffled or reduced hearing, constitutional symptoms,
nasal discharge or epistaxis, as well as family history of cancer and previous
tumors [5].
3.3 Physical Examination
General Examination
General physical examination should include the different systems of the body
including the rest of the neck, the skin of the head and neck, oral cavity, nasal cavity,
larynx, and pharynx. A targeted physical examination relevant for a patient with a
midline neck mass at increased risk for malignancy is summarized in Table 3.2. In
cases where pathology is suspected in the nasopharynx, hypopharynx, and larynx,
patients should be referred to an otolaryngologist for detection of an “occult” pri-
mary [7].
Local Examination of the Swelling
The major midline neck structures are the hyoid bone, thyroid cartilage, cricoid
cartilage, trachea, and thyroid gland (isthmus) [5]. The size, consistency, tender-
ness, and mobility of the mass provide the clinician with diagnostic clues. In gen-
eral, congenital masses are usually soft, mobile, and non-tender unless infected [5].
Acute inflammatory masses tend to be soft, tender, and mobile, while chronic
inflammatory masses are often non-tender, rubbery, and either mobile or matted.
Malignant masses may be hard, non-tender, and fixed [5].
Table 3.2 Targeted physical examination in a patient at high risk of head and neck cancer
Anatomical site Rationale
Skin and scalp May reveal a cutaneous malignancy
Oral cavity Visual and digital examination of ventral and lateral surfaces of oral
tongue and floor of mouth
Teeth (dentition) Teeth may be the infective cause of submental lymphadenitis
Oro-pharynx Inspection of soft palate, tonsillar fossae, and posterior wall, in
addition to palpation of the tongue base and tonsillar fossae
Nasal cavity Inspection of the septum, floor, and turbinates
Naso-pharynx Inspection of Eustachian tube orifices and superior and posterior walls
Hypo-pharynx Visual examination of pyriform sinuses and posterior pharyngeal wall
Larynx Visual examination of the epiglottis, vocal folds, and sub-glottis
Neck Assessment of the neck mass (consistency, size, fixation, location), and
LNs. Bimanual palpation of the floor of mouth and entire neck
Salivary glands Palpation of sublingual glands for detection of any mass
Thyroid gland Palpation for detection of an isthmic nodule or cyst
Chest Search for evidence of tuberculosis (TB) or lung metastases
Abdomen May reveal liver and/or splenic involvement (metastases)
Spine May demonstrate rigidity and tenderness in TB (cold abscess)
Inspection
The site, size, shape of the swelling and the skin overlying as well as pulsations are
all noticed. Movement of the swelling with swallowing and/or protrusion of the
tongue should be observed.
Palpation
The swelling is palpated for tenderness, consistency, mobility, and movement with
deglutition. With the mouth of the patient open and the swelling held between the
thumb and index of the clinician, the patient is asked to protrude the tongue. A thy-
roglossal cyst will move upward with protrusion of the tongue. The thyroid gland
should also be palpated (median ectopic thyroid may be the only thyroid tissue
present).
The size, consistency (texture), mobility, location, laterality, and tenderness of a
neck mass are characteristics that can aid in assessing the risk of malignancy.
Malignant neck masses are likely to be more than 1.5 cm in diameter [8–10] and
firm (or hard) in consistency [11, 12]. Malignant neck masses may also have no or
restricted mobility [9, 13] or may ulcerate the overlying skin. Additional findings
that suggest malignancy are the presence of multiple, grouped, matted LNs [9] and
progressive enlargement of the neck mass [12, 14].
3.4 Investigations
Deciding on the course of investigation depends on history and physical examina-

tion and relies mainly on ruling out malignancy. First-line investigations for adults
at risk of malignancy include CT scan of the neck with contrast and FNA, both of
which provide complementary information regarding primary tumor histopatho-

logical detection, anatomical localization, and nodal staging.
Imaging Studies
ontrast-Enhanced Computed Tomography (CT) Scan of the Neck

C
Contrast-enhanced CT of the neck is considered a first-line investigation for all
patients at increased risk of malignancy unless contraindicated due to iodine allergy
or renal impairment [15]. It assists in localization of the primary mass, assessment
of cervical LNs and aids in staging of the tumor. In addition, it may provide infor-
mation that suggests the diagnosis of a benign process rather than malignancy (e.g.,
dental infection) [16]. On the other hand, Di Martino et al. (2000) have shown a low
negative predictive value of contrast-enhanced CT scan in the detection of primary
and recurrent head and neck tumors [17].
agnetic Resonance Imaging (MRI) of the Neck with Contrast

M
Although MRI provides better soft tissue contrast [15] and can help detect subclini-
cal tumors not evident with nasal endoscopy [18], CT scan is the preferred primary
imaging modality, as MRI demonstrates more motion artifacts, longer scan times,
and generally poorer availability and tolerability [16]. Moreover, the presence of
some implantable medical devices, such as pacemakers and neuro-stimulators, pre-
cludes MRI scanning [16]. Gadolinium, the MRI contrast agent, may cause nephro-
genic systemic fibrosis, a rare but highly morbid condition associated with fibrosis
of the skin, joints, eyes, and organs [19]. In case of severe renal insufficiency, a
non-contrast MRI offers a small benefit over non-contrast CT because of its inher-
ent superior soft tissue characterization [16].
Ultrasonography (US)
Ultrasonography (US) is both non-invasive and inexpensive and can be used to
characterize a neck mass to guide percutaneous tissue sampling and to search for
additional masses [20]. Diagnostic US, however, is not recommended as a first-line
investigation in preference to contrast-enhanced CT or MRI, as it is operator-
dependent and cannot adequately visualize deeper structures from which many pri-
mary tumors arise. On the other hand, US may be considered a first option in certain
clinical situations such as thyroid swellings, in situations where there will be a delay
in obtaining CT scan or MRI, if the use of contrast medium is contraindicated, or as
an adjunct to expedite FNA biopsy.
omputed Tomography Angiography or Magnetic

C
Resonance Angiography
Computed tomography angiography (CTA) or magnetic resonance angiography
(MRA) may provide useful information in the setting of pulsatile lesions but are not
considered as part of routine neck imaging protocols.
Chest X-Ray
The role of routine chest X-ray in the setting of a neck mass has not been estab-
lished. However, if the patient is at risk of a primary lung cancer on clinical basis,
then the results of a chest X-ray can guide further testing and management.
ositron Emission Tomography with Computed Tomography

P
(PET/CT)
Positron emission tomography with CT (PET/CT) using fluoro-deoxyglucose tracer
has shown excellent sensitivity and specificity in the assessment of primary and
recurrent tumors of the head and neck [17]. It is also playing an increasingly greater
role, in the detection of residual or recurrent head and neck tumors post-treatment
[21]. PET/CT is ideally reserved for those patients in whom malignancy was already
diagnosed, and it is generally utilized as part of the staging process. However, given
its limited availability, PET/CT is not appropriate as a first-line imaging study [21].
Panendoscopy
Panendoscopy by an otorhinolaryngologist is particularly important for detection of

a hidden primary (occult tumor) in the head and neck where the patient presents
with metastatic cervical lymphadenopathy of unknown primary.
Cytology/Histology
ine Needle Aspiration (FNA)

F
It is highly recommended that FNA be utilized as an initial diagnostic test for a
patient at increased risk of a malignant neck mass, and the use of open biopsy be
limited. Open biopsy may result in non-healing wounds, regional recurrence, and
distant metastasis when not performed as part of definitive treatment in the neck [22].
It is well established that FNA is safe [23], cost-effective, and has an overall
accuracy of 93.1% (73.3–98.0%) according to a meta-analysis [24]. It is useful in
the diagnosis of malignancy in case of metastatic SCC, thyroid carcinoma, and lym-
phoma. Given its low risk, there are no absolute contraindications to FNA of a neck
mass [23], including the use of anti-coagulation therapy [25]. Vascular lesions and
carotid body tumors are sometimes considered as contraindications, but some
reports described uncomplicated aspiration of such lesions [26]. However, imaging
is recommended prior to FNA for any clinically suspected vascular lesion [26].
ore Needle Biopsy

C
Core needle biopsy is considered an option after an initial inadequate or indetermi-
nate FNA. In 2012, a meta-analysis by Novoa et al. showed that US-guided core
biopsy was highly accurate (96% detection rate for cancer) with low complication
rates (1%) [27]. If lymphoma is strongly suggested on clinical grounds, then a core
needle biopsy may be considered as the first-line tissue sampling technique. In this
case, it has a higher sensitivity than FNA (92% vs. 74%, respectively) [28].
Open Biopsy
Examination of the upper aero-digestive tract under anesthesia is recommended
before open biopsy for patients with a neck mass who are at increased risk of
malignancy and without a diagnosis or primary site identified with FNA and
imaging [5]. The reasons for attempting at avoiding open neck biopsy, if possi-
ble, aside from known operative risks of bleeding, infection, and nerve injury,
include the potential for higher rates of tumor seedling, surgical site sepsis and
necrosis, local recurrence, and distant metastasis in patients undergoing open
biopsy for malignancy [22, 29].
Open biopsy could be performed in the same setting as the examination under
anesthesia, provided appropriate consent and patient engagement in the decision
process. The incision for open biopsy should be planned so that it could be extended
if a neck dissection is indicated [27, 30–33]. Excisional biopsy is preferable to pre-
vent tumor spillage, but may not be feasible in case of large, solid, or matted masses
adherent to vital structures, where excisional biopsy may increase the risk of bleed-
ing and nerve injury [34, 35].
Ancillary Investigations
Ancillary tests are intended to assist clinicians when malignancy is unlikely or when
initial investigations (imaging and FNA) do not yield a diagnosis. These tests should
be based on clinical suspicion for specific diseases and should be obtained along
with the malignancy work-up to avoid a delayed diagnosis [14]. Table 3.3 provides
summarizes the more common ancillary tests useful in the evaluation of a neck mass
of unknown etiology [36].
Table 3.3 Ancillary investigations for adult neck masses

Ancillary investigation Possible diagnosis
CBC Leukocytosis may indicate infection or lymphoma
ANA Elevated levels may indicate autoimmune diseases
ESR Elevated ESR may indicate autoimmune diseases or systemic
inflammation
TSH TSH abnormalities may indicate a thyroid pathology
PTH Elevated PTH may indicate a pathology
Thyroid US Thyroid nodules or parathyroid adenomas
CT chest with contrast Lung malignancy, TB, or sarcoidosis
Tg FNA–needle wash Thyroid cancer
assay
Specific infection tests Positive tests may indicate an infectious cause (e.g., HIV, EBV,
CMV, TB)
CBC complete blood count, ANA antineutrophil antibody, SLE systemic lupus erythematosus, ESR
erythrocyte sedimentation rate, TSH thyroid-stimulating hormone, MNG multinodular goiter, PTH
parathyroid hormone, US ultrasonography, Tg thyroglobulin, FNA fine needle aspiration, CT com-
puted tomography, HIV human immunodeficiency virus, EBV Epstein-Barr virus, CMV cytomega-
lovirus, TB tuberculosis
3.5 Differential Diagnosis
To reach the proper diagnosis, it is essential to answer the following questions:
Does the Swelling Move with Deglutition?
Swellings that move with deglutition include the following:
–– Thyroid nodule (goiter)

–– Thyroglossal cyst
–– Median ectopic thyroid tissue
–– Parathyroid swellings (if ever palpable)
–– Pre-laryngeal and pre-tracheal LNs
–– Sub-hyoid bursitis
–– Adam’s apple bursitis
–– Pharyngeal pouch
–– Laryngeal cold abscess
–– Laryngocele
Does the Swelling Move with Protrusion of the Tongue?
A thyroglossal cyst is characterized by moving upward with protrusion of the

tongue, which can be detected by inspection and palpation of the swelling.
What Is the Level of the Swelling?
–– Below the chin: For example, submental LN or sublingual dermoid cyst

–– Level of the greater cornua of the hyoid bone: For example, sub-hyoid bursa
–– Supra-sternal space of Burn: For example, lipoma
Is it Solid or Cystic?
–– Solid swellings: For example, LNs, tumors, thyroid nodule, median ectopic thy-
roid tissue
–– Cystic swellings: For example, mandibular abscess, sublingual dermoid cyst,
ranula (hour-glass), thyroglossal cyst, sub-hyoid bursitis, bursa of Adam’s
apple, cold abscess, retro-pharyngeal abscess, laryngocele, thyroid
cystadenoma
References 39
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Midline Neck Swellings: Cervical
Lymphadenopathy 4
Contents
4.1 Etiology of Cervical Lymphadenopathy (CLA) 41
4.2 Infections 42
4.3 Malignancy (Metastatic Lymphadenopathy) 45
4.4 Diagnostic Approach 49
References 54
4.1 Etiology of Cervical Lymphadenopathy (CLA)
Lymphadenopathy is not a disease by itself; rather, it is a sign of an underlying

pathology that ranges from a trivial infection to a metastatic malignant neoplasm.
Enlargement of the cervical lymph nodes (LNs) is the commonest cause of a swell-
ing in the neck. Even when only one LN is palpable, the adjacent nodes are invari-
ably diseased. Based on distribution, cervical lymphadenopathy (CLA) may be
localized or part of generalized disease. Based on duration, CLA is further classi-
fied into acute (2 weeks), subacute (2–6 weeks), and chronic (does not resolve by
6 weeks).
The most likely cause of CLA depends on age; reactive or nonspecific inflamma-
tion is the commonest cause in those less than 14 years old; tuberculous (TB)
lymphadenopathy was the predominant pathology in the 14–59-year group, while
cancer should be suspected if the patient is 60 years or older [1]. The various causes
of CLA are listed in Table 4.1.

Switzerland AG 2024
42 4 Midline Neck Swellings: Cervical Lymphadenopathy
Table 4.1 Possible causes of cervical lymphadenopathy (CLA)

Causes Examples
Infections – IMN, infectious hepatitis, HSV, rubella, measles, adenovirus, HIV
– Viral – Streptococcus, staphylococcus, CSD, tularemia, TB, syphilis, leprosy,
diphtheria
– Bacterial – LGV, trachoma
– Chlamydia – Scrub typhus, rickettsial pox
– Rickettsia – Histoplasmosis, coccidioidomycosis
– Fungal – Toxoplasmosis, leishmaniasis
– Parasitic
Malignancy HD, NHL, ALL, CLL, hairy cell leukemia, T-cell lymphoma, multiple
myeloma, metastatic
Immunological RA, SLE, Sjogren’s syndrome, drug hypersensitivity, silicone-associated,
disease serum diseases, GVHD
Endocrine disease Hyperthyroidism, thyroiditis, adrenal insufficiency
Lipid storage Gaucher’s disease, Niemann-Pick disease
disorders
Medications Allopurinol, atenolol, captopril, cephalosporin, gold, hydralazine,
penicillin, phenytoin, primidone, pyrimethamine, quinidine
Miscellaneous Sarcoidosis, histiocytosis-X, Kikuchi’s disease, Kawasaki’s disease,
Castleman’s disease, lymphomatoid granulomatosis
IMN infectious mononucleosis, HSV herpes simplex virus, HIV human immunodeficiency virus,
CSD cat scratch disease, TB tuberculosis, LGV lymphogranuloma venereum, HD Hodgkin disease,
NHL non-Hodgkin lymphoma, ALL acute lymphoblastic leukemia, CLL chronic lymphoblastic leu-
kemia, RA rheumatoid arthritis, SLE systemic lupus erythematosus, GVHD graft versus host disease
4.2 Infections
Acute Bacterial Infections
Acute bacterial infections are most commonly caused by Staphylococcus aureus or

Streptococcus pyogenes and should be suspected in patients with lesions of the face or
scalp [2]. Clinically, lymphadenopathy is often solitary and unilateral and usually
involves the submandibular, upper deep cervical (UDC), submental, and occipital areas
in decreasing order. Enlarged LNs are tender and may be fluctuant, and the overlying
skin is warm and erythematous. If untreated, multiple nodes coalesce and central
breakdown occurs, and later on, suppuration and abscess formation take place [2].
Local signs and symptoms of infection include warmth, erythema of the overly-
ing skin, and a localized, tender swelling [3, 4]. Systemic signs include fever, tachy-
cardia, and other symptoms specific to head and neck infections such as rhinorrhea,
odynophagia, otalgia, and odontalgia. Even in the absence of these findings, infec-
tion can be suspected if the mass developed within a few days of an upper respira-
tory infection, dental problem, trauma, travel, or exposure to bites of insects and
certain animals [4–9].
4.2 Infections 43
Management is by treating the primary focus and appropriate antibiotics. If

infected, drainage is necessary [2]. Antibiotics should be used to treat a neck mass
only if there is evidence of bacterial infection. In general, if signs and symptoms
suggesting infection are lacking, empiric treatment with antibiotics should be
avoided, and the mass should undergo further workup to rule out possible
malignancy.
Acute Viral Lymphadenitis
Typically, acute viral adenitis follows an upper respiratory infection by rhinovirus,

influenza or parainfluenza virus, coronavirus, and adenovirus. Other less common
etiologies are mumps, measles, rubella, varicella, and herpes simplex. Clinically,
lymphadenopathy is commonly multiple and bilateral. The LNs are relatively small,
not tender, and rarely suppurate. Characteristically, the overlying skin is neither
warm nor erythematous. Patients usually have a low-grade fever and complain of
cough, rhinorrhea, conjunctivitis, or skin rash [2, 10].
Infectious mononucleosis (IMN) (also known as glandular fever) most com-
monly affects children and young adolescents between the ages of 15 and
24 years in developed countries [11]. In the developing world, people are more
often infected in early childhood when there are fewer symptoms [2]. The dis-
ease occurs equally at all times of the year [11]. It is caused by Epstein-Barr
virus (EBV), which spreads primarily by saliva and rarely through semen or
blood. The virus replicates inside B-lymphocytes and epithelial cells of the phar-
ynx. In young adults, the disease often results in fever, sore throat, enlarged
cervical LNs, and tiredness. Usually, the posterior group of cervical LNs is
involved with or without axillary and/or inguinal LNs, or splenomegaly. In less
than 1% of cases, splenic rupture may occur [12].
Diagnosis of IMN is confirmed serologically by Paul-Bunnell test, which detects
heterophil antibodies by agglutination of sheep red cells, or via the more sensitive
detection of antibodies to viral capsid antigens. Treatment is symptomatic and usu-
ally ends in recovery. Cortisone may be used in persistent cases [13].
Chronic Nonspecific Infectious Lymphadenitis
Chronic nonspecific infectious lymphadenitis is defined by failure to resolve or

improve despite a 2–6 weeks of appropriate therapy. It usually occurs in associa-
tion with chronic tonsillitis and pediculosis of the scalp. Clinically, the LNs are
enlarged, firm, and slightly tender. Abscess formation may occur. These LNs do
not become matted or adherent. Treatment of the primary focus of infection is
essential. If persistent and suspicious, a biopsy should be taken to rule out malig-
nancy [2, 10].
Chronic Specific Infectious Lymphadenitis: Tuberculosis (TB)
A study by Bruzgielewicz et al. [14] of patients with head and neck tuberculosis
(TB) found that among the 26 patients with tuberculous LNs, 15 patients had
infected LNs of cervical levels II and III, and 11 had infected LNs of cervical level
I (involving the midline of the neck) [14].
Locally, patients with tuberculous lymphadenitis (TBLA) report a painless,
enlarging, or persistent mass consisting of a single group of LNs [15, 16]. The dura-
tion of symptoms at the time of presentation is typically 1–2 months [15, 16]. The
affected LNs are enlarged but remain discrete. The median LN size is approxi-
mately 3 cm, but LNs may reach up to 8–10 cm in diameter [17]. Lymph nodes then
coalesce and break down to form tuberculous pus, which may perforate the deep
fascia and present as a cold abscess. If the abscess bursts through the deep fascia
into the subcutaneous tissues, it will have two compartments, one on either side of
the fascia, connected by a small central track, forming what is known as “collar-stud
abscess.” In 4–11% of cases, the skin overlying may show breakdown and form a
sinus [15, 16]. Cord-like structures (lymphatics) may be felt between the enlarged
LNs due to TB lymphangitis.
In general, TBLA is classified into five distinct stages: discrete LNs, matted LNs,
cold abscess, collar-stud abscess, and TB sinus/ulcer (Table 4.2).
Mycobacterium TB infection is not considered a localized disease; thus, systemic
chemotherapy should be instituted. Medical treatment alone is the standard treatment
of TBLA for which the antibiotic regimens effective for pulmonary infection can
also be applied. Several options exist, including daily, twice-weekly, and thrice-
weekly administration. The Infectious Disease Society of America (IDSA) recom-
mends 6 months of the following treatment for lymphadenitis caused by
drug-susceptible organisms [18]: isoniazid, rifampin, pyrazinamide, and ethambutol
for 2 months, followed by isoniazid and rifampin for another 4 months. The 6-month
recommendation is supported by studies that showed no difference between 6 and
9 months of treatment in cure rates (89–94%) [19, 20] or relapse rates (3%) [21].
Table 4.2 Stages of tuberculous lymphadenitis (TBLA)

Stage Description Pathogenesis Clinical features
1 Discrete LNs Nonspecific reactive Large, firm, and mobile LNs
hyperplasia with formation of
tuberculous nodules
2 Matted LNs Periadenitis (caseation starts) Large, rubbery LNs, fixed to
surrounding tissues
3 Cold abscess Central softening and caseation Soft, smooth, non-tender, fluctuant
deep to the deep fascia swelling without skin involvement
4 Collar-stud Caseous material perforates Abscess adherent to the overlying
abscess the deep fascia due to skin
increased pressure
5 TB sinus/ulcer Results from bursting of the Chronic nonhealing sinus or ulcer
cold abscess with thin, bluish, undermined edges
and scanty watery discharge
Surgery for treatment of TBLA is usually reserved for establishing diagnosis,

advanced local disease, persistent disease, or draining fistula [22, 23]. Failure to
provide adequate chemotherapy at the time of surgery may lead to postoperative
fistula formation and hematogenous spread [24]. Traditionally, surgical intervention
ranging from simple aspiration to complete excision has been considered the treat-
ment of choice.
4.3 Malignancy (Metastatic Lymphadenopathy)
Overview
Nodal metastases of head and neck neoplasms account for approximately 80% of
cystic neck masses in adults above the age of 40 years [25]. Exclusion of malig-
nancy is the single most important aim sought by physicians when evaluating
CLA. The rate of malignant etiologies rises with age and male gender. Malignant
cervical LNs may be caused by secondary metastasis from another primary lym-
phoma or chronic lymphatic leukemia.
Metastatic LNs are important to diagnose early as they significantly alter prog-
nosis and management. They most commonly arise from papillary thyroid carci-
noma (PTC) or head and neck squamous cell carcinoma (SCC). Hallmark imaging
findings include multiple, round masses with central cystic necrosis, eccentric solid
component(s), and disruption of the usual fatty hilar architecture. Punctate calcifica-
tions may suggest metastases from PTC. Hypermetabolism can be confirmed on
positron-emission tomography (PET) imaging. Additionally, advanced magnetic
resonance imaging (MRI) with diffusion-weighted or dynamic contrast-enhanced
sequences has been shown to differentiate benign from malignant nodes based on
low apparent diffusion coefficient (ADC) value or enhancement kinetics, respec-
tively [26, 27].
Regional Lymph Nodes—TNM Staging
Neck staging under the “TNM Staging System” for head and neck tumors (AJCC)
is summarized in Table 4.3 [28].
Metastases from Cervical Draining Areas (Overt Primary)
The most common site of metastatic malignancy is “LNs” due to lymphatic

extension from a primary lesion in their draining areas. The primary tumor may
be a carcinoma, melanoma, or sarcoma. Metastatic LNs are usually painless,
hard in consistency, and mobile but become fixed later on. They may ulcerate
and fungate in neglected cases. Clinically, there is a short history and progres-
sive course.
Table 4.3 TNM staging system for head and neck tumors
LN Description
Nx Regional LNs cannot be assessed
N0 No regional LN metastasis
N1 Metastasis in a single ipsilateral LN, 3–6 cm or less in greatest dimension
N2 Metastasis in a single ipsilateral LN, >3–6 cm; or in multiple ipsilateral LNs, none
>6 cm; or in bilateral or contralateral LNs, none >6 cm in greatest dimension
N2a Metastasis in a single ipsilateral LN, >3 cm but not >6 cm in greatest dimension
N2b Metastasis in multiple ipsilateral LNs, none >6 cm in greatest dimension
N2c Metastasis in bilateral or contralateral LNs, none >6 cm in greatest dimension
N3a Metastasis in an LN >6 cm in greatest dimension, E−
N3b Metastasis in an LN >6 cm in greatest dimension with clinically overt E+
LN lymph node. Clinical/radiological extranodal extension (ENE) should be recorded as E− or E+
Squamous cell carcinoma (SCC) is the most common cancer of the upper aerodi-
gestive tract, accounting for more than 90% of cancers with a high propensity
toward deposition in the regional LNs. Despite many common features, SCCs of the
head and neck vary in their metastatic potential. Certain subsites such as the oro-
pharynx and supraglottic larynx have a high risk of LN metastasis owing to the rich
lymphatics of the area. Other sites such as the glottic larynx are much less likely to
metastasize.
athophysiology: Lymphatic Spread of Tumor Cells

P
Most head and neck SCCs progress from carcinoma in situ to microinvasive carci-
noma, to invasive carcinoma with invasion of the stroma, and to a deeply invasive
tumor with lymphatic metastasis. Cellular events involved in the development of
metastases include detachment of a malignant cell from the primary cancer, entry of
the cancer cell into the lymphatic space, and further local and distant dissemination
[29]. Cancer cells can also spread locally through direct infiltration into the sur-
rounding soft tissues. Although cancer cells carried in the blood can spread to essen-
tially any location in the body, lymphatic spread follows a more stepwise fashion,
moving through successive nodal stations.
rimary Sites: Patterns of Drainage and Treatment

P
Oral cavity: Cancers of the oral cavity most commonly drain to levels I–III of the
ipsilateral neck. The majority of N0 patients are adequately treated by dissection of
these three levels, with only 3–6% of patients having disease in level IV [30]. Level
V is almost always associated with clinical disease in other levels.
Oropharynx: The oropharynx has a significantly higher rate of occult metastasis,
and therefore patients with even small primary tumors should have their neck
treated. The oropharynx most commonly drains to levels II through IV. Levels I and
V are rarely involved without other levels being involved as well. The retropharyn-
geal LNs drain the soft palate, posterior pharyngeal wall, and less commonly tonsil-
lar fossae. Cancers that involve or approach these areas put the retropharyngeal
nodes at risk.
Hypopharynx and cervical esophagus: Approximately, 70% of patients with

hypopharyngeal malignancy present with palpable CLA. Hypopharyngeal cancers
most commonly drain to levels II through IV, with I and V rarely involved. The
retropharyngeal and level VI central (anterior) LNs have also been shown to be at
risk for metastasis in cancers of the hypopharynx. Some authors advocate routine
inclusion of these nodal basins along with thyroidectomy to address this risk [31].
Larynx: Due to its embryologic development, the larynx behaves as two separate
compartments with distinct lymphatic drainage pathways. Lymphatic drainage of
the “supraglottic” larynx follows the superior laryngeal vessels and drains into lev-
els II and III bilaterally. In contrast, the “glottis and sub-glottis” drain inferiorly into
the level VI central compartment and level IV. While less often involved with metas-
tasis, addressing levels II–IV without addressing the central neck compartment is at
risk for leaving metastatic disease behind [32].
Thyroid gland: In large studies, PTC involved the thyroid gland only in 67% of
cases, the thyroid and LNs in 13%, and LNs alone in 20% [33–40]. In another study,
35% of patients with PTC presented with locoregional LN metastases [41]. Some
authors reported the incidence of cervical metastatic LNs in children with PTC to be
as high as 90% [42]. Cervical metastases from PTC were reported to occur in pre-
dictable patterns commonly presenting at levels II–V, with level III being the most
commonly involved area and level I being the least [43–46]. Level VI represents the
central compartment and is mentioned in many other series as the first station of
nodal spread from PTC [47, 48]. Despite the recognized sequence of lymphatic dis-
semination, discontinuous lymphatic spread, or skip metastasis, in node-positive
PTC, has been reported to range between 11.1% and 37.5% [49–51]. Thus, clearing
the central LN compartment should be considered when lateral or mediastinal LN
compartments are involved [52].
Salivary glands: Spread of parotid malignancy occurs through the well-
established routes of metastases, where the first echelon LN is the intra- and peri-
glandular nodes. The next echelon is level II LNs. The incidence of cervical LN
metastases in submandibular carcinomas at the time of presentation varies from 8%
to 33% [53–56], which reduces the 5-year survival rates from 40% to 9% [53–55,
57–60]. The most common levels of neck involvement in submandibular (and sub-
lingual) malignant tumors are levels I–III [57, 59].
Cervical Lymph Node Metastases of Unknown Primary
Metastatic LNs may represent the first clinical manifestation of disease (occult pri-
mary) where the primary tumor is not detected after clinical examination and
extended diagnostic procedures (cancer of unknown primary—CUP). Reasons may
be involution or a slower growth rate at the primary tumor site, due to different
genetic alterations in the primary or the metastases [61].
Metastatic cervical LNs are mostly located in level II (30–50%), followed by
levels I and III (10–20%) and levels IV and V (5–10%) [62, 63]. Bilateral involve-
ment of the neck is reported in less than 10% of the cases [64–69]. When node
metastases are found in levels I–III, the site of the occult primary is suspected to be
in the nasal sinuses (e.g., maxillary sinus), nasopharynx (fossa of Rosenmüller),
hypopharynx, pyriform fossa of larynx, and thyroid gland (PTC). Upon affliction of
the levels IV–V, the primary tumor is most likely located in the lower neck (e.g.,
thyroid gland) or below the clavicles [70–72].
Clinically, the patient usually presents with a painless, unilateral, hard, mobile,
cervical mass that becomes fixed later. The head and upper aerodigestive tract are
further explored using nasopharyngoscopy.
Investigations
Fine Needle Aspiration Biopsy (FNAB)

Fine needle aspiration biopsy of the cervical LN is the first and most commonly
used diagnostic procedure, as it is a minimally invasive procedure, associated with
a negligible risk of tumor spread. The diagnostic sensitivity of FNAB for metastatic
cervical LNs ranges from 83% to 97% with a specificity of 91–100% [73].
Immunohistochemistry (IHC)
General staining identifies cell morphologies and abnormal/malignant cell popula-
tions of the tissue’s origin. Afterwards, an initial IHC panel for broad cancer types
including epithelial, melanocytic, and lymphoid markers is used. Markers for lym-
phomas are common leukocyte antigen (CLA), anaplastic lymphoma kinase
(ALK1), CD30, and CD43. For melanomas, there are S-100, anti-human melano-
some (HMB45), and Melan-A [74]. In case of carcinoma, its subtype is evaluated
by considering morphological aspects followed by specific antibodies, such as CK5,
CK6, CK7, or TTF-1 [74].
Imaging
A quick, inexpensive, procedure with high spatial resolution is the contrast-enhanced
CT scan from the skull base to clavicles, complemented or substituted by a gado-
linium contrast-enhanced MRI with superior soft tissue resolution [75]. The chance
for CT, MRI, or both to detect the primary site ranges from only 9% to 23% [76–
79]. 18F-fluoro-2-deoxyglucose PET (FDG-PET) is a useful diagnostic tool when
standard radiological workup is completed with negative or inconclusive results. It
should be performed before any invasive procedures that induce tissue alteration,
which may hamper proper evaluation of the scans [15–17, 80, 81]. The capability of
FDG-PET for tumor detection is down to a size of ≥5 mm [82–86].
Panendoscopy with Biopsies

Panendoscopy of the upper aerodigestive tract is performed under general anesthe-
sia. Biopsies are taken from radiologically or clinically suspicious sites [75]. It is
only repeated when directed biopsy fails during the first procedure [87, 88].
Waltonen et al. (2009) [77] reported the highest success rate (59.6%) for detection
of the primary tumor by PET-CT scans plus panendoscopy with directed biopsies,
with or without tonsillectomy.
Molecular Studies
Human papillomavirus (HPV) status can be determined by in situ hybridization
(ISH) or polymerase chain reaction (PCR), by detecting HPV-DNA, or by HPV-E6/
E7 RNA expression detected by quantitative reverse transcriptase-PCR (qRT-PCR).
Epstein-Barr virus (EBV) is consistently associated with nasopharyngeal carci-
noma, especially with the poorly or undifferentiated and non-keratinizing types
[89]. EBV-DNA is routinely detected by PCR with sensitivity and specificity close
to 90% each, from FNAB samples [90–94].
Treatment
Therapeutic strategies differ widely and are based on retrospective studies, clinical
experience, and institutional policy. They range from surgery or chemoradiotherapy
alone to surgery plus adjuvant radiotherapy with or without concomitant chemo-
therapy [68, 95, 96]. Therapeutic options depend on patient’s age, performance sta-
tus, local extension, site of the LN metastases, and their histology. In early-stage
neck disease, mono-modal therapy is possible, whereas an advanced-stage neck
disease usually requires an aggressive multimodal approach, comparable to locally
advanced head and neck cancer [97].
Prognosis
Prognosis highly depends on the histology and involved region. It ranges from
“poor” (adenocarcinoma metastatic to bone, brain, and/or viscera) with a median
survival of 7–11 months to “favorable” (e.g., SCC metastatic to cervical LNs) with
a median survival similar to head and neck carcinomas with known primaries (e.g.,
HN-SCC) [62, 75, 98, 99].
4.4 Diagnostic Approach
The first target during the evaluation of CLA is to determine whether it is localized
or generalized. Factors related to the LN size, consistency, and mobility should also
be considered as they may point to a malignant nature. When dealing with localized
CLA, the draining sites of the affected levels should be thoroughly examined for
sources of infection or possible malignant lesion. If the history and physical exami-
nation reveal a source of infection, then no further workup is required and treatment
can be initiated and followed up.
Clinical Assessment
History-Taking
–– Age: The probability of malignant nature is higher in older age populations.
–– Symptoms: Fever, conjunctivitis, sore throat, dental pain, ulcers, or discharge
denotes infection. Night sweats and shivers can suggest TB. Localized symp-
toms of malignancy include hoarseness of voice, dysphagia, stridor, ulcers, and
pain, while generalized symptoms of malignancy include unexplained weight

loss of more than 10% over a period of 6 months.
–– Duration and response to previous medications: A short history of lymphade-
nopathy may favor acute infectious etiology, while persistent nodal enlargement
(>4 weeks) accompanies chronic infections, collagenic diseases, and malignan-
cies. Also, response to previous medications (e.g., antimicrobials) may help vali-
date the underlying pathology.
Physical Examination
–– Distribution: It is crucial to determine whether CLA is isolated (localized
enlargement of LNs in one region), regional (enlargement of LNs in two or more
contiguous regions), or part of generalized lymphadenopathy.
–– Size: The LNs of <1 cm in diameter are usually of no clinical significance, while
LNs >2 cm and of persistent nature mandate thorough diagnostic workup.
–– Mobility: Fixed LNs suggest metastatic causes, while freely movable nodes have
a wide range of underlying etiologies including primary cancer (e.g., lymphoma).
–– Consistency: Hard LNs usually suggest a malignant nature. However, other
forms of consistency can still accompany malignant nodes.
–– Tenderness: A tender LN can point out an underlying inflammatory process.
Investigations
In case of low estimated risk of malignancy, patients with localized LNs and nondi-
agnostic initial workup can be followed up for 4 weeks. Empirical antimicrobials
and steroids should be avoided for their lympholytic effect, which influences the
results of biopsy.
Imaging Modalities
The main target of US examination is to distinguish reactive, tuberculous, lympho-
matous, and metastatic LN etiologies. In addition, serial monitoring of nodal size
and vascularity is useful in assessing treatment response [100].
Reactive LNs: They are usually found in the upper part of the neck and the pos-
terior triangle. There are no suspicious criteria such as irregular margins, peripheral
halo, internal echoes, and tendency for fusion. There is preservation of the echo-
genic hilum representing hilar vascularity, which can be further confirmed by color
Doppler.
Tuberculous LNs: Characteristic features on US include the presence of multiple
LNS with tendency to fusion (nodal matting), hypoechoic core, posterior enhance-
ment, adjacent soft tissue edema (peripheral halo), and presence of strong internal
echoes denoting calcifications, caseation, and granuloma formation.
Lymphomatous LNs: They are usually rounded, hypoechoic with absent echo-
genic hilum and may show intranodal reticulation. On Doppler studies, they show
Fig. 4.1 Ultrasonography

showing metastatic
cervical lymph node from
papillary thyroid
carcinoma (black arrows).
Note the hyperechoic
component within the node
(white arrows), which may
be related to intranodal
deposition of thyroglobulin
mixed or peripheral vascularity. This applies for both Hodgkin disease (HD) and
non-Hodgkin lymphoma (NHL).
Metastatic LNs: Metastatic LNs usually display a rounded contour with
hypoechoic nature with absence of an echogenic hilum. Echogenic foci of cystic
necrosis should suggest a metastatic nature, particularly from SCC. Metastatic LNs
from PTC may display hyper-echogenicity (Fig. 4.1) and punctate calcifications.
Extranodal extension is suspected when the outline is ill-defined. On color Doppler,
metastatic LNs show mixed or peripheral vascularity.
Computed Tomography (CT) Scan and Magnetic Resonance Imaging (MRI)

The main application of CT scan for cervical nodal assessment is in the setting of
evaluation of metastatic LNs in the head and neck region in different clinical
scenarios:
–– Documented head and neck malignancy (by biopsy) with no clinically palpable
LNs, for confirmation of the N0 state
–– Documented head and neck malignancy with palpable LNs on one side of the
neck, for evaluation of the contralateral neck side
–– Metastatic LN proven by biopsy without a clinically proven source for the detec-
tion of the primary site of malignancy
–– For evaluation of carotid artery invasion by metastatic nodal tissue
–– For postoperative follow-up for evidence of recurrent primary and nodal disease
Other Imaging Modalities

Other imaging modalities such as FDG-PET scan have a high sensitivity for detec-
tion of affected LNs. It also has a great role in the diagnostic approach for carci-
noma of unknown primary. PET-CT is helpful in identifying occult primary
carcinomas of the head and neck, especially when applied as a guiding tool prior to
panendoscopy [101]. Another modality is the MRI diffusion, which is being widely
tested for better detection of affected LNs.
Biopsy
Biopsy is required for generalized lymphadenopathy when the initial workup is
nondiagnostic and for persistent CLA with a high estimated risk of malignancy. The
available biopsy techniques include FNA, core needle biopsy, and excisional
biopsy [102].
Fine Needle Aspiration (FNA)

Fine needle aspiration cytology (FNAC) is a safe [103, 104], simple, cost-effective
procedure that yields results promptly [105] and has been reported to be accurate in
the diagnosis of reactive hyperplasia, infections, granulomatous lymphadenopa-
thies, lymphomas, and metastatic malignancies [106], with an overall accuracy of
93.1% (73.3–98.0%) [104]. It is highly recommended that FNA be promoted as an
initial diagnostic test for a patient at increased risk of a malignant LN, and the use
of open biopsy be limited [107].
The most important limitations of FNAC are inadequate specimen [108] and
high rate of false-negative diagnoses in HD and incomplete classification of NHL
[104]. Ultrasonography-guided FNAC gives more precise information than does
blind FNAC. It can identify metastasis in the LN whenever physical examination
and imaging techniques suggest malignancy [109].
Core Needle Biopsy

Core needle biopsy is indicated when results of FNAC are equivocal and a high
index of suspicion is present, especially when excisional biopsy carries a higher risk
for the patient considering his general medical condition or is impossible due to
nodal fixation. Core needle biopsy provides more specimen from the tissue than
does FNAC. If an imaging technique guides the procedure, the results will be more
accurate, and it may thus prevent unnecessary excisional biopsy. A US-guided core
needle biopsy using automated needles allows for a larger yield of tissue sample and
obtaining a specimen with preserved histological architecture allowing for more
precise diagnosis and allows for the use of various histological and immunohisto-
chemical (IHC) techniques [110]. Disadvantages include probable tumor cell spill-
age (needle track metastasis) and injury of neural or vascular elements (this can be
improved by using imaging-guided biopsy).
Excisional Biopsy
Excisional biopsy has the highest sensitivity and diagnostic yield because it pro-
duces sufficient material and simultaneously allows the analysis of the LN architec-
ture. It should be taken from the most abnormal or the largest LN site. If results of
biopsy show atypical lymphoid hyperplasia, this should be considered nondiagnos-
tic and further workup including another biopsy should be considered.
Vassilakopoulos et al. (2000) [111] evaluated 475 patients with peripheral
lymphadenopathy older than 14 years old and reported that six variables inde-
pendently predicted the need for an excisional LN biopsy, namely, age above
40 years, lack of tenderness on the LN, size of the LN, generalized pruritus,
supraclavicular location, and hard consistency. Soldes et al. (1999) [112] identi-
fied some parameters that increased the risk of malignancy in children older
than 8 years, namely, node size >1 cm, multiple sites of adenopathy, supracla-
vicular location, fixed LNs, and abnormal chest X-ray. Moreover, the authors
recommended that younger children with a single small LN be preferably man-
aged by laboratory tests and clinical follow-up because of the low risk of malig-
nancy (≤5%).
Tissue biopsy of LNs remains a standard requirement whenever a reactive nature
of LNs due to a bacterial or viral cause cannot be confirmed by imaging or serologi-
cal tests [113]. However, excisional lymph node biopsies have the disadvantage of
being more invasive and often require general anesthesia in addition to the associ-
ated surgical complications.
Endoscopy
In possible malignancy of cervical LNs, it is routine to perform a throat examination
including mirror and/or endoscopy [114].
Differential Diagnosis
Models available to categorize peripheral lymphadenopathy include the following:
1. Using the acronym “CHICAGO” helps to consider causes of lymphadenopa-

thy [115]
Cancers: Hematologic malignancies (HD, NHL, leukemia)—metastatic (breast tumor,

C: lung, kidney, others)
H: Hypersensitivity syndromes: serum sickness, drugs
I: Infections: viral (EBV, CMV, HIV), bacterial (TB) fungal, protozoan, rickettsial (typhus)
C: Connective tissue disorders: SLE, RA, dermatomyositis
A: Atypical lymphoproliferative disorders: Castleman’s disease, Wegener
G: Granulomatous: histoplasmosis, mycobacterial infections, cryptococcus, berylliosis, cat
scratch disease, silicosis
O: Others
2. Using the region of LN enlargement and its localization provides useful infor-
mation about causes. CLA may be localized to the neck or part of generalized
lymphadenopathy.
The algorithm in Fig. 4.2 helps in differential diagnosis of CLA.

Fig. 4.2 Algorithm for differential diagnosis of cervical lymphadenopathy. URI upper respiratory
infection, IMN infectious mononucleosis, TB tuberculosis, HIV human immunodeficiency virus,
HD Hodgkin disease, NHL non-Hodgkin lymphoma, SLE systemic lupus erythematosus
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Swellings of the Submental Region
5
Contents
5.1 Overview 61
5.2 Submental Lymphadenopathy 62
5.3 Cervical Dermoid Cyst 63
5.4 Plunging Ranula (Dumbbell-Shaped) 71
5.5 Abscess in Relation to Odontogenic Infections 77
5.6 Submental Ectopic Thyroid Tissue 79
References 84
5.1 Overview
Swellings in the submental region (triangle) include the following:
–– Submental lymph nodes (LNs)

–– Cervical dermoid cyst (plunging sublingual dermoid)
–– Hourglass ranula
–– Abscess related to the mandible (central incisors)
–– Rare Causes (Miscellaneous): Lymphoma, sarcoidosis, hemangioma, lipoma,
fibroma, ectopic thyroid tissue
Ural et al. (2011) conducted a retrospective study to identify the clinical and
histopathological features of masses confined to the submental space and to outline
an approach to the diagnosis and treatment of these lesions. The study population
was made up of 24 patients (17 males and 7 females), their ages ranged between 13
and 68 years with a mean of 45.88 ± 8.48 years. Data reviewed included

Switzerland AG 2024
62 5 Swellings of the Submental Region
demographic data, signs and symptoms, diagnostic and therapeutic methods, histo-
pathological outcomes, and recurrence rate. Fine needle aspiration biopsy (FNAB)
and ultrasonography (US) were performed for all patients. Surgical excision was the
mainstay of treatment, although abscesses were treated with local drainage and sys-
temic antibiotics. Histopathology identified a wide variety of entities, including
reactive lymphadenopathy (n = 12), non-Hodgkin lymphoma, dermoid cyst, and
abscess (3 patients each), sarcoidosis, hemangioma, and lipoma (1 patient each).
Nine patients had associated dental problems and two had cheilitis. During a fol-
low-up of up to 74 months, no local recurrences were detected. They concluded that
lesions confined to the submental space are most likely to occur secondary to local
and benign pathologies of the head and neck. However, malignancies or systemic
diseases must also be ruled out. Careful assessment of the nasal and oral cavities is
essential, and adequate treatment is based on the underlying pathology [1].
5.2 Submental Lymphadenopathy
Anatomical Location
The submental group of lymph nodes (LNs) lies within the submental triangle
bounded by the anterior belly of the digastric muscles on both sides, the symphysis
menti superiorly, and the hyoid bone inferiorly (level IA).
Drainage
This group of LNs drains the skin of the chin, the middle part of the lower lip, the
anterior portion (apex) of the tongue, and the floor of the mouth. Efferents of these
LNs drain partly to the submandibular LNs (cervical level IB) and partly to the
upper jugular group of LNs (cervical level II).
Metastatic Lymphadenopathy
Submental LNs may contain metastatic deposits, most often from malignancies of
the floor of the mouth, anterior oral tongue, mandibular alveolar ridge, and lower
lip [2].
Infective Lymphadenopathy
Submental lymphadenopathy may occur due several infections including Epstein-
Barr virus (EBV), cytomegalovirus (CMV), and toxoplasmosis. Associated clinical
findings and relevant laboratory tests are summarized in Table 5.1.
Table 5.1 Clinical findings and laboratory tests in infective lymphadenopathy

Disorder Associated findings Laboratory tests
Epstein-Barr virus Splenomegaly in 50% of Monospot, IgM EA or VCA
patients
Cytomegalovirus Often mild symptoms; patients IgM CMV antibody, viral culture of
may have hepatitis urine or blood
Toxoplasmosis 80% to 90% of patients are IgM toxoplasma antibody
asymptomatic
5.3 Cervical Dermoid Cyst
Epidemiology
Dermoid cysts of the head and neck are not common. Pirgousis and Fernandes
(2011) reported that up to 6.9% of all body dermoid cysts occur in the neck region
[3, 4]. A cervical dermoid cyst may present anywhere along the midline. The floor
of the mouth is the second most common site for the presentation of dermoid cysts
in the head and neck region, after the periorbital region [5]; approximately, 23–34%
occurs in the floor of the mouth [6, 7]. Etarbi et al. (2017) reported that epidermoid
and dermoid cysts of the oral cavity are rare, representing<0.01% of all oral cavity
cysts [8].
The vast majority of dermoid cysts of the floor of the mouth are located in the
midline (sublingual 52% and submental 26%) (Fig. 5.1); however, about 16%
involve more than one of the three anatomical spaces of the floor of the mouth (sub-
lingual, submental, and submandibular) [9], and up to 6% are located only in the
submandibular space, presenting clinically as lateral neck cysts [3].
Etiology/Pathogenesis
Dermoid cyst could be congenital or acquired. There are two theories involving
the pathogenesis of congenital (developmental) dermoid cysts. Most researchers
believe that a dermoid cyst developing in the midline of the floor of mouth is a
dysembryogenetic lesion resulting from entrapped ectodermal tissue of the first
and second branchial arches [10], which fuse during the third and fourth weeks in
utero [11–13]. Such congenital cysts usually lie in the midline. They may lie
above (suprahyoid) or below (infrahyoid) the mylohyoid muscle [12, 14]. The
second theory suggests that these cysts may be a variant of the thyroglossal duct
cyst with predominantly ectodermal components [15]. Acquired dermoid cysts
may result from iatrogenic or traumatic implantation of epithelial cells that subse-
quently grow [12].
a b
Fig. 5.1 (a) Central sublingual dermoid cyst in a 23-year-old patient (front view), (b) dermoid
cyst plunging into the submental triangle in the same patient (lateral view)
Anatomical Classification
Dermoid cysts can be classified according to their anatomical location into three
categories: (1) sublingual, (2) submental, and (3) submandibular cysts [16]. Dermoid
cysts may also be categorized according to their relation to the mylohyoid muscle;
(1) suprahyoid (above the muscle) or (2) infrahyoid (below the muscle).
Pathology
Histologically, midline cervical dermoid cysts are divided into three types: (1) epi-
dermoid cysts consisting of a wall lined with stratified squamous epithelium that
may be partly keratinized, (2) dermoid cysts showing evidence of skin appendages
(adnexal tissues) such as hair follicles, hair, sweat, and sebaceous glands (Fig. 5.2),
and (3) teratomas (teratoid cysts) containing all three germinal layers (mesodermal
elements) such as bone, muscle, respiratory and gastrointestinal tissues, and fibrous
capsules, in addition to skin appendages [17]. The latter is the rarest type [18, 19].
This type of teratoma is nearly always benign; in rare cases, squamous cell carci-
noma may develop from the wall of the cyst in adults [8]. Contents of the dermoid
cyst are variably keratinous, caseous, sebaceous, or purulent with hair, nails, fat
globules, and cholesterol clefts [4].
Clinical Picture
Dermoid cysts usually occur in the second or third decades of life, most commonly
between 10 and 25 years [20], affecting both sexes equally [9]. Of the 14 patients
with sublingual dermoid cysts reported by Oluleke and colleagues, 8 patients
(57.1%) were male and 6 (42.9%) were female, with a statistically nonsignificant
male-to-female ratio of 1.3:1.0 [21].
Fig. 5.2 Histopathology

of a cervical dermoid cyst
showing the cyst was lined
by keratinizing stratified
squamous epithelium with
granular cell layer. Small
adnexal structures were
also seen in the cyst wall
(arrow) (H&E stain)
The patient usually presents with a slow-growing, painless swelling, which

becomes painful and tender if secondarily infected [22]. The swelling may
involve one or more of the sublingual, submental and submandibular spaces and
can progress to reach a significant size before producing symptoms. Cystic
lesions occurring superior to the mylohyoid muscle have the potential to dis-
place the tongue toward the palate resulting in difficulty with mastication, dys-
phagia, speech difficulties and airway obstruction [17]. For cystic lesions
developing below the mylohyoid musculature, a submental (or submandibular)
swelling is observed.
On physical examination, the swelling is non-tender (unless infected), smooth,
spherical, opaque, clearly defined, and fluctuant. Several authors have also described
it as having a doughy consistency [22, 23]. Its size varies from 1.2 to 12 cm when
noticed [24, 25]. When it reaches a very large size, it may involve more than one
anatomical area and touch the hyoid bone when in the neck [20]. It may even fill the
whole oral cavity. In certain situations, these cysts may show sudden increase in
size. A possible explanation may be the onset of puberty with a subsequent increase
in sebum secretion from the sebaceous glands [26]. Another reason may be second-
ary infection of the cyst contents with associated fever, pain, trismus, and cervical
lymphadenopathy [10, 22].
Complications
The reported major complications associated with sublingual dermoid cysts include
upper respiratory tract infection, anemia, respiratory obstruction, feeding difficul-
ties, and esthetic challenges [10].
Investigations
Diagnostic imaging modalities include computed tomography (CT) scan, magnetic

resonance imaging (MRI) and ultrasonography (US). Both, CT scan and MRI, pro-
vide excellent tissue characterization and precise anatomical localization with
respect to the geniohyoid and mylohyoid muscles [25, 27]. This would be most
valuable to the surgeon during excision of the cyst [28, 29]. Recent advances in the
management of sublingual dermoid cyst advocates the inclusion of thyroid scintig-
raphy in the preoperative diagnosis of the cyst of the floor of the mouth, to assess if
thyroid gland is involved [30, 31].
On US, a dermoid cyst usually appears as a unilocular cystic mass, which can be
heterogenous depending on the presence or absence of dermal appendages in
the cyst.
omputed Tomography (CT) Scan

C
Computed tomography (CT) scan of the neck would typically require contrast
enhancement. On CT scans, dermoid cysts appear as well-defined, unilocular, fluid-
filled hypodense lesions [9] (Fig. 5.3). Dermal appendages nay show up as multiple
stippled calcifications [32].
agnetic Resonance Imaging (MRI)

M
Magnetic resonance imaging (MRI) demonstrates a sharply circumscribed cystic
mass in the floor of the mouth (Fig. 5.4). A dermoid cyst would appear iso-intense
or hypo-intense to muscle on T1-weighted MRI scans, and hyper-intense or heter-
ogenous on T2-weighted images [23, 33, 34].
Fig. 5.3 Axial non-

contrast CT image showing
a dermoid cyst as a midline
neck mass (arrow) located
anterior to the thyroid
cartilage and superficial to
the strap muscles. The
lesion demonstrates the
same attenuation as
adjacent subcutaneous fat
Fig. 5.4 Axial

T1-weighted magnetic
resonance imaging (MRI)
showing sharply
circumscribed, central,
cystic mass (arrow)
Cytology/Histology
Fine needle aspiration (FNA) has been described by some authors as an adjunct in
diagnosing dermoid cysts of the floor of mouth. Contents of the dermoid cysts are
often keratinous, caseous, sebaceous, or purulent with hair, nails, cholesterol and
even cartilage. Therefore, FNA from these cysts may yield a cheesy, keratinous-like
substance, which may suggest dermoid cysts and aid the clinician to differentiate
from a salivary pathology or a vascular lesion [10, 35]. However, in some cases, the
high density of the cystic content prevents any meaningful aspiration and hence
limits the usefulness of this technique [36].
Histopathological examination of the lesion reveals fragments of fibrous connec-
tive tissue with a central cavity lined by keratinizing stratified squamous epithelium.
In some areas, there is prominent stratum granulosum with ortho-keratinization.
Foci of sebaceous glands and hair follicles are usually present within the cyst wall
(Fig. 5.5). The microscopic features are those of a dermoid cyst and confirm diag-
nosis. In some cases, a foreign body giant cell reaction may result due to rupture of
the cyst causing spillage of cystic contents.
Fig. 5.5 Dermoid cyst is

lined by keratinizing
stratified squamous
epithelium with sebaceous
glands within the cyst
(arrow) H&E stain (×4
magnification)
In general, the differential diagnosis of a dermoid cyst can be largely grouped into
three categories: infections/inflammations, neoplasms, and cystic lesions [17, 37].
Histologically, the contents of a dermoid cyst often contain keratin, sebaceous
glands, hairs, nails, fat globules and even cartilages may be present [29]. These
characteristic features settle the diagnosis of a dermoid cyst.
Infections/Inflammations
Infections may include odontogenic, salivary gland etiologies, and granulomatous
infections such as mycobacterial disease (tuberculosis), actinomycosis and histo-
plasmosis. In an infection, there is normally pain or tenderness, erythema of the
overlying mucosa, cervical lymphadenopathy, an obvious intraoral source of infec-
tion, fever and/or malaise. Leukocytosis is usually present, and CT scan usually
reveals a multilocular collection with surrounding inflammatory changes. In a der-
moid cyst without superimposed infection, these cardinal signs of infection are not
present. If the lesion is “nodal” in nature, then the diseases to be considered, espe-
cially in teenagers or young adults, are cat scratch disease, tuberculosis, infectious
mononucleosis (IMN), sarcoidosis (noninfectious granulomatous lesion), and
actinomycosis.
Neoplasms
Neoplastic lesions may include benign and malignant salivary gland tumors,
lipoma, cystic hygroma, cystic lymphangioma, neurofibroma, lymphoma and
metastatic lesions. Benign neoplasms usually have a smooth and well-defined
surface while malignant neoplasms often have an ulcerated, irregular, and ragged
surface. Moreover, benign neoplasms tend to displace adjacent structures while
malignant tumors tend to infiltrate underlying structures causing symptoms like
restricted tongue mobility, speech impediment, and dysphagia due to invasion
into the tongue musculature. Metastatic cervical lymphadenopathy may be pres-
ent. On CT scan, a neoplastic lesion appears as a dense solid mass that may or
may not show invasion.
–– Mixed salivary gland tumor (minor salivary glands): It usually presents as a

submucous, rounded, firm, mobile lobulated mass that increases in size
with eating.
–– Cystic hygroma and cystic lymphangiomas: These are neoplasms that involve the
lymphatic vessels. They are frequently seen in children, most commonly at the
posterior cervical triangle [38].
–– Lipoma: It can present in the oral cavity although rarely seen; the incidence
of oral lipomas is nearly 1.0–4.4% of all benign oral lesions [39, 40]. It pres-
ents as a well-defined, slow growing, painless mass, with a soft-firm consis-
tency [41].
–– Lymphoma: About 28% of non-Hodgkin lymphomas (NHLs) initially present in
the head and neck region and 9.5% of such cases present in the oral cavity [42].
Although they are usually associated with cervical lymphadenopathy, oral pre-
sentations are very rare.
Cystic Lesions
Cysts to be differentiated from a dermoid cyst include thyroglossal cyst, ranulas,
and bronchogenic cysts [9, 17]. Cystic lesions tend to displace rather than invade
adjacent structures. On CT scan, a cystic lesion usually appears as a well-
circumscribed hypodense unilocular or multilocular collection with normal sur-
rounding structures.
–– Thyroglossal cysts: These are painless, non-tender, slow-growing, midline cystic

lesions. They are usually soft and fluctuant. Characteristically, a thyroglossal
cyst moves upward with protrusion of the tongue or swallowing since the cyst
arises from a tract between the foramen caecum of the tongue and the thy-
roid gland.
–– Ranulas: These are usually unilateral, to one side of the frenulum, containing
thick mucus. They are blue to translucent, do not blanch on compression and
may cross the mylohyoid muscle (plunging ranula) presenting as a neck mass.
–– Detached branchogenic cysts: These are very rare and are usually found in the
mediastinum [43].
Differences between dermoid and epidermoid cysts and plunging ranula are
Table 5.2 Differences between epidermoid cyst, dermoid cyst, and plunging ranula
Criteria Epidermoid cyst Dermoid cyst Plunging ranula
Incidence in Less common in More common in the Very common, especially in
the head and H&N region head and neck region younger patients
neck
Location Midline and Midline Non-midline
non-midline
Type of cyst Inclusion cysts lined Inclusion cysts lined by Pseudocysts of the floor of
by ectoderm ectoderm the mouth, visible in the
submental region, and
parapharyngeal space
(plunging ranula)
Thickness of Thin lining due to Thick lining Thick lining
the lesion lack of dermal
wall appendages
Presence of Absent Present Absent
skin
appendages
Contends Keratinaceous, Keratinaceous, cheesy Collected mucin from a
cheesy material due material due to ruptured salivary gland/duct
to squamous squamous epithelium,
epithelium often with cutaneous
elements
Treatment Surgical excision Surgical excision Excision in continuity with
the sublingual and
sometimes the
submandibular gland of
origin
Treatment
The only effective treatment option for a dermoid cyst is complete surgical exci-
sion (enucleation) [30, 31, 44, 45]. Various surgical approaches can be used
depending on the location of the lesion in relation to the geniohyoid and mylohy-
oid muscles [46]. Lesions of the floor of mouth located superficial to these mus-
cles are preferably removed via a transoral approach because it gives a good view
of the cyst, an easy access as well as satisfactory esthetic results (hidden scar)
[47]. Large dermoid cysts plunging in the sublingual space have been reported to
be enucleated successfully via the intraoral approach. Jain et al. (2012) [10]
reported the excision of a large (9 × 9 cm) sublingual plunging dermoid cyst via
the intraoral route. More recently, Aydin et al. (2016) also reported a case of a
giant plunging dermoid cyst (measuring 12 × 5 × 4 cm) that was removed via the
intraoral approach [25].
The extraoral (cervical) approach is usually used for very large sublingual der-
moid cysts plunging in the submental and/or submandibular spaces, and in cases of
infection that could compromise the patient’s airways [4, 36]. A dermoid cyst is
often located between the geniohyoid and mylohyoid muscles, when it bulges out in
the submental or submandibular region. In such cases, careful dissection is needed
during surgery to avoid injury of the hypoglossal nerve. In exceptionally huge cysts,
a combined intraoral and extraoral approach may be necessary to provide direct
visualization of important adjacent structures [23, 48].
Prognosis
Prognosis of sublingual dermoid cysts is generally good. With complete excision,

recurrence is very rare because the fibrous capsule around the cyst facilitates its
enucleation [23, 49]. Sometimes, a recurrence may not be noticed until the child is
older or becomes an adult [20]. In one study of 14 patients with sublingual dermoid
cysts, recurrence was encountered in two (14.3%) probably due to incomplete exci-
sion as their first surgeries were performed under local anesthesia. A 5% rate of
malignant transformation of the oral dermoid cysts into the teratoid type has been
reported in literature [44, 45].
5.4 Plunging Ranula (Dumbbell-Shaped)
Definition
A ranula is a large mucous retention (extravasation) cyst in the floor of the mouth
(The Latin word ranula means “little frog”) [50]. Plunging ranula (cervical ranula)
is a non-epithelial-lined salivary gland cyst that forms following escape (extravasa-
tion) of mucus from the sublingual gland and its subsequent herniation via the
mylohyoid muscle into submandibular space [51, 52]. However, a ranula may be
central in the floor of the mouth taking a dumbbell shape (hourglass ranula) and
hence bulge in the submental region [51, 52].
Classification
A ranula is a type of mucocele and is therefore classified as a disorder of sali-

vary glands. Ranulae are anatomically grouped into three different types,
namely (1) superficial ranula (“simple” or “oral” ranula), which is confined to
the floor of the mouth lying above the mylohyoid muscle, (2) plunging ranula
(also called cervical ranula, diving ranula, deep ranula, and oral ranula with
cervical extension) [53], which is an unusual variant found in the neck beneath
the mylohyoid muscle, and (3) mixed type, which has both an oral and a cervi-
cal component [54, 55].
The etiology of plunging ranula can be described by either of two processes. The
first is by incomplete blockage of the duct of a sublingual gland, which leads to the
development of a true retention cyst lined by epithelium. About 10% of all ranulas
develop in this manner [56]. Secondly, the duct or deeper areas of the body of the
sublingual gland may become damaged by direct trauma thus initiating mucus to
escape into the surrounding area with subsequent formation of a non-epithelial-
lined cyst [50, 57, 58].
Most plunging ranulae usually have also oral components, and four mechanisms
have been described by which they may arise.
1. Part of the sublingual gland may pass through the mylohyoid muscle, or an aber-
rant sublingual gland may be present below this muscle; this mechanism
describes cases without an oral part.
2. The lateral part of the anterior two-thirds of the mylohyoid muscle may have a
deficiency through which mucus from the sublingual gland may slip, most com-
monly to the submandibular area [53].
3. Escape of mucus saliva from the sublingual gland, dissecting its way through the
mylohyoid muscle [54] that separates the sublingual space from the subman-
dibular space, and retention of this mucus and its extension into neighboring
tissues [58].
4. The observation that patients with plunging ranula in the series reported in 2017
by Olojede et al. [59] were young children, and the existence of the mass since
birth in one of the cases could suggest that plunging ranula is congenital in origin
as has previously been proposed by Chin et al. (2016) [60] and Morton and col-
leagues (2010) [61].
Epidemiology
The prevalence of ranula is approximately 0.2 cases per 1000 individuals, account-
ing for approximately 6% of all intraoral cysts of the salivary glands [50]. Age of the
patients ranges from 3 to 61 years, with children and young adults in the second and
third decades of life have been affected more than others [62].
Plunging ranula has been noted to be generally more prevalent in people of Asian
origin, especially the Chinese, natives of New Zealand, and Eskimos. This racial
predilection could be attributed to a genetic alteration, perhaps predisposing people
of this race to either develop areas of deficiencies within the mylohyoid muscle, or
an altered variant of the sublingual gland with easy extravasation of mucus follow-
ing minor trauma [60, 61].
Clinical Picture
A ranula is usually seen in children, teenagers, and young adults (Fig. 5.6), affecting
both sexes equally. The patient presents with a painless swelling in the floor of
mouth between the symphysis menti and tongue, just to one side of the frenulum
(midline), which helps to distinguish it from a midline dermoid cyst [54].
The swelling is characteristically translucent and has a bluish tinge. It is spheri-
cal in shape, but only the top half of the cyst is visible and varies from 1 to 5 cm in
size. If the ranula reaches a large size (up to 10 cm), it results in elevation of the
tongue and possibly interferes with swallowing causing dysphagia [56]. The edge of
the swelling is difficult to feel because it is deep, related to the arch of the mandible.
The surface is smooth, covered by tortuous veins and the mucous membrane is
mobile over the swelling, which is soft, usually fluctuant and transilluminates, but
cannot be compressed. The fluid within a ranula has the viscous, jellylike consis-
tency of egg white.
The plunging (cervical) ranula clinically presents as an asymptomatic, progres-
sively expanding swelling in the lateral side of the neck; it may or may not have an
intraoral component [63]. It is not tender unless it becomes secondarily infected,
and is not fixed to the overlying mucosa, tongue, or jaw. Cervical lymph nodes
(LNs) should not be enlarged in the absence of infection, and local tissues should be
normal [54]. Other than the submandibular triangle, plunging ranulae have been
reported to spread into the submental area below the chin (Fig. 5.7), the contralat-
eral side of neck, the nasopharyngeal region, including the skull base, retropharynx,
and sometimes to the upper mediastinum [50, 53].
Complications of ranula generally include infection, repeated trauma, bursting
and reformation, and dysphagia (if large in size).
Fig. 5.6 Ranula in a

young adult male patient.
Swelling in the floor of the
mouth to the right side of
the tongue. Note the bluish
tinge of the cyst
Fig. 5.7 Plunging ranula.

Cystic swelling bulging
into the anterior triangle of
the lateral side of the neck
and spreading into the
submental triangle
Investigations/Workup
Imaging Studies
Simple ranula is confined to the sublingual space above the mylohyoid muscle, but
plunging ranula dives into the neck with a collapsed sublingual portion called the
“tail.” Imaging studies to investigate plunging ranula include ultrasound (US), com-
puted tomography (CT) scan, and magnetic resonance imaging (MRI) [64].
High-resolution US has been demonstrated to be quite successful in evaluating
plunging ranulae [59], and the status of the mylohyoid muscle [53, 56]. It is a non-
invasive test with no known biological cost [65] and has been recommended as the
preferred test [63]. Uncomplicated ranulas appear as thin-walled cystic lesions and
can be imaged either from the skin or transorally with a small probe. If infected, the
walls are thicker and the fluid content is more echogenic. This technique will also
differentiate plunging ranulae that have plunged behind the posterior border of
mylohyoid into the submental space and the less common ranula that has herniated
through a mylohyoid muscle defect into the submental space.
Computed Tomography (CT) Scan

The classical CT scan finding of plunging ranula is a lesion with a small “tail” that
extends into the sublingual space [65]. In the absence of this sign, the diagnosis of
a plunging ranula should be made if an identical cyst is seen in the neck with con-
nection to the sublingual space [53]. Uncomplicated ranula appears as a thin-walled
cystic lesion with central fluid attenuation (10–20 HU). If a superimposed infection
is present at the time of imaging, a plunging ranula will be indistinguishable from
an abscess, with thicker walls and surrounding fat stranding [66].
Fig. 5.8 Histology of a

plunging ranula showing
distended acini and
ruptured duct with spilled
mucin causing granulation
tissue formation, which
contains foamy histiocytes
(H&E stain ×40)
Magnetic Resonance Imaging (MRI)

Magnetic resonance imaging (MRI) of plunging ranula shows a T1-low signal and
T2-high signal. With Gadolinium (Gd) contrast (T1 C+), the wall of the lesion may
demonstrate some enhancement that is best seen with fat saturation [67].
Histopathology
The histological appearance of a plunging ranula is typically that of a pseudocyst,
i.e., without epithelial lining; it consists of a fibrovascular stroma, which contains
chronic inflammatory cells including macrophages filled with mucin [56].
Histiocytes or foamy macrophages predominate in the pseudocyst wall and mucin
is also often observed [54] (Fig. 5.8). Occasionally, partial epithelial linings are seen.
High amylase and protein are seen on biochemical analysis of the cystic fluid of
a ranula [50].
The differential diagnosis of plunging ranula depends on its location. A plung-

ing ranula presenting as a submental swelling should mainly be differentiated
from dermoid/epidermoid cyst, cystic hygroma (usually in infants), cervical
abscess (usually associated with tooth caries), thyroglossal cyst (mobile with
tongue protrusion), second branchial cleft cyst (usually lateral, at the anterior
border of the SCM muscle), lymph node enlargement (cystic/necrotic), laryngo-
cele, thymic cyst, cysts of endocrine glands of the neck, benign salivary gland
tumors, and some benign mesenchymal tumors such as lipoma and neurofi-
broma [51, 53, 56, 68, 69].
Treatment
Methods that have been used for the treatment of plunging ranulae include surgical
excision, use of cryosurgery, marsupialization, excision of the oral portion and asso-
ciated salivary gland. Other reported procedures include intraoral excision of the
sublingual gland with drainage of lesion, and transcervical excision of the swelling
combined with excision of the sublingual gland [50]. When the sublingual gland
together with the associated lesion is excised, a low recurrence rate is recorded
[70, 71].
Marsupialization
Marsupialization is the oldest and most widely used procedure for the treatment
of oral ranula; this involves de-roofing of the cyst and suturing the edges to sur-
rounding tissues in the floor of the mouth, with the aim of allowing the sublin-
gual gland to re-establish connection with the oral cavity. A high recurrence rate
reaching up to 61–89% was reported within 6 weeks to 12 months of surgery.
Early closure of the surgery site due to compression of the tongue on the cyst
has been known to increase the recurrence rate. Marsupialization and filling
(packing) the cavity with gauze for 7–10 days significantly reduced the recur-
rence rate [59].
Micro-marsupialization involves the placement of a silk suture (Seton) for a
minimum of 7 days during which an epithelial tract forms to allow for mucus drain-
age between the surface and the underlying salivary glandular tissue. This proce-
dure is simple; still however, treatment failure or recurrence is the primary
complication [53].
ublingual Gland Excision and Cyst Drainage

S
In the management of plunging ranula, intraoral excision of the sublingual gland
and drainage of the associated cervical content is enough to achieve cure and is
currently considered as the treatment of choice [58]. With the transcervical
approach, total excision of the sublingual gland is challenging because this
method requires division of the mylohyoid muscle [53]. However, this method is
recommended for recurrent cases and when the plunging ranula is large in size
[72]. Cases restricted to the neck are also best treated by the transcervical
approach [53].
arbon Dioxide Laser

C
Carbon dioxide laser has also been used as a treatment option for plunging ranula;
this has shown by Mintz et al. (1994) to provide good success with a significant
reduction of the recurrence rate [73].
Radiotherapy
Radiotherapy is considered a worthwhile alternative to surgery in the very few
patients who cannot tolerate the stress of the operation. Low doses (20–25 Gy)
have been known to be effective for the treatment of plunging ranula. The
attendant complications of radiotherapy especially xerostomia can be circum-

vented by using low doses and protecting the contralateral parotid gland with a
shield. The danger of malignancies developing as a result of treatment with radia-
tion is very low [57].
Sclerosing Therapy
Although considered experimental, sclerosing agents have been employed in the
treatment of plunging ranula [74, 75]. Woo et al. (2003) reported that Bleomycin
and OK-432 has also been used with good effect have been successfully used to
manage plunging ranulae [75]. Rho et al. (2006) reported that OK-432 has been
shown to collapse and cause adhesion of the pseudocyst wall of a plunging ranula
[74]. In a study of 32 cases of plunging ranula, 31 (97%) achieved a marked decrease
in size of lesion with injection of OK-432. While about 50% of all cases experi-
enced local pain or fever, this however, resolved after some days. Rho and col-
leagues (2006) thus advocate that sclerotherapy is a safe and potentially curative
procedure that may be used as a primary treatment before considering surgery for
plunging ranula [74].
Complications/Prognosis
Complications common to intraoral ranula are also associated with plunging ranula
with the most common being recurrence, lingual nerve injury, and injury to the duct
of the submandibular gland. Less common complications are hematoma formation,
infection, and dehiscence of the wound. Complications such as marginal mandibu-
lar nerve (MMN) paralysis tend also to occur because of the proximity of this nerve
to the cyst [76].
Parekh et al. (1987) reviewed 139 surgeries for plunging ranulae in 89 patients
and recorded a recurrence rate of over 50% for cases where the sublingual gland
was not excised. On the other hand, a recurrence rate as low as 3.8% or less was
recorded when the sublingual gland was excised, alone or in association with other
treatments [51]. In addition, in the 15 patients treated by Davison et al. (1998) with
sublingual gland excision [55], only two cases (13%) recurred after a 2-year follow-
up period. This further substantiates the suggestion that the sublingual gland be
removed at all times.
5.5 Abscess in Relation to Odontogenic Infections
Etiology
Submental abscess usually develops from an odontogenic infection, especially of

the second and third mandibular molars. Contributing factors may include poor den-
tal hygiene, tooth extractions, and trauma (e.g., fractures of the mandible and lac-
erations of the floor of the mouth).
Pathophysiology
When odontogenic infections from the lower central and lateral incisors progress to
the labial aspect of the alveolar processes of the mandible and break through the
bone under the attachment of the mentalis muscle, they usually appear as an abscess
or fistula on the skin in the chin area. Plain X-ray appearance is diagnostic, showing
a central area of destruction around the root of the tooth with bone rarefaction sur-
rounded by sclerosis. Occasionally, odontogenic infections can spread out into the
submental space and form an abscess [77]. The swelling occurs around the chin and
in the submental triangle.
Incidence
The prospective study conducted by Flynn et al. in 2006 included 37 patients with a
mean age of 34.9 years. It showed that dental caries was the most frequent dental
disease (65%) and the lower third molar was the most frequently involved tooth
(68%). Trismus and dysphagia were present on admission in over 70% of cases. The
masticator, peri-mandibular (submandibular, submental, and/or sublingual), and
peripharyngeal (lateral pharyngeal, retropharyngeal, and/or pre-tracheal) spaces
were infected in 78%, 60%, and 43% of cases, respectively. Abscess was found in
28 (75.6%) of patients [78].
Pokharel et al. (2021) conducted a prospective clinical study at the Department
of Otorhinolaryngology, Kathmandu University Dhulikhel Hospital between March
2018 and June 2020. They reported that out of 75 patients with deep neck infections
enrolled in the study, submandibular abscess was most frequently observed (41.3%),
followed by submental abscess (25.3%) [79]. In the study by Ural et al. (2011), out
of 24 patients with neck masses confined to the submental space, only 3 (12.5%)
had an abscess [1].
Diagnosis
In general, diagnosis is made by a complete medical history and physical examina-

tion. The abscess is painful and tender, and the overlying skin is red and hot. Culture
from the pus is recommended, primarily to identify Methicillin-resistant
Staphylococcus aureus (MRSA). In addition, diagnostic procedures for a neck
abscess may include (1) throat culture; taking a swab of the back of the throat to
determine the type of organism causing the infection, (2) blood tests including com-
plete blood count, erythrocyte sedimentation rate, C-reactive protein to measure the
body’s response to infection, (3) US to determine consistency of the mass (cystic or
solid), and (4) CT scan; it shows detailed images of the mass and its relations to
surrounding structures.
Treatment
Specific treatment is usually based on extent of the condition, and the patient’s age,
overall health, and medical history. In general, the treatment of a submental abscess
is incision and drainage under sterile conditions, preferably under general anesthe-
sia, plus appropriate antibiotics. The risk of complications from this cervical inci-
sion is very low because structures within the submental triangle are sparse and
include no arteries.
Some small abscesses resolve without draining. Warm compresses help acceler-
ate the process. Incision and drainage are indicated when significant pain, tender-
ness, and swelling are present; it is unnecessary to wait for fluctuance.
5.6 Submental Ectopic Thyroid Tissue
Definition
Ectopic thyroid tissue is defined as “thyroid tissue not located in its normal anatomi-
cal position, anterolaterally to the second and fourth tracheal cartilages” [80, 81].
When thyroid tissue is present in an ectopic location along with an ectopic thyroid,
it is referred to as “accessory thyroid” [81].
Overview
Ectopic thyroid affects roughly 1/100,000 people, with the majority of patients
having hypo-functional thyroid tissue and an absent orthotopic thyroid gland.
If not recognized early, ectopic thyroid may cause diagnostic dilemmas and
result in unnecessary surgical intervention. Through the use of basic imaging
(US, CT scan, MRI, scintigraphy) and histological (FNA) studies, these lesions
can be properly identified while also ruling out more common clinical entities.
Conservative management remains a legitimate option for many patients, with
surgical intervention reserved for those with severe symptoms or malig-
nancy [82].
Etiology
Normally, migration of the thyroid gland is from the foramen cecum to the pre-
tracheal position [83]. Although the exact cause of ectopic thyroid is not well
defined, it could be due to the abnormal descent of the primitive thyroid tissue in the
embryonic life [84]. It has been suggested that gene mutations play a role in the
development of ectopic thyroid [85]. “Thyroid transcription factor 2” (TTF-2)
mutation is associated with thyroid agenesis and other defects. “PAX8 gene” muta-
tion has been found to be associated with various forms of thyroid dysgenesis,
whereas TTF-1 gene mutation has been found to be associated with thyroid agenesis
or dysgenesis. These gene mutations also cause ectopic migration [85].
Location
Ectopic thyroid gland can be seen in any localization from the base of the tongue to
the mediastinum in the midline on the neck [86, 87]. Ectopic thyroid tissue is mostly
detected in the lingual area. Other sites include the lungs, adrenal gland, pancreas,
gall bladder, ovary, and heart [86–88].
Classification
Based on location, ectopic thyroid has been classified as medial ectopic, lateral
ectopic, and mixed ectopic. Medial ectopic thyroid constitutes 90% of all the ecto-
pic thyroid glands and can be lingual, suprahyoid, infrahyoid, and endothoracic.
Lateral ectopic are para-jugular, para-carotid and submandibular. Rarely, it can be
mixed ectopic where thyroid tissue can be found in multiple sites in the neck includ-
ing the pre-thyroid muscles, and para-jugular area, without involvement of the
lymph nodes [89].
Pathology
In 70% of the ectopic thyroid tissues, only thyroid tissue is present [80]. All diseases
that involve thyroid tissue in its normal localization also involve ectopic thyroid tis-
sue with similar histopathological features. Neoplastic changes have been noticed in
2–3% of cases of ectopic thyroid and most of them (80%) are papillary carcinoma
of thyroid (PTC) [90].
Clinical Picture
Ectopic thyroid gland is more prevalent in females than in males and is usu-
ally asymptomatic [91]. Asymptomatic ectopic thyroid tissue may become
symptomatic particularly in the adolescence and pregnancy period due to an
increase in thyroid-s timulating hormone level and to thyroid tissue hyper-
plasia [92]. The majority of patients with submental ectopic thyroid present
with features of hypothyroidism; hyperthyroidism is rarely seen [93].
In general, patients can present with a painless swelling, dysphagia, dyspnea,
and dysphonia depending upon the site and compression over the adjacent
structures [94]. Less than 1% of ectopic thyroids have malignant transformation, of

which papillary carcinoma is the most common (approximately, 85%) malignancy
[95]. It has been reported that possibility of malignant degeneration in ectopic thy-
roid tissue is not higher than in normal tissues [96].
Diagnosis
A detailed clinical history, biochemical studies, imaging investigation, and FNAC

are the mainstay of diagnosis of the ectopic thyroid.
The role of imaging in the primary differential diagnosis of ectopic thyroid tis-
sues is to detect the normal thyroid tissue in its lodge and to decide removal or
transplantation of the whole ectopic tissue. Contrast-enhanced CT/MRI is very
much useful for diagnosing the structural integrity of the thyroid gland and ruling
out the other benign diseases [97]. In CT, the contrast uptake of the ectopic tissue is
observed to be homogenous. In MRI, ectopic tissue is observed to be iso- or hyper-
intense compared to muscles.
Thyroid scan using Technetium-99m scintigraphy (Fig. 5.9) is always confirma-
tory of the final diagnosis of the disease suggesting the location of the ectopic thy-
roid with its functional integrity and should be always correlated with the cytology
report. Although FNAC (Fig. 5.10) is always indicated in all suspected cases of
ectopic thyroid, it is diagnostic in less than 50% of cases [98].
Fig. 5.9 Thyroid scan

demonstrating the presence
of functional thyroid tissue
in the submental area with
the absence of iodine
uptake in the neck
Fig. 5.10 Ectopic thyroid

shown on FNAC as
clusters of benign follicular
epithelial cells showing
involutional changes in a
background of thin colloid
Differentials of submental ectopic thyroid include adenoma, sublingual sialadenitis,

minor salivary gland tumor, neurogenic tumor, paraganglioma, fibro-lipoma, thyro-
glossal duct cyst, cervical lymphadenitis, hyperplastic lymphoid tissue, lymphan-
gioma, dermoid cyst, squamous cell carcinoma, lymphoma, and vascular tumors
[86, 95, 99]. Metastatic thyroid carcinoma should also be taken into account in the
differential diagnosis, and it should be considered first among the diseases that will
be excluded in the differential diagnosis [86, 95].
The gold standard test for the diagnosis of the ectopic thyroid is the
Technetium-99m scintigraphy, confirming both the anatomical location and func-
tional aspect of the ectopic gland.
Treatment
In asymptomatic cases or those with very minimal symptoms, conservative man-

agement and close follow-up with routine ultrasound of neck are all that is required
[100]. Surgery is indicated in very specific cases in the view of the compressive
symptoms, hemorrhage, and neoplastic changes [98, 101].
Recently Reported Cases
Perdoni and Eustaquio reported, in 2017, a case of a lady with an impressive sublin-
gual ectopic thyroid gland that presented in the submental triangle and who was
successfully managed with conservative strategies [82].
Pradhan et al. (2019) [100] reported a 16-year-old young lady who presented
with a painless submental swelling of 3 years duration. It was smooth, oval in shape
and approximately, 4 × 3 cm in size. Ultrasonography revealed a hypoechoic lesion
in the submental region with multiple septations suggestive of a cyst without the
identification of the normal thyroid tissue. Contrast-enhanced CT scan revealed a
well-defined, homogeneous, non-enhancing mass in the submental region with the
absence of the normal thyroid tissue. Thyroid scan showed the presence of func-
tional thyroid tissue in the submental area with absence of iodine uptake in the
region of normal thyroid gland. Ultrasound-guided FNAC revealed clusters of
benign follicular epithelial cells showing involutional changes along with numerous
foamy and pigment-laden macrophages in a background of thin colloid suggestive
of ectopic thyroid with colloid cyst and no nuclear features of malignancy. Thyroid
profile revealed increased TSH suggestive of hypothyroidism. Based on the clinical,
biochemical, and imaging modality patient was diagnosed as an ectopic thyroid cyst
with hypothyroidism. She was treated conservatively with thyroxin (75 μg, once
daily) and was followed-up regularly without any clinical/radiological change of the
swelling.
In 2021, Lim et al. [102] reported a 35-year-old lady with known congenital
hypothyroidism due to thyroid agenesis who was incidentally found to have dual
thyroid ectopia as an adult. CT scan showed two well-circumscribed globular-
shaped enhancing lesions in the base of tongue and submental triangle. On exami-
nation, there was a midline submental swelling of about 2 × 2 cm in size; it had a
smooth contour and firm consistency. Serum thyroid-stimulating hormone (TSH)
was 9.65 mIU/L (normal 0.40–3.50), suggestive of subclinical hypothyroidism.
FNA demonstrated Bethesda II thyroid tissue. The radiological appearance of the
lingual thyroid was reassuring for a benign lesion. They continued monitoring the
lingual thyroid based on symptomology, ultrasound surveillance, and thyroid func-
tion tests. The submental ectopic thyroid tissue was completely excised using a
Sistrunk procedure. Histopathology of the submental lump showed thyroid tissue
with features of multinodular goiter.
More recently, in 2022, Mak [103] reported a 59-year-old lady who presented
with a painless, slowly enlarging submental swelling of a 10-year duration. The
swelling was non-tender, smooth, and mobile, measuring about 3 cm in size. She
had no history of dyspnea, dysphagia, fever, or local trauma. Laboratory studies
showed mild elevation of TSH reaching 6.7 mU/L (normal: 0.5–5.5 mU/L). Neck
US showed multinodular goiter and a well-defined, lobulated hyperechoic nodule
measuring 2.9 cm × 1.6 cm × 2.7 cm in the submental region. Intra-nodular vascu-
larization was detected with color-Doppler sonography. FNAC showed a macro-
follicular lesion composed of moderate follicular cells arranged in honeycomb flat
sheets, abundant macrophages, and some colloid materials. Cell block section
revealed variable-sized follicular glands filled with colloid. Given that the patient
was asymptomatic and only TSH was mildly elevated, the patient was only fol-
lowed-up regularly.
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Swellings of the Hyoid Bone Region
6
Contents
6.1 Hyoid Bone Region Swellings 89
6.2 Thyroglossal Cyst 89
6.3 Median Ectopic Thyroid Tissue 101
6.4 Sub-hyoid Bursitis 107
6.5 Hyoid Bone Tumors 110
References 134
6.1 Hyoid Bone Region Swellings
Midline cervical swellings that are commonly found in the hyoid bone region
include the following:
–– Thyroglossal cyst
–– Median ectopic thyroid tissue
–– Sub-hyoid bursitis
–– Tumors of the hyoid bone
6.2 Thyroglossal Cyst
Embryology and Pathogenesis
The thyroglossal duct is a transient epithelial-lined midline channel serving as the

path of descent of the thyroid primordium from the foramen cecum, located at the
junction of the anterior two-thirds and posterior third of the tongue, down to the

Switzerland AG 2024
90 6 Swellings of the Hyoid Bone Region
thyroid cartilage where definitive thyroid formation occurs [1]. The inferior portion
of the duct may develop into the pyramidal lobe, and the remainder involutes by the
10th week of gestation. The “descent” of the thyroid is intimately connected with
the development of the hyoid bone. Residual thyroglossal duct system left behind in
the migration may persist and subsequently present as a thyroglossal duct cyst in the
midline of the neck. Rarely, midline ectopic thyroid tissue masquerades as a thyro-
glossal duct cyst and may represent the patient’s only thyroid tissue [2–4].
Incidence
Thyroglossal duct cyst is the most common non-odontogenic cyst in the neck [5]
and the most common congenital anomaly (pediatric cyst) of the central portion of
the neck [6]. Remnants of thyroglossal duct are estimated to persist in approxi-
mately 7% of the population. Cystic remnants are the commonest congenital anom-
aly. The lesion is most commonly seen in a 2- to 4-year-old child when the baby fat
disappears. However, it may be seen in older children, teenagers, and young adults
(between 15 and 30 years). Although some researchers reported that the incidence
of a thyroglossal cyst is higher in females, others deny any gender predilection [2,
7]. Approximately, 90% of cases occur in the midline, and the remaining are lateral,
of which 95% are left and only 5% are right. Suprahyoid thyroglossal duct cysts are
usually midline, while infrahyoid thyroglossal duct cysts may be para-midline.
Thyroglossal cyst is three times more common than the branchial cysts [2, 8].
Sites
A thyroglossal cyst may present in the substance of the tongue (lingual thyroglossal
cyst), in the suprahyoid region (in the floor of the mouth or submental triangle), or
in the infrahyoid region, which is the commonest site, as the duct obliterates from
above downwards (Fig. 6.1). This latter type might present in front of the thyroid
Fig. 6.1 Sites of

thyroglossal cyst in the
midline of the neck
(suprahyoid, sub-hyoid,
pre-tracheal)
cartilage, cricoid cartilage, or even at the suprasternal notch. Occasionally, it pres-

ents as an intrathyroidal mass. The commonest site of all is the peri-hyoid bone cyst
[3, 7, 8].
Pathology
A thyroglossal cyst is lined by cubical or stratified squamous epithelium. It contains

mucoid fluid or cheesy yellowish material rich in cholesterol. Sometimes, the wall
may contain “ectopic thyroid tissue” [3].
Clinical Picture
The thyroglossal cyst is painless and slow growing, presenting for a long time. Pain,
tenderness, and an increase in size occur only with secondary infection, usually fol-
lowing upper respiratory tract infection. On physical examination, the cyst is usu-
ally about 0.5–5 cm in size, well-defined, smooth, rounded or spherical in shape,
occurring in the midline of the neck of children (Fig. 6.2) or young adults (Fig. 6.3),
where it may attain a larger size (Fig. 6.4). It moves vertically up with protrusion of
the tongue (characteristic sign) or swallowing. It is not attached to the skin, and
local lymph nodes (LNs) should not be enlarged, unless the cyst is secondarily
infected.
With the lower jaw held still with the mouth opened, the clinician holds the cyst
between the finger and thumb and feels it tugged upwards when the tongue pro-
trudes. This sign is due to the cyst being abnormally attached to the hyoid bone by
a fibrous tissue remnant and the hyoid bone being normally attached to the tongue
Fig. 6.2 A thyroglossal

cyst in a 12-year-old girl
presenting as a midline
neck swelling in the region
of the hyoid (arrow)
Fig. 6.3 A thyroglossal

cyst in a 32-year-old girl
presenting as a midline
neck swelling in the region
of the hyoid (arrow)
Fig. 6.4 Thyroglossal cyst

in a 23-year-old young
gentleman attaining a huge
size in the midline of
the neck
through the hyoglossus muscle (Fig. 6.5). Although diagnostic, its absence does not
exclude the diagnosis. This sign is absent from most of the cysts, which are below
the thyroid cartilage (rare). Such a fibrous tissue track allows the cyst to be moved
sideways, but not up and down. Some cysts may form on both sides of the hyoid
a b
Fig. 6.5 (a) Thyroglossal cyst with the tongue in place (white arrow). (b) With the tongue pro-
truded (black arrow). Note the upward movement of the cyst
bone, i.e., dumbbell-shaped lesion. It fluctuates easily; however, few are not, being
so tense. Many thyroglossal cysts are opaque due to desquamated epithelial cells or
debris of previous infection, few are illuminant, and many are too small to illumi-
nate [7–11].
Complications
Complications of thyroglossal cyst include infection, which is rather common,

as the lymphatic tissues in its wall communicate with the cervical LNs. If ecto-
pic thyroid tissue is present in the cyst, it may lead to goiter manifestations.
However, the most serious complication is the development of thyroglossal duct
carcinoma [2, 8].
Evaluation
Although benign midline neck swellings such as thyroglossal duct cysts are often
diagnosed clinically, the clinical presentation of infected cysts, thyroglossal duct
carcinoma, or other pathological lesions may be indistinguishable, necessitating
diagnostic imaging. In patients with low clinical suspicion of neoplasm, imaging
evaluation may begin with ultrasound (US).
In the presence of high clinical suspicion of tumor or atypical US features such
as solid component or abnormal vascularity, CT scan or MRI is recommended to
document an orthotopic thyroid gland and to assess the anatomical extent and com-
plications of the cyst, as well as pretreatment planning [12]. In selected cases,
diffusion-weighted or dynamic contrast-enhanced MRI can be performed for the
evaluation of vascular malformations, abscess, or suspicious cervical lymph
nodes [13].
If serum thyroid function test results are abnormal, thyroid scanning should be
performed to determine the amount of thyroid tissue in the neck. Some investigators
advocate routine ultrasonography (US) or nuclear scanning to avoid permanent
hypothyroidism [6].
Ultrasonography (US)/Doppler
Ultrasound of the neck will show a thyroglossal cyst as a well-circumscribed
anechoic to hypoechoic structure with posterior through transmission [13]; there
may be some internal debris (Fig. 6.6).
In active or recent infection of a thyroglossal cyst, US reveals a thick-walled
cyst with rim enhancement and inflammatory changes of the surrounding subcu-
taneous tissues (Fig. 6.7). Internal contents may vary, with higher complexity
reflecting proteinaceous debris, which may be seen in acute or remote infection.
In advanced cases, abscess formation can occur [14]. Fistula formation may
develop in severe infections with external cyst rupture and may cause recurrence
after resection [14].

C
A thyroglossal cyst appears on CT scan as a smooth, thin-walled hypo-attenuating
mass in close relation to the hyoid bone (Fig. 6.8) [15–17].
Fig. 6.6 Ultrasound image

with color Doppler
demonstrating a well-
circumscribed hypoechoic
cyst containing tiny
hyperechoic foci (debris)
Fig. 6.7 Ultrasound image

with color Doppler
demonstrating a thick-
walled hypoechoic cyst
containing low-level
echoes with peripheral
hyperemia in the para-
midline anterior neck
Fig. 6.8 Contrast-

enhanced CT scan of the
neck showing the close
relationship of a
thyroglossal duct cyst
(non-enhancing cystic
lesion in the midline neck)
(yellow arrow) with the
hyoid bone (white arrow)

M
On MRI, a thyroglossal cyst will be high signal on T2-weighted images (Fig. 6.9)
and low to intermediate signal on T1-weighted images, depending on the degree of
proteinaceous or hemorrhagic contents [16].
A thyroglossal cyst should be differentiated from other swellings in the midline of

the neck, namely dermoid cyst, sebaceous cyst, lipoma, enlarged LN, hypertrophied
thyroid pyramidal lobe, and choristoma (mass of normal tissues found in abnormal
locations). Imaging characteristics on ultrasound (US), computed tomography (CT)
scan, and magnetic resonance imaging (MRI) may at times be equivocal; differen-
tial considerations should also include branchial cleft cyst (mainly in case of
Fig. 6.9 Sagittal

T2-weighted MRI showing
the thyroglossal cyst as a
fluid signal lesion
extending posterior to the
hyoid bone (arrow)
Table 6.1 Distinguishing imaging features of cystic lesions in the midline of the neck
Cystic lesions Main differentiating imaging features
Thyroglossal duct cyst – Close association with the posterior aspect of the hyoid bone
– Midline if suprahyoid, may be para-midline if infrahyoid
Branchial (second) cleft cyst – Located along the anteromedial border of the
sternocleidomastoid muscle, lateral to the carotid space
– Beak sign may be present (curved rim of the lesion
extending between the internal and external carotid arteries)
Dermoid/epidermoid – Located in the subcutaneous tissues, superficial to the strap
muscles, typically near the suprasternal notch
– Presence of fat or calcification
Laryngocele – May be primarily air-filled or with air-fluid levels due to
airway communication
– Involvement of the laryngeal ventricle
Thymic cyst – Close association with the carotid sheath, sometimes
splaying the carotid artery and jugular vein
– Dumbbell or bilobed appearance can be seen with
extension into the anterior mediastinum
Necrotic metastases – Multiple, growing masses
– Irregular solid and cystic components
– Calcifications suggestive of papillary thyroid carcinoma
Lymphatic malformation – Trans-spatial lesion
– Fluid-fluid levels from recent hemorrhage
paramedian thyroglossal cyst), dermoid/epidermoid cyst, laryngocele, thymic cyst,

lymphatic malformation, and metastatic disease.
Close attention to the age at presentation, location of the lesion, relation to sur-
rounding structures, and internal architecture can direct the clinician to the correct
diagnosis.
The distinguishing imaging features of cystic lesions in the midline of the neck
are summarized in Table 6.1.
Treatment
Sistrunk Operation
Patients with TGDC have various problems such as cosmetic concerns, diffi-
culty in breathing, pain, swelling, neck discomfort, and dysphasia. Therefore,
surgery has been considered the treatment of choice in this condition [18–20].
The procedure of choice of a thyroglossal cyst is the Sistrunk operation, which
was introduced in 1920 by Sistrunk [21]. It is performed through a transverse
incision over the cyst and involves complete excision of the cyst, its tract, and
the central portion of the hyoid bone. If necessary, excision extends to the base
of the tongue [3, 4, 6, 10, 11].
Prior to excision, an imaging study is performed to identify functioning thyroid
gland in the lower neck. This ensures that the cyst does not contain the only func-
tioning thyroid tissue in the patient, if any. The recurrence rate could be decreased
significantly after Sistrunk procedure (1–5%) [18, 20, 22] as compared to simple
cyst excision (40–65%) [18–20, 23–26].
Gioacchini et al. (2015) reported that in their meta-analysis study that included
24 articles, comprising a total of 1371 subjects, the mean local wound infection rate
was 4% (range, 3–6%), this being the most frequent complication following treat-
ment [27].
Incomplete excision of the cyst leads to recurrence, and a recurrent lesion is
more liable to recur again. Factors predictive of recurrence included more than two
infections prior to surgery, age below 2 years, and inadequate initial operation.
Failure to remove the central part of the hyoid bone results in recurrence in three out
of four patients [3, 4, 10, 11]. In the meta-analysis by Gioacchini et al. (2015), the
mean rate of overall recurrence was 11% (range, 9–14%) [27].
ercutaneous Ethanol Ablation (PEA)

P
Although surgery is the treatment of choice for a thyroglossal cyst, it still has some
drawbacks such as the use of general anesthesia, scars, and surgical morbidity [11,
18, 20, 22, 25, 26]. Therefore, minimally invasive treatment modalities have been
introduced as they have the potential to benefit these patients without surgical risk
or morbidity. Ethanol ablation (EA) has been reported to be effective, easy, and safe
for the treatment of cystic thyroid lesions [28–32]. Fewer studies are reporting the
results in case of thyroglossal cysts, and successful treatment was achieved in 60%
of cases [33, 34].
Kim et al. (2011) [35] assessed the technical feasibility and evaluated the
efficacy and safety of ethanol ablation for thyroglossal duct cysts in 11 patients
(male/female = 3:8; mean age, 34.9 years; range, 23–44 years) who refused
surgery and fulfilled the following inclusion criteria: cosmetic concerns and/or
symptomatic problems such as pain, swelling, discomfort, or dysphasia; a single
clinically palpable midline mass in the anterior aspect of the neck that was diag-
nosed as a benign lesion; a cystic component of >90% of the total nodule vol-
ume; recurrent cysts after aspiration of the internal content in at least two
separated sessions; and follow-up for >3 months. US-guided aspiration of the
cystic fluid was followed by injection of absolute ethanol (99%). The injected
volume of ethanol was 50–80% of the volume of fluid aspirated. Therapeutic
success (volume reduction of >50%) was observed in eight patients with signifi-
cant (p = 0.005) improvement of symptoms and cosmetic grading scores [35].
Kim et al. (2008) previously reported that transient mild local pain related to
needle puncture and low-grade fever were observed, but there were no signifi-
cant treatment-related complications [36].
In 2021, Karatay and Javadov evaluated thyroglossal cyst volumes before and
after treatment with US, and the cosmetic scores in 28 patients who underwent
PEA. At the 12th month after PEA, there was a 95.1% reduction in mean cyst vol-
ume (p < 0.001). The mean cosmetic score was reduced from 2.7 ± 0.8 (pretreat-
ment) to 1.0 (posttreatment, at 12 months) (p < 0.001) [37].
More recently, in 2022, Park et al. evaluated the long-term efficacy and safety of
PEA for the treatment of thyroglossal cysts in 68 patients. Immediate success was
defined as a volume reduction ratio (VRR; ratio of the volume difference after EA
to the initial TGDC volume) >50% within 3 months. Long-term success was defined
as VRR >50% or resolution or improvement of cosmetic problems and symptoms
without recurrence at last follow-up. The immediate success rate of the first PEA
was 81% (55/68), with a mean VRR within 3 months of 73 ± 31%. One patient
(1.5%, 1/68) developed wound inflammation after the first PEA. Forty-two patients
were followed up for longer than 2 years. The long-term success rate was 83%
(35/42) [38].
Dual Thyroglossal Cysts
Double thyroglossal cysts are very rare. Several imaging techniques are used to
verify the diagnosis. Double thyroglossal cysts may present as cystic swellings
nearby or far away from each other. On literature search, there are nine cases
reported till 2020 of double thyroglossal cysts [39–47]. Sarmento et al. (2013)
described a patient with double thyroglossal cysts on the floor of the mouth in
geniohyoid muscles and sublingual region [44]. Yorgancılar (2011) mentioned a
double thyroglossal cyst in the hyoid region and base of the tongue [43]. Pueyo
and colleagues (2008) reported a double thyroglossal cyst with one part intrathy-
roidal and inferred that failure of involution of TDC remains responsible for cyst
development [42]. Yıldız et al. (2014) mentioned in a review that double TDCs
are rare and suggested that thyroid scintigraphy is essential in such cases to dif-
ferentiate it from aberrant thyroid tissues. They added that a classical Sistrunk
operation suffices as treatment for double cysts [40]. On the other hand, Valentino
et al. (2012) mentioned that ultrasonography (US) is a must in cases where sus-
picion of double thyroglossal cysts is suspected. However, it is not sensitive
enough to detect all [48].
Triple Thyroglossal Cysts
In 2020, Bhardwaj et al. reported an atypical case of triple thyroglossal cyst, at the
levels of hyoid, thyrohyoid membrane, and thyroid isthmus in a 48-year-old lady.
The condition was successfully treated by modified Sistrunk’s procedure, without
any complications or recurrence on follow-up for 6 months. They added that there
is no other case reported in English literature with a triple thyroglossal cyst. An
awareness that thyroglossal cyst can present as multiple cysts is important for clini-
cian in order to perform correct surgical management and to avoid the most feared
complication of recurrence [49].
Thyroglossal Duct Cyst Carcinoma
Incidence
Thyroglossal carcinoma occurs in approximately 1% of cases. It was first reported
by Brentano in 1911 [50]. An estimate of up to 60% of cases are found in children
less than 5 years of age. Nevertheless, up to one-third of cases may occur in patients
aged 20 years and older [51, 52]. In adults, the peak incidence is in the fourth decade
of life in females and in the sixth decade in males [53, 54]. There is no gender pre-
dominance; both sexes are equally affected.
Histopathology
Malignant thyroglossal tumors are most commonly papillary thyroid carcinoma
(PTC), which is seen in 75–80% of cases, followed (equally) by mixed papillary-
follicular and squamous cell carcinoma. Adenocarcinoma has also been reported.
Pure follicular and anaplastic carcinomas are extremely rare. Medullary cancer has
never been reported in the literature [53–55].
Pathogenesis
There are two theories as to how a thyroglossal duct cyst carcinoma develops. These
include metastasis to the thyroglossal remnant from the thyroid gland versus tumors
developing de novo within the remnant. The two theories seem to be likely, as there
are findings supporting both. A primary lesion in the thyroid gland is not detected in
all cases, which would favor tumor development within the remnant. However, the
presence of a primary lesion in the thyroid in one-third of the cases or more would
suggest a metastasis as the cause [56, 57].
Clinical Presentation
Thyroglossal carcinoma is the most serious complication of thyroglossal duct cyst.
The most common presentation is a rapidly growing and tender midline cervical
mass. The presence of dysphagia, dysphonia, weight loss, or rapid growth in size
could be manifestations of malignancy [58]. However, this neoplasia is characteris-
tically relatively nonaggressive and rarely involves the thyroid gland or spreads to
locoregional lymph nodes (LNs) [50].
Diagnosis
Diagnosis of thyroglossal carcinoma is difficult, but imaging and fine needle aspira-
tion (FNA) biopsies can help with the diagnosis [59]. However, FNA has been
reported to have a low diagnostic accuracy of 53%, and therefore, its role is still
debated [60]. Accuracy of diagnosis of FNA is improved by sampling the solid
component if present [60]. In case of PTC, it will demonstrate nuclear overlapping
and nuclear grooves with pseudo-nuclear inclusions.
Thyroglossal cyst carcinoma should be suspected whenever the cyst grows rap-
idly or the mass becomes firm in consistency [53, 54, 56], when the ultrasound (US)
demonstrates a complex anechoic pattern or shows a solid component within the
cyst [54], and in the presence of calcifications [60]. Glastonbury et al. (2000)
reported that calcifications are a more specific indicator of malignancy than solid
components, as the latter can also be seen in inflammatory processes [61]. A com-
puted tomography (CT) scan may show a cystic lesion with calcifications and a
solid component [62].
Treatment
Given the rarity of TGDC carcinoma, treatment algorithms are not clearly defined
[53]. Treatment can include the Sistrunk procedure, thyroidectomy, nodal dissec-
tion, and postoperative radioactive iodine (RAI) treatment [62].
Currently, there are four approaches regarding surgical management of thyro-
glossal carcinoma [63]: (1) Sistrunk procedure alone [51], (2) Sistrunk procedure
with thyroid lobectomy or pyramidal lobe resection [64], (3) Sistrunk procedure
with total or near-total thyroidectomy in all patients [52, 65], and (4) Sistrunk pro-
cedure with selective thyroidectomy for high-risk patients [66, 67]. Consideration
to adding thyroid resection in all patients is based on three aspects: (1) presence of
thyroid malignancy, (2) use of radioactive iodine as adjuvant therapy, and (3) role of
thyroglobulin as a follow-up marker [52].
Recurrence rate after Sistrunk operation is low. This may be followed by thy-
roxin suppression therapy and regular measurements of thyroglobulin, which
becomes undetectable if successful removal of the carcinoma was achieved, as long
as TSH is adequately suppressed by thyroxin [2, 8].
The role of including total thyroidectomy for the treatment of thyroglossal cyst
carcinoma is not as uniformly agreed upon [60, 68, 69]. It is estimated that thyroid
involvement is present in 33–45% of cases of thyroglossal carcinoma. It is widely
accepted to perform a total thyroidectomy in those patients with known synchro-
nous neoplasms in both the thyroid and the thyroglossal cyst as well as in those
patients with high clinical or radiological suspicion of synchronous tumors [11, 69].
Based on the study by Balalaa et al. (2011), total thyroidectomy is indicated
without considering the presence of thyroid gland involvement clinically or
radiologically based on the premise that this procedure could assist staging and
detect metastasis, and the risk of injury of the recurrent laryngeal nerve or
parathyroid gland is considerably low, especially in the hands of experienced
surgeons [51].
There is also no clear recommendation regarding when to implement radioactive

iodine (RAI) treatment. It is appropriate to consider RAI treatment in those patients
with large tumors and LN involvement or those with malignancy present in both the
thyroid and thyroglossal cyst. The risk of metastatic spread of thyroglossal carci-
noma is low, and therefore elective neck dissection is not generally recommended
but should be performed for clinically positive nodal disease [53].
Prognosis
Thyroglossal duct cyst carcinoma has been reported to have an excellent prognosis,
with a survival rate of 100% and 95.6% at 5 years and 10 years, respectively. High-
risk characteristics have been proposed by some authors and include (1) male gen-
der, (2) age 45 years and above, (3) tumor size more than 4 cm, (4) previous radiation
exposure especially in the neck area, (5) presence of nodal metastasis, (6) presence
of extracystic invasion (positive histological margins), and (7) presence of a cold
nodule in the thyroid gland on imaging [57, 70].
6.3 Median Ectopic Thyroid Tissue
Embryogenesis/Etiology
Ectopic thyroid is a rare clinical entity, resulting from abnormal embryonic devel-
opment and migration of the thyroid gland. Normally, at 7 weeks of gestation, the
thyroid gland assumes its normal anatomical position in the neck below the larynx
and hyoid bone, anterolateral to the second, third, and fourth tracheal cartilaginous
rings [71, 72]. Development of the thyroid gland begins at the pharyngeal floor, and
it begins to descend at 4 weeks of gestation as a diverticulum from an invagination
at the foramen cecum. It remains connected to the tongue via the thyroglossal duct,
which solidifies and is normally obliterated by the eighth week of gestation [71, 72].
Disturbances during embryogenesis such as partial descent or excessive migra-
tion can lead to an abnormal development of the gland resulting in anomalous loca-
tions of the thyroid tissue. Ectopic thyroid tissue is defined as “thyroid tissue not
located anterolaterally to the second and fourth tracheal cartilages” [14, 73]. When
thyroid tissue is present in an ectopic location along with a eutopic thyroid, it is
referred to as “accessory thyroid,” but the existence of ectopic thyroid glands at two
different locations is very rare [14]. True ectopic thyroid is when thyroid tissue is
absent in the normal location. While an absent normal thyroid can make diagnosis
rather easy, accessory thyroid tissue in addition to normal thyroid gland can make
diagnosis difficult.
Ectopic thyroid tissue in the midline of the neck may also occur as a result of
postsurgical seeding. It was reported that this tissue becomes hypertrophic under the
influence of increased thyroid-stimulating hormone (TSH) in thyroidectomized
patients [74, 75].
Location/Classification
Anatomically, ectopic thyroid can be divided into two types: (1) lingual type,
which constitutes almost 90% of cases and is found between the circumvallate
papillae and epiglottis, along the midline of the tongue base, and (2) sublingual
type, making up approximately 10% of all ectopic thyroids, found along the
course of the thyroglossal duct cyst at either supra- or infrahyoid locations, out-
side the tongue parenchyma, located between the geniohyoid and mylohyoid
muscles [14, 76, 77].
Lateral aberrant presentations are extremely rare [72]. Only 1–3% of all ecto-
pic thyroid tissues are located in the lateral neck, of which 70% are submandibu-
lar [71]. Ectopic thyroid tissue can also be seen rarely in distant locations such as
mediastinum or very rarely in subdiaphragmatic areas such as the porta hepatis
[78, 79].
Having two or more simultaneous sites of ectopic thyroid tissue is a rare phe-
nomenon, with a variety of management strategies [77, 80, 81]. Dual ectopic thy-
roid has been reported to occur in approximately 1 in 50,000–70,000 live births
[82]. In dual thyroid ectopia, the foci may respond differently to TSH stimulation,
as evidenced by their different sizes within the one subject [78]. In 2014, Rahalkar
et al. reported a rare case of triple thyroid ectopia, i.e., thyroid tissue at three loca-
tions along the tract of descent of the thyroglossal duct, demonstrated on CT
scan [83].
Although ectopic thyroid is a congenital condition due to abnormal migration of

thyroid gland in embryonic stage, it usually manifests later in life, especially during
increased physiological demand of thyroid hormones such as puberty, pregnancy,
and menopause [84]. The prevalence of this entity is 1/100,000–300,000 people and
1/4000–8000 patients with thyroid diseases. Interestingly, Oguz et al. (2015)
reported that in autopsy studies, up to 7–10% of population may have ectopic thy-
roid tissue along the thyroglossal duct [75].
Ectopic thyroid can manifest clinically in any age group, occurring more com-
monly in females with a male-to-female ratio of 1:4 [75]. Apart from the cervical
swelling, the patient may be asymptomatic or present with symptoms depending
on the size, location, and associated endocrine dysfunction of the ectopic glands.
These may include dysphagia, dyspnea, and choking sensation, which are mainly
related to the mass effect caused by the ectopic thyroid. Ectopic thyroids have
been shown to continue performing thyroid hormone biosynthesis, albeit in
reduced quantities [85]. Approximately, 70% of patients present with hypothy-
roidism, probably due to disrupted vascular supply secondary to abnormal migra-
tion of the thyroid [86].
The ectopic thyroid tissue is susceptible to the same disorders that may affect a
normal thyroid gland, including simple and toxic goiters, Hashimoto’s thyroiditis,
benign adenomas, and malignancies [87]. The incidence of carcinoma in ectopic
thyroid is reported to be approximately 1%. A rapid increase in size of an anterior
neck lump may be the only symptom of thyroid carcinoma at any site, and although
exceedingly rare, follicular and papillary carcinomas in ectopic thyroids have been
documented [88, 89]. In contrast to the malignancies found in the orthotopic thyroid
gland, follicular carcinoma is the most common subtype in ectopic thyroid, instead
of the more common papillary subtype [90]. In case of malignancy, resection of
other thyroid tissue should be considered to help with treatment, staging, and moni-
toring of metastases and disease recurrence [51].
Pathology
Macroscopic Appearance
The average size of a manifested lesion of ectopic thyroid tissue is 2–4 cm (range,
0.2–7.3 cm). It is often encapsulated and can be cystic. Cut surface resembles nor-
mal thyroid parenchyma (brownish red) [91].
icroscopic (Histological) Features

M
The microscopic features of ectopic thyroid tissue may show (1) the same histologi-
cal appearance as the orthotopic thyroid tissue composed of colloid-filled follicles,
(2) signs of hyperplasia or thyroiditis in relevant clinical situations, and (3) ectopic
thyroid tissue showing cytological or histological features of thyroid carcinoma
(should be considered as metastases until proven otherwise), although there are sev-
eral tumors arising de novo in ectopic thyroid tissue that have been reported in the
literature [92]. These are summarized in Table 6.2.
Since 70–90% of patients with ectopic thyroid tissue do not have a normal thy-
roid gland [84] and the ectopic thyroid is the only thyroid tissue present [103],
Table 6.2 Tumors arising de novo in ectopic thyroid tissue

References Year Tumor pathology
Deshmukh et al. [93] 2014 Follicular adenoma
Ruchti et al. [94] 1987 Follicular carcinoma
Kushwaha et al. [95] 2012 Classic variant of papillary thyroid carcinoma
Hari et al. [96] 2009 Follicular variant of papillary thyroid carcinoma
Mishriki et al. [97] 1983 Hurthle cell carcinoma
Yaday et al. [98] 2008 Medullary thyroid carcinoma
Seoane et al. [99] 2002 Poorly differentiated thyroid carcinoma
Camargos et al. [100] 2010 Anaplastic carcinoma
Ranaldi et al. [101] 2009 Teratoma
Demirag et al. [102] 2009 B-cell lymphoma
hypothyroidism is common, whereas hyperthyroidism is very rare [104]. Therefore,

it must be kept in mind that when surgical excision is considered, these patients are
at risk of developing permanent hypothyroidism postoperatively [105].
Workup
Multiple image modalities are available for the diagnosis of ectopic thyroid.
Ultrasound, CT scan, and MRI may show an ectopic thyroid as well as the presence
or absence of orthotopic thyroid. The algorithm proposed by Prado in 2012 advises
ultrasound (US) imaging early during the diagnostic workup for a suspected ectopic
thyroid (Fig. 6.10a). US scan should follow clinical palpation for the orthotopic
thyroid gland, but precede CT scan or MRI, FNAB, and thyroid function testing
[71]. A US scan is a noninvasive, simple, and cost-effective study that offers no
exposure to ionizing radiation unlike scintigraphy, CT scan, or MRI. With the use of
color Doppler imaging, sensitivity in detecting ectopic thyroid tissue is increased
(Fig. 6.10b) [14, 106].
Any palpable lesion within the neck should be evaluated with a complete high-
resolution neck US first, which includes assessment of all the salivary and thyroid
glands as well as cervical lymph nodes (LNs). The absence of a normally located
Fig. 6.10 Midline ectopic

thyroid in a 49-year-old
a
lady with thyroiditis. (a)
Transverse ultrasound
showing a 1.6 × 0.8 cm
solid, well-defined,
heterogeneous area (arrow)
in the midline, superior to
the thyroid gland. It is
iso-echogenic to the
thyroid gland with no
definite connection to it.
(b) Transverse color
Doppler ultrasound b
showing significant
increase in vascularity
(arrow)
Fig. 6.11 Axial enhanced

neck CT scan at the level
of thyroid cartilage
demonstrating a midline
infrahyoid soft tissue mass
(white arrow) embedded
within the strap muscle
that proved to be ectopic
thyroid tissue by histology
thyroid gland would influence the differential diagnoses and prevent unnecessary
iatrogenic hypothyroidism.
An advantage that a CT scan may have over MRI is the display of uniform high
attenuation, similar to a normal thyroid gland, which is characteristic of ectopic
thyroid tissue (Fig. 6.11) [14]. Ibrahim and Fadeyebi (2011) reported that MRI can
show an elevated signal on T1- and T2-weighted images compared with the sur-
rounding musculature and is more useful for lingual thyroid identification particu-
larly when there is difficulty in differentiating thyroid tissue from tongue muscle.
Further advantages of CT scan include a lower cost of the procedure and shorter
imaging time, whereas MRI offers no exposure to radiation as opposed to CT
scan [14].
Scintigraphy with technetium-99m (99mTc) remains the gold standard for ectopic
thyroid diagnosis, not only confirming the location and extension of the ectopic
thyroid and the presence or absence of the orthotropic thyroid, but also providing
information about the shape and overall activity of the thyroid, which is often unob-
tainable with other imaging modalities (Fig. 6.12). Drawbacks of a radionuclide
scan are that it may not clearly demonstrate small-volume thyroid tissue or nonfunc-
tioning thyroid vestiges, and depending on the chosen isotope, its accuracy may be
hindered by thyroid replacement therapy or iodine-containing contrast media
[88, 107].
If ectopic thyroid or neoplasia is suspected, particularly in the presence of an
orthotopic thyroid gland, FNA is suggested because it can identify thyroid tis-
sue with a 95–97% accuracy rate (Fig. 6.13) and is reliable in excluding malig-
nancy [84].
Fig. 6.12 Scintigraphy

with technetium 99m
(99mTc) pertechnetate
showing a diffusely
enlarged thyroid gland
with homogenous uptake,
suggesting diffuse toxic
goiter. Uptake of the
ectopic thyroid tissue
(arrow) is seen apart from
the pyramidal lobe
(arrowhead)
Fig. 6.13 Ectopic thyroid

tissue: Small cluster of
benign thyroid follicles
seen in close vicinity to the
main thyroid, i.e.,
peri-thyroid thyroid
follicles (H&E stain, low
power)
The differential diagnosis of a midline ectopic thyroid tissue should include

thyroglossal duct cysts, midline branchial cysts, lymphadenopathy, lipomas,
epidermoid cysts, and neoplasm. Since ectopic thyroid is solid in consistency,
thyroglossal duct cyst and branchial cyst are easily excluded. The presence of
vascular flow and absence of hyperechoic hilum in the ectopic thyroid nodule
help to exclude the possibility of lipomas, epidermoid cysts, and
lymphadenopathy.
Ectopic thyroid tissue should also be considered in the differential diagnosis of
lateral neck masses including those of the submandibular gland, branchial cleft
cysts, lymphangiomas, carotid body tumors, and lymphadenopathy [71–73].
Treatment
The treatment options of ectopic thyroid depend on size, symptomology, complica-

tions, thyroid functions, and suspected malignancy [108]. If the patient is asymp-
tomatic or minimally symptomatic, observation is recommended and no other
intervention procedure is necessary. On the other hand, bulk reduction with thyroxin
replacement therapy is suggested for hypothyroid patients with lingual thyroid and
those having symptoms attributable to mass effect caused by compensatory gland
hypertrophy [109].
Surgical intervention is reserved for patients having ectopic sublingual thyroids
or lingual thyroids, which are refractory to bulk reduction, or in symptomatic
patients having dyspnea, dysphagia, and hemorrhagic or cystic degeneration or sus-
picious for malignancy [77, 80, 84, 103, 108]. In cases where the ectopic thyroid is
the only functioning thyroid tissue, or when the remaining thyroid tissue is thought
to be insufficient, autotransplantation has recently (2020) been performed to restore
a euthyroid state [110].
6.4 Sub-hyoid Bursitis
Overview
A bursa is a closed fluid-filled, synovium-lined, saclike structure that functions to

provide a gliding surface to reduce friction between tissues of the body. It is found
throughout the body near bony prominences and between bones, muscles, tendons,
and ligaments.
Sub-hyoid bursa lies between the posterior surface of the body of the hyoid bone
and the thyrohyoid membrane (hence also known as retro-hyoid bursa or bursa ret-
rothyroid) (Fig. 6.14). It has been known in the past as Boyer bursa, named after
Baron Alexis de Boyer, French surgeon (1757–1833).
There are over 150 known bursae in the human body, and their function is to
facilitate movement in the musculoskeletal system, creating a cushion between
tissues that move against one another. When bursitis occurs, the bursa enlarges
with fluid, and any movement against or direct pressure upon the bursa will
precipitate pain for the patient. There are many causes of bursitis, including
Fig. 6.14 Location of sub-hyoid bursa between the hyoid bone and the thyrohyoid membrane
overuse injury, infectious disease, trauma, and inflammatory disorders. The

term “bursitis” refers to pathological enlargement of the bursa. The name “bur-
sitis” itself is often a misnomer, as not all forms of bursitis are due to a primary
inflammatory process but are rather a swelling of the bursa due to a noxious
stimulus [111–114].
Etiology
There are several causes of bursitis. The most common etiology is prolonged pres-
sure, whereby the bursa is stressed between a hard surface and bony prominence.
The second most common cause is trauma when direct pressure is applied to the
bursa, although often the patient will not be able to recall the inciting incident
[115, 116].
Traumatic bursitis puts the patient at risk for septic bursitis, which is most
often caused by direct penetration of the bursa through the skin, often by inva-
sive procedures. Septic bursitis through hematogenous spread is rare due to the
relatively poor blood supply of the bursa. Staphylococcus aureus causes the
majority of septic bursitis. Another important cause of bursitis is autoimmune
conditions and systemic inflammatory conditions. Lastly, bursitis can be idio-
pathic in origin [115, 116].
Pathophysiology
The bursa itself is a synovial lining that represents a potential space, insofar as it is
collapsed upon itself until a resulting trigger causes the bursa to become irritated
and fill with synovial fluid resulting in the formation of a swelling. The patient
experiences pain when the inflamed bursa is then compressed. However, not all
bursitis is associated with an overt inflammatory process.
Clinical Picture
Sub-hyoid bursitis is encountered equally in the male and female population.

While sub-hyoid bursitis affects people of all ages, the elderly may be at greater
risk. In general, immunocompromised patients, such as diabetics and those with
human immunodeficiency virus (HIV), are at increased risk of developing septic
bursitis.
Clinically, there are two forms of bursitis: acute and chronic. Acute bursitis typi-
cally arises from trauma or infection, while chronic bursitis is more likely the result
of inflammatory arthropathies and repetitive pressure/overuse, or “micro-traumas.”
In acute bursitis, patients generally present with pain on palpation of the bursa,
contrary to chronic bursitis, which is often painless. The bursa itself has had time to
expand to accommodate the increased fluid, and the result is significant swelling
and thickening of the bursa. An examination of the skin is very important in the
evaluation of acute or chronic bursitis. The skin should be evaluated for trauma,
erythema, and warmth.
The swelling in chronic sub-hyoid bursitis is usually painless and non-tender and
occurs at the lower border of the hyoid bone, in front of the thyrohyoid membrane.
It is characteristically sausage-shaped with its long axis transvers and mobile with
deglutition. It is usually translucent but becomes turbid when infected.
Evaluation
The diagnosis of certain types of bursitis can be made clinically and without further
studies; however, imaging plays a role in the diagnosis and management of bursitis.
Imaging can be helpful to narrow down the differential diagnosis or even provide a
precise answer in cases of diagnostic uncertainty.
Ultrasound (US) is particularly helpful for visualizing cobblestoning of the fat
overlying a bursa, which can help differentiate cellulitis from infectious bursitis.
The bursa is seen as a fluid-filled anechoic structure lined by a hyperechoic wall.
Color Doppler can likewise be used to show signs of infection, such as hyperemia
of the bursa and the surrounding tissues [116].
Aspiration of the inflamed bursa can be helpful when there is a question of septic
bursitis. Aspirated fluid should be sent for cell count, gram stain, and culture. A
white blood cell count of less than 500/mm3 from the aspirated fluid is consistent
with noninfectious bursitis [117–119].
Sub-hyoid bursitis should be differentiated from midline neck swellings, particu-

larly those that move with deglutition including mainly thyroglossal cyst, median
ectopic thyroid tissue, midline laryngocele, and enlarged lymph nodes.
Management
The vast majority of bursitis will heal on its own. Conservative treatment for symp-
tomatic improvement involves the use of anti-inflammatory drugs and oral antibiot-
ics (in septic bursitis). Local injections of corticosteroid are not recommended for
such a superficial bursa, as it carries an increased risk of iatrogenic septic bursitis,
skin atrophy, or draining sinus tracts [119]. In general, the evidence supporting the
use of corticosteroid injections for chronic bursitis is lacking. In bursitis caused by
systemic inflammatory conditions, it is important that the physician treats the under-
lying condition. Finally, for certain cases, the bursa can be excised surgically.
Prognosis
Bursitis is not a fatal disorder, and most patients have a good outcome. The vast
majority are managed as outpatients. However, patients who do not avoid the trigger
tend to develop recurrences [120, 121].
6.5 Hyoid Bone Tumors
Anatomy of the Hyoid Bone
The hyoid bone consists of five segments: a body, two greater cornua, and two lesser
cornua. With the exception of the cervical vertebrae, the hyoid bone is the only bone
located in the anterior neck. Infrahyoid muscles are attached to its lower surface,
and suprahyoid muscles are inserted on its upper surface. Unlike other bony struc-
tures, the hyoid bone does not directly articulate with other bones. Instead, it is
connected to neighboring bones by one membranous and two ligamentous
attachments.
The thyrohyoid membrane is an extrinsic membrane of the larynx that connects
the superior border of the thyroid lamina and its superior horns to the superior
aspect of the greater cornua and body of the hyoid bone. The hyoepiglottic liga-
ments are one of several extrinsic ligaments of the larynx. The bilateral ligaments
are responsible for attaching the anterior and lateral aspects of the epiglottis to the
body and greater cornu of the hyoid bone. The stylohyoid ligament commences at
the apex of the styloid process and inserts in the lesser cornu of the hyoid bone. It
provides a point of attachment for the middle pharyngeal constrictors and some
fibers of styloglossus muscle.
The blood supply of the hyoid bone is through the lingual artery, which runs
down from the tongue to the greater horns of the bone. The suprahyoid branch of the
lingual artery runs along the upper border of the hyoid bone and supplies blood to
the attached muscles.
Tumors of the Hyoid Bone
Solid primary lesions of the hyoid bone are exceedingly rare, and the reported cases
have included plasmacytoma, osteosarcoma, giant cell tumor, aneurysmal bone
cysts, osteoma, chondroma, chondroblastoma, multiple myeloma, and chondrosar-
coma [122–130].
Chondrosarcoma
Histological Grades of Chondrosarcoma

Chondrosarcoma is a malignant tumor characterized by the formation of chondro-
genic cartilage matrix [131]. The histopathological grades of chondrosarcoma
(grades I–III) [132] in correlation with the 5-year survival rate [133] are summa-
rized in Table 6.3. The hyoid chondrosarcoma in the literature is mainly grade I,
with only four cases of grade II chondrosarcoma [134].
Epidemiology
Chondrosarcomas constitute approximately 11% of all primary bone tumors
[131]. Although it is the third most common primary malignant bone tumor (fol-
lowing osteosarcoma and multiple myeloma) [135] and the second most common
sarcoma arising in bone [131], most cases occur in the pelvic bones, proximal
femur, proximal humerus, distal femur, and ribs [123]. Less frequently, 1–12% of
chondrosarcomas originate in the head and neck region, with the skull base,
Table 6.3 Histological grades of chondrosarcoma [133] and related 5-year survival rates [134]
Grade Histopathology 5-year SR (%)
I The lesion exhibits a preponderance of small, densely stained nuclei 90
II The lesion contains areas with moderate-sized nuclei, but with a low 81
mitotic rate
III The lesion has large nuclei, with foci of dense cellularity and a high 43
mitotic rate
SR survival rate
maxilla, and larynx more commonly involved [131], representing about 0.1% of
malignancies developing in these regions [124]. Chondrosarcoma of the hyoid
bone is a very rare entity, and only 23 cases have been reported in the literature
till 2019 [123, 134, 136–146].
Chondrosarcoma may involve any part of the hyoid bone. Involvement of the
body and greater or lesser cornua have already been reported in the literature [122,
136–146]. The size of the lesions varies between 0.5 and 7 cm. No significant gen-
der difference is found in the incidence of chondrosarcoma [147]. Age of the patients
varies widely between 30 and 82 years with an average of approximately
50 years [148].
Evaluation/Diagnosis
Clinical Evaluation
The diagnosis of a chondrosarcoma of the hyoid bone may be missed because of its
infrequent occurrence. Clinically, patients with hyoid bone tumors usually present
with painless, asymptomatic, and palpable neck masses. Associated symptoms may
include dyspnea, voice anxiety, and dysphagia [146]. On physical examination,
hyoid chondrosarcomas tend to be lobular, firm-to-hard, masses that enlarge and
alter the morphology of the hyoid bone. They are usually hardened by calcification
[149]. The majority of chondrosarcomas are of low grade, and the metastatic rate is
low. Metastatic potential peaks are only around 5% and spread to the lung and skel-
etal system [150].
Ultrasonography can help determine the texture of the mass, but often not the struc-
ture of the origin (Fig. 6.15). Although the common associated calcifications may be
detected by US, they are not well demonstrated as well as with a computed tomog-
raphy (CT) scan. Ultrasonography usually demonstrates a solid echoic mass with
calcifications; however, it is difficult and may be impossible to suggest the correct
diagnosis of chondrosarcoma by US [148].

A computed tomography (CT) scan is the imaging technique of choice because it
can better clarify a tumor’s structure of origin and its extension. The CT scan usu-
ally reveals a destructive, heterogeneous mass at the level of, and replacing or
expanding, the hyoid bone (Fig. 6.16). CT is the best imaging method to show oste-
oclasis or cortical erosion, which is usually associated with such tumors as well as
the characteristic calcification pattern [146].
The location beneath the mylohyoid muscles and the expansion of the hyoid
bone with chondroid calcification should suggest the correct diagnosis of a carti-
laginous tumor of the hyoid. Approximately 75% of chondrosarcomas will demon-
strate intrinsic matrix calcification [122, 126].
Fig. 6.15 Ultrasound of

the neck demonstrating an
inhomogeneous solid
echoic mass with
calcifications within the
hyoid bone region. It
proved histopathologically
to be a chondrosarcoma of
the hyoid bone
Fig. 6.16 Contrast-

enhanced axial CT scan at
the level of hyoid bone
showing a well-defined
mixed attenuation mass
that has expanded to the
left lesser cornu and has
replaced the normal body
of the hyoid bone with
peripheral rim calcification
and internal chondroid
calcification. The right
lesser cornu could not be
demonstrated

The multiplanar capabilities and better tissue contrast of MRI can more precisely
define the extension of the tumor and its relationship to surrounding structures and
aid in planning the surgical approach [122, 141]. On MRI, chondrosarcomas
characteristically provide a high signal on T2-weighted images and a low-to-

medium signal on T1-weighted images. The associated calcifications are revealed
as areas of signal intensity void [122, 136]. A strongly enhancing mosaic appear-
ance within the high-signal-intensity area on T2-weighted image may be an impor-
tant diagnostic clue for chondrosarcoma of the hyoid bone; however, osteogenic
tumor and aneurysmal bone cysts may have a similar MRI appearance [136].
It is very difficult and may be impossible to distinguish chondroma [151–154]
from low-grade chondrosarcoma radiographically [122, 135, 155]. Geirnaerdt et al.
(2000) reported that fast contrast-enhanced MRI may assist in differentiation
between benign and malignant cartilaginous tumors. Early enhancement is seen in
chondrosarcoma, not seen in chondroma, and seen in osteochondroma only when
growth plates were unfused [156].
Histopathology
Chondrosarcoma can be histologically graded from I to III on the basis of the mitotic
rate, cellularity, and nuclear size [132]. Pathological differentiation between low-
grade chondrosarcoma and chondroma can be very difficult. Histopathological
diagnosis of the grade of chondrosarcoma is also sometimes very difficult. This is
worrisome because the treatment of first-degree chondrosarcomas and second-
degree chondrosarcomas is different [157].
Grade I chondrosarcoma (Fig. 6.17) is composed of mature chondrocytes with
minimal nuclear and cytoplasmic atypia [148]. Higher grade chondrosarcomas have
an increased cellularity, more nuclear pleomorphism, and identifiable mitotic
figures.
Treatment
Surgical excision of chondrosarcoma is considered the treatment of choice. The
recommended treatment is extensive local surgical excision with total hyoidectomy

of the midline mass in the
hyoid bone region showing
grade I chondrosarcoma
seen as mature
chondrocytes with minimal
nuclear and cytoplasmic
atypia
to provide histological differentiation and reduce the chance of recurrence [146].

Neither radiotherapy (RT) nor chemotherapy plays a significant role as either pri-
mary or adjuvant treatment. Chondrosarcoma is considered to be radioresistant,
though a trial of RT may be considered for patients who decline surgery or are not
surgical candidates [136, 141].
Since the hyoid bone is the insertion of the musculature of the tongue and also is
attached to the thyroid cartilage and extrinsic muscles of the larynx, total hyoidec-
tomy to completely excise the tumor may cause abnormal phonation and difficulties
in swallowing and respiration [148].
Prognosis
Surgical excision adequacy, necessity of additional or adjuvant treatment, tumor
location, and tumor histological grade are the most important prognostic factors of
hyoid chondrosarcoma. The possibility of metastasis correlates with poor prognosis-
inducing malignancy grade [158]. Five-year survival rates for all chondrosarcoma
cases were 90% for grade I, 81% for grade II, and 43% for grade III [132]. For this
reason, periodic monitoring is necessary. In addition, local regional recurrences
should be investigated. Chest radiography is recommended every 6 months because
lung metastasis is the most common form of metastasis [146].
Chondroma
Introduction
Chondroma is a rare, slow-growing, benign tumor composed of hyaline cartilage
and forms on or in bones or soft tissue such as synovial sheaths of tendons or in the
soft tissues adjacent to the tendons in the hand and feet of adults; in such cases, it is
referred to as soft tissue or synovial chondroma. This tumor is called “enchon-
droma” when it occurs in the medullary canal of the bone [159] and is called “peri-
osteal” or “juxtacortical” chondroma when it occurs on the surface of the bone.
Incidence
Chondroma is well-encapsulated, has a limited growth potential, and is not locally
aggressive [160, 161]. It usually occurs in the hands or feet, but it may also occur in
the upper arm, thigh, collarbone, ribs, pelvis, spine, skull, and nasal sinuses.
Chondroma of the hyoid bone is extremely rare. Nakagawa et al. (1999) reported a
24-year-old woman with a chondroma of the greater cornu of the hyoid bone [153].
Back in 1967, Grayson and Bain reported a case of juxtacortical chondroma of the
hyoid bone [152], while Tamura and Sato reported a case of cystic enchondroma of
the hyoid bone in 1961 [154].
Enchondroma of the hyoid bone is usually asymptomatic. Expansile lesions can
appear as bulbous swellings in the midline of the neck. Pain is a rare accompanying
finding. Hence, the sudden appearance of pain in a previously asymptomatic lesion
could suggest a transformation to a malignant lesion [154]. Because periosteal
(juxtacortical) chondroma is a surface lesion, it may present as a palpable swelling

that may interfere with function [152].
Complications
Complications of chondroma in general include the following: (1) malignant trans-
formation to chondrosarcoma, (2) pathological fracture (especially in short tubular
bones), (3) growth disturbance of the bone (periosteal chondroma), and (4) recur-
rence, which should be treated as a suspected malignancy.
Clinical and Imaging Diagnostic Considerations
Enchondroma
In middle-aged or elderly patients, enchondroma should be differentiated from low-
grade chondrosarcoma. Clinical distinctions can be made on the basis of pain, and
radiological distinctions are based on the preservation of cancellous bone or adja-
cent cortex. Imaging features demonstrating extensive destruction of the cortex or
soft tissue infiltration by the cartilage tumor should be considered evidence of
malignancy. Dynamic contrast-enhanced (DCE) MRI appears useful in differentiat-
ing enchondroma from low-grade chondrosarcoma, and it has been suggested that
the combination of DCE MRI with standard MRI may be more accurate for differ-
entiating these cartilaginous tumors [162].
In terms of histological features, chondromas lack cellular atypia. In enchon-
droma, the cartilage cell nuclei are small and uniform. A homogenous chromatin is
present, and multinucleated chondrocytes are infrequent. The cartilage matrix is
well formed, without prominent myxoid features [163].
Periosteal (Juxtacortical) Chondroma

Juxtacortical chondrosarcoma may appear similar to periosteal chondroma.
However, juxtacortical chondrosarcomas are usually large (>5 cm), and although in
periosteal chondroma, there may be excavation of the underlying cortex, it is not
associated with complete cortical disruption [164].
Biopsy
If the diagnosis of chondroma is still in doubt, biopsy is indicated. Two approaches
are used: (1) the usual practice is to perform biopsy first and defer definitive resec-
tion. However, biopsy is not appropriate for cartilaginous lesions that are clinically
and radiologically benign and is thus not routinely performed for such lesions.
Furthermore, histological examination may not always help in correctly differenti-
ating benign lesions from malignant ones, and it should not be relied on in isolation
from the clinical and radiological findings; (2) in rare cases, the approach is to plan
definitive resection simultaneously with biopsy and to confirm the diagnosis by
examining frozen sections [165].
Histologically, chondromas consist of lobules of mature hyaline cartilage with
varying cellularity. In general, the chondrocytes are similar to those seen in hyaline
cartilage. Normal marrow separates the cartilaginous lobules, which may be
partially encased in mature lamellar bone. Within the lesion, one may observe areas
of myxoid change, ossification, or focal necrosis. Foci of fine or coarse calcifica-
tions may be seen [165].
Treatment and Prognosis
Surgical Treatment
Wide surgical excision and histopathological examination are recommended for
symptomatic lesions particularly when they clinically and radiologically mimic
chondrosarcoma. Wide local excision is a curative procedure [153].
Prognosis
Given the appropriate treatment, patients with benign chondromas generally have a
good prognosis, and most remain asymptomatic [153].
Osteoblastoma
Frequency/Locations
Osteoblastoma is a rare bone tumor first described by Lichtenstein [166] and Jaffe
[167] as a distinct neoplasm in 1956. This disease accounts for 1% [168, 169] or less
[170] of all bone tumors and most commonly involves the spine and sacrum of
young individuals [171]. The second most common location is the mandible, fol-
lowed by other craniofacial bones [168]. Other more rare locations in the head and
neck include the temporal bone [169] and larynx [172].
In 2010, Rivera-Serrao et al. presented a case of osteoblastoma arising in the
hyoid bone, in a 51-year-old gentleman who presented with a neck mass and dys-
phagia. Physical examination revealed a hard non-tender neck mass at the level of
the hyoid bone. This mass was freely mobile and moved up and down with degluti-
tion. The overlying skin was intact. The radiographical appearance of the tumor was
similar to that of low-grade chondrosarcoma, with well-defined expansion of the
bone and central chondroid matrix. Computed tomography (CT) scan revealed a
3 cm well-defined spherical mass with a calcified ring and a partially calcified cen-
tral matrix, arising within the hyoid bone, causing extrinsic compression of the
hypopharynx. The patient underwent hyoid resection, and the histopathological
diagnosis was a 3 cm hyoid osteoblastoma with a secondary aneurysmal bone cyst
component [173].
Clinically, osteoblastomas present mainly with pain, swelling, and expansion of the
bone cortex [171]. These typical symptoms occur in approximately 80% of patients
[168]. An osteoid osteoma is histopathologically similar but is smaller in size and is
associated with pain that is often nocturnal and relieved with the use of nonsteroidal
anti-inflammatory drugs (NSAIDs) [168]. Unlike osteoid osteoma, the pain of
osteoblastoma is not generally more severe at night and usually does not respond to
NSAIDs [170].
Fig. 6.18 Radiography of

osteoblastoma of the hyoid
bone showing radiolucent
and radiopaque patterns
without a sclerotic border
or periosteal reactions
Imaging
The goal of imaging is to distinguish benign from malignant causes and to assist
in surgical planning. Radiographical features of osteoblastoma are variable, usu-
ally showing a combination of radiolucent and radiopaque patterns, depending
on the degree of lesional calcification, but without a sclerotic border or periosteal
reactions (Fig. 6.18) [171]. An osteoid osteoma should demonstrate a radio-
graphic nidus of <1 cm, whereas an osteoblastoma should measure >2 cm in
greatest dimension. Neoplasms that measure between 1 and 2 cm fall into an
arbitrary zone in which classification is determined by individual prefer-
ence [168].
The radiographic differential diagnosis for osteoblastoma includes other benign
bone tumors. If a central calcified matrix is present, chondrosarcoma or enchon-
droma is an important consideration. If the lesion is lucent, aneurysmal bone cyst or
other bone cysts should be considered. Other calcification patterns may suggest
diagnoses such as ossifying fibroma or fibrous dysplasia [173].
Histopathological Diagnosis
Histologically, osteoblastoma is considered benign [170]. It is a bone-forming
tumor characterized by osteoid and woven bone deposition and abundant osteo-
blasts that are frequently in close association with newly formed bone. Occasionally,
osteoblastomas may appear richly cellular, contain an abundant osteoclast-like
component, and show plump osteoblasts that may evoke a diagnosis of osteosar-
coma, thus leading to unnecessary overtreatment [171]. The histopathological fea-
tures are similar to those described for osteoid osteoma [168], and such resemblance
is a particular challenge to the pathologist [170].
Treatment
Surgical excision of the hyoid bone and histopathological examination are
recommended for hyoid osteoblastoma; surgical excision is a curative

procedure [173].
Osteoma
Definition/Classification
Osteoma is a slow-growing, benign osteogenic tumor characterized by the prolifera-
tion of mature cancellous or compact bone and usually presents as a protruding
mass composed of abnormally dense, but otherwise almost normal bone [174, 175].
Osteoma is classified into three types according to the site of origin. Central
osteoma arises from the endosteum, peripheral osteoma originates from the perios-
teum, and extra-skeletal osteoma develops within the muscle [174, 176].
Pathogenesis
The pathogenesis of osteoma remains exactly unknown [177]. Various theories have
been proposed to explain the pathogenesis of osteomas. One theory is that the
lesions are “true” neoplasms. Another theory is that the lesions are associated with
abnormal enlargement of embryonic tissues, previous traumas, or chronic inflam-
matory processes. According to Thoma and Goldman (1960), growth starts sponta-
neously and is associated with trauma and not with inflammation [178]. Schneider
et al. (1980) reported on six cases with a positive history of prior trauma [179]. In
osteomas located in the muscle, pulling activities are suspected to develop the
lesion. Varboncoeur et al. (1990) considered osteomas to be cartilage or periosteal
embryonic remains [180]. However, a specific cause-effect relationship is difficult
to establish.
Locations
The sites of osteoma development are usually restricted to the craniofacial bones
and rarely include other bones. The most common site is the mandible (particularly
the angle), followed by the nose and paranasal sinuses; the frontal and ethmoidal
sinuses are more frequently involved than the sphenoid and maxillary sinuses [181].
On rare occasions, osteomas had been found in the temporal bone [182], middle ear
[183, 184], and tongue (soft tissue osteoma) [185, 186].
In 2014, Hagiwara et al. reported an 84-year-old man presenting with a huge
mass occluding the pharyngeal space. Computed tomography (CT) scan of the neck
showed a large (4 cm) osseous tumor of the hyoid bone. Transoral resection with
tracheostomy was performed to prevent dysphasia and respiratory distress.
Histopathologically, the tumor consisted of mature lamellar bone without a fibrous
component. For 2 years postoperatively, the patient remained asymptomatic with no
evidence of recurrence.
Diagnosis and Treatment

A diagnosis of osteoma can be easily made by CT scan. It defines the full extent and
the site of origin of the osteoma, which is usually seen as a well-defined bony mass
without enhancement effects [187].
Surgical excision of osteoma is often unnecessary; however, surgery is needed to
reduce significant symptoms whenever present and to avoid dysfunction because of
the growing tumor. The type of procedure selected depends on the location and
extent of the osteoma and the nature of any existing or anticipated complica-
tions [187].
Solitary Plasmacytoma of Bone (SPB)
Frequency/Classification of Plasma Cell Tumors

Plasma cell neoplasms constitute approximately 10–15% of hematopoietic tumors
and about 1% of all malignancies with the frequency of 4–6 cases per 100,000 a
year. It is a malignancy, which occurs in older age with a slight predominance in
males [188].
Plasma cell tumors localized to the head and neck have been classified, in 1992,
by Batsakis as multiple myeloma, solitary plasmacytoma, plasma cell myelomato-
sis, and extramedullary plasmacytoma [189]. Solitary plasmacytoma of bone (SPB)
is a plasma cell neoplasm occurring in red marrow areas. It is an uncommon plasma
cell tumor that constitutes less than 10% of all plasma cell tumors [190].
Location of SPB and Reported Cases

Solitary plasmacytoma of bone (SPB) may involve any bone, but the most common
site is the vertebrae (about one-third of patients) [191], and less frequently, the
extremities [126]. The hyoid manifestation of a plasma cell tumor as SPB is
extremely rare, and to our knowledge, only four cases of SPB of the hyoid have
been published in the literature [125, 126, 192, 193].
In 1994, Goel et al. [126] reported the first case of hyoid plasmacytoma men-
tioned in literature. They indicated that this is a distinctly unusual site, as the
marrow-containing flat bones are more commonly affected. The patient underwent
plain radiographs and a CT scan, and diagnosis was reached by histopathology. In
1999, Danac et al. [125] reported a case of a 60-year-old gentleman who had a pain-
less, midline, swelling in the hyoid bone region that had increased in size during a
6-month period. On physical examination, there was a firm, nodular, fixed mass
4 cm in diameter. The hyoid bone was seen to be destroyed on lateral neck radio-
gram. A lytic-destructive mass that caused thinning of the cortex and expansion at
the hyoid bone was found on CT scans. The diagnosis of plasmacytoma was made
on histological examination after total excision of the mass. Skeletal surveys, bone
marrow biopsy, and myeloma protein in blood and urine were normal.
The third case was reported in 2008 by Li et al. [192]. They presented a case of
primary small cell carcinoma of the thyroid gland associated with a solitary plasma-
cytoma of the hyoid bone. More recently, in 2013, Sychra et al. [193] reported a
case of an 81-year-old gentleman with a plasma cell tumor, which manifested pri-
marily as a solitary plasmacytoma of the hyoid bone and as an extramedullary infil-
trate of the oropharynx, representing a late-stage dissemination of a multiple
myeloma (MM). The patient suffered from a progressive midline neck swelling
over a period of 3–4 months, a swallowing disorder, and weight loss. Contrast-
enhanced CT scan showed a huge destructive tumor of the hyoid bone with calcifi-
cation at the tumor margin, and an asymmetry of the pyriform recess. The disease
was diagnosed by histological evaluation with immunohistochemical positivity for
VS38c (marker of plasma cells) and CD138 (expressed in plasma cells of bone mar-
row and differentiates them from B-cell precursors, which are CD138 negative).
The disease was classified as nonsecretory MM stage IIIA according to Durie and
Salmon (1975) [194]. Because of the systemic disease, chemotherapy with benda-
mustine and prednisolone together with anti-hypercalcemic therapy with pamidro-
nate was initiated.
In cases of hyoid SPB, local symptoms such as swelling, pain, obstruction of the
airways, swallowing disorders, or bleeding are dominant. Symptoms are caused by
expansion of the hyoid mass and its impact on the pharynx, larynx, and upper
esophagus [193]. Men are usually more frequently affected than women. The age of
patients is usually younger in SPB than in multiple myeloma, and the average age
in SPB is between 30 and 40 years [126].
Diagnosis
Diagnostic Criteria
The diagnosis of a localized form of plasma cell tumor assumes the exclusion of
MM [195], which means (1) that bone marrow biopsy taken from a site remote
from the tumor should be normal with no malignant plasma cells or less than 10%
of plasma cells in the specimen and (2) absence of anemia [196]. However, the
progression of an SPB into MM is known and documented in the literature [195–
200]. Corwin and Lindberg (1979) [196] reported progression from solitary forms
to MM within 24 months. They suggested a 3-year disease-free interval as a crite-
rion for the distinction of SPB from extramedullary plasmacytoma (EMP). The
relationship between MM and SPB is not yet clear; two contradictory opinions
were proposed in the literature; SPB is solely a manifestation of an MM [201], or
SPB is a true precursor of subsequently developing MM [202]. The tendency of
SPB to progress to MM has been attributed to an occult MM at the time when SPB
manifests [203].
Imaging
Radiologically, a plasmacytoma appears as a highly destructive, often expanding or
ballooning, lesion with thinning of the overlying cortex, without other skeletal
roentgenographic changes. The margins are usually well-defined, sharply demar-
cated, and characteristically without a sclerotic reaction. Coarse trabecular strands
may give a network appearance in the area of destruction. Larger lesions in flat
bones are described as having a soap bubble appearance [126, 204]. In recent years,
CT scan and MRI have shown abnormalities in bone even when standard radio-
graphs were considered normal [191].
Electrophoretic Studies
In patients with SPB, electrophoretic studies may reveal a myeloma protein in the
serum and/or urine; however, contrary to multiple myeloma, myeloma protein has
not been detected in most patients with SPB even on immuno-fixation studies
[126, 191].
Histopathology
Plasma cell histology should be shown by biopsy without skeletal involvement,
hyper-calcemia, renal involvement, anemia, and bone marrow infiltration [126].
Because the bone marrow involvement may be patchy, SPB cannot always be diag-
nosed by histopathological examination of the bone marrow [189].
Treatment
The treatment of choice in the localized forms of SPB or EMP is the surgical exci-
sion and/or radiotherapy (RT) [205]. Local RT has been used for the treatment of
SPB. The treatment fields should include diseased areas with a wide margin of
normal tissue. The dose of RT may change from 1000 cGy to more than 6000 cGy
[206]. All patients usually achieve pain relief, and the recurrence rate is less than
10% [126, 191]. The radioresistant tumor can be detected earlier by MRI, which
also allows consideration of surgery or intra-arterial chemotherapy, if anatomic
localization is suitable [126].
Serum and urinary myeloma proteins should be measured at least twice a year,
and skeletal surveys should be performed every 6 months, even if patients do not
have bone pain [8]. Multiple myeloma develops in approximately 70% of patients
with SPB when followed up for long periods. The progression criteria are new bone
lesions, rising myeloma protein levels (in blood and/or urine), and diffuse marrow
plasmacytosis. Treatment by local RT or chemotherapy may delay conversion to
multiple myeloma [191].
Prognosis
In general, the prognosis in SPB is better than that in multiple myeloma [126, 191].
About one-third of patients with SPB remain disease free for more than 10 years.
The median overall survival of all patients with SPB exceeds 10 years, and 10–20%
of patients die of unrelated causes [126, 191].
Giant Cell Tumor
Introduction
Giant cell tumor of bone (GCTB) is a locally aggressive, osteolytic, benign tumor
that predominantly occurs in the epiphyses of the mature skeleton, especially in the
long bones of young adults, with a slight female preponderance [207, 208]. Due to
its locally aggressive nature, GCTB leads to significant bone destruction, compres-
sive symptoms, and skeletal morbidity [209]. Surgical resection remains the main-
stay of treatment. Radiation therapy has a debatable role [210, 211]. On rare
occasions, malignant transformation may occur [207, 212, 213]. Recently, data have
emerged supporting the use of denosumab, an IgG2 monoclonal antibody, which
inhibits osteo-clastogenesis through the RANK–RANK ligand (RANKL) pathway.
It acts by inhibiting the growth of a GCTB [214, 215].
Epidemiology
GCTB accounts for 4–9.5% of all primary bone tumors and approximately 20% of
all benign bone tumors [207, 216–219]. There is an unusually high prevalence in
Southern India and China, where GCT represents 20% of all primary bone tumors
[216, 217]. Although some studies have reported an equal gender distribution, most
show an increased prevalence among females [216–218, 220, 221]. The prevalence
of GCT peaks during the third decade, with 80% of cases occurring between 20 and
50 years of age. Less than 3% of cases occur before the age of 14 years, and only
13% of cases occur in patients over the age of 50 years [216–218, 220–222].
Most lesions (75–90%) develop in long bones (typical location), with the major-
ity of cases (50–65%) occurring about the knee. The three most common locations
are the distal femur, proximal tibia, and distal radius, respectively [216–218, 220,
223]. Atypical locations are seen in the hands, feet, patella, talus, pelvis, spine,
skull, and facial bones [224, 225]. These atypical sites are commonly associated
with multicentric GCTB [224]. Giant cell tumor of bone (GCTB) of the head and
neck region is very rare, with an occurrence of approximately 2% of all GCTBs.
The most common sites are the sphenoid, ethmoid, and temporal bones [124, 127,
226–228]. Purely neck GCTBs are extremely rare, with 18 cases involving the
laryngeal framework [127] and only few cases involving the hyoid bone being
reported in the literature (Table 6.4) [124, 127, 209, 229, 230].
Rarely (less than 1%), GCTB may undergo malignant transformation as a result
of dedifferentiation of the primary tumor or secondary to prior radiation therapy
[221, 231, 232]. Usually a high-grade sarcoma is diagnosed, which has a relatively
poor prognosis. Bertoni et al. (2003) [232] reported that the average latent period
between diagnosis of GCTB and diagnosis of a secondary malignancy was 9 years
in patients treated with radiation therapy and 19 years in cases of spontaneous
transformation.
Clinically, patients with giant cell tumor of the hyoid bone present with anterior
neck mass, hoarseness of voice, dyspnea, and difficulty in swallowing. These tumors
are generally difficult to differentiate from benign laryngeal swellings and other
laryngeal malignancies. Clinically, GCTB can masquerade a malignant neoplasm
because of its large size and rapid growth, making a diagnosis of such tumors not
straightforward, and unless accurate FNA and radiological studies are performed,
diagnosis is most often made postoperatively [127].
Table 6.4 Previous cases of giant cell tumor of the hyoid bone reported in the literature
No. Authors Journal Year References
1 Commins et al. The Journal of Laryngology and Otology 1999 [124]
2 Iype et al. British Journal of Oral and Maxillofacial Surgery 2000 [127]
3 Singh et al. Indian J Otolaryngol Head Neck Surgery 2016 [229]
4 Bihani et al. Journal of Cancer Research and Therapeutics 2022 [209]
5 Mohd Sharif et al. Journal of University of Malaya Medical Centre 2022 [230]
Commins et al. presented in the literature the first GCTB affecting the hyoid
bone in 1999. It presented as a firm-to-hard lump, in the midline of the neck, overly-
ing the greater cornu of the hyoid [124]. In 2000, Iype et al. reported a giant cell
tumor of the hyoid bone in a 45-year-old gentleman, which we excised along with
the left half of the hyoid bone. It recurred locally 1 year later and was cured by exci-
sion and split-course radiotherapy (RT). The patient was documented to be disease-
free after 30 months of follow-up [127].
Singh et al. (2016) reported a case of a 28-year-old gentleman with GCTB aris-
ing from the left cornu of the hyoid bone. The patient presented with a huge mass in
the anterior neck, mild dysphagia, mild dyspnea, and change in voice. The mass was
large in size (9.8 × 12 cm), hard in consistency, fixed, and non-tender. The skin
overlying the swelling was normal, and local temperature was not raised. The CT
scan revealed a large multi-loculated heterogeneously enhancing expansile lesion
attached to the hyoid bone, causing extrinsic compression of the hypopharynx. Fine
needle aspiration cytology (FNAC) showed small number of multinucleated giant
cells with uniform dispersed nucleoli and light staining cytoplasm, a picture sugges-
tive of benign giant cell tumor. Histopathological examination confirmed the diag-
nosis of giant cell tumor of the hyoid bone. The patient underwent transcervical
complete excision of the tumor. Postoperatively, the patient did well without recur-
rence or metastasis for 2-year follow-up [229].
Recently, in 2022, Bihani et al. presented a case report of a 35-year-old young
gentleman, with GCTB of the hyoid bone. The patient presented with a painless,
progressive cervical swelling, 7 × 10 cm in size, along with trismus, dysphagia,
dyspnea, and mild slurring of speech. A core biopsy established the histopathologi-
cal diagnosis of a GCTB of the hyoid bone, and bone scan confirmed that the dis-
ease was only at the primary site with no other skeletal lesions or metastases
elsewhere. The tumor was treated with neoadjuvant denosumab (6 cycles of 120 mg
each, scheduled at 0, 8, 15, 30, 60, and 90 days post-diagnosis), followed by radio-
therapy (RT) and subsequently salvage surgery [209].
Mohd Sharif et al., in 2022, reported a case of a 63-year-old lady who presented
with a cervical swelling associated with dysphagia and voice changes. A contrast-
enhanced CT scan revealed a large mass seen arising from the hyoid bone with local
mass effect and airway compression. No distant metastasis was seen. Multiple biop-
sies were performed, and histopathology concluded the diagnosis of malignant
GCTB (MGCTB). The tumor was unresectable. The patient was thus treated with
denosumab (subcutaneous injection at 120 mg every 4 weeks for 1 year) and showed
encouraging improvement posttreatment [230].
Investigations
Imaging
Plain radiograph and contrast-enhanced magnetic resonance imaging (MRI) are the
standard imaging modalities used to diagnose GCTB [223]. On a plain radiograph,
GCTB is typically seen as a well-defined lytic bone lesion with non-sclerotic mar-
gins, located at the eccentric location, and usually extends to the subchondral
regions. Magnetic resonance imaging characteristics of GCTB usually display low-

to-intermediate signal in T1-weighted images and a high signal in T2-weighted
images and enhance post-gadolinium contrast. Approximately, 10–14% of the cases
show fluid levels within the tumor suggestive of aneurysmal bone cyst compo-
nent [224].
Computed tomography (CT) scan and MRI are useful in identifying the extent of
the tumor and in planning surgical excision. In general, CT scan of GCTB typically
shows purely osteolytic lesion with a geographical bony destruction. However,
GCTB may also have aggressive features or fluid-fluid levels and can mimic other
lesions at both radiological evaluation and histological analysis. Contrast-enhanced
CT is also used in patients with GCTB/MGCTB to rule out distant metastasis and
for disease follow-up. On the other hand, ultrasound is used mainly to assist in the
tissue biopsy [233].
Cytology/Histopathology
Giant cell tumor of bone is generally benign and characterized on FNAC by the
presence of dual population of mononucleated tumor cells and multinucleated
tumor cells with cohesive cell groupings of the two types of cells [234]. The multi-
nucleated giant cells appear similar to osteoclasts, which led to the older term
“osteoclastoma” [235].
Histology shows fibroblast, histiocytes, and multinucleated osteoclast-like giant
cells. The giant cells are found dispersed throughout the tumor. The giant cell con-
tains variable number of nucleoli, but there are no mitosis and nuclear atypia in
these cells (Fig. 6.19) [236]. However, there is a poor correlation between histologi-
cal findings and tendency to recurrence and malignant transformation [237]. Lesions
invariably demonstrate bone lysis, most commonly associated with narrow zone of
transition and lacking surrounding sclerosis with associated soft tissue mass.
Hudson et al. (1984) reported that GCTBs often demonstrate prominent trabecula-
tion (33–57% of cases) with a resultant multi-loculated appearance (soap bubble
Fig. 6.19 Microscopic

picture of giant cell tumor
of the hyoid bone showing
mononuclear cells and
multinucleated osteoclast-
type giant cells, both
arranged in compact
fashion (H&E, 10×)
appearance) [238]. Despite being categorized as a benign lesion, GCTB may be

locally aggressive and recur after surgical resection [222].
The differential diagnosis of GCTB occurring in the neck includes giant cell repara-
tive granuloma, brown tumor of hyperparathyroidism, osteoblastoma, chondroblas-
toma, aneurysmal bone cyst, non-ossifying fibroma, benign fibrous histiocytoma,
and osteosarcoma with abundant giant cells [228]. The differentiation based on
imaging alone is difficult [230]. A combination of a high clinical index of suspicion,
accurate imaging, and histopathological analysis can assist in arriving at the correct
diagnosis [209]. Giant cell tumors are usually benign but can be locally aggressive
and can rarely metastasize [229].
Treatment
Invariably, surgery is the treatment of choice of giant cell tumor of the hyoid, and an
adequate resection is imperative to ensure optimal control rates. Some authors also
advocated postoperative radiotherapy (RT) [239]. The indications of RT include
inoperable and incomplete resected lesions and lesions that recur locally despite
definitive operation [237].
Malignant Transformation
Malignant transformation of GCTB (MGCTB) is rare and is estimated to be approx-
imately 2–9% of the GCTB cases [219]. Palmerini et al. (2019) suggested that
MGCTB occurs when the conventional GCTB undergoes a sarcomatous transfor-
mation into a malignant tumor (osteosarcoma, fibrosarcoma, or undifferentiated
pleomorphic sarcoma) [240]. Malignant transformation of GCTB is further charac-
terized into two subgroups: primary MGCTB and secondary MGCTB. Primary
MGCTB is diagnosed when the malignant cells are found at juxtaposition to the
benign GCTB or intermixed within it at the initial presentation. Secondary MGCTB
is described as the presence of malignant cells at previously benign GCTB sites
post-surgery and/or post-radiotherapy [241]. In a study by Chakarun et al. (2013)
involving 2315 GCTB patients, the overall incidence of MGCTB constituted 1.6%
of primary MGCTB and 2.4% of secondary MGCTB [223].
In imaging, MGCTB has no specific characteristics to differentiate it from benign
GCTB [224]. Palmerini et al., in 2019, also highlighted that it is difficult to differ-
entiate GCTB and MGCTB due to lack of specific malignant features, complicated
by aggressive features that can also be seen in the benign lesion [241]. According to
Van Langevelde (2020), post-denosumab CT demonstrates tumor matrix with mar-
ginal sclerosis. Hounsfield unit (HU) is used in CT to quantify tumor density, indi-
cating the tumor response [233].
The mainstay treatment for MGCTB is surgery, by either en bloc resection or
curettage [242]. Curettage has a higher recurrence rate as compared to en bloc
resection (65% vs. 16%, respectively) [224]. In cases of unresectable tumors or
when surgery is not feasible due to postsurgical morbidity/functional disability,
denosumab has been the ultimate choice of treatment [214, 215, 224]. Denosumab
is a human monoclonal antibody that prevents RANK–RANKL interactions, which

stops the osteoclastic activity in GCTB by inhibiting the osteoclast differentiation,
activation, and survival [243, 244]. In 2016, Park et al. stated that denosumab was
used in a phase II trial involving 169 GCTB patients of whom 96% showed improve-
ment of the disease [243]. This is further supported by another study by Mavrogenis
et al., in 2017. In this phase II study, 100 GCTB patients where surgery was planned
at initial diagnosis were treated with denosumab. Only 26 patients proceeded with
the operation, while the other 74 patients showed positive improvement post-
denosumab and did not require surgery [224].
Over the years, denosumab has found wider applications as a neoadjuvant ther-
apy, resulting in beneficial surgical downstaging including either no surgery or a
less morbid surgical procedure [245]. It has also been observed to result in symp-
tomatic improvement including reduction in pain [246]. However, isolated case
reports have also speculated rapid progression of disease with cessation of deno-
sumab therapy [209, 247]. Radiation therapy has been described as an alternate
modality of treatment in unresectable or recurrent tumors with an acceptable level
of toxicity [248, 249].
Prognosis
Transformation of GCTB into MGCTB is associated with poor prognosis due to
tumor recurrence posttreatment and the development of distant metastasis [223].
The most common site for distant metastasis is the lung [219]. A review of literature
has shown that the recurrence rate of benign GCTB and MGCTB is estimated to be
9% and 20%, respectively. The 5-year survival rate of MGCTB patients is 87%,
with a 16% total mortality rate [240].
Aneurysmal Bone Cyst (ABC)
Definition
Aneurysmal bone cyst (ABC) is defined as “a benign, locally destructive multi-
loculated blood-filled cystic lesion of bone.” There are primary and secondary
forms. A related term is “giant cell lesion of small bones.”
Epidemiology
Aneurysmal bone cyst (ABC) is rare; it represents only 2.5% of all primary bone
tumors. It affects males and females equally and is more common in skeletally
immature patients. The peak incidence is in the second decade of life [250]. It has a
broad skeletal distribution affecting mainly the metaphyseal region of long tubular
bones, most commonly the femur, tibia, and humerus. It also involves the posterior
elements of vertebrae and has also been reported in the larynx, maxillary sinus, and
hyoid bone [129].
Etiology
The exact etiology of ABC is unknown, but its association with trauma is certain.
Historically, ABC is thought to be a reactive process in bone to underlying vascular
events, i.e., as a sequel to hemorrhage from a primary lesion such as a fracture, lead-
ing to an osseous arteriovenous fistula [251]. Recently, molecular data are support-
ive of a neoplastic etiology [252, 253].
Pathology
Aneurysmal bone cyst is classified as a tumor of blood vessels, a cystic, osteolytic,
vascular tumor. It usually presents as a single cavity usually containing unclotted
flowing blood. There are multiple cavernous vascular spaces that honeycomb the
lesions, unlined by endothelium with lack of characteristic blood vessels. The
benign-appearing stroma of spindle cells is sprinkled with giant cells [254]. In most
cases, areas of resemblance to aneurysmal bone cyst occur adjacent to lesions of
fibrous dysplasia, giant cell tumor, osteogenic sarcoma, and benign osteoblas-
toma [251].
Diagnosis
Clinical Features
Diagnosis of ABC requires correlation of clinical, radiological, and histological
findings to distinguish primary from secondary forms. The clinical diagnosis of
aneurysmal bone cyst of the hyoid bone may be difficult in view of more likely pos-
sibilities such as thyroglossal cyst, hemangioma, and ectopic thyroid. The patient
usually presents with pain and swelling. A pathological fracture may be present. A
definite chronological relationship between the occurrence of an aneurysmal bone
cyst and an undisplaced fracture was noted by Dabezies and Ferguson (1982)
[251, 254].
Imaging Studies
Several authors, in their reports of an aneurysmal bone cyst in the sphenoid sinus,
noted radiological findings of bony destruction, opacification, and expansion [255–
257]. Computed tomography (CT) scan shows a well-delineated lytic lesion, usu-
ally with thin rim of reactive bone. Fluid-fluid levels are occasionally visible.
Beltran (1986) advocates the use of MRI for diagnosis of an aneurysmal bone cyst,
as this particular cyst has multiple fluid levels caused by intracystic hemorrhages of
varying ages [258]. Isotope scan demonstrates peripheral uptake with central photo-
penia imparting a donut-like appearance.
Histological (Microscopic) Appearance

Histological diagnosis can be reached by differentiation from giant cell variants.
Diagnosis should be based on a composite of multiple random sections of the tumor
along with clinical and radiographical evidence [254]. Histological characteristic
features of ABC include (1) blood-filled cystic spaces separated by cellular septa
containing fibroblasts, giant cells, and woven bone; (2) calcified, basophilic mate-
rial (blue reticulated chondroid-like material); (3) necrosis being not common, but
mitotic activity being easily identified; and (4) no cytological atypia [259]. Lack of
immunoreactivity for H3G34W (and other histone antibodies) is helpful in exclud-

ing giant cell tumor with cystic features.
Molecular/Cytogenetic Description
Characteristic molecular features of ABC include (1) abnormalities of 17p13.2
locus in 63% [260], i.e., fusion of USP6 with CDH11 (most frequent, approxi-
mately 30%), TRAP150 (THRAP3), ZNF9 (CNBP), OMD, COL1A1, RUNX2,
PAFAH1B1, CTNNB1, SEC31A, E1F1, FOSL2, STAT3, USP9X, ASAP1, FAT1,
SAR1A, and TNC [261–263]; (2) unusually aggressive aneurysmal bone cyst with
RUNX2-USP6 fusion (rare, case report) [264]; (3) rearrangement of USP6 gene
detected by FISH or fusion panel analysis by next-generation sequencing; and (4)
other lesions with USP6 gene rearrangement including myositis ossificans and nod-
ular fasciitis [265].
The differentials of ABC include the following:
–– Telangiectatic osteosarcoma: It is the most important differential diagnosis,

characterized by (1) similar architecture, but containing anaplastic stromal cells;
(2) frequent atypical mitoses; (3) no specific diagnostic immunohistochemical
stain; and (4) lack of USP6 gene rearrangement [266].
–– Central giant cell granuloma: It involves gnathic bones; it is usually solid with
no/minimal cystic component (mimics solid aneurysmal bone cyst) and lacks
USP6 gene rearrangement [267].
–– Secondary aneurysmal bone cyst: It lacks USP6 gene rearrangement. Extensive
sampling is critical to rule out an underlying primary lesion. It is more common
in fibrous dysplasia, giant cell tumor of bone, chondroblastoma, osteoblastoma,
and osteosarcoma [268].
Treatment
Several methods for treatment of aneurysmal bone cyst have been advocated:
curettage with or without grafting or en bloc resection, cryotherapy, and radio-
therapy (RT) [269–271]. However, RT for the treatment of a benign lesion with a
tendency to spontaneous regression is unjustified [272]. In addition, RT has been
avoided on account of its potential carcinogenicity [273] and damage to the grow-
ing ends of bone [274]. All these modes of treatment are associated with recur-
rence between 8% and 30% [275, 276]. Shadaba and Zaidit (1992) proposed total
en bloc excision of aneurysmal bone cyst as the treatment of choice when mechan-
ical or functional failure is likely. They added that no recurrence follows this
mode of treatment [129].
Recently, treatment options introduced include (1) steroid or calcitonin injection,
(2) percutaneous sclerotherapy with doxycycline [277], and (3) arterial emboliza-
tion; as thrombosis and fibrinolysis play a leading part in healing, therapeutic embo-
lization has been used successfully to achieve spontaneous regression [273, 278].
Reported Case
In 1992, Shadaba and Zaidit [129] provided the first report of an aneurysmal bone
cyst (4 × 6 cm in size) occurring in the hyoid bone of an 18-year-old boy. He pre-
sented with a progressive midline suprahyoid swelling of a 7-month history associ-
ated with odynophagia and dysphagia. There was a past history of neck trauma.
Plain radiographs showed a diffuse circumscribed swelling of the soft tissues with
scattered patches of ossification in the hyoid bone. CT scan showed a large midline
rounded non-enhancing fluid dense mass, with an amorphous ring and eccentric
calcification at the level of the hyoid bone. It extended from the tongue to the thy-
roid isthmus through the body of the hyoid bone. Ultrasound showed a midline
cervical complex mass with bright echogenicity and well-defined walls. Fine needle
aspiration (FNA) revealed frank blood even on repeated attempts. Carotid angiogra-
phy did not show a vascular tumor. Exploration revealed that the body of the hyoid
bone was deficient and only the remnants of the right greater cornu could be identi-
fied. Approximately 50 mL of serosanguineous aspirate was withdrawn. The cyst
was dissected away along with a patchily ossified cyst wall. Keeping the age and
history of trauma in mind, as well as the numerous cavernous spaces and absence of
endothelial lining, a diagnosis of an aneurysmal bone cyst was histologically
confirmed.
Hyoid Bone Metastasis
Overview
Primary malignancies that frequently metastasize to the hyoid bone arise from
the adjacent tissues such as the larynx, vallecula, and pyriform sinus [279]. Only
a few studies have reported cases of hyoid bone metastasis from distal primary
malignant tumors, such as lung adenocarcinoma [280], breast cancer [281], renal
cell carcinoma [282], hepatocellular carcinoma [283], sigmoid adenocarcinoma
[284], melanoma [285], and prostatic cancer [286]. The patient usually presents
with a midline neck swallowing that may be associated with dysphagia. Computed
tomography (CT) scan usually shows an osteolytic lesion affecting the hyoid
bone (Fig. 6.20). For the detection of skeletal metastases, FDG-PET-CT and
bone scans have been compared. The sensitivity and specificity of FDG-PET-CT
were 100%, whereas the sensitivity of bone scan was 77.5% and specificity was
59.6%. Diagnosis of a metastatic lesion in the hyoid bone is settled by cytology/
histology.
Hyoid resection is well tolerated and of diagnostic and therapeutic benefit in
patients with tumors metastatic to the hyoid bone, with the potential for an excellent
functional outcome postoperatively.
Distant Primary Malignancies
Lung Adenocarcinoma
Lung cancer is one of the most common malignant tumors in the world. Although
this disease usually spreads to the liver and brain through the blood or lymph
Fig. 6.20 Neck contrast-

enhanced computed
tomography showing
osteolysis of the hyoid
bone (arrow)
circulation [287], bone metastases are also very common [288], most commonly to
the spine, ribs, and pelvis [289].
Zhang et al. (2021) reported a 68-year-old male patient having hyoid bone ade-
nocarcinoma metastasis from lung adenocarcinoma. The initial symptom was neck
pain exacerbated by swallowing. Physical examination revealed a palpable solid
midline neck mass with ill-defined borders and mobile with deglutition. It appeared
on contrast-enhanced computed tomography (CECT) scan as a semicircular soft
tissue mass shadow of 4.5 × 2.5 cm in size in the anterior lower part of the epiglottic
cartilage. The hyoid bone mass was resected based on comprehensive studies
including histopathological analysis and whole-body bone imaging. The middle
segment of hyoid bone disappeared after surgery. The patient recovered well, the
anterior cervical pain was significantly alleviated after surgery, and the patient
underwent corresponding chemotherapy [280]. Lung adenocarcinoma is most likely
to metastasize to the hyoid through the circulatory system, and the most likely route
is the branch of the superior laryngeal artery. Since the lingual artery supplies blood
to the hyoid bone, metastasis may occur through these vessels [280].
Renal Cell Carcinoma

In 2011, Passah et al. reported a 55-year-old gentleman who presented with histo-
pathologically proven clear cell type of renal cell carcinoma (RCC). He underwent
right radical nephrectomy and received radiotherapy (RT) to bilateral pelvic bones,
right femur, D7–D9 vertebrae, and right scapulae. He was on sunitinib therapy. For
restaging, 18F-fluorodeoxyglucose (FDG)-positron-emission tomography-
computed tomography (PET-CT) scan was performed. It showed recurrence in the
right renal bed and metastases to bilateral lungs and multiple skeletal sites including
a rare site of hyoid bone metastases. Trans-axial PET-CT and CT images showed
lytic lesion in hyoid bone with increased tracer uptake, suggestive of hyoid bone
metastasis [290]. FDG-PET-CT is useful for the restaging of patients with RCC and
has a diagnostic accuracy of 89%. It also has a diagnostic accuracy of 84% for clas-
sifying biopsy-proven anatomical lesions as malignant or benign [291].
Hepatocellular Carcinoma
The incidence of bone metastasis in patients with hepatocellular carcinoma (HCC)
has reportedly been increasing; however, the hyoid bone is rarely a target of meta-
static HCC. Iguchi et al. (2012) reported a unique case of HCC with a single distant
metastasis to the hyoid bone in an 81-year-old gentleman. The patient complained
of a painful neck mass when swallowing of 1-month duration. He had a history of
nonsurgical treatments for HCC in the previous 6 years. PET-CT demonstrated a
mass, which had destroyed the hyoid body, particularly on the left side.
Ultrasonography-guided fine needle aspiration cytology (FNAC) provided a diag-
nosis of poorly differentiated carcinoma. The mass was completely resected com-
bined with the hyoid bone. Postoperative histopathology was consistent with
metastatic HCC. The patient was relieved from pain with deglutition just after sur-
gery [283]. Iguchi et al. concluded that minimally invasive surgery can be an effec-
tive treatment modality for pain relief even in patients with bone metastasis
from HCC.
Sigmoid Adenocarcinoma
Gastrointestinal adenocarcinoma is among the most common malignancies world-
wide and one of the most common causes of cancer-related death. Although it com-
monly spreads to the regional lymph nodes (LNs), liver, and lungs, it may also
metastasize to unusual sites, such as paranasal sinuses and cryptorchid testis [292].
Its metastases to the larynx and adjacent structures have been only occasionally
reported [292]. In general, sigmoid tumors have the highest rate of bone metastasis
in long-term follow-up in comparison to the right and left colon [293].
In 2017, Bracanovic et al. reported a case of the hyoid bone and thyroid carti-
lage metastases in a 63-year-old gentleman treated for sigmoid colon adenocarci-
noma. Four years after sigmoid colon adenocarcinoma was diagnosed and treated
with surgery and chemotherapy, the patient developed bone metastases in the left
sacroiliac joint and right proximal humerus. Moreover, in a bone scintigraphy, the
accumulation of technetium-99m (99cTm) was incidentally detected in two sites of
the anterior neck: the hyoid bone and thyroid cartilage. Physical examination
revealed two small, painless, palpable masses located anteriorly at the level of the
hyoid bone and superior to the thyroid gland. Ultrasound examination showed two
hyperechoic and heterogeneous masses with calcifications in front of the hyoid
bone and thyroid cartilage, while CT scan demonstrated massive destruction of
both [284].
Breast Cancer
In 2014, Kusama et al. reported a case of a 69-year-old woman who had under-
gone breast-conserving surgery and axillary LN dissection for left breast cancer
10 years previously. Adjuvant tamoxifen and RT were administered to the con-
served breast for 5 years. The patient detected a painless neck mass 1 year
previously. Computed tomography (CT) scan revealed a hyoid bone mass, and
FNAC indicated a diagnosis of adenocarcinoma. Positron-emission tomography
(PET) combined with CT (PET-CT) revealed masses in the pelvis, spine, hyoid
bone, and cervical LNs. For definitive diagnosis, excisional biopsy of the hyoid
bone was performed. Immuno-histostaining revealed that the cells were CK7 (+),
CK20(−), mammaglobin (+), GCDFP-15 (+), ER (+), PgR (+), and HER2 (−).
The final diagnosis was multiple bone metastases (hyoid, pelvis, spine) as well
as cervical LN metastases from breast cancer. The patient thus received anastro-
zole and denosumab, and she achieved a partial response. She has experienced
progression-free survival for 12 months. Metastasis to the hyoid bone is uncom-
mon for breast cancer [284]. They concluded that, based on the results of exci-
sional biopsy, hormone therapy is effective for treatment of hyoid bone metastasis
from breast cancer [284].
Melanoma
Cutaneous melanoma is a malignant tumor originating from melanocytes and is the
fifth most common cancer in men and sixth most common in women in the United
States. The most common sites of distant metastases from melanoma are the skin,
lungs, brain, liver, bone, and intestine [294]. Bone metastases from melanoma are
relatively common, observed clinically in 11–17% of patients and in 23–49% of
melanoma patients in autopsy studies. However, bony metastases usually occur in
the axial skeleton, most commonly the spine [294].
Recently, in 2020, Ryan et al. described the first report of melanoma metastatic
to the hyoid bone in a 27-year-old gentleman [285]. The patient presented in 2012
with a friable, pigmented lesion on his left posterior neck that bled with palpation.
A biopsy demonstrated melanoma with Breslow thickness of 5 mm, and treatment
included a wide local excision with 2 cm margins with no sentinel LN biopsy or
adjuvant therapy. Six years later, the patient developed lung metastasis in the right
lower lobe. In addition, PET-CT revealed an intensely FDG-avid and partially calci-
fied mass on the hyoid bone. The patient received chemotherapy for both lesions,
which resulted in complete metabolic response of the lung mass, but with the devel-
opment of right neck adenopathy and growth of the hyoid bone mass. Four months
after initiating chemotherapy, the patient underwent surgical resection of the hyoid
mass and 75% of the hyoid bone including a 1 cm margin of normal-appearing bone
away from the mass, in addition to selective neck dissection. Histopathology of the
hyoid mass demonstrated metastatic melanoma. The patient recovered well func-
tionally after surgery tolerating well a regular diet. Postoperatively, he began adju-
vant immunotherapy with nivolumab for metastatic melanoma treatment. Imaging
was performed 15 months after initial hyoid mass resection demonstrated no evi-
dence of neoplasm. Ryan et al. [285] suggested that metastatic melanoma should be
included in the differential diagnosis for any patient who presents with a hyoid
tumor and has a prior history of melanoma. Hyoid bone resection may be consid-
ered in such patients with hyoid tumors given ease of exposure, diagnostic and
therapeutic benefit, and potential for an excellent functional outcome
postoperatively.
Prostatic Cancer
Metastasis from an occult primary carcinoma has been reported to occur in 3–4% of
all cancer patients. Skeletal metastases are the first lesions to be detected in approxi-
mately 10–15% of these patients [281]. The most probable origin of occult primary
cancer is lung cancer, followed by prostate, breast, and liver cancers. Metastasis to
the head and neck region from prostate carcinomas is rare, and metastasis to the
hyoid bone has only been reported once in the literature [286].
Wang et al. (2011) reported the unique case of occult prostate cancer in a 77-year-
old gentleman. The patient presented with a painless, movable anterior neck mass
of several months’ duration. Physical examination revealed a 2 × 2 cm, soft, non-
tender mass that was movable with deglutition, just above the thyroid cartilage. It
was initially diagnosed as a thyroglossal duct cyst. A sagittal T1-weighted MRI
showed a well-circumscribed, homogeneous, cystic mass attached to the hyoid
bone. Two foci of metastatic carcinoma lesions in the hyoid bone were detected
after Sistrunk’s operation, and occult prostate cancer was confirmed by immunohis-
tochemical staining of prostate-specific antigen (PSA) [286]. The patient received
combined hormone therapy and chemotherapy without complications for 3 years
[286]. The unique presentation of this case reiterates the importance of prostate
cancer bone metastasis. The authors suggested that, although it is rare, prostate
cancer with bone metastasis should be taken into consideration in the differential
diagnosis of tumors involving the hyoid bone [286].
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Swellings of the Laryngeal/Pharyngeal
Region 7
Contents
7.1 Overview 147
7.2 Pre-laryngeal (Delphian) Lymph Node 148
7.3 Laryngeal Tumors 156
7.4 Prominence of Adam’s Apple 168
7.5 Chondritis of the Thyroid Cartilage 170
7.6 Retropharyngeal Abscess (RPA) 176
7.7 Laryngocele 184
References 188
7.1 Overview
Midline cervical swellings that may occur in the laryngeal/pharyngeal region

include the following:
–– Pre-laryngeal (Delphian) lymph node

–– Laryngeal tumors (mainly squamous cell carcinoma and adenoid cystic carci-
noma of the larynx)
–– Bursa in front of Adam’s apple
–– Chondritis of thyroid cartilage (pyogenic chondritis—tuberculous chondritis)
–– Retropharyngeal abscess (pyogenic—tuberculous)
–– Laryngocele

Switzerland AG 2024
148 7 Swellings of the Laryngeal/Pharyngeal Region
7.2 Pre-laryngeal (Delphian) Lymph Node
History and Etymology
The Delphian lymph node (DLN) (also called pre-laryngeal or pre-cricoid node, and
often shortened to Delphian node) is one of the cervical LN groups that comprise
level VI cervical LNs and is not routinely excised in radical neck dissection (RND).
The expression “Delphian” was first used by Raymond B. Randall in 1948, at the
time a medical student at Harvard Medical School, because a metastasis to the DLN
may predict the poor prognostic outcome of laryngeal and thyroid cancers, in the
same way the prophecy of Apollo at the temple of Delphi foretold the future in
ancient Greece [1–3].
Surgical Anatomy
The Delphian lymph node (DLN) is the highest of the central (level VI) cervi-
cal group of LNs. The classic DLN is ascribed to one or more LNs above the
isthmus of the thyroid gland between the cricoid and thyroid cartilage, although
it also includes any midline node placed over the cricothyroid membrane, cri-
coid cartilage, or that lies anterior to the lower half of the thyroid cartilage
[1, 4, 5].
The DLN receives afferent lymphatic drainage from the larynx (supraglottis and
sub-glottis via the anterior commissure) and the thyroid gland (upper and anterior
portions of both lobes and isthmus). The DLN has two main efferent lymphatic
drainage routes; one flows toward the pre-tracheal (sub-DLN), mediastinal, and
supraclavicular LNs, and the other to the paratracheal and lower jugular (level IV)
nodes [4] as demonstrated in Fig. 7.1. Thus, DLN status should be critically evalu-
ated in patients with cancers involving the larynx, hypopharynx, and thyroid
gland [6].
Pathology
Involvement of the DLN can be as a result of diffuse nodal involvement in head and
neck squamous cell carcinoma (SCC), or in isolation from direct lymphatic spread
of laryngeal cancer through the anterior commissure. Thyroid carcinomas may also
involve this node, in which case it usually signifies disease spread to the central and
lateral cervical LNs [6, 7]. Although Delphian lymph node metastasis (DLNM) is
generally identified in advanced-stage cancers, T1b or occult glottic cancer may
also metastasize to the DLN [8, 9].
Fig. 7.1 A diagram showing the lymphatic drainage of the Delphian lymph node (DLN)
Delphian LN in Thyroid Cancer
Clinicopathological Factors
The clinicopathological factors of the positive DLN in thyroid cancer are still not
completely understood. Papillary thyroid carcinoma (PTC) is the most common
type of differentiated thyroid malignancy, accounting for approximately 90% of all
thyroid carcinomas [10, 11]. Cervical lymph node metastasis is commonly observed
in patients with PTC and is significantly associated with an increased risk of regional
recurrence [12, 13]. The central lymph node (CLN) compartment seems to be the
first station of cervical LN metastasis, which then travels to the ipsilateral lateral
compartment and finally to the contralateral compartment, whereas skip metastasis
rarely occurs [14, 15]. The CLNs include the DLN, pre-tracheal, and paratracheal
LNs. Several reports were published in recent years addressing the predictive value
of DLN metastasis (DLNM) in PTC [3, 6, 7, 16–22]. The clinical data from some
studies indicate that DLNM is a predictor of further disease in both the central and
lateral neck compartments. However, some investigators reported that DLN is fre-
quently found without extensive LN disease and even stated that DLN involvement
is a misleading and unreliable sign [23, 24].
In 2022, Zou et al. reported that the DLN was detected in 53.9% (522/969) of
patients with PTC, and DLNM occurred in 20.3% (106/522) of cases. The
independent predictors of DLNM included tumor size >1 cm, tumor located in the
upper 1/3 thyroid or isthmus, CLN metastasis (CLNM), and lateral LN metastasis
(LLNM). DLN-positive individuals exhibited a higher incidence and number of
CLNM, contralateral CLNM (CCLNM), and LLNM as compared to DLN-negative
patients. Whether it is cN0 or cN+, the CLNM incidence was increased among
DLN-positive patients as compared to that of DLN-negative patients [25]. Likewise,
Alibakhshi et al. (2022) reported that of the 61 PTC patients, DLN involvement was
reported in 13 (21.3%). A statistically significant relationship was also noted
between DLNM and CLNM, and CLNM and CCLNM. Vascular invasion was also
significantly higher among patients with DLNM [26].
In 2021, Yan et al. reported that among the 516 PTC patients with DLN detec-
tion, the DLNM rate was 25.39% (131/516). Tumor size >1 cm, upper 1/3 tumors,
CLNM, LLNM, and lympho-vascular invasion were independent risk factors for
DLNM. Patients with DLNM had a higher incidence of ipsilateral CLNM, CCLNM,
and LLNM and larger numbers and size of metastatic central LNs than those with-
out DLNM. The incidence of CLNM and CCLNM among cN0 patients with DLNM
was higher than that among those without DLNM [27].
In the series reported by Wang et al. (2019) [22], DLN metastasis was detected
in 19 (9.9%) of 192 papillary thyroid carcinoma (PTC) patients and was signifi-
cantly associated with tumor size ≥1 cm, multifocality, and extra-thyroid extension
(ETE) in the multivariate analysis. Female gender was a significant protective factor
for DLN metastasis. In addition, DLN metastasis was highly predictive of further
central LN metastasis (CLNM) (positive predictive value [PPV] = 89.5%, negative
predictive value [NPV] = 67.6%) and moderately predictive of lateral LN metastasis
(LLNM) (PPV = 26.3%, NPV = 95.4%). Compared with patients without DLN
metastasis, patients with DLN metastasis were approximately 13.7 times more
likely to have further CLNM and 4.9 times more likely to have LLNM. A study by
Isaacs et al. (2010) indicated that DLN positivity predicted a 9-fold higher fre-
quency of LLNM and a 40-fold higher frequency of any nodal disease [16].
In a meta-analysis [22] that included seven studies published between May 2011
and February 2017 (Table 7.1), among the PTC patients, 247 (16.2%) were found to
have DLN metastasis. There was a strong significant correlation between DLN
metastasis and aggressive clinicopathological characteristics in terms of multi-
focality, bilaterality, ETE, lympho-vascular invasion, further CLNM, and LLNM [3,
7, 17–21].
Table 7.1 Characteristics of individual studies included in the meta-analysis [22]

Reference Year Country Sample size DLNM %
Lyer et al. [18] 2011 USA 25/76 24.8
Kim et al. [19] 2012 Korea 53/255 17.2
Lee et al. [20] 2013 Korea 13/54 19.4
Oh et al. [7] 2013 Korea 49/196 20.0
Chai et al. [17] 2014 Korea 46/324 12.4
Tan et al. [3] 2017 China 19/212 8.2
Zheng et al. [21] 2017 China 42/164 20.4
DLNM Delphian lymph node metastasis
Preoperative Evaluation
In PTC with DLN metastases, LN metastasis is detected in up to 95.9% of the cen-
tral group [7] and 47.2% of the lateral group [19]. According to nodal staging for
thyroid cancer, N1a refers to metastatic disease in the central compartment and N1b
refers to metastasis to the lateral nodal chains. Because DLN positivity is predictive
of lateral compartment disease, Isaacs et al. (2008) have suggested that nodal metas-
tasis to the DLN should be upstaged to N1b [6].
The status of DLN has important implications in extending the scope of surgical
procedures, planning radiotherapy (RT), and determining outcome. Current meth-
ods for preoperative evaluation of DLN status such as ultrasonography (US), com-
puted tomography (CT) scan, or magnetic resonance imaging (MRI) are considered
imperfect [17, 28] owing to the small median size of positive DLN [18]. According
to the 2015 American Thyroid Association (ATA) guidelines, preoperative US is
recommended for the initial evaluation of PTC [29]. However, there are still limita-
tions for the use of preoperative US in effectively identifying suspicious central LNs
because of the presence of an overlying thyroid gland [29].
Intraoperative frozen section is generally accepted as one of the sensitive and
useful tools for evaluation of the status of DLN. The current American Thyroid
Association (ATA) guidelines [29] do not recommend prophylactic central LN dis-
section (CLND) for small tumors (T1 or T2). However, even in cases of PTC with
small tumors, a high rate of CLNM is well documented [30]. Therefore, DLN could
be sent for frozen section evaluation because of its predictive value for widespread
nodal metastasis [18]. If the DLN is positive, CLND should be carefully considered
even in clinically node-negative PTC.
Prognosis
There are few reports addressing the recurrence of PTC with DLN metastasis [7, 17,
21]. Studies showed that PTC recurrence was slightly higher in DLN-positive than
in DLN-negative patients, although the difference did not reach statistical signifi-
cance [7, 17]. However, Zheng et al., in 2017, reported that DLN-positive patients
had a significantly higher rate of unstimulated thyroglobulin (Tg) ≥1 ng/mL than
DLN-negative patients [21].
Metastasis to the DLN is a poor prognostic factor in many malignant neck can-
cers [2, 28], and it is associated with several poor prognostic factors in PTC, includ-
ing ETE [31], and a heavier nodal burden, in terms of number of metastatic nodes
and node size [32]. These factors could be considered as the confounders for the
relationship between DLNM and prognosis of PTC [33]. It is worth noting that the
proportions of aggressive pathological variants, which included tall cell variant, dif-
fuse sclerosing variant, solid variant, oncocytic variant, Warthin-like variant, and
clear cell variant, were higher in the DLN-positive group of patients than in the
DLN-negative group (10.1% vs. 4.4%, p = 0.009) as recently reported by Yan et al.
in 2021 [27].
To date, there is no published evidence or definitive studies on the association
between survival and DLN involvement in PTC, although in 2021, Yan et al. reported
that in their series (DLNM in 131/516, i.e., 25.39%), no patients died during a
20-month follow-up. The difference was not statistically significant, which required
larger sample size and further long-term follow-up [27].
Delphian LN in Laryngeal and Hypopharyngeal Cancer
Clinicopathological Factors/Prognosis
Most studies to date on the DLN address its significance in laryngeal and hypopha-
ryngeal carcinoma, and emerging evidence suggests that DLNM is a poor prognos-
tic factor in such cancers [1, 2, 5, 8, 9, 16, 18, 34–41]. In laryngeal and hypopharyngeal
carcinomas, the presence of DLNM increases LLNM, resulting in a high recurrence
rate and low survival rate [1, 2, 4, 34].
The role in tumor spread and the prognostic value of DLN were investigated by
Resta et al. (1985) in 124 cases of laryngeal and hypopharyngeal carcinoma selected
from 900 (13.8%) total laryngectomies and pharyngolaryngectomies. DLNM was
noted in 26 cases: 22 without capsular rupture (N+) and 4 with capsular rupture (N+
R+). Vascular embolism (E+) was never noted. Resta et al. stated that DLNM
reaches this node directly through the anterior lymphatic peduncle. In their series,
patients with DLNM had involvement of the cervical nodes and of the thyroid gland
more frequently than those without DLNM. The 5-year disease-free survival rate of
those patients with DLNM was very poor, reaching only 11.54% (3/26) [34].
Between 1960 and 1985, Olsen et al. (1987) identified 20 cases of histologically
proven DLNM. In 12 (60%) of these patients with glottic cancer (T1–T3), the neck
was clinically negative, but DLNM was discovered at partial or total laryngectomy.
In six (30%) patients, ipsilateral neck metastasis developed. Eleven (55%) of the 20
patients died from their laryngeal cancer. Olsen et al. concluded that the frequency
of neck metastasis and/or mortality from cancer is unusually high in patients with a
DLNM [1].
Szmeja et al. (1995) reported that between 1984 and 1994, 1573 patients with
laryngeal carcinoma were operated upon. Total laryngectomy was performed in
1069 patients and partial laryngectomy in 504. The DLNs were identified in 109
patients. Histologically, DLNMs were found in only eight cases (7.48%). The prog-
nosis of the patients with DLNM was poor; only two patients survived and were free
of neoplastic disease [39].
In the study by Modrzejewski et al. (1996), between the years 1965 and 1987,
920 patients with cancer of the larynx were operated on, and 9 cases of histologi-
cally proven DLNM were identified. In all patients except one, the neck was clini-
cally negative, but the positive DLN was discovered at partial or total laryngectomy.
Five patients developed metastasis postoperatively, and seven of nine patients died
from their laryngeal cancer [40]. Modrzejewski et al. concluded that the frequency
of neck metastasis and local recurrences is very high in patients with a positive
DLN [40].
The incidence of DLNM in laryngeal carcinoma was studied by Thaler et al.
(1997) in 92 laryngectomy specimens. Histological examination revealed that
DLNM was noted in eight (8.7%) specimens. All eight patients had submucosal
involvement of the conus elasticus, seven had involvement of the sub-glottic

mucosa, and six had invasion of the cricoid cartilage. Four patients (50%) with
DLNM died of the disease, three of whom had stomal recurrence [5].
In 2001, Gawlak-Prycka et al. reported that between 1984 and 1998, 2145 laryn-
gectomies were performed (1435 total and 710 partial). Samples from macroscopi-
cally changed tissues (n = 192) were collected from pre-laryngeal area during
operations. Histological examination revealed that 24 cases had DLNM. During a
2-year follow-up period after surgery, tumor recurrence was found in 62.4% of
patients (15/24) with positive DLN as compared to 17.4% (23/132) in DLN-negative
patients. In the group with DLNM, metastases were also found in lateral LNs of the
neck in eight cases (53.3%, 8/15) of whom tumor recurrence was observed in six
(75%, 6/8) [41]. They concluded that the presence of DLNM is a significant unfa-
vorable prognostic factor [41].
Pignataro et al. (2003) investigated the role of DLN in a selected group of 53
patients with T1b glottic squamous cell carcinoma (SCC) who underwent horizon-
tal glottectomy. The DLN was isolated in 46 (86.8%) patients. Histological evalua-
tion revealed the presence of metastasis in three cases (6.5%) of whom two died
because of neoplastic recurrence. Mortality was statistically higher in DLN-positive
patients [8].
Kocatürk et al. (2003) investigated the incidence of the DLN in 20 patients who
underwent supra-cricoid laryngectomy (SL) for SCC of the larynx. Preoperatively,
no DLNs were detected by palpation. Intraoperative exploration revealed 13 LNs in
eight patients. Histopathological examination showed DLNM in only one patient.
Surgical resection in that patient included the perichondrium of the cricoid cartilage
as the lowest surgical margin, and neck dissection was extended to include level VI
LNs. Postoperative RT was administered including the superior mediastinum.
However, the patient died 8 months after surgery from lung metastasis and neck
recurrence [37]. Kocatürk et al. recommended evaluation of DLNM, particularly in
patients with tumors involving the anterior commissure, anterior sub-glottic area,
epiglottic petiole, and pyriform sinus, in order to exclude the possibility of leaving
metastatic nodes behind in surgical techniques in which partial or total preservation
of the cricoid cartilage is considered [37].
In 2011, Nakayama et al. reported the presence of DLN (by frozen-section exam-
ination) in 27 of 65 (41.5%) patients who underwent supra-cricoid laryngectomy
with cricohyoidoepiglottopexy; among these 27 patients, 3 (3/65 = 4.6%) were
positive for metastasis. One of these three patients died of lung metastases 32 months
after surgery [4]. Nakayama et al. concluded that DLN is exclusively encountered
in advanced laryngeal cancers and suggests an ominous outcome. They advised
evaluation of DLN for all supra-cricoid laryngectomy surgeries and recommended
sufficient dissection of the paratracheal and lateral neck nodes [4].
In 2012, Wierzbicka et al. reported that between 1989 and 2008, 212 consecutive
patients with T1b and T2 glottic cancer with anterior commissure involvement were
treated by supra-cricoid partial reconstructive laryngectomy, without adjuvant
RT. In 16 cases out of the whole group, DLNM was found. Local and regional recur-
rence developed in 37 out of the 212 patients (17.5%). There was significant
correlation between local relapse and DLNM; out of 20 cases with local recurrence,
13 had positive DLN. There was also significant correlation between nodal relapses
and DLNM; out of 22 cases with nodal relapse, 12 had positive DLN. The organ
preservation rates for patients with DLNM and those without were 62.5% and
93.88%, respectively. Moreover, survival rate was significantly lower in patients
with DLNM as compared to those without DLNM (38.7 vs. 49.3 months, respec-
tively) [28]. Wierzbicka et al. concluded that that DLNM seems to be a strong iso-
lated factor influencing prognosis in patients with early glottic cancer. DLNMs are
responsible for the increased rates of local and nodal relapses, decreased chances of
organ preservation, and poor overall survival rates [28].
A summary of medical literature related to laryngeal cancer and DLNM is given
in Table 7.2. The presence of the Delphian node ranged from 6.9% to 86.8%; the
rates of metastasis were between 0.9% and 8.7%; and the mortality rates ranged
from 11.5% to 100%.
Management
Management of the regional neck nodes is another important subject when DLNM
is encountered. Head and neck surgeons, particularly those using laryngeal preser-
vation procedures, should pay close attention to the pathophysiology of the DLN
and to the subsequent management of the regional neck nodes when DLNM is
encountered.
Based on the observation of a higher incidence of stomal recurrence in
DL-positive patients, paratracheal node dissection has been encouraged [5].
Although the DLN drains to the bilateral neck, with unilateral glottic cancers and a
clinically negative neck, it rarely metastasizes to the contralateral side. On the other
hand, supraglottic cancers have a marked predisposition to bilateral neck
Table 7.2 A summary of published articles related to laryngeal cancer and DLNM
Author [references] Year Presence of DLN (%) DLNM (%) Mortality (%)
Resta et al. [34] 1985 124/900 (13.8) 26/900 (2.9) 3/26 (11.5)
Olsen et al. [1] 1987 – 20/2232 (0.9) 11/20 (55.0)
Szmeja et al. [39] 1995 109/1573 (6.9) 8/1573 (0.5) 6/8 (75.0)
Modrzejewski et al. [40] 1996 – 9/920 (0.9) 7/9 (77.8)
Thaler et al. [5] 1997 – 8/92 (8.7) 4/8 (50.0)
Gawlak-Prycka [41] 2001 192/2145 (8.9) 24/2145 (1.1) 15/24 (62.5)
Pignataro et al. [8] 2003 46/53 (86.8) 3/53 (5.6) 2/3 (66.7)
Kocaturk et al. [37] 2003 8/20 (40) 1/20 (5) 1/1 (100.0)
Luna-Ortiz and 2005 27/65 (41.5) 3/65 (4.6) 1/3 (33.3)
Mosqueda-Taylor [38]
Nakayama et al. [4] 2011 27/65 (41.5) 3/65 (4.6) 1/3 (33.3)
DLN Delphian lymph nodes, DLNM Delphian lymph node metastasis
metastasis, and therefore bilateral neck dissections are advised [5]. The unilateral
thyroid gland might be removed along with the paratracheal nodes [4]. There is still
not sufficient evidence supporting adjuvant treatments, but the treatment options
should be discussed with patients demonstrating DLNM [4].
Delphian Lymph Node (DLN) in Thyroiditis
Involvement of the DLN in autoimmune thyroiditis has gained wide acceptance,

although it has been mentioned only superficially in some reference books [42, 44].
Some studies discussed the coexistence of subacute thyroiditis and central cervical
LNs [45] and the coexistence of various stages of autoimmune thyroiditis and cervi-
cal LNs [47].
The diagnosis of autoimmune thyroiditis is based on clinical findings and labora-
tory tests, such as elevated thyroglobulin antibody (Tg Ab) and thyroid peroxidase
antibody (TPO Ab). However, antithyroid antibodies may be negative in cases of
thyroiditis, as evidenced by a histological examination [48]. Some authors advocate
the use of ultrasonography (US) in cases of autoimmune thyroiditis [49, 50],
whereas others did not find it useful in such cases [51]. The combination of US with
clinical and serological findings significantly improves sensitivity and specificity
for diagnosing autoimmune thyroiditis [52, 53]. An additional advantage of US is
that it is a noninvasive modality that provides information about the level of inflam-
matory activity [54] and the severity of thyroiditis [55].
Ormeci et al. (2016) evaluated the association between autoimmune thyroiditis
and DLN in the different stages of thyroiditis. A total of 126 patients were divided
into four groups according to thyroid US findings: group 1: control cases; group 2:
indeterminate cases; group 3: established thyroiditis cases; and group 4: advanced-
late-stage thyroiditis cases. Indeterminate cases attended a 1-year follow-up, and
the cases with a sonographic finding matching thyroiditis formed group 2. The DLN
was detected in only 3 of 30 control patients (10%). The DLN detection rates were
15.1% for indeterminate cases, 41.6% for established thyroiditis cases, and 56.4%
for advanced-late-stage thyroiditis cases [56]. Ormeci et al. reported that not only
the presence of DLN was highly correlated with the progress of autoimmune thy-
roiditis, but also its dimensions. Ormeci and colleagues suggested that with progres-
sion of thyroiditis, evaluating the thyroid gland with the DLN provides more
information about its different stages and evaluating the DLN might prevent miss-
ing diagnosis of the disease [56].
In 2013, Giovagnorio et al. also observed an increase in the rate of DLN detec-
tion with advancing thyroiditis stage, albeit with no significant increase in lymph
node size, in their study that included 366 patients with autoimmune thyroiditis
[47]. The authors recommended thorough evaluation of anterior cervical LNs for all
patients presenting with suspected thyroiditis [47].
7.3 Laryngeal Tumors
Benign Laryngeal Neoplasms
Background
While the most common benign laryngeal neoplasm is laryngeal papillomatosis or
recurrent respiratory papillomatosis (RRP), there are a number of more rare neo-
plasms that also involve the larynx including those of mesenchymal, neural, and
vascular origin. Depending on tumor size and location, laryngeal functions may be
variably affected warranting treatment [57].
ecurrent Respiratory Papilloma (RRP)

R
Recurrent respiratory papilloma (RRP) or laryngeal papillomatosis is the most com-
mon benign laryngeal tumor, affecting approximately 4.6/100,000 children and
1.8/100,000 adults. It has a bimodal age distribution with juvenile- and adult-onset
forms. It is caused by human papillomavirus (HPV) with types 6 and 11 most com-
monly implicated [58].
Clinically, patients with RRP most commonly present with dysphonia due to
papilloma formation on the vocal folds, though larger exophytic lesions involving
the supraglottis can lead to airway obstruction, rarely requiring tracheotomy.
Lesions frequently recur with unpredictable rates of growth and varying locations
[59]. There is a low risk of malignant transformation (3–7%) [60].
Although RRP has characteristic appearance on laryngoscopy (exophytic warty
lesions with fibrovascular cores), biopsy is necessary to confirm diagnosis and to
rule out carcinoma. Treatment is guided by disease severity with the general aims of
eliminating gross disease, improving airway and voice, as well as reducing spread
or seeding of disease. Several surgical excisions are often required throughout a
lifetime; the primary goal is to improve the quality of life related to voice and swal-
lowing while limiting cumulative damage to the larynx, including scar and stenosis.
Debulking techniques are varied and include cold knife, micro-debrider, and LASER
(ablative and angiolytic). Adjuvant therapy is reserved for refractory or aggressive
forms of RRP and can include intralesional cidofovir and bevacizumab (can be
given systemic for fulminant disease) [58–60].
Rhabdomyoma
Rhabdomyoma arises from intrinsic laryngeal musculature. The true vocal fold is
the most common site of laryngeal involvement. Treatment involves complete surgi-
cal excision. Multicentricity may play a role in recurrence, so careful inspection and
surgical planning are advised [61].
Lipoma
Laryngeal lipoma comprises approximately 0.1–0.6% of all benign laryngeal
tumors. It occurs predominantly in older men, and the majority arise from the
supraglottis (especially aryepiglottic folds, epiglottis, and vestibule). Lipoma of the

larynx is usually solitary and is often confused with retention cysts. When multicen-
tric, it can be associated with syndromes such as neurofibromatosis and Gardner
syndrome. For larger lesions, imaging can be considered with MRI providing better
margin delineation. Biopsy and histological examination are necessary to distin-
guish it from liposarcoma, its malignant counterpart. Treatment involves surgical
excision depending on symptoms [62, 63].
Neural Tumors
A variety of neurogenic tumors of the larynx have been described in the literature.
Treatment consists of endoscopic excision, though external approaches may be nec-
essary for larger lesions [64].
Neurinoma (Neurilemmomas, Schwannoma)

Neurinoma originates from Schwann cells and is the most common laryngeal tumor
of neural origin. It is usually solitary, and well encapsulated, arising most com-
monly in the laryngeal vestibule, probably from the branch of superior laryngeal
nerve. Being benign, it tends to displace, rather than invade, the nerve of origin,
which facilitates complete excision. Malignant transformation is rare [65].
Neurofibroma
Neurofibroma is also derived from Schwann cells. Complete excision can be diffi-
cult for the following reasons: (1) neurofibroma grows within the nerve sheath
encompassing the nerve as it grows making it difficult to excise without sacrificing
the nerve of origin; (2) it is often multiple; and (3) it is not encapsulated. The chance
of malignant transformation is approximately 12%. Multifocality should raise the
suspicion of neurofibromatosis syndromes [66].
Paraganglioma
Laryngeal paragangliomas (LPGs) are benign neuroendocrine tumors. They are
often slow growing, though highly vascularized, and usually occur in adults in the
fourth to sixth decades of life. Histologically, LPG is composed of “chief” and “sus-
tentacular” cells and characteristic “zellballen” pattern. It may stain positive for
chromogranin, synaptophysin, and neuron-specific enolase (NSE). Given the poten-
tial for hemorrhage due to high vascularity, some authors advocate for the external
over-the-endoscopic approach to provide improved visualization and facilitate more
complete excision [67].
Granular Cell Tumors

Granular cell tumors are derived from Schwann cells. They are more common in
females and African Americans and are most commonly located in the posterior 1/3
of the true vocal fold. It is usually solitary, but there may be satellite nodules in 15%
of cases. Grossly, it is pink and firm in appearance, well circumscribed, but
unencapsulated. Histologically, it stains positive for S-100 and NSE. Pseudo-

epitheliomatous hyperplasia of the overlying mucosa may occur in 50% of cases,
which leads to confusion with squamous cell carcinoma (SCC). Surgical excision is
the mainstay of treatment; however, recurrence may occur at a rate of 2–20%. Long-
term surveillance is recommended as up to 5% of tumors may contain malignancy
[68, 69].
Hemangiomas
Hemangiomas are endothelial cell tumors, classically categorized into infantile and
adult forms.
Infantile Hemangioma
Infantile hemangioma is a capillary hemangioma that presents in the first 6 months
of life, occurring in females more than males (2:1). It is usually subglottic and con-
sidered the mirror pattern of cutaneous hemangioma. It is sessile and characteristi-
cally self-involuting. Natural history of infantile hemangioma consists of two
phases: (1) proliferative phase, characterized by progressive airway obstruction,
biphasic stridor, and “croupy” cough, and (2) involution phase, which may take
years to complete and is characterized by reduced symptoms by 18–24 months [70].
Direct laryngoscopy and bronchoscopy are necessary to determine the true extent
of the tumor. Treatment aims to maintain the airway during the proliferative phase.
Observation is recommended for less severe cases. Medical therapy commonly used
includes propranolol and judicious use of steroids. Surgical therapy may include
open and endoscopic techniques depending on the extent of the disease. A variety of
ablative and angiolytic lasers have been used with varying degrees of success [71].
Adult Hemangioma
Adult hemangioma is a cavernous hemangioma that is usually supraglottic but may
be sub-glottic. It is pedunculated, grows slowly, and rarely involutes. It is important
to rule out extra-laryngeal involvement with MRI, and angiography is sometimes
utilized to determine the extent of the lesion. Most adult hemangiomas can be man-
aged conservatively with observation [72].
Malignant Laryngeal Neoplasms
Overview
Laryngeal cancer constitutes about 25% of all head and neck malignancies. It is the
second most common malignancy of the upper aerodigestive tract, with over 13,000
cases annually reported in the United States alone [73]. Although most (85–95%)
malignant laryngeal tumors are squamous cell carcinoma (SCC), a wide variety of
tumors of other histological types may occur in the larynx [74].
Laryngeal cancer commonly presents in adults between 50 and 70 years and

shows a strong male predominance [75]. Tobacco or alcohol use is known to be a
major risk for laryngeal cancer. Either primary or metastatic tumors in the region of
head and neck, lung, or mediastinum may cause airway obstruction at the level of
the larynx, trachea, or bronchi. The severity depends on the level and degree of
obstruction and may range from just minimal stridor to almost complete airway
obstruction. The lif-saving measure is to have a rapid and accurate diagnosis with
proper management [76].
In 2017, Chew et al. reported an atypical presentation of laryngeal cancer in an
87-year-old gentleman. The patient presented with respiratory distress and an ante-
rior midline neck swelling, which moved with swallowing, mimicking a thyroid
tumor, which was the initial diagnosis. There was a history of progressive hoarse-
ness of voice over 5 months prior to the stridor. Physical examination of the neck
revealed an anterior neck mass measuring 3 cm ×3 cm at the level of the thyroid
cartilage. It was firm and fixed, with no overlying skin changes, and it moved with
swallowing. There was an absence of laryngeal crepitus. No neck nodes were pal-
pable. Flexible naso-pharyngo-laryngoscopy demonstrated a very narrow airway
opening at the glottis area. The right vocal cord had minimal mobility, and the left
cord was fixed. A mass, superior to the site of anterior commissure (laryngeal
tumor), was seen, which was the cause of intraluminal airway compression. The
chest radiograph showed hyperinflated lungs, whereas the neck radiographs showed
airway narrowing at the sub-glottic region [76].
Thyroid cancer with laryngeal involvement is relatively rare, occurring in about
12% of patients [77]. Stridor presents in approximately one-third of patients with
laryngotracheal invasion. However, direct extensions of tumors into the thyroid
gland, especially of carcinomas from pharynx, larynx, trachea, or soft tissue of the
neck, have been documented [78]. Stridor in laryngeal carcinoma may be caused by
recurrent laryngeal nerve (RLN) involvement, intraluminal laryngeal tumor that
causes glottic stenosis, or arytenoid cartilage involvement [79].
The immediate goal of management of laryngeal cancer is to provide prompt
relief of airway obstruction with low morbidity and mortality and not interfering
with future definitive therapy [80]. The indication for the tracheostomy is well
described and is an accepted management of acute obstructive upper airway in both
children and adults [81]. If it is a thyroid mass, endotracheal intubation should be a
priority as it usually occupies the space for tracheostomy to be performed. However,
if laryngeal cancer is suspected, tracheotomy is the choice [76]. Following the tra-
cheotomy, a definitive laryngectomy should be planned within 48–72 h to minimize
the risk of stomal recurrence. Once the airway is stabilized, direct laryngoscopy,
bronchoscopy, and imaging studies should be performed. For patients with resect-
able cancers, radical surgical resection with systemic nodal dissection is the stan-
dard approach [80].
Squamous Cell Carcinoma (SCC)
Epidemiology
Squamous cell carcinoma (SCC) of the larynx is the most common primary malig-
nant tumor that affects the laryngeal framework, reflecting its origin from the epi-
thelium of the larynx. It accounts for 98% of laryngeal tumors. Males are more
affected than females, and the median age of occurrence is in the sixth and seventh
decades with less than 1% arising in patients younger than 30 years of age [82].
Risk Factors
The most important risk factor of developing laryngeal SCC is tobacco smoking.
Death is 20 times more likely for heavy smokers than for nonsmokers. Heavy
chronic consumption of alcoholic spirits is also a significant risk factor. When pres-
ent in combination, the usage of alcohol and tobacco appears to have a synergistic
effect. Other reported risk factors include Greek/Turkish coffee [83], being of low
socio-economic status, male gender, or age above 55 years. In addition, occupa-
tional exposure to environmental factors such as asbestos [84], wood dust, paint
fumes, and certain chemicals used in the metalworking, petroleum, plastics, and
textile industries is also believed to be a risk factor. Infections by some strains of
Papillomaviridae also carry some risk of laryngeal carcinoma [85].
People with a history of head and neck cancer are known to be at a higher risk
(about 25%) of developing a second, separate cancer of the head, neck, or lung. This
is likely due to chronic exposure to the carcinogenic effect of alcohol and tobacco.
In this situation, a field change effect may occur, where the epithelial tissues start to
become diffusely dysplastic with a reduced threshold for malignant change. This
risk may be reduced by quitting alcohol and tobacco.
Classification
Typically, SCC of the larynx is categorized by the laryngeal subsite involved, which
affects presentation, treatment, and prognosis of the disease. Laryngeal SCC is clas-
sified according to its relation to the glottis into (1) supraglottic carcinoma (20–30%),
(2) glottic carcinoma (50–60%), (3) sub-glottic carcinoma (5%), and (4) trans-
glottic carcinoma (involving two or more of these spaces) [86].
–– Supraglottic carcinoma: SCC arises from the epiglottis, aryepiglottic fold, false
vocal fold, and deep pre-epiglottic and para-glottic spaces. It metastasizes early
to cervical LNs.
–– Glottic carcinoma: SCC arises from the true vocal fold. It manifests early due to
hoarseness of voice and rarely metastasizes due to the poor lymphatic drainage
of the glottis.
–– Sub-glottic carcinoma: SCC arises from anywhere below the true vocal fold to
the inferior edge of the cricoid cartilage. It produces minimal symptoms result-
ing in late diagnosis, which coupled with early LN metastasis leads to a poor
prognosis.
The symptoms depend on the size and location of the tumor. Symptoms may include
the following: voice changes (mainly hoarseness), a lump in the neck, sore throat or
feeling that something is stuck in the throat, persistent cough, stridor (a high-pitched
wheezing sound indicative of a narrowed or obstructed airway), foul breath, earache
(due to referred pain), and dysphagia [87].
Although rare, SCC of the upper aerodigestive tract can present as an anterior
midline neck mass mimicking a thyroid swelling. Presence of hoarseness, dyspha-
gia, and inspiratory stridor should trigger the close differential diagnosis of primary
aerodigestive intraluminal pathology. It is easy to assume that such aerodigestive
symptoms are secondary to a pressure effect of a primary thyroid goiter [88]. The
scenario may be complicated by the presence of anterior midline neck mass that
moves with swallowing, which is considered pathognomonic of a thyroid lesion.
The prompt and precise diagnosis is crucial in order to initiate timely adequate
intervention. Delay in diagnosis may increase the risk of the patient to suffer from
the complications of hypoxia such as cardiac arrest.
Laryngeal SCC may spread by direct extension to adjacent structures or metas-
tasis to regional cervical LNs or via the bloodstream. The most common site of
distant metastases is the lung. Op de Beeck et al. (2001) reported two cases of laryn-
geal SCC presenting with a midline pre-laryngeal neck mass. Pathological examina-
tion after total laryngectomy showed cancer localized in one of the true vocal cords,
invading the anterior commissure and thyroid cartilage. However, the pre-laryngeal
soft tissues were free of tumor, showing only inflammatory changes and collections
of pus and presenting as a pre-laryngeal neck abscess [89].
Imaging Studies
Both CT scan and MRI can be used to assess and stage laryngeal SCC, while
PET-CT can be used to assess for post-resection recurrence [86]. The radiological
features of supraglottic, glottic, and sub-glottic laryngeal SCC are summarized in
Table 7.3.
Diagnosis
Diagnosis can be reached by thorough medical history, physical examination, and
special investigations, which may include a chest X-ray, CT or MRI scans, and tis-
sue biopsy.
Physical examination includes a general systematic examination to assess gen-
eral health and to look for signs of associated conditions and metastatic disease. The
neck and supraclavicular fossa are palpated to feel for cervical adenopathy, other
masses, and laryngeal crepitus. The oral cavity and oropharynx are examined under
direct vision. The larynx may be examined by indirect laryngoscopy. Many special-
ists now use fiber-optic nasal endoscopy where a thin and flexible endoscope,
inserted through the nostril, is used to clearly visualize the entire pharynx and larynx.
If there is a suspicion of cancer, biopsy is performed, usually under general anes-
thesia, to provide histological proof of type and grade of cancer. If the lesion appears
Table 7.3 Characteristic features of CT scan and MRI in SCC of the larynx
Imaging Supraglottic carcinoma Glottic carcinoma Sub-glottic carcinoma
CT scan – Supraglottic soft – Enhancing exophytic or – Enhancing soft
tissue mass with infiltrative true vocal fold mass tissue at the level of
moderate enhancement, the cricoid cartilage
causing asymmetry of
the laryngeal sides, and
cartilage sclerosis
– Enlarged LNs – It can assess tumor
>1.5 cm in short axis extension to anterior
– It can assess tumor commissure, posterior
extension commissure, supra- or
sub-glottis
MRI – T1: low signal – T1: low signal – T1: low signal
– T2: high signal – T2: high signal – T2: high signal
– T1C + (Gd): – T1 C + (Gd): – T1 C + (Gd):
homogeneous/ homogeneous enhancement heterogeneous
heterogeneous enhancement
enhancement ±
obliteration of
para-glottic fat
Gd Gadolinium
to be small and well localized, the surgeon may undertake a complete excision
biopsy with free margins. A full endoscopic examination of the larynx, trachea, and
esophagus is often performed at the time of biopsy.
Treatment
The final management plan depends on the site, stage, and histological type of the
tumor, as well as the overall health of the patient. Treatment may involve surgery,
RT, or chemotherapy, alone or in combination. Adverse effects of treatment can
include changes in appearance, dysphagia, dry mouth, or loss of voice that may
require learning alternate methods of speaking. A prognostic multigene classifier
has been shown to be potentially useful for the distinction of laryngeal cancer of low
or high risk of recurrence and might influence the treatment choice in future [90].
Surgical Treatment: It may involve partial or complete tumor [91]. Neighboring
tissues and structures may or may not be removed, depending on their involvement
[92]. Total laryngectomy may be necessary in some cases. Although small tumors
may be treated with laser therapy or RT, larger tumors may require combination RT
and total laryngectomy. Voice-sparing supraglottic laryngectomy for supraglottic
lesions with no cord fixation is also possible [86].
Adjunct Treatment: Adjunct treatment, most commonly the administration of
chemotherapy or RT, may be necessary [92]. Chemotherapy or RT may be
necessary singly, in combination with each other, or in combination with surgery

[93]. Adjunct treatment may be necessary prior to surgical treatment, alongside sur-
gical treatment, or after surgical treatment.
Multidisciplinary Treatment: Often, successful treatment of and recovery from
laryngeal cancer will involve expertise outside of the realms of surgery or oncology.
Physical, occupational, and speech therapists, psychiatrists/psychologists, oral/
maxillofacial surgeons, dentists, neurologists, neurosurgeons, and endocrinologists
may all become involved in the care of patients with laryngeal SCC.
Adenoid Cystic Carcinoma of Larynx (ACCL)
Epidemiology
Adenoid cystic carcinoma of larynx (ACCL) is extremely rare representing less
than 1% of all laryngeal malignant tumors, with the sub-glottis the most common
location (60%) followed by the supraglottis (35%) and glottis [82, 94–96], probably
due to the higher distribution density of subepithelial glands in the sub-glottic and
supraglottic areas compared to the glottis [97, 98].
The incidence of ACCL has been reported as 0.005 per 100,000 population [99].
According to literature review, fewer than 200 case reports have been published on
ACCL worldwide [100]. ACCL is slightly predominant in men, with a male:female
ratio of 1.5:1 [97]. However, some authors reported that the gender distribution of
this tumor is equal [82, 96]. The mean age is in the 50s (range, 12–84 years), with
clear predominance of the white race [94, 97, 99].
Etiology
The exact etiology of ACCL remains unknown [95, 96]. There are no distinct risk
factors that predispose patients to this malignancy [101, 102]. Unlike squamous cell
carcinoma (SCC), the most common laryngeal tumor, smoking has not been shown
to be a risk factor for the development of ACCL [82, 96, 101–103].
Clinical Picture
As a result of the submucosal location of ACCL, it tends to present late, as a large
mass. Symptoms are indicative of tumor location with supraglottic lesions com-
monly causing dysphagia, sub-glottic tumors presenting with dyspnea, and glottic
lesions associated with hoarseness of voice [96, 97, 104–106].
In their systematic review of 50 articles and 120 cases, Marchiano et al. reported
that the most common presenting symptom of ACCL was dyspnea (48.8%), fol-
lowed by hoarseness (43.9%). A midline neck mass was found in 9.8% of patients,
and 14.6% (13 of 89) of patients had regional disease at presentation [97]. In addi-
tion, ACCL can present with pain, most likely secondary to perineural invasion
[103]. In general, ACCL is characterized by slow growth, multiple recurrences, and
late distant metastasis, commonly to the lungs [100, 102, 104, 107].
Pathology
Histopathological analysis is essential because the symptoms do not differ greatly
from SCC. It is generally believed that ACCL arises from submucosal glands pres-
ent within the larynx [108]. Histologically, ACCL is categorized into three discrete
phenotypes: (1) cribriform (most common—best prognosis) [102, 109], (2) tubular
(good prognosis), and (3) solid (poor outcome) [97, 101, 102, 110, 111]. In all these
three types, the cells are surrounded by hyaline or mucoid material, which gives it a
cribriform or lacelike pattern [112].
The cribriform pattern is described as being characterized by fenestrated cells
arranged in nests or sheets and composed of pseudocysts surrounded by basaloid
cells (Fig. 7.2). It may also involve the cartilage (Fig. 7.3) and striated muscle [109].
Immunohistochemistry (IHC) confirms the diagnosis of ACCL, being positive
for p63 and cytokeratin (CK) 7, but negative for CK 20 (Fig. 7.4).

picture of adenoid cystic
carcinoma of larynx
(ACCL) showing a
cribriform pattern with
small, bland
hyperchromatic cells
forming pseudo-glandular
spaces filled with a
mucinous, pink to pale
purple material (H&E
×400)

picture of adenoid cystic
carcinoma of larynx
(ACCL) deeply infiltrating
the laryngeal mucosa. The
tumor shows a
predominant cribriform
pattern, composed of
pseudocysts, filled with
basophilic mucin,
surrounded by basaloid
cells, and invading the
cartilage (H&E ×200)
a b
Fig. 7.4 Microscopic picture of adenoid cystic carcinoma of larynx (ACCL) with immunohisto-
chemical stains. (a) Cytokeratin 7 stained the luminal epithelial cells rimming the
mucopolysaccharide-
filled spaces (×200), (b) p63 stained the nuclei of outer myoepithelial
cells (×400)
Characteristically, ACCL has an infiltrative growth pattern, a tendency for peri-

neural invasion, and a susceptibility for hematogenous spread. Moreover, ACCL
tends to infiltrate into the surrounding structures in a slow manner and occasionally
causes late recurrence or distant metastases [102, 112].
Imaging Studies
The most common imaging technique used for ACCL is computed tomography
(CT) scan, which provides valuable information regarding tumor location, exten-
sion, and regional invasion [102]. Findings on CT imaging most often describe a
heterogeneous mass and may show invasion of the cricoid or thyroid cartilage
(Fig. 7.5).
Treatment
Due to their rarity, treatment of choice of ACCLs is still controversial. Surgical exci-
sion is the mainstay of management of LACC [96, 99, 113, 114]; however, the
appropriate surgical resection, as well as the role of radiotherapy (RT), remains
controversial and has not been standardized yet [102]. Some authors recommend
radical surgery (total laryngectomy) [82, 102, 115] even if wide local excision
allowed to preserve laryngeal function. Their choice is argued by the relative radio-
resistance of this kind of tumor [116] as ACCL is radiosensitive, but not radio-
curable [82, 97]. On the other hand, other authors support combined treatment with
preservative surgery (partial laryngectomy) and postoperative RT and recommended
reservation of more aggressive measures for treatment of tumor recurrence [103,
113, 117–119].
Some authors argue that the extent of resection should be based on tumor loca-
tion, with sub-glottic tumors necessitating a total laryngectomy and supraglottic
lesions being managed with a partial laryngectomy [115]. Other indications of
Fig. 7.5 Computed

tomography (CT) scan of
the larynx showing left
vocal cord mass and
destruction of the left side
of thyroid cartilage
partial laryngectomy include small, well-defined tumors and negative surgical

resection margins [103, 113, 115]. In addition, neck dissection should be performed
in patients who are clinically or histologically confirmed to have nodal metastases
[101, 120, 121]. Regular close and long-term follow-up is mandatory in patients
with ACCL to detect late relapse and metastasis [122].
The role of adjuvant RT for LACC is debated in the literature [14–18]. Adverse
features such as close or positive margins, T3–4, intermediate or high grade, neural
and perineural spread, lymphatic or vascular invasion, or LN metastases should
indicate adjuvant treatment to improve the outcome and local control irrespective of
the type of surgery performed [114]. The use of standard chemotherapies has sys-
temic toxicities and limited efficacy in ACCL [123, 124]. Chemotherapy, as an adju-
vant or neoadjuvant therapy, may be useful for high-grade tumors [96, 125], and
some authors have reported positive responses to chemotherapy, recommending it
as palliative therapy in advanced cases [126].
Prognosis
In the review by Marchiano et al. [97], distant metastasis was reported in 30 cases
(33.3%) at an average follow-up period of 54 months. Surgery alone (43.3%) and
surgery with RT (43.3%) were used most frequently and resulted in a disease-free
survival rate of 57.1% and 55.3%, respectively.
The prognosis of ACCL depends mainly on the tumor characteristics, rather than
the LN extension and distant disease. Indeed, LNs are usually negative, and distant
metastasis rarely occurs, while the tumor size and invasion are often advanced at the
time of diagnosis [100]. It appears that histological subtypes have a prognostic sig-
nificance, with the “tubular” subtype reported to have the best prognosis and the
“solid” the worst [102, 111].
ecent Case Reports

R
Testa et al. (2013) presented an unusual case of ACCL in a 61-year-old asthmatic
lady treated as ultrasound-confirmed benign nodular goiter. However, dyspnea
persisted after thyroidectomy, and the final pathological examination was char-
acteristic for ACCL. Fiber-optic laryngoscopy showed hypertrophy of the left
vocal fold, in the midline position, ipsilateral hypo-glottic region, and subcom-
missural region neoformation, with narrowing of the lumen. The subsequent cer-
vicothoracic CT scan showed a nodular lesion of the left part of larynx, associated
with partial destruction of the thyroid cartilage, cricoid ring, and ipsilateral ary-
tenoid cartilage, in the presence of bilateral cervical lymphadenopathy.
Accordingly, the patient was submitted to a total laryngectomy with functional
bilateral LN dissection of II–VI levels. The pathological examination confirmed
the diagnosis of ACCL deeply infiltrating the laryngeal mucosa, cricoid carti-
lage, and striated muscle tissue, with a predominantly cribriform pattern, con-
sisting of pseudocysts, filled with mucin basophilic basaloid cells, surrounded by
areas of intra-tumoral necrosis and absence of cervical LN metastases. The
patient then underwent RT with a total dose of 66 Gy. Follow-up endoscopy and
laryngeal magnetic resonance imaging (MRI) at 3 years after treatment showed
no recurrence of the tumor [82].
Recently, Naim et al. (2019) described an unusual clinical and radiological pre-
sentation of histologically proven ACCL in a 38-year-old lady with a history of
asthma who presented with acute inspiratory dyspnea that required an emergency
tracheotomy. Physical examination revealed a large anterior cervical mass without
any lymphadenopathy suspecting thyroid origin. Cervical CT scan showed a tumor
(34 × 25 × 50 mm) between the thyroid lobe, edge of the sub-glottic area, and first
tracheal rings filling all the lumen, respecting the vocal cords and arytenoids, but
invading the cricoid cartilage. Panendoscopy confirmed a sub-glottic extension of
the tumor, and multiple biopsies showed a malignant salivary origin of the mass in
the sub-glottic floor without invasion of neither vocal cords nor trachea. The patient
underwent total laryngectomy and thyroidectomy with bilateral selective neck dis-
sections (levels II–IV). Anatomo-pathological examination showed an infiltrative
carcinomatous proliferation, arranged in tubes and in cribriform masses compatible
with ACCL. The tumor was classified as pT4aN0 since it infiltrated the thyroid and
cricoid cartilages as well as the thyroid gland. Adjuvant radiation therapy (RT) was
indicated for this case [100].
In 2022, Eslami et al. reported a case of ACCL in a 41-year-old gentleman that
was treated with chemotherapy. Seven years later, the patient presented with dys-
pnea, hoarseness, and stridor. Indirect laryngoscopy detected a sub-glottis
submucosal mass. Computerized tomography (CT) scan showed a submucosal

mass in the sub-glottic area that extended to the cricoid and thyroid cartilages
and thyroid gland. Histopathological examination showed recurrence of ACCL
that showed the three defined patterns: cribriform, solid, and less frequently
tubular. Diagnosis was confirmed by IDC. The patient underwent total laryngec-
tomy and total thyroidectomy without neck dissection. Final pathology showed
ACCL with free surgical margins and no perineural invasion. However, the thy-
roid gland was involved by tumor. The patient was then scheduled for adjuvant
RT, and during 2 years’ follow-up, there was no evidence of recurrence or metas-
tasis [122].
7.4 Prominence of Adam’s Apple
Introduction
The Adam’s apple (laryngeal prominence or laryngeal protuberance) (Latin:

Prominentia laryngea) is the protrusion in the human neck formed by the angle of
the thyroid cartilage where the two halves of the cartilage meet [127]. It is typically
larger and more externally noticeable in adult males. The classic measurement of
the interlaminar angle (ILA) at the level of the vocal processes is 90° in the male
population and 120° in females. The broader angle in women causes it to be less
visible. There are two reasons for this phenomenon. Firstly, the structural size of the
thyroid cartilage in males tends to increase during puberty, and the laryngeal protu-
berance becomes more anteriorly focused. Secondly, the larynx, which the thyroid
cartilage partially envelops, increases in size in male subjects during adolescence,
moving the thyroid cartilage and its laryngeal protuberance toward the front of the
neck. The adolescent development of both the larynx and the thyroid cartilage in
males occurs as a result of hormonal changes, especially the normal increase in
testosterone production in adolescent males [128].
lood Supply and Lymphatics

B
The thyroid cartilage is supplied by the superior laryngeal artery, which divides
from the superior thyroid artery soon after its origin from the external carotid artery,
and before it courses inferiorly. The artery travels with the internal branch of the
superior laryngeal nerve and pierces the thyrohyoid membrane.
The area surrounding the thyroid cartilage is drained by the superior laryngeal
vein superiorly, as it protrudes from the thyrohyoid membrane to join the superior
thyroid vein, which empties into the internal jugular vein (IJV).
The lymphatic drainage of this area is provided by the superior deep cervical
LNs and pre-tracheal nodes that drain into the superior deep cervical lymphatic
basins. The superior deep cervical chain runs underneath the SCM muscle along
7.4 Prominence of Adam’s Apple 169
with the IJV and accessory nerve. On the left side, this merges with the thoracic duct
and with the brachiocephalic vein on the right.
Related Nerves
The laryngeal prominence of the thyroid cartilage is a supportive, protective struc-
ture with no distinct, named innervation. However, its location sits in between the
internal and external branches of the superior laryngeal nerve, of the vagus nerve.
Superiorly, the internal branch pierces the thyrohyoid membrane to provide sensa-
tion to the laryngeal mucosa. Inferiorly, the external branch reaches to innervate the
cricothyroid muscle. Other important related nerves include the vagus nerve (CN-
X) laterally, coursing down inferiorly in the carotid sheath, and the ansa cervicalis,
which innervates the overlying strap muscles.
Muscles
The thyrohyoid membrane connects the thyroid cartilage to the hyoid bone superi-
orly. The laryngeal prominence itself is directly attached to the hyoid by the median
thyrohyoid ligament. The thyrohyoid muscle receives innervation from hypoglossal
nerve (CN-XII) and C1 and works to depress the larynx. The infrahyoid, or “strap,”
muscles (sternohyoid and sternothyroid muscles) serve to depress the hyoid bone
and course anteriorly to the thyroid cartilage.
Function and Clinical Significance
The Adam’s apple primarily acts to protect the walls of the larynx and the vocal
cords posteriorly. Another function is related to the deepening of the voice. During
adolescence, the thyroid cartilage grows together with the larynx. Consequently, the
laryngeal prominence grows in size mainly in men. Together, a larger soundboard is
made up in the phonation apparatus and, as a result, men get a deeper voice
note [129].
The Adam’s apple is one of the most significant laryngeal structures visible exte-
riorly. Its location is important in many surgical and emergency procedures, most
notably in identifying the cricothyroid membrane for a cricothyroidotomy. This pro-
cedure is more difficult in women, given the more pronounced angulation in men.
Additionally, as the Adam’s apple is a secondary sex characteristic, its appear-
ance is a cosmetic consideration in the transsexual community and those exploring
gender affirmation/reassignment surgery.
Surgical Considerations
Chondrolaryngoplasty (thyroid cartilage reduction), also known as “tracheal shave”

or “laryngeal shave,” is a cosmetic outpatient procedure done to reduce the visible
prominence of the Adam’s apple. The surgery is effective and has an excellent prog-
nosis, such that complications tend to be few and, if present, transient [130]. In
patient’s post-gender affirmation surgery, it is occasionally performed in conjunc-

tion with a crico-thyroidopexy procedure that aims to raise the pitch of the patient’s
voice [131].
The ala, or laminae, of the thyroid cartilage can also provide donor tissue for
cartilage grafts. It has been used in laryngotracheoplasty to repair pediatric tracheo-
cutaneous fistulas [132], as well as commonly being used in laryngotracheal recon-
struction in the pediatric population [133].
7.5 Chondritis of the Thyroid Cartilage
Purulent Chondritis
Definition
Purulent chondritis of the laryngeal cartilage is defined as chondritis of the laryn-
geal framework cartilage with abscess formation between the inner and outer peri-
chondria. It is a rare clinical entity with only few reports of this condition in the
literature [134, 135].
Etiology
Reported possible causes of purulent chondritis include prolonged intubation,
relapsing polychondritis or other autoimmune disease, previous radiotherapy (RT),
and trauma. It may be idiopathic [134, 135]. Risk factors include diabetes mellites
(DM), prolonged steroid use, and immune incompetence [136, 137].
Learned et al. (2020) reported a 77-year-old lady who presented with dry cough and
hoarseness of voice, without night fever and night sweating. She received medical
treatment (antihistaminics and antibiotics), but did not improve, and developed ody-
nophagia and a midline neck swelling. She was referred for laryngeal neoplasm;
however, the correct imaging assessment avoided misdiagnosis and allowed prompt
appropriate surgical management [138].
In 2007, Lee et al. presented a patient who suffered from generalized weakness,
myalgias, and sore throat for 1 month and hoarseness for 10 days before diagnosis.
Fiber-optic laryngoscopy demonstrated a granuloma-like, whitish, exophytic mass
in the anterior commissure of the false vocal cords and erythema and edema in both
the arytenoid and false vocal cord mucosa. On CT scan, abscess formation between
the intact inner and outer perichondria of the thyroid cartilage was found. Treatment
included rigid endoscopy, external incision and drainage, and steroid and antibiotic
therapy. The culture resulted in no growth [135].
Eliashar et al. (2005) reported three patients with purulent chondritis of the thy-
roid cartilage. The probable causes were relapsing polychondritis, a previous pro-
longed intubation, and an idiopathic cause. The patients suffered from hoarseness of
voice and inspiratory stridor for 1–3 months before diagnosis. None complained of
pain in the neck. Laryngoscopy showed supraglottic edema, while CT scan revealed
abscess formation between the intact inner and outer perichondria of the thyroid
cartilage. Treatment included rigid endoscopy, external incision and drainage, and
prolonged medical therapy. The culture results were Staphylococcus aureus in the
first two cases and Aspergillus fumigatus in the third. The second patient (in whom
the cricoid cartilage was also affected) required emergency tracheotomy. The other
two patients did not require airway intervention. They concluded that the rarity of
this condition and the relatively mild symptoms require a high index of suspicion
for its diagnosis [134].
Investigations
Blood tests should include complete blood count (CBC), basic metabolic panel,
Cryptococcal and Aspergillus antigen assay, Coccidioides antibody, rapid plasma
reagin, human immunodeficiency virus (HIV) types 1 and 2 RNA, T-spot tubercu-
losis test (to exclude tubercular abscess), C-reactive protein (CRP), erythrocyte
sedimentation rate (ESR), autoimmune panel, and histoplasma urine antigen
test [138].
Recognizing the unique imaging features of purulent chondritis of the laryn-
geal cartilage is the key to the correct diagnosis, guiding prompt and appropri-
ate clinical evaluation and management. Ultrasound (US) of the anterior
midline neck at the level of larynx usually shows diffuse expansion of bilateral
thyroid cartilage ala with internal anechoic/hypoechoic fluid and debris. The
unique CT imaging features of expansile laryngeal cartilage with peripheral
rim enhancement and central fluid attenuation correlate with abscess formation
between the inner and outer perichondria (purulent chondritis) (Fig. 7.6) [134,
Fig. 7.6 Contrast-

enhanced CT of the neck
showing expansion of the
thyroid cartilage (arrows)
with internal hypo-
attenuation and peripheral
rim enhancement denoting
abscess formation between
the perichondria. The
anterior midline enhancing
tissue (arrowhead)
corresponds to the
exophytic lesion at the
petiole/anterior
commissure
135]. Such unique CT imaging features differ from the invasive soft tissue
SCC, lytic expansile chondrosarcoma with ring-and-arc matrix, or autoimmune
disorders.
Ultrasound-guided FNA reveals yellowish, turbid, material, with abundant neu-
trophils and no malignant cells on cytology, which is useful for initial tissue biopsy
and microbiology [138]. Flexible nasopharyngeal laryngoscopy (under anesthesia)
may show hyperemic and edematous vocal cords with a round lesion at midline
petiole/anterior commissure [138].
The differential diagnosis of this rare entity includes invasive squamous cell carci-
noma (SCC), chondrosarcoma, and rare autoimmune diseases [139].
Symptoms of SCC depend on the size and location of the tumor. Symptoms may
include voice changes, a lump in the neck, sore throat, persistent cough, stridor, foul
breath, earache (due to referred pain), and dysphagia. Usually, there is a history of
chronic smoking and heavy alcohol consumption, the main risk factors. Diagnosis
can be reached by thorough medical history, physical examination, and special
investigations, which may include a chest X-ray, CT or MRI scans, flexible endos-
copy, and tissue biopsy.
Laryngeal framework chondrosarcoma comprises less than 1% of all laryngeal
tumors and affects males more than females, in the sixth decade of life [140]. The
most common symptoms are hoarseness and dyspnea. Laryngeal chondrosarcomas
arise from the cricoid cartilage more commonly than the thyroid cartilage [140]. It
exhibits an expanded low attenuation appearance with stippled or coarse intra-
tumoral calcification [139].
The common autoimmune diseases that can clinically present with laryngeal
symptoms in adults include relapsing polychondritis and granulomatosis with
polyangiitis. Relapsing polychondritis is characterized by inflammation and
destruction of different cartilaginous structures, including the ear, nose, larynx,
trachea, bronchi, and peripheral joints as well as the heart’s connective compo-
nents [141]. The disease is associated with other autoimmune diseases in about
30% of cases [141]. Laryngo-tracheo-bronchial involvement appears in nearly
half of the patients, but the common clinical presentations are sudden onset of
painful auricular and nasal chondritis, or polyarthritis. Typical CT findings of
relapsing polychondritis include sub-glottic stenosis, tracheobronchial wall
thickening with calcification with sparing of the posterior membranous wall,
calcifications of the pinnae, and nasal cartilage collapse [142, 143].
Granulomatosis with polyangiitis is an idiopathic vasculitis of medium and
small arteries, characterized by necrotizing granulomatous inflammation. The
disease typically affects upper and lower respiratory tract with coexisting glo-
merulonephritis and is generally diagnosed by the presence of antineutrophil
cytoplasm antibodies [144]. The sino-nasal cavity is most commonly affected in
the upper respiratory tract with mucosal thickening, soft tissue nodules, and
bone destruction.
Treatment
Appropriate treatment of purulent chondritis of the thyroid cartilage entails external
incision and drainage of the anterior midline neck at the level of the thyroid carti-
lage. The anterior commissure lesion can be excised through direct laryngoscopy
exam under anesthesia in the operating room.
Tuberculous Chondritis
Epidemiology
Tuberculosis (TB) was a highly prevalent disease in humans for many decades until
the early 1900s and is still the main cause of death in some parts of the world. In
2007, approximately 13.7 million people contracted TB and 1.8 million died as a
result of the disease. A total of 68% of newly infected people were of Asian or
African origin, whereas ethnic Europeans only made up 5% of global TB cases
[145]. After the introduction of antituberculous agents, preventive programs, and
improvement of socio-economic conditions, TB incidence decreased dramatically
up until the 1980s [145–148]. However, in subsequent years, the epidemic spread of
human immunodeficiency virus (HIV), illicit drug use, and emergence of multidrug-
resistant mycobacteria have resulted in a resurgence of TB. In 1993, it became the
leading cause of death from a single infectious agent. Increased numbers of migra-
tion and traveling to and from less developed countries also contributed to the
worldwide spread of TB [147–151]. A minority of underdeveloped, mainly African,
countries have been the major contributors to the global incidence growth [145].
Extrapulmonary TB in the head and neck region most frequently occurs in the
cervical lymph nodes (LNs) (>90%), followed by the larynx (2–6%) [152, 153].
Temporal bone, sino-nasal cavity, eye, pharynx, thyroid gland, and skull base are
even less frequently involved [148, 152, 153].
Laryngeal tuberculosis (LTB) is the most common granulomatous disease of the
larynx and used to be a common complication of pulmonary TB. At the beginning
of the twentieth century, it affected 25–30% of all infected patients. Today, laryn-
geal TB occurs in only 1% of cases [148, 152–154]. The pattern and clinical symp-
toms of laryngeal TB have also changed. It might be localized in the larynx as a
primary lesion without pulmonary involvement [155], which makes its diagnosis
rather difficult [156]. Currently, it has many similarities to laryngeal carcinoma, and
it more closely resembles a laryngeal carcinoma than any other laryngeal illness
[148–151, 157]. Moreover, in the past, LTB typically affected young people, with
advanced pulmonary TB, in the second or third decade of life. However, today, LTB
involves mainly people in their 50s or 60s [158].
Laryngeal TB can involve all parts of the larynx, and there is no longer an unmistak-
able association with pulmonary TB. The larynx becomes infected either by direct
spread from the lungs or by hematogenous spread from other sites [149, 157, 159],
with no evidence of pulmonary disease [147, 151, 153]. Symptoms of LTB usually
include cough, fever, hemoptysis, weight loss, and night sweats. An ulcerative gran-
ulomatous lesion is generally caused on the posterior part of the larynx, in bedrid-
den patients, due to accumulation of sputum in the arytenoid region. Currently,
patients with LTB primarily present with hoarseness of voice (80–90%), odynopha-
gia (50–67%), and to a lesser extent dysphagia, dyspnea, stridor, cough, and hemop-
tysis [158]. In a physical examination, the true vocal cords are most frequently
affected by LTB, followed by the epiglottis, false vocal cords and ventricles, aryte-
noids, posterior commissure, and sub-glottic area [148, 151, 159]. Laryngeal TB
can manifest as edema, hyperemia, or ulcerative lesions in the larynx and can also
present as a nodule, an exophytic mass, or diffuse obliteration of an anatomical
structure [159]. Systemic symptoms have become rare [146, 148–151, 157].
In 2016, Monga et al. reported a 26-year-old young gentleman who presented
with a painful swelling over the thyroid region. He had no dysphagia, hoarseness of
voice, or cough, and no constitutional symptoms of fever, weight loss, or loss of
appetite. On examination, there was a small ill-defined, tender indurated area about
1 × 1 cm over the thyroid region with hyperemic overlying skin. There was no cervi-
cal lymphadenopathy. Indirect laryngoscopic examination was normal, and FNAC
was suggestive of subacute thyroiditis. His hematological and biochemical investi-
gations were normal, and serology for HIV was negative. He was treated with oral
steroids and oral antibiotics in view of subacute thyroiditis. However, he returned
after 1 week with an abscess over the thyroid region, approximately 3.5 × 4 cm in
size, fluctuant, and tender on palpation. Ultrasonography showed a well-defined
superficial collection around 3.5 × 1.5 × 2.5 cm in size suggestive of cervical abscess
with normal thyroid gland. The patient did not respond to IV amoxiclavulanic acid,
gentamicin, and metronidazole. In addition, he developed hoarseness of voice and
dysphagia. Contrast-enhanced CT scan revealed an infiltrating mass destroying the
left lamina of thyroid cartilage and strap muscles, reaching up to the subcutaneous
plane with asymmetrical thickening of left vocal cord, suggestive of a malignant
process. Biopsy of the larynx was taken through the necrosed cartilage, and histo-
pathological examination settled the diagnosis of LTB. The patient finally responded
to anti-TB standard therapy [160].
Diagnosis/Differential Diagnosis
Diagnostic studies for detecting TB infections include histopathological tissue
examinations with Ziehl-Neelsen histochemical staining for acid-fast bacilli and
identification of M. tuberculosis by polymerase chain reaction (PCR) or bacterial
culture. The latter method, although time-consuming, is considered the reference
standard [161].
A computed tomography (CT) of the neck cannot definitively identify LTB since,
as in a chest X-ray, it can imitate many other diseases. However, characteristic CT
scan findings of LTB include bilateral involvement, thickening of the free margin of
the epiglottis, good preservation of the pre-epiglottic and para-laryngeal fat spaces,
as well as primary integrity of the laryngeal structure (even in the presence of exten-
sive mucosal involvement). Thus, cartilage destruction is not usually seen on CT
scans in LTB [162].

showing a necrotizing
granulomatous
inflammation; granulomas
on the left side and
necrosis on the right (H&E
stain)

showing red-stained
Mycobacterium
tuberculosis in Ziehl-
Neelsen acid-fast stain
Histopathology settles the diagnosis of LTB by demonstrating epithelioid cell

granulomas with chronic inflammatory cells and caseous necrosis, without features
of malignancy [158] as shown in Fig. 7.7. Ziehl-Neelsen staining of the tissue biop-
sies and sputum will reveal acid-fast bacilli (Fig. 7.8).
Laryngeal carcinoma is the main differential diagnosis of LTB. Other differen-
tials include sarcoidosis, cat scratch disease, syphilis, leprosy, lethal midline granu-
loma (midfacial necrotizing lesion characterized by destructive mucosal lesions of
the upper aerodigestive tract), Wegener’s granulomatosis, fungal infections, and
chronic nonspecific laryngitis [152, 163].
The distinction between LTB and chronic laryngitis or laryngeal carcinoma in
particular has become difficult. Odynophagia is described as an important discrimi-
nating symptom, since it is considered rare in laryngeal cancer [146, 149–151, 157].
Laryngeal carcinoma characteristically presents with unilateral involvement, infil-

tration of the pre-epiglottic and para-laryngeal fat spaces by a submucosal mass,
cartilage destruction, and extra-laryngeal invasion [164]. In 2003, Kenmochi et al.
reported a case of LTB involving the right wing of thyroid cartilage combined with
whole-bone metastasis that included the cervical spine and thoracic spines [165].
Treatment
The primary treatment of LTB is by standard antituberculous therapy for 6 months.
It includes isoniazid 300 mg/day, rifampicin 600 mg/day, pyrazinamide 1500 mg/
day, and ethambutol 1400 mg/day. Improvement of dysphagia and resolution of
cavernous lung lesions are expected to occur within several weeks [150, 159, 166].
Monga et al. (2016) reported that, in their case, the tuberculous swelling disap-
peared in 2 weeks and hoarseness in 2 months [160]. If not treated early, LTB can
result in sub-glottic stenosis, muscular involvement, and vocal cord paralysis when
the cricoarytenoid joint or recurrent laryngeal nerve (RLN) is involved [149, 159].
7.6 Retropharyngeal Abscess (RPA)
Pyogenic Retropharyngeal Abscess (RPA)
Introduction
Retropharyngeal abscess (RPA) is an uncommon but potentially life-threatening
abscess, located in the tissues behind the posterior pharyngeal wall (retropharyngeal
space). It is most common in children under the age of 5 years but also occurs in
adults. Typically, patients under the age of 5 have an antecedent upper respiratory
tract infection (URTI) leading to suppurative cervical lymphadenitis and eventually
RPA. In older children and adults, an RPA can be caused by trauma to the posterior
pharynx, which leads to inoculation of the retropharyngeal space and abscess
formation.
Because RPAs typically occur in deep tissue, they are difficult to diagnose by
physical examination alone. RPA is relatively uncommon and therefore may not
receive early diagnosis in children presenting with stiff neck, malaise, or dysphagia.
Early diagnosis is key, while a delay in diagnosis and treatment may lead to death.
The parapharyngeal space communicates with the retropharyngeal space, and an
infection of the latter can pass down behind the esophagus into the mediastinum.
As an RPA grows in size, it can lead to airway obstruction or septicemia—both
life-threatening emergencies [167]. Mortality usually occurs from patients not
receiving treatment immediately and suffocating prior to correct diagnosis of this
serious condition. Treatment of RPA ranges from prolonged courses of intravenous
(IV) antibiotics to surgical incision and drainage (I&D) [168–170].
Epidemiology
Although an uncommon diagnosis, the incidence of RPA has been increasing in
recent years, according to data collected from 2000 through 2009 [168, 171]. Older
studies reported the incidence of retropharyngeal abscesses to range between 1 and

4.5 cases per year [172–175]. This low value was attributed to improvements in
health care, immunization, and development of new antibiotics [176]. However,
within the last two decades, the incidence seems to have increased, reaching up to
six cases/year [177]. Two reasons may explain this finding. First is an apparent
increase in cases due to the increased availability and use of CT scans in hospitals
[178–180]. Second is the inappropriate antibiotic use, which may have contributed
to a rise in antibiotic-resistant organisms [181].
Retropharyngeal abscess typically occurs in children between the ages of 2 and
4 years but may occur at any age. Approximately, 60% of retropharyngeal abscesses
are believed to be attributed to antecedent URTIs, and nearly 25% are attributed to
retropharyngeal trauma [182].
Etiology
The retropharyngeal space extends cranio-caudally from the base of the skull to the
posterior mediastinum and is enclosed by the buccopharyngeal and alar fascia.
Retropharyngeal abscess is a suppurative collection within this space. The retropha-
ryngeal space contains chains of lymph nodes (LNs) that drain the nasopharynx,
adenoids, posterior paranasal sinuses, and middle ear. These LN chains are present
in young children but undergo atrophy and involution typically by the age of
4–5 years. Retropharyngeal abscess (RPA) is usually caused by a bacterial infection
originating from the nasopharynx, tonsils, sinuses, adenoids, molar teeth, or middle
ear. Any upper respiratory tract infections (URTIs) can be caused by lymphatic or
contiguous spread. Direct expansion from spinal discitis or osteomyelitis is a rare
cause of an RPA as well.
Retropharyngeal abscesses are often polymicrobial infections. Bacteria that
commonly contribute to these infections include group A Streptococcus pyogenes,
Staphylococcus aureus, Fusobacterium, Haemophilus species, and other respiratory
anaerobes [168–170].
While approximately 60% of RPAs in children are caused by URTI, most infec-
tions in adults are caused by direct infection due to penetrating injury or pharyngeal
trauma from endotracheal intubation, nasogastric tube insertion, endoscopy, as well
as foreign body (FB) ingestion or removal. Pharyngeal FBs are quite common. In
adults, it is common in patients with dental prosthesis, psychotics or those with
mental retardation, alcoholics, and those in old age. The most common pharyngeal
FB encountered is fish bone or chicken bone fragment [183, 184]. Approximately,
one-fourth of retropharyngeal abscesses are attributed to the trauma of the posterior
pharynx resulting in inoculation of the retropharyngeal space, cellulitis, phlegmon
formation, and eventually RPA formation [185–187]. Primary infections of the ton-
sils and of the dentition in young children who do not have adequate dental care or
brush their teeth properly can also evolve into retropharyngeal abscesses, though
more commonly into peritonsillar (quinsy) or parapharyngeal abscesses, respec-
tively [168–170].
Risk factors of RPA include poor oral hygiene, diabetes mellites, immuno-
compromise, and low socio-economic status. As the RPA grows in size, it results in
gradual upper airway obstruction and eventually asphyxia if left untreated. Although
mortality from sepsis does occur in these patients, the number one cause of death in
patients with RPA remains upper airway occlusion [188, 189].
Clinical Picture/Complications
Early RPA presents similarly to uncomplicated pharyngitis. Generally, aspects of a
patient’s history of concern for early RPA are antecedent URTI in children or trauma
to the posterior pharynx in adults. As this infection progresses, symptoms related to
upper aerodigestive obstruction become more prominent and typically progress
over days. Red flags in a patient’s history, which should be concerning for upper
aerodigestive obstruction, include dysphagia, odynophagia, inability to tolerate oral
secretions, neck stiffness, torticollis, refusal to extend the neck due to pain or dis-
comfort, change in voice, “hot potato voice,” muffled voice, trismus, neck swelling,
cervical lymphadenopathy (CLA), chest pain (mediastinal extension), and respira-
tory distress (stridor, tachypnea, retractions) [190, 191].
Initially, RPA was thought to be a disease limited to children around 5 years of
age, but now it is being encountered with an increasing frequency in adults.
Symptoms in adults mainly include sore throat, fever, malaise, dysphagia, odyno-
phagia, front neck pain, and dyspnea. Symptoms in children may include also neck
stiffness, palpable neck swelling, rhinorrhea, croup-like cough, poor oral intake,
and lethargy [192].
Patients who present with retropharyngeal abscesses typically are febrile and ill-
appearing. Physical examination usually reveals posterior pharyngeal edema or
bulge, neck rigidity, stridor, torticollis, trismus, and CLA [179]. Symptoms and
signs of RPA are summarized in Table 7.4.
A patient with neglected RPA would suffer from complications, which may
include airway obstruction, bronchial erosion, mediastinitis, sepsis, acute respira-
tory distress syndrome (ARDS), cranial nerve palsies, esophageal perforation, ero-
sion into the carotid artery or jugular vein, and meningoencephalitis [171].
Table 7.4 Main symptoms and signs of RPA

Symptoms Signs
– Sore throat – Posterior pharyngeal edema (37%)
– Fever – Nuchal rigidity
– Malaise – Cervical lymphadenopathy
– Dyspnea and stridor – Fever
– Neck stiffness – Drooling
– Neck pain – Stridor
– Odynophagia – Torticollis
– Cough – Trismus
– Rhinorrhea – Neck mass
Workup
Laboratory Studies
Laboratory tests including complete blood count and blood cultures are necessary if
an RPA is suspected. However, obtaining these labs should be delayed if phlebot-
omy will result in additional distress to the patient and cause early upper airway
obstruction to become complete obstruction, especially in younger children [179,
193, 194].
Both aerobic and anaerobic blood cultures should be obtained. In patients with
RPA, shooting leukocytosis is characteristic, with white blood cell counts greater
than 12,000 in 91% of individuals [179, 193, 194].
Imaging Studies
Lateral neck radiography is typically the imaging study of choice in the initial eval-
uation of a suspected RPA, particularly in young children. It has the benefit of lower
radiation exposure and tends to be better tolerated by patients who are exhibiting
signs of airway compromise. Lateral neck X-rays should be obtained during inspira-
tion with the neck held in normal extension. Improper techniques can result in false-
positive results of retropharyngeal infection. In the presence of RPA, the depth of
the prevertebral space will be increased on the lateral neck X-ray. In healthy chil-
dren, the upper limit of normal prevertebral space is 7 mm at C2 and 14 mm at C6,
while in healthy adults, it is 7 mm at C2 and 2 mm at C6. If the retropharyngeal
space is more than half of the size of C2 vertebra, it may indicate an RPA [195]. A
width of 30 mm at C6 indicates also abscess collection.
Lateral neck X-ray shows the retropharyngeal soft tissue mass with encroach-
ment on the pharynx (Fig. 7.9) in approximately 80% of cases. It may also show
air-fluid level (Fig. 7.10). Additionally, patients who are presenting with a concern-
ing story for RPA including chest pain should have a chest X-ray obtained to inves-
tigate for mediastinal involvement.
Contrast-enhanced computed tomography (CECT) of the neck is the most widely
informative (Fig. 7.11) imaging study and is considered the definitive diagnostic
test as it provides details of the abscess and its anatomical relations to surrounding
structures including large vessels and other deep neck spaces [195]. If there is a
concern for airway compromise, a clinician who is trained in emergency airway
management should be present while the CT scan is being obtained. Patients may
require an emergent surgical airway if upper airway obstruction occurs. The sensi-
tivity of CT scan for detecting RPA ranges from 64% to 100%. In children, ultra-
sound (US) is preferred as it does not involve radiation and is portable. In experienced
hands, US can help determine the size and location of the abscess [170]. Magnetic
resonance imaging (MRI) has a limited role in RPA [195].
The differentials of an RPA are numerous and include the following: foreign body
in airways, pneumonia, mediastinitis, parapharyngeal abscess, peritonsillar abscess,
Fig. 7.9 Plain X-ray of

the neck (lateral view)
showing a retropharyngeal
abscess (RPA). Note the
encroachment on the
lumen of the pharynx (blue
arrow)
Fig. 7.10 Plain X-ray of

the neck (lateral view)
air-fluid level (blue arrow)
Fig. 7.11 Contrast-

enhanced computed
tomography (CECT) scan
large size of the abscess
and the rim of contrast
enhancement (blue arrow)
odontogenic infection or abscess, sialadenitis, epiglottitis, pharyngitis, meningitis,

esophagitis epidural and subdural infections, infectious mononucleosis (IMN),
tuberculosis (TB), and other causes of torticollis [182].
Treatment
Surgical Intervention
All patients presenting with a confirmed diagnosis of RPA require hospital admis-
sion; retropharyngeal abscesses frequently require surgical intervention. Factors
that have been associated with an increased need for surgical incision and drainage
include an abscess with a cross-sectional area greater than 2 cm2 and symptoms for
greater than 2 days. There is no evidence that patients presenting with mature
abscesses greater than 3 cm2 benefit from surgical intervention before 24–48 h of
antibiotic therapy [193, 194].
Securing the Airway

Patients presenting airway compromise should have immediate surgical incision
and drainage performed to relieve their upper airway obstruction [196–198]. A ton-
sillectomy approach is typically used to access and drain the abscess; the outcome
is usually good. Surgery in adults may be done without general anesthesia because
of the risk of abscess rupture during tracheal intubation. This could result in aspira-
tion of pus into the lungs. In complex cases, an emergency tracheotomy may be
required to prevent upper airway obstruction caused by edema in the neck [199]. All
patients must have careful airway monitoring when undergoing treatment of RPA,
especially during the first 24–48 h of therapy. Fluid resuscitation should be started
if necessary, and frequent vital sign checks should also be carried out [199].
Antimicrobial Therapy and Resuscitation

High-dose intravenous (IV) antibiotics are required in order to control the infection
and reduce the size of the abscess prior to surgery. Antibiotic therapy should cover
upper respiratory organisms, including anaerobic organisms. Antibiotics alone may
occasionally be sufficient for children with small abscesses up to 2 cm. Most
abscesses over 2 cm are still treated by surgical drainage only [179, 180, 200–202].
Initial antibiotic therapy should include either ampicillin-sulbactam (50 mg/kg
every 6 h) or clindamycin (15 mg/kg every 8 h). If patients appear septic or do not
respond to initial antibiotic therapy, vancomycin or linezolid should also be admin-
istered. Parenteral antibiotics should be continued until patients are clinically
improved and afebrile for 24 h. After patients demonstrate clinical improvement
and remain afebrile, they may be transitioned to oral antibiotics. Amoxicillin-
clavulanate (45 mg/kg every 12 h) and clindamycin (13 mg/kg every 8 h) are accept-
able oral regimens. Oral antibiotics should be prescribed for 14 days, and the patient
may be discharged home with strict return precautions [197]. A chronic RPA is
usually secondary to tuberculosis (TB). In such cases, the patient needs to be started
on antitubercular therapy as soon as possible [198, 199].
Postoperative and Rehabilitation Care

After surgery, patients should be kept off oral feeding until all signs of the abscess
have subsided. Close monitoring of the patient is required in an intensive care unit
(ICU) setting initially for airway monitoring. Broad-spectrum IV antibiotics are
begun initially, and placement of alternate enteral feeding means is required. Once
the patient has stabilized, they may be transitioned to culture-directed oral
antibiotics.
Tuberculous Retropharyngeal Abscess
Chronic RPA is usually of tuberculous etiology and is commonly seen in adults
[203]. Tuberculous RPA is rare, even in the presence of extrapulmonary TB [204] or
extensive pulmonary TB [205]. It is reported that in only 7% of the patients with
extrapulmonary ΤΒ involving the cervical spine, pus erodes into the retropharyn-
geal space on both sides of the midline [206, 207]. Chronic RPA can also be trans-
mitted to the retropharyngeal space via the lymphatics resulting in tuberculous
infection of the retropharyngeal LNs, which is usually limited to one side of the
midline [206, 208]. In rare cases, the abscess may be caused by hematogenous
spread from pulmonary or extrapulmonary TB [207–209]. In 2020, Alazigha et al.
reported a 40-year-old gentleman who presented with neck pain and odynophagia.
A diagnosis of an isolated primary retropharyngeal TB presenting as a deep neck
abscess without cervical and pulmonary involvement was made based on the his-
tory, physical examination, laboratory studies, and CT scan findings. The patient
made remarkable improvement following a 6-month course of anti-TB ther-
apy [210].
The incidence of chronic RPA is increasing because of the resurgence of TB
secondary to HIV infection; thus, all patients should be screened for this disease
[203]. Moreover, the use of immunosuppressive medication is also one of the caus-
ative factors, particularly in developed countries.
Tuberculous RPA can be life-threatening [211], as it can cause airway obstruc-
tion, infection of the carotid sheath, proliferation into the mediastinum, or septic
shock [153]. These complications can cause a mortality rate of 40–50% [212].
Additional deficits common in patients with tuberculous RPA are muscle weakness
and myelopathy [203].
Diagnosis
Early diagnosis is essential to prevent complications of RPA and Pott’s disease. It
should be suspected in patients who present with a retropharyngeal mass and a
destructive lesion of the vertebra [206]. However, the clinical diagnosis is difficult
due to nonspecific symptoms, such as dysphagia and neck pain. Diagnosis is mainly
based on a high index of clinical suspicion particularly in an endemic area, radio-
logical features, aspiration for bacteriologic culture, biopsy for histopathological
examination, and polymerase chain reaction (PCR) [211].
Lateral view radiography of the neck can be helpful in the diagnosis.
Individuals with a widening of or air in the prevertebral soft tissues, osteolytic
lesion in the cervical vertebrae, or loss of the cervical spine lordosis or vertebral
height should be suspected of the condition [203, 211]. Chest radiograph is use-
ful in screening pulmonary TB or complications such as mediastinitis, pneumo-
nia, and pleural effusion. Meanwhile, CT scan is a useful diagnostic tool that can
confirm the abscess location, size, extensions, and Pott’s disease [211]. A con-
trast-enhanced CT (CECT) scan finding of a central hypo-density mass with sur-
rounding ring enhancement suggests the presence of an abscess [212]. Lateral
view radiography of the neck has sensitivity and specificity of 80% and 100% in
diagnosing RPA, while for a CT scan, it is 100% and 45%, respectively [206].
However, CT scan has a limitation in differentiating cellulitis from abscess with
an accuracy of 73.5%, false-positive rate of 11.8%, and false-negative rate of
14.7% [206]. The decision for drainage or surgical intervention must be guided
by CT findings and diagnosis [206].
Ultrasonography (US) is an affordable, simple, and non-irradiating choice of
examination, but a negative result cannot rule out RPA [211]. Magnetic resonance
imaging (MRI) findings of low signal intensity on T1-weighted images and high
signal intensity on T2-weighted images also suggest an abscess [212], and MRI can
diagnose any complications more precisely, such as vein thrombosis [206].
Treatment
Early treatment includes antitubercular chemotherapy and surgical intervention,
and the combination of these treatments may be optimal. If an abscess is large
enough to be detected on clinical examination, drainage should be performed [212].
Surgical drainage includes the simple intraoral approach, extensive external cervi-
cal approach, or minimally invasive technique such as image-guided needle aspira-
tion [213]. The need for external drainage of RPA has been controversial [212].
Needle aspiration has several advantages; it can be repeated if necessary, can be
performed under local anesthesia, and can be used to rule out other differential
diagnoses such as a malignant tumor presenting clinico-radiologically as an abscess
[214]. In patients whose pus cannot be successfully and completely aspirated, exter-
nal drainage may be performed.
Antituberculous medication and conservative neck stabilization should be the
initial treatment for Pott’s disease [215]. Surgical intervention in Pott’s disease is
indicated in the presence of a neurological deficit, spinal deformity with instability
or pain, no response to antitubercular chemotherapy, and large paraspinal abscess
[216]. The majority of patients with tuberculous RPAs with neurological complica-
tions recover following prompt surgical drainage and antitubercular medica-
tions [217].
Kosmidou et al. (2020) reported a 20-year-old gentleman with atypical tubercu-
lous RPA evidenced by CT scan. The patient was subjected to intraoral aspiration
under local anesthesia, and the sample was sent for analysis. The results of direct
microscopic examination of PCR gene probe demonstrated mycobacterium
TB. Subsequently, the patient was successfully treated with standard 9-month anti-
TB chemotherapy (ethambutol, rifampicin, and pyrazinamide). Kosmidou and col-
leagues emphasized the importance of early diagnosis with targeted therapy [218].
Menon et al. (2014) described an insidiously presenting RPA treated success-
fully with intraoral aspiration and antitubercular chemotherapy in a 33-year-old
lady who presented mainly with neck pain and dysphagia. MRI revealed a large
RPA that was aspirated intraorally under local anesthesia. Diagnosis of TB was
confirmed by positive culture, and the patient improved significantly following the
initiation of antitubercular therapy [219].
7.7 Laryngocele
Definition
Laryngocele is defined as “an abnormal dilatation or herniation of the laryngeal sac-

cule that extends upward within the false vocal fold in communication with the
laryngeal lumen.”
7.7 Laryngocele 185
Classification
Laryngocele is a rare benign lesion of the larynx and has been classified as either
internal or combined, which is the most common type. The formerly used classifica-
tions of internal, external, and combined laryngoceles are being abandoned because
a purely external laryngocele cannot exist since laryngoceles originate at the laryn-
geal saccule. An internal laryngocele is medial to the thyrohyoid membrane, while
a combined laryngocele lies both medial and lateral to the thyrohyoid membrane
[220–223].
Clinical Picture
Laryngoceles are more commonly found in the fifth or sixth decade of life occurring
more in men than women in a 5 to 7:1 ratio. Approximately, 80–85% of laryngo-
celes are unilateral with no predominance of occurrence on the left or right side
[224–228].
Symptoms may vary according to the type of laryngocele. The internal laryngo-
celes may cause hoarseness of voice, snoring, or even upper airway obstruction.
Other symptoms include a foreign body sensation, sore throat, dysphagia, and
cough [229]. In case of combined laryngocele, there will be a neck swelling with or
without associated laryngeal symptoms [230, 231]. The swelling usually occurs in
the lateral side of the neck but may be central (in the midline of the neck) and may
extend in front of the trachea. Clinically, the swelling is soft, resonant, translucent,
and compressible and increases in size on Valsalva maneuver, coughing, or straining.
The simple laryngocele is filled with air. When the neck of the laryngocele is
obstructed, it becomes filled with the mucus of glandular secretion and is altered to
a laryngo-mucocele. When this lesion becomes infected, a laryngo-pyocele (or pyo-
laryngocele) is formed and the mass becomes tender and tense [232, 233]. Byard
and Gilbert [230] reported that the risk of death due to laryngo-pyocele was
increased not only as a result of obstruction by the mass, but also by the discharge
of pus into the airway, leading to aspiration, jugular vein thrombosis, or formation
of mediastinal abscess [234].
Etiology
There is much controversy regarding the etiology of laryngoceles. Three main theo-
ries have been proposed: (1) congenital factors (as occurs in neonates) [235]; (2)
increased laryngeal pressure such as chronic cough, straining, blowing into musical
wind instruments, and glass blowing; and (3) mechanical obstruction such as laryn-
geal tumors causing mechanical obstruction and increased intra-laryngeal pressure
[232, 236, 237]. Association between laryngocele and laryngeal cancer has thus
been reported [232, 238]. Other causes may be attributed to amyloidosis, chon-
droma, scleroderma, etc. [233]. The neck of the saccule has been postulated to act
as a one-way valve allowing accumulation of air and preventing its egress [225,
237]. However, many patients do not have any predisposing factor, and most laryn-
goceles are unilateral [224, 231, 237].
Diagnosis/Workup
The diagnosis of laryngocele is based on clinical findings, imaging studies, and

endoscopic examination of the larynx.
Plain X-Ray
Plain radiograph of the soft tissue of the neck in anteroposterior (AP) and lateral
views is valuable especially if the Valsalva maneuver is performed. It shows air-
filled sac protruding from the soft tissues of neck. When X-ray is repeated on
Valsalva’s maneuver, the size of the mass shows increase in size. However, small
internal laryngoceles are difficult to identify radiologically in plain films.

C
Computed tomography (CT) scan of the neck is the most accurate imaging modal-
ity. It provides a definitive diagnosis of a laryngocele through cross-sectional imag-
ing and contrast resolution being superior to plain X-ray. It shows the extension,
anatomical relationships, and content of both internal and external components of
laryngoceles. Furthermore, this imaging is necessary to differentiate laryngoceles
from saccular cysts of the larynx and to reveal evidence of an occult laryngeal
tumor, because the incidence of laryngocele in laryngeal carcinoma has been esti-
mated to be around 10% [221, 226, 227, 239, 240].

M
Magnetic resonance imaging (MRI) gives detailed information about the boundar-
ies of the laryngocele and its relation to the thyrohyoid membrane, distinguishing
the internal from the external component. In case of laryngo-mucocele and laryngo-
pyocele, MRI is the imaging technique of choice and may distinguish obstructed
mucus and inflammation from neoplastic disease [223]. In cases in which a laryn-
gocele is associated with a laryngeal squamous cell carcinoma (SCC), magnetic
resonance imaging (MRI) is particularly important to corroborate the diagnosis,
evaluate the disease extent in soft tissues, stage the tumor, and provide better surgi-
cal planning [223, 241, 242].
Internal laryngoceles have been described on US to be echo-free, well-defined
structures inside the thyroid cartilage. Combined laryngoceles have an additional
cystic mass outside the laryngeal skeleton, at the thyrohyoid membrane [243].
7.7 Laryngocele 187
Laryngoscopy
Indirect laryngoscopy is diagnostic. Combined laryngocele appears as submucosal
mass in the region of the false vocal cord. If a fiber-optic laryngoscope is used, this
mass can be seen to enlarge during a Valsalva maneuver.
Treatment
Currently, various modalities of treatment have been used for the management of
laryngocele. The treatment of choice of laryngocele is surgical excision. Surgeries
are performed via the external approach, mainly for combined laryngocele, and the
endo-laryngeal approach mainly for internal laryngocele. Initially, excision of both
types of laryngoceles was done using an external approach [244]. However, micro-
laryngoscopic surgery and CO2 laser have gained popularity during the last two
decades as the endo-laryngeal technique for internal and mixed type of laryngocele
[236, 245].
xternal (Open) Approach

E
The external (open) approach is commonly favored by most surgeons because of its
advantages: excellent exposure, precision, minimal morbidity, and reduced chances
of recurrence. Disadvantages include skin scarring, higher morbidity, longer dura-
tion of surgery, longer hospitalization period, and higher cost [222].
Three types of external procedures have been described: (1) the trans-thyrohyoid
membrane approach, (2) thyrotomy with resection of the upper third of the thyroid
cartilage, and (3) V-shaped thyrotomy [222, 223, 238, 244, 246, 247]. Complications
of this procedure include airway compromise due to mucosal edema, laryngo-
cutaneous fistula, subcutaneous emphysema, and injury to the superior/internal
laryngeal nerve [222, 223, 232].
Internal (Endoscopic) Approach
Endo-Laryngeal (Micro-Laryngeal) Approach

Internal laryngoceles are routinely managed by an endo-laryngeal CO2 laser
approach [245], though cold steel and combined pen surgical approaches have also
been utilized though with reports of increased risk of bleeding [222]. The endo-
laryngeal CO2 laser approach has the advantages of being a quick, precise, and safe
alternative to an external approach excision, with fewer complications and faster
postoperative recovery in terms of swallowing and speech [43, 46, 223, 245].
Disadvantages of the approach are the limited surgical exposure, postoperative
endo-laryngeal scarring, risk of incomplete resection, and call for expertise and the
need for specialized equipment [222]. However, no clinical recurrence has been
reported.
Robotic Surgery
The first endo-laryngeal resection of a combined laryngocele using robotic surgery
was reported in 2013 by Ciabatti et al. [248]. According to the authors, this tech-
nique seems to have several advantages when compared with micro-laryngoscopic
surgery. The optics are placed in the oral cavity allowing closer, angulated vision of
the surgical field. In addition, rather than using traditional laryngoscopes, instru-
ments are introduced through mouth gags, offering a wider view and range of
motion. Furthermore, small size, angulation, and wristed tips enable it to reach far
hidden areas [248].
Combined Approach
The combined approach is advocated to treat mixed laryngoceles. This approach
involves internal endoscopic laser resection, with a variety of open surgical
approaches including a midline transcervical incision or V-shaped lateral thyrot-
omy [232].
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Swellings of the Tracheal Region
8
Contents
8.1 Overview 199
8.2 Pre-tracheal Lymphadenopathy 199
8.3 Tracheal Adenoid Cystic Carcinoma 201
8.4 Solid Nodule in the Thyroid Isthmus 208
8.5 Cystic Nodule in the Thyroid Isthmus 248
References 263
8.1 Overview
Swellings of the tracheal region include the following:

–– Pre-tracheal lymph nodes (LNs)
–– Tracheal adenoid cystic carcinoma
–– Solid nodule in the isthmus of the thyroid gland
–– Cystic and partially cystic nodule in the isthmus of the thyroid gland
8.2 Pre-tracheal Lymphadenopathy
Tuberculous Lymphadenitis
Tuberculous lymphadenitis (TBLA) may affect the midline of the neck by involving
cervical lymph nodes (LNs), level IA (submental LNs), and level VI (pre-laryngeal
and pre-tracheal LNs). Usually, multiple sites are involved, and thus, physical
examination may reveal the presence of other enlarged LNs in the neck [1].
Locally, patients with tuberculous lymphadenitis (TBLA) usually present with a
painless, enlarging, or persistent mass consisting of a single group of LNs [2, 3]. At

Switzerland AG 2024
200 8 Swellings of the Tracheal Region
the beginning, affected LNs are enlarged and discrete. They then coalesce and break
down to form TB pus, which may perforate the deep fascia and present as a cold
abscess. If the abscess bursts through the deep fascia into the subcutaneous tissues,
it will form a “collar-stud abscess,” with one compartment, one on either side of the
fascia, connected by a small central track. In 4–11% of cases, the skin overlying
may show breakdown and form a “sinus” [2, 3]. Lymphatics may be felt, as cord-
like structures, between the enlarged LNs due to TB lymphangitis [4].
Tuberculous lymphadenitis is not considered a localized disease; thus, systemic
chemotherapy should be prescribed. The Infectious Diseases Society of America
(IDSA) recommends 6 months of the following treatment for lymphadenitis caused
by drug-susceptible organisms [5]: isoniazid, rifampin, pyrazinamide, and etham-
butol for 2 months, followed by isoniazid and rifampin for another 4 months. The
6-month recommendation is supported by studies that showed no difference between
6 and 9 months of treatment in cure rates (89–94%) [6, 7] or relapse rates (3%) [8].
Surgery for treatment of TBLA is usually reserved for establishing diagnosis by
excisional biopsy, advanced local disease, persistent disease, or a draining fistula [9,
10]. Adequate chemotherapy should be provided at the time of surgery to avoid
postoperative fistula formation and hematogenous spread [11]. Traditionally, surgi-
cal intervention ranging from simple aspiration (shows caseous material) to com-
plete excision has been considered the treatment of choice [10].
Metastatic Lymphadenopathy
The thyroid isthmus is usually located at the second and third tracheal rings and is
covered by skin, fascia, and strap muscles. The reported frequency of papillary thy-
roid cancer (PTC) arising in the thyroid isthmus ranges from 2.5% to 9.2%, proba-
bly reflecting variation in the study populations [12, 13]. Previous studies have
demonstrated that isthmic PTCs are more likely to exhibit extra-thyroidal extension
(ETE) and multiple foci in bilateral lobes than those located in the other parts of the
thyroid [12–15]. This may be explained by the anatomical characteristics of the
isthmus, which is located in a thin space enclosed by solid structures such as the
trachea and strap muscles. However, most reports about isthmic PTC have focused
only on the tumor characteristics and not on the pattern of central lymph node (LN)
metastasis.
The central LNs are the most common LNs to which PTCs metastasize; those
mainly involved are the pre-laryngeal, pre-tracheal, and right and left paratracheal
LNs [16]. LN metastasis in PTC could be a risk factor for recurrence and further
metastasis. Thus, preoperative detection of LN metastasis and subsequent LN dis-
section are crucial for preventing local recurrence and avoiding reoperation. The
extension of LN dissection for PTC is still a matter of debate. To determine the
optimal extent of prophylactic central LN dissection, it is important to establish a
pattern of LN metastasis in isthmus PTC.
Several reports have suggested that tumor location is associated with neck metas-
tasis [17–20]. However, the controversy remains regarding whether PTC located in
the isthmus is correlated with central LN metastasis. In 2010, Lee et al. reported that
the frequency of central LN involvement in isthmus PTCs was similar to non-
isthmus PTCs, whereas lateral LN involvement was more commonly observed in
non-isthmus PTCs [13]. On the other hand, Goldfarb et al. demonstrated that
patients with a malignant dominant thyroid nodule of the isthmus had higher rates
of LN involvement [15].
In 2016, Lee et al. published the results of their retrospective cohort study of 190
consecutive patients with papillary thyroid carcinoma (PTC) who underwent total
thyroidectomy and bilateral central neck dissection. Clinicopathological factors
including age, gender, tumor size, ETE, margin, angiolymphatic invasion, and nodal
metastasis were evaluated. Fourteen patients (7.3%) had a tumor located in the isth-
mus. As compared to non-isthmus PTC, tumors located in the isthmus were more
likely to have ETE (54% vs. 100%, respectively, p = 0.001) and central LN involve-
ment (44.6% vs. 71.4%, respectively, p = 0.048). There were no significant differ-
ences in lateral LN metastasis and extranodal extension between the two groups
[21]. This may be explained by the differences in the lymphatic system according to
the anatomical locations of the thyroid gland. Although the isthmus has poor lym-
phatic channels, lymphatics from the isthmus usually drain into the pre-laryngeal
and pre-tracheal regions [13].
There are no specific guidelines for the surgical management of thyroid cancers
confined to the isthmus [22]. However, because isthmus PTCs may have a higher
incidence of both multifocality and capsular invasion than PTCs located in the
lobes, total thyroidectomy is indicated, and thyroid isthmusectomy should be
reserved for highly selected patients without major ETE or adhesion to adjacent tis-
sues [15]. In addition, considering the high frequency of involvement of the pre-
laryngeal and pre-tracheal compartments, careful preoperative evaluations of these
compartments and possible neck dissection should be considered when a tumor is
located in the isthmus.
8.3 Tracheal Adenoid Cystic Carcinoma
Introduction
Primary tracheal tumors are rare and constitute only 2% of all respiratory tract
tumors [23]. The majority of primary tracheal tumors in adult patients are malig-
nant, with approximately two-thirds being squamous cell carcinomas (SCCs) [24],
while adenoid cystic carcinomas (ACCs) were the second most common, account-
ing for approximately 10–15% of cases [25–30]. These are followed by pleomor-
phic adenoma, acinar cell carcinoma, and epithelial-myoepithelial carcinoma [31].
Most patients with tracheal ACC present with symptoms usually related to air-
way obstruction such as cough, hoarseness, hemoptysis, shortness of breath, and
wheezing. Patients may be incorrectly diagnosed and treated for bronchial asthma
or chronic bronchitis for months or years before the lesion is recognized [32]. Very
rarely, a tumor arising in the cervical trachea may extend anteriorly and presents as
thyroid tumor [33–37]. As the incidence of tracheal ACC is relatively low, thyroid
involvement is even rarer [33, 35]. In addition, owing to the close anatomical prox-
imity of the trachea and the thyroid, it is difficult to accurately determine the nature
of the tumor preoperatively, thereby resulting in misdiagnosis [37].
The largest reported series of tracheal ACC comes from a Surveillance, Epidemiology,
and End Results (SEER) analysis of 578 cases of primary tracheal carcinoma identi-
fied over a 31-year period [28]. In that series, the majority of cases were seen in
middle-aged patients with a median age of 63 years, and 56% of patients were male.
The clinical presentation is directly related to the size and location of the tumor
within the trachea. These tumors may grow to near-obstructive level and produce
cough, hoarseness, wheezing, dyspnea, hemoptysis, and recurrent pneumonitis
[37]. Recently, Ran et al. (2021) reported that in their systematic review of litera-
ture, a total of 76 articles and 1252 cases of tracheal ACC were included; the most
common presenting symptom was dyspnea (86.0%), followed by cough (58.0%)
[38]. In general, it must be acknowledged that patients with tracheal ACCs may
present with a midline swelling on their neck, without any respiratory complaints,
hoarseness of voice or dysphagia, and a large, firm, non-tender, multi-lobular mass
in the thyroid gland on physical examination. The differential diagnosis of primary
tracheal ACCs includes basal cell adenomas, pleomorphic adenomas, and basal cell
adenocarcinomas [39].
Adenoid cystic carcinoma (ACC) is a slow-growing tumor, but metastasis often
occurs [40, 41], especially multiple metastases [42] and late metastasis up to
15 years after initial diagnosis [43]. Approximately one-third of patients with ACC
will develop distant metastasis, with common sites being the lungs, brain, bone, and
liver [44, 45]. Primary tracheal ACC spreads by direct extension, perineural inva-
sion, and hematogenous metastasis, particularly to the lungs and bones [42]; lym-
phatic spread is uncommon [46]. In a retrospective study of 108 patients who
underwent resection of ACCT, 85% presented with tumors with extramural exten-
sion: 15% were intramural; in 20%, there was invasion of adjacent structures, 15%
involved esophageal muscular layers, 9% involved the thyroid gland, 6% involved
recurrent laryngeal nerve, 4% involved infrahyoid muscles, and 1% involved large
vessels and pericardium. In several cases, invasion occurred in more than one
organ [47].
In 2010, Nowal et al. reported a rare case of primary ACC of the trachea in a
44-year-old lady presenting as a painless, midline, cervical swelling, mimicking a
thyroid tumor. Local examination revealed a 2.5 × 2.0 cm, firm, rounded, non-tender
swelling, fixed to the underlying structures. It was slightly moving with deglutition.
Operative findings, bronchoscopy, and histopathological diagnosis of the excised
mass revealed trachea with extra-tracheal extension anteriorly into the soft tissues
of the neck, without actual invasion of the thyroid gland [48].
Table 8.1 Reported cases of tracheal adenoid cystic carcinoma involving the thyroid gland
Age Adjuvant
References Year Gender (years) Size (cm) Other metastases therapy
Zirkin and Tovi [33] 1984 F 66 4 × 3.5 No No
Idowu et al. [35] 2004 F 68 NA No RT
Idowu et al. [35] 2004 M 60 3 Lung RT
Kukwa et al. [39] 2014 F 17 3.7 × 3.4 Cricoid cartilage/ RT
muscle/esophagus
Subramaniam et al. [24] 2015 F 37 8 × 6.5 No RT/ChT
Qi et al. [37] 2016 M 46 2.7 × 2.2 Esophagus No
F female, M male, NA not available, RT radiation therapy, ChT chemotherapy
Several reports in the literature have described tracheal ACC involving the thy-
roid gland (Table 8.1) [33, 35, 37, 39, 49]. These cases included four female (66.7%)
and two male patients (33.3%). Their ages ranged from 17 to 68 years, with the
average age being 49.8 years.
Direct extension of ACC of the laryngotracheal complex into the thyroid gland,
with clinical manifestation as a thyroid nodule, has been reported in the literature
[33–37]. Zirkin and Tovi (1984) reported a case of an ACC that originated in the
trachea and invaded the thyroid gland and recurrent laryngeal nerves, presenting
as a thyroid mass and causing vocal cord paralysis [33]. Li et al. (1990) retrospec-
tively reviewed 54 cases of primary tracheal malignancies. The most frequent was
SCC (54.5%), followed by ACC (18%) and adenocarcinoma (9%). The radiologi-
cal appearance of the tumors was divided into intraluminal, wall-thickening, and
exophytic forms. Wall-thickening and exophytic forms in this study accounted for
62% of the tumors, which indicates that tracheal malignant tumors can result in
extra-luminal invasion. Four cases (7%) in their series presented as thyroid tumors
due to direct extension into the thyroid gland [37]. Moreover, Na et al. (1995)
described the CT characteristics of ACCs of the trachea, in four patients, mimick-
ing thyroid tumors. The masses encircling the trachea and circumferential thick-
ening of the tracheal wall were demonstrated in all four cases. The tumors had a
broad base on the trachea and convex margin on the thyroid gland. They were all
homogeneous, generally smoothly marginated, and iso-attenuating on post-con-
trast CT scans [34].
Idowu et al. (2004) [35] reported two cases of ACC of the larynx and trachea
extending to the thyroid and manifesting as a thyroid nodule. In both, the initial
clinical manifestation was a suspected thyroid mass for which FNAC was performed
and papillary thyroid carcinoma (PTC) was the cytological diagnosis in one case.
Kukwa et al. (2014) reported a 17-year-old patient with a tracheal ACC mimick-
ing a thyroid tumor. Computed tomography (CT) scan confirmed a 34 × 37 × 50 mm
tumor surrounding the trachea, infiltrating the two thyroid lobes and causing esoph-
ageal constriction. Due to the microscopically positive surgical margin of the tumor
after surgical resection, the patient received postoperative RT with a fractional dose
of 2 Gy and a total dose of 70 Gy. Three years later, she developed lung metastases
and underwent pulmonary metastasectomy. Scheduled follow-up CT scans of the

patient’s chest and neck revealed complete pathological remission [39].
In 2015, Subramaniam et al. presented a 37-year-old gentleman with primary
tracheal ACC. Preoperative bronchoscopy revealed a highly vascular tumor 4 cm
distal to the cricoid with no gross disease extending to the carina. Imaging revealed
circumferential tracheal irregularity immediately inferior to the cricoid, with no
definite cricoid invasion. Locoregional extension of disease was noted invading the
thyroid and abutment of the carotid approximately 180°. Total thyroidectomy was
performed in addition to a 5 cm sleeve resection of the trachea with a crico-tracheal
anastomosis following suprahyoid muscle release and laryngeal drop-down. The
patient was treated with adjuvant RT and platinum-based chemotherapy in an effort
to maximize local control. A follow-up PET scanning 3 months after therapy
revealed no FDG uptake locally or distally [49].
In 2016, Qi et al. presented a 46-year-old man with primary ACC of the trachea
with thyroid invasion. The patient sought consultation due to a 6-month history of
dysphagia and associated dyspnea. A contrast-enhanced computed tomography
(CECT) scan revealed bilateral thyroid masses and tracheal wall thickening.
Intraoperatively, the thyroid masses were fused to the trachea and esophagus with-
out discernible borders. Frozen section pathology suggested poorly differentiated
cancer, and a bilateral partial thyroidectomy was performed. Postoperative immu-
nohistochemistry (IHC) showed that the ductal epithelial cells were positive for
pan-cytokeratin (CK), CK7, and CD117. The myoepithelial cells were positive for
vimentin, S-100, P40, and P63. The cells were negative for thyroid transcription
factor-1, CD56, calcitonin, synaptophysin, and thyroglobulin. Thus, postoperative
pathology revealed the diagnosis of primary tracheal ACC with thyroid inva-
sion [37].
In 2017, Al-Khatiba et al. reported a 54-year-old female patient with unresect-
able histologically proven ACC of the trachea, with thyroid invasion, presenting
with dyspnea, dysphagia, and a midline neck swelling, 3 × 3 cm in size, mimicking
a primary thyroid [50]. The patient received an RT course of 60 Gy over 30 fractions
via 3D conformal radiation therapy [50].
More recently, Nicolini et al. (2019) discussed a case of tracheal ACC in a
62-year-old gentleman. Computed tomography (CT) of chest showed an expan-
sive lesion in the anterior wall of the trachea with an extension of approximately
3.1 cm, ending at the level of the carina, measuring 3.4 × 2.8 cm, with moderate
stenosis of the tracheal lumen, with an exophytic component to the mediastinum.
The patient was submitted to right lateral posterolateral thoracotomy with resec-
tion and distal tracheal anastomosis with en bloc tumor resection. Histopathology
provided the diagnosis of low-grade ACC, confirmed by IHC, presenting cyto-
keratin AE1/AE3, cytokeratin 7, CD117, p63, and ki-67 positive, 2.5 cm in size,
with compromised microscopic margins, with infiltration of cartilage and adja-
cent soft tissues, as well as perineural and angio-lymphatic invasion. The patient
received adjuvant RT. Follow-up posterior bronchoscopy showed good heal-
ing [51].
Imaging Studies
The imaging procedure of choice for ACC is CT scan. It is highly accurate in the
assessment of the tumor location, depth of invasion, extra-luminal extensions, and
carinal involvement, as well as lymphogenic and distant metastases or primary syn-
chronic lesions [52, 53]. With the use of helical CT datasets, multi-planar recon-
structions have been shown to facilitate the assessment of patients with airway
disease and are known to provide excellent image quality. The reformatted images
help to assess both the intra- and extra-luminal growth of the tumor and its longitu-
dinal extent along the tracheal or bronchial wall by allowing the evaluation of extra-
luminal surrounding tissues [54]. Therefore, helical CT provides precise information
about the extent of a tumor, which is important for planning a surgical resection.
Tracheo-Bronchoscopy
Bronchoscopy is the most useful test in tracheal cancer diagnosis. It provides a pre-
cise evaluation of the tumor’s nature and extent. The site and length may be associ-
ated with anatomical landmarks, such as carina and cricoid cartilage, and tumor
sizes may be correlated with the airway caliber. Furthermore, for pathological eval-
uation, a tumor biopsy may be performed. The main pillars for the diagnosis and
staging of primary tracheal tumors are CT scans of the chest and neck together with
trachea-bronchoscopy [53].
Pathology/Diagnosis
Adenoid cystic carcinoma arises more commonly in the submandibular glands and
minor salivary glands [55, 56], but it can also occasionally occur in the mammary
glands, cervix, Bartholin glands, sinuses, skin [57, 58], and even larynx and trachea
[39, 59]. Tracheal ACC originates in the glands of the tracheal and bronchial walls
and most commonly arise in the lower or upper third, with a tendency to originate
at the lateral and posterolateral wall near the junction of the cartilaginous and mem-
branous portions [52].
Pathologically, these tumors characteristically grow into the airway lumen, form-
ing a smooth-surfaced, somewhat polypoid tumor; occasionally, growth is circum-
ferential and annular. Submucosal extension, sometimes to a considerable distance
from the main tumor, is not uncommon. Histologically, three patterns are seen: tra-
becular, cribriform, and solid type. The cribriform pattern (Fig. 8.1) is most com-
mon consisting of uniform cells with relatively little cytoplasm arranged in
well-defined nests of variable sizes. The cells in these nests are separated by well-
defined cystic spaces containing a mucinous substance that stains strongly with
alcian blue and weakly with periodic acid-Schiff (PAS) [46].
Fig. 8.1 Cribriform

pattern of adenoid cystic
carcinoma (ACC) (H&E
stain). Note the biphasic
ducts and basal
myoepithelial cells with
cystic spaces
Cytological features of ACC are high cellularity with cribriform or trabecular

pattern. The cytoplasm is scanty and basaloid. The nucleus is oval to angulate with
coarse chromatin, small indistinct nucleoli, and no inclusions. The background ele-
ment may show hyaline globules. These features usually differentiate ACC from
other common primary thyroid neoplasms. If enough aspirates are obtained, immu-
nohistochemical (IHC) analysis is helpful. Primary thyroid neoplasms will express
thyroglobulin (Tg), thyroid transcription factor-1, and/or calcitonin, while these
antibodies will be negative in ACC and most other tumors of extra-thyroid origin. In
addition, myoepithelial components of ACC express muscle-specific actin and,
occasionally, S-100, which usually are absent in thyroid neoplasms [35].
The defining molecular feature of ACCs is the presence of a recurrent chromo-
somal translocation, [t(6;9);(q22–23; p23–24)], with the fusion transcript involving
the MYB genes (transcriptional activator Myb) and nuclear factor 1 B-type [9].
ACC is positive for cytokeratins (CKs), CK8, CK14, and CK17. The expression of
c-kit may not serve as a useful marker for predicting outcomes in ACC patients [60].
Metastatic ACC cells demonstrate epithelial-mesenchymal transition (EMT) and
sphere-forming abilities. These cells exhibit a high expression of EMT-related
genes, including Snail, Twist1, Twist2, Slug, zinc finger E-box binding homeobox 1
and 2 (Zeb1 and Zeb2), glycogen synthase kinase 3β and transforming growth factor
β2, and stem cell markers (Nodal, Lefty, Oct-4, Pax6, Rex1, and Nanog), as well as
differentiation markers (sex-determining region Y), brachyury and α-fetoprotein [61].
Currently, the main treatment method for tracheal ACC is still surgical resection and
primary reconstruction [49, 62], which has been shown to improve survival [40];
however, in population-based studies, this treatment is only applied in 10–25% of
patients [63]. Determination of the type of resection depends on the location of the
tumor and its infiltration of other tissues. It may involve tracheal, laryngotracheal,
or carinal resection, with primary reconstruction or end-to-end anastomosis. In
young patients, anastomosis is feasible even when 6–7 cm of the trachea must be
resected [39, 64]. Wurtz et al. (2010) described a novel surgical technique using an
aortic allograft to enable extended tracheal resection [65]. The surgical approach
includes transverse cervical incision for tumors restricted to the cervical trachea.
Right posterolateral thoracotomy is reserved for lower parts of the airway tree; how-
ever, a combination of these methods may be used [66]. The occurrence of postop-
erative adverse effects is related to the length of the resection, tension on the suture
line, histological type of the tumor, and requirement for laryngeal release.
Subcutaneous emphysema is the most common complication [67]. The identifica-
tion of surgery-associated risk factors is important due to a high mortality rate
(≤10.8%) soon after surgery [66].
In recent years, adjuvant treatments, such as radiotherapy (RT) and chemother-
apy, have been reported to provide some treatment effect [68–72]. The function of
RT in patients with ACC has been evaluated in several studies [69, 72, 73], with
varying results, and its role remains uncertain [69, 74]. Neutron beam RT may be
used for adjuvant therapy [75]. Furthermore, ACC cells are less sensitive to ionizing
radiation than SCC cells; however, this treatment must be recommended for all
patients with unresectable disease or as adjuvant therapy. Patients with unresectable
disease must be considered as candidates for definitive RT with a conventional pho-
ton dose of 80 Gy [69]. In selected cases, it is recommended that the administered
dose be provided as five 2 Gy fractions per week over 6 weeks, with a total dose of
60–70 Gy [69]. Intensity-modulated radiation therapy (IMRT) [76] or positron-
emission tomography CT-directed IMRT [73] may be employed rather than stan-
dard procedures. However, in contrast to SCC patients, studies have shown that
ACC patients with node involvement who underwent complete resection may not
receive any benefits from this treatment modality [77, 78]. Although RT alone is not
recommended in the treatment of tracheal ACC, it may provide local disease con-
trol, and the majority of tumors respond to RT, which often results in long periods
of remission [79].
Review of literature by Ran et al. (2021) showed that surgical resection alone
(40.9%), surgery with postoperative radiotherapy (RT) (36.4%), and RT alone
(19.2%) were the most frequently used treatment modalities. Of the 1129 cases with
disease control and survival data, there was no evidence of disease in 78.7% of cases
and local recurrence was reported in 3.8%. Distant metastasis rate was 24.9% of 418
reported cases; the lung was the most commonly involved organ (44.2%) [38].
If distant metastases are diagnosed, palliative treatment, including endobronchial
treatment, low-dose irradiation, and best supportive care, is advisable [63]. Surgery
must be selected first whenever possible; however, for palliative treatment, RT, che-
motherapy, or chemo-RT based on cisplatin may also be effective [78]. Chemo-RT
may lead to sustained locoregional tumor control in patients with non-resected
ACCs. Surgical metastasectomy has also been reported as a useful treatment method
[80–82]. In a single case report, liver metastasectomy showed clinical efficacy [80].
Pulmonary resections may result in locoregional control of primary disease and
may extend disease-free survival [80, 83]. Endotracheal procedures, including for-
ceps biopsy and suction, electrocoagulation, cryotherapy, laser, photodynamic ther-
apy, or argon-beam coagulation and stents, are used in palliative treatment to
maintain upper airways patency [63].
Identification of cytogenetics, tumor suppressor genes, oncogenes, epigenetic
alterations, and mitochondrial abnormalities specific for ACCs is critical to the
development of targeted therapies. So far, large studies have only reported the tran-
scriptional activator Myb and mammalian target of rapamycin signaling pathway to
be disrupted in ACCs [39].
Overall, patients with ACC exhibit improved treatment outcomes when com-
pared with SCC patients, with a 5-year survival rates of 84% and 34%, respectively
[83]. The 5- and 10-year survival rates of patients treated with surgery alone and
surgery with postoperative RT were 86.4%, 55.6% and 97.3%, 44.4%, respectively
[38]. However, it must be noted that the long-term outcome may be poor due to late
local recurrences and late metastatic spread [84]. Thus, oncological follow-up must
be conducted for much longer than 5 years [39]. No molecular markers have been
found to be useful in predicting the progression of the disease or patient progno-
sis [39].
8.4 Solid Nodule in the Thyroid Isthmus
Epidemiology
A solitary thyroid nodule (STN) is a discrete localized lesion within the thyroid
gland in an otherwise normal gland, confirmed by ultrasonography (US) as being
distinct from the surrounding thyroid parenchyma [85]. A non-palpable nodule by
US or other imaging studies is termed “incidentaloma” [86].
The prevalence of thyroid nodules depends on several factors that include age,
gender, diet, iodine deficiency, as well as therapeutic and environmental radiation
exposure [87]. Thyroid nodules are more common in women than in men through-
out all age groups [88]. True STNs occur in 0.22–1.35% of children and in nearly
4% of the adult population. Such nodules are much more likely to be malignant in
children [87] and more aggressive with early metastasis to regional lymph nodes
(LNs) and distant organs [89, 90] than they are in adults. Prevalence increases with
age; thyroid nodules are found in 5% of persons aged an average of 60 years.
Exposure of the head and neck to ionizing radiation increases the incidence of thy-
roid nodules.
Pérez-Ruiz et al. (2008) reported that out of 330 consecutive patients with simple
uni-nodular goiter who underwent thyroidectomy at their institution between April
1994 and June 2006, 31 patients (9.39%) had their lesion limited to the thyroid
isthmus, with evidence of benign or undetermined pathology on ultrasound-guided
fine needle aspiration biopsy (FNAB) [91].
In 2010, Lee et al. reported that thyroidectomy was performed in 1973 thyroid
cancer patients in their hospital between January 2006 and December 2007. Only
181 patients (9.17%) had tumors located in the isthmus [13].
Goldfarb et al. (2012) stated that of 942 patients who underwent preoperative
surgeon-performed ultrasound (SUS) and FNA, followed by thyroidectomy,
between January 1, 2002, and April 10, 2010, a total of 28 patients (2.97%) had a
dominant thyroid nodule of the isthmus. Final pathological results showed that 16
patients had a benign lesion and 12 had a malignant lesion [15].
Etiology/Pathological Classification
Most thyroid nodules are benign hyperplastic lesions, but 5–20% of thyroid nod-
ules are true neoplasms. In a retrospective study of 61 patients, Keh et al. (2015)
reported that 75.4% of STNs had a neoplastic pathology and 34.6% were malig-
nant [87].
Many thyroid diseases can present clinically as an STN such as colloid cysts,
adenomas, Graves’ disease, thyroiditis, infections, and malignancies (Table 8.2).
The most important issue is whether or not it represents a malignant lesion.
Benign Thyroid Nodule

In general, the majority of solid STNs is benign and can be classified as adenomas,
colloid nodules, congenital abnormalities, infectious nodules, lymphocytic or gran-
ulomatous nodules, or hyperplasia.
Thyroid Adenoma
Follicular Adenoma
Follicular adenoma is the most common type and arises from the follicular epithe-
lium within the thyroid gland. It usually occurs in adults, usually between 20 and
50 years, affecting women more than men with a ratio of 6:1. A follicular adenoma
Table 8.2 Pathology of benign and malignant thyroid nodules

Benign nodule Malignant nodule
– Adenoma (follicular, papillary) – Papillary thyroid carcinoma (PTC)
– Hyperplastic nodule – Follicular thyroid carcinoma (FTC)
– Colloid nodule – Hurthle cell carcinoma (HCC)
– Toxic nodule – Mixed papillary/follicular carcinoma
– Inflammatory lesion (thyroiditis) – Medullary thyroid carcinoma (MTC)
– Infectious nodule – Anaplastic thyroid carcinoma (ATC)
– Lymphocytic/granulomatous – Poorly differentiated thyroid carcinoma (PDTC)
nodule
– Developmental (congenital) nodule – Lymphoma
– Metastatic disease
shows evidence of follicular differentiation, but lacks evidence of capsular and vas-
cular invasion and lacks the nuclear features of PTC. It may be the precursor of
anaplastic thyroid carcinoma (ATC). Grossly, a follicular adenoma is seen as a soli-
tary, encapsulated, tumor of variable sizes, typically, homogeneous, solid, fleshy,
and tan to light brown. Microscopically, it is seen completely enveloped by a thin
fibrous capsule and made up of closely packed follicles, trabeculae, or solid sheets.
It may be normo-follicular (simple), macro-follicular (colloid), micro-follicular
(fetal), or trabecular/solid (embryonal—atypical). Fine needle aspiration cytology
(FNAC) cannot rule out follicular carcinoma based on cytological findings.
Papillary Adenoma
Papillary adenomas are the least common type of thyroid adenoma. “Papillary
hyperplasia in a follicular adenoma” is the term that is preferred to “papillary ade-
noma.” The basic lesion is a follicular adenoma or adenomatous nodule in which
hyperplastic changes occur. This lesion tends to occur, most often in children and
adolescents, as an STN that develops approximately at the age of puberty [90].
Grossly, the nodule is always well-circumscribed, often encapsulated, and may
show cystic change centrally. The papillae, which are directed to the center of the
nodule, contain extremely edematous stalks with follicles in them. The nuclei are
round and tend to be polarized at the basal or central part of the cell. It is generally
suggested that any papillary architecture seen on histological examination should be
diagnosed as papillary thyroid carcinoma (PTC) and treated as such.
Hyperplastic Nodule
A hyperplastic nodule is an area of the thyroid gland that is stimulated to undergo
follicular hyperplasia and accumulation of colloid. It is differentiated from colloid
goiter by the presence of excessive cellularity, acinar formation, marginal vacuoles,
and papillary formation. Neoplasms have a higher degree of papillary formation,
intranuclear inclusions, and nuclear grooves, and fewer marginal vacuoles.
Solitary Toxic Nodule

A solitary toxic nodule is a discrete, “autonomous, hyperfunctioning” nodule that
occurs in an otherwise normal thyroid gland and causes hyperthyroidism. It accounts
for nearly 3–10% of all cases of spontaneous thyrotoxicosis, functions indepen-
dently of the hypothalamic-pituitary-thyroid feedback mechanism (autonomous),
and secretes thyroid hormone despite suppressed TSH levels. The pathology of a
toxic STN is almost uniformly either a follicular adenoma or an adenomatous nod-
ule. Carcinoma occurs in only about 1% of cases [92].
Congenital Thyroid Nodule

Congenital thyroid nodules include congenital hemangioma, thyroglossal duct
anomalies, and familial disorders, such as multiple endocrine neoplasia (MEN) syn-
dromes and congenital goitrous hypothyroidism.
Thyroiditis
Hashimoto’s Thyroiditis (HT)

Grossly, the goiter in Hashimoto’s thyroiditis (HT) is generally symmetrical, often
with a conspicuous pyramidal lobe. The involved tissue is pinkish tan to yellowish
in color and tends to have a rubbery consistency. The capsular surface is gently
lobulated and non-adherent to peri-thyroid structures. Microscopically, there is dif-
fuse epithelial cell destruction, lymphoid cellular infiltration, and fibrosis. The thy-
roid cells tend to assume an acidophilic staining character; they are then called
Hurthle or Askanazy cells and are packed with mitochondria. The follicular spaces
shrink, and colloid is absent or sparse. Fibrosis may be completely absent or present
in degrees ranging from slight to severe. Foreign body giant cells and granulomas
are not features of HT, in contrast to subacute thyroiditis.
Other Forms of Thyroiditis

Subacute granulomatous thyroiditis is probably viral in origin, and patients usually
present with a tender goiter. The exact pathogenesis is still unknown; however, the
“postpartum form” may be autoimmune. It presents mainly with goiter and sponta-
neously reversible hyperthyroidism.
Acute suppurative thyroiditis results from bacterial or fungal infection causing
abscess formation. The presence of clinical or metabolic hyperthyroidism in combi-
nation with painful nodular thyroid disease strongly suggests thyroiditis as a poten-
tial diagnosis.
Malignant Thyroid Nodule
Papillary Thyroid Carcinoma (PTC)

Papillary thyroid carcinoma (PTC) is derived from follicular epithelial cells and is
the most common histological type, constituting about 80% of all thyroid carcino-
mas [93]. Women are more affected than men in ratios of 2:1 to 4:1. The mean age
at the time of initial diagnosis is approximately 40 years. However, PTC accounts
for more than 90% of thyroid malignancies in children [94].
The size of the primary tumor ranges from microscopic to huge. Grossly, most
cases are solid, whitish in color, firm, and clearly invasive [95]. Microscopically,
classical or non-otherwise specified (NOS) PTC is characterized by the formation
of papillae and distinctive nuclear features [89, 90, 92]. Tumors with a combination
of papillary and follicular structures have the biological behavior of PTC [96–99].
Diagnosis of PTC depends on the characteristic “nuclear features” rather than the
“papillary architecture,” which may be minimal or absent. These nuclear features
include ground glass nuclei [100], nuclear pseudo-inclusions [101], and nuclear
grooves [96, 97]. Mitosis is very scanty or absent [102], and stromal lymphocytic
infiltration is seen in nearly 25% of cases [103]. In about 50% of cases, extensive
fibrosis and psammoma bodies, which are considered pathognomonic, are seen
[104]. Blood vessel invasion is found in only 5% of cases. The mode of spread of
PTC is most commonly via lymphatics within the thyroid leading to “multifocal”
disease and to cervical LN metastases [96, 105]. About 50% of PTCs have nodal
metastases at initial diagnosis [106].
Follicular Thyroid Carcinoma (FTC)

Follicular thyroid carcinoma (FTC) accounts for 5–15% of primary thyroid cancers
but is more frequent, reaching 25–40%, in areas with dietary iodine deficiency.
Grossly, FTC appears as a single nodule that may be well-circumscribed (simulat-
ing follicular adenoma) or widely infiltrative into the adjacent neck structures. It is
gray to tan pink in color on cut section, and degenerative changes and foci of calci-
fication are sometimes present.
Microscopically, most FTCs are composed of fairly uniform cells forming small
follicles containing colloid. The nuclei lack the features typical of PTC, and psam-
moma bodies are absent. There are no reliable cytological differences between fol-
licular adenomas and minimally invasive follicular carcinomas [107]. Up to 80% of
patients with widely invasive FTC can develop metastases with a mortality rate of
50%. Unlike in papillary cancers, lymphatic spread is uncommon in follicular can-
cers [108].
Hurthle Cell Carcinoma (HCC)

The incidence of Hurthle cell neoplasm (HCN) varies from 3% to 10% in all thyroid
nodules [109–111]. The mere presence of Hurthle cells does not necessarily signify
a neoplastic process. The presence of a capsule surrounding Hurthle cells, on the
other hand, is the defining characteristic of HCNs, which contain at least a 75%
Hurthle cell component. Hurthle cell tumors are generally believed to be a variant
of follicular neoplasms [112].
Diagnosis of an HCN by FNA can typically be classified as a follicular lesion of
undetermined significance (FLUS) or atypia of undetermined significance (AUS)
with Hurthle cell features. The projected risk of malignancy for this category is
5–15%. A cytological diagnosis of suspicion for HCN carries a projected 15–30%
risk of malignancy [113]. Intraoperative frozen section examination is unhelpful in
discriminating benign from malignant HCNs [114–117]. The sole distinction is
based on the presence or absence of capsular invasion and vascular invasion, which
can only be demonstrated on paraffin section [118].
Medullary Thyroid Carcinoma (MTC)

Medullary thyroid carcinoma (MTC) is a neuroendocrine neoplasm derived from
the parafollicular cells (C cells) of the thyroid and accounts for approximately 5%
of thyroid neoplasms [119]. Similar to normal C cells, MTCs secrete calcitonin,
which is helpful in diagnosis and postoperative follow-up. Nearly 70% of tumors
are sporadic, while the remainder occurs in the setting of multiple endocrine neopla-
sia (MEN) syndrome 2A or 2B or as familial tumors without an associated MEN
syndrome (familial MTC).
Grossly, sporadic lesions are usually solitary, in contrast to the common bilateral
and multicentric familial cases. The tumor tissue is firm, pale gray, and infiltrative.
Larger lesions often contain areas of necrosis and hemorrhage and may extend
through the thyroid capsule. Microscopically, MTC is composed of polygonal to
spindle-shaped cells, which may form nests, trabeculae, and even follicles [120].
Acellular amyloid deposits derived from calcitonin polypeptides are present in the
stroma in approximately 75% of cases. Calcitonin is readily demonstrable within
the cytoplasm of the tumor cells [121].
Anaplastic Thyroid Carcinoma (ATC)

Anaplastic thyroid carcinoma (ATC) is an undifferentiated tumor of the thyroid fol-
licular epithelium, accounting for approximately 5% of thyroid tumors. It is an
aggressive tumor with a mortality rate approaching 100%. Grossly, ATC appears as
a large, necrotic, and hemorrhagic mass that is typically widely invasive, often
replacing most of the thyroid gland parenchyma with infiltration of the surrounding
soft tissue and adjacent structures of the neck. Cut surface may be brownish or whit-
ish in color, usually with evident, discrete, yellowish areas of necrosis.
Microscopically, these tumors are composed of highly anaplastic cells, with vari-
able morphologies, including large spindle cells, pleomorphic giant cells, squamoid
cells resembling squamous carcinoma, and mixed spindle and giant cells [122].
Poorly Differentiated Thyroid Carcinoma (PDTC) (Insular Carcinoma)

Poorly differentiated thyroid carcinoma (PDTC) is a heterogeneous group of malig-
nant thyroid tumors originating from the follicular epithelium. The common patho-
logical features are solid/trabecular/insular growth, large size, frequent
extra-thyroidal extension, vascular invasion, necrosis, and increased mitotic activ-
ity. They may be associated with well-differentiated PTC or FTC components and,
less frequently, with ATC [123].
Thyroid Lymphoma
Thyroid lymphomas comprise <5% of thyroid malignancies and 2% of all lympho-
mas [124–126]. The majority are non-Hodgkin’s lymphomas (NHL) of B-cell ori-
gin [125, 127, 128]. Primary lymphoma of the thyroid occurs, in most cases, on a
background of HT (the only known risk factor) [129, 130] and can increase the risk
of developing thyroid lymphoma by up to 60 times [131]. Secondary thyroid lym-
phoma occurs in 20% of patients with generalized lymphoma [132]. Advances in
FNA technology and immunocytochemical studies have now made FNA diagnosis
of lymphoma possible in most patients [133]. Incision biopsy is not essential for the
diagnosis of thyroid lymphoma [134].
Metastatic Thyroid Lesions

Metastatic lesions reach the thyroid by direct extension from adjacent tumors, by
retrograde lymphatic spread, or hematogenously, most commonly from primary
carcinomas of the kidneys, lung, colon, or melanoma [135]. They account for 1–7%
of all thyroid malignancies identified during the workup of a thyroid nodule [136,
137]. Fine needle aspiration is the diagnostic procedure of choice for any patient
with a new thyroid nodule and a history of malignancy [136, 138–140].
Clinical Approach
Generally, only nodules more than 1 cm in size should be evaluated, since they have
a greater potential to be clinically significant cancers. A malignant nodule is usually
hard with fixation to surrounding tissue and regional lymphadenopathy. Early mani-
festations of a malignant thyroid nodule include limited mobility with deglutition,
hard consistency, rapid increase in size, and development of pain in the swelling
itself or referred to the ear. Late signs include fixation to the overlying skin, RLN
involvement, carotid artery infiltration (diminished pulse), lymphadenopathy, and
distant metastases (mainly to bone and lungs). In general, several aspects of the his-
tory and physical examination can raise the suspicion of cancer (Table 8.3).
History-Taking: Risk Factors
Demographic Data
Several studies have reported a bimodal age distribution of thyroid carcinoma in
STNs. Reported prevalence of thyroid carcinoma in an asymptomatic STN is
3.4–29%. More than 50% of all thyroid nodules in children are malignant [141].
The incidence of malignancy is also higher in nodules that develop after the age of
65 years.
Solitary thyroid nodules are encountered more frequently in women. Benign
nodules are more common than malignant nodules in both males and females; how-
ever, the proportion of malignant nodules in males is twice that of females.
Exposure to Radiation
Reported factors predicting malignancy include a history of childhood head and
neck radiation therapy, total-body radiation for bone marrow transplantation [142],
and exposure to ionizing radiation from fallout in childhood or adolescence [143].
Table 8.3 Important clinical factors that raise suspicion of thyroid cancer (risk factors)
History-taking Physical examination
– Family history of thyroid cancer – Solitary versus multiple nodules
– Gender (♂:♀ = 2:1) – A hard nodule
– Age <20 or >60 years – Fixed nodule
– History of head and neck irradiation – Size (diameter: 4 cm or more)
– Rapidity of growth – Vocal cord paralysis
– Associated symptoms (pain, dysphagia, dysphonia, – Cervical lymphadenopathy
dyspnea)
– Growth on thyroid hormone suppression – Suspicion of distant metastases
If a patient with an STN has a history of head or neck irradiation in childhood, the
prevalence of cancer is 30–50% [144].
Time Course
The time of initial appearance of the nodule, rate of growth, and associated symp-
toms can assist the clinician in determining the malignancy potential of the STN. A
nodule that has been stable in size for years is almost always benign. Rapid growth
(over weeks or months—not sudden growth) is an indicator of possible malignancy.
Symptoms of Local Infiltration or Spread

Entrapment of the RLN, invasion of thyroid capsule, or spread into adjacent tissues
can lead to local pain in the neck or radiating to the jaw and ear. Symptoms such as
dysphagia, dysphonia, dyspnea, hoarseness, or hemoptysis may all reflect esopha-
geal and/or tracheal involvement by thyroid cancer.
Thyroid Dysfunction
Although most patients with STNs are euthyroid, some exhibit evidence of altered
levels of thyroid hormones. Symptoms of hyperthyroidism include nervousness,
heat intolerance, diarrhea, muscle weakness, and loss of weight and appetite.
Hypothyroidism may result in cold intolerance, constipation, fatigue, and weight
gain, which, in children, is primarily caused by the accumulation of myxedematous
fluid. Nodules associated with hyperthyroidism are usually benign “functioning
adenomas,” whereas a nodule in a patient with hypothyroidism is often caused by
“autoimmune thyroiditis.”
Medical History
Other risk factors to consider in the past medical history include symptoms of pheo-
chromocytoma or hyperparathyroidism (HPT), long-standing constipation and/or
diarrhea, hypertension, and/or episodes of nervousness. These should alert the clini-
cian to the possibility of MTC in association with a familial MEN syndrome. Other
risk factors also include a history of other malignancy, hamartoma tumor syndrome
(Cowden’s disease), familial adenomatous polyposis, Carney complex, Werner syn-
drome/progeria, or MEN-2.
Family History
A family history of thyroid disease, benign or malignant, can be found in a signifi-
cant number of patients with thyroid cancer and may help determine which patients
have an increased risk. Fowler et al. (1989) reported that a family history of thyroid
disease was present in 41% of their patients with thyroid nodules [145]. However, a
family history of thyroid disease also increases the risk of autoimmune thyroiditis,
and malignancy should not be assumed automatically.
hysical Examination: Risk Factors

P
Although it is almost impossible to distinguish a benign nodule from a malignant
nodule by palpation, a thorough physical examination should be performed. Careful
examination of the neck reveals the nature, location, and tenderness of the mass;
fixation of the thyroid to surrounding tissue; and presence of other cervical masses,
which can be metastases or lymphadenopathy.
Physical Characteristics of the Thyroid Nodule

Physical characteristics of a thyroid nodule are considered poor predictors of malig-
nancy since both malignant and benign STNs can be soft or firm, and smooth or
irregular upon examination. In contrast, a recent study by Uyar et al. (2017) indi-
cated that characteristics such as hard consistency, irregular borders, microcalcifica-
tion, increased vascularity, and cervical lymphadenopathy are malignancy risk
factors for STNs [146].
A relatively rapidly growing hard nodule is associated with a higher risk of
malignancy. Moreover, size is used in tumor staging and is highly predictive of the
outcome. Hard nodules raise the suspicion of malignancy but may also result from
calcifications in benign adenomas. Fixation to or invasion of surrounding structures
such as the trachea or strap muscles is also highly suggestive of malignancy.
However, fixation can also occur with severe chronic thyroiditis. Vocal cord paraly-
sis strongly suggests an invasive cancer, but again, benign conditions such as HT or
multinodular goiter can rarely affect vocal cord function, which is thus not a reliable
indicator of malignancy.
Cervical Lymph Nodes (LNs) (Regional Lymphadenopathy)

The most significant physical findings suggestive of malignancy are the unilateral,
firm/hard, non-tender, discrete LNs resulting from metastatic thyroid cancer, most
commonly PTC.
General Examination
Thyroid cancer is found in the contralateral lobe in as many as 66% of individuals
with thyroid malignancy, which also metastasizes to the lungs in 10% of patients,
particularly in those with FTC. Other sites of spread include the spinal cord, base of
the tongue, and bone, especially the skull, tibia, and costochondral junction. If MTC
is suspected in conjunction with MEN, the characteristic features of MEN syn-
drome may also be evident. The MEN-2A consists of MTC, adrenal pheochromo-
cytoma, and hyperparathyroidism (HPT). The MEN-2B causes mucosal neuromas,
typical facies, marfanoid body habitus, and MTC. The associated thyroid cancer is
especially aggressive and often appears when the individual is aged almost 5 years.
Investigations
Laboratory Studies
Thyroid Function Tests

Thyroid function tests can determine whether a nodule is functioning or autono-
mous and thus should be a part of the initial evaluation of an STN; findings are
usually normal in case of a malignant nodule. A suppressed TSH level is suggestive

of benign pathology such as an autonomous adenoma or HT [147]. A strong asso-
ciation, however, exists between HT and primary thyroid lymphoma. Chami et al.
(2014) reported that measurement of serum TSH levels is not effective in screening
autonomously functioning thyroid nodules [148].
Serum Thyroglobulin (Tg)

Measurement of serum thyroglobulin (Tg) levels has historically not been recom-
mended in the evaluation of STN because it is also elevated in benign thyroid
disorders.
Serum Calcitonin
Although calcitonin is a marker for MTC, calcitonin levels may also be increased,
although infrequently, in other clinical conditions such as C-cell hyperplasia, pul-
monary and pancreatic neuroendocrine tumors, renal failure, and hypergastrinemia.
Routine measurement of serum calcitonin for screening may detect C-cell hyperpla-
sia and MTC at an earlier stage, and overall survival may consequently be improved
[149–153].
DNA Testing
DNA testing has proven to be an effective method for the diagnosis of MEN-2A
and -2B syndromes. Patients with MTC should undergo direct DNA analysis to
identify possible germline mutations in the ret proto-oncogene. All family members
should undergo similar testing if a ret mutation is identified. It is now possible to
detect thyroid cancer cells in peripheral blood samples by measuring the mRNA of
thyroid-specific genes, such as the mRNA of Tg and the thyrotropin receptor. In
addition, micro-RNAs, which are small endogenous noncoding RNAs involved
with the regulation of gene expression, can be detected in the serum of patients with
thyroid cancer.
Imaging Studies
Once a thyroid nodule is palpated and thyroid function obtained, several imaging
studies are necessary to determine the nature of the lesion.
Ultrasonography (US) is the imaging study of choice for thyroid nodules (Fig. 8.2).
It is safe and effective in determining the size and consistency of a thyroid nodule
[79]. Three orthogonal diameters, including the largest diameter, should be mea-
sured by US, and nodule or tumor volume could be calculated using the eq.
V = πabc/6, where V is the volume, a is the maximum diameter, and b and c are the
other two perpendicular diameters [154–156].
High-resolution US can be used to determine the presence of non-palpable nod-
ules as small as 1 mm within the thyroid tissue. It can also identify the presence of

(US) of the thyroid
showing a hypoechoic
nodule with ill-defined
margin and micro-
calcifications (white
arrow). Histology showed
papillary thyroid
carcinoma (PTC)
other nodules, which indicates a multinodular disease process and central or lateral
neck lymphadenopathy predictive of malignant involvement and provides accurate
measurements of nodule diameter allowing serial scans and better assessment
of growth.
Ultrasound (US) features of a thyroid nodule are categorized into those with high
suspicion, intermediate (moderate) suspicion, low suspicion, very low suspicion,
and benign as shown in Table 8.4 [157–159]. Such features can also guide FNA
from the thyroid nodule. Ultrasound-guided FNA is also recommended for cervical
LNs that are sonographically suspicious for thyroid cancer [160].
Doppler Scan
Color flow patterns on Doppler scan are categorized as (a) type 1: no blood flow,
(b) type 2: peri-nodular flow, and (c) type 3: intra-nodular blood flow (peri-nodu-
lar vessels may or may not be present). Although nonspecific, thyroid cancers may
have internal hyper-vascularity, whereas benign nodules may have peripheral vas-
cularization. However, type 3 vascularization can be found in both benign and
malignant nodules. Completely avascular nodules are more likely to be
benign [161].
ltrasound Elastography (Elasto-Sonography)

U
A thyroid nodule with firm or hard consistency is associated with an increased risk
of malignancy. Elastography has recently been applied in the diagnostic approach to
nodular thyroid disease and has shown a high sensitivity and specificity in selected
patients, and its predictive value seems to be independent of nodule size [149, 150].
Multinodular goiters with coalescent nodules are not suitable for this analysis [150].
Table 8.4 Sonographic patterns of thyroid nodules, risk of malignancy, and fine needle aspiration
(FNA) guidance [157–159].
Risk of FNA size cutoff
malignancy (largest
Sonographic pattern Ultrasonographic features (%) dimension)
High suspicion Solid markedly hypoechoic nodule or >70–90 Recommend
solid hypoechoic component of a FNA at ≥1 cm
partially cystic nodule with one or
more of the following:
– Irregular margins
– Micro-calcifications
– Taller-than-wide shape
– Rim calcifications with small
extrusive soft tissue component
– Evidence of ETE
– Suspicious cervical LNs
Intermediate suspicion – Hypoechoic solid nodule with 10–20 Recommend
smooth margins without micro- FNA at ≥1 cm
calcifications, ETE, or taller-than-
wide shape
– Firm-to-hard nodule by
sono-elastography
– Increased intra-nodular vascularity
– Absence of halo
Low suspicion – Isoechoic or hyperechoic solid 5–10 Recommend
nodule, or partially cystic nodule with FNA at ≥1.5 cm
eccentric solid areas, without
micro-calcification, irregular margin or
ETE, or taller-than-wide shape
– Peripheral calcification (eggshell)
– Macro-calcification
Very low suspicion Spongiform or partially cystic nodules <3 FNA at ≥2 cm
without any of the suspicious OR observation
sonographic features without
Benign Purely cystic nodules (no solid <1 No biopsy
component)
ETE extra-thyroid extension, LN lymph node
adionuclide Imaging (Thyroid Scintigraphy)

R
Iodine-123 (123I) and technetium (99mTc) are the most commonly used radionuclides
for thyroid imaging. Radioactive iodine (RAI) scintigraphy (Fig. 8.3) can determine
whether the nodule is cold (no RAI uptake—malignant or cystic nodule), warm
(functioning adenoma), or hot (takes RAI > surrounding thyroid tissue—toxic nod-
ule) [162, 163]. Hot nodules often require antithyroid medications before surgery,
whereas cold nodules have a much higher incidence of malignancy. Scintigraphy is
also used postoperatively to exclude the presence of metastases, especially after
total thyroidectomy (TT). Scintigraphy can also be used to detect ectopic thyroid
tissue or identify the thyroid tissue that will be lost with thyroglossal duct cyst
removal, requiring lifelong thyroid hormone replacement.
Fig. 8.3 Radioactive

iodine (RAI) scintigraphy
showing a huge solitary
thyroid nodule (STN)
omputed Tomography (CT) Scan and Magnetic Resonance

C
Imaging (MRI)
Indications of CT scan and MRI include suspected involvement of adjacent struc-
tures, extension into the mediastinum, recurrent disease, presence of cervical LNs,
and hemoptysis indicating pulmonary metastasis [164]. Both CT scan and MRI are
relatively expensive and have a limited role in the initial evaluation of an STN as
they have a limited ability in distinguishing between benign and malignant lesions.
However, they are necessary in some cases for staging, determining the extent of the
disease, and in planning surgery [165].
Positron-Emission Tomography (PET)

18F-2-fluoro-2-deoxy-d-glucose-positron-emission tomography (FDG-PET) and
PET-CT are nuclear medicine imaging tests that use a small amount of radiolabeled
glucose to identify cancer. Since cancer cells are more metabolically active than
normal cells, the cancer cells take up more of the radiolabeled glucose than normal
cells and show up on the FDG-PET scan. FDG-PET scans are frequently combined
with PET-CT to accurately identify where in the body a cancer may be located. A
recent meta-analysis confirmed that approximately 35% of 18FDG-PET-positive
thyroid nodules proved to be malignant [166]. Currently, the routine use of PET
scans in the evaluation of STNs is still not recommended [167].
Biopsy (Cytology/Histology)
ine Needle Aspiration (FNA): Freehand or US-Guided

F
Fine needle aspiration biopsy (FNAB) has become the diagnostic procedure of
choice of STNs and the cornerstone in the management of thyroid nodules because
Table 8.5 Diagnostic FNA categories and recommended actions (BTA guidelines)
Category Description Recommended action
Thy 1 Nondiagnostic, insufficient sample To repeat FNAC
Thy 2 Benign, nonneoplastic Repeat FNAC in 3–6 months. Two
nonneoplastic results 3–6 months apart
exclude neoplasia
Thy 3 Follicular or Hurthle cell lesion/ MDT discussion—diagnostic lobectomy
suspected folic, or Hurthle tumor
Thy 4 Suspicious of malignancy MDT discussion—total thyroidectomy
Thy 5 Diagnostic of malignancy MDT discussion—total thyroidectomy
MDT multidisciplinary team, FNAC fine needle aspiration cytology
of its accuracy, safety, and cost-effectiveness. It is a simple, outpatient procedure,

and complications such as hematoma or infections are rare.
Freehand or palpation-guided FNAC has a sensitivity of 65–98% and a specific-
ity of 72–100% [168]. The US-guided FNAC improves the accuracy of FNAC [160,
168]. Moreover, it helps to localize impalpable nodules, lesions <1 cm, or when
initial freehand FNAC was nondiagnostic [169]. However, FNA may not be able to
distinguish follicular adenoma from FTC as it does not identify capsular or vascular
invasion. Likewise, FNA may not be able to distinguish between Hurthle cell ade-
noma and Hurthle cell carcinoma [170, 171].
A study by Yuan et al. (2015), however, indicted that the patterns of enhancement
differ significantly between benign and malignant STNs examined with real-time,
contrast-enhanced US, with most malignant lesions demonstrating an irregular
shape, ill-defined margins, and inhomogeneous and incomplete enhancement [172].
The combination of the newer US techniques with molecular markers now available
for FNAB may prove to be able to accurately distinguish malignant from benign
thyroid nodules.
Cytology results are of five diagnostic categories (Thy 1–Thy 5) as indicated by
the British Thyroid Association (BTA) Guidelines [173]. This will help with subse-
quent management as summarized in Table 8.5.
The recently issued Bethesda System for Reporting Thyroid Cytopathology
(BSRTC) [174] is currently considered to be the most suitable for communicating
findings from thyroid smears. The cytodiagnostic categories of Bethesda
Classification, with the corresponding estimated risk of malignancy, are listed in
Table 8.6.
arge-Needle Biopsy (LNB) and Core Needle Biopsy (CNB)

L
Large-needle biopsy can also increase the diagnostic accuracy of FNAB, but it also
increases the risk of hematoma formation, laryngeal nerve injury, injury to the tra-
chea or other neck structures, and cutaneous implantation of malignant cells.
In patients with suspicious anaplastic tumor, thyroid lymphoma, pathological
LNs, or other malignant neck disease, US-guided CNB should be considered [123].
However, CNB offers no additional diagnostic value in distinguishing a cellular
hyperplastic nodule from a follicular adenoma or carcinoma [175]. Hence,
US-guided CNB should not be seen as an alternative to FNAB, but as a
Table 8.6 Bethesda system for reporting thyroid cytopathology

Risk of
Category Description cancer (%)
I Nondiagnostic or unsatisfactory: Cyst fluid only—virtually 5–10
acellular specimen, other (obscuring blood-clotting artifact)
II Benign: Consistent with a benign follicular nodule, Hashimoto’s 0–3
thyroiditis, or granulomatous thyroiditis
III Atypia of undetermined significance (AUS) or follicular lesion of 10–30
undetermined significance (FLUS)
IV Follicular neoplasm (FN) or suspicious for a follicular neoplasm 25–40
(SFN)
V Suspicious for malignancy (SUSP) 50–75
VI Malignant 97–99
complementary investigational tool [123]. Without US guidance, LNB or CNB is

not recommended for thyroid nodules because of local pain and risk of cervical
bleeding. In addition, it does not add any further diagnostic information to FNAB in
nodules with follicular cytological characteristics [176].
I ntraoperative Frozen Section Biopsy

Intraoperative frozen section analysis of thyroid nodules requires excisional biopsy
in the form of thyroidectomy and may provide no additional information. Some
authors report a high degree of accuracy with intraoperative frozen section; how-
ever, its contribution to the management of STNs remains controversial.
Staging of a Malignant Thyroid Nodule
ell-Differentiated Thyroid Carcinoma (WDTC)

W
According to the TNM staging system (tumor, node, metastases), the lack of distant
metastases in patients with WDTC (papillary or follicular) younger than 45 years
designates cancer stage I, whereas the presence of metastases signifies stage II
[177]. In patients older than 45 years, WDTC is staged as usual into four stages
(stages I–IV) where the presence of metastases signifies stage IV (Table 8.7).
naplastic Thyroid Carcinoma (ATC)

A
Any anaplastic cancer is considered stage IV. Staging of anaplastic thyroid carci-
noma (ATC) is summarized in Table 8.8.
edullary Thyroid Cancer (MTC)

M
Medullary thyroid cancer (MTC) is classified differently, as shown in Table 8.9. The
TNM stage “grouping” of medullary thyroid carcinoma (MTC) is summarized in
Table 8.10. As may be seen, it ranges from stage I to stage IVC.
Table 8.7 TNM staging of well-differentiated thyroid carcinoma (papillary/follicular)

TNM Description
Tumor (T)
Tx Primary cannot be assessed
T0 No evidence of primary
T1 Limited to thyroid, 1 cm or less
T2 Limited to thyroid, >1 cm but <4 cm
T3 Limited to thyroid (or minimal extension beyond capsule), >4 cm
T4 Extending beyond capsule, any size
Nodes (N)
Nx Cannot be assessed
N0 No regional node metastases
N1 Regional node metastases
Metastases
Mx Cannot be assessed
M1 No metastases
M2 Metastases present
Stage Under 45 years Over 45 years
I Any T, any N, M0 T1, N0, M0
II Any T, any N, M1 T2, N0, M0 or T3, N0, M0
III – T4, N0, M0 or any T, N1, M0
IV – Any T, any N, M1
Table 8.8 TNM staging of anaplastic thyroid carcinoma (ATC) (stage IV)
Stage Tumor (T) Nodes (N) Metastases (M)
IVa T4a (tumor does not extend beyond the thyroid capsule) Any N M0
IVb T4b (tumor extends beyond the thyroid capsule) Any N M0
IVc Any T Any N M1
Table 8.9 TNM staging of Stage Description

medullary thyroid I T1 tumor, <10 mm, with no LNs (N0) or
cancer (MTC) metastases (M0)
II Larger tumors (T2), also without LNs (N0) or
metastases (M0)
III Classification involves LNs
IV Indicates the presence of distant metastases
Table 8.10 Stage grouping Stage TNM stage grouping

of medullary thyroid I T1, N0, M0
carcinoma (MTC)
II T2–3, N0, M0
III T1–3, N1a, M0
IVA T4a, N0-1a, M0 or T1-4a, N1b, M0
IVB T4b, any N, M0
IVC Any T, any N, M1
Management
Although most benign nodules can be safely observed, a portion of these nodules
require definitive management due to significant size, continued growth, compres-
sive symptoms, cosmesis, and/or autonomous function leading to hyperthyroidism
[178, 179]. The management of an STN depends on several factors: demographic,
clinical, biochemical, imaging, and cytological/histological.
Recent guidelines [118, 180] do not recommend thyroid-stimulating hormone
(TSH)-suppressive therapy with levothyroxine for benign nodules because the
effect of medication in volume reduction of a thyroid nodule is uncertain [181–183]
and may result in side effects such as long-term osteoporosis or atrial fibrillation.
Surgical excision has been established as a treatment for symptomatic benign
thyroid nodules. Although associated with excellent outcomes in experienced hands,
thyroidectomy still carries a low risk of complications (2–10%) [184, 185] that
include recurrent or superior laryngeal nerve injury leading to voice changes, hypo-
parathyroidism, bleeding, infection, hypothyroidism with need for thyroid hormone
supplementation, and scarring [186]. Thyroid surgery is also costly and may not be
appropriate for patients who have a high risk of surgical morbidity or those who
refuse surgery.
Therefore, image-guided nonsurgical procedures such as percutaneous ethanol
ablation (PEA) and thermal ablation such as radio-frequency ablation (RFA) and
percutaneous laser ablation (PLA) have been proposed as alternative and less inva-
sive approaches for the management of benign symptomatic thyroid nodules [187].
Ultrasound (US)-guided radio-frequency ablation (RFA) for thyroid lesions is a
minimally invasive treatment modality that may be an alternative to surgery in
patients with benign thyroid nodules and may also have an effective complementary
role in the management of recurrent thyroid cancers [188–190].
enign Simple Nodule

B
If FNAB indicates a benign nodule, options of treatment include surgery (hemithy-
roidectomy), observation, and hormone suppression, in addition to the novel
US-guided minimally invasive procedures, i.e., percutaneous ethanol ablation
(PEA) and thermal ablation using radio-frequency ablation (RFA), and percutane-
ous laser ablation (PLA).
Surgery (Hemithyroidectomy)
Hemithyroidectomy may be considered if the nodule is causing symptoms or disfig-
urement and in those patients who are at increased risk of thyroid cancer despite a
benign FNA. Complications are generally low, and full thyroid suppression postop-
eratively is recommended. Compared to the other treatment methods of thyroid
nodule, surgery has been always higher in the risk of complications (2–10%) of
patients, and it is considerably more expensive [191, 192]. Long hospitalization,
scar formation, iatrogenic hypothyroidism, and difficulty in reoperation with a
higher risk of morbidity or complications can be mentioned as the most common
drawbacks of surgery [191, 193, 194].
Observation
If the patient does not require surgery, the nodule may be either observed or sup-
pressed with levothyroxine (L-T4) as the initial treatment modality.
Levothyroxine (L-T4) (Thyroid-Stimulating Hormone Suppression)

A sufficient dose of exogenous levothyroxine (L-T4) is administered to cause the
thyroid gland and hence the nodule to stop growing. It is typically given for
6–12 months to determine if the STN decreases in size. If it does, medication is
discontinued, with follow-up examination of the thyroid nodule in 3–6 months.
Growth of a thyroid nodule during L-T4 therapy is a strong indication for surgery.
There is no agreement on the efficacy and safety of this method, and the outcome
has been questioned when the nodule is larger [195].
Radioactive Iodine (RAI)

The use of radioiodine for benign nodules has had a continuous discussion on its
potential to make the nodule malignant. Thyroid absorbs almost all iodine the body
takes, and does so with RAI (131I), if taken by the patient, so the tissue will be
destroyed [196].
Percutaneous Ethanol Ablation (PEA) (Ethanol Injection or Sclerotherapy)

Highly concentrated ethanol can be used to destroy the undesired tissue. Before
ethanol injection, the whole fluid or colloid inside the cyst (if present) has to be
aspirated. The amount of ethanol used will be a little more than half of the aspirated
fluid, and the retention time is about 2 min [197, 198]. Percutaneous ethanol abla-
tion (PEA) is significantly superior to aspiration alone for inducing volume reduc-
tion in cysts and complex nodules with a dominant fluid component [199–202] and
for disappearance of local pressure symptoms [198]. However, PEA is not generally
indicated for hyperfunctioning nodules because of the high recurrence rate and the
availability of effective alternative treatment options. Clinically, significant
decreases in nodule size after PEA are reported in solid, cold, thyroid nodules [203,
204]. However, the response is less impressive than in cysts; more treatments are
needed, and adverse effects are more frequent [199]. Thus, the use of PEA in solid
nodules has been limited due to the seepage of ethanol into peri-nodular tissue,
which is the cause of pain and other complications [205]. In addition to the adverse
effects of ethanol seepage, the fact of not being able to ablate the undesired tissue of
the solid nodule in a regular, homogeneous, and reproducible way has been men-
tioned as the limitation of PEA [206].
Ultrasound-Guided Minimally Invasive Procedures/Thermal Ablation

Minimally invasive thyroid surgery may be performed with minimum surgical risk
in patients with a small nodule [207, 208]. Recently, percutaneous, image-guided,
minimally invasive therapeutic procedures have been proposed for the nonsurgical
management of a thyroid nodule in selected cases [209, 210]. New thermal ablation
techniques such as radio-frequency ablation (RFA), percutaneous laser ablation
(PLA), microwave ablation (MWA), and high-intensity focused US have been used
to treat thyroid nodules. Many researchers recommend PEA for the treatment of
cystic thyroid tumors and thermal ablation for solid nodules [211–216]. Because of
potential complications, thermal ablation procedures should be performed only by
experienced operators and only in selected patients and not as a routine manage-
ment of benign thyroid nodules.
Radio-Frequency Ablation (RFA)

Radio-frequency ablation (RFA) of thyroid nodules is the application of radio-
frequency waves to cause thermal injury and subsequent necrosis of the tissue.
Gradual reabsorption of the ablated tissue results in overall volume reduction of the
thyroid nodules [217]. Thus, RFA, under local anesthesia or conscious sedation, has
been proposed for debulking a large benign thyroid nodule. It is based on percutane-
ous insertion of large needle electrodes or hook needles. A high-frequency electrical
current moves from the electrodes into the tissues, and the alternate movement of
ions results in frictional heating of the target tissue. Monopolar probes produce heat
by ionic agitation within a 2 mm radius; tissue heating beyond this zone is due to
heat conduction [218, 219].
Several studies have reported that RFA has shown good efficacy and safety in the
management of thyroid nodule-related cosmetic problems and pressure symptoms
[154–156, 190, 220–225]. Thyroid nodules should be confirmed as benign on at
least two US-guided fine needle aspirations (FNAs) or core needle biopsy (CNB)
before RFA [226]. Table 8.11 summarizes the results of 21 studies on the efficacy of
RFA for nonfunctioning thyroid nodules [154–156, 221, 227–243]. These studies
included 1503 patients with a mean follow-up of 11.9 months (range:
3.6–49.4 months). The efficacy of RFA was measured based on the symptomatic
score, cosmetic score, and volume reduction rate (VRR). At baseline, the mean
symptomatic score in 14 available studies was 3.83 (range: 2.4–5.6), and the mean
cosmetic score in 12 available studies was 3.43 (range: 1.14–5.7). The mean initial
volume of thyroid nodules in all 21 studies was 12.3 mL (range: 5.4–30 mL). After
treatment, the mean symptomatic score was 1.09 (range: 0.2–2.1), and the mean
cosmetic score was 1.51 (range: 0.53–2.5). At the last follow-up, the mean volume
of thyroid nodules was 2.86 mL (range: 0.4–8.6), and the mean VRR was 80.1%
(range: 64.9–93.9).
Radio-frequency ablation (RFA) is safe and well-tolerated and is associated with
a low incidence of complications when performed by experienced operators. Several
guidelines and studies, including meta-analyses, suggest that RFA is safe, well-
tolerated, and associated with a low incidence of complications [188, 190, 225,
244–248]. For benign nodules, the overall complication rate was 2.11%, and the
major complication rate was 1.27%.
Both minor and major complications of RFA have been reported in the literature.
Major complications included nerve injuries (RLN, cervical sympathetic ganglion,
brachial plexus, and spinal accessory nerve), nodule rupture, and permanent hypo-
thyroidism. Minor complications included hematoma, vomiting, skin burn, tran-
sient thyrotoxicosis, lidocaine toxicity, hypertension, and pain. However, there were
no life-threatening complications including injury to the trachea and esophageal
rupture [244, 245, 247].
Table 8.11 Efficacy of radio-frequency ablation (RFA) for nonfunctioning thyroid nodules
Follow-up Symptom Symptom Cosmetic Cosmetic Nodule volume
period score at score after score at score after at baseline Nodule volume
Authors Sample size (months) baseline RFA baseline RFA (mL) after RFA (mL) VRR (%)
Ahn et al. [227] 22 3.6 NA NA NA NA 14.3 4.7 74.3
Aysan et al. [228] 100 15.4 NA NA NA NA 16.9 2.6 84.6
Baek et al. [155] 15 6.43 3.33 1 3.6 1.53 7.5 1.3 82.7
Baek et al. [229] 200 5.21 NA NA NA NA 6.8 1.8 73.2
Baek et al. [230] 22 6 2.9 0.2 3.8 1.5 8.6 1.1 87.5
Bernardi et al. [231] 37 12 NA NA NA NA 12.4 3.91 68.4
Cesareo et al. [232] 42 6 2.8 0.4 2.6 1.7 24.5 8.6 64.9
8.4 Solid Nodule in the Thyroid Isthmus
Che et al. [233] 200 12 NA NA NA NA 5.4 0.4 84.8

Deandrea et al. [234] 40 6 3.6 0.4 3.6 1.7 15.1 4.2 71
Hong et al. [235] 18 18.1 2.4 1.4 3.8 2.5 24.4 6.3 74.2
Huh et al. [236] 30 6 5.4 2.1 3.8 2 13.2 3.4 74.3
Jeong et al. [154] 302 NA NA NA NA NA 6.13 1.12 84.1
Kim et al. [237] 73 11.5 3.97 1.84 NA NA 17 6 69.7
Kim et al. [221] 35 6.4 3.4 1.83 NA NA 6.31 0.74 88.2
Li et al. [238] 35 6 NA NA NA NA 8.81 1.59 82
Lim et al. [239] 111 49.4 4.3 0.8 3.2 1.3 9.8 0.9 93.5
Sung et al. [156] 21 19.5 4 0.39 3.2 0.71 10.19 0.79 92.19
Sung et al. [240] 25) 6 3.5 0.5 3.6 1.1 9.3 0.57 93.9
Ugurlu et al. [241] 33 6 3.9 1.1 1.14 0.53 7.3 1.2 74
Valcavi et al. [242] 40 24 5.6 1.9 5.7 2 30 7.9 80.1
Yue et al. [243] 102 12 4.5 1.5 3.1 1.6 5.7 0.93 83.6
RFA radio-frequency ablation, NA not available, VRR volume reduction rate
227
The most common major complication after RFA is “voice change,” caused by
injury to the RLN or vagus nerve, possibly due to direct thermal injury, stretching
of the nerve over the thyroid swelling, or hematoma on the nerve against the trachea
[244, 247, 249]. The incidence has been reported to be 1.45%, with a permanent
voice change of 0.17% [244]. The trans-isthmic approach and moving-shot tech-
nique are recommended to prevent injury of the RLN [249, 250]. Variation of vagus
nerve location or a bulging thyroid nodule may alter the location of the vagus nerve
so that it is closer to the thyroid gland, where it can be damaged during the proce-
dure. Therefore, operators should be aware of the location of the RLN and vagus
nerve [249, 251].
Horner’s syndrome (ipsilateral ptosis, miosis, and anhidrosis of the face) could
be caused by thermal damage to the middle cervical sympathetic ganglion (mCSG).
The mCSG is usually located at the lower level of the thyroid gland and is visible as
a spindle-shaped hypoechoic structure around the common carotid artery (CCA).
Medial to the CCA, the mCSG is closely adjacent to the thyroid gland and could be
damaged during RFA of benign thyroid nodules [249, 252]. Spinal accessory nerve
injury and brachial plexus injury have also been reported during RFA [245, 247].
The second most common major complication of RFA (0.17%) is “nodule rup-
ture,” which may result from acute volume expansion of a nodule due to delayed
hemorrhage or a tear in the tumor wall after neck massage. It usually presents as a
sudden neck bulging and pain at the RFA site during follow-up. Imaging with US or
CT scan usually shows breakage of the thyroid capsule, with bulging of the tumor
into the anterior neck. Patients with nodule rupture are usually managed conserva-
tively using antibiotics and/or analgesics, but surgical treatment may be required in
case of abscess formation [244, 247, 249].
Hematoma, caused by mechanical injury to the vessels by the electrode, can
develop in the peri-thyroidal, subcapsular, and intra-nodular locations. It is usually
managed with simple compression for 30–120 min, with most hematomas disap-
pearing within 1–2 weeks. For prevention, peri-thyroidal vessels, including the
superior and inferior thyroid arteries, should be carefully evaluated using Doppler
US before inserting the electrode [244–247, 249].
The risk of hypothyroidism is rare after RFA with only few reports in patients
with elevated anti-TPOAb before ablation, or in patients with AFTN [245, 247].
Transient hyperthyroidism could also occur after the procedure, but it usually
resolves spontaneously within a month without symptoms [244–247, 249].
Pain is the most common complaint during RFA. Various degrees of pain could
occur in the lower neck, sometimes radiating to the head, ears, shoulders, chest,
back, or teeth. Although most patients can tolerate pain, which is relieved rapidly
when the generator output is reduced or turned off momentarily, there are few
reports in which patients were incompletely treated due to severe pain and required
additional medication to reduce pain after RFA [248]. Analgesics can be prescribed
for 2–3 days to reduce post-procedural pain in these cases [244–247].
Although there is no absolute contraindication for thyroid RFA, it is not recom-
mended to use monopolar electrodes for pregnant women or patients with electrical
devices such as a cardiac pacemaker because there is insufficient evidence regarding
safety of monopolar electrodes in these patients [253–255]. Bipolar electrodes can

be a safer selection for those patients because, unlike monopolar electrodes, the
electric current of bipolar electrodes is limited to the area surrounding the active tip
of the electrode [250, 256–258].
Ultrasound-Guided Percutaneous Laser Ablation (PLA)

Percutaneous laser ablation (PLA) of thyroid nodules is a minimally invasive proce-
dure indicated to treat benign thyroid nodules. The feasibility of the use of PLA in
benign thyroid nodules was first published in 2000 by Pacella et al. who suggested
to limit the use of this method to only benign cases in which reducing the size of
nodule itself alleviates the problem [206]. Two years later, Døssing et al. [259] pub-
lished a satisfactory result of one session of percutaneous laser ablation (PLA),
using one illuminating fiber, in benign thyroid nodules of 16 patients; PLA resulted
in a reduction of about 46% before 6 months. Later, in 2003, Spiezia et al. [260]
published further results confirming the efficacy of this method on seven patients
with autonomous hyperfunctioning thyroid nodules and five patients with compres-
sive nodular goiters. In 2004, Papini et al. [261] completed their first introduced
method by providing clinical results of volume and symptom reduction of benign
thyroid nodules. After several successful clinical results were published, the
American Association of Clinical Endocrinologists/Associazione Medici
Endocrinologi (Italian Association of Clinical Endocrinologists)/European Thyroid
Association (AACE-AME-ETA) recommended in 2010 that PLA therapy can be a
safe and effective option for the treatment of benign thyroid nodules [262].
The technique entails tissue destruction by the insertion of optical fibers, which
convey the light energy, causing a complete and irreversible tissue necrosis. The
therapeutic outcome is the reduction in volume of the nodule, and hence of local
compressive symptoms, and reduction or loss of visibility of the nodule [196]. PLA
is performed as a “day surgery” under mild sedation and local anesthesia [192, 262].
One needle (or two, depending on the size of the nodule) is placed inside the nodule
under US guidance. Through the lumen of the needles, extremely thin optical fibers
are placed, which are connected to a laser light source. The total time of the proce-
dure is about 30 min, with the laser energy applied for approximately 10–12 min
[262]. Beginning the day after PLA, patients receive prednisone 25 mg for 3 days
and 5 mg for 4 days. Proton pump inhibitors (lansoprazole 30 mg) are simultane-
ously administered for 10 days. In most patients, one to three sessions of PLA or a
single treatment with multiple fibers induces a clinically significant decrease in nod-
ule volume and amelioration of local symptoms [263].
The procedure (PLA) has been proposed as an alternative to surgical treatment of
benign thyroid nodules causing compressive symptoms or cosmetic concerns, in
patients who decline surgery or at surgical risk [193, 210, 262].
Gambelunghe et al. (2006) [264] conducted a randomized controlled study (RCT)
on 26 patients who had either a high risk of surgery or compressive symptoms due to
benign thyroid nodules. After 2 weeks, patients showed a reduction of 22% in the
volume of their nodule, which reached up to 44% after 30 weeks. They also reported
a positive correlation between the amount of energy exerted and the reduction in
volume of the nodule [264]. In a comparative study on 62 randomly grouped patients

with solid benign nodules, Papini et al. (2007) [265] examined the results of a 10 min
of 1.064 pm 3 W radiation of neodymium yttrium-aluminum-garnet (Nd:YAG) laser
(group 1) and also the effect of a dose of levothyroxine-suppressive therapy (group 2)
against a non-treated control group. They reported a significant reduction, of about
42.7%, of nodule volume in group 1, no significant shrinkage in group 2, and nonsig-
nificant increase in the control group [265]. Valcavi et al. (2010) [266] reported the
results of a 3-year follow-up post-PLA ablation in 122 patients with benign cold
STNs, or a dominant nodule within a normo-functioning MNG. The authors observed
a nodule volume reduction of 47.8%, improved symptoms in 73.0% of patients, and
improved cosmetic signs in 71.3%. There were only few cases of laryngeal dysfunc-
tion, voice changes, and hypothyroidism [266].
Døssing et al. (2011) [267] published a 10-year result of their follow-up after
PLA therapy on 78 patients with solitary benign thyroid nodules, which showed a
reduction with a median of 51% in nodule volume. Twenty-one patients retired from
the follow-up earlier due to surgery, but side effects were limited to mild local pain.
Two years later (2013), Døssing and colleagues [268] reported the effect of PLA on
improving the results of cystic benign nodule aspiration on 44 randomly grouped
patients. Six months after the aspiration session, they achieved a cyst volume of
<1 mL in 68% of patients who underwent an additional session of PLA, and only
18% of the control group with no laser therapy. Moreover, the size of the solid part
of the nodules was reduced from 1.8 to 1.0 mL by PLA, while it had no significant
change in the control group.
Achille et al. (2015) [269] evaluated PLA therapy, using Nd:YAG laser at
1064 nm 3 W power with varying durations, on 45 patients with either pressure or
cosmetic distress due to benign solid (max fluid 20%) thyroid nodules. Evaluations
were done at baseline and 6 and 12 months. Results showed a reduction of nearly
20 mL at 12 months (84 ± 13%), with resolved cosmetic signs in 87% of patients
and resolved pressure symptoms in 88%. They reported voice change in only one
patient (2.2%).
The reported complications of PLA have not been serious. Cakir et al. (2006)
[270] observed slight ipsilateral intraoperative ear pain and subsequent pain during
swallowing, for a few days, that ceased with paracetamol, in 4 of their 12 patients.
Controlled intra-nodular bleeding during needle placement that did not terminate
the procedure has also been reported in the literature. In 2011, Baek et al. [262]
reported that thyroid peri-capsular bleeding, vagal symptoms with bradycardia,
voice change, and cough each appeared in about 2% of their patients; fluid leakage
into the neck muscle fascia in 3%; and pseudocyst formation in 5%. Six months
after PLA, 3% of patients experienced thyroid dysfunction, with no clue if it has
been due to laser ablation. Other adverse effects such as dysphonia, hematoma
burns, and transient stridor were rarely reported [192]. In a recent report, Achille
et al. (2016) [269] observed that only one patient out of 40 (2.5%) experienced dys-
phonia that resolved after 8 weeks of care, one other patient (2.5%) experienced
intense local pain, and another (2.5%) suffered from hyperpyrexia; however, mild-
to-moderate local pain occurred in 12 patients (30%).
Compared to drug therapy, PLA has the advantages of immediacy and efficacy in
single nodules and especially when they have already reached a certain volume. In
these cases, PLA not only prevents the growth of the nodules, but also precludes the
necessity to perform a therapy protracted over many years. Compared to surgery,
PLA does not involve the presence of scars, is a day-hospital procedure that does
not require hospitalization, is a short-term treatment (about 30 min including patient
preparation), takes place under conscious sedation which avoids any risk related to
general anesthesia, produces predictable and repeatable volumes of necrosis, and
does not affect further therapeutic actions.
In comparison with minimally invasive options for treatment of benign solid
thyroid nodules, PEA therapy has not been reported to be successful in ablation of
the solid component of thyroid nodules, which has been known to cause the recur-
rences observed a few months later. When a nodule is categorized as predominantly
solid, ethanol ablation has not been considered as an appropriate method [197], and
it has been completely abandoned for the solid ones [269].
Among thermal ablation therapies for thyroid benign ablation, RFA has shown a
little superiority compared to PLA [188, 271]. Ha et al. [272] reviewed 33 published
clinical results that have evaluated either RFA or PLA method. They concluded that
a single electrode RFA therapy would result in better (76.1%) reduction volumes
than a single fiber PLA treatment (49.9%). They suggested that this superiority
could be a result of the moving-electrode technique in RFA, while managing mul-
tiple fibers in the thyroid could be more difficult. In addition, they suggested that
RFA has been better in the ablation of marginal components, which may have pre-
vented marginal regrowth.
Ultrasound-Guided Microwave Ablation (MWA)

Microwave ablation (MWA) is another new minimally invasive approach to the
treatment of benign thyroid nodules. It is an “active” ablation, whereas RFA is a
“passive” ablation. In vivo, microwave conduction does not need to depend on the
electrical conductivity of tissue. It is less affected by tissue carbonization and dehy-
dration as compared to radio frequency. The ablation range is larger, and the tem-
perature in the tumor is high enough. The ablation time is shorter, and tumor
inactivation is more complete [273]. Compared with RFA, MWA is less affected by
the cooling effect caused by blood perfusion and can also uniformly inactivate the
tumor target area near the blood vessel. Multiple microwave energy sources can be
applied at the same time, without the mutual interference phenomenon as in
RFA [273].
The MWA system consists of a generator, a flexible cable, and an antenna. It uses
electromagnetic energy in the form of high-frequency waves ranging between
915 MHz and 2450 GHz [274]. This energy produces oscillation of water mole-
cules, the friction of which generates an increase in temperature inducing coagula-
tive necrosis of the target tissue. The generated heat dissipates around the tip of the
antenna, in a variable ablation area determined by the power and the time of applica-
tion. Cellular destruction is caused by the denaturing of intracellular proteins and
the cell membrane. When the tissue registers temperatures of 60–100 °C,
coagulative necrosis begins. With temperatures above 100 °C, tissue vaporization
and carbonization may occur [275]. A 3 mm microwave antenna is inserted into the
center of the nodule through a 2 mm incision to ablate it by microwave radiation.
This approach of treatment seems to be safe, with a relatively low cost and short
duration; however, there are issues remaining to be resolved; for example, a fixed-
antenna ablation will result in a cylindrical ablated zone despite the fact that most
nodules are rather elliptical, and prolonged fixation of the antenna can harm sur-
rounding structures. Further studies are needed to shed light on the efficacy and
safety of this procedure [193].
In the treatment of benign thyroid nodules, the comparison of MWA with a con-
trol group concluded that it was effective in reducing the volume of benign thyroid
nodules. It also improved clinical symptoms and obtained adequate cosmetic results
[276]. Recently, Gao et al. (2021) reported the results of MWA in 267 patients with
benign thyroid nodules causing cosmetic or compression symptoms. The average
age was 50.1 ± 11.7 years (21–83 years), 214 patients were women (80.1%), and 53
(19.9%) were men. The average number of nodules per patient was 4.02 ± 1.8 (1–8).
The average size of the nodules was 5.28 ± 3.63 cm2 (0.09–23.45 cm2). The average
ablation time was 11 ± 5.36 min (3–20 min). The hospitalization period was
24 ± 10.16 h (7–48 h). Complications were reported in 18 patients (8.41%) only.
Post-ablation volume reduction rates were 54.74% and 93.3% at 3- and 12-month
follow-up, respectively (p < 0.05). Thyroid function tests, pre- and post-ablation,
showed no significant changes (p > 0.05). The authors concluded that US-guided
MWA of thyroid nodules is safe and effective, but more clinical trials are needed to
define the effectiveness and safety of MWA [273]. In the study by Wu et al. (2017)
[276], it was reported that, at 3 months after MWA, the nodule VRR was 50%,
which is similar to that reported by other authors [273, 277, 278] in the same period.
When RFA and MWA were compared, their results showed no great differences
[243, 279–284]. On the other hand, when compared to surgery, there were signifi-
cant advantages of MWA over thyroidectomy in terms of the stress response, intra-
operative blood loss, operation time, postoperative hospitalization duration, and
complication rate [284, 285].
High-Intensity Focused Ultrasound (HIFU)

High-intensity focused ultrasound (HIFU) is the most recent thermal ablation tech-
nique that can cause effective shrinkage of thyroid nodules and alleviate pressure
symptoms. Its main treatment indication remains benign thyroid nodules. It is the
only truly noninvasive method as it does not require the insertion of any device into
the neck and thereby prevents the risk of bleeding, infection, or thermal injury to the
skin reported for the other TA procedures [286–288]. HIFU, however, is still not a
thoroughly assessed procedure for the management of thyroid lesions.
Monpeyssen et al. (2020) [289] assessed the safety and long-term (3-year follow-
up) efficacy of HIFU in benign thyroid nodules among four European centers, treat-
ing solid benign thyroid nodules causing pressure symptoms and/or cosmetic
concerns. Nodule volume reduction was assessed at 1, 3, 6, 12, 24, and 36 months
posttreatment. Technical efficacy, defined as a volume reduction rate (VRR) >50%,
was evaluated at 6, 12, 24, and 36 months. Sixty-five patients (mean age
51.1 ± 14.0 years; 86.2% women) with a single thyroid nodule and a mean baseline
nodule volume of 9.8 ± 10.3 mL were treated with a mean energy of 7.1 ± 3.1 kJ
(range: 2.0–15.5 kJ). Median nodule VRR was 31.5% at 12 months and 31.9% at
36 months. Technical efficacy was obtained in 17.2% of patients at 6 months, 17.8%
at 12 months, 3.4% at 24 months, and 7.4% at 36 months. The procedure duration
was inversely correlated with treatment failure (p = 0.014). Improvement of cervical
pressure symptoms or cosmetic complaints was observed in <15% of patients at 12,
24, and 36 months. Horner’s syndrome that disappeared 6 months following treat-
ment occurred in one case (1.5%), and minor complications (subcutaneous cervical
edema), not requiring treatment, in three (4.6%). No recurrent laryngeal nerve palsy,
hematoma, local blistering, subcutaneous abscess, nodule rupture, or thyroid dys-
function was encountered. In conclusion, HIFU carried a low risk of complications.
A single treatment resulted in a 30–35% thyroid nodule VRR within 1 year that
remained sustained for 2 years. Outcomes varied significantly between centers with
different HIFU expertise. Focus on improved HIFU technology, adequate training,
and appropriate selection of patients is needed to achieve efficacy comparable to
other thermal ablation procedures [289].
Very few studies have compared in prospective randomized controlled trials
HIFU versus RFA, LTA, or MWA. In a recent cohort study, RFA showed a slightly
better mean volume reduction (50%) than MWA (44%) and HIFU (49%), but the
differences between RFA, MWA, and HIFU were not statistically significant [290].
Notably, these nearly similar outcomes were biased by the different baseline sizes
of the nodules, being significantly smaller in the HIFU group. Robust data from the
literature demonstrate a greater efficacy of LTA and RFA versus HIFU for both
VRR and symptom improvement in patients with nodular thyroid disease. Thus,
based on the greater efficacy, lower cost, and shorter time of RFA and LTA proce-
dures, HIFU treatment should mainly be considered for selected small-size nodules
and for patients who decline other thermal ablation procedures because of the risk
of cervical skin damage [289].
Combined Methods of Treatment

In order to be more effective, RFAs can be usually preceded by a preparatory aspira-
tion of internal fluid if present, which may cause internal bleeding. Yoon et al.
(2014) [291] proposed and evaluated a PEA to control this problem before starting
RFA, and obtained successful feasibility and safety results, with less complications
and shorter treatment time.
Benign Toxic (Hyperfunctioning) Nodule
Observation
An asymptomatic hyperfunctioning thyroid nodule can be observed. Treatment is
recommended in the presence of subclinical hyperthyroidism if the nodule is large
(>3 cm in diameter) and for patients who are at high risk of cardiac side effects, and
for postmenopausal women with decreased bone mineral density. Both RAI (131I)
and surgery (hemithyroidectomy) have been reported to be effective in the treatment

of a solitary toxic nodule.
Surgical Treatment
Once the patient becomes euthyroid with antithyroid medications, hemithyroidec-
tomy is performed. It has the advantages of immediate symptomatic relief, avoid-
ance of radiation exposure, and low risk of complications. All toxic nodules in
children should be removed, and after thyroidectomy, thyroid hormone replacement
is necessary for the child’s lifetime.
Radioactive Iodine (RAI)

Radioactive iodine (RAI) treatment usually requires higher doses of 131I than are
normally used for treatment of Graves’ disease. It has the disadvantages of delay in
symptomatic relief, exposure of normal thyroid tissue to radiation which may result
in hypothyroidism in up to 35% of patients, and concerns related to persistence of
the nodule [292].
Antithyroid Drugs (ATDs)

Antithyroid drugs are not curative and must be given lifelong to avoid recurrence of
hyperthyroidism. Their use is limited to preparing patients for surgical treatment but
may also be considered in elderly patients with medical problems that preclude
surgery. Methimazole (Tapazole) inhibits thyroid hormone by blocking oxidation of
iodine in thyroid gland. Caution should be taken during pregnancy because it can
cause fetal hypothyroidism and fetal aplasia cutis. Propylthiouracil blocks oxidation
of iodine in the thyroid gland, thereby inhibiting thyroid hormone synthesis. It is
indicated in pregnancy but should be used in lowest effective dose because of risk
of hypothyroidism to fetus.
Percutaneous Ethanol Ablation (PEA)

Ultrasound-guided PEA has been proposed as an alternative therapy to surgery and
RAI for hyperfunctioning thyroid nodules [293–298]. The nodules have been
reported to decrease in size and hyperthyroidism to resolve after PEA therapy [299].
However, the larger the size of the nodule, the harder it is to achieve a therapeutic
effect [296]. Therapy with PEA has been reported to have the greatest effectiveness
against hyperfunctioning solitary thyroid nodules (STNs) with a volume <30 mL
[293–296]. However, recent studies reported very good results for hyperfunctioning
thyroid nodules with a volume >40 mL [300, 301].
When ethanol is used to treat cystic nodules, ethanol is confined within the cystic
space, and hence the incidence of complications is low. However, it is difficult to
control leakage when ethanol is injected into solid nodules. This may cause
unwanted complications such as transient recurrent laryngeal nerve (RLN) paresis
[192]. In addition, uneven distribution of ethanol in the nodules requires more ses-
sions of treatment (multiple painful injections) as compared to cystic nodules and to
thermal ablation when treating the same sized nodules. Due to these drawbacks, the
use of PEA in large solid nodules has been limited [302, 303].
Thermal Ablation

As an alternative therapeutic modality to RAI and surgery, RFA for treating toxic
thyroid nodules has been reported in recent studies [205, 220, 222, 231, 241, 303–
305]. An Italian group suggested that hyperthyroidism caused by an autonomically
functioning thyroid nodule (AFTN) can be completely, or at least partially, cured by
RFA when surgery and RAI are contraindicated or declined [306]. In addition, pre-
toxic nodules, which are characterized by normal thyroid hormone and suppressed
thyrotropin (TSH) levels, are also often recommended for treatment, because they
could evolve toward overtly toxic nodules (annual risk, approximately 4%), and,
over time, subclinical hyperthyroidism may have adverse effects, particularly on the
skeletal and cardiovascular systems [222, 303, 304, 307]. For large AFTN (>20 mL
volume), RFA has been reported to be less responsive; further studies for these cases
should be performed [222, 304, 306]. In addition, RFA is more expensive than RAI
therapy, requires radio-frequency equipment, and has a distinct learning curve
[303]. In a comparison of surgery and RFA, the cost of RFA was similar to that of
surgery [233].
Percutaneous Laser Ablation (PLA)

Døssing et al. (2007) [308] compared the efficacy of one PLA (interstitial laser
photocoagulation) session with one radioiodine (131I) dose on two randomized
groups of 15 patients with subclinical or mild hyperthyroidism. Comparing the
results at baseline and 1, 3, and 6 months, they observed the normalization of serum
TSH in 7 out of 14 patients in the interstitial laser photocoagulation group and in all
15 patients in the radioiodine group. They also found a nodule volume reduction of
about 44% in the first and about 47% in the latter group [308]. Amabile et al. (2011)
[309] studied the effect of 1–3 cycles of PLA with an interval of 1 month on 51
patients with nonfunctioning thyroid nodules and 26 patients with hyperfunctioning
thyroid nodules. They observed that a significant nodule volume reduction occurred
in both groups, 87% of whom were cured with no major complications.
I ntermediate Nodule (Follicular or Hurthle Cell Neoplasm)

The principal surgical approach to solitary, undetermined nodule is hemithyroidec-
tomy. When FNAC demonstrates follicular or Hurthle cell neoplasm, surgery is
indicated to reach a definite diagnosis.
Definite Diagnosis
Currently, no clear-cut morphologic criteria are available to distinguish benign from
malignant follicular lesions [310, 311]. Repeated biopsy of nodules classified as
follicular neoplasm is not recommended [312]; however, FNAB may be repeated in
cases diagnosed as “atypical cells” to exclude a follicular neoplasm [310]. At surgi-
cal intervention, about 20–30% of such specimens are determined to be malignant
lesions [310, 313]. Core needle biopsy is not recommended in the management of
follicular nodules because it does not provide additional information [310].
Surgical Treatment
Patients with follicular thyroid lesions can be treated with hemithyroidectomy or
total thyroidectomy (TT). Frozen section biopsy is usually not recommended [310,
314] but may be useful in nodules with an ill-defined capsule, or in case of non-total
thyroidectomy to decrease the risk of completion thyroidectomy in case of cancer
diagnosis. In cases with favorable clinical, cytological, and US features, a multidis-
ciplinary team (MDT) may consider clinical follow-up without immediate diagnos-
tic surgery [314–316].
Suspicious Nodule
A suspicious STN should be treated with TT to avoid missing thyroid cancer. The
rate of histologically confirmed malignancy in these cases is about 60–75% [317].
Most of these cases are determined to PTC on definitive histological analysis
[119, 316].
Malignant Nodule
The type of carcinoma should be stated in the cytological report (whenever possi-
ble) [312, 316]. If cytological results are compatible with a WDTC, surgical treat-
ment is necessary [315, 318–320]. If cancer is due to metastatic disease, efforts
should be directed toward finding the primary lesion, which often precludes a thy-
roid surgical procedure. For ATC and lymphoma, further diagnostic workup is rec-
ommended before surgery [316].
Are there indications for thermal ablation (RFA or PLA) in primary thyroid
cancer? Surgery is a standard treatment for primary thyroid cancer; indications for
RFA in primary thyroid cancers have not yet been clearly established. However,
in patients with primary thyroid cancer who refuse or cannot undergo, thermal
ablations can be considered as an alternative [226]. In addition, palliative treat-
ment is another option for advanced thyroid cancers. There are several reports
concerning the palliative treatment of anaplastic or advanced medullary thyroid
cancer (MTC) using RFA or PLA [321–324]. Some authors reported that PLA can
improve compressive symptoms by advanced anaplastic thyroid (ATC) cancer,
but others reported no clinical effect of thermal ablation in advanced ATC or MTC
[321–324].
Treatment of Well-Differentiated Thyroid Cancer (WDTC)

The primary treatment for WDTC is resection, albeit with controversy about its
extent: total thyroidectomy (TT), near-total thyroidectomy (NTT), or hemithy-
roidectomy. Whereas TT involves removal of the entire thyroid gland and its
capsule, NTT preserves the posterior capsule of the thyroid contralateral to the
tumor. Both procedures are considered as completely ablative approaches.
However, they expose the patient to the risk of bilateral dissection and necessi-
tate lifelong thyroid hormone supplementation. Hemithyroidectomy on the other
hand allows preservation of normal thyroid tissue, thereby obviating the need for
lifelong supplementation and eliminating the risk for hypoparathyroidism and
bilateral vocal cord paralysis. Subtotal thyroidectomy is not recommended due to
the higher complication rates encountered when subsequent surgery is indi-

cated [325].
Depending on the postoperative risk stratification of the patient, the primary goal
of postoperative administration of RAI after thyroidectomy may include (i) RAI
remnant ablation, (ii) RAI adjuvant therapy, or (iii) RAI therapy (to improve disease-
specific and disease-free survival by treating persistent disease in higher risk
patients).
Treatment of Papillary Thyroid Cancer (PTC)

Total Thyroidectomy (TT): In patients with high-risk lesions or extra-thyroidal
extension (ETE), TT is the appropriate treatment; it has a low rate of complications
(<2%) when performed by experienced surgeons [326, 327]. After a TT (or NTT),
postoperative RAI can be used to identify and ablate any residual thyroid cancer,
and serum thyroglobulin (Tg) is a more accurate marker of recurrent or persistent
PTC following TT when compared with more conservative thyroid resections.
Pacini et al. (2001) [328] reported that 44% of 182 patients studied harbored histo-
logically confirmed PTC at completion thyroidectomy and suggested TT in order to
eradicate all neoplastic tissue in patients with PTC. The authors also recommended
completion thyroidectomy for patients with a history of PTC that were initially
treated with hemithyroidectomy. Moreover, Hay et al. (1998) [329] reported that
patients who underwent hemithyroidectomy for PTC had a higher recurrence rate
(14%) and nodal metastases (19%) as compared to TT. Finally, elimination of all
PTC via TT may prevent progression to ATC from residual tissue left behind during
hemithyroidectomy.
Hemithyroidectomy: The use of hemithyroidectomy for the treatment of PTC is
supported by some authors as it avoids the risk of some potential complications of
bilateral procedures such as RLN and parathyroid injuries and also provides similar
survival benefit to TT [330–332]. In patients with excellent prognosis (tumor size
<1 cm, absence of metastatic disease, in an otherwise healthy female below
45 years), hemithyroidectomy may be used.
Lymph Node Dissection: Gross nodal disease occurs in 20–30% of adult patients
with PTC [333]. Nodal metastases confirmed by preoperative US or CT scan, or by
intraoperative exploration should be treated with node dissection [325], specifically
removal of ipsilateral central neck LNs and lateral compartment nodes. Retrospective
studies showed that removal of central neck LNs is associated with improved sur-
vival and regional recurrence rates [334–336]. Prophylactic lateral neck node dis-
section is not recommended because it is not associated with improved survival and
involves violation of additional tissue planes.
Recently, RFA, PLA, and microwave ablation have been attempted for patients
with papillary thyroid microcarcinoma (PTMC). These studies reported effective
local tumor ablation over the short term and after a 4-year follow-up period [337–
342]. Two randomized trials confirmed the safety and clinical efficacy of PLA [343,
344]; however, because of the novelty of the PLA technique, long-term follow-up
studies are lacking [345].
Treatment of Follicular Thyroid Cancer (FTC)

Differential diagnosis of FTC from adenoma is based on the presence of capsular,
vascular, or extra-thyroidal tissue invasion, as well as nodal or distant metastasis
[346, 347]; therefore, surgical resection is the standard treatment tool and the pri-
mary method of therapy for FTC [118]. If the tumor is confined to the thyroid
(T1–2 N0 M0), TT and hemithyroidectomy with extirpation of central LNs are both
adequate. For larger tumors (T3–T4), TT along with postoperative RAI therapy is
indicated. Cervical LN metastases are not as common in FTC as with PTC (35% vs.
67%, respectively). Still, however, therapeutic modified neck dissection is appropri-
ate for patients with clinically apparent disease. Postoperative RAI scans and abla-
tion are essential to help detect any residual disease and eliminate it.
Fine needle aspiration (FNA) results have a relatively high false-positive rate
(22.2–35%) in follicular neoplasms that are often shown to be thyroiditis or nodular
goiter upon surgical histopathology [348, 349]. Therefore, the demand for conser-
vative medical treatment has increased for patients who are at high surgical risk or
who are ineligible for surgery.
A recent 5-year follow-up study by Ha et al. (2017) showed that RFA can be an
effective and safe method to treat patients with FTC <2 cm in size [350]. No recur-
rences or metastatic lesions were found during the follow-up period. However,
another study, by Dobrinja et al. (2015), reported that RFA should not be recom-
mended as a first-line therapy for follicular neoplasm. In this study, two out of six
lesions, graded as Bethesda-3 or Bethesda-4 and larger than 2 cm in size, regrew
after RFA and were finally shown to be minimally invasive FTC and follicular neo-
plasm of indeterminate malignant behavior, respectively. In this regard, the authors
claimed that RFA might have the potential to grow residual cancer or neoplasm of
Bethesda-3- or Bethesda-4-grade lesions and delay surgery in case of malig-
nancy [351].
Treatment of Oncocytic (Hurthle Cell) Thyroid Cancer

Treatment strategies of oncocytic (Hurthle cell) carcinoma are similar to those of
FTC because of similarities in the natural history and prognosis. However, RAI
uptake in oncocytic carcinoma is much less than that of FTC; hence, postoperative
diagnosis and ablation of residual disease with RAI are more difficult [352].
Treatment of Medullary Thyroid Carcinoma (MTC)

Prior to surgery, patients with MTC should have baseline calcitonin levels, and
assessment of catecholamine secretion to rule out pheochromocytoma. MTC must
be treated with a TT. A central LN dissection is indicated for occult cancers detected
after family screening, whereas palpable lesions require an ipsilateral modified radi-
cal neck dissection.
Treatment of Anaplastic Thyroid Carcinoma (ATC)

Though rare, ATC is a very aggressive neoplasm with a very poor prognosis;
approximately, two-thirds of patients die within 1 year of diagnosis. In the rare case
that all gross disease can be excised, resection may be appropriate. Chemotherapy
and radiotherapy may be used for palliative treatment.
Treatment of Metastatic Thyroid Cancer

The preferred treatment for metastatic disease in order is (1) surgical excision of
locoregional disease in potentially curable patients, (2) 131I therapy for RAI-
responsive disease, (3) external beam radiation therapy (EBRT) or other directed
treatment modalities such as thermal ablation, (4) TSH-suppressive thyroid hor-
mone therapy for patients with stable or slowly progressive asymptomatic disease,
and (5) systemic therapy with kinase inhibitors for patients with significantly pro-
gressive macroscopic refractory disease.
Localized treatments may be beneficial in patients with a single or a few metas-
tases and in those with metastases at high risk of local complications. These treat-
ments include thermal (radio-frequency or cryo-) ablation [353], ethanol ablation
[354], or chemoembolization [355] and should be performed before the initiation of
any systemic treatment. These modalities may control treated metastases, avoid
local complications, and delay initiation of systemic treatment. Additionally, surgi-
cal therapy in selected incurable patients is important to prevent complications in
targeted areas, such as the central nervous system (CNS) and central neck compart-
ment. Conversely, conservative intervention with TSH-suppressive thyroid hormone
therapy may be appropriate for selected patients with stable asymptomatic local
metastatic disease and most patients with stable asymptomatic non-CNS distant
metastatic disease.
Treatment of Pulmonary Metastases

Key criteria for therapeutic decisions include (1) size of metastatic lesions, (2) avid-
ity for RAI and/or response to prior RAI therapy, and (3) stability of metastatic
lesions. Pulmonary pneumonitis and fibrosis are rare complications of high-dose
RAI treatment. Dosimetric approaches to therapy with a limit of “80 mCi whole-
body retention at 48 h and 200 cGy to the bone marrow” should be considered in
patients with diffuse 131I pulmonary uptake [356].
Patients with pulmonary “micrometastases” that are RAI-avid should be treated
with RAI repeatedly every 6–12 months as long as disease continues to concentrate
on RAI and respond clinically [357–360]. “Macronodular” pulmonary metastases
may also be treated with RAI if shown to be iodine-avid. Number of RAI doses
must be individualized based on disease response, age, and presence or absence of
other metastatic lesions [357, 358]. Patients may also be considered for surgical
resection, although the potential benefit weighed against the risk of surgery is
unclear.
Treatment of Bone Metastases

Radioactive iodine (RAI) therapy for patients with bone metastases is rarely cura-
tive but may benefit some patients with RAI-avid metastases [358, 361]. Focal treat-
ment modalities may include surgery and EBRT. These patients should also be
considered for systemic therapy with bone-directed agents.
Treatment of Brain Metastases

Brain metastases typically occur in older patients with more advanced disease and
are associated with a poor prognosis [362]. Surgical resection and stereotactic
EBRT, which is preferred to whole-brain radiation because it may prolong life
expectancy, induce less short- and long-term toxicity and may be effective even in
patients with multiple brain lesions.
Treatment of Recurrent Thyroid Cancer

In general, the primary treatment for local recurrent thyroid carcinoma is surgery, if
indicated, followed by radioactive iodine (RAI) therapy and/or thyroid hormone
therapy [118]. However, reoperation may be technically difficult and subject to
more surgical complications due to distortion of the normal tissue planes by scar-
ring and fibrosis of the previous operation. External beam radiation therapy (EBRT)
can be considered for (1) locoregional recurrence that is not surgically resectable,
(2) cases with extranodal extension, and (3) cases with involvement of soft tissues,
particularly in patients without distant metastasis [118]. However, EBRT may
increase morbidity due to complications [363, 364]. Therefore, image-guided non-
surgical procedures such as PEA or RFA have been proposed as alternative thera-
pies for patients who (1) are concerned about the complications of EBRT or refuse
this modality, (2) may have serious complications following surgery, or (3) may be
at high risk of surgery [24, 211–216, 237, 302, 353, 354, 365–378].
Although only a few studies have evaluated the efficacy of PEA to treat recurrent
thyroid carcinoma, PEA has limited effectiveness in terms of complete disappear-
ance of recurrent malignant nodules and a relatively higher RR during follow-up
than RFA [213]. Since the reports of Lewis et al. [354] in 2002, a few studies have
reported favorable outcomes after PEA treatment of recurrent thyroid cancers [24,
354, 365–369]. In four recent studies with a mean follow-up period ranging from
28.2 months to 5.4 years, three studies reported reduction of nodular size in
92.7–100% of cases [24, 365, 368]. However, Guenette et al. (2013) [369] reported
local progression in 23.8% of cases. Concordantly, Kim et al. (2017) [374] reported
an increase in tumor size in 17.1% of cases while there was no change in size in
24.4% of cases after PEA for locally recurrent PTC based on a minimum of
60 months of follow-up.
Hay et al. (2013) [368] and Heilo et al. (2011) [379] reported 45.9% and
66.1% complete disappearance rates, respectively. In contrast, Hay et al. (2013)
[368] and Kim et al. (2008) [365] reported recurrence at sites other than the etha-
nol ablation sites. There were local recurrences at ablation sites in 5.5% and
23.8% of cases enrolled by Heilo et al. (2011) [33] and Guenette et al. (2013)
[369], respectively.
In general, PEA may be recommended for complete ablation in patients with
recurrent thyroid carcinoma with three or fewer local recurrent nodules without
known distant metastasis, or for palliative purposes in patients with known distant
metastases with recurrent tumors that are increasing in size. PEA requires several
treatment sessions (one to six injections). The larger the recurrent tumor size, the
more treatment sessions are required [365, 374]. Before performing PEA,
recurrence should be confirmed via US-guided FNAC and/or measurement of the

washout thyroglobulin (Tg) or calcitonin concentration [380].
According to the comparison meta-analysis of RFA and PEA performed by Suh
et al. (2016) [213], RFA resulted in greater volume reduction and a greater complete
disappearance rate than PEA, while PEA tended to show a higher RR and a higher
reduction rate of serum thyroglobulin level. Fontenot et al. (2015) [377] compared
surgery and PEA and reported that the success rate of surgery was higher, but local
recurrence at the treated site was similar for the two methods.
Based on a systemic review of the use of PEA or RFA to treat recurrent thyroid
cancer, the pooled proportion of the rate of complications of PEA was lower than
that of RFA (0.8% vs. 5.8%, respectively), although this difference was not statisti-
cally significant (p = 0.8479) [213]. Several studies reported the complications of
PEA of recurrent thyroid cancer [24, 354, 365–369, 373, 375, 381] (Table 8.12).
Potential complications of PEA include local pain or discomfort; transient hoarse-
ness that resolves within 3–6 months [378]; radiating pain to the teeth, jaw, head,
and chest; and rarely, tumor implantation through the needle track [375, 381].
Delayed complications have not been reported in studies that performed long-term
follow-up (mean, 74 months) [368, 374].
Kim et al. (2018) in their thyroid RFA Guideline by the Korean Society of
Thyroid Radiology recommended that RFA can be performed for curative or pallia-
tive purposes in the recurrent thyroid cancers at the thyroidectomy bed and cervical
lymph nodes (LNs) for patients at high surgical risk or who refuse surgery [226].
When recurrent thyroid cancer is detected, surgery followed by RAI and thyroid
hormone therapy is the standard treatment modality. However, repeated neck opera-
tions carry a high risk of complications due to distortion of normal tissue planes and
fibrosis caused by scar tissue at the surgical site [382]. In 2001, Dupuy et al. [353]
firstly reported RFA for recurrent papillary and follicular carcinomas in eight
patients, after which several studies treating recurrent thyroid cancers by RFA have
been reported, including two meta-analyses [211–216, 237, 366, 369–371]. In these
reports, an indication for RFA included patients with recurrent thyroid cancer at
high risk for surgery or refusal of surgery, but who need surgery clinically. The high
risk for surgery included previous repeated surgery, poor lung function, poor sys-
temic condition, severe cardiovascular disease, or old age. Favorable results of RFA
were achieved in recent studies regarding RFA undertaken for curative purposes
(complete removal) of recurrent thyroid cancer in which the number of the locally
recurrent tumors was <3–4 per patient and the greatest tumor diameter was
<1.5–2 cm, in patients with no metastasis beyond the neck [216, 237, 370]. RFA can
be performed for complete removal of a recurrent tumor or for palliative purposes.
Recurrent thyroid cancer can cause various symptoms such as dysphagia, hoarse-
ness of vice, dyspnea, or cosmetic problems due to a protruding mass. In such cases,
RFA can be applied, for palliative purposes, when it is judged that size reduction by
RFA can reduce symptoms and improve quality of life of the patient, even if radio-
logical complete removal is not possible [371]. In contrast to the potential complica-
tions of repeated surgeries for recurrent cancer, RFA usually could treat the recurrent
tumor successfully without significant complications [237]. For recurrent thyroid
242
Table 8.12 Complications of percutaneous ethanol ablation (PEA) of recurrent thyroid cancer
Mean Complications
No. of treated follow-up Mild pain or
Authors Year No. of patients lesions (months) discomfort Radiating pain Transient hoarseness
Lewis et al. [354] 2002 14 29 18 Most cases Several cases 0
Monchik et al. [366] 2006 6 6 18.7 N/A N/A 1
Lim et al. [367] 2007 16 24 24 16 N/A 1
Kim et al. [365] 2008 27 47 26 73/100 N/A 1
sessions
Heilo et al. [379] 2011 63 109 38.4 N/A N/A N/A
8
Hay et al. [368] 2013 25 37 65 Most cases N/A 1

Guenette et al. [369] 2013 N/A 21 38.5 N/A 0 0
Vannucchi et al. [373] 2014 3 4 2 3 0 0
cancers, the overall complication rate of RFA was 10.98%, and the rate of major
complications was 6.71% [244]. Voice change due to injury of the RLN or vagus
nerve was reported in 7.95% of cases. Injury of the middle cervical sympathetic
trunk (mCST) lateral to the common carotid artery (CCA) was also reported after
RFA for recurrent thyroid cancer [249, 252].
ollow-Up and Further Care of Patients with a Malignant STN

F
After surgery for a diagnosed thyroid malignancy, outpatient follow-up care is vital
to optimize patient survival. Radioiodine scintiscan may be used 6 weeks post-
surgery to monitor for metastases. Uptake in the lungs, lateral neck, or around the
RLN indicates metastasis or residual disease. If these are discovered, therapeutic
dosing of 131I is indicated to ablate remaining tumor cells. Thyroxine in full replace-
ment doses is prescribed to suppress TSH stimulation of malignant cells, even if
some thyroid tissue remains. Thyroglobulin levels may also be used to monitor for
recurrence in case of TT. Levels >1 ng/mL in patients on replacement therapy and
10 ng/mL in patients off thyroxine indicate recurrence of disease. In patients with
MTC, calcitonin levels may be used to monitor for recurrence. Late mortality
caused by unmonitored recurrence of disease is tragic.
Cross-sectional imaging of the neck and upper chest (CT, MRI) with IV contrast
should be considered in (1) bulky and widely distributed recurrent nodal disease, (2)
assessment of possible invasive recurrent disease to the aerodigestive tract, or (3)
when neck US is inadequately visualizing possible neck nodal disease (high Tg,
negative neck US).
Chest CT imaging should be considered in high-risk DTC patients with elevated
serum Tg (>10 ng/mL) or rising Tg antibodies. Imaging of other organs including
MRI brain, MR skeletal survey, and/or CT or MRI of the abdomen should be con-
sidered in high-risk DTC patients with elevated serum Tg (>10 ng/mL) and negative
neck and chest imaging who have symptoms referable to those organs or who are
being prepared for TSH-stimulated RAI therapy (withdrawal or rhTSH) and may be
at risk for complications of tumor swelling.
Prognosis
Prognosis of an STN is generally quite good, even with diagnosed malignancy and
early metastasis in the pediatric population.
Age of the Patient

In the pediatric population, pubertal females are more likely to develop a thyroid
nodule, although the risk of malignancy in these individuals is less than in younger
girls or in boys. In a study of 329 pediatric patients with thyroid cancer, Newman
et al. (1998) reported that the progression-free survival rate was 67% at 10 years and
60% at 20 years [383]. Factors contributing to less favorable prognosis vary among
studies; however, patients younger than 10 years are generally considered to have an
increased risk of poor outcomes.
Gender
Thyroid nodules are 2–3 times more common in girls than in boys, with pubertal
girls being at the highest risk. However, the probability that a nodule has associated
malignancy has been reported to be higher (twice) in boys than in girls (26.3% vs.
13.5%, respectively) [384].
Histological Findings
Patients exhibiting WDTC can have excellent recovery with adequate treatment.
Undifferentiated FTC and ATC carcinoma have poor outcomes. MTC in association
with MEN has an increased mortality rate, up to 50% at 10 years with MEN-2B. For
this reason, prophylactic thyroidectomy is recommended for patients who have a
family history of MEN and the proper genetic markers [342].
Genetic Markers
Genetic markers indicating poor prognosis include non-diploid DNA, overexpres-
sion of p21 ras, and mutations of the n-ras gene. Well-characterized and clinically
applicable prognostic genetic markers are best exemplified by BRAF V600E and
TERT promoter mutations. The genetic duet of BRAF V600E/RAS and TERT pro-
moter mutations has particularly robust prognostic power for poor clinical outcomes
of DTC. The negative predictive values of these prognostic genetic markers are
equally important clinically [385].
ther Risk Factors

O
Other risk factors of poor prognosis are residual cervical disease after thyroidec-
tomy, extensive pulmonary metastases, and tracheal and laryngeal invasion [386].
Operative Morbidity
The most common complications of thyroidectomy are injuries to the RLN and
PTGs. Permanent hypocalcemia may occur in 6–27% of operative cases, whereas,
in some studies, temporary hypocalcemia has affected an additional 29%. Overall,
permanent damage rates have been estimated at 0–24%. Millman et al. (1997) assert
that, with experience and proper technique, the rates of both these complications
should approach 1% [387].
Other major complications can very rarely affect recovery. Damage can occur in
cranial nerves VII, X, and XI and the superior laryngeal nerve. An occasional post-
operative pneumothorax has been reported. Postoperative hemorrhage can be dev-
astating because of possible airway compromise and may cause emergent
reoperation. In addition, required tracheostomy and extensive wound necrosis or
infection can occur, severely delaying recovery [388]. Minor complications include
hypertrophic scarring, delayed healing, seromas, temporary dysphagia, facial
edema, and serous otitis media.
onsequences of Hypothyroidism in Children

C
The consequence of hypothyroidism in a child can be devastating, whether the child
is rendered hypothyroid by surgery, ablation, or pathology. Growth delays and
mental retardation can be severe if hormone deficiency is prolonged. Adequate

replacement is fundamental to prevent hypothyroidism. Lifetime treatment from
childhood involves adjustment in dosing based on changing size and development
needs. Compliance with therapy and follow-up may become an issue [389].
Isthmic Nodule: Higher Risk of Malignancy?
Nodules in the thyroid gland are extremely common. Although the majority of these
lesions prove to be benign, data from the Surveillance, Epidemiology, and End
Results (SEER) program estimated 52,070 new cases of thyroid cancer and 2170
associated deaths in the United States in 2019 [390]. Clinical aspects and ultrasound
(US) characteristics of the nodules have been used for a long time to determine
which nodules should or should not be biopsied. The 2016 American Thyroid
Association (ATA) guidelines [118] and the American College of Radiology Thyroid
Imaging Reporting and Data System (TI-RADS) [391] have proposed a series of US
features and a point system that should be used to classify which nodules must be
investigated further, combining characteristics such as size, echogenicity, shape,
composition, margin, and presence of echogenic foci (particulates within the nodule
of differing echogenicity) [391–393].
According to the TIRAD system, the total point value is divided into five levels,
with TR1 and TR2 being the lowest, with no recommendation for an FNA. The need
for an FNA at levels TR3, TR4, and TR5 is supported not only by the TIRAD points,
but also by nodule size. The following are recommendations for FNA: (1) TR3: 3
points, nodule size ≥2.5 cm; (2) TR4: 4–6 points, nodule size ≥1.5 cm; and (3)
TR5: >7 points, nodule size ≥1 cm. If a thyroid nodule meets the point level, but not
the size requirements, then the recommendation is follow-up. Overall, the accuracy
of the ACR-TIRAD is high [391–393], but there is another nodule quality that has
been overlooked and may provide an easier path to the FNA decision.
Recently, the location of the thyroid nodule within the gland has also been found
to be associated with a distinct risk of malignancy, with isthmic and upper lobar
nodules presenting the highest risk [394–396], and lower lobar nodules the lowest
[396]. One meticulous and large cohort study analyzed 3419 nodules obtained from
3313 patients and demonstrated that the odds of malignancy among patients with
isthmic nodules were the highest (odds ratio, 2.4), demonstrating a statistical differ-
ence (p = 0.005) when compared with other locations, even after adjustment of
clinical and imaging variables [396]. Thus, location without any other additional
information can provide insight into the need for an FNA [396]. It is worth mention-
ing that the multivariate regression of the study by Jasim et al. (2020) [396] also
confirmed previous expectations regarding thyroid nodules, such as gender and age,
as independent factors. Despite women having a disproportionate number of nod-
ules, men were at higher risk of having a cancerous nodule (OR = 1.8, CI = 1.4–2.5).
Malignancy risk also decreased with age. While older individuals had more nod-
ules, they were also more likely to be benign (OR = 0.9, CI = 0.97–0.98). Younger
individuals had a slightly greater risk of malignant nodules. The ACR-TIRAD, as
expected, was also an independent predictor of malignancy, although nodule size

was not. The likelihood of malignant tumors increased with each TR level. Compared
to TR1, the risk of a cancerous nodule in TR2 was 4.4 times more likely, 13 times
greater in TR3, and at least 25 times more likely in TR4 and TR5.
In 2020, Pastorello et al. [397] reported that out of a total of 9535 cytology
reports from thyroid fine needle aspirations (FNAs), a total of 340 cases (3.57%)
were reported as malignant according to The Bethesda System for Reporting
Thyroid Cytopathology [174]. Of these, 97% proved to be malignant on histopa-
thology, a finding that is compatible with the estimated risk of malignancy of
97–99% described in The Bethesda System [174]. A malignant diagnosis was more
than twice as common in the isthmus compared with the lateral lobes of the thyroid
gland. When considering all 915 cases in the study cohort that underwent a subse-
quent surgical resection, irrespective of their previous cytology diagnoses, isthmic
nodules also demonstrated a significantly higher percentage of malignancy, with 41
of 51 nodules (80.4%) found to be malignant on histology compared with 288 of the
469 resected nodules in the right lobe (61.4%) and 215 of the 395 resected nodules
in the left lobe (54.4%) (p = 0.001).
There is no definite explanation for the higher risk of malignancy for nodules
located in the isthmus, but a few factors may be involved, such as the embryological
nature of the gland. Some authors have claimed that during embryology, the early
formation of the thyroid lobes would depend on the incorporation of the two lateral
anlagen (derived from the ultimobranchial bodies). Conversely, the isthmus would
be a remnant of the median anlage (developed from the primitive pharynx) [398],
which possibly could reflect a different cellular composition and higher associated
risk of malignancy. In addition, the isthmus has less thyroid tissue compared with
the lobes, and therefore when a nodule is present, it most likely would represent a
“neoplastic” rather than a “hyperplastic” process. Although malignant nodules in
the isthmus have been reported to be smaller in size than elsewhere in the thyroid
gland [396], they were associated with a smaller percentage of nondiagnostic sam-
ples, probably due to their more superficial location allowing easier sampling,
which could explain in part the larger percentage of malignant nodules in this loca-
tion [397].
In addition, recent studies have also demonstrated that patients with thyroid car-
cinomas arising from the isthmus have a worse prognosis compared with patients
with lesions located elsewhere [13, 21, 22, 399–402] and that this location has been
associated with more aggressive tumors and more frequent LN metastases and ETE,
possibly due to the smaller and thinner size of this portion of the gland and its
unique lymphatic drainage [13, 21, 22, 397, 399–402].
Papillary Thyroid Carcinoma (PTC) of the Isthmus
Introduction
The thyroid isthmus is the part of the thyroid gland that connects the lower third of
the right and left thyroid lobes. The isthmus is usually located at the second and
third rings of the trachea and is covered by skin, fascia, and strap muscles. The
reported frequency of papillary thyroid cancer (PTC) arising in the thyroid isthmus
ranges from 1% to 9.2% [12–15, 21, 403–409], probably reflecting variation in the
study populations due to selection bias [13, 14].
Clinicopathological Characteristics
Previous studies have demonstrated that PTCs located in the isthmus are more likely to
exhibit multifocality (multiple foci in bilateral lobes) [13, 14, 21, 403], capsular inva-
sion [13, 403, 404], extra-thyroidal extension (ETE) [14, 21], and central LN metasta-
sis [13, 14, 21, 403, 404, 406] than those located in the other parts of the thyroid.
This may be explained by the anatomical characteristics of the isthmus, which is
located in a thin space enclosed by solid structures such as the trachea and strap
muscles. In fact, since the isthmus is a very small portion of the parenchyma and its
location is in the center of the thyroid, it is reasonable that isthmus cancer could
spread into one of the two lobes explaining the higher rate of multifocality [13].
Moreover, the isthmus thickness is 2–6 mm; therefore, capsular invasion and ETE
could be more frequent in the isthmus cancer than in those originating in the thyroid
lobes [14, 21]. Literature data confirmed that capsular invasion and ETE were inde-
pendent of tumor size in the isthmus cancers because these findings were also fre-
quent in the isthmus microcarcinoma [403].
Several studies in the literature also demonstrated a higher frequency of LN
metastases in thyroid cancer located in the isthmus compared to non-isthmus carci-
noma [13, 14, 21, 403, 404, 406]. Thyroid isthmus has a different lymphatic drain-
age compared to the thyroid lobe, and in particular, lymphatic isthmic vessels
usually drain into the pre-laryngeal (Delphian), pre-tracheal, and paratracheal LNs,
predicting an unfavorable prognosis [400]. Interestingly, Karatzas et al. (2015)
[403] reported that there was no statistically significant difference between LN
metastasis with isthmus cancer <10 mm and >10 mm, suggesting that the isthmus
location could be a risk factor for central LN involvement, regardless of tumor size.
Therefore, many authors considered total thyroidectomy with bilateral central LN
compartment dissection as an appropriate surgical approach for patients with isth-
mic PTC, due to the high rate of bilateral central LN metastasis [13, 22, 405].
Lee et al. (2016) analyzed the clinicopathological characteristics and pattern of
cervical LN metastasis in patients with PTC located in the isthmus [21]. This retro-
spective study included a total of 190 consecutive PTC patients who underwent total
thyroidectomy (TT) and bilateral central LN dissection. Of the 190 PTC patients, 14
patients (7.3%) had a tumor located in the isthmus. The PTCs located in the isthmus
had a significantly more ETE and central LN involvement than those located in the
lobes, with no significant difference in the frequency of lateral LN involvement [21].
Treatment
There are no specific guidelines for the surgical management of thyroid cancers
confined to the isthmus. However, because isthmus PTCs may have a higher inci-
dence of both multifocality and capsular invasion than PTCs located in the lobes,
thyroid isthmusectomy should be reserved for highly selected patients without
major ETE or adhesion to adjacent tissues [15]. In addition, regarding the high fre-
quency of involvement of the pre-laryngeal and pre-tracheal compartments, careful
preoperative evaluation of these compartments and possible neck dissection should
be considered when a tumor is located in the isthmus.
Recent guidelines do not support the surgical management of thyroid cancer with
procedures other than thyroid lobectomy and near-total and total thyroidectomy
[118]. Isthmusectomy is not reported in the ATA guidelines as an appropriate surgi-
cal procedure for differentiated thyroid cancer [399]. International guidelines have
not formulated specific recommendations for a correct surgical approach of the isth-
mus nodule, neither for carcinoma nor for indeterminate nodules [399].
Vasileiadis et al. (2018) [22], in their systematic review of literature, analyzed
the surgical management strategies and published outcomes of PTC located in the
isthmus. They concluded that the extent of the surgical resection, the role of prophy-
lactic central neck dissection (CND), and the extent of CND in surgery for isthmic
PTC remain highly controversial. However, total thyroidectomy (TT) and central
node dissection may be an appropriate treatment for these patients. Lee et al. (2010)
reported that TT is an appropriate initial surgical procedure for the isthmic
PTC. Their study included 181 patients with thyroid cancer located in the isthmus
[13]. In addition, Goldfarb et al. (2012) reported that of 28 patients with a dominant
thyroid nodule of the isthmus, 12 had malignant final pathologic results. They rec-
ommended that for malignant isthmus nodules, TT and possible CND are indicated
owing to high rates of multifocal disease and LN involvement [15].
Finally, a limited experience from an Italian group suggests the possible effec-
tiveness of radioiodine (RAI) ablation in patients with isthmic thyroid cancer [410].
8.5 Cystic Nodule in the Thyroid Isthmus
Introduction
Thyroid cysts represent 15–25% of all thyroid nodules and are usually diagnosed by
aspiration of fluid from a solitary thyroid nodule (STN). A palpated mass may be
solid, cystic, or mixed in nature; a large proportion has mixed cystic and solid compo-
nents. In some studies, a nodule is called a cyst only if it is “predominantly cystic on
ultrasonography (US),” but in others, the term is applied to “nodules that have any
areas of cystic degeneration,” which may include up to 50% of thyroid nodules [411].
Pure cystic thyroid lesions are considered almost always benign (Fig. 8.4), but
their diagnosis and treatment are sometimes very important especially when having
atypical morphology and location [412]. Most cysts recur after fine needle aspira-
tion (FNA).
Etiology
True simple thyroid cysts lined by benign epithelial cells are rare. As an example, in
one US study of 1985 patients with 3483 nodules larger than 10 mm, there were

of the neck showing a
purely cystic nodule,
which is completely
anechoic without any
identifiable solid
component. It is most
likely a colloid cyst or, less
likely, a true cyst of the
thyroid and is considered
benign
only seven completely cystic nodules [413]. Most cystic nodules are partly solid
structures that have undergone cystic degeneration (mixed or complex nodules).
Complex nodules are common. In a review of 1128 patients with 1458 thyroid nod-
ules who underwent US-guided FNA, 53.5% were partially cystic, with 13.7%
described as >75% cystic [310].
Thyroid cystic nodules are often caused by cystic degeneration of normal thyroid
tissue, hemorrhage or trauma, occult follicular adenoma or carcinoma, multinodular
goiter (MNG), or branchial anomalies that involve the thyroid gland. Simple
epithelium-lined cysts, hemorrhagic colloid nodules, or necrotic PTCs can be found
in resection specimens. To improve the diagnostic accuracy of aspiration biopsy,
biochemical analysis of cyst fluid is advised.
Clinical Manifestations
Like most thyroid nodules, cystic thyroid nodules often come to attention when
noted by the patient or as an incidental finding during a routine physical examina-
tion or imaging procedure such as carotid US, computed tomography (CT) scan, or
magnetic resonance imaging (MRI) of the neck (so-called thyroid incidentalo-
mas) [164].
However, some patients develop symptoms, and cystic thyroid lesions (not sub-
acute thyroiditis) are the most common cause of thyroid pain. As an example, sud-
den hemorrhage or hemorrhagic infarction of a solid thyroid nodule can result in a
predominantly cystic and painful neck mass. Even relatively small hemorrhagic
cysts of only 1–2 mL may be associated with considerable neck discomfort and
dysphagia. More extensive hemorrhage may cause hoarseness of voice and transient
or permanent vocal cord paralysis and may even compromise the airway, especially
if the cystic nodule is located in the midline [412]. In addition, chronic intermittent
degeneration of a thyroid tumor can result in intermittent neck discomfort.
Benign cystic thyroid nodules not infrequently present with symptoms and signs
that mimic an aggressive thyroid cancer, including pressure symptoms and rapid
growth; however, a cystic PTC may provide few clues of its malignant nature,
including a soft consistency to palpation and little or no apparent growth over the
course of several years. The physical and biochemical features of the aspirated fluid
of a nodule provide little diagnostic information; both benign and malignant lesions
may yield grossly bloody aspirates or translucent yellow fluid. Cystic thyroid nod-
ules not only have a higher than usual likelihood of yielding cytology specimens
that are inadequate for diagnosis, but also have higher than usual rates of false-
negative cytology specimens. However, using a careful clinical assessment, US,
Doppler studies, and US-guided FNAB, the malignant or benign nature of most
cystic thyroid nodules can be identified [412].
Clinically, a nodule in the isthmus of the thyroid gland is mobile with deglutition.
Other parts of the thyroid gland may be affected as well. Absence of a track between
it and the hyoid bone as well as being not mobile with tongue protrusion differenti-
ates it from a thyroglossal tract cyst.
Treatment
Approximately 5% of patients with cystic or predominantly cystic thyroid nodules

(PCTNs) may experience compressive symptoms or cosmetic concerns, and treat-
ment may be required in these cases [414].
Nonsurgical Treatment
Currently, ultrasound-guided minimally invasive procedures are widely used to treat
many thyroid diseases.
Aspiration
Simple aspiration is generally the initial management option for symptomatic
benign pure cysts and predominantly cystic thyroid nodules (PCTNs) for the pur-
pose of diagnosis and cyst volume reduction. However, the recurrence rate has been
reported to be high, ranging from 40% to 59%, depending on the number of aspira-
tions and extent of fluid evacuation [415–418]. Therefore, percutaneous ethanol
ablation (PEA) is a reasonable approach in patients with recurrent cystic fluid accu-
mulation after initial aspiration. In cases of PCTNs with some solid portion, at least
two benign FNA results are essential before performing the PEA procedure. In one
study, the recurrence rate (RR) of thyroid cysts was reported to decrease to less than
20% after PEA [419].
Benign cysts can be evacuated successfully by aspiration; the aspirated fluid is
usually clear yellow or bloody, with high levels of thyroid hormones. Rarely, a para-
thyroid cyst is aspirated. In such a case, the fluid is clear and colorless, with high
levels of parathyroid hormone (PTH). A true cyst has a very low risk of malignancy.
However, the presence of a cyst does not exclude neoplasia, especially if the mass
is mixed. Desjardins et al. (1987) found that 50% of their patients with thyroid car-
cinoma had a cystic component in the tumor [420].
Percutaneous Ethanol Ablation (PEA)

Percutaneous ethanol ablation (PEA), using ethanol of high purity (95–99%), is
widely used as a nonsurgical treatment usually for cystic (pure cyst) or predomi-
nantly cystic benign thyroid nodules (PTCNs) (cystic portion >50%) [380]. The first
interventional attempt to treat a thyroid nodule was simple aspiration of a thyroid
cyst in 1966 by Crile [421]. In 1974, Miller et al. [422] reported that simple aspira-
tion alone was associated with a high recurrence rate (RR) of 58%, which limits the
value of this treatment. Thereafter, various sclerosing agents were used to treat
recurrent thyroid cysts [423–425]. In 1985, Rozman et al. [426] first used ethanol to
treat thyroid cysts. In 1990, Livraghi et al. [427] used ultrasound (US) for PEA of
functional thyroid nodules. Subsequently, US-guided PEA of benign thyroid nod-
ules was performed by several authors [417, 419, 427–435]. In recent years, PEA
has also been used to treat recurrent thyroid cancer [24, 354, 365–369].
It has recently been reported that US-guided PEA is an effective and safe alterna-
tive to surgery in cases of benign recurrent pure cysts or predominantly cystic thy-
roid nodules (PCTNs) causing pressure symptoms or complaints of neck bulging.
The efficacy of PEA for the management of pure cysts or PCTNs has been well
documented [419, 432, 436–440]. The reported volume reduction ratio (VRR) after
PEA in thyroid cysts (cystic portion >90%) and PCTNs (cystic portion of 50–90%)
ranges from 80% to 100% and from 60% to 90%, respectively [240, 419, 432, 438,
441–444]. Although PEA is effective and safe for both pure cysts and PCTNs, it is
more effective for pure cysts in terms of volume reduction, therapeutic success, and
requirement for additional treatment [240, 438, 445]. The success-related factors of
PEA include the nature of the nodule itself (proportion of solid portion, vascularity,
and initial volume), intra-nodular echo staining during the procedure, retention time
of ethanol, and sufficient evacuation of internal content before injection [446]. In
contrast, the efficacy of PEA for treating benign solid thyroid nodules remains con-
troversial, and PEA is not recommended in recent guidelines for solid nodules [180].
The therapeutic mechanism of PEA is a combination of coagulative and isch-
emic necrosis. The former is caused by direct ethanol toxicity leading to cell dehy-
dration and protein denaturation due to diffusion, while the latter is induced by the
entrance of ethanol into the local circulation and inhibition of enzymatic activity in
surrounding tissues, resulting in endothelial injury, subsequent thrombosis, and
ischemia [417, 447]. Coagulative necrosis is considered to be the predominant
effect on cystic lesions [447–449].
Percutaneous ethanol ablation has been proposed as the first-line treatment for
relapsing symptomatic cystic thyroid nodules in most guidelines [118, 180, 226,
446, 450, 451]. The 2018 consensus statement on PEA released by the Korean
Society of Thyroid Radiology accentuated the role of EA in treating benign thyroid
cysts and PCTNs and further expanded its clinical scope for the management of
hyperfunctioning thyroid nodules and local recurrent thyroid carcinoma in selected
cases [446].
In 2021, Yang et al. [452] published the results of their meta-analysis that
included 19 studies (4 randomized controlled trials and 15 non-randomized studies)
with 1514 participants. The cumulative volume reduction ratio (VRR) of PEA was
83.9%. PEA had a significantly higher pooled VRR (p = 0.030), but not a signifi-
cantly higher pooled therapeutic success rate (p = 0.880), than other forms of non-
surgical management including radio-frequency ablation (RFA), polidocanol
sclerotherapy, and simple aspiration with or without saline flush. However, the VRR
and therapeutic success rate were not significantly different between PEA and
RFA. This outcome is consistent with previous reports of high VRRs of RFA in both
thyroid cysts and PCTNs (92.2–93.3% and 83.7–87.5%, respectively) [156, 240,
444, 453]. However, RFA is more expensive than PEA and requires more treatment
sessions to have an effect (1.67 ± 0.86 vs. 1.19 ± 0.4, p = 0.03). It is also associated
with a greater tendency for the patient to experience pain, both during and after the
procedure [156, 445]. Unlike with RFA ablation, the ablative effect of ethanol is
limited to the nodule; thus, PEA does not disrupt thyroid function [437, 441, 454].
Moreover, local anesthesia is not required in most PEA procedures.
PEA is a safe treatment option for cystic thyroid nodules, and complications are
mostly mild and transient, if performed by experienced hands [155, 227]. Localized
pain at the puncture site is most common, and hematoma, facial flushing, drunken
sense, hoarseness, dyspnea, and temporary hyperthyroidism have been reported
[293, 445]. Immediately after the procedure, most patients complain of mild, tran-
sient pain that resolves spontaneously or by analgesics. Hematoma, due to injury of
the vessels in the thyroid capsule at the time of puncture, is a common complication
associated with pain [293, 438]. However, if the puncture site is tightly compressed
for 10 min after the procedure, hematoma can be prevented. In the meta-analysis by
Yang et al. (2021), major complications with PEA were recorded only in six patients
(0.53%) with self-limiting dysphonia and one patient with transient voice change
that resolved spontaneously within 2 months. Yang et al. concluded that the role of
PEA as the first-line treatment for benign thyroid cysts and PCTNs is supported by
its high effectiveness and good safety profile compared to other currently available
nonsurgical options [452]. The demographic characteristics and results of PEA in
the literature are summarized in Table 8.13.
In addition to ethanol, several sclerosants have been adopted for the treatment of
cystic thyroid nodules, including tetracycline, sodium tetradecyl sulfate, N-butyl
cyanoacrylate, and polidocanol [424, 462–464]. Among them, polidocanol and
sodium tetradecyl sulfate were compared with PEA and were reported to have simi-
lar VRRs, albeit with higher costs [443, 462].
Several factors are known to compromise the efficacy of PEA, particularly for
the treatment of PCTNs. These include (1) a relatively large initial nodule volume
(>20 mL), (2) hyper-vascularity, (3) a solid portion >20% of the total nodule, and
(4) a relatively low degree of cystic fluid aspiration prior to ethanol instillation [445,
456, 465, 466]. Technical factors have also been studied; Kim et al. (2005) [439]
and Park et al. (2019) [467] compared retention and aspiration methods of injected
ethanol and reported no significant difference between the two methods in terms of
Table 8.13 Demographic data and results of percutaneous ethanol ablation
PEA technique
No. of cases Study Mean Nodule Ethanol conc. Retention Major
Study [Ref] (Y) Nodule type (M/F) design age (Y) volume (mL) % time (min) Sessions Side effects (N) complications (N)
[156] (2011) Cyst 36 (10/26) RCS 47.69 12.2 95–99 10 Multiple Mild pain None
[240] (2013) Cyst 25 (2/23) RCT 45.0 13.83 99 10 Single None None
[444] (2015) PCTN 24 (6/18) RCT 50.8 14.7 99 2 Single None Voice change that
resolved in
2 months (1)
[443] (2018) Cyst, PCTN 135 (50/85) RCS 46.83 15.23 NA 10 NA Mild pain None
[437] (1994) Cyst 42 (NA) PCS NA 20.10 95 5 Single Mild None
self-limiting
pain
8.5 Cystic Nodule in the Thyroid Isthmus
[419] (2003) Cyst 33 (4/29) RCT 48 8.0 99 2 Multiple Transient pain Transient
dysphonia for
1 h (1)
[440] (2004) Cyst, PCTN 135 (NA) RCT NA 19.0 95–100 No Multiple Transient Dysphonia
burning that resolved
sensation in 2 months (1)
[441] (2016) Cyst, PCTN 36 (2/34) PCS 40.4 10.4 99 NA Multiple Mild pain, None
edema
[442] (1999) Cyst 40 (NA) BA NA 33.7 NA NA Multiple Transient mild None
pain
[455] (2000) Cyst 22 (4/18) BA 40.7 13.0 NA NA Multiple Local pain None
due to leakage
(2)
[438] (2003) Cyst 20 (NA) BA NA 15.7 99.9 NA Multiple Transient pain None
due to leakage
(4)
(continued)
253
Table 8.13 (continued)
254
PEA technique
No. of cases Study Mean Nodule Ethanol conc. Retention Major
Study [Ref] (Y) Nodule type (M/F) design age (Y) volume (mL) % time (min) Sessions Side effects (N) complications (N)
[293] (2004) Cyst 58 (NA) BA NA 13.7 95 NA Multiple None Transient
dysphonia (2)
[456] (2012) Cyst, PCTN 94 (21/73) BA 40.4 13.2 99 10 Single Mild pain None
[457] (2014) Cyst 14 (NA) BA NA 12.2 99 NA Multiple Transient pain None
due to leakage
[458] (2015) Cyst 30 (5/25) BA 46.0 18.2 ± 15.5 99 No Multiple Mild pain None
[459] (2017) Cyst 101 (30/71) BA 42.3 14.8 Absolute NA Multiple Transient pain None
ethanol (21)
[460] (2018) Cyst 75 (3/72) BA 57.0 18.4 95 NA Multiple Transient pain Transient
(1) dysphonia (1)
[454] (2018) Cyst, PCTN 42 BA NA 15.3 ± 14.0 96 NA Multiple Transient mild None
pain
[461] (2020) Cyst 193 BA 49 8.5 96 No Multiple Mild pain (59) Dysphonia that
(43/150) resolved in
14 days (2)
8
Values are expressed as mean

Ref reference, Y year, min minutes, PEA percutaneous ethanol ablation, RFA radio-frequency ablation, RCS retrospective cohort study, RCT randomized con-
trolled study, PCTN predominantly cystic thyroid nodule, PCS prospective cohort study, NA not available, BA uncontrolled before and after comparison
therapeutic success rate and VRR, respectively. Similarly, different durations of

temporary ethanol retention (2, 5, and 10 min) did not significantly affect the VRR
in a study by Kim et al. (2012) assessing the treatment of cysts and PCTNs [445].
Moreover, the efficacy of PEA is also influenced by the number of treatment ses-
sions. Negro et al. (2017) [459] reported that the VRRs in thyroid cysts after the
first, second, and third PEA sessions were 66%, 74.4%, and 79.4%, respectively.
Yang et al. (2021), in their meta-analysis study, reported that only studies that per-
formed multiple PEA sessions demonstrated a significantly higher pooled VRR
than the control management [452].
The reported recurrence rates (RRs) in thyroid cysts after PEA were low
(3.1–18%) and also varied according to the technique that was used [418, 419, 437].
However, in a recent study of PCTNs, by Suh et al. (2015), the 1-month RR was
18.7%, whereas delayed recurrence (mean, 10.1 ± 8.5 months) occurred in 24.1%
of patients who initially did not show recurrence at 1 month of follow-up [466].
When faced with unsatisfactory results after PEA, current guidelines [226, 450]
recommend performing subsequent RFA, based on previous studies reporting that
significant reductions in nodule volume and improvements in symptomatic and cos-
metic problems were achieved after this combination therapy [13, 456]. Similarly,
for incomplete ablation of solid nodules adjacent to critical structures after RFA,
using PEA as an adjunct technique was shown to be an effective way to eliminate
the residual solid component [468, 469].
Percutaneous Polidocanol Injection (PPI)

Polidocanol is an effective sclerosant consisting of 95% hydroxy-polyethoxy-
dodecane and 5% ethyl alcohol. Its injection is well known as a novel foam scle-
rosant that is currently administered by injection mostly for the treatment of
hemangiomas [470], hemorrhoids [471], symptomatic hepatic cysts [472], gastric
varices [473], and reticular veins of the lower limbs [474]. Gong et al. (2017) pro-
spectively evaluated the efficacy and safety of percutaneous polidocanol injection
(PPI) in treating benign cystic (>90% cystic component) (N = 59) and PCTNs
(>80% cystic component) (N = 55) in 114 patients with compressive symptoms or
aesthetic complaints. Results were evaluated at 1, 3, 6, 9, and 12 months postinjec-
tion. Nodules shrunk in size significantly with time after PPI (p < 0.001). The mean
baseline volume of 15.6 ± 18.9 cm3 was significantly reduced at 1-month follow-up
to 5.1 ± 5.6 cm3 and finally at 12 months to 0.6 ± 0.9 cm3. At 12 months post-PPI, a
complete therapeutic response (≥70% decrease) occurred in 100% of cases with no
reported recurrence [475]. The observed success rate was better than that reported
previously with PEA [438, 445]. The mechanism of action of polidocanol is prob-
ably by destroying endothelial cells of capsule wall, which causes aseptic inflamma-
tion that results in atrophy of endothelial tissue and adherence occlusion of the
cavity in a single session [476]. Side effects reported by Gong et al. were mild; 20
patients (17.5%) developed mild localized pain, and 14 (12.3%) experienced mild
or moderate fever after PPI. The authors concluded that PPI is a safe and effective
alternative to treat benign cystic or PCTNs [475].
Thermal Ablation

In recent years, thermal ablation has emerged as a popular nonsurgical treatment for
benign solid thyroid nodules and recurrent thyroid cancers [453]. In particular, RFA
has been shown to be effective for treating cystic thyroid nodules [154, 156, 221,
228, 239, 240, 444]. Comparison of the efficacy of RFA between cystic nodules and
solid nodules has been reported in three studies (Table 8.14) [221, 228, 239], with a
mean volume reduction rate (VRR) of 91.1% (range: 79.8–97.6) in cases with cystic
nodules and 71.8% (range: 54–92) in cases with solid nodules.
Comparison of the efficacy of PEA and RFA for cystic and/or PCTNs has been
reported in three studies (Table 8.15) [156, 240, 444]. The mean VRR of thyroid
Table 8.14 Comparison of efficacy of RFA between cystic thyroid nodules and solid nodules
Cystic nodules Solid nodules
Nodule Nodule Nodule
Nodule volume volume at volume
Sample baseline after RFA VRR Sample baseline after RFA VRR
Authors size (mL) (mL) (%) size (mL) (mL) (%)
Aysan 14 32.48 0.79 97.55 51 9.99 3.07 69.21
et al.
[228]
Kim 22 NA NA 79.8 13 NA NA 54.2
et al.
[221]
Lim 45 NA NA 96 81 NA NA 92
et al.
[239]
Table 8.15 Comparison of efficacy for cystic thyroid nodules between percutaneous ethanol
ablation (PEA) and radio-frequency ablation (RFA)
Percutaneous ethanol ablation (PEA) Radio-frequency ablation (RFA)
Nodule Nodule Nodule Nodule
vol. at vol. after vol. at vol. after
Sample baseline treatment VRR Sample baseline treatment VRR
Authors size (mL) (mL) (%) size (mL) (mL) (%)
Baek 24 14.7 2.45 83.1 22 8.6 1.1 87.1
et al.
[444]
Sung 36 13.83 0.95 93.1 21 10.19 0.79 92.2
et al.
[156]
Sung 25 12.2 0.38 96.9 25 9.3 0.62 93.3
et al.
[240]
nodules was 91% (range: 83.1–96.9) in cases with PEA and 90.9% (range:
87.1–93.3) in cases with RFA. In a single-session treatment non-inferiority random-
ized clinical trial for cystic thyroid nodules, PEA was not only non-inferior, but also
superior to RFA [240]. In addition, PEA was a simple and less expensive procedure
with the fewer number of treatment sessions, compared to RFA [156, 444]. It is thus
recommended that patients with cystic or PCTNs that regrow after simple aspiration
of internal fluid should be treated with PEA rather than RFA [156, 213, 224,
444, 456].
These results may also be useful to avoid expensive clinical trials or treatment
modalities for cases with symptomatic cystic thyroid nodules that can be success-
fully managed using PEA. For PCTNs, EA has also been suggested as the first-line
treatment modality in single-session treatment superiority randomized clinical trial,
by Baek et al. (2015) comparing PEA and RFA [444]. However, 18.7–33% of cases
revealed recurrence following PEA for PCTNs at a 1-month follow-up [224, 456,
466]. In a longer follow-up study with a mean 17.1 months, by Suh et al. (2015)
38% of patients required additional treatment [466]. The solid component was sug-
gested as the main cause of recurrence after PEA [224, 456]. RFA is recommended
as an effective treatment method, regarded as the next step for cases of cystic or
PCTNs when patients have incompletely resolved symptoms or recurrence follow-
ing PEA. Therefore, PEA-RFA combination therapy is recommended for incom-
pletely resolved symptoms after initial PEA [250, 291, 468].
Percutaneous Laser Ablation (PLA)

Percutaneous laser ablation (PLA) (also known as interstitial laser photocoagula-
tion—ILP) is a minimally invasive procedure that has been reported to reduce the
need for surgery patients with a benign solid thyroid nodule. Døssing et al. (2013)
evaluated the efficacy of US-guided aspiration and subsequent PLA on remission
rates in 22 consecutive patients with a symptomatic, recurrent, and cytologically
benign PCTNs (cyst volume ≥2 mL). Patients were followed up at 1, 3, and 6 months
post-PLA. Successful outcome (cyst volume ≤1 mL) was obtained in 15 patients
(68%). The solid part of the nodule was significantly reduced from a median of
1.8–1.0 mL (p = 0.02). The reduction in median visual analog score (0–10 cm) for
pressure symptoms was also significantly reduced from 3.0 to 0.0 cm. No major
side effects occurred, and thyroid function was unaffected throughout. They con-
cluded that PLA constitutes an important alternative to surgery in patients with
symptomatic, recurrent PCTNs [268].
Colloid Cyst
Introduction
Colloid nodules having cystic component are termed as colloid cysts (CC), and
these nodules are the commonest thyroid nodules [477]. Colloid nodules are fre-
quently formed nodules in a thyroid gland and can be either purely cystic or a part
of solid thyroid nodule [411]. Sonographic detection of thyroid colloid cyst as an
incidentaloma is not less common. Primary epithelial lined simple thyroid cysts are
rare (2–4%), but degenerative colloid nodules are seen frequently (82%) [412, 478].
The sequence of formation of colloid nodules is still debatable. In experimental
studies, colloid cyst was found to be rich in thyroglobulin (Tg); thus, it is proposed
to be formed as a result of destabilization in the physiological steps of thyroid hor-
mone formation, i.e., imbalance between endocytosis of a colloid droplet into the
follicular cell and exocytosis of Tg into the follicular lumen containing colloid
[479]. It is conceivable that colloid cysts are formed as a consequence of excess
accumulation of colloid in the thyroid follicle due to many proposed factors
or causes.
Although a colloid cyst is mostly asymptomatic, it has the potential to cause pre-
senting symptoms due to its size, location, and intra-cystic secondary complica-
tions. Most symptoms result from mass effect on the airway, digestive tract, or
neurovascular bundle. More serious presentation can be neck pain due to internal
hemorrhage or even its rupture, which can be life-threatening. Spontaneous infec-
tion in a colloid cyst is unexpected, but any cyst can be infected if subjected to
needle aspiration [412, 480]. Colloid cysts are nonfunctional and have no effect on
thyroid function [412]. In 2021, Khan et al. reported a 68-year-old gentleman who
presented with a progressive midline lower neck swelling, which appeared sud-
denly, increased in size progressively, and became prominent over 6 weeks. On
examination, the swelling was about 5 × 2 cm in size, mobile, with deglutition, and
not with protrusion of the tongue. It was not adherent to the skin or underlying
structures. The thyroid gland was impalpable, and the patient was clinically euthy-
roid with no evident Graves’ disease features. Pressure symptoms included mild
dysphagia to solids, but the patient did not encounter any respiratory complaints
[481]. The patient was subjected to US and CT scan imaging, and diagnostic aspira-
tion, which revealed 18 mL of fluid having abundant colloid, few scattered foamy
macrophages, and hemosiderin. It was consistent with benign cystic colloid nodule
with hemorrhagic changes, Bethesda Category II. Diagnostic aspiration was later
followed by therapeutic colloid aspiration [481].
Imaging Studies
Radiological imaging is fundamental in the diagnosis of a colloid cyst, and ultra-
sound (US) is usually adequate. Sonographically, anechoic thyroid cyst with mul-
tiple comet tail or reverberation artifacts are universally accepted to be a peculiar
feature of colloid cyst indicating inspissated calcified colloid crystals and are con-
sidered diagnostic. If the cyst is very small in size having a single echogenic focus
of colloid, it gives a “cat’s eye” appearance. Studies in the literature have rarely
mentioned some other appearances such as isoechoic or hypoechoic cyst,
honeycomb pattern due to a large colloid clot, and dependent avascular echogenic
component due to debris or hemorrhage [411, 412, 482]. Hemorrhagic or debrinous
changes seen at the base of the cyst are believed to form a flat upper margin.
Complete anechoic cyst without colloid crystal artifacts is not considered as colloid
cyst, but a simple thyroid cyst (which is epithelial lined and arises from pathological
dilatation of any preexisting tubules, ducts, or cavities formed during any stage of
life). If these simple cysts become hemorrhagic or infected, they can mimic other
uncommon appearances of colloid cyst [412].
If a colloid cyst is enlarged more than 2 cm in size, it is at risk of intra-cystic
hemorrhage (due to increased intravenous pressure), which could be spontaneous,
after strenuous activity, external pressure, or trauma [412, 483].
Computed Tomography (CT) Scan and Magnetic Resonance Imaging (MRI)

Cross-sectional radiological examination like CT scan or MRI is not routinely
required after US as they have less spatial resolution and lack of ability to describe
the colloid crystals and varied cystic content. In doubtful cases, “claw sign” (beaked
extension of organ solid tissue around the lesion) demonstration on these modalities
can determine whether a lesion is intrinsic or extrinsic, particularly in large lesions
and small organs. It is more convincingly seen on cross-sectional imaging than
US. The clawlike appearance is formed when the mass originates within an organ
parenchyma and grows toward its surface leading to thinning of partially surround-
ing spared parenchyma, which is in between mass and superficial surface of an
organ. This parenchyma has sharp pointed ends unlike extrinsic mass, which makes
blunt parenchymal ends [481].
Nuclear Imaging
Generally, nuclear imaging is unjustified in cystic thyroid lesions [484–487].
Colloid cysts are usually not much large but can be of variable sizes and found in
any part of thyroid gland, though larger cysts have occasionally been observed in
thyroid lobes [483].
ine Needle Aspiration (FNA)

F
Many societies have guided the clinicians and radiologists for management and
categorization of cystic thyroid lesions. According to the American College of
Radiology Thyroid Imaging Reporting and Data System, colloid cyst comes under
Thyroid Imaging Reporting and Data System 1 category of benign lesions, which
do not need FNA [391, 484]. Thus, colloidal cysts usually do not require aspiration
or even follow-up because they have no risk of malignancy and show no significant
changes even on long-term follow-up. Only symptomatic benign cystic nodules can
be simply aspirated, both for diagnostic and therapeutic purposes [380, 483, 484].
Histopathology
From the histopathological viewpoint, colloid nodules are under benign Bethesda
Category II (0–3% risk of malignancy). It is subcategorized under benign follicular
nodules, which are defined as having predominantly colloid and follicular cells in
variable amounts. Microscopically, colloid cysts are dilated follicles having flat-
tened follicular cells lining with abundant central colloid. Other subcategories are
hyperplastic or adenomatoid nodules, nodules in Graves’ disease, and macro-
follicular subtype follicular adenoma [479, 488].
Some possible differentials of a colloid cyst can be included according to the site of
cyst, for example infrahyoid/intra-thyroid thyroglossal cyst, intra-thyroidal parathy-
roid cyst, branchial clef tryst, intra-thyroidal bronchogenic cyst, and unilocular
hydatid cyst. None of them were reported in the isthmus [489–491].
Treatment
The management recommendation of a colloid cyst in the isthmus is neither follow-
up nor surgical intervention, but occasionally its presenting symptoms set it out for
aspiration [412], but recurrence rate is as high as 80%, which is dependent on the
size and number of cysts. Post-aspiration ethanol and radio-frequency ablation
treatments of thyroid cysts are other options [50, 380, 483].
Partially Cystic Thyroid Nodules
With the application of high-resolution US, thyroid nodules are found in 19–67% of
US examinations [118]. A portion of them (15–53.8%) are mixed echoic nodules
with both cystic and solid components (Fig. 8.5) [413, 492].
Fig. 8.5 An ultrasound

image in a 57-year-old
gentleman showing a
mixed echoic nodule with
both cystic and solid
components. The solid part
has a non-smooth free
margin and multiple
micro-calcifications (white
arrows). It proved to be a
papillary thyroid
carcinoma by both fine
needle aspiration and
postoperative
histopathology
Fig. 8.6 An ultrasound

image in a 32-year-old
lady showing a partially
cystic thyroid nodule with
an eccentric solid position
with an ill-defined margin
and a micro-calcification
(arrow). The internal solid
component accounted for
approximately 66% of the
total volume of the nodule.
Papillary thyroid
carcinoma was diagnosed
by fine needle aspiration
and confirmed by
histopathology
A nodule is considered “partially cystic” if the cystic component is <50% of the

nodule, and such nodules comprise 18–35% of surgical specimens [493, 494]
(Fig. 8.6). Partially cystic thyroid nodules are the result of cystic degeneration due
to hemorrhage, ischemia, necrosis, and liquefaction. Thyroid nodules with cystic
degeneration, such as nodular goiters and thyroid adenoma, are mostly benign
lesions. Previous studies have shown that the proportion of cystic components in
nodules is inversely proportional to their malignant potential [492, 495, 496].
However, 13–26% of thyroid carcinomas may have cystic degeneration [497], often
related to size [498, 499]. For partially cystic thyroid nodules, the percentage of
malignancy varies from approximately 2% to 18% [118, 413, 500].
Currently, the ultrasound-guided fine needle aspiration (US-FNA) of thyroid
nodules is considered the most reliable method for preoperative differential diagno-
sis. This method, however, may be limited by several factors, such as its invasive-
ness, insufficient sampling and/or indeterminate cytology, and operator dependence
[501–503]. Moreover, its diagnostic accuracy may be further reduced by the pres-
ence of cystic components in partially cystic thyroid nodules [504]. There are few
studies on the US features related to malignant partially cystic thyroid nodules, and
these features may differ from those of solid nodules [485, 505–507].
Lee et al. (2009) reported that among 1056 thyroid nodules undergoing US with
FNAC in their study, 392 nodules (37.1%) were mixed echoic. Features of the solid
portion of the nodule were analyzed, namely, its position (eccentric or not), shape,
margin, and echogenicity, and whether there were micro/macro-calcifications. In
the FNA sample, 52 nodules were inadequate for cytological diagnosis, but the
remaining 340 (86.7%) were adequate, and 216 nodules were partially cystic, of
which 16 (7.4%) were malignant. Among sonographic findings, eccentric place-
ment (p = 0.007) and presence of micro-calcifications (p < 0.001) significantly cor-
related with malignancy [508].
In 2010, Kim et al. reported that the rate of malignancy in partially cystic thy-
roid nodules was 5.2% and that an eccentric solid portion with an acute angle,
micro-calcifications, and macro-lobulations or irregular free margin can signifi-

cantly increase the risk of malignancy [485]. More recently (2017), out of 281
partially cystic thyroid nodules, Li et al. reviewed the US characteristics of 13
surgically confirmed partially cystic thyroid carcinomas (12 PTCs and 1 anaplas-
tic) and compared them with those of 80 benign partially cystic nodules [nodular
hyperplasia (n = 69), colloid with benign follicular cells (n = 7), and benign fol-
licular lesion (n = 4)]. The rate of malignancy in their series was 4.6% (13/281).
A taller-than-wide shape (100%, p < 0.001) and speculated or micro-lobulated
margin (58.3%, p = 0.003) was significantly associated with malignancy. In terms
of internal solid portion of the nodule, eccentric configuration (68.0%, p < 0.001),
non-smooth margin (81.3%, p < 0.001), hypo-echogenicity (30.0%, p < 0.042),
and micro-calcification (89.5%, p < 0.001) were more frequently demonstrated in
malignant nodules than in benign ones [504]. The authors concluded that fewer
than 5% of the partially cystic thyroid nodules in this FNA series were malignant
and that sonographic characteristics can be used to prioritize nodules for FNA
biopsy [504].
More recently, in 2021, Liu et al. reported the results of their study on a total of
91 patients with 94 partially cystic thyroid nodules who had undergone US-FNAB
and thyroid surgery. The sonographic features of hypo-echogenicity, micro-
calcification, composition, and an eccentric solid component with an acute angle
had statistically significant associations with malignant nodule (p < 0.05) by uni-
variate analysis. Binary logistic regression analysis showed that micro-calcification
and hypo-echogenicity were significantly associated with malignancy [509].
Moreover, in 2021, Xin et al. reported the results of their cohort study in
which they assessed the US features of partially cystic thyroid nodules (n = 262)
and established a scoring system, using logistic regression analysis, to further
improve the diagnostic accuracy [510]. The scoring was based on eight US fea-
tures, namely (1) composition (solid portion <50% vs. solid portion ≥50%); (2)
position of the solid portion (concentric vs. eccentric blunt angle vs. eccentric
acute angle); (3) shape (ovoid to round vs. taller than wide); (4) margins (smooth
vs. speculated/micro-lobulated vs. ill-defined); (5) echogenicity of the solid por-
tion (marked hypoechoic vs. hypoechoic vs. isoechoic/hyperechoic); (6) free
margin, i.e., the interface between the cystic and solid components (smooth vs.
non-smooth); (7) calcification (micro-calcifications vs. rim calcifications vs.
macro-calcifications vs. no calcification or comet tail); and (8) vascularity (intra-
nodular vs. peripheral vs. avascular). The interpretation of FNA was based on
The Bethesda System for Reporting Thyroid Cytopathology [174]. The final
diagnosis of all malignant partially cystic thyroid nodules was verified by histo-
pathology after surgery.
The scoring system is presented in Table 8.16, and the score ranged from 0 to 11
points. The optimal cutoff value for the diagnosis of malignant PCTNs was four
points, with a good specificity of 87.63% and a sensitivity of 71.05% [510].
References 263
Table 8.16 Scoring Ultrasound features Feature description Score

system for partially cystic Composition – Solid portion <50% 0
thyroid nodules
– Solid portion >50% 1
Position – Concentric 0
– Eccentric blunt angle 0
– Eccentric acute angle 2
Shape – A/T <1 0
– A/T ≥1 1
Margin – Smooth 0
– Ill-defined 0
– Speculated/macro-lobulated 1
Echogenicity – Hyperechoic/isoechoic 0
– Hypoechoic 1
– Marked hypoechoic 1
Free margin – Smooth 0
– Non-smooth 1
Calcification – No calcification 0
– Macro-calcification 0
– Rim calcification 0
– Micro-calcification 3
Color Doppler – Avascular 0
– Peripheral blood flow 0
– Internal flow 1
A/T axial/transverse
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Swellings of the Suprasternal Space
of Burns 9
Contents
9.1 Introduction 289
9.2 Lymphadenopathy 290
9.3 Lipoma 293
9.4 Teratoma 297
9.5 Dermoid/Epidermoid Cyst 305
9.6 Thymic Lesions 307
9.7 Aneurysm of the Innominate Artery (IA) 334
9.8 Aortic Arch Aneurysm (AAA) 335
9.9 Cervical (High) Aortic Arch 342
References 346
9.1 Introduction
The superficial layer of the deep cervical fascia divides into anterior and posterior
leaves to attach to the respective borders of the suprasternal (jugular) notch, forming
a small space, approximately 2 cm superior to the manubrium, known as the “supra-
sternal space” (SSS). It is also known as the “Burns space” or “space of Burns.”
Thus, the SSS lies in the inferior part of the front of the neck, inferior to the hyoid
bone. It is anterior to the sternohyoid muscle, posterior to the sternocleidomastoid
(SCM) muscle, medial to the lateral border of the sternohyoid muscle, and superior
to the clavicle and sternum.
Swellings of the suprasternal space of Burn include mainly the following:
–– Enlarged LNs (lymphadenopathy)

–– Lipoma

Switzerland AG 2024
290 9 Swellings of the Suprasternal Space of Burns
–– Teratoma
–– Thymoma
–– Aneurysm of the aorta or innominate artery
–– High aortic arch
9.2 Lymphadenopathy
Anatomically, the suprasternal space (SSS) of Burns contains a small amount of

areolar tissue, the lower parts of the anterior jugular veins (AJVs), and the jugular
venous arch, as well as the sternal heads of the sternocleidomastoid (SCM) muscles,
interclavicular ligament, and sometimes a lymph node (LN) (Fig. 9.1)—considered
as part of level VI of cervical LNs [1].
Little attention has been paid to date to the SSS as an area with the potential for
LN metastasis from either head and neck cancer in general or thyroid cancer, in
particular. Suprasternal space metastasis has been reported to occur occasionally in
patients with LN metastases in levels III and IV.
Sun et al. (2013) first reported LN metastasis between SCM and sternohyoid
muscles in clinically node-positive PTC. They defined the LN between the SCM
and sternohyoid muscle (LNSS) as follows: the anterior boundary is the SCM mus-
cle, posterior boundary the sternohyoid muscle, superior boundary the intersection
of SCM and sternohyoid muscles, and inferior boundary the suprasternal fossa and
clavicle. Its external and internal boundaries were defined as the lateral and internal
borders of the sternohyoid muscle, respectively. They mentioned that the space
forms part of the SSS [2]. The LNSS is very close to level VI but divided from it by
a strap musculature involving the sternohyoid and sternothyroid muscles and is not
included in level VI. The surgical boundary of the medial border of levels III and IV
is the lateral border of the sternohyoid muscle [3]. Therefore, the space anterior to
the sternohyoid muscle above the clavicle and the sternum, which could not fall
Fig. 9.1 A diagram Anterior jugular vein

showing a lymph node in
the suprasternal space of
Burns
Sternal head of Anterior

sternomastoid jugular arch
1st costal
cartilage
Manubrium
sterni
Lymph node
9.2 Lymphadenopathy 291
under the normal subdivisions of the central compartment and lateral neck areas, is
also included in the concept of the LNSS.
Homma et al. (2015), reported two cases of papillary thyroid carcinoma (PTC)
patients with level III and IV LN metastases as well as metastasis in the SSS [4]. In
2019, Yu et al. (2019) reported that metastatic LN in the SSS in pathological node-
positive (pN+) PTC patients was 20.7% and was correlated with primary cancer site
in the inferior thyroid pole, strap muscle invasion, level IV metastasis, and LNSS
metastasis [5].
Direct lymphatics from the thyroid gland and other head and neck cancer to the
SSS have not been reported in the literature. However, it is supposed that LNSS
(hereafter SSS) metastasis is seen once in a while, especially in advanced cases. Sun
et al. reported that, without exception, patients with SSS metastasis also had lateral
cervical LN metastasis, particularly level III and IV metastases [2]. Level VI metas-
tasis, on the other hand, was not correlated with SSS metastasis. Sun et al. specu-
lated that SSS metastasis could be a result of the increasing tumor load after lateral
cervical metastasis, or the communication between the superficial or deep anterior
cervical chain and the deep lateral cervical chain [2]. It is also speculated that fibro-
fatty tissue including level III and IV metastatic LNs moves into the SSS little by
little due to the daily motion of the neck.
There is some debate as to whether prophylactic dissection of the SSS should be
undertaken or not. Sun et al. reported that the positive rate for the SSS was 22.6%
among 115 patients with clinically node-positive thyroid PTC who underwent neck
dissection that included the SSS [2]. If dissection is performed, pathological metas-
tasis is suspected to be found in a considerable number of cases. While the fre-
quency of central LN metastasis in thyroid carcinoma is high (60–80%), recurrence
rates remain low at 0–15%, even in patients undergoing total or partial thyroidec-
tomy [7–9]. Therefore, dissection of the SSS is not necessary as part of routine
treatment, but it should be undertaken when preoperative examination suggests SSS
metastasis. Dissection of the SSS is less invasive and easy to achieve and is not time
consuming, unlike central compartment dissection, which increases the risk of RLN
palsy and hypocalcemia. Therefore, in cases where SSS metastasis is suspected,
dissection of the SSS should be performed without hesitation. Excising the nodal
tissue in the SSS in patients with level III and/or IV nodal metastases should also be
considered [2].
Patients with PTC have a favorable prognosis with central neck locoregional
recurrence varying from 0% to 20% [11]. The goal of a prophylactic or therapeutic
central neck dissection (pCND or tCND) is to decrease the incidence of local recur-
rence by removing all lymphatic tissue within the level VI and VII compartments,
which are generally the first and the most commonly involved with metastasis [12].
For patients without evidence of LN metastasis on preoperative evaluation, the addi-
tive value of a pCND at the time of thyroidectomy is controversial. Some authors
advocate pCND, considering high rate (24–88%) of occult metastatic nodal disease
in cN0 PTC [11], while other authors consider that there is no high-level evidence
in favor of pCND [13]. The performance of pCND is dependent on the weight given
to the risks and benefits of pCND [14]. Considering the oncological benefits of
CND and the risks of a repeat neck operation, performing pCND is recommended
to every patient in China [15, 16].
Although the American Thyroid Association (ATA) guideline has defined the
boundary of central neck compartment, there is also significant variability in terms
of the extent of CND. In routine clinical practice, CND can range from sampling a
few nodes in the paratracheal region to a complete clearance from left carotid artery
to right carotid artery and down to and including the upper mediastinum [17].
Owing to the variant extent of CND, some central compartments are easily neglected.
For thyroid carcinoma patients with specific clinicopathological characteristics,
incomplete LN dissection may result in increased recurrence, reoperation, and
reoperation-associated complications [18].
Lymph Node between investing layer of Cervical fascia and deep fascia of infra-
hyoid strap Muscles (LNCM) has not been reported. The LNCM compartment is
bounded superiorly by the hyoid bone, laterally by the carotid arteries, anteriorly by
the investing layer of cervical fascia, and posteriorly by the deep fascia of infrahy-
oid strap muscles. Anatomically, LNCM is located anterior to the strap muscles and
includes the SSS and intra-infrahyoid strap muscle space [19]. What is special about
the concept of the LNCM is that although it belongs to level VI, it is an easily over-
looked anatomical area by a strap musculature involving the sternohyoid and ster-
nothyroid muscles during selective or modified neck dissection. Although the
metastasis in LNCM is rare, it did occur in some PTC patients with regional recur-
rence. As part of LNCM, SSS metastasis for thyroid cancer was investigated in three
studies [2, 4, 5].
Yuan et al. (2020) conducted a retrospective study to evaluate the clinicopatho-
logical characteristics of Lymph Node metastasis between investing layer of
Cervical fascia and deep fascia of infrahyoid strap Muscles (LNCM) in PTC. A
total of 2104 consecutive patients with PTC who underwent thyroidectomy and
central node dissection (CND) were included in the review. Results showed that
21.4% of cases (451/2104) were confirmed to be positive in the LNCM. In total, the
metastasis rate of LNCM in PTC patients was 3.2% (68/2104). Multivariate analy-
sis revealed that a primary site in the inferior pole, ETE, and level III and IV metas-
tases were of higher LNCM metastasis rate, which was consistent with the findings
by the previous report of LN metastasis between SCM and sternohyoid muscle
(LNSS) [2]. The authors concluded that including LNCM as an anatomical part of
the central neck allows removal of previously unrecognized micrometastatic disease
in 3.2% of PTC patients with the inferior portion lesions, ETE, and level III and IV
metastases [19]. Dissection of the LNCM space is less invasive and easy to achieve
and is not time consuming. It is at the entrance of central neck compartment, which
is easy to expose and has low risk of damaging RLN or parathyroid glands [19, 20].
Therefore, in cases where LNCM space metastasis is suspected or preoperative US
and CT scan suggests LNCM metastasis, greater attention should be paid to the
nodal tissue in the LNCM space in thyroid carcinoma patients. These patients might
benefit from a reduced risk of regional recurrence, central neck reoperative morbid-
ity, and improved decision-making in relation to the use of RAI ablation [19, 20].
9.3 Lipoma 293
9.3 Lipoma
Etiology
Lipoma, also known as “universal” or “ubiquitous” tumor, due to its wide distribu-
tion in the human body, is derived from mature fat. Despite the increasing under-
standing of fatty tissue and fat metabolism, the exact etiology of lipoma is still
unknown. Some authors believe that trauma could be a causative factor [21]. Certain
factors such as heredity, hormones (endocrine disorders), congenital factors, pro-
gressive infection, radiation, insulin injection, and corticosteroid therapy have been
implicated in the genesis of lipoma, regardless of the site [22]. Other factors reported
also include diabetes mellitus (DM), hypercholesterolemia, obesity, and rheumatoid
arthritis [23]. Some authors believe that lipomas develop secondary to hamartoma-
tous proliferation of mature fat cells [24]. Finally, lipoma could be “idiopathic” [25].
Classification
There are multiple varieties of lipomas: encapsulated, diffuse, and a condition

termed “lipomatosis” (multiple lipomas associated with neurofibromatosis,
Gardner’s syndrome, Dercum’s disease, or visceral lipomas in respiratory tract)
[26]. Based on the location, lipomas are classified as subcutaneous (SC) type, sub-
fascial type, or intramuscular type [27]. A few lipomas may contain other tissues in
excess along with fat cells such as fibrous tissue (fibro-lipoma), vascular tissue
(angio-lipoma), nerve tissue (neuro-lipoma), and salivary gland tissue (sialo-
lipoma) [28, 29]. Based on the histology, lipomas are generally classified into sim-
ple lipoma, fibro-lipoma, myxo-lipoma, chondroid lipoma, angio-lipoma,
angiomyolipoma, myelolipoma, spindle cell lipoma, sialo-lipoma, pleomorphic
lipoma, and atypical lipoma [30].
Although they may be congenital, lipomas are seen in patients between fourth and
fifth decades of life in more than 50% of cases [23, 31], with no sex predilection
[32–34]. In the head and neck region, men are more often affected than women [35].
In a series of 25 cases of head and neck lipomas reported by Ahuja et al. (1998) [36],
68% were men. Similarly, in the series of Som et al. (1986) [37], 52% of the cases
reported were men.
Lipomas are the most common, slow-growing, benign, mesenchymal neoplasms
that can be found in any location where fat is normally present, predominantly
affecting subcutaneous tissues of the trunk, neck, and limbs. The hands, legs, and
feet are rarely involved [28]. In the head and neck region, where only 13% of lipo-
mas are seen, the posterior neck space is the most common site, but the anterior
neck space is a rare location (Fig. 9.2) [38, 39].
Fig. 9.2 Front view of a

35-year-old lady with a
large lipoma in the midline
of the neck occupying the
suprasternal space
Lipoma usually presents as a solitary lesion, and multiple site involvement may
be seen, particularly in alcoholics, diabetics, and syndromes such as Madelung’s
disease and Kobberling-Dunnigan syndrome [40].
Lipomas are mobile, non-tender, and soft to cheesy in consistency [21, 41].
Clinical features depend on the size, location, and rate of growth of the lesion. The
majority of lipomas are less than 3 cm in size, but occasionally they can become
much larger. Lipomas either become static after achieving a size of 1–5 cm or con-
tinue to grow reaching greater than 10 cm. They may even reach 50–60 cm in some
cases or weigh at least 1000 g (giant lipoma) [42]. Infiltrating lipoma is a rare vari-
ant invading muscles, vessels, nerves, or deep soft tissues [43]. When presenting as
a giant lipoma, or rapidly progressing infiltrating lipoma, especially in head and
neck region, it should be worked up for malignancy [25].
Naik et al. (2011), reported ten cases of lipomas, four oral and six extraoral (cer-
vical), of which one was in the SSS [44]. Literature reports lipomas as common
neoplasms occurring with a frequency of 15–20%, involving the head and neck
region [23, 41, 45, 46].
In 2020, Jain et al. [25] reported a 50-year-old gentleman who presented with a
swelling in the anterior neck of 2-year duration. It was a slow-growing, painless
mass that was not associated with any pain or overlying skin changes. On examina-
tion, a 11 × 5 cm, oval-shaped, well-circumscribed, soft, non-compressible, non-
tender, mass was seen over the anterior neck, extending to the suprasternal notch,
and not mobile with deglutition. The skin over the swelling was normal. There was
no accompanying lymphadenopathy. On US, a homogenous hypoechoic, fusiform
mass of size 60 × 42 mm, with no abnormal vascularity, was demonstrated. On
FNAC, findings were suggestive of “lipoma.” On contrast-enhanced magnetic reso-
nance imaging (CE-MRI) of neck, T1W and T2W axial and sagittal images showed
a well-defined lobulated hyper-intense mass lesion measuring 9.5 × 4.9 cm in the
anterior neck. No evidence of restricted diffusion was seen, and post-contrast scan
9.3 Lipoma 295
showed no enhancement. Complete excision with the capsule was done via a trans-
cervical incision along the skin crease. Histopathology report confirmed the diagno-
sis of a “lipoma” [25].
Diagnosis
Imaging
Ultrasonography (US) remains as the initial imaging modality in the diagnosis of
head and neck lipomas, while FNAC, CT scan, or MRI is indicated for confirmation
of diagnosis. Modality of choice for imaging lipomas is MRI, not only to confirm
the diagnosis, which is usually strongly suggested by US and CT scan, but also to
better assess for atypical features suggesting liposarcoma. Additionally, MRI is bet-
ter able to demonstrate the surrounding anatomy.
Ultrasound (US)
On ultrasonography (US), lipomas appear as soft, variably echogenic masses; how-
ever, if encapsulated, the capsule may be difficult to identify [47]. Inampudi et al.
reported that there is a wide range of appearance of biopsy-proven lipomas on US,
with wide inter-reader variability [48]: hyperechoic (20–52%), isoechoic (28–60%)
(Fig. 9.3), and hypoechoic (20%). Lipomas tend also to display other US character-
istic features, such as absence of acoustic shadowing and no or minimal color
Doppler flow [49]. Heterogeneous echotexture, more than minimal color Doppler
flow, or large size is suspicious for liposarcoma [49].

C
On CT scan, classic appearances of a lipoma are of a superficial circumscribed, low-
attenuation mass (typically approximately −65 to −120 HU) [47] with minimal
internal soft tissue component (Fig. 9.4). Similar to plain radiography, areas of
Fig. 9.3 Neck ultrasound

showing a “lipoma,” which
is isoechoic to adjacent
muscle. It also shows
linear internal striations.
No calcification or cystic
changes are noted. It is
compressible. No internal
flow is noted in the lesion
Fig. 9.4 Computed

the neck showing a very
large “lipoma” as a
superficial, well-
circumscribed, low-
attenuation mass in the
midline of the neck (long
arrow), anterior to the
trachea (short arrow)
calcification may be present although are more frequently associated with well-
differentiated liposarcoma [47]. Deeper or larger lipomas may have scattered areas
of internal soft tissue density. These may represent areas of fat necrosis, fibrous
tissue, blood vessels, or muscle fibers; these lesions cannot be confidently differen-
tiated from liposarcoma by imaging.

M
Lipomas follow SC fat signal on all sequences of MRI: T1 (high signal, saturates on
fat-saturated sequences, no or minimal enhancement) and T2 (high signal on FSE
T2, saturates on fat-saturated sequences: persistent areas of high T2 signal are
worrisome).
When no suspicious features are present, the diagnosis of lipoma can be made
with confidence with MRI being 100% specific [50]. Similarly, if suspicious fea-
tures are present, then the sensitivity of MRI is 100% [50], although specificity is
lower, as some masses with atypical features will nonetheless be lipomas.
Biopsy/Histopathology
Classic benign lipomas often show chromosomal rearrangements of 12q14–15, 6p,
and 13q.9.5. Histopathologically, a typical lipoma is similar to normal adipose tis-
sue, and differentiation may be impossible without gross evidence of encapsulation
or circumscription. A lipoma is a circumscribed soft mass composed of lobules of
fatty areolar tissue enclosed within a thin true capsule, surrounded by a fibrous
pseudo-capsule (from surrounding tissues) and separated from the true capsule by a
plane of cleavage along which the tumor can be enucleated. Histology demonstrates
mature adipocytes with no cellular atypia or pleomorphism (Fig. 9.5). Any non-
adipose components must be carefully assessed to exclude a more aggressive com-
ponent [31].
For proper diagnosis, the biggest challenge is differentiating a lipoma from a
well-differentiated liposarcoma. The absence of vacuoles in the irregularly shaped
9.4 Teratoma 297

of a lipoma shows that the
mass is composed of
lobules of mature white
adipose tissue divided by
delicate and inconspicuous
fibrous septa containing
thin-walled capillary-sized
vessels (H&E, ×100)
nuclei and increased size of the cells may be helpful for the diagnosis of a well-
differentiated liposarcoma [51]. Malignant degeneration of lipoma and transforma-
tion to liposarcoma are extremely rare [52].
Management
Treatment of lipoma is complete surgical excision of the tumor with its capsule.
Recurrence is rare except for the intramuscular variety, which is infiltrative and has
a high recurrence rate [41].
Asymptomatic cases can be kept under observation; however, they need excision
if there is diagnostic uncertainty, lack of homogeneity to palpation, large neck
masses (more than 10 cm), rapid growth, associated pain, deep-seated locations, or
cosmetic concern [53]. While doing excision, the surgeon should be careful to
remove the tumor with capsule to prevent recurrence.
Liposuction is sometimes preferred especially in certain locations particularly
for cosmetic reasons, as there is less scarring following the procedure, but there is
higher chance of recurrence, compared with excision [54].
9.4 Teratoma
Definition
Teratoma is derived from the Greek word “teratos,” which means “monster.”
Virchow coined this term in 1863. Teratoma is a tumor with the potential of poly-
dermal differentiation, which originates from ectoderm, mesoderm, and
endoderm in gonads or embryonic leftovers with polydermal differentiation

potential cells. Most of the tumor tissues are mature, and a few are immature
[55]. The degree of immaturity of the tissue determines the malignant potential
of the lesion [56].
Location/Epidemiology
Teratomatous tumors have been described in a variety of sites and organs. They
occur most frequently in the ovary and testis, less frequently in the mediastinum
and retroperitoneum, and rarely in other non-gonadal sites such as the central
nervous system, liver, nasal sinuses, thyroid, and cervical area [55, 57–59]. In all
teratoma reports, the cervical teratoma is very rarely encountered [59] and often
occurs in the fetal neck [60, 61]. It is much more common in newborns or infants
than adults [62]. In adulthood, the occurrence of neck teratoma is extremely rare,
accounting for only 10.6% [63]. On the other hand, the reported incidence rates
of cervical teratoma in the newborn and children aged 1 month to 18 years are
75.1% and 14.3%, respectively [57]. In contrast to the pediatric cases, adult tera-
tomas are highly malignant [56] with a tendency to metastasize and have a poor
prognosis [64–67].
Cervical teratomas predominate in females (75% of the cases) [68]. Mediastinal
teratomas account for 7–9.3% of mediastinal tumors and 5–7% of all mediastinal
germ cell tumors. Most mediastinal teratomas originate in the anterior mediastinum,
with occasional reports of teratomas occurring in the posterior mediastinum [69].
Teratomas of the anterior mediastinum may extend to the neck due to intra-tumoral
hemorrhage, tissue necrosis, infection, or tumor invasion. In such case, they are
symptomatic and can be easily detected by US [70]. In adults, primary teratoma in
the SSS that does not displace thyroid gland upward and does not invade the medi-
astinum is very rare. It usually has no obvious clinical symptoms and is discovered
in most patients by chance [71].
Pathogenesis
Teratomas are embryonal neoplasms that arise when totipotent germ cells escape
the developmental control of primary organizers and give rise to tumors containing
tissue derived from all three blastodermic layers, i.e., ectoderm, endoderm, and
mesoderm [68]. The germinal cells migrate from the vitelline sac during the first
week of intrauterine life and colonize the sexual cordon forming primitive undif-
ferentiated gonads. During this migration, they arrest and form a germinal tumor
[62]. The pathogenesis of these tumors in extra-gonadal sites is likely related to the
displacement of primitive germ cells during embryogenesis [69]. The first proved
case of cervical teratoma was published by Hess in 1854 and was restudied micro-
scopically by Wetzel in 1895 [72].
9.4 Teratoma 299
Classification
Some researchers have made, in the past, an attempt to classify cervical teratomas
on the basis of their relationship to the thyroid gland. Accordingly, cervical terato-
mas are divided into “thyroid teratomas” and “extra-thyroid teratomas” depending
on where they originated [58]. For the diagnosis of primary thyroid teratoma, one of
the three conditions must be met: (1) the tumor must occupy a portion of the thyroid
gland, (2) a direct connection must exist between the tumor and the thyroid, and (3)
a teratoma is accompanied by the absence of the thyroid. It is still debated and stirs
controversy among researchers whether teratomas of the thyroid gland and teratoma
of a neck origin are distinctively different entities [57, 73, 74]. However, most cervi-
cal teratomas have some type of relationship with the thyroid, and the clinical pic-
ture and prognosis between both tumors are the same [64, 65]. Therefore, many
researchers have abandoned separating these tumors and classify all neck teratomas
as “cervical teratomas” [75].
Pathology
Teratomas have diverse histopathological differentiations due to a wide range of

cellular differentiation and variable degrees of maturation [64, 76]. However, histo-
logical immaturity should not be equated to malignancy [76]. In general, they can
be categorized into three types: mature teratomas, immature teratomas, and terato-
mas with malignant transformation [77].
Mature teratoma is benign and is called “mature cystic teratoma,” also known as
“dermoid cyst” if composed of tissues of ectodermal origin only (Fig. 9.6) [78]. It is
composed of fully differentiated tissue elements of all three germ layers although
the presence of only two germinal components does not exclude this diagnosis
(Fig. 9.7) [79]. Immature teratomas and mature teratomas contain the same ele-
ments as the primitive tissues found in fetus but differ in the degree of differentia-
tion of the tissue elements, especially neurocutaneous tissue [10, 62]. Immature
teratoma is often solid and malignant and is more common in teenagers [61].
Teratoma with malignant transformation occurs in approximately 30% of cases and
is usually an adenocarcinoma occurring in a mature teratoma or angiosarcoma or
rhabdomyosarcoma occurring in an immature teratoma [80].
Cervical teratoma can reach enormous size and cause airway obstruction. The
symptoms are mostly attributed to the mass effect of these lesions. The specific
symptoms associated with cervical teratomas vary depending upon the size of the
tumor. Small tumors may not cause any symptoms. However, a large teratoma may
cause disfigurement and compress nearby structures such as the trachea and

of mature cystic teratoma.
The section shows a cyst,
lined with skin epithelium,
and its appendages,
including hair follicles and
sebaceous glands along
with mature adipose tissue
(H&E stain)

of mature cystic teratoma.
The section shows that the
tumor is composed of
mature elements of
mesenchymal and
ectodermal origin: hair
follicle, sebaceous gland,
mature cartilage, mature
intestinal epithelium,
mature lymphoid tissue,
and respiratory-type
epithelium (H&E stain)
esophagus [75]. Teratomas extending from the anterior mediastinum to the neck can
cause pain or dyspnea due to internal bleeding or infection, while microcystic tera-
tomas within the SSS are usually asymptomatic [68]. Thus, there are some difficul-
ties in detection, diagnosis, and treatment of the disease at an early stage.
In 2017, Ansari et al. [56] reported a 24-year-old young gentleman who pre-
sented with an asymptomatic suprasternal swelling, progressively increasing in
size, since 3 months. The mass was 5 × 4 cm in size, soft in consistency, non-tender,
and non-fluctuant in nature. There were no palpable cervical LNs, and systemic
examination was unremarkable. Ultrasound of neck revealed a walled, anechoic,
midline cystic lesion in the SSS, 45 × 36.9 mm2 in size, lying in the SSS below the
thyroid gland, which was normal in size and shape. A diagnosis suggestive of bra-
chial cyst was given on FNAC. The mass was completely excised via an anterior
9.4 Teratoma 301
cervical incision. Final diagnosis of mature cystic teratoma was reached by histo-
pathological examination, which revealed stratified squamous epithelium and pilo-
sebaceous structures, lymphoid tissue with prominent lymphoid follicles,
fibro-collagenous tissue, mature adipose tissue and mature cartilage, ciliated pseu-
dostratified columnar respiratory epithelium, and intestinal columnar epithelium
with goblet cells.
In 2020, Liu et al. reported a rare case of mature cystic teratoma in the SSS of a
33-year-old gentleman, about 40 mm × 20 mm in size and not mobile with degluti-
tion. Preoperative US showed an SSS tumor with less calcification and more adi-
pose tissue. Immunopathology showed that the tumor was CK (epithelial +), CD68
(partial cell +), and Ki-67 (scattered +). The final pathological diagnosis was reached
after surgical excision through open surgery with a suprasternal neck incision. The
patient was followed up for 9 months, and there was no recurrence [81].
Investigations
Ultrasound (US) neck is the first-line modality for evaluating cervical neck abnor-
malities, especially for the assessment of concomitant thyroid pathology.
Ultrasonography (Fig. 9.8) and CT scan (Fig. 9.9) show clear round or quasi-round
thick-walled hyperechoic masses and uneven internal density, especially for thick-
walled cysts with oil, hair, bone tissue, teeth, and calcification, which were often
characteristic manifestations of teratoma [82]. The CT density of mature cystic tera-
tomas is often close to water, because of less calcified tissue and more adipose tissue
in the tumor [70]. Fat-fluid levels could be used as one of the diagnostic criteria of
teratoma [59, 61, 63, 83] but are less frequently seen [84]. Moreover, CT scan can
Fig. 9.8 Ultrasound neck

showing teratoma as a
mixed echocyst in the
suprasternal space. The
shape is regular, the
boundary is clear, and the
cystic part has good sound
penetration. A papillary
slightly higher echo and a
line-like strong echo can
be seen in the cyst wall
(red arrow)
Fig. 9.9 Computed

the neck showing teratoma
as a round low-density
focus mass in the
suprasternal space. The
trachea is central in
position, and there is no
obvious compression or
displacement (red arrow)
determine the encroachment of adjacent structures and aid in surgical planning [85].
Magnetic resonance imaging (MRI) usually shows high T1- and T2-weighted sig-
nals in teratomas [86]; however, different types of teratomas have different tissue
types and internal components, so they are heterogeneous on T1- and T2-weighted
images [87].
Even though cervical teratoma in adults is extremely rare, it should be considered as

an important differential diagnosis in patients with a midline cystic neck swelling.
Preoperative imaging requires high index of suspicion. Teratoma with more cystic
components often needs to be differentiated from thyroid cysts, cystic hygroma,
branchial cleft cyst, thyroglossal duct cyst, cervical echinococcosis, and cystic
squamous cell carcinoma of cervical LN arising in the oro/nasopharynx [68].
Teratoma with more solid components should be differentiated from cervical
lipoma, lymphoma, and follicular adenoma of the thyroid gland [88].
Treatment
The principal treatment of cervical mature cystic teratoma is complete surgical exci-
sion of the mass along with the surrounding adherent tissue through a suprasternal
cervical incision (Fig. 9.10) [81]. If there is a fistula, the fistula should be eliminated
to prevent recurrence and malignant transformation. Early and thorough resection
results in a good prognosis [61, 63].
The scope of surgical resection must be based on rapid pathological examination
during the operation. If it is benign, the tumor and its appendages can be removed.
9.4 Teratoma 303
Fig. 9.10 Complete

surgical excision of a
mature cystic teratoma of
the suprasternal space.
Note the yellowish
discoloration denoting
abundant adipose tissue
If it is malignant or the lesion grows rapidly within a short period of time, and
malignant changes are suspected, the scope of surgical resection should be expanded.
Adjuvant radiotherapy or chemotherapy is generally considered ineffective [68].
Some scholars believe that plasma AFP can be used as a follow-up index after oper-
ation. The half-life of AFP in recurrent tumor is longer than that in nonrecurrent
teratoma, and the half-life of AFP in immature teratoma is longer than that in mature
teratoma [89, 90].
Prognosis
Infants with a benign cervical teratoma rarely experience recurrence of the tumor.
Malignant cervical teratomas such as those found in adults recur more often. They
have a tendency to metastasize and have a poor prognosis [64–67]. Affected indi-
viduals must be monitored periodically to check for recurrence [56].
nterior Mediastinal Teratoma Presenting

A
in the Suprasternal Space
Approximately 20% of primary mediastinal neoplasms are of germ cell origin,

and of these, roughly 80% are teratomatous in origin. Mediastinal teratomas are
five times more common in adults than in children. The reason behind how
exactly these lesions originate remains an area of conjecture and discussion [91].
Teratomas of anterior mediastinum are rare tumors accounting for 8–13% of

tumors in this region [92], while only 3–8% arise from the posterior mediastinum
[93, 94]. They are often slow growing, asymptomatic, and detected incidentally
on chest imaging. Complications such as atelectasis, adhesion to or compression
of adjacent structures, or malignant transformation are occasionally encoun-
tered [70].
A superior mediastinal teratoma may rarely present as a cystic neck swelling
due to its cephalad extension. This entity needs to be considered in cases where
clinical and investigative workup fails to provide a convincing clue to a primary
neck pathology as cause of a cystic neck swelling [70]. Agarwal and Kar (2008)
reported the case of a young 19-year-old male who presented with a cystic neck
mass, due to degeneration of a cervical extension of a mature teratoma of the
anterior mediastinum. This is an unusual presentation of an uncommon pathol-
ogy. The patient presented with an asymptomatic cystic, non-tender, non-translu-
cent, and smooth neck mass. The lower limit of the swelling could not be reached.
There was no cervical lymphadenopathy. Plain X-ray and CT scan of chest and
neck showed an extra-thyroidal multi-septate, predominantly cystic neck mass,
which was continuous with a solid intrathoracic mass extending up to the level of
right atrium and which contained areas of calcification and cystic necrosis. There
were no mediastinal lymph nodes and pulmonary lesions. The tumor
(16 × 7 × 2 cm) was completely excised via a combined cervical and trans-sternal
route, with preservation of nearby vital structures. Histopathology of the resected
specimen confirmed the diagnosis of a mature cystic teratoma; on microscopy,
the cyst wall showed predominantly degenerate necrotic area, associated with
inflammatory cells. Sections from the solid areas revealed cartilage, osseous tis-
sue and nerve bundles with ganglionic cells, respiratory epithelium, and sero-
mucinous glands embedded in dense fibro-collagenous and fibro-muscular tissue.
Recovery was uneventful, and a 5-year follow-up showed no clinical or radio-
logical evidence of recurrence [70].
Chest X-ray is an important aid in the diagnosis of a mediastinal teratoma; how-
ever, mediastinal CT scan can demonstrate the extent of a mass better than conven-
tional radiography (Fig. 9.11). It is also helpful in defining the invasion of adjacent
structures and thus assists planning surgical intervention [85]. Moreover, CT scan
can also detect fatty or cystic areas in mediastinal masses, but this will not obviate
the need for surgical resection to establish the final diagnosis [94].
Complete curative surgical excision of a mediastinal teratoma is the treatment of
choice, as it establishes the diagnosis and prevents life-threatening complications in
many patients [95]. Malignant mediastinal teratomas account for approximately
1–5% of all mediastinal tumors [96, 97]. Invasion of great vessels, myocardium,
lung, and phrenic nerves should be taken as indicators of malignancy and may
necessitate extensive surgery in selected patients [96]. Adherent mediastinal pleura
and pericardium can be dealt with by excision of the involved portions. As most
mediastinal teratomas are benign, even a subtotal resection conserving adherent
vital structures provides excellent outcome [97].
9.5 Dermoid/Epidermoid Cyst 305
Fig. 9.11 Contrast-

enhanced CT scan of the
neck showing a multi-
septate cystic neck mass,
lying superficial to the
thyroid lobes and strap
muscles
9.5 Dermoid/Epidermoid Cyst
Definition
Dermoid and epidermoid cysts of the head and neck region are rare and constitute
only 1.6–6.9% of all cases in the body [98]. Approximately 7% of the swellings in
head and neck regions are epidermoid or dermoid cysts [99, 100]. “Epidermoid
cysts” are known as benign, squamous epithelium-lined cystic spaces, while “true
dermoid cysts” contain skin adnexa (dermal elements) such as hair follicles, seba-
ceous glands, and sweat glands. Although they have very similar imaging appear-
ances, dermoid cysts and teratomas have a fundamental histological difference: a
dermoid is composed only of epidermal and dermal elements, which are both ecto-
dermal in origin, whereas “teratomas” also comprise mesodermal and/or endoder-
mal elements such as cartilage, bone, muscle, and respiratory or gastrointestinal
epithelium [101, 102].
Etiology
Epidermoid and dermoid cysts can be congenital or acquired with similar clinical
presentation and histological appearance [103]. Congenital cysts are dysembryonic
lesions that arise from ectoderm elements being entrapped during fusion of the first
and second branchial arches [103]. Acquired cysts are derived from traumatic or
iatrogenic inclusion of epithelial cells or from the occlusion of a sebaceous gland
duct. Dermoid cyst of the head and neck is thought to be a congenital inclusion cyst
[103]. With the exception of very few cases (Bowen’s disease, Paget’s disease, and
squamous cell carcinoma), they are generally benign lesions [104].
Clinical Picture and Diagnosis
Mediastinal dermoid cysts are not uncommon. They are occasionally diagnosed
incidentally in chest X-ray or CT scan. Sometimes, they attain large sizes and pres-
ent as a suprasternal fleshy mass (Fig. 9.12).
Biswas (2006) reported an 18-year-old girl who presented with a fleshy lobulated
mass protruding through the suprasternal area. Prior to presentation, she had left-
sided and retrosternal discomfort, pain, and cough for 6 months. Finally, a sinus
developed at the SSS through which a small mass protruded out. The mass gradu-
ally increased in size and hanged over the sternum to attain an enormous size. Chest
X-ray revealed left chest opacity with collapse and consolidation of the left lung,
while CT scan of thorax revealed multi-loculated collections in the left chest with
collapse–consolidation. The variegated left intrathoracic mass lesion extended into
the mediastinum and was in continuity with the suprasternal neck mass. The intra-
thoracic mass was successfully excised via thoracotomy, while the protruding neck
mass with the stalk was excised as a separate piece from a cervical incision. The
mass was cut open; it was fleshy and variegated with hair and toothlike elements
inside. Histopathology of the mass revealed the picture of “terato-dermoid” [102].
The natural history of epidermoid cysts is slow and progressive growth, and they
remain asymptomatic unless they enlarge in size. The rapid growth of the cyst may
indicate either an infectious process or a malignancy [105]. Squamous cell carci-
noma arising from epidermoid cyst, although rare, has been reported in the literature
[106]. Epidermoid cysts may occur at any age; however, most commonly, they arise
in the third and fourth decades of life [107]. In a retrospective study by Armon et al.
(2010), among 89 children, only 13.33% cases of cysts in the head and neck region
were found to be epidermoid, compared to 58.88% of dermoid cysts [108]. In a
20-year study, it was shown that dermoid and epidermoid cysts consist of only 3.7%
of all congenital non-salivary cysts of the suprahyoid neck in children [109]. Thus,
the SSS is an uncommon site of presentation for epidermoid cyst; the first case was
Fig. 9.12 A computed

tomography (CT) scan
showing a dermoid cyst as
a heterogenous well-
defined rounded mass that
has no connection to the
thyroid gland
documented in Turkey by Ciftci et al. in 2008 [104], and later, in 2013, six more
cases were reported from India by Dutta et al. [101].
In 2017, Pandyan and Shambulingegowda reported a 5-year-old girl who pre-
sented with a cystic, mobile, non-tender swelling in the SSS of 3-year duration,
about 2.5 × 2 cm in size. The lower border of the mass was difficult to palpate, and
there was no movement with swallowing or protrusion of the tongue. Although US
and FNAC were suggestive of a dermoid cyst, histopathological examination con-
firmed it to be an epidermoid cyst. The cyst was excised under general anesthesia
through a 2 cm transverse cervical incision. There was no recurrence over a 6-month
period of follow-up [110].
More recently, in 2020, Al Bin Manie et al. [111] reported a case of an epider-
moid cyst in the SSS, presenting as a large mass (2.5 × 2.5 cm) in a 13-year-old boy,
associated with odynophagia and weight loss. The mass was firm, not tender, with
no overlying skin changes, discoloration, or ulceration. The lower border of the
mass was difficult to palpate, and no movement of the mass could be elicited with
swallowing or protrusion of the tongue. No other neck swelling or lymphadenopa-
thy was noted. CT scan of the neck showed a cystic mass in the suprasternal region,
not attached to deep structure, located in the midline, at the anterior side of the neck
below the thyroid gland. It was very well defined and had fluid contents showing
wall enhancement on contrast scan. The mass was resected en bloc with intact cap-
sule through a 2 cm transverse cervical incision. Histopathological examination
demonstrated a cyst in the dermis lined by stratified squamous epithelium with kera-
tinization and no adnexal structures consistent with the diagnosis of an epidermoid
cyst. There was no recurrence over a 1-year period of follow-up.
The differential diagnoses of such anterior cervical swellings in children include
thyroglossal duct cyst, thyroid mass, cystic hygroma, cervical bronchogenic cyst,
and ectopic thymic mass [112].
Treatment
Surgical excision of epidermoid cyst is the treatment of choice [113]. Usually, it is

performed under general anesthesia, in the operating room. But office-based surgi-
cal excision with local anesthesia was found to be successful in small epidermoid
cysts in different anatomic positions [114]. In addition, the use of carbon dioxide
laser has been reported in the treatment of multiple small epidermoid cysts [115].
9.6 Thymic Lesions
Introduction
The thymus is a specialized primary lymphoid organ of the immune system, located
in the anterior superior mediastinum. Thymus cell lymphocytes (T cells), critical to
the adaptive immune system, mature within the thymus. The thymus is made up of
two lobes, each consisting of a central medulla and an outer cortex, surrounded by
a capsule. Although the thymus has been identified since the time of the Ancient
Greeks, it is only since the 1960s that its function in the immune system has become
clearer. T cells that successfully develop react appropriately with major immune
histocompatibility (MHC) immune receptors of the body (positive selection) and
not against proteins of the body (negative selection). The thymus is largest and most
active during the neonatal and preadolescent periods. By the early teens, the thymus
begins to decrease in size and activity, and the tissue of the thymus is gradually
replaced by fatty tissue. Nevertheless, some T-cell development continues through-
out adult life.
Abnormalities of the thymus can result in a decreased number of T cells and
autoimmune diseases such as autoimmune polyendocrine syndrome type 1 and
myasthenia gravis. These are often associated with cancer of the tissue of the thy-
mus (thymoma) or tissues arising from immature lymphocytes such as T cells
(lymphoma).
History
The “thymus” comes from the Greek word “thumos,” meaning “anger,” or in
Ancient Greek, “heart, soul, desire, life,” possibly because of its location in the
chest, near where emotions are subjectively felt, or else the name comes from the
herb “thyme” (also in Greek), which became the name for a “warty excrescence,”
possibly due to its resemblance to a bunch of thyme. Galen was the first to note that
the size of the thymus changes over a person’s life [116]. In the nineteenth century,
a condition was identified as “status thymicolymphaticus” defined by an increase in
lymphoid tissue and an enlarged thymus. It was thought to be a cause of “sudden
infant death syndrome,” but is now an obsolete term [117].
As reported by Miller (2011), until the discovery of its immunological role, in
1961 by Jacques Miller, the thymus had been dismissed as an “evolutionary acci-
dent,” without functional importance [118]. Jacques Miller discovered the impor-
tance of the thymus in the immune system by thymectomy in 1-day-old mice, and
observing the subsequent deficiency in the lymphocyte population, subsequently
named T cells after the organ of their origin [119, 120]. The role the thymus played
in ensuring tolerance of mature T cells to body tissues was uncovered in 1962, with
the finding that T cells of a transplanted thymus in mice demonstrated tolerance
toward tissues of the donor mouse [118]. B cells and T cells were identified as dif-
ferent types of lymphocytes in 1968, and the fact that T cells required maturation in
the thymus was understood [118]. The subtypes of T cells (CD8 and CD4) were
identified by 1975 [118]. The way that these subclasses of T cells matured—posi-
tive selection of cells that functionally bound to MHC receptors—was known by the
1990s [118]. The important role of the AIRE gene, and the role of negative selection
in preventing autoreactive T cells from maturing, was understood by 1994, and
more recently, advances in immunology have allowed the function of the thymus in
T-cell maturation to be more fully understood [118].
Embryological Development
The thymocytes and the epithelium of the thymus have different developmental
origins [121]. The epithelium develops first, appearing as two outgrowths, one on
either side, of the third pharyngeal pouch, and sometimes also involves the fourth
pharyngeal pouch [121]. These extend outward and backward into the surrounding
mesoderm and neural crest-derived mesenchyme in front of the ventral aorta. Here,
the thymocytes and epithelium meet and join with connective tissue. The pharyn-
geal opening of each diverticulum is soon obliterated, but the neck of the flask per-
sists for some time as a cellular cord. By further proliferation of the cells lining the
flask, buds of cells are formed, which become surrounded and isolated by the invad-
ing mesoderm [121].
The epithelium of the thymus forms fine lobules and develops into a spongelike
structure. During this stage, hematopoietic bone marrow precursors migrate into the
thymus [121]. Normal development is dependent on the interaction between the
epithelium and the hematopoietic thymocytes. Iodine is also necessary for thymus
development and activity [122].
In children, the thymus is pinkish gray in color and soft in consistency and has a
lobulated surface [123]. At birth, it is about 4–6 cm long, 2.5–5 cm wide, and about
1 cm thick [124]. It increases in size until puberty, where it may reach a weight of
40–50 g [121] following which it undergoes involution and decreases in size [121].
The thymus is located in the anterior superior mediastinum [125] lying beneath
the sternum and resting on the pericardium; it can extend laterally to the phrenic
nerves. It is separated from the aortic arch and great vessels by a layer of fascia, and
the left brachiocephalic vein may even be embedded in it [123]. The thymus is cov-
ered by a capsule and is made up of two lobes that meet in the upper midline and
stretch from below the thyroid gland in the neck to as low as the cartilage of the
fourth rib [123]. In the neck, it lies on the front and sides of the trachea, behind the
sternohyoid and sternothyroid muscles [123].
Variations are occasionally seen; the two lobes may differ slightly in size, with
the left lobe being usually higher than the right. Thymic tissue may be found scat-
tered on or around the gland, and occasionally within the thyroid [124]. The thymus
in children stretches variably upwards, at times to as high as the thyroid gland [124].
Microanatomy
The thymus consists of two lobes, merged in the middle, surrounded by a capsule
that extends with blood vessels into the interior [124]. The lobes consist of an outer
cortex rich with cells and an inner less dense medulla [121] (Fig. 9.13). These lobes

picture showing a lobule of
the thymus. The cortex
(deeper purple area)
surrounds a less dense and
lighter medulla (H&E
stain)
are divided into smaller lobules 0.5–2 mm in diameter, between which extrude radi-
ating insertions from the capsule along septa [123].
The cortex is mainly made up of thymocytes and epithelial cells. The thymo-
cytes, immature T cells, are supported by a network of the finely branched epithelial
reticular cells, which is continuous with a similar network in the medulla. This
network forms an adventitia to the blood vessels, which enter the cortex via septa
near the junction with the medulla [123]. Other cells are also present in the thymus,
including macrophages, dendritic cells, and a small amount of B cells, neutrophils,
and eosinophils.
In the medulla, the network of epithelial cells is coarser than in the cortex, and
the lymphoid cells are relatively fewer in number [123]. Concentric, nest-like bod-
ies called “Hassall’s corpuscles” or “thymic corpuscles” are formed by aggregations
of the medullary epithelial cells (Fig. 9.14). These are concentric, layered whorls of
epithelial cells that increase in number throughout life [123]. They represent the
remains of the epithelial tubes, which grow out from the third pharyngeal pouches
of the embryo to form the thymus [126].
Blood Supply and Innervation
The arteries supplying the thymus are branches of the internal thoracic, and inferior
thyroid arteries, with branches from the superior thyroid artery sometimes seen
[124]. The branches reach the thymus and travel with the septa of the capsule into
the area between the cortex and medulla, where they enter the thymus itself, or
alternatively directly enter the capsule [124]. The veins of the thymus end in the left
brachiocephalic vein, internal thoracic vein, and inferior thyroid veins. Occasionally,
the veins end directly in the superior vena cava (SVC). Lymphatic vessels travel
only away from the thymus, accompanying the arteries and veins. These drain into
the brachiocephalic, tracheobronchial, and parasternal lymph nodes (LNs) [124].

picture showing a Hassall’s
corpuscle (thymic
corpuscle), found within
the medulla of the thymus
and formed by
aggregations of the
medullary epithelial cells
(H&E stain)
The nerves supplying the thymus arise from the vagus nerve (CN-X) and the
cervical sympathetic chain. Branches from the phrenic nerves reach the capsule of
the thymus but do not enter into the thymus itself [124].
Thymic Involution
The thymus is most active in fetal and neonatal life. It continues to grow after birth
reaching the relative maximum size by puberty [124]. It then begins to decrease in
size and activity in a process known as “thymic involution” [121]. After the first
year of life, the amount of T cells produced begins to fall [121]. Fat and connective
tissue fill a part of the thymic volume [124]. During involution, the thymus decreases
in size and activity [121]. Fat cells are present at birth but increase in size and num-
ber markedly after puberty, invading the gland from the walls between the lobules
first and then into the cortex and medulla. This process continues into old age, such
that where the thymus may be difficult to detect whether with the human eye or
under a microscope [121]. The atrophy is due to the increased circulating level of
sex hormones; chemical or physical castration of an adult results in the thymus
increasing in size and activity. Severe illness or human immunodeficiency virus
(HIV) infection may also result in involution [127].
Function
T-Cell Maturation
The thymus facilitates the maturation of T cells, an important part of the immune
system providing cell-mediated immunity [128]. T cells begin as hematopoietic pre-
cursors from the bone marrow and migrate to the thymus, where they are referred to
as thymocytes. In the thymus, they undergo maturation, which involves ensuring
that the cells react against antigens (“positive selection”), but that they do not react
against antigens found on body tissue (“negative selection”) [128]. Once mature, T
cells emigrate from the thymus to provide vital functions in the immune sys-
tem [128].
Each T cell has a distinct T-cell receptor, suited to a specific antigen. Most
T-cell receptors bind to the MHC on cells of the body. The MHC presents an
antigen to the T-cell receptor, which becomes active if this matches the specific
T-cell receptor. In order to be properly functional, a mature T cell needs to be
able to bind to the MHC molecule (positive selection), which occurs in the cortex
of the thymus, and not to react against antigens that are actually from the tissues
of body (negative selection), which occurs in the medulla. After this process, T
cells that have survived leave the thymus, regulated by sphingosine-1-phosphate.
Further maturation occurs in the peripheral circulation, partly because of hor-
mones and cytokines secreted by cells within the thymus, including thymulin,
thymopoietin, and thymosins [121].
Positive Selection
T cells have distinct T-cell receptors (TCRs), which are formed by the process of
V(D)J recombination gene rearrangement stimulated by RAG1 and RAG2 genes.
This process is error-prone, and some thymocytes fail to make functional T-cell
receptors, whereas other thymocytes make TCRs that are autoreactive [118]. If a
functional T-cell receptor is formed, the thymocyte will begin to express simul-
taneously the cell surface proteins CD4 and CD8. The survival and nature of the
T cell then depend on its interaction with surrounding thymic epithelial cells.
Here, the TCR interacts with the MHC molecules on the surface of epithelial
cells. A T cell with a receptor that does not react or reacts weakly will die by
“apoptosis.” A T cell that does react will survive and proliferate. A mature T cell
expresses only CD4 or CD8, but not both. This depends on the strength of bind-
ing between the TCR and MHC class 1 or class 2. A T-cell receptor that binds
mostly to MHC class I tends to produce a mature “cytotoxic” CD8-positive T
cell; a T-cell receptor that binds mostly to MHC class II tends to produce a CD4-
positive T cell [118].
Negative Selection
T cells that attack the body’s own proteins are eliminated in the thymus by “negative
selection.” Epithelial cells in the medulla and dendritic cells in the thymus express
major proteins from elsewhere in the body. The gene that stimulates this is
AIRE. Thymocytes that react strongly to self-antigens do not survive and die by
apoptosis. Some CD4-positive T cells exposed to self-antigens persist as T-regulator
cells [118].
Immunodeficiency
As the thymus is where T cells develop, congenital problems with the development
of the thymus can lead to immunodeficiency, whether because of an error with the
development of the thymocytes or the thymus itself. Loss of the thymus at an early
age through genetic mutation (as in DiGeorge syndrome and CHARGE syndrome)
results in severe immunodeficiency and subsequent high susceptibility to infection
by viruses, protozoa, and fungi.
The most common congenital cause of thymus-related immune deficiency results
from the deletion of the 22nd chromosome, called DiGeorge syndrome. This results
in a failure of development of the third and fourth pharyngeal pouches, resulting in
failure of development of the thymus, and variable other associated problems, such
as congenital heart disease, tracheoesophageal fistula, hare lip and cleft palate, and
failure of parathyroid gland development. Very low numbers of circulating T cells
are seen, and the condition is diagnosed by fluorescent in situ hybridization and
treated with thymus transplantation.
Severe combined immunodeficiency (SCID) is a group of rare congenital genetic
diseases that can result in combined T-, B-, and NK-cell deficiencies. These syn-
dromes are caused by mutations that affect the maturation of the hematopoietic
progenitor cells, which are the precursors of both B and T cells. A number of genetic
defects can cause SCID, including IL-2 receptor gene loss of function, and mutation
resulting in deficiency of the enzyme adenine deaminase.
Autoimmune Disease
utoimmune Polyendocrine Syndrome (APS)

A
Autoimmune polyendocrine syndromes (APSs), also called polyglandular autoim-
mune syndromes (PGASs) or polyendocrine autoimmune syndromes (PASs), are a
heterogeneous group of rare diseases characterized by autoimmune activity against
more than one endocrine organ, although non-endocrine organs can be affected.
There are three types of APS, and there are a number of other diseases which involve
endocrine autoimmunity [129].
Autoimmune polyendocrine syndrome type 1 is a rare genetic autoimmune syn-
drome that results from defects in the autoimmune regulator (AIRE) gene, which
stimulates the expression of self-antigens in the epithelial cells within the medulla
of the thymus. Self-antigens are thus not expressed, resulting in T cells that are not
conditioned to tolerate tissues of the body, and may treat them as foreign, stimulat-
ing an immune response and resulting in autoimmunity resulting in hypothyroid-
ism, Addison’s disease, and candida infection of body surfaces. Many other
autoimmune diseases may also occur [130]. Treatment is directed at the affected
organs [130].
hymoma-Associated Multiorgan Autoimmunity

T
Thymoma-associated multiorgan autoimmunity can occur in people with thy-
moma. In this condition, the T cells developed in the thymus are directed against
the tissues of the body. This is because the malignant thymus is incapable of
appropriately educating developing thymocytes to eliminate self-reactive T cells.
The condition is virtually indistinguishable from graft-versus-host disease
(GVHD) [131].
yasthenia Gravis (MG)

M
Myasthenia gravis (MG) is an autoimmune disease most often due to antibodies
that block acetylcholine receptors, involved in signaling between nerves and
muscles. It is often associated with thymic hyperplasia or thymoma, with anti-
bodies produced probably because of T cells that develop abnormally [132]. As
reported by Quddus in 2009, the relation between MG and thymomas was deter-
mined incidentally in 1939, when Blalock et al. reported the first excision of a
thymic cyst in a 19-year-old girl with MG [133]. This patient achieved long-term
remission; thus, thymectomy became the definitive therapy for treatment of gen-
eralized MG.
Myasthenia gravis most often develops between young and middle age, causing
easy fatiguing of muscle movements [134]. Investigations include demonstrating
antibodies (such as against acetylcholine receptors or muscle-specific kinase) and
CT scan to detect thymoma or thymectomy [134]. Thymectomy may be considered
as a treatment, particularly if a thymoma is found [134]. Other treatments include
increasing the duration of acetylcholine action at nerve synapses by decreasing the
rate of breakdown. This is done by acetylcholinesterase inhibitors such as pyr-
idostigmine [134].
Thymomas
Background
Thymomas are tumors that originate from the thymic epithelial cells. They are gen-
erally detected when they cause symptoms, such as a suprasternal neck mass, or
affect nearby structures such as the SVC [132]. A thymoma may also be detected
because of screening in patients with myasthenia gravis (MG), which has a strong
association with thymoma and hyperplasia, and it may also be detected as an inci-
dental finding on imaging such as chest X-rays [132]. The presence of histological
heterogeneity is common among thymomas, and as a result, benign and malignant
thymomas cannot simply be differentiated based on history; however, malignant

thymomas are much more invasive compared to their benign counterpart [135].
Epidemiology
Thymoma is the most common neoplasm of the anterior mediastinum, accounting
for 20–25% of all mediastinal tumors and 50% of anterior mediastinal masses. Its
peak incidence occurs in the fourth and fifth decades of life; the mean age of patients
is 52 years. No sexual or racial predilection exists [136].
Etiology
The etiology of thymomas has not been elucidated; however, these lesions have
been associated with various systemic syndromes. As many as 30–40% of patients
who have a thymoma experience symptoms suggestive of MG. An additional 5% of
patients who have a thymoma have other systemic autoimmune syndromes, includ-
ing red cell aplasia, systemic lupus erythematosus (SLE), Cushing syndrome, syn-
drome of inappropriate antidiuretic hormone secretion (SIADH), Graves’ disease,
hypogammaglobulinemia, pernicious anemia, and dermatomyositis, most probably
due to defects in negative selection in proliferating T cells [6, 137–139].
Pathophysiology
A thymoma is an epithelial tumor most commonly found in the pre-vascular medi-
astinum. It can also be found in the neck, pulmonary hilum, thyroid, lung, pleura, or
pericardium. In gross examination, it is a well-circumscribed, tan, firm mass that
ranges in size from microscopic to over 30 cm in diameter. It is lobulated with bands
of fibrous stroma and, at times, cystic changes.
Thymic carcinomas lack a lobulated architecture in contrast to thymomas. They
possess the cytoarchitectural features of carcinoma and lack immature T-cell lym-
phocytes. Thymic carcinomas and thymomas can be synchronous. Thymomas at
times can develop into carcinomas; however, they often take 10–14 years to do so.
Grossly, they are large, firm, infiltrating masses with numerous areas of cystic
change and necrosis. Approximately, 15% or less are encapsulated.
Approximately, one-third to one-half of patients with a thymoma are asymptomatic,
and one-third present with local symptoms related to the tumor’s encroachment on
surrounding structures. These patients may present with cough, chest pain, phrenic
nerve palsy, superior vena cava (SVC) syndrome, dysphagia, and hoarseness if the
recurrent laryngeal nerve (RLN) is involved. Pleural and pericardial effusions in
patients with thymoma tend to be due to disseminated disease. Few cases of patients
who presented with severe chest pain secondary to infarction or hemorrhage of the
tumor have been reported [140]. A thymoma may also present with a midline cervi-
cal mass in the suprasternal space. One-third of cases are found incidentally on
radiographical examinations during a workup for myasthenia gravis (MG).
Although development of a thymoma in childhood is rare, children are more
likely than adults to have symptoms because (1) children are more likely to have
malignancy, (2) lesions are more likely to cause symptoms by compression or inva-
sion in the smaller thoracic cavity of a child, and (3) the most common location for
mediastinal tumors in children is near the trachea, which results in respiratory
symptoms.
Patients with thymomas may also have paraneoplastic manifestations, which can
occur at any time in the diagnosis and treatment process of thymomas. The most
common is myasthenia gravis (MG), an autoimmune disorder that results in an
immunologic attack of acetylcholine receptors at the neuromuscular junction of
skeletal muscle. These patients tend to present with diplopia, ptosis, dysphagia,
weakness, or fatigue. Approximately half of the patients with thymoma have MG
and usually have less advanced disease since their symptoms lead to an earlier diag-
nosis. A thymectomy leads to attenuation of the severe symptoms of MG.
Another autoimmune disorder associated with thymomas is pure red cell aplasia.
This is a nonproliferation of erythrocyte precursors in the bone marrow. It occurs in
5–15% of patients with thymomas and is more common in older women. It is often
seen in thymomas with a spindle cell pathology. Various immunodeficiency syn-
dromes can also be seen in association with thymomas. Less than 5% of patients with
thymomas have hypogammaglobulinemia or pure white cell aplasia. These syn-
dromes are also more common in older women. Approximately, 10% of patients with
acquired hypogammaglobulinemia have a thymoma (also known as Good syndrome).
This is usually a thymoma with spindle cell pathology. Symptoms of these immuno-
deficiency syndromes include recurrent infections, diarrhea, and lymphadenopathy.
However, unlike MG, thymectomy does not resolve immunodeficiency. Finally,
there is a syndrome known as thymoma-associated multiorgan autoimmunity
(TAMA). This is similar to graft-versus-host disease (GVHD). These patients pres-
ent with a morbilliform skin rash, chronic diarrhea, and liver enzyme abnormalities.
A biopsy will show similar histopathology as GVHD in skin or bowel mucosa.
Thymic carcinoma presents differently. It is more aggressive compared to a thy-
moma and usually is associated with invasion of other mediastinal structures.
Patients usually present with cough, chest pain, phrenic nerve palsy, or SVC syn-
drome. Extra-thoracic metastases are seen in less than 7% of patients with thymic
carcinoma and include the kidney, extra-thoracic lymph nodes, liver, brain, adrenal
glands, thyroid gland, and bone.
Imaging Studies
Plain Radiography
Posteroanterior (PA) and lateral chest radiographs can detect most thymomas.
On the PA view, the lesion typically appears as a smooth mass in the upper half
of the chest, overlying the superior portion of the cardiac shadow near the junc-
tion of the heart and great vessels. The mass usually projects predominantly into
one of the hemithoraces. On the right, the silhouette sign is present, and the
ascending portion of the aortic arch is obliterated. Conversely, if the thymoma is
on the left, the silhouette sign is obscured, and the aortic knob is identified behind
the mass.
Computed Tomography (CT) Scan/Magnetic Resonance Imaging (MRI)

Computed tomography (CT) scan or MRI may delineate a mass further or may
detect a smaller tumor that was missed by radiography. Chest CT is the imaging
procedure of choice in patients with MG. Thymic enlargement should be deter-
mined because most enlarged thymus glands visualized on CT scan represent
thymomas. CT with intravenous contrast dye is preferred to show the relations
between the thymoma and surrounding vascular structures, to define the degree
of its vascularity, and to guide the surgeon in the removal of a large tumor, pos-
sibly involving other mediastinal structures. Thymic carcinomas tend to have
areas of necrosis, cystic changes, or calcifications. In contrast, thymomas tend to
be smooth and well-circumscribed. MRI can differentiate between solid and cys-
tic masses.
Positron-Emission Tomography (PET) Scan

Bagga and Bloch (2006) reported that positron-emission tomography (PET) is
invaluable in confirming the diagnosis of an invasive malignant thymoma [141].
Although CT scan, in their study, revealed evidence of an anterior mediastinal mass,
PET scan showed a hypermetabolic mass consistent with this location, thereby rais-
ing suspicion of malignancy. Subsequent resection of the mass revealed a minimally
invasive thymoma due to capsular invasion. Thus, they recommended that PET
should be added to the armamentarium as an available diagnostic modality to aid in
staging and excluding extra-mediastinal involvement [141].
Laboratory Tests
In addition to imaging, the patient should have various laboratory studies including
germ cell markers (beta-hCG and AFP) and lymphoma markers (LDH and CBC)
since both germ cell tumors and lymphomas are in the differential of anterior medi-
astinal masses. Pulmonary function tests and a cardiac stress test should also be
performed on any patient in whom surgical resection is being considered to deter-
mine if they have enough cardiopulmonary reserve to withstand a significant resec-
tion of the thymus.
Pathological Studies
A definitive diagnosis of a thymic tumor needs tissue [142]. This can be obtained
via either surgical resection (in the case of small encapsulated tumors and resectable
larger tumors) or a percutaneous or open biopsy in instances in which the tumor is
unresectable, the tumor requires neoadjuvant therapy, or surgery is contraindicated
due to age or comorbidity. The percutaneous route is done using CT guidance and
can be a fine needle aspiration (FNA) or a core needle biopsy. An open biopsy can
be performed thoracoscopically, via a cervical mediastinoscopy, via an anterior
mediastinotomy (Chamberlain procedure), or at times via endobronchial ultrasound

(US). Correct pathological identification and staging are critical in determining the
proper treatment.
Fine Needle Aspiration and Biopsy

If a patient presents with atypical features or is found to have an invasive tumor
and is under consideration for induction therapy, a preoperative biopsy is indi-
cated. The limited anterior mediastinotomy (Chamberlain approach) is the stan-
dard approach that typically is performed over the projection of the tumor. A
thoracoscopic approach for biopsy can also be used. Controversy exists over the
efficacy of fine needle aspiration (FNA). It has been reported by some authors to
be beneficial in reaching the diagnosis of a thymoma. Performing a core biopsy
in conjunction with FNA is a modality that can increase the accuracy with which
thymomas can be differentiated from other neoplasms, such as lymphomas and
germ cell tumors.
Histopathology
Benign tumors confined to the thymus are most common, followed by locally
invasive tumors and then by carcinomas. However, some authors report that
malignant tumors are more common. Invasive tumors, although not technically
malignant, can still spread (metastasize) to other areas of the body. Even though
thymomas occur from epithelial cells, they can also contain thymocytes. No clear
histological distinction between benign and malignant thymomas exists. The
propensity of a thymoma to be malignant is determined by the invasiveness of the
thymoma into the vasculature, lymphatics, and adjacent structures within the
mediastinum.
Traditionally, thymomas have been classified into three histological types
according to the cell type that is predominant—lymphocytic, epithelial, or lympho-
epithelial. Thymomas can be (1) benign; (2) locally invasive and benign, but by
virtue of expansion invading beyond the capsule of the thymus; or (3) malignant
(carcinoma).
A pathological classification was developed by the World Health Organization
(WHO) (Table 9.1) but is not used as part of standard clinical practice.
In a study conducted in Japan by Kondo et al. (2004) between 1973 and 2001 of
a series of 100 resected thymomas, prognostic categories were distinguished by
using this WHO classification as shown in Table 9.2 [143].
Histological heterogeneity is common among thymomas such that many thymo-
mas will possess multiple subtypes of these WHO classifications and can be divided
into 10% increments. Thymomas have a lobulated architecture. The cellular lobules
consist of neoplastic epithelial cells and reactive thymocytes that are intersected
with fibrous bands. They are at least partially surrounded by fibrous capsules.
Thymoma subtypes A and AB have some characteristic growth patterns. They
possess microcystic changes, storiform growth, staghorn-shaped vessels, rosettes,
gland-like structures, or papillary growth patterns. They often show prominent
plasma cell infiltrates and myoid cells (rhabdo-myomatous thymoma).
Table 9.1 World Health Organization (WHO) pathological classification system

Type Characteristics
A Composed of bland spindle cells and few scattered lymphocytes (Fig. 9.15). 60% of
these are in stage I, and they tend to have good outcomes. There is an atypical variant
that is hypercellular, possesses increased mitotic activity, and/or is necrotic, which tends
to predict an advanced stage
AB This is a mixture of type A and type B1 or B2. It is composed of intermixed or distinct
components. 67% of these are in stage I
B1 Composed of predominantly lymphocytes with scattered epithelial cells, not in clusters.
Also paler medullary islands with rare Hassall’s corpuscle-like structures. 50% of these
are in stage I (Fig. 9.16)
B2 Composed of mostly epithelial cells forming clusters, and medullary islands may be
present. Atypia may be more present and may show anaplastic features. 32% of these
are in stage I
B3 Composed predominantly of large, polygonal cells with increased atypia and few
scattered lymphocytes. Its prognosis is worse than other thymomas but is better than
thymic carcinomas. Only 19% of these are in stage I (Fig. 9.17)
C Thymic carcinoma composed of a distorted architecture with various sized cell nests.
Cytological malignant and cystic changes are often present along with certain amounts
of necrosis, atypia, and mitoses

picture of a thymoma (type
A) showing scattered
neoplastic thymic
epithelial cells surrounded
by nonneoplastic
lymphocytes. The
epithelial cells have pale
oval or round nuclei with
inconspicuous nucleoli
(400×, H&E)

B1) showing scattered
neoplastic epithelial cells
surrounded by a dense
infiltrate of nonneoplastic
lymphocytes. The
epithelial cells have pale
eosinophilic cytoplasm
with ill-defined
cytoplasmic borders,
uniform round to oval
vesicular nuclei, and
punctate nucleoli
(400×, H&E)

B3) showing perivascular
space. A small vessel
(arrow) is located within a
space that contains a few
scattered lymphocytes and
is surrounded by palisading
neoplastic cells and
scattered thymocytes
(400×, H&E)
Table 9.2 World Health Organization (WHO) pathological classification and associated prognos-
tic categories
Type Histological description 10-Year DFS (%)
A Medullar thymoma 100
AB Mixed thymoma 100
B1 Predominantly cortical thymoma 83
B2 Cortical thymoma 83
B3 Well-differentiated thymic carcinoma 35
C Thymic carcinoma 28
DFS disease-free survival
A dilated perivascular space is seen in thymoma subtypes B1, B2, and B3. These
are filled by plasma fluid and may contain a few lymphocytes, plasma cells, or
foamy macrophages. In the center of these spaces, there are often small vessels with
hyalinized walls. Neoplastic cells surround these spaces in palisades. Hassall’s cor-
puscles are specifically seen in subtype B1 thymomas. Both subtype B1 and B2
thymomas are rich in lymphocytes; however, they possess some important histo-
logical differences. Subtype B1 has areas of medullary differentiation (medullary
islands) and scattered epithelial cells without clustering (<3 contiguous epithelial
cells). These are often mistaken for small lymphocytic lymphomas and can be dif-
ferentiated by using a keratin stain. Subtype B2 has more epithelial cells that cluster
(3+ contiguous epithelial cells). Subtype B3 is often confused with thymic carci-
noma or metastatic SCC from other sites.
Immunohistochemistry (IHC) is helpful in identifying thymomas. Thymic epi-
thelial cells are positive for keratins, epithelial membrane antigens, p63, p40, and
PAX8. Thymic lymphocytes stain with terminal deoxynucleotidyl transferase
(TdT), CD1a, CD3, CD45, and CD99. Subsets of thymoma subtype A and AB stain
for CD20 and rarely thyroid transcription factor (TTF-1).
Histologically, thymic carcinomas have a distorted architecture with various

sized cell nests and even single cells in desmoplastic stromal reactions. There are
often cytologic malignant and cystic changes along with variable amounts of necro-
sis, atypia, and mitoses. T cells found in thymic carcinomas exhibit the phenotype
of mature T cells (TdT negative, CD1a negative, CD3 positive, CD4 or 8 positive).
B cells and plasma cells are also seen.
There are a variety of histological subtypes of thymic carcinoma, emphasizing
the ability of the thymic epithelium to differentiate. These histological subtypes are
Staging
Several different systems are used for the staging of thymomas, including the AJCC/
TNM staging system (Table 9.4) and the Masaoka staging system (Table 9.5). The
latter is the most commonly accepted staging system for thymomas. These two sys-
tems are summarized below.
AJCC/TNM Staging System

See Table 9.4.
Masaoka Staging System

See Table 9.5.
The differential diagnoses of thymomas include (1) thymic carcinoid tumors (often
seen in patients with multiple endocrine neoplasia syndrome type 1), (2) thymic
cysts (differentiated from solid tumors by MRI), (3) non-Hodgkin lymphomas, (4)
germ cell tumors (especially in young males with prior testicular masses), (5) ecto-
pic parathyroid glands (can be identified by a sestamibi scan), (6) goiter, and (7)
paragangliomas (rarely).
In order to narrow down the differential, one must order appropriate laboratory
studies [including germ cell markers (AFP and hCG) and lymphoma markers (LDH
and CBC with differential)]. Imaging studies can help to differentiate between these
various masses, e.g., an MRI differentiates between a cystic and solid mass, a sesta-
mibi scan can detect ectopic parathyroid tissue, and a thyroid scan can detect a
mediastinal thyroid mass.
Treatment
Treatment and management of thymic tumors include chemoradiotherapy, immuno-
therapy, corticosteroids, tyrosine kinase inhibitors, and surgical resection. The utili-
zation of multidisciplinary tumor boards is vital in determining the correct method
of treatment of these neoplasms. There has been no randomized controlled trial that
provides definitive guidance for management strategies [144–146].
Table 9.3 Subtypes of thymic carcinoma

Carcinoma subtype Characteristics
Squamous cell carcinoma Keratinizing or non-keratinizing
Lympho-epithelioma-like Composed of malignant, large, polygonal cells. It grows in a
carcinoma syncytial pattern in sheets and nests and possesses the
morphology of nasopharyngeal lympho-epithelial carcinoma.
There is usually a dense lymphoid infiltrate. Epstein-Barr virus
(EBV) may play a role in its pathogenesis. It is highly
aggressive with a poor prognosis
Sarcomatoid carcinoma It possesses sarcoma-like areas and possible heterologous
components (rhabdo-myoblastic or cartilaginous
differentiation). Diagnosis is confirmed by identification of
t(X;18) (p11.2;q11.2), SYT-SSX1, or SYT-SSX2 gene fusion
Clear cell carcinoma It possesses a lobulated growth pattern and is composed of
uniform clear cells with minimal nuclear atypia, glycogen, and
no mucin. It is very rare and has a poor prognosis due to local
recurrence or metastases
Basaloid carcinoma It possesses nests of polygonal and spindle cells with
peripheral palisades, a high nuclear-cytoplasmic ratio, and
absence of keratinization often with cystic changes
Mucoepidermoid carcinoma Composed of intermediate cells (polygonal cells with
eosinophilic cytoplasm, small round nuclei, and inconspicuous
nucleoli), squamous cells, and mucin-producing cells. It is
defined as low or high grade
Presence of a mastermind-like transcriptional coactivator 2
(MAML2) rearrangement is disease defining
Adenocarcinoma This subtype is based on histological features; papillary,
adenoid cystic carcinoma like, mucinous, and not otherwise
specified. Occasionally, it has an intestinal phenotype
Undifferentiated carcinoma Consists of sheets of undifferentiated cells. Epithelial nature
confirmed by immunohistochemistry (IHC)
NUT (nuclear protein of It is a rare and very aggressive carcinoma, which is a subset of
testis) carcinoma squamous cell carcinoma. Immunostain shows a speckled
nuclear expression pattern. About 70% have a rearrangement
of the NUT gene. The median age of presentation is between
16 and 50 years, with no gender predilection. Approximately,
51% have metastases at the time of presentation. The median
survival is 6.7 months
A SMARCA4-deficient It possesses sarcomatous or carcinomatous features and has
tumor (SWI/SNF-related, focal rhabdoid morphology. Loss of BRG1 expression is
matrix-associated, actin- diagnostic. About 83% possess cytokeratin expression. The
dependent regulator of median age of diagnosis is 59 years. The 2-year survival rate is
chromatin, subfamily A, worse with BRG1-retained tumors (12.5% vs. 64.4%,
member 4) respectively)
Table 9.4 AJCC/TNM staging system

T-classification
T1 Encapsulated or extending into mediastinal fat
T1a No mediastinal pleural invasion
T1b Mediastinal pleural invasion
T2 Partial- or full-thickness pericardial invasion
T3 Invasion of the lung, brachiocephalic vein, SVC, phrenic nerve, chest wall, or extra-
pericardial pulmonary artery or veins
T4 Invasion of the aorta (ascending, arch, or descending), arch vessels, intrapericardial
pulmonary artery, myocardium, trachea, or esophagus
N-classification
N0 No nodal metastases
N1 Peri-thymic nodal metastases
N2 Deep thoracic nodal metastases
M-classification
M0 No distant metastases
M1a Individual pleural or pericardial nodule(s)
M1b Pulmonary nodule or distant organ metastases
Stage grouping
I T1a/b N0 M0
II T2 N0 M0
III A T3 N0 M0
III B T4 N0 M0
IV Any T N1 M0—any T N0, 1 M1a
A
IV Any T N2 M0, 1a—any T any N M1b
B
SCV superior vena cava
Table 9.5 Masaoka staging system of thymomas and corresponding therapy

Stage Definition Treatment
I Encapsulated tumor with no gross or Complete surgical excision
microscopic invasion
II Microscopic invasion of the capsule Complete surgical excision and postoperative
RT to decrease the incidence of local
recurrence
III Macroscopic invasion of the Complete surgical excision and postoperative
pericardium, great vessels, or lung RT to decrease the incidence of local
recurrence
IV A Pleural or pericardial metastatic Surgical debulking, RT, and chemotherapy
spread/nodules
IV B Lymphogenous or hematogenous Surgical debulking, RT, and chemotherapy
(distant) metastases
RT radiotherapy
Medical Therapy
Chemotherapy
A few reports in the literature suggest that thymomas are chemosensitive tumors
[147]. Potential candidates for chemotherapy include approximately one-third of
the patients with an invasive thymoma that later metastasizes and all patients with
stage IV disease.
Fornasiero et al. (1991) reported successful cases and some long-term survivors
for incompletely resected invasive thymomas or cases with unresectable disease
following the administration of a regimen of cisplatin/vincristine/doxorubicin/
cyclophosphamide [148]. In 32 patients, a 47% complete and 90% overall response
rate was noted with a median survival time of 15 months.
Corticosteroids
Case reports in the literature have documented that the administration of oral gluco-
corticoids results in regression of an invasive thymoma. In one case, the patient
showed complete regression to the thymoma and associated symptoms and has
remained without radiological recurrence after 12 months [149].
Surgical Treatment
In the setting of resectable disease, i.e., an encapsulated tumor or a tumor invading
resectable structures (the pericardium, the pleura, or an area of the lung), surgery is
indicated since an R0 resection is feasible. Typical management includes total thy-
mectomy and a lymph node dissection (LND). The likelihood of long-term survival
depends on the completeness of the resection. Surgical excision provides the histo-
logical characteristics of the tumor and provides staging information that helps
determine the need for adjuvant therapy. This may also result in temporary remis-
sion of any associated autoimmune conditions. Small and encapsulated thymomas
are excised for diagnosis and treatment. In the past, obtaining a preoperative biopsy
of large invasive thymomas was shunned for fear of local implantation of tumor
cells. Currently, biopsies are performed for these atypical tumors to discover the
histology of the tumor and to ascertain its invasive potential [147, 150].
Wright (2006) reported a single-institution retrospective study that was con-
ducted on five patients with stage IVA thymoma treated with pleuro-pneumonectomy
[151]. There was no operative mortality, and the 5-year survival rate was 80%. It
was suggested that in selected patients, this approach with complete resection and
neoadjuvant chemotherapy may be promising [151].
Although there has been controversy regarding the use of postoperative radiation
therapy (RT) for invasive thymomas, the preponderance of evidence indicates that
all thymomas, except completely encapsulated stage I tumors, benefit from adjuvant
RT [152].
Preoperative Care
Preoperative adjuvant RT has been used to increase the possibility of complete
resection when CT scan suggests that a tumor is very large or invasive. Although
doses of 30–45 Gy have been used in this approach, complete responses have rarely
been reported. One caveat to this therapy is that the patient is placed at increased
risk for radiation pneumonitis because of the large size of ports required to cover
the field.
Patients with a preoperative diagnosis of myasthenia gravis (MG) and a thy-
moma should optimize their medical condition before surgery by using cholinester-
ase inhibitors and plasmapheresis if indicated.
Operative Details
Although the preferred approach for thymectomy is a median sternotomy to provide
adequate exposure of the mediastinal structures and allowing complete removal of
the thymus, the cervical approach is also adequate.
If the tumor is small and appears readily accessible, a total thymectomy with
contiguous removal of mediastinal fat should be performed. If the tumor is invasive,
a total thymectomy in addition to en bloc removal of involved pericardium, pleura,
lung, phrenic nerve, innominate vein, or SVC is advisable. Resection of one phrenic
nerve can be performed; however, if both phrenic nerves are involved, neither one is
resected, and debulking the involved area is recommended. Areas of close margins
or residual disease are clipped to assist the radiation oncologist in treatment
planning.
Controversy persists with regard to whether biopsy or subtotal excision is supe-
rior for treating unresectable tumors. Some studies have supported subtotal exci-
sion, whereas others have shown no difference between the two modalities. A
generally accepted rule is that patients with invasive or residual disease should
receive adjuvant therapy. Other indications of thymectomy include the treatment of
myasthenia gravis. Finally, in cases of recurrent disease, surgical resection is rec-
ommended in cases of localized recurrence (drop metastases) and has been shown
to lead to prolonged survival. In other cases of more extensive recurrence, chemo-
therapy or palliative RT is recommended.
It is noteworthy that the usual reason for thymectomy in the neonatal period is to
gain access to the heart for surgery to correct congenital heart defects. In neonates,
the relative size of the thymus obstructs surgical access to the heart and its surround-
ing vessels. Thymectomy in infancy results in often fatal immunodeficiency, because
functional T cells have not developed. In older children and adults, which have a
functioning lymphatic system with mature T cells also situated in other lymphoid
organs, the effect is reduced and limited to failure to mount immune responses
against new antigens.
Minimally Invasive Approaches

With the advent of video-assisted minimally invasive surgery, many of the tradi-
tional thoracic procedures have been abandoned. Video-assisted thoracoscopic sur-
gery (VATS) for thymoma has been described; however, there remains a need for
additional long-term data, and the optimal approach is yet to be established.
Roviaro et al. (1994) performed video thoracoscopy on six patients with thy-
moma; however, they did not describe the extent of resection, size of the tumor, or
tumor stage, and long-term follow-up data are unavailable [153]. Kaiser (1994)
advocated the use of transcervical dissection in conjunction with video thoracos-
copy, allowing better exposure [154]. In 1997, Mack et al. presented a series of
photographs of thymus glands removed by means of thoracoscopy confirming that
the thymus gland can be resected completely by experienced surgeons [155]. Long-
term follow-up data are required to determine the true efficacy of this procedure in
comparison with traditional thymectomy.
More recently, in a study of 140 patients with stage I and II thymoma, Chao et al.
(2015) compared perioperative and oncological outcomes after VATS resection for
stage I and II thymoma with those obtained after median sternotomy [156]. No
operative deaths occurred, and although there were no statistically significant differ-
ences in 5-year survival between the two study groups, VATS was associated with
better perioperative outcomes shown by less intraoperative blood loss, greater fre-
quency of extubation in the operating room after surgery, and a shorter length
of stay.
In 2023, in a propensity score-matching analysis, Yang et al. compared the safety
and feasibility of subxiphoid-approach thoracoscopic thymectomy (SATT; n = 144)
and lateral intercostal-approach thoracoscopic thymectomy (LATT; n = 144) for
Masaoka-Koga stage I and II thymomas [157]. The SATT group had a significantly
higher rate of exposure to the bilateral phrenic nerves than the LATT group did, as
well as greater maximum length and width of resected tissue. The SATT group also
had lower postoperative high-sensitivity C-reactive protein (hs-CRP) levels; better
visual analog pain scale (VAS) scores on postoperative days 1, 3, and 7; and better
quality of life on postoperative days 30 and 90.
Postoperative Treatment
Adjuvant radiation therapy (RT) in completely or incompletely resected stage III or
IV thymoma is considered the standard of care. However, the use of postoperative
RT in stage II thymoma has been questioned [147].
Thymomas are indolent tumors that may take at least 10 years to recur; therefore,
short-term follow-up will not depict relapses accurately. Furthermore, the gross
appearance of tumor invasiveness is subjective, depending on the opinion of the
surgeon. In one report from the Massachusetts General Hospital, 5 (22%) of 23
patients with stage II disease developed recurrences, leading to a proposed recom-
mendation that postoperative RT be instituted in all patients with stage II thy-
moma [158].
In a study conducted by Curran et al. (1988) that included 21 patients with stage
II and III diseases who did not receive postoperative (total resection) RT, 8 patients
had recurrences in the mediastinum as compared to none in 5 patients who received
postoperative adjuvant RT [159].
A series from Memorial Sloan Kettering Cancer Center, however, showed that
adjuvant RT did not improve survival or decrease recurrence in stage II and III dis-
eases [160]. To reduce the incidence of local relapse, postoperative adjuvant RT is
indicated in patients without completely encapsulated stage I tumors.
In a retrospective review of 241 patients with thymoma who received RT after

total thymectomy, partial resection, debulking, or biopsy, Wu et al. (2009) reported
10-year survival rates of 87% for stage I thymoma, 78.7% for stage II, 57.4% for
stage III, and 24.3% for stage IV, respectively [161]. They concluded that surgery
and postoperative RT should be the standard treatment for stage II or III but that
further research was needed to establish whether this is true for stage I.
A database analysis by Jackson et al. found that postoperative RT was associated
with longer overall survival in patients with stage IIB thymoma, but no significant
effect could be demonstrated for stage IIA disease.
Complications
Postoperative Complications: There are several postoperative complications associ-
ated with thymectomy. These include (1) respiratory failure and prolonged intuba-
tion (commonly seen in patients with MG); (2) pleural effusion, pneumonia,
atelectasis, pneumothorax, and acute lung injury; (3) phrenic and RLN injury; and
(4) infection (surgical site infection and mediastinitis).
Postoperative Radiotherapy Complications: As with most oncological therapies,
there are associated toxicities, all of which are treated symptomatically. These
include esophagitis, radiation pneumonitis, radiation pericarditis, and rarely myeli-
tis. Some late sequelae of postoperative RT also include lung fibrosis and a small
chance of constrictive pericarditis. Patients are also at increased risk of accelerated
coronary atherosclerosis and secondary malignancies. Deaths from these complica-
tions have been reported; accordingly, clinicians must carefully consider the risk-to-
benefit ratio of adjuvant RT [162].
Multidisciplinary Approach
A multidisciplinary approach to treatment of unresectable thymomas has been
advocated [150, 163]. In a trial conducted by the MD Anderson Cancer Center, 12
patients received a treatment regimen consisting of induction chemotherapy (three
courses of cyclophosphamide, doxorubicin, cisplatin, and prednisone), surgical
resection, postoperative RT, and consolidation chemotherapy (three courses of
cyclophosphamide, doxorubicin, cisplatin, and prednisone) [164]. Of the 12
patients, 3 (25%) had a complete response, 8 (67%) a partial response, and 1 (8%)
a minor response [164]. One patient refused surgery, nine (82%) had complete
resection, and two (18%) who had been receiving RT and consolidation chemo-
therapy had incomplete resection. All 12 patients (100%) were alive at 7 years, and
10 (73%) were disease-free at 7 years. The authors suggested that aggressive multi-
modal treatment is effective and may be curative in locally advanced, unresectable,
malignant thymomas.
Octreotide (0.5 mg SC q8hr) alone or with prednisone (0.6 mg/kg/day) was eval-
uated by Loehrer et al. (2004) in 38 patients with advanced thymomas that expressed
somatostatin receptors [165]. Of the 38 patients, 4 (10.5%) had a partial response
with octreotide alone. Of the 21 patients who received octreotide plus prednisone, 2
had a complete response and 4 had a partial response. Octreotide plus prednisone
yielded better progression-free survival than octreotide alone. Octreotide therapy

may thus be a valuable treatment option when chemotherapy is ineffective.
Future Treatment Options

Studies have investigated the molecular changes in thymomas. In one study, 10 out
of 12 thymomas exhibited epidermal growth factor receptor (EGFR) expression.
Thus, EGFR tyrosine kinase inhibitors can be utilized in selected patients with thy-
mic carcinomas that have been refractory to initial chemotherapeutic regimens.
Other areas of investigation include apoptosis-related markers, such as p63, a mem-
ber of the p53 family. This marker is expressed in virtually all thymomas. Further
research pertaining to the biology of thymomas will allow more adequate approaches
to treatment.
Prognosis
The prognosis of thymoma is worse for patients with symptomatic disease because
these patients are more likely to have a malignant thymoma. Prognosis is dependent
on the stage of the disease and the complete resectability of the tumor. The single
most important factor predicting the outcome of patients with thymomas is evidence
of invasion of the thymic capsule or surrounding tissue. Histological characteristics,
such as microscopic capsular invasion, should therefore be assessed [152].
Thymic tumors tend to recur as pleural nodules, most commonly with a mean
length of 8–68 months after treatment. It is recommended that a CT chest is ordered
every 6 months for 2 years and annually for 5 years in cases of thymic carcinoma
and 10 years in cases of thymomas. Because of the well-documented propensity for
late recurrences, long-term survival should be considered in terms of a 10-year fol-
low-up after treatment of the thymoma.
A study conducted by the Memorial Sloan Kettering Cancer Center reported
5-year and 10-year survival rates for various stages of thymomas as shown in
Table 9.6 [160]. The 15-year survival rate is 12.5% for a person with an invasive
thymoma and 47% for a person with a noninvasive thymoma. Death usually occurs
from cardiac tamponade or other cardiorespiratory complications.
Thymomas are associated with the development of second malignancies (approx-
imately 17–28% risk after thymectomy). A review of the Surveillance, Epidemiology,
and End Results (SEER) database of thymoma cases in the United States
(1973–1988) identified 849 cases, of which 66 had second malignancies. There was
an excess occurrence of B-cell non-Hodgkin lymphoma (NHL), and soft tissue sar-
coma, but of no other specific cancers. Notably, an increase in digestive system
Table 9.6 Survival of Stage 5-Year survival (%) 10-Year survival (%)
thymoma by stage: Memorial I 90 80
Sloan Kettering
II 90 80
experience [160]
III 60 30
IV <25 N/A
N/A not applicable
cancers (colon/rectum, stomach, esophagus, liver/biliary tract) occurred; however,

these increases were not statistically significant [166].
Wu et al. (2009) reported that the following tended to have a more favorable
prognosis: (1) female patients, (2) those with early-stage thymoma, and (3) patients
who underwent surgical extirpation of the neoplasm [161].
Lymphomas
Tumors originating from T cells of the thymus form a subset of acute lymphoblastic
leukemia (ALL). These are similar in symptoms, workup, and treatment to other
forms of ALL. Symptoms that develop, like other forms of ALL, relate to deficiency
of platelets, resulting in bruising or bleeding; immunosuppression resulting in
infections; or infiltration by cells into parts of the body, resulting in an enlarged
liver, spleen, and LNs. Blood tests might reveal a large amount of white blood cells
(WBCs) or lymphoblasts and deficiency in other cell lines—such as low platelets or
anemia (pancytopenia). Immunophenotyping will reveal cells that are CD3, a pro-
tein found on T cells, and help further distinguish the maturity of the T cells. Genetic
analysis including karyotyping may reveal specific abnormalities that may influence
prognosis or treatment, such as the Philadelphia translocation. Management includes
multiple courses of chemotherapy, stem cell transplant, and treatment of associated
conditions, such as treatment of infections (antibiotics) and bleeding (blood transfu-
sions). Very high leukocytosis may also require cyto-reduction with apheresis.
Tumors originating from the small population of B cells present in the thymus
lead to primary mediastinal (thymic) large B-cell lymphomas [167]. These are a rare
subtype of non-Hodgkin lymphoma (NHL); although by the activity of genes and
occasionally with microscopic shape, unusually they also have the characteristics of
Hodgkin lymphoma. It occurs most commonly in young and middle-aged individu-
als and is more prominent in females. Most often, symptoms occur because of com-
pression of nearby structures, such as the SVC or the upper respiratory tract; when
LNs are affected, it is often in the mediastinum and neck groups. Such tumors are
often detected with a biopsy that is subject to immunohistochemistry (IHC). This
will show the presence of clusters of differentiation and cell surface proteins,
namely, CD30, with CD19, CD20, and CD22, and with the absence of CD15. Other
markers may also be used to confirm the diagnosis. Treatment usually includes the
typical regimens of CHOP or EPOCH or other regimens, generally including cyclo-
phosphamide, an anthracycline, prednisone, and other chemotherapeutics, and
potentially also a stem cell transplant.
Thymic Cysts
Epidemiology
Thymic cysts in the neck are very rare representing only 1% of cystic cervical
masses [168]. Hsieh et al. (2003) conducted a study on 331 patients under the age
of 18 years presenting with cystic neck masses. They reported that 181 (54.68%)
patients had thyroglossal cysts, followed by cystic hygromas (n = 83, 25.08%),
branchial cleft cysts (n = 54, 16.31%), and bronchogenic cysts (n = 3, 0.91%), and
nine cases (2.72%) remained unclassified. Only one case was diagnosed as thymic
cyst (0.30%) [109]. The increasing number of cervical thymic cysts reported
recently probably reflects greater awareness of this condition among pathologists. It
is also possible that in the past, many cases of thymic cyst had been misdiagnosed
because of inadequate sampling of the specimen. The frequent atrophic condition of
the thymic remnants may require sampling from various portions of specimen
before a diagnosis of thymic cyst could be rendered [169].
Patients with thymic cysts usually present in the first decade of life, being more
common in males.
Etiology
Thymic cysts are among the rarest cysts found in the neck. They may be congenital
or acquired [170]. Congenital thymic cysts arise from persistent thymo-pharyngeal
duct, a derivative of the third pharyngeal pouch at the sixth week of gestation; it
extends from the pyriform sinus to the anterior mediastinum. The duct eventually
separates from the pharynx. By the eighth week of gestation, the thymic buds have
descended into the mediastinum to create the thymus. Acquired thymic cysts arise
from degeneration of Hassall’s corpuscles within ectopic thymic remnants.
Multilocularity of thymic cysts also implies an inflammatory cause [171]. Acquired
thymic cysts are seen in association with the acquired immunodeficiency syndrome
(AIDS), thymic inflammation, or malignancy (e.g., carcinoma, mediastinal Hodgkin
disease, but not NHL). Thymo-pharyngeal duct cysts are rarer variety of thymic
cysts [172]. The presence of thymic tissue differentiates thymic cysts from third and
fourth branchial cysts [173].
Location
Congenital thymic cysts can occur along the neck or in the chest (mediastinum)
[174]. They are usually located in the infrahyoid neck (Fig. 9.18), and they can be
distinguished based on the close association with the carotid sheath, sometimes
splaying the carotid artery and jugular vein; the classic dumbbell or bilobed appear-
ance can be seen with extension into the anterior mediastinum. Mediastinal exten-
sion is seen in 50% of cervical thymic cysts. Among the mediastinal cysts, thymic
cysts have been reported to occur in about 3–28.6% of the cases [175–177].
Classification
Cervical thymic lesions include the following categories distinguished by their ana-
tomical location and the nature of the thymic gland tissue [178].
Accessory Cervical Thymus

Solid cervical thymic tissue is sequestered from the main gland, along the normal
descent path, with or without parathyroid glands. Previous terms include aberrant,
ectopic, undescended, persistent, or accessory thymus.
Fig. 9.18 A thymic cyst

presenting as a suprasternal
cervical mass (red arrow)
in a 17-year-old young
gentleman
Cervical Thymic Cyst

Sequestered cystic cervical thymus is found along a normal path of descent, with or
without parathyroid glands. It is a cystic version of accessory cervical thymus and
may have fibrous band or a solid thymic cord connection to the pharynx or
mediastinum.
Undescended Cervical Thymus

This type occurs when a solid lobe of the thymus fails to descend entirely, with or
without a parathyroid complex. It differs from accessory cervical thymus in that
only half of the normally bilobed thymus is present in the mediastinum; conceiv-
ably, it may also become cystic.
Persistent Thymo-Pharyngeal Duct Cyst

This is the same as undescended cervical thymus; however, the thymic duct is cys-
tic. The thymus is solid, with or without parathyroid complex, and probably repre-
sents undescended thymus. A variant would be the cervical cystic duct leading to
the mediastinal thymus.
Persistent Thymic Cord

This is the cervical prolongation of a solid thymic cord, which is continuous with
the mediastinal thymus. The cystic variant may overlap with the histology and
clinical appearance of the cervical thymic cyst if a true connection to the mediasti-
nal thymus cannot be documented.
Cervical Extension of Mediastinal Thymus

This type appears as a low midline thymus at the thoracic inlet due to incomplete
mediastinal descent. It may transiently present with increased intrathoracic pressure.
Ectopic Thymus
This type is rare where solid thymic tissue is present in abnormal locations, for
example, in the pharynx, trachea, or base of skull [179, 180].
Pathology
Since congenital thymic cysts are remnants of the thyro-pharyngeal ducts, they can
occur in the neck or mediastinum. Cervical thymic cysts are morphologically identi-
cal to their mediastinal counterparts. Congenital thymic cysts are usually <6 cm, are
uni-loculated or multi-loculated, and have thin walls; on the other hand, acquired
cysts are multi-loculated with variable cyst wall thickness and size ranging from 3
to 17 cm [181]. In cases of thymic cyst with thymomas, the thymoma arises from
the wall of the cyst.
Histopathologically, thymic cysts usually just contain a brownish fluid. The cyst
wall lining ranges from flattened squamous or cuboidal cells to multilayered strati-
fied squamous epithelium to even primitive respiratory epithelium. Lobulated lym-
phoid tissue in the cyst wall contains Hassall’s corpuscles characteristic of thymic
origin of the cyst (Fig. 9.19) [173].
Thymic cysts are usually detected incidentally and do not generally cause symp-
toms. Despite this, the presence of a thymic cyst can cause symptoms similar to
those of a thymoma, by compressing nearby structures, and some may be difficult
to distinguish from tumors [174]. Hegde et al. (2012) reported a thymic cyst that
presented with a palpable lower midline neck mass in a 13-year-old boy. The mass
only appeared when the patient was asked to perform Valsalva maneuver. The lower
border of the mass was not palpable [182].
The common symptoms reported in the literature for thymic cysts are chest pain,
dyspnea, cough, and rarely severe respiratory distress and hoarseness of voice [177].
Myasthenia gravis may be the presenting symptom in a few cases. Malignant trans-
formation has been reported in adults, but not in children [182].
Imaging Studies
When thymic cysts are found, investigations may include a workup for
tumors, including US, CT scan, or MRI (Fig. 9.20) of the area the cyst is
suspected to be in. Radiologically, thymic cysts manifest as well-circum-
scribed, uni-loculated, or multi-loculated masses with septa and linear wall
calcification [175].

picture showing the cyst
wall with thymic tissue
(white arrow), lymphoid
aggregates (black arrow),
and Hassall’s corpuscles
(dashed arrow) (H&E
×100)
Fig. 9.20 Magnetic

resonance imaging (MRI):
sagittal T1-WI images
show a hypo-intense and
T2-WI hyper-intense
midline cervical cystic
lesion of the thymus
(arrow)
High-resolution US of the neck may show a well-circumscribed cystic mass with
lobulated outlines, multiple small echogenic foci, and linear echogenic lines in the
midline of the lower neck anterior to the cervical trachea.

On CT scan, thymic cysts usually have a homogeneous low attenuation (10–20 HU)
with a thin uniformly smooth wall. Thymic cysts may be unilocular or multilocular.
After contrast injection, the cyst wall shows smooth regular enhancement. When a
cyst becomes infected, its protein content increases, and this is seen on CT as an
increase in attenuation.

On MRI, thymic cysts are homogeneous with a low or intermediate signal on
T1-weighted and a high signal on T2-weighted images. Relationship of the cyst
with surrounding structures can be clearly demonstrated on CT scan and MRI
[178, 182].
The differential diagnosis of midline suprasternal neck mass in children includes
thyroglossal duct cyst, dermoid-epidermoid cyst, cystic hygroma, thyroid mass, and
ectopic thymic mass [183]. Laryngocele and phlebectasia may produce similar clin-
ical presentation and can be easily differentiated from one another on imaging.
Laryngocele, an abnormal dilatation of laryngeal saccule, can occur in children, but
is more common in adult men in the fifth decade, and CT scan is the preferred imag-
ing technique for evaluating laryngocele [184]. Phlebectasia is dilatation of an iso-
lated vein, which affects the internal jugular vein and the anterior jugular vein
[185, 186].
Treatment
Surgical excision is the recommended treatment of thymic cysts. Open procedure
involving thoracotomy/sternotomy and minimally invasive procedures like VATS/
mediastinoscopy are used for surgical removal.
9.7 Aneurysm of the Innominate Artery (IA)
Introduction
Tracheal compression by innominate artery (IA) pathology requiring surgical repair

is rarely encountered, with only a few cases of IA aneurysms and congenital anoma-
lies in the literature [187]. Innominate artery aneurysms may also present with a
pulsating suprasternal lump [187].
Clinical Presentation and Diagnosis
In 2013, Sayed et al. reported a 70-year-old lady who complained of shortness of

breath while lying flat and a sense of suprasternal discomfort in the upright position.
There were no apparent medical diseases (cardiac and/or respiratory) that could
explain these symptoms. Examination revealed the presence of a pulsating supra-
sternal lump (4 cm in diameter). The lower border of the lump was not felt, denoting
that the lump arose from inside the thorax. A CT scan of the neck and chest sug-
gested an IA dilatation in close contact to the trachea. Exploration through a median
sternotomy and dissection of the IA, right common carotid artery (CCA), and right
subclavian artery revealed very tortuous and redundant arteries making a loop after
being liberated from the surrounding tissues. The IA showed mild dilatation (2 cm
in diameter). In addition, the left CCA was found arising from a common trunk with
the innominate artery (bovine trunk). The trachea was partially released from com-
pression after liberation of the looped arteries, but the junction of the left CCA to
the origin of the dilated IA was still pressing on it. The IA was divided just distal to
the left CCA origin, a 2 cm segment was excised to shorten its length, and the artery
was reimplanted at a proximal site at the ascending aorta to straighten the redundant
right CCA and right subclavian arteries. Reconstruction led to a more anatomical
alignment of cervical blood, and the patient’s symptoms completely disappeared
after the procedure [187].
De Feiter et al. described an IA aneurysm compressing the trachea after thoracic
aortic aneurysm repair in a patient with Marfan’s disease [188]. Montgomery et al.
also reported tracheal compression by an IA aneurysm, but they declined to perform
surgical repair as the mild symptoms did not justify the operative risk [189].
Constenla et al. [190] and Choi et al. both reported cases of IA aneurysm with air-
way compression in patients with bovine aortic arch [191].
Brewster et al. published their experience with IA lesions. Among their 71
patients, 6 underwent operation for relief of tracheal compression. In five pediatric
patients, this was attributed to presumed anomalous origin of IA more distally on
the aortic arch. The remaining elderly patient in this group had tracheo-malacia and
respiratory insufficiency caused by prolonged pressure from an elongated and tortu-
ous atherosclerotic IA [192].
Management
The method of revascularization varied in the different reports in the literature. The
five pediatric patients reported by Brewster et al. underwent a pexy operation ante-
riorly to the sternum with relief of respiratory symptoms. The single elderly adult
patient in this group required prolonged respiratory support for tracheo-malacia
[192]. Choi et al. resected the segment of IA with pseudoaneurysm and recon-
structed with an 8 mm Dacron graft [191]. Constenla et al. placed a bypass from the
ascending aorta (side-to-end anastomosis) to both CCAs (end-to-end anastomoses)
using a handmade bifurcated Dacron graft [190].
9.8 Aortic Arch Aneurysm (AAA)
Introduction
An isolated aortic arch aneurysm (AAA) is an uncommon disease entity and often
remains clinically silent, given its indolent growth pattern. Aneurysms of the aortic
arch are commonly found in association with aneurysms of the adjacent ascending
or descending aorta. The true incidence and natural course are still relatively
unknown; however, aneurysms involving the arch pose a significant challenge per-
taining to surgical management and can be complicated by neurological injury and
life-threatening cardiovascular events [193]. To avoid the high morbidity and mor-
tality associated with the life-threatening complications of this condition, it must be
promptly diagnosed, monitored, and timely treated.
Definition
A true aneurysm is defined as a “pathological dilation of a segment of a blood vessel

involving all three layers of the vessel wall (tunica intima, media, and adventitia)
and having at least a 50% increase in diameter compared with the expected normal
diameter of the artery [193]. Aortic arch aneurysms include any thoracic aneurysm
that involves the brachiocephalic vessels [194, 195].
Surgical Anatomy
The aortic arch is derived from the left branch of the fourth pharyngeal arch during
embryonic development. It represents the continuation of the ascending thoracic
aorta, which begins at the level of the upper border of the second sternocostal joint
of the right side. It courses posteriorly, superiorly, and to the left. The distal portion
of the aortic arch lies to the left of the trachea, transverses downwards, and termi-
nates adjacent to the lower border of T4, where it continues as the descending aorta.
The upward convexity of the aortic arch stems out the following three main
branches:
1. Brachiocephalic trunk (innominate artery): It further divides into the right sub-
clavian and right CCAs and supplies blood to the right arm and right head
and neck.
2. Left CCA: It carries blood to the left side of the head and neck.
3. Left subclavian artery: It is the most distal branch and distributes blood to the
left arm [196].
Epidemiology
The true incidence and prevalence of aortic aneurysms are difficult to determine as
most of them are often asymptomatic, with a large number of cases being diagnosed
incidentally [197]. Thoracic aortic aneurysms (TAAs) have an estimated incidence
of approximately 10 cases per 100,000 persons per year. Aneurysms involving the
aortic arch constitute a minor proportion of TAAs, accounting for about 10% of the
total cases of TAAs [195, 198].
Males are 2–4 times more commonly affected than females, with the majority of
patients in the sixth and seventh decades of life [199]. With the improvement in
screening and advancement in imaging techniques, it is difficult to decipher whether
the apparent increase in the number of patients with aortic arch aneurysms is a result
of increased detection or due to a rise in the incidence of the disease [200].
Etiology
Atherosclerosis or plaque buildup is the predominant etiology for an isolated AAA

as well as for those associated with descending aorta. The aneurysms found in rela-
tion to ascending thoracic aorta often result from cystic medial degeneration. The
causes include Marfan’s syndrome, Loeys–Dietz syndrome, Ehlers-Danlos syn-
drome, Turner syndrome, familial thoracic artery aneurysm (TAA) syndrome, and
Behcet disease [201]. Deceleration injuries have been seen to cause dilation of the
segment just after the aortic arch [193, 202].
Both infectious and noninfectious inflammatory conditions of the aorta (aortitis)
can also result in TAA. These include syphilis, giant cell arteritis, and Takayasu
arteritis [202]. Along with the risk factors for atherosclerosis such as smoking,
hypertension, and hypercholesterolemia, factors that increase aortic wall stress,
including pheochromocytoma, cocaine use, coarctation, weight lifting, also increase
the likelihood of development of TAA [199].
Pathophysiology
The literature on the pathophysiology of aortic aneurysm is continuously evolving

and reflects an interplay of protein degeneration, thrombosis, hemodynamic stress,
and inflammatory cytokines contributed by genetic triggers and developmental risk
factors.
Major theories on the development of aneurysm have surfaced from in vitro stud-
ies that emphasize the role of the breakdown of extracellular matrix proteins by
proteolytic enzymes such as elastase, collagenase, plasmin, and matrix metallopro-
teinases (MMPs) [203]. Endothelium, smooth muscle cells, and inflammatory cells
infiltrating the media and adventitia act as the source for these proteases [204]. The
resultant medial degeneration leads to the weakening of the aortic wall, which in
turn results in aortic dilatation and aneurysm formation.
As most of the cases of an isolated AAA are seen in relation to underlying ath-
erosclerosis, laboratory findings suggest that inflammatory cells present within the
atheroma accelerate the breakdown of matrix protein by the release of the inflam-
matory mediators [200]. In addition, narrowing of the arterial lumen by an athero-
sclerotic thrombus triggers a compensatory process in the media in response to the
shear stress on the wall. This matrix remodeling promotes the expansion of the
vessel in an attempt to normalize diameter and hemodynamic forces. Along with the
mechanical weakening, atherosclerosis may also induce aneurysm formation by

degenerative ischemic changes, through the obstruction of the vasa vasorum.
Independent risk factors of both atherosclerosis and aneurysm, including hyper-
tension and smoking, exert a direct effect on the vasculature, adding to the multifac-
torial pathophysiology of aneurysm formation.
Histopathology
Histopathology of aortic aneurysm described as cystic medial degeneration is char-

acterized by disintegration and loss of elastic fibers with an increase in the deposi-
tion of proteoglycans. Loss of smooth muscle cells in tunica media is typically seen
[193, 195]. Increased penetration of vasa vasorum into the medial layer was reported
[205]. As atherosclerosis has been found commonly in relation to the AAA, histo-
logical data also depicts the presence of atheroma or fibro-fatty plaque in the lesion.
However, these changes have been seen superimposed on the degenerative medical
disease [206].
History and Physical Examination
Most patients with an AAA are asymptomatic or directly present with life-
threatening complications. Aneurysms are typically discovered incidentally on
imaging ordered for other indications. Vague chest discomfort, neck, and jaw pain
may occur with aneurysms involving the arch. A large-sized aneurysm can impinge
upon the adjacent anatomical structures and exert a local mass effect including
hoarseness, from left recurrent laryngeal nerve (RLN) stretching; stridor, from tra-
cheal or bronchial compression; cough, dyspnea, and recurrent pneumonitis, from
lung compression; dysphagia, from esophageal compression; and plethora and
edema, from compression of the SVC [194].
The most serious consequence of TAA is aortic dissection or aortic rupture,
which presents as tearing, chest pain, and hypotension [202].
Other less frequent manifestations include systemic embolization as a result of
athero-embolism and gastrointestinal hemorrhage secondary to the formation of an
aorto-esophageal fistula.
Investigations
Chest X-rays are not sensitive to exclude the presence of aortic aneurysms and are
inadequate to differentiate between an aneurysm and conditions like mediastinal
mass, torturous aorta, or aortic dissection with similar radiographic features and
require definitive aortic imaging.
Computed tomography angiography (CTA) or magnetic resonance angiography
(MRA) are the imaging modalities of choice for accurate detection and
measurement of TAA. It is preferred to delineate aortic anatomy, size, and branch

artery involvement and to rule out other differentials [194]. These can be of disad-
vantage to patients with decreased kidney function as CTA requires the administra-
tion of intravenous contrast dye, and MRA usually requires the use of
gadolinium [207].
Echocardiography can also be used to visualize the aorta and its major branches;
the suprasternal view is best for viewing the aortic arch [207]. Coronary angiogra-
phy and echocardiography are also performed as part of usual preoperative investi-
gations done in order to determine the need for a concomitant cardiac procedure. In
addition, as maintaining brain perfusion is critical while performing surgeries
involving the aortic arch, carotid duplex scanning is also routinely instituted in
order to assess for carotid stenosis [199]. If TAA is detected, it is recommended to
image the abdominal aorta to screen for an abdominal aortic aneurysm.
Other aortic arch conditions causing dilation of the vessel segment, including pseu-
doaneurysm, intramural hematoma, and aortic dissection, can manifest with similar
symptoms to those of aortic arch aneurysm. Pseudoaneurysms usually develop sec-
ondary to deceleration injury or torsional trauma from accidents and falls. The chest
pain from aortic dissection is usually very severe and described as tearing and sharp
in nature [194].
These aortic lesions, along with some other conditions including mediastinal
mass, torturous aorta, and senile ectasia, mimic the plain radiographic findings of
the thoracic aneurysm, including widened mediastinal silhouette and altered aortic
profile, and hence necessitate the need for confirmatory diagnostic imaging studies
such as angiography to rule out these disorders.
Management
Medical Management
The primary step in the management of AAA is to control the risk factors of athero-
sclerosis, to slow the rate of expansion, and to lower the likelihood of development
of the complications, including dissection or rupture [208, 209]. Stringent control of
hypertension, optimization of the lipid profile, smoking cessation, and other athero-
sclerosis risk reduction measures should be implemented [208, 209].
Other important conservative treatment strategies include patient education
regarding the signs and symptoms indicating the development of complications,
serial imaging of aneurysm to evaluate for expansion, screening for aneurysms at
other locations including noncontagious aortic segments, and counseling for those
suspected of having an associated genetic disorder. It is reasonable to reimage using
CT or MRI at 12-month intervals for isolated AAAs <4 cm in diameter and at
6-month intervals for AAAs >4 cm in diameter, in order to detect enlargement of the
aneurysm.
Surgical Treatment
Surgical intervention for treatment of AAAs raises a particular concern due to high
rates of mortality, need for creating a bloodless field with circulatory arrest, and
challenges in maintaining perfusion to the head, neck, and upper extremities [210].
The risk of a surgical procedure should be weighted against hazards of aortic rup-
ture while formulating a decision on when and if to operate.
The management of AAA is becoming increasingly complex and multidisci-
plinary. It has evolved since the first successful repair by De Bakey et al. in 1957
[211]. After these initial repairs, the improvement in open surgical techniques, car-
diopulmonary bypass, anesthesia, and perioperative care were the primary drivers
of the decrease in morbidity and mortality associated with repair. The development
of endovascular technology has spurred another revolution in the management of
AAA aneurysms. These techniques are varied and have different advantages and
disadvantages, depending on patient anatomy and perioperative surgical risk. For
low- and intermediate-risk patients, open surgery remains the gold standard.
However, just as improvements in technique, monitoring, and perioperative care led
to progress in open repair, similar advancements in endograft technology, anatomi-
cal customization, and embolic protection will expand the use of endovascular
repair [211].
Candidates for Operative Management

The 2014 European Society of Cardiology (ESC) guidelines recommend that sur-
gery should be considered in patients who have an isolated AAA with a maximal
diameter of >5.5 cm. Aortic arch repair may also be considered in patients with
AAA who are already going to have surgery of an adjacent aneurysm located in the
ascending or descending aorta [207]. In general, surgical treatment is often recom-
mended for all symptomatic patients, patients with aneurysm size >5.5 cm, and any
patient of TAA with a growth rate exceeding 0.5 cm/year [203].
Operative Procedures
Advancements in open surgical techniques, safer anesthetic practices, and impro-
vised methods of maintaining cerebral perfusion have revamped the most widely
used conventional open repair procedure. The newer endo-vascular and hybrid
modalities have also emerged. These newer technologies have made surgical treat-
ment possible even for a larger spectrum of patients, including those at high risk and
with multiple comorbidities. Each of these techniques has its own merits and demer-
its, and the choice is tailored considering perioperative risks, comorbidities, and
anatomy of the lesion.
Recommendations for open surgical repair of asymptomatic patients with AAAs
are as follows [210]:
–– For thoracic aortic aneurysms also involving the proximal aortic arch, partial
replacement of the arch and repair of the ascending aorta using right subclavian/
axillary artery inflow and hypothermic circulatory arrest are reasonable.
–– Replacement of the entire arch is reasonable for acute dissections when the arch
is aneurysmal, or there is excessive aortic arch destruction and leakage.
–– Replacement of the entire aortic arch is reasonable for aneurysms of the whole
arch, for chronic dissection when the arch is dilated, and for distal arch aneu-
rysms that also involve the proximal descending thoracic aorta, usually with the
elephant trunk procedure.
Open arch replacement usually employs the use of a classical two-staged ele-
phant trunk (ET) or a frozen elephant trunk (FET) procedure wherein the first stage
is an open repair of the ascending aorta and aortic arch along with the placement of
the trunk followed by a second-stage completion surgery, which involves the inter-
vention of the descending aorta via either open or endo-vascular approach using
thoracic endo-vascular stent graft (TEVAR) [212].
Hybrid procedure renders a less invasive intervention and also often obviates the
need for hypothermic circulatory arrest (HCA) and cardiopulmonary bypass (CPB),
hence making the surgical treatment of aneurysms acceptable to a larger subset of a
patient population with comorbid conditions who otherwise would not tolerate the
technical demands of open repair under HCA. As described above, TEVAR can be
integrated with conventional open repair as a safe alternative to open thoracotomy
to complete distal aneurysm repair or is combined with open debranching of cere-
bral vessels [213].
Supra-aortic arch debranching involves bypass to all three arch branches from
the ascending aorta followed by TEVAR, including the arch [214]. This can be
achieved by sequential anastomosis of affected arch vessels to the Dacron graft. In
some patients with favorable anatomy, the hybrid procedure is carried out by con-
struction of the extra-anatomic bypass, either carotid-carotid or carotid subclavian,
to allow an endo-graft to cover the origin of the carotid artery. To accommodate
TEVAR, the landing zone is created in the non-aneurysmal segment of the aorta
having appropriate dimensions [203].
With increasing competence in endo-vascular procedures, total endo-vascular
repair surgeries of the aortic arch with the use of advanced generations of branched
or fenestrated endo-grafts or with chimney technique have been tried at some cen-
ters with technical success and low perioperative morbidity and mortality [214–217].
Prognosis
The prognosis of AAA largely depends on the size of the aneurysm and rate of
expansion, which are the most significant predictors of the rupture. Prognosis is
usually good if timely intervention is instituted before rupture, which can have mor-
tality as high as 80% [210, 218, 219].
Complications
Aortic arch aneurysms can lead to life-threatening cardiovascular and neurological

complications, including aortic rupture presenting as severe chest pain and hypoten-
sion or shock, aortic dissection, and athero-embolism causing ischemic strokes.
Some rare complications such as aorto-esophageal or aorto-bronchial fistula have
also been documented [220]. Embolization during the placement of the graft lead-
ing to stroke or spinal ischemia from obstruction of spinal arteries, endoleaks, and
hematoma formation are also some of the well-known and concerning perioperative
complications associated with the aortic repair [210].
9.9 Cervical (High) Aortic Arch
Definition
Cervical aortic arch (CAA) is a rare aortic arch anomaly with a prevalence of less
than 1 of 10,000 live births. Its prevalence among adults has not been reported [5].
It is characterized by an elongated, high-lying aortic arch extending at or above the
level of the medial ends of the clavicles [221].
Pathology
A cervical aortic arch develops most likely from the persistence of the embryonic
third aortic arch instead of the fourth [222–234].
Classification
According to Haughton and colleagues, there are five distinct forms of cervical
aortic arch, which are classified according to the configuration of the aorta, sequence
of brachiocephalic branching, and embryogenesis (Table 9.7) [222].
In 2020, Zhong et al. [235] proposed a categorization scheme, which is simpler
and more intuitive with respect to pathological classification and surgical decision-
making proposed earlier in 1975 by Haughton et al. [222]. The recently proposed
classification system of CAA consists of two types and six subtypes on the basis of
the presence of vascular ring (i.e., retro-esophageal aortic segment and/or aberrant
subclavian artery) and the relationship of DTA to the side of the aortic arch. Type A
refers to CAAs without vascular ring, including two subtypes: A1, left-sided arch
with ipsilateral descending thoracic aorta (DTA), and A2, which is the mirror image
Table 9.7 Classification of cervical aortic arch (CAA) [222]
Type Configuration of aorta Branching Embryogenesis
A Contralateral descending aorta and Has separate ECA and ICA branches from Results from persistence of the entire third
absence of one CCA the aortic arch primitive aortic arch on one side and involution
9.9 Cervical (High) Aortic Arch
of the contralateral ductus caroticus and of the

fourth aortic arches bilaterally
B Contralateral descending aorta and Dual common carotid arteries Development is similar to type A, but with
presence of both CCAs formation of CCAs rather than separate ICA
and ECA proximally
C Contralateral descending aorta and Usually, left cervical arch with a Results when the distal aorta is connected with
bicarotid trunk right-sided descending aorta. Cases have a a right-sided ductus arteriosus and the
common trunk from which right and left transverse aorta has migrated abnormally
CCAs originate (bicarotid trunk)
D Ipsilateral descending aorta with Usually left cervical arch with a normal Forms when the process of involution is
normal sequence of brachiocephalic branching pattern, redundant transverse conventional, but the aortic segment between
branching aorta, and left-sided often hypoplastic the left CCA and left subclavian arteries is
descending aorta excessively long
E Right aortic arch and right descending An aberrant left subclavian artery Formed by the development of a right arch and
aorta failure of migration of the apex of the arch to
the thoracic region
ECA external carotid artery, ICA internal carotid artery, CCA common carotid artery
343
Table 9.8 Recent Type Description

classification system of Type A CAAs without a vascular ring
cervical aortic arch
A1 Left-sided arch with ipsilateral descending thoracic
(CAA) [235]
aorta (DTA)
A2 The mirror image pattern of type A1
Type B CAA with a vascular ring
B1 Right-sided arch with ipsilateral DTA and aberrant
left subclavian artery (LSCA)
B2 Right-sided arch with contralateral DTA
B3 Left-sided arch with ipsilateral DTA and aberrant
right subclavian artery (RSCA)
B4 Left-sided arch with contralateral DTA
pattern of type A1. Type B refers to CAA with vascular ring, in which subtype B1
is right-sided arch with ipsilateral DTA and aberrant left subclavian artery (LSCA),
subtype B2 is right-sided arch with contralateral DTA, subtype B3 is left-sided arch
with ipsilateral DTA and aberrant right subclavian artery (RSCA), and subtype B4
is left-sided arch with contralateral DTA (Table 9.8).
Associations
Reported associations in the literature include (1) aneurysms (approximately in

20% of cases [226, 228], predominant in women [234], pathophysiology is not clear
but possible explanations include abnormal embryological development, abnormal
connective tissue, altered hemodynamics, aortic wall stress, atherosclerosis, and
trauma), (2) coarctation of the aorta, (3) aortic pseudocoarctation, (4) congenital
cardiac anomalies, (5) DiGeorge syndrome [232], and (6) Turner syndrome [232].
Radiographic Features
Plain Radiograph
Plain X-ray usually shows that the high-riding arch may be seen as a mass-like
paratracheal soft tissue density, the normal aortic knob may be absent, and widened
mediastinum can be observed. Compression and displacement of the trachea and
esophagus may be demonstrated.
Echocardiography
Echocardiography may demonstrate color flow jets in opposite directions indicative
of tortuous aneurysmal dilatation of the aortic arch at the cervical position [231].
9.9 Cervical (High) Aortic Arch 345
Angiography
Computed tomography angiography (CTA), magnetic resonance angiography
(MRA), and digital subtraction angiography (DSA) will allow direct visualization
of arch anatomy and associated anomalies.
Clinical Presentation and Diagnosis
Patients with cervical aortic arch are usually asymptomatic. Symptomatic patients
may present with a palpable cervical mass, dysphagia, wheezing, coughing, hoarse-
ness, stridor, choking, apneic spells, chest pain, and recurrent pulmonary infection
[222–234].
Ilyas et al. (2018) reported a case of type B Haughton cervical aortic arch [222]
in a 19-year-old male who presented with an asymptomatic swelling in the SSS,
more to the right side. There was no history of pain and fever. He was diagnosed as
having bicuspid aortic valve on echocardiography with evidence of mild aortic
regurgitation. His blood pressure was 124/80 mmHg. The breath rate and pulse rate
were within normal limits. He had no significant family history. There was no his-
tory of change in voice and dysphagia. On inspection, the neck swelling appeared
pulsatile, and palpation revealed an elongated pulsatile soft neck swelling. There
was no skin discoloration or erythema over the swelling. An early diastolic murmur
was noted at the aortic site. Plain radiograph of the neck and upper chest revealed
an elongated soft tissue shadow displacing the trachea to the left. CT angiography
(CTA) revealed an elongated ascending aorta with cervical aortic arch. The arch was
at the level of C6 vertebra (normal D4 level). The descending aorta was seen to
cross the midline to descend on the left side. No vessel was seen arising from the
aortic arch. The brachiocephalic trunks were absent, and all major vessels were aris-
ing separately. The right CCA was arising from the ascending aorta at the level of
C7 vertebra, while the left CCA was arising from the ascending aorta at D3 level.
The right subclavian artery was arising from the descending aorta (before its cross-
ing to the left) at D1 level, and the left subclavian artery was arising from the
descending aorta (after crossing to the left) at D4 level. The origin of the left subcla-
vian artery was mildly dilated with evidence of pseudocoarctation. The trachea was
displaced to the left side. There was no evidence of any aneurysmal dilatation in the
course of aorta or its major branches, and no associated cardiac anomaly was evi-
dent [236].
Possible differential considerations for certain variants include aortic pseudocoarc-

tation, chronic Takayasu arteritis, and thoracic aortic aneurysm.
Surgical treatment is commonly indicated for (1) the relief of symptoms resulting
from compression of the trachea and esophagus, (2) correction of associated intra-
cardiac defects, and (3) repair of associated aneurysms and aortic obstruction
[223, 224].
Surgery includes surgical correction by excision and re-localization into the tho-
rax. Other options include endo-vascular stenting to exclude aneurysms and dissec-
tions [226].
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aneurysms—diagnosis and treatment strategies. Dtsch Med Wochenschr. 2019;144(3):146–51.
216. Zhang J, Liu X, Tian M, Chen H, Wang J, Ji M, et al. Endovascular aortic repairs combined
with looping-chimney technique for repairing aortic arch lesions and reconstructing left com-
mon carotid artery. J Thorac Dis. 2020;12(5):2270–9.
217. Mehmedovic A, Konstantinou N, Jerkku T, Pichlmaier M, Kölbel T, Rantner B, et al. Aortic
aneurysm: fenestrated/branched endovascular aortic repair (EVAR) and fenestrated/branched
thoracic endovascular aortic repair (TEVAR). Is total endovascular repair already here?
Zentralbl Chir. 2020;145(5):432–7.
218. Davies RR, Goldstein LJ, Coady MA, Tittle SL, Rizzo JA, Kopf GS, et al. Yearly rupture or
dissection rates for thoracic aortic aneurysms: simple prediction based on size. Ann Thorac
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219. Yiu RS, Cheng SW. Natural history and risk factors for rupture of thoracic aortic arch aneu-
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221. Yahay Hamid SA. Cervical aortic arch with hypoplastic left common carotid artery and sub-
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Follow-Up and Patient Education
10
Contents
10.1 Follow-Up of Patient Not at Increased Risk 357
10.2 Education of Patient at Increased Risk 358
References 360
10.1 Follow-Up of Patient Not at Increased Risk
For patients with a neck mass who are not at increased risk of malignancy, patients
should be advised of the criteria that would trigger the need for additional evalua-
tion. These include persistence of the mass for more than 2–3 weeks, voice change,
difficulty or pain with swallowing, trouble hearing or ear pain, sore throat, unex-
plained weight loss, and fever over 38 °C. The aim is to decrease the risk associated
with delayed or missed diagnosis of a malignant neck swelling in a patient who is
felt not to be at increased risk of malignancy. In addition, clinicians should docu-
ment a plan for follow-up to assess complete resolution or final diagnosis of
the lesion.
Follow-up of patients who present with a midline neck swelling and not consid-
ered at an increased risk of malignant is necessary because some neck masses ini-
tially diagnosed as benign prove later to be malignant. Examples include those with
clinically diagnosed branchial cleft cysts but proved on subsequent pathological
diagnosis to be metastatic head/neck squamous cell carcinoma (HNSCC) [1–3], or
patients who develop infection in a necrotic metastatic lymph node (LN) [4, 5].
Presumptive diagnosis of a benign etiology may give the patient a false sense of
security and dissuade the patient from seeking additional evaluation when needed.
Clinicians should inform patients of the expected response to treatment. Printed

Switzerland AG 2024
358 10 Follow-Up and Patient Education
educational material (patient handout) may supplement the discussion. If antibiotics

are provided, the patient should be informed about the expected time until response
of the neck mass (i.e., return of the LN to normal size, <1.5 cm) as well as the need
for clinical follow-up if the mass persists. The patient and clinician are jointly
responsible to ensure that the neck mass decreases in size or that a final diagnosis is
made. The nature of follow-up is at the discretion of the patient and the clinician.
Follow-up may entail a revisit or telephone call with the clinician, referral to a spe-
cialist, or additional investigations [6].
10.2 Education of Patient at Increased Risk
Importance of Timely Diagnosis
Delay in diagnosis may result from patient delay or professional delay. Timely diag-
nosis of a midline neck mass due to metastatic HNSCC is of paramount importance
because delayed diagnosis directly affects tumor stage and worsens prognosis [7–
9]. Delays in diagnosis of 3–6 months have been reported [10–13]; delays as short
as 2 months are associated with worse functional outcomes [14–16], poorer quality
of life, cancer recurrence, and death [17–19].
Unfortunately, despite substantial advances in diagnostic modalities over the last
few decades, diagnostic delays are still common. About 40 years ago, patients with
a neck mass experienced an average of a 5- to 6-month delay from the time of initial
presentation to the diagnosis of malignancy [10]. Currently, studies continue to
report delays as long as 3–6 months [11–13]. It is thus mandatory to promote the
efficient, effective, and accurate diagnostic workup of neck masses to ensure that
adults with potentially malignant disease receive prompt diagnosis and intervention
to optimize outcomes.
Patient Education and Counseling
For patients with a cervical swelling who are deemed at increased risk of malig-
nancy, clinicians should explain to the patient the significance of being at increased
risk and explain any recommended diagnostic tests. The aim is to highlight the
importance of patient education, counseling, and shared decision-making when car-
ing for a patient with a neck mass. Open communication and education empower
patients to make informed decisions, improve treatment adherence, and promote
greater satisfaction and better outcomes [20–22].
The clinician should ensure that the patient understands the clinical significance
of a neck mass at increased risk of malignancy. Thus, the patient should be coun-
seled about risk factors of malignancy, including tobacco use, excessive alcohol
consumption, increased numbers of sexual partners, oral sex, and prior history of
head and neck squamous cell carcinoma (HNSCC). When possible, the clinician
should encourage the patient to reduce such modifiable risk factors. The clinician
10.2 Education of Patient at Increased Risk 359
may choose to discuss human papillomavirus (HPV) vaccine, recognizing that most
patients will exceed the age limit and that the possible preventions of HNSCC are
unproven. However, discussion of this issue is important for primary prevention.
The clinician should also inform the patient that a lack of any of these risk factors
does not mean that the mass is not cancer.
The clinician should also explain to the patient relevant aspects of the evaluation,
including diagnostic investigations and specialty consultation, and discuss possible
diagnoses, including carcinoma, and help the patient understand the importance of
further evaluation and diagnostic testing to obtain a final diagnosis.
Furthermore, the clinician should discuss that if a neck mass is malignant, the
primary site will often be in the nasopharynx, oropharynx, or larynx, and that symp-
toms related to the primary site may develop later. Clinicians may improve patients’
adherence to the evaluation process with effective communication and education.
The patient should be allowed time for questions and discussion. Cultural diversity,
language difficulties, and educational backgrounds should be considered during
these discussions. Written information can be an important supplement to patient
understanding and may increase patient involvement and encourage shared decision-
making [21, 22].
Diagnostic Procedures
The patient should have a clear understanding of necessary diagnostic examina-

tions, including the process, urgency, risks, and benefits of each, as well as the
expected time frame of test results and follow-up. It should be made clear to the
patient that this is a shared decision process. The clinician will order and interpret
the diagnostic procedures and give his or her opinion regarding what surgical inter-
vention is needed. The clinician and the patient will share in the decision on what
procedure will follow [23].
A detailed follow-up plan should be reviewed with the patient to include diag-
nostic investigations and to ensure that those results are communicated in a clear
and timely manner.
Preoperative Patient Education
To support the patient physically and emotionally, the surgeon or his or her designee
should provide patient-friendly information. This should include explanation of the
rationale, risks, and benefits of surgery as well as discussion of the patient’s expec-
tations regarding management of postoperative pain. Patients should be encouraged
to ask questions and to promptly inform the surgeon of unexpected symptoms that
arise postoperatively. In a systematic review of preoperative education for cancer
patients undergoing surgery, patients receiving preoperative education overall had
increased satisfaction, increased knowledge, and, in some studies, reduced anxi-
ety [24].
360 10 Follow-Up and Patient Education
References
1. Goldenberg D, Begum S, Westra WH, Khan Z, Sciubba J, Pai SI, et al. Cystic lymph node
metastasis in patients with head and neck cancer: an HPV-associated phenomenon. Head
Neck. 2008;30:898–903.
2. Gourin CG, Johnson JT. Incidence of unsuspected metastases in lateral cervical cysts.
Laryngoscope. 2000;110:1637–41.
3. Sira J, Makura ZGG. Differential diagnosis of cystic neck lesions. Ann Otol Rhinol Laryngol.
2011;120:409–13.
4. Wang C-P, Ko J-Y, Lou P-J. Deep neck infection as the main initial presentation of primary
head and neck cancer. J Laryngol Otol. 2006;120:305–9.
5. Soon SR, Kanagalingam J, Johari S, Yuen HW. Head and neck cancers masquerading as deep
neck abscesses. Singap Med J. 2012;53:840–2.
6. Franco J, Elghouche AN, Harris MS, Kokoska MS. Diagnostic delays and errors in head and
neck cancer patients: opportunities for improvement. Am J Med Qual. 2017;32:330–5.
7. Urjeet AP, Brennan TE. Disparities in head and neck cancer: assessing delay in treatment ini-
tiation. Laryngoscope. 2012;122:1756–60.
8. Seoane J, Alvarez-Novoa P, Gomez I, Takkouche B, Diz P, Warnakulasiruya S, et al. Early oral
cancer diagnosis: the Aarhus statement perspective. A systematic review and meta-analysis.
Head Neck. 2016;38(Suppl 1):E2182–9.
9. Seoane J, Taccouche B, Varela-Centelles P, Tomas I, Seoane-Romero JM. Impact of the delay
in diagnosis in survival of head and neck carcinomas: a systematic review with meta-analysis.
Clin Otolaryngol. 2012;37:99–106.
10. Bruun JP. Time lapse by diagnosis of oral cancer. Oral Surg Oral Med Oral Pathol Oral Radiol
Endod. 1976;42:139–49.
11. McGurk M, Chan C, Jones J, O’regan E, Sherriff M. Delay in diagnosis and its effect on out-
come in head and neck cancer. Br J Oral Maxillofac Surg. 2005;43:281–4.
12. Smith MM. Assessing delays in laryngeal cancer treatment. Laryngoscope. 2016;126:1612–5.
13. Brouha XDR, Tromp DM, Koole R, Hordijk GJ, Winnubst JA, de Leeuw JR. Professional
delay in head and neck cancer patients: analysis of the diagnostic pathway. Oral Oncol.
2007;43:551–6.
14. Hutcheson KA, Holsinger FC, Kupferman ME, Lewin JS. Functional outcomes after TORS
for oropharyngeal cancer: a systematic review. Eur Arch Otorhinolaryngol. 2015;272:463–71.
15. Gallagher KK, Sacco AG, Lee JS-J, et al. Association between multimodality neck treatment
and work and leisure impairment: a disease-specific measure to assess both impairment and
rehabilitation after neck dissection. JAMA Otolaryngol. 2015;141:888–93.
16. Wopken K, Bijl HP, van der Schaaf A, Christianen ME, Chouvalova O, Oosting SF, et al.
Development and validation of a prediction model for tube feeding dependence after curative
(chemo-) radiation in head and neck cancer. PLoS One. 2014;9:e94879.
17. Koivunen P, Rantala N, Hyrynkangas K, Okinen K, Alho OP. The impact of patient and profes-
sional diagnostic delays on survival in pharyngeal cancer. Cancer. 2001;92:2885–91.
18. Teppo H, Koivunen P, Hyrynkangas K, Alho OP. Diagnostic delays in laryngeal carcinoma:
professional diagnostic delay is a strong independent predictor of survival. Head Neck.
2003;25:389–94.
19. Huang J, Barbera L, Brouwers M, Browman G, Mackillop WJ. Does delay in starting treat-
ment affect the outcomes of radiotherapy? A systematic review. J Clin Oncol. 2003;21:555–63.
20. Coulter A, Ellins J. Effectiveness of strategies for informing, educating, and involving patients.
BMJ. 2007;335:24–7.
21. Institute of Medicine. Health literacy: a prescription to end confusion. Washington, DC:
National Academies Press; 2004.
22. O’Connor AM, Stacey D, Entwistle V, et al. Decision aids for people facing health treatment
or screening decisions. Cochrane Database Syst Rev. 2003;2:CD001431.
23. Brook I. A piece of my mind: rediscovering my voice. JAMA. 2009;302:236.
24. Waller A, Forshaw K, Bryant J, Carey M, Boyes A, Sansun-Fisher R. Preparatory education
for cancer patients undergoing surgery: a systemic review of volume and quality or research
output over time. Patient Educ Couns. 2015;98:1540–9.

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Midline Neck

Midline Neck Swellings

ISBN 978-3-031-48564-0 ISBN 978-3-031-48565-7 (eBook)

Paper in this product is recyclable.

In this authored book, we aim at emphasizing established concepts, displaying the

Alexandria, Egypt Mahmoud Sakr

5.5 Abscess in Relation to Odontogenic Infections���������������������������������� 77

1.1 Triangles and Muscles of the Neck

Triangles of the Neck

© The Author(s), under exclusive license to Springer Nature 1

consists of three and half triangles, namely, digastric (submandibular) triangle,

Muscles of the Neck

1.2 Surgical Levels of the Neck

1.3 Anatomical Regions of the Central Neck

1. Submental (suprahyoid) region

Table 1.1 Surgical levels of the neck [5]

Suprahyoid Region: Level 1A (Submental Triangle)

Fig. 1.2 Front view of the

 ransfer of Submental Lymph Nodes

Hyoid Bone Region

Fig. 1.4 Anatomy of the

Intrinsic Laryngeal Muscles

Extrinsic Laryngeal Muscles

Table 1.2 Intrinsic muscles of the larynx

Table 1.3 Extrinsic muscles of the larynx

Table 1.4 Pathological disorders of the larynx [25]

 lood Supply and Lymphatic Drainage

Inflammation and Infection

pressure ventilation (PPV), or surgery. A tracheal stenosis <5 cm in length can be

Suprasternal Space (SSS) of Burns

1.4 Lymph Nodes of the Central Neck

Cervical lymphadenopathy (CLA) is a significant clinical finding associated with

 ymphatic Drainage of Superficial Tissues of the Head and Neck

Table 1.5 Superficial cervical lymph nodes

 ymphatic Drainage of Deeper Tissues of the Head and Neck

Cervical Lymph Node Levels Involved in Midline Swellings

 evel IA (Submental Region)

 evel VI (Central or Anterior Compartment Group)

2.1 Classification According to Anatomical Region

Swellings Superficial to the Cervical Deep Fascia

Swellings superficial to the cervical deep fascia (DF) arise from:

Swellings Deep to the Cervical Deep Fascia

© The Author(s), under exclusive license to Springer Nature 25

Table 2.1 Midline neck swellings according to anatomical location

2.2 Classification According to the Structure of Origin

Table 2.2 Midline neck swellings according to structure of origin

2.3 Classification According to Consistency

Table 2.3 Midline neck swellings according to consistency

2.4 Classification According to Age

Table 2.4 Midline neck swellings in adults [3–5]

Table 2.5 Midline neck swellings in children [6]

Table 2.5 (continued)

3.1 Introduction to Clinical Approach

© The Author(s), under exclusive license to Springer Nature 31

and/or magnetic resonance imaging (MRI) is dictated by the patient’s presentation.

Table 3.1 History-taking of a patient presenting with a midline neck swelling

3.3 Physical Examination

Local Examination of the Swelling

Deciding on the course of investigation depends on history and physical examina-

which provide complementary information regarding primary tumor histopatho-

 ontrast-Enhanced Computed Tomography (CT) Scan of the Neck

 agnetic Resonance Imaging (MRI) of the Neck with Contrast

 omputed Tomography Angiography or Magnetic

 ositron Emission Tomography with Computed Tomography

Alexandria, Egypt Mahmoud Sakr

5.5 Abscess in Relation to Odontogenic Infections�� 77

1.1 Triangles and Muscles of the Neck

Triangles of the Neck

Muscles of the Neck

1.2 Surgical Levels of the Neck

1.3 Anatomical Regions of the Central Neck

Suprahyoid Region: Level 1A (Submental Triangle)

ransfer of Submental Lymph Nodes

Hyoid Bone Region

lood Supply and Lymphatic Drainage

Suprasternal Space (SSS) of Burns

1.4 Lymph Nodes of the Central Neck

ymphatic Drainage of Superficial Tissues of the Head and Neck

ymphatic Drainage of Deeper Tissues of the Head and Neck

Cervical Lymph Node Levels Involved in Midline Swellings

evel IA (Submental Region)

evel VI (Central or Anterior Compartment Group)

2.1 Classification According to Anatomical Region

Swellings Superficial to the Cervical Deep Fascia

Swellings Deep to the Cervical Deep Fascia

2.2 Classification According to the Structure of Origin

2.3 Classification According to Consistency

2.4 Classification According to Age

3.1 Introduction to Clinical Approach

3.3 Physical Examination

Local Examination of the Swelling

ontrast-Enhanced Computed Tomography (CT) Scan of the Neck

agnetic Resonance Imaging (MRI) of the Neck with Contrast

omputed Tomography Angiography or Magnetic

ositron Emission Tomography with Computed Tomography

ine Needle Aspiration (FNA)

ore Needle Biopsy

3.5 Differential Diagnosis

Does the Swelling Move with Deglutition?

Does the Swelling Move with Protrusion of the Tongue?

What Is the Level of the Swelling?

Is it Solid or Cystic?

4.1 Etiology of Cervical Lymphadenopathy (CLA)

Acute Bacterial Infections

Acute Viral Lymphadenitis

Chronic Nonspecific Infectious Lymphadenitis

Chronic Specific Infectious Lymphadenitis: Tuberculosis (TB)

4.3 Malignancy (Metastatic Lymphadenopathy)

Regional Lymph Nodes—TNM Staging

Metastases from Cervical Draining Areas (Overt Primary)

athophysiology: Lymphatic Spread of Tumor Cells

rimary Sites: Patterns of Drainage and Treatment

Cervical Lymph Node Metastases of Unknown Primary

4.4 Diagnostic Approach

5.2 Submental Lymphadenopathy

5.3 Cervical Dermoid Cyst

omputed Tomography (CT) Scan

agnetic Resonance Imaging (MRI)

Fig. 5.3 Axial non-

5.4 Plunging Ranula (Dumbbell-Shaped)