Jurnal

Chapter
16
Neoplasms of the Larynx

and Trachea
CLASSIFICATION OF NEOPLASTIC LESIONS OF THE LARYNX
AND TRACHEA (Box 16-1)
BOX 16-1 Classification of Laryngeal and Tracheal Neoplasms
Benign • Verrucous carcinoma

• Spindle cell squamous carcinoma
Epithelial
• Basaloid squamous carcinoma
• Papilloma/papillomatosis (recurrent respiratory
• Adenosquamous carcinoma
papillomatosis)
• Lymphoepithelial-like carcinoma
• Minor salivary gland tumors
• Giant cell carcinoma
Mesenchymal/Neuroectodermal • Minor salivary gland tumors:
• Granular cell tumor – Adenoid cystic carcinoma
• Nodular fasciitis – Mucoepidermoid carcinoma
• Inflammatory myofibroblastic tumor – Others
• Chondroma
Neuroectodermal
• Rhabdomyoma
• Neuroendocrine carcinomas:
• Hemangioma
– Carcinoid tumor
• Neurilemoma/neurofibroma
– Atypical carcinoid tumor
• Leiomyoma
– Small cell undifferentiated neuroendocrine carcinoma
• Fibrous histiocytoma
– Large cell neuroendocrine carcinoma
• Lipoma
• Mucosal malignant melanoma
• Paraganglioma
• Others Mesenchymal
• Chondrosarcoma
Premalignant Epithelial Lesions
• Synovial sarcoma
• Dysplasias, keratinizing and nonkeratinizing
• Liposarcoma
Malignant • Rhabdomyosarcoma
• Angiosarcoma/Kaposi sarcoma
Epithelial
• Leiomyosarcoma
• Squamous cell carcinoma:
• Hematolymphoid
– Carcinoma in situ
• Others
– Microinvasive carcinoma
– Invasive squamous cell carcinoma Secondary Tumors
• Papillary (exophytic) squamous cell carcinoma
GENERAL CONSIDERATIONS • Primary tumors of the trachea are rare and ratio of
benign to malignant tumors varies per age of the
• Similar to tumors of other upper aerodigestive tract patient:
sites, most common tumors of the larynx are of m In pediatric ages benign tumors > malignant
epithelial origin: tumors:

m Most common benign neoplasm is a (squamous) – 60% to 90% of tumors are benign:
papilloma ■ Most common are squamous papillomas,
m Most common malignant neoplasm is squamous hemangioma, granular cell tumor

cell carcinoma or variant thereof, accounting for – 10% to 40% are malignant:
greater than 95% of all malignant neoplasms of ■ Most common is mucoepidermoid
the larynx carcinoma
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CHAPTER 16 Neoplasms of the Larynx and Trachea 695
m In adult ages malignant tumors > benign tumors: • For more detailed discussion on a variety of factors
– 90% of tumors are malignant: related to laryngeal and tracheal carcinoma, see later
■ Most common (95% of total) are squamous in this chapter under site-specific squamous cell
cell carcinoma and its variants carcinoma.
m Most common benign neoplasm is a (squamous)
papilloma
BENIGN NEOPLASMS OF THE LARYNX AND HYPOPHARYNX
LARYNGEAL PAPILLOMA/
PAPILLOMATOSIS;
RECURRENT RESPIRATORY
PAPILLOMATOSIS
(Figs. 16-1 through 16-6)
Definition: Benign, exophytic epithelial neoplasm com-
posed of branching fronds of squamous epithelium with
fibrovascular cores that may be single or multiple and
may be associated etiologically with low-risk human
papillomavirus types 6 and 11.
Synonyms: Squamous papilloma; laryngeal papillo-
matosis; recurrent respiratory papillomatosis, juvenile
papillomatosis, adult papillomatosis; nonkeratinized
papilloma; keratinized papilloma; papillary keratosis
• At present, the preferred terminology for viral-
A
associated papillomas that are nonkeratinizing,
tend to persist or recur, and show a degree of
resistance to treatment is recurrent respiratory
papillomatosis.
• Most common benign neoplasm occurring in this
anatomic region
• Due to distinct clinical and histopathologic findings,
papillomas can be separated by:
m Age: juvenile versus adult forms
m Number of lesions: solitary versus multiple
m Histology: nonkeratinizing and keratinizing
Recurrent Respiratory
Papillomatosis (Nonkeratinizing
B
Papilloma) (Table 16-1)
Clinical Fig. 16-1. Recurrent respiratory (laryngeal)
• Divided into: papillomatosis.
m Lesions that occur in early years referred to as
A, The lesion is characterized by an exophytic, warty,
juvenile-onset recurrent respiratory papillomato- tan-white appearance. B, Resected portion of larynx
sis (JO-RRP) showing characteristic papillary appearance with
m Lesions that occur in older ages referred to as intraluminal growth.
adult-onset recurrent respiratory papillomatosis
(AO-RRP)
– Age separating juvenile versus adult onset
not established and different studies cite
different ages
696 SECTION 5 Larynx and Trachea
Fig. 16-2. Recurrent respiratory (laryngeal)

papillomatosis.
Left, Histologic appearance is characterized by papillary
fronds of multilayered squamous epithelium containing
fibrovascular cores. Right, Benign epithelium of the
papilloma is seen; the majority of these lesions lacks
keratinization.
– Although not universally accepted, 20 years

B
of age can serve as a potential dividing line
between JO-RRP and AO-RRP.
Fig. 16-3. Dysplasia in laryngeal papilloma.
JO-RRP
The dysplastic changes occurred over time and only after
• No gender predilection; most patients become symp- multiple recurrences. A, Dysplastic features include the
tomatic at an early age, including 2 to 5 years of age. presence of immature-appearing cells with nuclear
• Clinical presentation includes changes in phonation hyperchromasia, pleomorphism, increased nuclear-to-
(e.g., abnormal crying, hoarseness), dyspnea, cough, cytoplasmic ratio, and loss of cell polarity. B, HPV
dysphagia, stridor. cytopathic changes (i.e., koilocytes) are seen;
• Majority are multiple (rather than a single lesion) immunostaining confirmed the presence of HPV
with extensive growth and rapid recurrence: 6/11 (not shown).
m May remit spontaneously or persist into older
ages
– Extralaryngeal spread occurs more commonly
AO-RRP in children than in adults.
• More common in men than in women; affects all age – Extension into and down tracheobronchial tree
groups but most common from ages 20 to 40 occurs in approximately 5% of patients.
• Clinical presentation includes changes in phonation m RRP tends to localize to those junctional areas
(e.g., hoarseness). where ciliated respiratory epithelium meets

• Majority are single (rather than multiple) and tend squamous epithelium referred to as squamous
to recur less often. epithelial-ciliary respiratory epithelial junction
(SCJ) and include:
JO-RRP and AO-RRP – Histologically normal junctional mucosa
• Primarily a disease of the larynx: (e.g., supraglottic-glottic junction or glottic-
m May occur anywhere in the larynx but most often subglottic junction)
involve the true and false vocal cords, ventricles, – Areas in which there is metaplastic alteration
and subglottis secondary to an injury with squamous epithe-
m Spread to nearby (extralaryngeal) areas may lium replacing ciliated respiratory epithelium
occur and include oral cavity and tracheobron- creating a new squamous epithelial-ciliated
chial tree: respiratory epithelial junction
B Fig. 16-5. Malignant transformation.

Rare example of malignant transformation of recurrent
Fig. 16-4. Spread of papillomatosis. respiratory (laryngeal) papillomatosis that occurred in a
teenage girl. A, Laryngectomy specimen showing the
Progression of recurrent respiratory (laryngeal) neoplasm invading into and through cartilage. B, The
papillomatosis may include (A) extension of the papillomas histology of the carcinoma was that of a well-differentiated
from the glottic region into the subglottis and down the squamous cell carcinoma. C, The carcinoma metastasized
tracheobronchial tree; (B) extension into the lungs. The to paratracheal and cervical neck lymph nodes.
histology of all of these papillomata was that of typical
(benign) papilloma without dysplasia or evidence of
carcinoma.
• Cause: – Rarely, HPV 16, 18, 31, 33, and 35

m Virally induced caused by low-risk human papil- identified
lomavirus (HPV) m Mode of transmission:
m HPV types 6 and 11 most frequent types – In JO-RRP a significant percentage of patients
identified: (up to 70%) born to women with uterine cervi-
cal condylomas with transmission related to
maternal-genital infection:
■ JO-RRP has been correlated to the triad of
(1) first-born child, (2) vaginal delivery, and

(3) teenage mother.
■ Vaginal condyloma in pregnancy is strongly
predictive of JO-RRP.
■ Cesarean section rather than vaginal delivery
has been advocated in this clinical setting but

cesarean section has not been entirely protec-
tive from infection and the development of
RRP.
– In AO-RRP the mode of transmission remains
uncertain; considerations include:
■ Possibility of maternal transmission during
delivery with the virus remaining dormant

Fig. 16-6. Laryngeal verruca vulgaris. until adulthood when there is activation of
Laryngeal verruca vulgaris characterized by verrucoid virus
■ Orogenital contact with an infected
growth, marked keratosis, prominent granular cell layer,
and coarse, irregular keratohyaline granules. individual
TABLE 16-1 Laryngeal Papillomas: Clinical-Pathologic Features
JO-RRP AO-RRP Keratinizing Papilloma

Age Less than 20 years* 20 years and older* Occurs in adults
Gender No gender predilection Much more common in No gender predilection
men than in women
Symptoms Changes in phonation, Hoarseness Hoarseness
stridor, dysphagia, cough
Sites SCJ includes supraglottic- SCJ includes supraglottic- True vocal cord is the most common
glottic junction or glottic junction or location
glottic-subglottic junction glottic-subglottic junction
Lesions Majority are multiple (80% Majority are single (65% to Usually single
to 98%) 75%)
Pathology Papillary fronds of Papillary fronds of Papillary fronds of multilayered
multilayered benign multilayered benign benign squamous epithelium
squamous epithelium squamous epithelium containing fibrovascular cores
containing fibrovascular containing fibrovascular with associated keratinization
cores with little or no cores with little or no (parakeratosis or orthokeratosis);
keratin keratin kerato-hyaline granules may be
present
HPV Present usually 6 and 11 Present usually 6 and 11 Absent
rarely high-risk types rarely high-risk types
Treatment Surgical excision Surgical excision Surgical resection
Prognosis Variable often with recurrent Variable Usually cured after excision
disease
Malignant 2% in nonirradiated cases 2% in nonirradiated cases Rare
transformation 14% irradiated cases 14% irradiated cases
AO-RRP, Adult-onset recurrent respiratory papillomatosis; JO-RRP, juvenile-onset recurrent respiratory papillomatosis; SCJ, squamous
epithelial-ciliary respiratory epithelial junction.
*Not universally accepted as the dividing age limit.
mRNAs by underlying vascular endothelial cells,

Pathology suggesting a role for VEGF-A in the pathogenesis
Gross of RRP.
• Single or multiple exophytic, warty, friable, tan-
white to red growth(s) Differential Diagnosis
• Characteristic feature is ease of bleeding after minor • Verruca vulgaris:
trauma. m Typically occurs in cutaneous sites
m Infrequently occurs in mucosal sites, including
Histology lips
• Papillary fronds of multilayered benign squamous m Etiologically linked to HPV:
epithelium containing fibrovascular cores – HPV 2 and 4 typically associated with VV of

• Little or no surface keratin production although an the skin, lips, and oral cavity
occasional case may have keratinization (parakera- – HPV 6 and 11 identified in laryngeal VV
tosis or orthokeratosis) m Rare lesion of the larynx:
• Stroma well vascularized; variable amount of inflam- – Much more common in men than in women;
matory cells are present disease of adults
• A certain degree of cellular atypia may be seen espe- – Most common on the true vocal cord
cially in those lesions that recur over short periods – Hoarseness is the most common symptom.
of time: m Exophytic, demarcated warty-appearing white
m Generally the degree of dysplasia is limited and lesion usually measuring less than 1 cm
the risk of progression to a more significant dys- m Histologically similar to verruca vulgaris of the
plastic lesion or carcinoma is low. skin and includes:

m Atypical features include basal zone hyperplasia – Verrucoid appearance
with nuclear pleomorphism, increased nuclear-to- – Keratosis
cytoplasmic ratio, loss of cell polarity, prominent – Prominent granular cell layer
nucleoli, and increased mitotic activity; dyskera- – Coarse and irregular keratohyaline granules
tosis may also be identified. – Thin, pointy rete pegs
m Presence of severe atypia may be indicative of the – Presence of koilocytes
development of squamous carcinoma arising in m Simple excision is curative.
papillomatosis or may in fact represent an exo- m Recurrence may rarely occur.
phytic squamous cell carcinoma. • Verrucous carcinoma

m In presence of dysplasia majority are positive for • Papillary or exophytic squamous cell carcinoma
low-risk HPV subtypes so that high-risk HPV
subtypes do not predispose patients with laryn- Treatment and Prognosis
geal papilloma to dysplasia • Because of the unpredictable nature of disease, which
• Viral-induced changes (i.e., koilocytosis) may be may be characterized by periods of active growth
seen. and remission, best mode of treatment and the effi-
• Immunohistochemistry: cacy of treatment remain uncertain:
m Immunostains for HPV may be positive: m Presently recommended treatment for RRP is
– When virus is present majority are HPV 6/11. surgery, including microlaryngeal excision with
m p16 typically negative: CO2 laser surgery
– Patchy p16 reactivity may be present but m Adjunctive drugs used in treatment with varying
such reactivity does not represent positive success include interferon, various virostatics
staining. (e.g., acyclovir, valacyclovir, and cidofovir), and
– Positive staining requires diffuse and strong indole-3-carbinol
nuclear and cytoplasmic staining in at least m Vaccination with a quadrivalent vaccine against
75% of the lesions. HPV types involved most commonly in RRP may
m p53 negative provide the best hope to prevent severe forms of
• Cytogenetics and molecular genetics: this disease.
m Identification of viral antigens or genomes by • In general, treatment should be as conservative as
in situ hybridization and polymerase chain possible with the primary aims of therapy to include:
reaction m Airway maintenance
m In situ hybridization for angiogenic growth factor m Voice preservation
VEGF-A has shown strong expression in the epi- m Reduction of tumor burden with the goal of
thelium of squamous papillomas in RRP, as well disease eradication

as strong expression of VEGFR-1 and VEGFR-2 m Avoidance of tracheotomy:
– Tracheotomy may be required to maintain a respiratory tract parenchyma is associated with

functional airway in as high as 65% of patients. increased mortality rates.
– On average tracheotomy is required in approx- m Death may be caused by asphyxiation, superim-
imately one third of patients. posed infection, and malignant transformation.

– If tracheotomy is required, then the mainte- • Carcinoma developing in RRP may occur in nonir-
nance of airway patency and use of the shortest radiated and in irradiated patients:
tracheotomy tube are advised. m Overall incidence of developing carcinoma in
• Complications of surgery may include: nonirradiated patients is 2%.

m Laryngoceles m Overall incidence of developing carcinoma in
m Scarring irradiated patients is 14%.

m Stenosis m Carcinoma developing in the setting of RRP is
m Arytenoid fixation squamous cell carcinoma.

• Radiotherapy is contraindicated because of its asso- m Transformation of RRP to squamous cell carci-
ciated complications, including: noma may:

m Laryngeal destruction, scarring, and laryngeal – Be spontaneous, not characterized by histo-
stenosis and the risk of inducing malignant logic progression, through dysplasia over
transformation time
m 16-fold increased risk of developing carcinoma in – Develop through a continuum of dysplasia
patients who have been irradiated over time
• Recurrence of tumor is common, requiring long- m Transformation to squamous cell carcinoma may
term and repeated management: result in loss of HPV expression.

m Recurrence correlates with persistence of HPV. m Carcinoma developing in RRP may develop in
m HPV can be identified in nonpapillomatosis larynx or in the lung.

mucosa adjacent to the papilloma in as many as m Laryngeal carcinomas developing spontaneously
75% of patients: (i.e., in nonirradiated patients) tend to:

– Identification of HPV in nondiseased mucosa – Occur in JO-RRP
by in situ hybridization and polymerase chain – Develop decades after disease onset
reaction – Have lower mortality rates
• Variability of disease course is reflected in the unpre- m Laryngeal carcinomas developing in irradiated
dictable nature of recurrent tumor: patients tend to:

m Some patients experience one or two recurrences – Occur in JO-RRP
over a few-year period followed by spontaneous – Develop in shorter interval periods (decade or
remission. less) after disease onset
m Other patients have frequent recurrences over – Have higher mortality rates
very short periods of time (weeks), necessitating m Lung carcinomas developing in nonirradiated
multiple operative procedures. and nonsmoking patients tend to:

m Other patients may have repeated recurrences – Have early onset of RRP ranging in age from
over short periods of time and then remain disease 1 to 6 years with an average age of onset of
free for decades only to have multiple recurrent 2 1 2 years
diseases later in life, necessitating multiple opera- – Have disease extension down the tracheobron-
tive procedures. chial tree into the lungs
m Appears that patients with RRP are at risk – Develop carcinoma approximately 25 years
throughout their lives for the possibility of local after laryngeal disease
recurrence – Often have metastatic disease (regional lymph
m In approximately 80% of patients disease persists nodes and distant)
for 5 years or longer. – Have high mortality rates usually over short
m Effect of puberty and pregnancy on the course of periods of time following the diagnosis of
disease remains controversial: carcinoma
– In some patients the disease resolves or becomes m Factors in RRP reported to be associated with
less aggressive in puberty or pregnancy. increased risk of aggressive behavior with spread
– In some patients the disease progresses/becomes to lower airway passages, malignant transforma-
more aggressive in puberty or during tion, and death include:
pregnancy. – Patients with HPV type 11:
• Overall mortality rate varies from 2% to 14%: ■ Malignant transformation reported solely for
m Extension into the tracheobronchial tree occurs HPV 11–associated RRP in 2% to 4% of all
in 2% to 15% and involvement of lower RRP cases
■ Malignant transformation not reported to be

associated with HPV 6; however, a patient
with HPV 6 expressing E6 and E7 oncogenes
shown to follow similar aggressive clinical
course as patients with HPV 11
□ These patients developed disease at a
younger age and expressed higher levels of
E6 and E7 oncogenes compared with the
patients with more indolent course.
– Alterations of aldo-keto reductase 1C3 gene
(AKR1C3) on chromosome 10p15.1 may be
implicated in carcinogenesis.
– Severity score of greater than 4:
■ Includes functional assessment of clinical
parameters and an anatomic assessment of A

disease distribution
■ Anatomic score can then be used in combina-
tion with the functional score to measure

an individual patient’s clinical course and
response to the therapy over time.
– A high number of surgical procedures prior to
interferon-alpha therapy
Keratinizing Papilloma (Papillary

Keratosis) (see Table 16-1, Fig. 16-7)
Clinical
• No gender predilection; disease of adults but may B
occur over a wide age range, including patients
younger than 50 years of age
Fig. 16-7. Keratinizing papilloma.
• Tend to occur on the true vocal cord
• Patients usually present with hoarseness. A, B, Laryngeal keratinizing papilloma composed of
• Cause: papillary fronds of multilayered benign squamous
m Not etiologically linked to human papillomavirus epithelium containing fibrovascular cores and associated
(unlike nonkeratinizing papillomas) surface keratosis and parakeratosis; a sparse neutrophilic
m Reported to occur in patients with smoking
cell infiltrate is present.
history
Pathology Dysplasia can be seen ranging from mild to mod-

m
Gross erate to severe and should be reported as such

• Exophytic or papillary lesion with a white appear- (i.e., keratinizing papilloma or papillary keratosis
ance, usually does not exceed 2 cm in greatest with mild, moderate, or severe dysplasia).
dimension. m In general, a high threshold should be maintained
to diagnose dysplasia because laryngeal papillo-

Histology mas in general and squamous papillomas of the
• Papillary fronds of multilayered benign squamous entire upper aerodigestive tract tend to be resis-
epithelium containing fibrovascular cores with asso- tant to developing high-grade intraepithelial dys-
ciated keratinization plasia (i.e., moderate to severe dysplasia).
• Keratinization may be in the form of parakeratosis • A variable mixed inflammatory cell infiltrate may be
or orthokeratosis. present in the stroma.
• Keratohyaline granules can be identified.
• In most examples there is an absence of cytologic Differential Diagnosis
dysplasia (i.e., keratinizing papilloma or papillary • Verrucous carcinoma
keratosis without dysplasia): • Papillary or exophytic squamous cell carcinoma
Treatment and Prognosis

• Surgical resection is usually curative.
• Usually do not recur but occasionally may recur
• Rarely undergo malignant transformation to a
carcinoma
BENIGN SALIVARY
GLAND TUMORS
• Laryngeal benign salivary gland tumors are extremely
rare:
m Laryngeal malignant salivary gland tumors are
Fig. 16-8. Laryngeal inflammatory myofibroblastic
more common than benign ones. tumor (IMT).
• Most common tumor type is pleomorphic adenoma.
Laryngectomy specimen showing a polypoid and nodular-
• Most often occur in supraglottic larynx
appearing transglottic lesion. In general, aggressive surgery
• Histology is identical to pleomorphic adenomas of
is not indicated for laryngeal (or other mucosal-based)
more common locations (i.e., salivary glands). IMTs, but this is an unusual example of a multiply
• Another category of salivary gland lesions include recurrent lesion necessitating more radical treatment.
oncocytic papillary lesions:
m Controversial category
m Various designated oncocytic cyst, oncocytic pap-
illary cystadenoma
m Likely do not represent true neoplasms but meta- Inflammatory Myofibroblastic
plastic reaction Tumor (IMT) (Figs. 16-8
m See Chapter 15 under Laryngeal Cyst for a more
through 16-11)
complete discussion.
Definition: Distinctive lesion composed of myofibro-
blastic and fibroblastic cells with a variable admixture
of inflammatory cells, including mature lymphocytes,
BENIGN NONEPITHELIAL plasma cells, and/or eosinophils.
TUMORS m Predominantly soft tissue and visceral tumor
that may occur in mucosa of upper aerodigestive

• Benign mesenchymal tumors of the larynx and tract
trachea are rare. Synonyms: Inflammatory (myofibroblastic) pseudo-
• In this category, tumor types include: tumor, plasma cell granuloma, plasma cell pseudotu-
m Hemangiomas mor, pseudosarcomatous (myofibroblastic) lesions/
m Benign peripheral nerve sheath tumors (neurile- tumors
moma; neurofibroma), including granular cell
tumor Clinical
m Lipoma • IMT of upper aerodigestive tract are rare:
m Paraganglioma m Aside from scattered case reports there are very
m Leiomyoma (conventional leiomyoma, vascular few comprehensive studies detailing the clinico-
leiomyoma, and epithelioid leiomyoma) pathologic features of IMT in upper aerodigestive
m Chondroma tract sites.
m Rhabdomyoma • Male predominance; contrasting to soft tissue and
m Giant cell tumor (osteoclastoma) visceral IMT, which occur predominantly in children
• For more complete discussion of some of these tumor and young adults, IMT of the upper aerodigestive
types see other sections. tract occur over a wide age range that includes the
• This section includes discussion of the following pediatric population but is more common in adult
lesions: inflammatory myofibroblastic tumor, populations:
granular cell tumor, lipoma, paraganglioma, and m Relative to laryngeal IMT, median age of 59 years
chondroma. reported
A B
C D
Fig. 16-9. Laryngeal IMT.

Histology of (laryngeal) IMT may include (A, B) polypoid-appearing lesions characterized by the presence of a submucosal
loosely cellular proliferation of spindle-shaped to stellate cells with variably admixed inflammatory cells; surface squamous
epithelium is intact but may be ulcerated; (C, D) cellular proliferation is loosely arranged with a storiform to fascicular
growth pattern and an edematous myxoid stroma. The overall histologic appearance can be similar to that seen in nodular
fasciitis.
• In upper aerodigestive tract, IMT most commonly anemia, thrombocytosis, polyclonal hyperglobu-
occur in the larynx: linemia, and elevated erythrocyte sedimentation
m Laryngeal sites of involvement include glottis, rate seen in association with soft tissue and vis-
supraglottis, and subglottis. ceral IMT are not usually a component of upper
m Most common site of occurrence is the true vocal aerodigestive tract IMT. High fever, anemia and
cord weight loss may be present.
m Nonlaryngeal sites of occurrence include oral • IMT of the upper aerodigestive tract present as soli-
cavity, tonsil, parapharyngeal space, sinonasal tary (isolated) lesions, typically without lesions of
tract, salivary glands, and trachea. other upper aerodigestive tract sites or evidence of
• Clinical presentation varies per site of occurrence: myofibroblastic lesions of other sites of the body.
m Larynx: hoarseness, stridor, dysphonia, and/or a • Cause of IMT in general and upper aerodigestive
foreign body sensation in the throat; duration of tract in specific is unknown:
symptoms range from as short as 10 days up to m No specific link to tobacco smoking, trauma (e.g.,
4 months traumatic intubation), human herpesvirus-8

m Other aerodigestive tract sites may present (HHV-8), or Epstein-Barr virus (EBV)
as painless mass, ulcerative painful mass,
nasal obstruction, epistaxis, headaches, and Pathology
dysphagia. Gross
m Constitutional and/or systemic signs and symp- • Polypoid, pedunculated, or nodular firm lesion with
toms such as fever, weight loss, pain, malaise, a smooth appearance and fleshy to firm consistency
E F
Fig. 16-10. Myofibroblasts in IMT.

The myofibroblasts in IMT may have a varied appearance including (A) epithelioid or histiocytoid characterized by round
to oval nuclei, prominent nucleoli, and ample basophilic to eosinophilic granular cytoplasm; (B through D) spindle-shaped
to stellate-appearing cells with enlarged round to oblong nuclei, inapparent to prominent eosinophilic nucleoli, and
abundant basophilic to eosinophilic-appearing fibrillar cytoplasm; axonal-appearing (spider-like) cells with long cytoplasmic
extensions creating cells with a bipolar-to-multipolar (tadpole-like) appearance are seen; (E) the stroma in this example
has a neurofibrillar-like appearance; GFAP staining was negative (not shown). F, Intranuclear eosinophilic inclusions may
be seen and may represent a clue to the diagnosis of IMT.
C D
Fig. 16-11. Immunohistochemistry of IMT.

Immunohistochemical staining of the myofibroblasts in IMT may include (A) vimentin; (B) muscle-specific actin;
(C) smooth muscle actin; (D) anaplastic lymphoma kinase (ALK) reactivity including cytoplasmic staining and staining
of the intranuclear inclusions (arrowheads).
• Range in size from 0.4 to 3 cm in greatest m Overall appearance is similar to a reactive process
dimension resembling granulation tissue and nodular
fasciitis.
Histology
• Polypoid and unencapsulated characterized by the Myofibroblasts
presence of a submucosal loosely cellular prolifera- • Primarily spindle-shaped or stellate with enlarged
tion of spindle-shaped to stellate cells with variably round to oblong nuclei, inapparent to prominent
admixed inflammatory cells eosinophilic nucleoli, and abundant eosinophilic to
• Cellular proliferation loosely arranged with a stori- basophilic-appearing fibrillar cytoplasm:
form to fascicular growth pattern and an edematous m In some cases myofibroblasts may appear more
myxoid to fibromyxoid stroma, prominent vascular- epithelioid or histiocytoid, including round to

ity, and an inflammatory cell infiltrate composed of oval nuclei, prominent nucleoli, and ample
mature plasma cells, mature lymphocytes, eosino- cytoplasm.
phils, histiocytes, and scattered polymorphonuclear m Myofibroblasts may also appear as slender
leukocytes: axonal (spider-like) cells with elongated nuclei,
inapparent nucleoli, and long cytoplasmic exten- • Histochemistry:

sions creating cells with a bipolar-to-multipolar m Essentially noncontributory to the diagnosis
(tadpole-like) appearance. • Immunohistochemistry:

• In all their histologic forms myofibroblasts maintain m Strong diffuse cytoplasmic immunoreactivity for
a low nuclear-to-cytoplasmic ratio. vimentin

• A helpful feature may be the presence of intranuclear m Smooth muscle actin and/or muscle specific actin
eosinophilic inclusions: typically present but may vary from focal to

m Not unique to IMT but represent a rather char- diffuse
acteristic feature especially in the context of his- m Desmin staining may be present.
tologic findings associated with IMT m CD68 may be focal in histiocytic-appearing

• Focal nuclear pleomorphism may be present; marked cells.
nuclear pleomorphism and necrosis not usually m Epithelial markers (cytokeratins, EMA, others)
present typically absent but staining for cytokeratins may

• Mitotic figures are present and may be numerous but be present in up to 33% of cases:
atypical mitoses are not usually seen. – When present cytokeratin staining tends to be
focal rather than diffuse.
Stroma m No immunoreactivity for S100 protein, p63,
• Stromal component varies from an edematous HMB-45, myoglobin, myogenin (myf-4), MyoD1,
myxoid background to fibromyxoid and more CD34, CD117
fibrous (collagenized); rarely, a fibrillar appearing m Reactivity for anaplastic lymphoma kinase (ALK)
stroma resembling neurofibrillary matrix may be can be seen corresponding to the presence of ALK
seen. rearrangements (see Cytogenetics later):
• Vascular component varies from widely dilated – ALK reactivity is cytoplasmic.
medium-sized vascular channels to narrow, slit-like – Intranuclear inclusions may be ALK
blood vessels that can be obscured by the myofibro- positive.
blasts and inflammatory cells; vascular thrombosis – Wide range of ALK positivity reported varying
not present from 36% to 60% of cases
■ ALK lacks specificity and sensitivity.
Inflammatory Cells ■ Imperfect correlation to ALK mutations
• Admixture of different cell types, including mature ■ Different fusion partners (see Cytogenetics
lymphocytes, mature plasma cells, eosinophils, later) may result in different patterns of ALK
histiocytes, and scattered polymorphonuclear immunoreactivity
leukocytes: • Electron microscopy:
m Degree of inflammatory cell infiltrate may vary m IMTS show features of myofibroblastic and fibro-
from case to case blastic differentiation:

m Prominent mature plasma cell infiltrate may be – Cytoplasmic organelles include well-developed,
present: prominent rough endoplasmic reticulum, Golgi
– Previous designation for IMT was plasma cell complexes, bundles of microfilaments arranged
granuloma. in parallel along the long axis of the cells with
– In conjunction with sclerotic stroma as well as focal densities (“stress fibers”), fragmented
increased numbers of IgG4-positive plasma cell basal lamina, pinocytotic vesicles, and fibro
and IgG4/IgG ratio ≥0.10 may suggest a pos- nexus junctions.
sible diagnosis of IgG4-related disease (see Dif- – Fibronexus junctions represent foci on the
ferential Diagnosis below). cell surface in which intracellular myofila-
ments and extracellular fibronectin filaments
Surface Epithelium converge.
• Surface epithelium may be intact and unremarkable – Rarely, junctional complexes can be seen.
to ulcerated to hyperplastic. • Cytogenetics and molecular genetics:
• Myofibroblastic proliferation may approximate m In children and young adults from 50% to 70%
surface epithelium but usually there is a separa- of cases often contain clonal cytogenetic rear-
tion between the myofibroblasts and surface rangements involving chromosome band 2p23
epithelium. that fuse 3′ kinase region of ALK gene with
• Reactive epithelial atypia may be seen but significant various partner genes including:
epithelial dysplasia (i.e., moderate to severe dyspla- – TPM3, TPM4, CLTC, RANBP2, and ATIC
sia), carcinoma in situ, and invasive squamous car- m Such rearrangements are uncommon in adults
cinoma are not present. >40 years of age.
m Rearrangement restricted to myofibroblastic

cell component whereas inflammatory cell com- Treatment and Prognosis
ponent is normal without gene rearrangements or • Laryngeal IMT are treated by conservative surgical
expression of ALK protein resection, including local excision by laser removal
m Presence of immunohistochemical expression of or via laryngoscopic techniques.
the ALK C-terminal end in myofibroblastic com- • Conservative resection usually curative:
ponent of IMT and low to absent detection of m Rarely, recurrent tumor may occur after con
ALK protein in nonneoplastic myofibroblasts servative surgical resection necessitating

represent strong evidence for oncogenic activa- laryngectomy.
tion mechanism in IMT • Targeted therapy using ALK inhibitor crizotinib
has shown promising results in ALK-translocated
Differential Diagnosis IMT
• Contact ulcer of the larynx • Recurrence rate of approximately 25% has been
• Pyogenic granuloma reported for extrapulmonary IMT.
• Nodular fasciitis: • Rare examples of extrapulmonary (not head and
m Myofibroblastic dominant proliferation neck) IMT metastasize (less than 2%):
m Typically a lesion of soft tissue but rarely may be m May be linked to presence of RANBP2 and round
mucosal based, originating in mucosal sites of cell morphology

upper aerodigestive tract, including the larynx m ALK-negative IMT may have higher risk of
and pharynx metastasis.

m For a more complete discussion, see Section 4, • Difficult to predict on the basis of pathologic fea-
Neck. tures which IMTs may behave more aggressively:
• IgG4-related disease: m No correlation between behavior and tumor size,
m Although there may be some overlap in histologic nuclear atypia, mitotic activity, necrosis
findings and presence of increase IgG4 plasma m Aggressive behavior may correlate to round cell
cells between IgG4-related disease and IMT, these transformation characterized by:
two entities have distinct clinical and pathologic – Sheets of round to epithelioid cells with vesicu-
findings: lar nuclei, prominent nucleoli, amphophilic to
– IgG4-related disease is typically systemic but eosinophilic cytoplasm, increased mitotic activ-
may be localized, whereas IMT are generally ity including atypical mitoses, myxoid stroma,
localized. and prominent neutrophilic infiltrate
– Histologic findings often seen in IgG4- – Distinct nuclear membrane or perinuclear
related disease include obliterative phlebitis pattern of ALK staining
and lymphoid aggregates, features not seen – RANBP2-ALK fusion detected by reverse tran-
in IMT. scription polymerase chain reaction
– IgG4-related disease is ALK negative. – To date, such changes reported in IMT located
– IgG4-related disease responds to steroid within the abdomen arising from omentum or
treatment. mesentery
m For a more complete discussion of IgG4-related – Terminology of epithelioid inflammatory myo-
disease see Section 6, Salivary Glands. fibroblastic sarcoma suggested for this lesion
• Spindle cell squamous carcinoma: conveying malignant behavior
m Overtly malignant cell infiltrate that may be asso-
ciated with intraepithelial dysplasia and/or inva-

sive squamous cell carcinoma Granular Cell Tumor
m Reactivity may be seen for epithelial markers
(cytokeratins, others) and p63.
m Consistently reactive for vimentin and may be Definition: Benign tumor of neurogenic (Schwann cell)
reactive for mesenchymal markers including origin characterized by lysosome-rich cells with abun-
actins and desmin dant granular eosinophilic-appearing cytoplasm.
m ALK negative Synonyms: Granular cell myoblastoma; granular cell
m Spindle cell squamous carcinomas, especially neuroma; granular cell schwannoma; granular cell neu-
those with associated surface ulceration and reac- rofibroma; Abrikossoff tumor; granular cell schwannoma
tive changes, may have coexisting (reactive) myo- • Two forms can occur:
fibroblasts, the latter representing part of the 1. Mucosal granular cell tumor
wound healing process. 2. Congenital granular cell epulis (see Section 2,
• Myofibrosarcoma Oral Cavity, for detailed discussion)
Fig. 16-12. Endoscopic appearance of granular

cell tumor.
A, Laryngeal granular cell tumor appearing as a large,
solitary tan-yellow mass along the posterior aspect of the
true vocal cord. B, Tracheal granular cell tumor appearing
as a mucosal-covered nodular intraluminal protrusion. C
Mucosal Granular Cell Tumor Fig. 16-13. Granular cell tumor.
Clinical A, Histologically, granular cell tumors are characterized by

the presence of round to polygonal shaped cells with
• Can occur in virtually any organ but most frequent round to oval, vesicular nuclei, coarse granular cytoplasm,
sites of occurrence include: and ill-defined cell borders. B, Markedly pleomorphic
m Skin > tongue > breast > larynx > gastrointestinal and hyperchromatic nuclei may be identified, which are
tract > bronchus, trachea not diagnostic for malignancy. C, Granular cells are
m Except for the larynx, granular cell tumors are immunoreactive for S100 protein, which is negative in
more common in women than in men the squamous epithelium (arrow).
m See Section 2 on the Oral Cavity for a discussion
of lingual granular cell tumor and congenital

granular cell epulis.
A B
Fig. 16-14. Pseudoepitheliomatous hyperplasia and granular cell tumor.

A, B, Pseudoepitheliomatous hyperplasia of the larynx with associated granular cell tumor. The epithelial proliferation may
be misinterpreted as an invasive squamous carcinoma unless attention is paid to the presence of granular cells deep to
and intermingled with the hyperplastic squamous epithelium.
• For laryngeal tumors: May occur synchronously or metachronously

m
m No gender predilection; primarily affects adults Multiple granular cell tumors may occur in
m
in third to fifth decades of life; uncommon in LEOPARD syndrome and Noonan syndrome
children associated with mutations in PTPN11.
m Hoarseness is most common complaint. • No known cause
m Most frequently identified along the posterior • Granular cell tumors felt to be of neural (Schwann
aspect of the true vocal cord (posterior one third) cells) origin supported by:
but can also be seen in the supraglottic and sub- m Involvement of small to medium nerves
glottic areas: m S100 protein, CD57, and neuron-specific enolase
– Vocal cord > arytenoids > false cord > anterior positive
commissure > subglottis > postcricoid area m Presence of myelinated and nonmyelinated axon-
• For tracheal tumors: like structures by ultrastructural analysis

m More common in women than in men m Presence of residual axons in many granular cell
m Wide age range but peak incidence is in the fourth tumors

decade
m Symptoms include stridor and airway Pathology
obstruction. Gross
m Most often arise in the cervical trachea • Often solitary, polypoid, or sessile, tan-white to
• Regardless of site, most GCTs are single lesions but yellow, measuring from 0.3 to 3.0 cm in diameter;
multiple tumors may be found: occasionally may have papillary or cystic areas
• Most are submucosal with an intact overlying surface S100 protein, calretinin, CD57 (Leu-7) positive
m
epithelium, although rarely may be associated with Strongly CD68 (KP-1) positive as well as alpha-
m
epithelial ulceration. 1-antitrypsin and alpha-1-antichymotrypsin

m Laminin and collagen type 4 are positive, high-
Histology lighting basement membranes around groups of
NOTE: Regardless of location, histology is the same. tumor cells.
• Unencapsulated or poorly circumscribed subepithe- m Additional consistent but nonspecific staining
lial lesion with a syncytial, trabecular, or nested seen for inhibin alpha-subunit and protein gene
growth pattern product 9.5:
• Neoplastic cells are round to polygonal with round – Significance of inhibin expression with regard
to oval, vesicular to hyperchromatic, centrally to cell differentiation and pathogenesis is
located small nuclei, and the presence of coarsely unclear.
granular eosinophilic-appearing cytoplasm with m Proliferative activity as seen by Ki-67 reactivity is
poorly delineated cell borders. low.

• Cellular pleomorphism varies but usually is minimal: m Negative for cytokeratins, neurofilament protein,
m Uncommonly markedly pleomorphic nuclei may and glial fibrillary acidic protein
be present. m Interstitial cells with angulate bodies are CD68
• Mitoses and necrosis not typically present positive and S100 protein negative.
• Occasionally, within the collagenous tissue and in • Electron microscopy:
the proximity of vessels, stromal histiocytes with m Characterized by presence of numerous intracel-
large refractile needle-shaped bodies may be seen: lular large granules (secondary lysosomes) con-
m Referred to as angulate bodies sisting of membrane-bound, autophagic vacuoles
• Pseudoepitheliomatous hyperplasia (PEH) may be containing mitochondria, rough endoplasmic
present: reticulum, myelin figures, and myelinated and
m Exuberant epithelial hyperplasia that may be nonmyelinated axon-like structures
associated with granular cell tumors m Interstitial cells contain membrane-bound struc-
m May be so exuberant as to suggest a diagnosis of tures with parallel arrays of microtubules repre-
invasive squamous cell carcinoma: senting angulated bodies as well as microfilaments
– In contrast to squamous cell carcinoma, PEH and lipid material.
typically displays no cytologic evidence of
malignancy. Differential Diagnosis
– However, some examples may be histolog • Rhabdomyoma
ically identical to invasive squamous cell • Invasive squamous cell carcinoma as a result of the
carcinoma: PEH
– A diagnosis of SCC should not be rendered in • Alveolar soft part sarcoma
the presence of granular cell tumor unless: • Malignant granular cell tumor:
■ Epithelial proliferation extends beyond/ m Rare neoplasms accounting for approximately
below the depth of associated granular cell 1% of all granular cell tumors
tumor: m Clinically are similar to benign granular cell
□ S100 protein and cytokeratins may be tumors except that they do not occur in newborns
needed to determine extent of the epithelial or children
proliferation relative to the granular cell m Usually measure >4.0 cm in diameter and tend to
tumor. occur in the extremities

■ Metastatic squamous cell carcinoma (locore- m Histologically, a diagnosis of malignancy can be
gional, distant) is present. made in the presence of three of the following

• Granular cell tumor cells may involve (“invade”) criteria:
nerves: – Necrosis
m Does not represent an indicator of malignancy – Spindle-shaped cells
(see below for malignant granular cell tumor) – Increased nuclear-to-cytoplasmic ratio
• Histochemistry: – Vesicular nuclei with prominent nucleoli
m Cytoplasmic granules are diastase-resistant, PAS- – Pleomorphism
positive, stain with alcian blue at pH 2.5, stain – Increased mitotic activity (greater than two
red with trichrome, and vary in size from being mitoses per 10 high-power fields)
minute to as large as red blood cells. m Any granular cell tumor in which one or two of
m Angulate bodies are intensely PAS positive. the above criteria are found can be referred to
• Immunohistochemistry: as atypical.
m Transition from benign granular cell tumor to

malignant granular cell tumor is frequently
apparent.
m Immunohistochemical staining similar to that of
benign granular cell tumors except:

– CEA reactivity reported, significance of which
is not known
– Increase proliferation rate from 10% to 50%
by Ki67 (MIB1) staining
– Extensive p53 staining in up to 70% of cases
m Differential diagnosis includes alveolar soft part
sarcoma and paraganglioma.

m Surgery is the preferred treatment (wide en A
bloc excision); radio- and chemotherapy are
ineffective.
m Metastasize via lymphatics and blood vessels
(lymph nodes, lung, liver, and bone)

• Conservative but complete surgical excision is con-
sidered curative:
m Small tumors can be excised endoscopically.
• Granular cell tumors are radioresistant.

• Local recurrence may occur in a minority of patients
(less than 10%):
m Recurrent tumor may represent a new primary
B
lesion in patients with multifocal disease.
Laryngeal Paraganglioma
(Figs. 16-15 and 16-16)
Definition: Benign neoplasm arising from the extra-
adrenal neural crest-derived paraganglia specifically
located in the larynx, and believed to arise from the
superior and inferior laryngeal paraganglia.
Synonym: Glomus tumor
Histoanatomy
• Laryngeal paraganglia are microscopic structures
with variable anatomic distribution in relation to
cricoid and thyroid cartilages.
m Most are paired structures located in superior
C
and inferior locations in lateral larynx.
m Sometimes found immediately adjacent to thyroid Fig. 16-15. Laryngeal paraganglioma.
gland or within capsule of thyroid gland
A and B, The tumor is located wholly within the
m Described in relation to laryngeal recurrent nerve
submucosa showing characteristic organoid or cell nest
• Physiologic role of laryngeal paraganglia unknown (“zellballen”) growth with the cell nests separated by
fibrovascular stroma. C, Cells nests are composed
Clinical predominantly of chief cells with uniform round to oval
• Uncommon laryngeal tumor nuclei, dispersed chromatin pattern, and abundant
• More common in women than in men; wide age eosinophilic, granular, or vacuolated cytoplasm;
range but most common in the fifth decade of life sustentacular cells situated at the periphery of the cell
• Vast majority (greater than 80%) predilect to the nests are difficult, if not impossible, to identify by light
supraglottic larynx with the aryepiglottic fold and microscopy.
false vocal cord representing the most common sites
of occurrence.
• Identical to paragangliomas of more usual sites:

m Histologic hallmark is the presence of a cell nest
or “Zellballen” pattern cell nest characteristic of

paragangliomas.
m Stroma surrounding and separating the nests
is composed of a prominent fibrovascular

tissue
m Neoplasm is composed predominantly of chief
cells, which are round or oval with uniform

nuclei, dispersed chromatin pattern, and
abundant eosinophilic, granular, or vacuolated
cytoplasm
A m Sustentacular cells difficult, if not impossible, to
identify by light microscopy:

– These cells represent modified Schwann cells.
– Are located at the periphery of cell nests
– Appear as spindle-shaped, basophilic-appearing
cells
• Glandular or alveolar differentiation is not seen.
• Histochemistry:
– Reticulin staining may better delineate the
cell nest growth pattern with staining of the
fibrovascular cores surrounding the neoplastic
nests
– Tumor cells are argyrophilic (Churukian-
Schenk)
B – Argentaffin (Fontana-Masson), mucicarmine,
and periodic acid Schiff stains are negative.
Fig. 16-16. Special stains in paraganglioma. • Immunohistochemistry:
m Chief cells:
Special stains that can be seen in (laryngeal)
– Chromogranin, synaptophysin, CD56, neuron-
paragangliomas may include (A) argyrophilic (Churukian-
specific enolase, neurofilaments, and a variety
Schenk) positive intracytoplasmic granules; (B) dedicated
chromogranin reactivity to the chief cells (left) and of peptides positive; GATA3 positive (nuclear)
dedicated S100 protein to the sustentacular cells (right). – May also be S100 protein positive
– Sustentacular cells:
■ S100 protein positive, Sox10 positive
• Clinical presentation includes hoarseness, dysphagia, m Vimentin is variably reactive in chief cells and
dyspnea, and stridor. sustentacular cells

• Generally are not hormonally (functionally) active, m In general, epithelial markers, including cytokera-
although exceptional cases may be functional. tins and p63, are negative:
• Rarely may be multicentric with other head and neck – Rare examples of cytokeratin-reactive para-
paragangliomas gangliomas are reported.
• Radiology: m Melanocytic markers (HMB45, melan-A, tyrosi-
m CT: enhancing mass nase, MITF, Sox10) negative

m MRI: intermediate signal intensity on T1-weighted m Myogenic markers (desmin, myogenin, others)
image and high signal intensity on T2-weighted negative

image • Electron microscopy:
m Abundant neurosecretory granules (100 to
Pathology 250 nm)
Gross m Cellular junctional complexes are rarely (if
• Submucosal tumors ranging in size from 0.5 ever) seen.
to 6.0 cm
Differential Diagnosis
Histology • Neuroendocrine carcinomas including carcinoid
• Located in submucosa without involvement of over- tumor and atypical carcinoid (see Box 16-5 and
lying intact epithelium Table 16-6)
• Involvement of Reinke space most probably repre-

Treatment and Prognosis sents a metaplastic rather than a true neoplastic
• Surgery is the preferred treatment and is curative. process with derivation from the vocal cord
• Malignant paragangliomas reported in the literature ligament.
more likely represent neuroendocrine carcinoma
Pathology
Chondroma (Fig. 16-17) Gross
Definition: Benign tumor of mature hyaline cartilage. • Lobulated, firm to hard, blue-gray, submucosal mass
seldom measuring greater than 1 cm:
Clinical m Although laryngeal chondromas seldom attain
• Cartilaginous neoplasms of the head and neck are sizes greater than 1 cm, occasionally they may
uncommon, and those of the larynx are rare: grow to sizes up to 4 cm.
m Laryngeal chondrosarcomas are more common
than chondromas. Histology

• Most common sites of occurrence of head and neck • Submucosal lobulated or nodular growth(s) com-
chondromas include: posed of chondrocytes recapitulating the normal his-
m Sinonasal tract tology of cartilage.
m Less common sites include maxilla and mandible, • Absence of cellular pleomorphism, binucleate chon-
larynx, palate, pharynx, nasopharynx, and ear. drocytes, or mitotic activity
• In the larynx, chondromas may originate from pos- • Immunohistochemistry:
terior lamina of cricoid cartilage and thyroid carti- m S100 protein positive
lage and less often from epiglottis and arytenoids. m Podoplanin (D2-40) positive
m May arise in soft tissues of the true vocal cords
(Reinke space) Differential Diagnosis

• May be incidentally identified or cause hoarseness: • Cartilaginous hamartoma
m A clinically significant cartilaginous tumor of the • Chondrosarcoma (see later in chapter)
larynx is most likely a chondrosarcoma.
• Radiology: Treatment and Prognosis
m Discrete soft tissue mass contiguous with its • Conservative but wide surgical excision including an
laryngeal cartilaginous origin adequate margin of normal tissue is the preferred
m Coarse calcifications and ossification may be treatment:
seen. • Surgical resection is curative.
A B
Fig. 16-17. Laryngeal chondroma.

A, Submucosal cartilaginous nodules with intact overlying squamous epithelium. B, At high magnification the chondrocytes
are bland in appearance, lacking significant nuclear pleomorphism, binucleate chondrocytes, or mitotic activity as may be
seen in low-grade chondrosarcomas.
m Recurrences are uncommon and according to Laryngeal sites of occurrence include aryepiglot-
m
most authorities do not occur in association with tic fold, vestibular fold, and epiglottis.
laryngeal chondromas. • Symptoms include dysphagia, dyspnea, acute airway
m Recurrent chondromas of the larynx should obstruction, hoarseness, dysphonia, and a lump in
prompt a diagnosis of a low-grade chondrosar- the throat.
coma. • Radiology:
m CT scan: low attenuation mass:
– Adipose tissue is the only soft tissue that

Lipoma (Fig. 16-18) has a density less than water (zero or negative
Definition: Benign tumor of mature adipocytes. Hounsfield units) so that CT scan reveals
extent of the mass and also its lipomatous
Clinical nature.
• In the head and neck, most often occur in the neck • No known cause:
region (see Section 4, Neck, for more complete m Rare cases reported in association with symmet-
discussion) ric lipomatosis (Madelung disease or Launois-

• Rare tumor of larynx (and hypopharynx) Bensaude syndrome)
• More common in men than in women; adult ages
usually sixth decade and older Pathology
• Solitary tumors often arising in the supraglottic Gross
larynx or project into the larynx from a hypopha- • Sessile to pedunculated mass measuring from a few
ryngeal mass: millimeters to 6.0 cm in greatest dimension
Histology
• Encapsulated tumor of mature adipose tissue
(adipocytes):
m Adipocytes are uniform, varying slightly in size
and shape.
m Atypical adipocytes and/or lipoblasts are not
identified.
• Richly vascularized but vascularity may be difficult
to appreciate due to compression by distended
adipocytes.
• Secondary changes may include hemorrhage,
calcification, cyst formation, fat necrosis, and
infarction.
• Metaplastic bone and cartilage may be identified.
• Laryngeal (and hypopharyngeal) lipomas may
A include:
m Lipomas with prominent myxoid stroma (myxo-
lipoma) or prominent fibrous tissue component

(fibrolipoma)
m Intramuscular lipomas:
– Also referred to as infiltrating lipoma

– Characterized by the presence of mature adi-
pocytes infiltrating skeletal muscle
m Spindle cell lipoma:
– Characterized by mature adipocytes admixed

with uniform, small spindle cells, and eosino-
philic collagen bundles set in a myxoid matrix
with a vascular pattern varying from incon-
B spicuous to prominent
– Mast cells can be seen in association with the
spindle cells.
Fig. 16-18. Laryngeal lipoma. m Other types of lipomas including angiolipoma,
A, B, Circumscribed submucosal tumor composed of pleomorphic lipoma, angiomyolipoma, and lipo-

mature adipocytes lacking evidence of cytologic atypia. blastoma not reported in these sites
• Immunohistochemistry (not needed for the • For spindle cell lipoma:

diagnosis): m Various spindle cell neoplasms of these sites
m Adipocytes are S100 protein positive.
m CD34 positive in spindle cell lipomas Treatment and Prognosis

m MDM2 and CDK4 negative • Surgery is curative.
• Hibernoma (benign tumors of brown fat) • May rarely recur:
m Rare examples reported to occur in the larynx m May be a function of inadequate excision
m Presence of recurrence should raise diagnosis of
Differential Diagnosis well-differentiated liposarcoma:

• For conventional lipoma: – Does not represent transformation from a
m Atypical lipomatous neoplasm/well-differentiated lipoma but initial lesion was a liposarcoma that
(lipoma-like) liposarcoma; see later in chapter. went undiagnosed due to overall bland mor-
• For myxoid lipoma: phology lacking overt evidence of malignancy
m Vocal cord polyp, myxoid type – In this setting staining for MDM2 and CDK4
m Myxoid liposarcoma may prove useful and diagnostic.
MALIGNANT NEOPLASMS OF THE LARYNX

AND HYPOPHARYNX
GENERAL CONSIDERATIONS neoplasia (SIN); laryngeal intraepithelial lesion (LIN);

laryngeal intraepithelial lesion (LIL); simple hyperpla-
• Squamous cell carcinoma or a variant thereof is most sia; basal/parabasal hyperplasia; atypical hyperplasia
common malignant neoplasm of the larynx • Recommended WHO terminology includes mild,
• See Section 2, Oral Cavity, for a more complete dis- moderate, and severe dysplasia and carcinoma in situ
cussion of the following topics related to head and (Table 16-2).
neck squamous cell carcinoma (HNSCC):
m Mutagen sensitivity Clinical
m “Field cancerization” • More common in men than in women; generally
m Second primary malignancy limited to the adult population with a mean age at
m Genetics of HNSCC diagnosis in the sixth decade of life
m Prognostic indicators, including: • May occur anywhere in the larynx but mainly identi-
– Status of the surgical resection margins fied along the true vocal cord:
– Nodal metastasis m Typically is a unilateral lesion but may be bilat-
– Lymph-vascular invasion eral in up to 30% of cases

– Invasion of soft tissue structures including • Most frequent symptom is hoarseness.
nerves and cartilage • May appear white (leukoplakia), red (erythropla-
– Distant metastasis kia), or mixed red and white (speckled leukoplakia):
– Multiple primary malignancies (second m See Section 2, Oral Cavity, for more complete
malignancy) discussion on leukoplakic and erythroplakic

– Host immunologic response lesions.
• Causes may include:
m Tobacco smoking (most common) and excess
LARYNGEAL EPITHELIAL alcohol use:

DYSPLASIA – Alcohol potentiates the effect of tobacco
smoking.
Keratinizing and Nonkeratinizing – Risk of developing dysplastic lesions increases
with duration of smoking and/or alcohol use.
Dysplasia (Figs. 16-19 through 16-22) m Chronic infections, including fungal infection
Definition: Alteration in a malignant direction in the m Less commonly secondary to voice abuse,
appearance of epithelial cells with an increased likeli- environmental/industrial exposure, and vitamin
hood to progress to squamous cell carcinoma. A deficiency
Synonyms: Keratosis with atypia; atypia; mild dys- m Role of human papillomavirus in development of
plasia; moderate dysplasia; severe dysplasia; squamous intraepithelial dysplasia of the larynx remains
intraepithelial lesion (SIL); squamous intraepithelial unproven:
A C
Fig. 16-19. Laryngeal nonkeratinizing dysplasia.

The grading in these dysplastic lesions is similar to that of the uterine cervix and includes (A) mild dysplasia when the
dysplastic changes are limited to the lower third of the surface epithelium; (B) moderate dysplasia when the dysplastic
changes involve two thirds of the surface epithelium; and (C) severe dysplasia (carcinoma in situ) when the dysplastic
changes involve the entire surface epithelium without violation of the basement membrane.
A B
Fig. 16-20. Laryngeal keratinizing mild dysplasia.

Laryngeal keratinizing mild dysplasia (low-grade squamous intraepithelial lesion) showing squamous epithelium with
associated keratosis and dysplastic cytologic changes limited to the basal zone with relatively flat-appearing epithelium
without associated elongated and downwardly extending rete ridges. Mitotic figures (arrowheads) are seen at the junction
(more or less) of the lower and mid-epithelial layers.
A C
Fig. 16-21. Laryngeal keratinizing moderate dysplasia.

Laryngeal keratinizing moderate dysplasia (high-grade squamous intraepithelial lesion) showing squamous epithelium with
associated keratosis and dysplastic cytologic changes involving at least two thirds of the thickness of the epithelium with
relatively flat to widened and/or slightly elongated and downwardly extending rete pegs. In these images there is still
maturation of the most superficial layer of the epithelium. However, given a shared risk to progression to invasive
carcinoma with keratinizing severe dysplasia, a classification that includes keratinizing moderate and severe dysplasias
within the category of high-grade squamous intraepithelial lesion appears justified.
TABLE 16-2 Classification Schemes for Epithelial Precursor Lesions

WHO* SIN Ljubljana Modified Ljubljana Two-Tiered
Mild dysplasia SIN 1 Basal/parabasal cell hyperplasia LGSIL LGSIL
Moderate dysplasia SIN 2 Atypical hyperplasia HGSIL HGSIL
Severe dysplasia SIN 3 Atypical hyperplasia HGSIL HGSIL
CIS SIN 3 CIS CIS HGSIL
CIS, Carcinoma in situ; HGSIL, low-grade squamous intraepithelial lesion; LGSIL, low-grade squamous intraepithelial lesion; SIN,
squamous intraepithelial neoplasia; WHO, World Health Organization.
*Currently recommended classification scheme.
A C
Fig. 16-22. Laryngeal keratinizing severe dysplasia.

A through C, Laryngeal keratinizing severe dysplasia tantamount to carcinoma in situ (high-grade squamous intraepithelial
lesion) including architectural alterations with widening and elongated and downwardly growing rete ridges coupled to
cytomorphologic changes. All of these examples include an absence of full-thickness intraepithelial dysplasia, thereby
falling short of the classic definition for carcinoma in situ. Nevertheless, these lesions all merit designation as keratinizing
severe dysplasia tantamount to carcinoma in situ as the risk of progression to invasive carcinoma is similar to that of
“classic” carcinoma in situ. Further, such lesions can progress to invasive carcinoma in the absence of full-thickness
intraepithelial dysplasia. D, Paradoxical maturation characterized by abnormal keratinization in the basal zone; associated
high-grade dysplastic cytomorphologic features are present.
BOX 16-2 Histomorphologic Changes Associated

with Dysplasia
Architectural Abnormalities
• Irregular epithelial stratification with elongated rete
ridges extending in a downward fashion into submucosa
• Loss of maturation with increased cellularity in the
superficial epithelium:
– Normally in mature squamous epithelium there is a
decrease in the cellularity from the basal zone toward
the keratinizing layers.
• Crowding of cells with loss of polarity especially in the
basal zone
• Increased mitotic activity, especially away from the basal
zone involving the mid- and upper (superficial) portions
of the surface epithelium:
– May include atypical forms
• Abnormal keratosis (dyskeratosis) and paradoxical
maturation:
– Occurs in individual cells
– Keratin pearls in elongated rete ridges
Cellular Abnormalities
• Abnormal variation in nuclear size (anisonucleosis)
• Abnormal variation in the nuclear shape (nuclear
pleomorphism)
• Increase nuclear size relative to cytoplasm (increased
nuclear-to-cytoplasmic ratio)
• Nuclear hyperchromasia with irregularities in nuclear
contour
E • Prominent nucleoli (not unique to dysplasia may be seen
in reactive or reparative processes)
Fig. 16-22, cont’d

E, Example of laryngeal invasive carcinoma originating m Architectural abnormalities:
from dysplastic changes limited to the basal zone – Irregular epithelial stratification with elongated
epithelium (“drop off” carcinoma) without full thickness rete ridges extending in a downward fashion
intraepithelial dysplasia. into submucosa
– Loss of maturation with increased cellularity in
the superficial epithelium:
– High-risk HPV uncommon finding in head and ■ Normally in mature squamous epithelium
neck squamous cell carcinoma from patients there is a decrease in the cellularity from the
who have history of tobacco or alcohol use basal zone toward the keratinizing layers
– Low-risk HPV not associated with such cases – Paradoxical maturation (abnormal keratiniza-
m Prevalence of HPV in precursor lesions (i.e., dys- tion or keratin pearl formation in the basal
plasia) reported in approximately 12% of cases zone)
m HPV DNA reported in 12% to 25% of normal – Crowding of cells with loss of polarity espe-
(clinically and histologically) larynges cially in the basal zone
– Increased mitotic activity, especially away
Pathology from the basal zone involving the mid- and
Gross upper (superficial) portions of the surface
• Localized, circumscribed flat, or papillary area with epithelium:
white (leukoplakic), red (erythroplakic), or gray ■ May include atypical forms
appearance – Abnormal keratosis (dyskeratosis):

■ Occurs in individual cells
Histology (Box 16-2) ■ Keratin pearls in elongated rete pegs
• Histomorphologic changes can be separated into m Cellular abnormalities:
architectural abnormalities and cellular abnormali- – Abnormal variation in nuclear size

ties and include proliferation of immature or (anisonucleosis)
“uncommitted” cells with process beginning in basal – Abnormal variation in the nuclear shape
and parabasal area: (nuclear pleomorphism)
– Increased nuclear size relative to cytoplasm III), with the latter representing full-thickness
(increased nuclear-to-cytoplasmic ratio) replacement of the squamous epithelium by atyp-
– Nuclear hyperchromasia with irregularities in ical, small, immature basaloid cells and referred
nuclear contour to as carcinoma in situ (CIS)
– Prominent nucleoli (not unique to dysplasia m Grading scheme is reproducible and is clinically
and may be seen in a reactive or reparative useful.

process) m “Classic” or nonkeratinizing dysplasia is uncom-
• Histomorphologic evaluation for dysplasia is pri- mon in the upper aerodigestive tract, especially in
marily predicated on the cellular abnormalities but the laryngeal glottis.
also include architectural abnormalities especially in • Majority of the upper aerodigestive tract lesions,
relationship to keratinizing dysplastic lesions. especially larynx and oral cavity (see Section 2), are
keratinizing dysplasias:
m Alterations occur in the presence of surface
Grading of Epithelial Dysplasia keratinization.

• Grading of upper aerodigestive tract intraepithelial m Criteria for evaluating keratinizing dysplasias are
dysplasias is controversial and fraught with subjec- less defined and diagnosis of severe keratinizing
tivity especially for keratinizing dysplasias. intraepithelial dysplasia remains controversial.
• Variety of grading schemes proposed (see Table 16-2) m Definition of severe dysplasia in the setting of
but at present the recommended classification scheme keratosis, especially in the laryngeal glottis, is
is three-tiered system of grading intraepithelial dys- broader than the highly reproducible pattern seen
plasias advocated by the World Health Organization in the uterine cervix and includes a microscopi-
to include: cally heterogeneous group of lesions.
m Mild dysplasia (grade I): m In the setting of keratinizing dysplasia in which
– Dysplasia limited to the lower portions or inner surface maturation is retained with only partial
third of the epithelium (basal zone dysplasia) replacement of the epithelium by atypical cells,
m Moderate dysplasia (grade II): severe dysplasia includes those lesions in which
– Dysplasia involves up to two thirds of the epithelial alterations are so severe that there
thickness of the epithelium. would be a high probability for the progression
m Severe dysplasia (grade III): to an invasive carcinoma if left untreated.
– Dysplasia involves from two thirds to almost m Severe dysplasia shows presence of aberrant cell
complete thickness of the epithelium. maturation with dyskeratotic cells and mitotic
– Carcinoma in situ is subsumed within this figures with or without atypical forms above the
grade. basal zone.
• Two-tiered system of grading intraepithelial dyspla- m In the evaluation of upper aerodigestive tract dys-
sias (see Table 16-2) is advocated to include: plasia, the presence of surface keratinization is
m Low-grade squamous intraepithelial dysplasia not significant; however, finding dyskeratotic cells
includes mild dysplasia. represents an important clue to the presence of
m High-grade squamous intraepithelial dysplasia significant dysplasia.
includes moderate and severe dysplasia/carcinoma m In conjunction with the cytomorphologic changes,
in situ. architectural alterations also factor into the

m More reproducible with greater consensus among evaluation and the presence of elongated and
pathologists than three-tiered system: irregular-appearing rete ridges extending down-
– Subject of Hershey Consensus Conference ward into the submucosa assists in determining
(unpublished data) the degree of dysplasia in the setting of a keratotic
m No statistical differences in risk of progression to proliferation.
invasive carcinoma between moderate and severe • Carcinoma in situ (CIS) as applied to the uterine
dysplasia justifying “lumping” these two lesions cervix by histologic definition requires loss of matu-
within a single category similar to Bethesda clas- ration of squamous epithelium:
sification of uterine cervical squamous intraepi- m By this definition keratotic dysplastic lesions
thelial lesions cannot be CIS owing to the presence of matura-

• Paradigm for grading epithelial dysplasia is one used tion of the squamous epithelium.
for uterine cervix referred to as “classic” or nonke- m Use of the specific term CIS relative to keratin-
ratinizing dysplasia: izing dysplasias has been questioned and is likely

m Absent keratosis inappropriate in this setting.
m Increasing gradations of dysplasia include mild m More appropriate designation that of severe kera-
(grade I), moderate (grade II), and severe (grade tinizing dysplasia tantamount to CIS
• Histopathologic interpretation and grading of epi- – Facilitates better interobserver agreement than
thelial dysplastic changes in the upper aerodigestive previous systems, and retrospective follow-up
tract are imprecise and subjective: study demonstrated highly significant differ-
m Given the complexities in the issues relative to ence in risk of malignant progression between
UADT intraepithelial lesions, confusion and mis- low-grade and high-grade SILs
understandings may occur between the clinician • At present preferred grading for dysplastic epithe-
and the pathologist that may result in inappropri- lial alterations of the upper aerodigestive tract
ate management of the patient. include mild, moderate, and severe dysplasia
m Uniformity in terminology is desirable so that depending on the degree and extent of cellular
there is a correlation between the pathologic diag and maturation alterations that are present:
nosis and the clinical import of that diagnosis. m Histologic grading is evolving and as previ-
m In an attempt to standardize the terminology of ously indicated a two-tiered system to include

upper aerodigestive tract, intraepithelial lesions low grade (mild dysplasia) and high grade
using a grading system akin to that of the cervical (moderate dysplasia and severe dysplasia/CIS)
mucosa, including terminology of squamous for upper aerodigestive tract epithelial dysplas-
intraepithelial neoplasia (SIN) with SIN I equiva- tic lesions may be adopted.
lent to mild dysplasia, SIN II to moderate dyspla- • Risk of progression to invasive carcinoma
sia, and SIN III to severe dysplasia m End point for the grading of dysplasia is to
– Similar gradations but using terminology of convey to the clinician what is the potential
laryngeal intraepithelial neoplasia (LIN) and biologic behavior of a given epithelial lesion.
laryngeal intraepithelial lesion (LIL) have been m Keratotic epithelium without dysplasia carries
proposed. a very low risk of developing subsequent

m Ljubljana classification (see Table 16-2) of laryn- carcinoma, with reported incidences of 1%
geal precancerous lesions was proposed; in this to 5%.
system the terms used include: m In contrast, keratotic epithelium with dysplasia
– Simple hyperplasia (i.e., keratosis without is associated with an increased risk for the sub-
atypia) sequent progression or development of prema-
– Abnormal hyperplasia (i.e., keratosis with lignant or overtly carcinomatous changes
atypia) varying from 11% to 18% of cases.
– Atypical hyperplasia (i.e., severe dysplasia) m This risk of malignant transformation repre-
– Carcinoma in situ sents an increase of three to five times as com-

m More recently amended Ljubljana classification pared with carcinoma arising in keratotic
(see Table 16-2) proposed dividing squamous lesions without atypia.
intraepithelial lesions (SIL) into low-grade, high- m The risk for progression to invasive carcinoma
grade, and carcinoma in situ (CIS): in lesions diagnosed as keratosis with atypia
– Low-grade SIL is considered to be most often varies depending on the degree of atypia/
benign, with low malignant potential, charac- dysplasia:
terized by a spectrum of morphologic changes – For mild dysplasia: approximately 6%
ranging from a simple hyperplastic process – For moderate dysplasia: approximately
with retention of the basal layer and an 23%
increased prickle cell layer, to augmentation of – For severe dysplasia: approximately 28%
basal and parabasal cells occupying up to the – For those lesions that progress to invasive
lower half of the epithelium, with the upper carcinoma the average latency period from
part remaining unchanged, containing regular the diagnosis of keratosis with atypia to
prickle cells. invasive carcinoma is 3.8 years
– High-grade SIL considered to be a potentially m Histologic features seen in those dysplasias pro-
premalignant lesion with ≥12% of patients gressing to invasive carcinoma as compared with
subsequently developing malignancy is mor- those lesions that remain stable and do not pro
phologically characterized by a spectrum of gress include:
changes, including augmentation of immature – Increased mitotic activity in the middle and
epithelial cells, which occupy the lower half or upper portions of the epithelium
more of the epithelial thickness. – Presence of atypical mitoses
– Carcinoma in situ reserved for lesions showing – Moderate to severe nuclear pleomorphism
features of conventional carcinoma, e.g., struc- – Proliferation of small uncommitted cells
tural and cellular abnormalities but without above the basal zone or lower third of the
invasion (intraepithelial carcinoma) mucosa
m Another important point to recognize is the clini-

cal concern attached to a diagnosis of severe kera- Treatment and Prognosis
tinizing intraepithelial neoplasia: • Excisional biopsy by vocal cord stripping or by
– Clinical concern is due to fact severe dysplasia forceps is preferred treatment.
is often multifocal and frequently occurs adja- • Close follow-up of the patient is advocated; if clini-
cent to or near synchronous foci of invasive cally warranted, rebiopsy may be necessary and
carcinoma should be performed months after any procedure to
– This form of dysplasia has a rate of progression allow adequate healing and fewer surgery-associated
to invasive carcinoma that is greater than that pathologic changes that may hamper the histologic
of “classic” carcinoma in situ in setting or non- evaluation and/or obscure a neoplastic process.
keratinizing dysplasia. • Cessation of contributing risk factors should be
– A diagnosis of severe dysplasia requires thera- undertaken:
peutic intervention, as well as clinical evalua- m In general, mild and moderate dysplasias are felt
tion of the entire upper aerodigestive tract to to be potentially reversible alterations.

exclude the possible presence of additional foci m Circumstantial evidence supports the idea that
of dysplasia or carcinoma. preinvasive dysplasias are potentially reversible

• Immunohistochemistry: after cessation or removal of an instigating factor
m No known reliable markers to assist in diagnosis such as tobacco use.
and differential diagnosis m Problem of predicting the malignant potential of
m Increased proliferation rates in suprabasal epithe- a dysplastic lesion is greatest in cases of moderate
lium by Ki67 (MIB1) staining seen in higher dysplasia:
grade dysplasias – Virtually impossible to differentiate the moder-
m Increased p53 immunoreactivity seen in higher ately dysplastic lesions that are reversible from
grade dysplasias those that represent the earliest forms of neo-
m p16 not a reliable marker in determining presence plastic transformation
or absence of dysplasia in the larynx: – Diagnosis of moderate dysplasia should engen-
– Predominance of keratinizing dysplasia in der enough concern to the clinician to warrant
larynx (often etiologically linked to tobacco close patient follow-up.
and alcohol use) not associated with transcrip- – Recurrence or persistence of this dysplasia may
tionally active virus: be indicative of malignant transformation.
■ p16 and p21 immunohistochemistry may be – Determination of whether a mild to moderate
present in laryngeal keratinizing dysplasia dysplasia is reactive or neoplastic, although a
but do not correlate to the presence of tran- desirable goal, is not always achievable; the
scriptionally active HPV. clinically abnormal lesions that show limited
■ p16 should not be used as the definitive sur- cytologic and architectural abnormalities
rogate marker of HPV-driven tumors in the falling under the designation of reactive atypias
larynx. or hyperplastic lesions represent reversible
• Cytogenetics and molecular genetics: changes that rarely, if ever, progress to
m Loss of heterozygosity at 3p21, 5q21, 9p21, carcinoma:
17p13 more likely to progress to invasive ■ These lesions are responsive to conservative
carcinoma management.
m Tumor suppressor gene p53 implicated in head – Uterine cervical moderate dysplasia (cervical
and neck carcinogenesis: intraepithelial neoplasia II) and severe dyspla-
– p53 mutations found in >50% of invasive head sia (cervical intraepithelial neoplasia III) are
and neck squamous cell carcinoma currently lumped in the category of high-grade
squamous intraepithelial lesion (HGSIL).
Differential Diagnosis – Risk of progression to invasive carcinoma
• Reactive epithelial changes relative to upper aerodigestive tract moderate
• Infectious disease(s) dysplasia (approximately 23%) and severe dys-
• Microinvasive carcinoma: plasia (approximately 28%) is not statistically
m Diagnosis of microinvasive carcinoma should be significant.
reserved for cases in which there is definitive evi- – To date, grouping of upper aerodigestive tract
dence of dissociated squamous cells at the keratinizing moderate and severe dysplasia into
epithelial-to-stromal interface with invasion of a single category as high-grade squamous
the lamina propria; see later in section for more intraepithelial lesion similar to the uterine
complete discussion. cervix has not been adopted but may be the
recommended grading scheme in the near CARCINOMA IN SITU (CIS)

future to include: (Fig. 16-23)
■ Low-grade squamous intraepithelial lesion/
neoplasia for mild dysplasia Definition: Classically defined as cellular dysplasia

■ High-grade squamous intraepithelial lesion/ involving the entire thickness of the mucosa without
neoplasia for moderate and severe dysplasias compromise of the basement membrane:
Fig. 16-23. Laryngeal “classic” carcinoma in situ (CIS).

A and B, Nonkeratinizing epithelium showing full-thickness intraepithelial dysplasia. C, CIS with extension to subjacent
minor salivary gland, a finding that still constitutes CIS and not invasive carcinoma.
m Dysplasia may extend into adjacent seromucous Presence of mitoses in all layers of the mucosa:
m
glands and is still considered as an in situ lesion. – May include normal and abnormal forms
m Keratosis and dyskeratosis may be present.
Clinical • In presence of a diagnosis of CIS, the pathologist

• Represents approximately 1% to 13% of all laryn- should liberally section the specimen to rule out the
geal carcinomas presence of an invasive squamous cell carcinoma.
• More common in men than in women; most fre- • As previously noted under epithelial precursor lesions
quently seen in the sixth to seventh decades of life (see above), classic carcinoma in situ histologically
• Can occur anywhere in the larynx but most often defined as full-thickness intraepithelial dysplasia is
involves the anterior one third of one or both true uncommon relative to upper aerodigestive tract
vocal cords: intraepithelial keratinizing dysplasias; CIS typically
m May involve the entire cord occur in nonkeratinizing dysplasia, which is an un
m May be bilateral common lesion in mucosal sites of the upper aerodi-
m Frequently associated with an invasive squamous gestive tract, especially the larynx and oral cavity:
cell carcinoma either lying adjacent to or remote m Keratinizing dysplasias are much more common,
from one another and in such lesions full-thickness intraepithelial

m May exist as an isolated lesion unrelated to inva- dysplasia (i.e., classically defined CIS) is uncom-
sive carcinoma mon and is not a prerequisite for development of
m Multifocal areas can occur. invasive carcinoma.
• Hoarseness is most frequent presenting complaint. – In setting of keratinizing dysplasia, marked
• CIS may be associated with invasive carcinoma: dysplastic alterations may be restricted to basal
m Invasive carcinoma may occur in association with zone epithelium only, from which invasive car-
CIS or may be separate from CIS. cinoma may develop.
m Clinically, evaluation is advised to exclude the – Given such findings, use of diagnostic terms
possible presence of invasive carcinoma. such as “keratinizing severe dysplasia, tanta-
• Risk factors include: mount to carcinoma in situ” conveys to the
m Tobacco smoking (most common) and excess surgeon alterations in a lesion that will behave
alcohol use: similarly to carcinoma in situ (i.e., irreversible
– Alcohol potentiates the effect of tobacco and likely to progress to invasive carcinoma
smoking. unless adequately treated).
– Risk of developing dysplastic lesions increases • Immunohistochemistry:
with duration of smoking and/or alcohol use m No known reliable markers to assist in diagnosis
m Role of human papillomavirus in development of and differential diagnosis

carcinoma in situ of the head and neck (other m Increased proliferation rates in suprabasal epithe-
than oropharynx) not proven lium by Ki67 (MIB1) staining seen in higher-
grade dysplasias
Pathology m Increased p53 immunoreactivity seen in higher-
Gross grade dysplasias

• Circumscribed or diffuse lesion with a white, red, or m p16 not a reliable marker in determining presence
gray color and a smooth to granular appearance or absence of dysplasia in the larynx:
– Predominance of keratinizing dysplasia in
Histology larynx (often etiologically linked to tobacco
• Dysplastic process involves the entire thickness of and alcohol use) not associated with transcrip-
the squamous epithelium without violation of the tionally active virus:
basement membrane: ■ p16 and p21 immunohistochemistry may be
m Extension into adjacent seromucous glands (par- present in laryngeal keratinizing dysplasia
ticularly in the region of the anterior true vocal but does not correlate to the presence of
cord) may occur and does not constitute transcriptionally active HPV.
invasion. ■ p16 should not be used as definitive surro-
• Squamous epithelium may or may not be thickened. gate marker of HPV-driven tumors in the
• Cytomorphologic changes include: larynx.
m Increased nuclear pleomorphism and nuclear size
m Loss of cellular maturation and polarity Progression to Invasive Carcinoma

m Nuclear hyperchromasia with irregular nuclear • Wide variation in the literature relative to the inci-
contours dence of laryngeal CIS progressing to invasive
m Increased nuclear-to-cytoplasmic ratio carcinoma:
m Discrepant statistics ranging from approximately

3% to as high as 90% reflect inconsistencies in
the diagnosis of CIS, which can be a notoriously
subjective diagnosis.
m Collated incidence of laryngeal CIS progressing
to invasive carcinoma is 23% to 27%.

m Latent period of 3 to 5 years from diagnosis of
CIS to invasive carcinoma
• Reactive epithelial changes
• Microinvasive carcinoma

• No standard treatment; treatment may include: Fig. 16-24. Microinvasive carcinoma.
m Vocal cord stripping
Endoscopic appearance of a microinvasive (T1) laryngeal
m Laser surgery
(vocal cord) squamous cell carcinoma.
m Cordectomy
m Radiation
• Diagnosis of carcinoma in situ should prompt abla- Synonym: Superficially invasive squamous cell
tive therapy followed by surveillance for recurrence carcinoma
or progression:
m Surgical excision is preferred treatment. Clinical
m Alternative therapies such as radiation may be • Clinical manifestations are similar to those of carci-
employed in selected patients when surgical noma in situ.
therapy is not the best option. • In the larynx, full cord mobility is present:
• Management offers a high cure rate (approximately m Any dysfunction in vocal cord mobility (fixation)
75%): by definition means muscle invasion, which

m Vigilant follow-up including periodic laryngo- excludes a diagnosis of microinvasive cancer.
scopic examinations should be maintained. • Biologically malignant lesion capable of metastasiz-
• Risk factor modification remains important not only ing either via lymphatic or vascular channels
as a primary prevention strategy but to reduce risk
of progression to invasive carcinoma. Pathology
• Treatment failures result from: Gross
m Extensive and/or multifocal disease • Similar to carcinoma in situ
m Associated undetected invasive squamous
carcinoma Histology
m Extension of CIS to subjacent seromucous glands
Diagnostic Criteria for Microinvasive Carcinoma
harboring residual disease following the mucosal • Definition of features constituting microinvasion
stripping: varies in literature:
– Particularly true for CIS of the anterior com- m Presence of scattered malignant cells within the
missure region, where seromucous glands may submucosa just below the basement membrane
be located distant from the opening of their m Presence of malignant cells limited to 2 mm of
ducts and may lie outside area that is stripped invasion

– For CIS of anterior commissure additional m Presence of malignant cells within 1 to 2 mm of
therapy including laser ablation or irradiation the basement membrane without angioinvasion
may be indicated. m Presence of tongues or discrete foci of malignant
epithelium invading through the basement

membrane
MICROINVASIVE CARCINOMA m Invasive carcinoma extending into the stroma no
(Figs. 16-24 through 16-27) more than 0.5 mm measured from the epithelial
basement membrane and without angioinvasion
Definition: Malignant cells that have penetrated the – Represents preferred definition
basement membrane and infiltrate into the superficial • Regardless of specific definition, diagnosis of micro-
compartment of the lamina propria. invasive carcinoma excludes those lesions that are
B C
Fig. 16-25. Invasive squamous cell carcinoma.

A, Nonkeratinizing severe dysplasia (carcinoma in situ) with development of microinvasive carcinoma; note the invasive
tumor nests that, while well-rounded, are below the level of submucosal small vascular spaces. B, Keratinizing dysplasia
with downward extension of the rete ridges and disruption (penetration) of basement membrane; in addition, a separate
nest of invasive carcinoma with associated dyskeratosis is present (left of center). C, “Drop-off” or “drop-down”
carcinoma in which invasive carcinoma originates from the basal zone of the surface epithelium which otherwise shows
bland cytomorphology without dysplasia.
restricted to the surface epithelium or carcinoma in – Typically occurs in the setting of a keratinizing
situ (CIS) and those carcinomas that are deeply inva- high-grade dysplasia (i.e., moderate to severe)
sive into muscle and cartilage, and extralaryngeal in which the (micro)invasive carcinoma is seen
structures (T2 or greater tumors). originating from dysplastic epithelial changes
• Microinvasive carcinoma can occur in two unrelated limited to the basal zone epithelium with the
phases: remainder of the more superficially located epi-
m Development from (and as a continuum of) car- thelium lacking dysplastic change:
cinoma in situ: ■ Such invasive carcinomas are referred to as
– Typically occurs in a setting of nonkeratinizing “drop off” or “drop down” carcinoma.

dysplasia with full-thickness intraepithelial ■ Reinforces the fact that in the upper aerodi-
dysplasia: gestive tract, particularly in the larynx and

■ Not a common occurrence relative to dys- oral cavity, “classic” carcinoma in situ is not
plastic lesions of the larynx (and oral cavity) a prerequisite for the development of a
m Invasion from an epithelium demonstrating (micro)invasive squamous cell carcinoma
dysplastic alterations representing severe dyspla- • In invasive carcinoma:
sia but lacking full-thickness intraepithelial m Tumor nests have an irregular outline with infil-
dysplasia: trative borders.
A B
Fig. 16-26. Keratin granuloma.

Keratin granuloma formation is considered as presumptive evidence of invasive carcinoma. A, Granulomatous response
including multinucleated giant cells rimming amorphous eosinophilic debris. B, Isolated keratinizing neoplastic cells are
present in and around the granuloma but may not be as overtly identifiable in other cases. C, Cytokeratin immunoreactivity
confirms the eosinophilic debris as keratin; note the absence of staining in the multinucleated giant cells (upper right),
which would be reactive for CD68 (not shown).
CIS MIC SEC DIC
Surface
epithelium
Basement
membrane
Lamina
propria
Vocalis
muscle
Fig. 16-27.
Diagrammatic depiction of superficial extending carcinoma (SEC) compared with carcinoma in situ (CIS), microinvasive
carcinoma (MIC), and deeply invasive carcinoma (DIC). (Adapted from Barnes L: Carcinoma in situ. In Barnes L, editor: Surgical
pathology of the head and neck, ed 2, New York, 2001, Marcel Dekker, pp 158-161.)
m Invasive nests are cytologically malignant, but m In contrast to microinvasive carcinoma, which
invasive carcinomas may be extremely well- is predominantly an in situ carcinoma with
differentiated with minimal if any malignant definite but limited invasion into the lamina
cytologic features. propria, superficial extending carcinoma shows
• Presence of invasive cancer generally results in a extensive invasion into (but not beyond) the
desmoplastic host response that includes edematous lamina propria.
change immediately around the tumor nests with m By definition there is no invasion into muscle or
granulation tissue and fibrosis: cartilage.

m Identifying tumor-related desmoplasia from reac- m Associated carcinoma in situ is often present.
tive stromal changes not straightforward: m May be multifocal
– There are no clear-cut criteria other than the m Establishing this diagnosis may be problematic in
presence of bona fide malignant cells (in nests limited biopsy sampling and may require surgical
or individual cells) to differentiate between excision with thorough histologic evaluation.
tumor-related desmoplasia and reactive stromal m Limited reports to date and the long-term prog-
changes to assist in a diagnosis of invasion. nosis remains uncertain

– In setting of well-differentiated squamous epi- m Presence of nodal metastasis in the setting of
thelium within the submucosa it can be very superficial extending carcinoma may exclude this
difficult if not impossible to determine neoplas- entity as an “early” carcinoma.
tic (malignant) epithelium from nonneoplastic
squamous epithelium that is reactive and/or Treatment and Prognosis
represents tangentially sectioned squamous • No standardized approach to treatment:
epithelium: m Most authorities advocate conservative manage-
■ No immunostains or molecular markers ment with endoscopic removal of the lesion

available to assist in such a differentiation (mucosal stripping with or without laser abla-
■ In such a scenario a diagnosis of carcinoma tion) and close clinical follow-up of the patient
may not be possible and a designation of rather than surgical resection (e.g., some type of
“well-differentiated squamous epithelial laryngectomy) or radiation.
proliferation, not further specified” may be m Behavior is similar to that of carcinoma in situ,
required with recommendation for: and if presence of a coexisting invasive squamous

□ Additional deeper biopsies cell carcinoma can be excluded, then therapy is
□ Conservative but complete excision of the similar to carcinoma in situ.
lesion • Conservative management supported by:
m Keratin granuloma formation in the submucosa m Studies have shown that in cases in which hemi-
represents supportive evidence of (at least) micro- laryngectomy was performed, no residual carci-
invasive carcinoma: noma was found in 20% of patients, indicating
– Represents a foreign body reaction to keratin that the lesion was totally excised in original
in the submucosa biopsy.
– Appears as relatively well-formed granuloma m For microinvasive carcinoma of the laryngeal
formation, including the presence of histiocytes glottis, several studies have shown that the clini-
and multinucleated giant cells cal significance is similar to CIS/severe dysplasia
– Keratin material may or may not be identified and that with appropriate therapy progression of
by light microscopy. disease from a microinvasive to a more invasive
– May require cytokeratin immunohistochemical carcinoma does not occur.
staining (e.g., AE1/AE3, CAM5.2, others) to – This finding may be due to earlier clinical
confirm the presence of keratin-positive material manifestations produced by glottic cancers,
– In the absence of cytokeratin-positive material, leading to an earlier diagnosis of cancer
a diagnosis of keratin granuloma cannot be before it has invaded into deeper aspects of the
rendered. larynx.
– Histiocytes and giant cells are CD68 (KP1) m Glottic microinvasive cancers are generally not
positive. associated with metastatic disease due to the fact

that glottic portion of the larynx has quantita-
Differential Diagnosis tively less lymph-vascular spaces as compared
• Pseudoepitheliomatous hyperplasia with the supra- and subglottis.
• Superficial extending carcinoma (see Fig. 16-27): • In contrast to laryngeal glottis, supraglottic microin-
m Early invasive carcinoma that does not extend vasive carcinomas are associated with metastatic
beyond lamina propria disease in approximately 20% of patients.
Fig. 16-28. Invasive well-differentiated squamous

cell carcinoma.
A, Invasion includes cohesive nests and cords.
B, Keratinization and intercellular bridges are readily Fig. 16-29. “Drop off” invasive squamous cell
apparent. carcinoma.
Example of a deeply invasive squamous cell carcinoma in
which the carcinoma “drops off” from the basal zone of
LARYNGEAL INVASIVE the surface epithelium, which otherwise shows bland
SQUAMOUS CELL CARCINOMA cytomorphology and absence of full-thickness dysplasia.

General Considerations
• Laryngeal squamous cell carcinoma (SCC) accounts Rarely occurs in pediatric ages (first and second
m
for approximately 0.8% of all cancers, 1.0% of all decades of life):

cancers in men, and approximately 0.3% of all – More common in girls than boys
cancers in women. – Most occur in glottic region
• Represents greater than 95% of all laryngeal – Hoarseness most common complaint
carcinomas – No known risk factors but possible relation-
• More common in men than in women; most com- ship to HPV and passive smoking exposure
monly occurs in the fifth through seventh decades of • Cause:
life: m Association with tobacco smoking:
m There has been an increase of laryngeal carci- – Tobacco linked to glottic carcinoma:
noma in women over the past 20 years, likely ■ Less than 5% of patients with laryngeal car-
linked to increase tobacco use in women over this cinoma are nonsmokers.
time period. m Alcohol linked to supraglottic carcinoma but less
m Less than 1% occur in patients under 30 years important risk factor as compared with tobacco
of age. use
association with invasive SCC; this component need

not be present.
• For all types of SCC, presence of invasion is diag-
nostic for malignancy:
m Invasion can be as single cells or small irregular
aggregates or can appear as large cords or cohe-

sive aggregates.
m Desmoplastic stromal response and foreign body
reaction to keratin (keratin granuloma; see

Fig. 16-24) in the stroma assist in identifying
invasion.
m Invasive cancer tends to efface normal histoana-
tomic architecture:
– In contrast, lobular growth of seromucous
Fig. 16-30. Extranodal extension.
glands is retained in association with
sialometaplasia.
Laryngeal squamous cell carcinoma metastatic to cervical m Invasion may be associated with lymph-vascular
neck lymph node with extranodal extension, the latter invasion, neurotropism, invasion into muscle,
characterized by the presence of carcinoma in perinodal bone, and cartilage:
soft tissues (upper left).
– Invasion of cartilage often occurs in cartilage
that has undergone ossification:
■ Ossification usually occurs in the third
m Other potential contributing etiologic factors decade and not before the third decade
associated with but not definitively linked as a of life.
direct cause of squamous cell carcinoma include: ■ Histology is similar to endochondral
– Genetic factors ossification.
– Human papillomavirus infection ■ Ossification of thyroid cartilage begins at
– Dietary deficiencies (vitamin A, vitamin posterior border near the root of the inferior
C, iron) cornu, spreads along inferior border and
– Previous irradiation to the neck reaches midline, where there usually is a
– Environmental/occupational exposure (asbes- separate center of ossification.
tos, nickel, wood, air pollution, isopropyl ■ Invasion of the laryngeal cartilage frame-
alcohol, mustard gas, others) work usually is in lower third of the thyroid
– Chronic gastroesophageal reflux disease cartilage.
• TNM staging of laryngeal carcinoma for all subsites □ Perichondrium appears to resist inva
detailed in Box 16-3: sion and remains intact even when
m TNM staging for hypopharyngeal cancers is the cancer infiltrates and expands the
detailed in Section 3. cartilage.
• See below for clinicopathologic features for site- ■ Reasons cited for the presence of invasion in
specific laryngeal cancers. ossified cartilage include the absence of peri-

chondrium in this areas.
Pathology – Cartilaginous invasion usually is found in asso-
Gross ciation with transglottic cancers.
• Variable and includes ulcerated, flat, exophytic, ver- m Once cancer invades beyond a few millimeters or
rucoid, or papillary growths extends into muscle, cartilage, or other soft tissue
components outside the anatomic structure from
Histology which it originates, then it is a higher clinical
• Histologic appearance of invasive SCC may be as stage neoplasm with potential for a more aggres-
variable as gross appearance without specific corre- sive behavior.
lation between gross appearance and the histopatho- m Immunohistochemical studies have shown that
logic findings. the presence or absence of basement mem-

• Invasive SCC includes keratinizing and nonkeratiniz- brane components around invasive cancer may
ing carcinomas varying from well to poorly correlate with pattern of tumor invasion:
differentiated. – Pattern of tumor invasion (single cell versus
• Severe dysplasia/carcinoma in situ of the surface epi- large cords) represents an inherent biologic
thelium may be a common component found in parameter of tumor aggressiveness.
BOX 16-3 TNM Classification of Laryngeal Carcinoma
Primary Tumor • T4a = Moderately advanced local disease

• T = extent of the primary tumor – Tumor invades cricoid or thyroid cartilage and/or
– Includes the clinical (T) and pathologic (pT) invades tissues beyond the larynx (e.g., trachea, soft
categories tissues of the neck including deep extrinsic muscle of
– T designation varies according to the anatomic site the tongue, strap muscles, thyroid, or esophagus)
involved • T4b = Very advanced local disease
• TX = Primary tumor cannot be assessed. – Tumor invades prevertebral space, encases carotid
• T0 = No evidence of primary tumor artery, or invades mediastinal structures
• Tis = Carcinoma in situ
Regional Lymph Nodes (N)
Supraglottis • N = Absence/presence and extent of regional lymph node
• T1 = Tumor limited to one subsite with normal vocal cord metastasis; includes the clinical (N) and pathologic (pN)
mobility categories
• T2 = Tumor invades mucosa of more than one adjacent • NX = Regional lymph nodes cannot be assessed.
subsite of supraglottis or glottis or region outside the • N0 = No regional lymph node metastasis
supraglottis (e.g., mucosa of base of tongue, vallecula, • N1 = Metastasis in a single ipsilateral lymph node, 3 cm or
medial wall of piriform sinus) without fixation of the less in greatest dimension
larynx • N2 = Metastasis in a single ipsilateral lymph node, more
• T3 = Tumor limited to the larynx with vocal cord fixation than 3 cm but not more than 6 cm in greatest dimension,
and/or invades any of the following: postcricoid area, or multiple ipsilateral lymph nodes, none more than 6 cm
pre-epiglottic tissues, paraglottic space and/or minor in greatest dimension or in bilateral or contralateral lymph
thyroid cartilage erosion (e.g., inner cortex) nodes, none more than 6 cm in greatest dimension
• T4a = Moderately advanced local disease – N2a = Metastasis in a single ipsilateral lymph node,
– Tumor invades through the thyroid cartilage and/or more than 3 cm but not more than 6 cm in greatest
invades tissues beyond the larynx (e.g., trachea, soft dimension
tissues of the neck including deep extrinsic muscle of – N2b = Metastasis in multiple ipsilateral lymph nodes,
the tongue, strap muscles, thyroid, or esophagus) none more than 6 cm in greatest dimension
• T4b = Very advanced local disease – N2c = Metastasis in bilateral or contralateral lymph
– Tumor invades prevertebral space, encases carotid nodes, none more than 6 cm in greatest dimension
artery, or invades mediastinal structures. – N3 = Metastasis in a lymph node, more than 6 cm in
greatest dimension
Glottis • Metastases at Level VII are considered regional lymph
• T1 = Tumor limited to the vocal cord(s) (may involve node metastasis
anterior and posterior commissures) with normal cord
mobility: Distant Metastasis (M)
– T1a = tumor limited to one vocal cord • M = Absence or presence of distant metastasis; includes
– T1b = tumor involves both vocal cords both the clinical (M) and pathologic (pM) categories
• T2 = Tumor extends to the supraglottis and/or subglottis • M0 = No distant metastasis
and/or with impaired vocal cord mobility • M1 = Distant metastasis present
• T3 = Tumor limited to the larynx with vocal cord fixation
Clinical Stage
and/or invades paraglottic space and/or minor thyroid
• Stage 0 = TisN0M0
cartilage erosion (e.g., inner cortex)
• Stage I = T1N0M0
• T4a = Moderately advanced local disease
• Stage II = T2N0M0
– Tumor invades through the outer cortex of thyroid
• Stage III = T3N0M0
cartilage and/or invades tissues beyond the larynx
– T1N1M0
(e.g., trachea, soft tissues of the neck including deep
– T2N1M0
extrinsic muscle of the tongue, strap muscles, thyroid,
– T3N1M0
or esophagus)
• Stage IVA = T4aN0M0
• T4b = Very advanced local disease
– T4aN1M0
– Tumor invades prevertebral space, encases carotid
– T1N2M0
artery, or invades mediastinal structures
– T2N2M0
Subglottis – T3N2M0
• T1 = Tumor limited to the subglottis – T4aN2M0
• T2 = Tumor extends to the vocal cord(s) with normal or • Stage IVB = T4b Any N M0
impaired mobility – Any T N3M0
• T3 = Tumor limited to the larynx with vocal cord fixation • Stage IVC = Any T Any N M1
• Sampling represents a major issue in the evaluation Diagnostic pitfalls in diagnosis of laryngeal
m
of SCC: SCC include pseudoepitheliomatous hyperpla-

m In absence of adequate representative tissue sia, necrotizing sialometaplasia, and radiation
including epithelial-to-stromal interface, one atypia.
should be circumspect relative to rendering a • Factors affecting prognosis:
diagnosis of invasive SCC. m Tumor location:
– Transglottic tumors have higher incidence of squamous cell carcinoma with positive
lymph node metastasis compared with supra- margins supporting organ sparing (conserva-
glottic and subglottic carcinomas. tive) laryngectomy may include:
m Tumor size: □ These patients have early-stage carci-
– Larger tumors have greater chance of noma associated with a more favorable
metastasis. prognosis.
m Tumor histology: □ Submucosa of the glottic region has (quan-
– Poorer differentiation (grade) more likely to titatively) fewer lymph-vascular spaces,

disseminate thereby decreasing the incidence of spread
m Cervical lymph node metastasis: and lowering the incidence of locoregional
– Metastatic tumor to cervical lymph nodes failure.
decreases survival by 50%.
– Tumor extending beyond the confines of the
lymph node into perinodal soft tissues (extra- Supraglottic Squamous Cell
nodal extension; see Fig. 16-30) represents an
important finding relating to:
Carcinoma (Fig. 16-31)
■ Recurrent disease in neck Definition: Squamous cell carcinoma that involves
■ Increased risk for distant metastasis structures of supraglottic larynx, including the epiglottis
■ Presence or absence of extranodal extension (laryngeal and lingual surfaces), aryepiglottic folds, ary-
should be specifically commented on in tenoids, false vocal cords, and ventricles.
pathology report.
m Multiple malignancies: Clinical
– Up to 12% of patients with laryngeal carci- • Accounts for 30% to 35% of all laryngeal
noma develop a secondary primary malignant carcinomas
tumor either in lung, another upper aerodiges- • In descending order supraglottic carcinomas involve
tive tract site, or, less commonly distant unre- epiglottis (45% to 55%) > false vocal cords (12% to
lated site. 33%) > aryepiglottic folds (8% to 21%) > ventricles
m Surgical resection margins: (4% to 7%) and arytenoids (5% to 6%):
– For laryngeal carcinomas, a margin of resec- m In combination with other sites epiglottis is
tion of 2 mm is considered adequate: involved in 70% to 90% of cases.

■ In larynx margins of 2 mm or greater m Marginal or epilaryngeal carcinomas represent
have been shown to have a similar behavior carcinomas involving the suprahyoid epiglottis
to margins with greater clearance (e.g., and aryepiglottic folds and account for approxi-
5 mm). mately 20% of cases.
■ Other studies have reported that in laryngeal • Symptoms include:
squamous cell carcinomas: m Dysphagia, changes in quality of voice, foreign
□ 18% develop local recurrence with positive body sensation in the throat, neck mass, hemop-
surgical margins tysis, odynophagia, and dyspnea
□ 6% develop local recurrence with negative m Marginal (epilaryngeal) carcinomas tend to
margins remain quiescent for longer periods and present
■ As compared with extralaryngeal mucosal with more advanced disease.
sites, patients with primary laryngeal squa-
mous cell carcinoma with positive surgical Pathology
margins have a significantly lower incidence Gross
of local recurrence: • Vary in size and appearance:
□ Larynx perhaps is an outlier in regard to m Tend to be large
positive margins and local recurrence. m Ulcerated, flat, exophytic, or rarely papillary
■ Above findings suggest that margin status
and local recurrence are site dependent Histology

and assist in explaining why surgeons • Tend to be moderately to poorly differentiated
are more apt to accept nearer margins carcinomas
for laryngeal carcinoma (free margins up • An in situ component is common and may be
to 2 mm) but require wider margins (5 to extensive.
10 mm) for carcinomas of extralaryngeal • Invasive pattern can be pushing or infiltrative.
mucosal sites. • Mitoses and necrosis can be seen and their presence
■ Factors that may contribute to the lower inci- relates to the grade of the tumor (tend to be more
dence of local recurrences in laryngeal common with poorer differentiated tumors).
Into vallecula (i.e., base of tongue)

m
High incidence of invasion of the preepiglottic

m
space:
– Involvement of the preepiglottic space is associ-
ated with an increased incidence of nodal
metastasis.
m Uncommon to spread posteriorly to arytenoids or
to glottis or thyroid cartilage

• Marginal carcinomas tend to spread to:
m Base of tongue
m Less common to spread to the pre-epiglottic space

• Treatment depends on stage:
m Early stage lesions (T1N0 and T2N0):
– Radiation therapy or supraglottic laryngec-

tomy with or without adjuvant radiotherapy
m Advanced-stage lesions (T3 and T4):
– Combined modalities often including total lar-

yngectomy and adjuvant radiotherapy:
• Decision to use radiation therapy or partial laryngeal
therapy depends on several factors, including:
m Anatomic extent of the tumor
m Medical condition of the patient
m Status of the surgical margins
m Presence or absence of nodal metastasis with or
without extracapsular spread

m Philosophy of the treating physician
A m Inclination of the patient and family
• Potential for nodal metastasis even in early-stage

lesions is substantial, and neck dissection is often
performed in conjunction with laryngeal surgery:
m Majority of supraglottic carcinomas are located
in epiglottis and many of these tumors are midline,

putting the patient at risk for contralateral neck
metastases, thereby necessitating bilateral neck
dissection.
m Site of treatment failure in supraglottic carcinoma
is neck, requiring neck management for supra-

glottic carcinomas.
m For the N0 neck, selective neck dissection or elec-
tive radiation is indicated.

m For clinically positive neck disease, neck dissec-
tion, therapeutic irradiation, or combination of

both indicated
B m Supraglottic larynx is rich in lymphatic spaces,
increasing the likelihood of cervical lymph node

Fig. 16-31. metastasis even in early-stage disease.
m Increased rates of cervical lymph node metastasis
A, B, Supraglottic laryngectomy specimens showing correlated to:
supraglottic-based (squamous cell) carcinoma.
– Tumor size: larger tumors (>4 cm) have higher
rate of metastasis
Spread – Location:
• Tendency for supraglottic carcinomas to spread: ■ Tumors arising from marginal supraglottis
m Upward toward the free margins of the epiglottis have higher rate of metastasis
and aryepiglottic folds ■ Anterior tumors or tumors that cross the
m Into piriform sinus midline may produce bilateral metastases
m Supraglottic lymphatic drainage is to upper and

middle jugular chains.
m Distant metastasis (i.e., below the clavicle) from
supraglottic cancers is uncommon (5% to 15%)

and when it occurs more commonly involves the
lung and mediastinal lymph nodes
• Overall 5-year survival rate for all stages of supra-
glottic carcinomas is 65% to 75%:
m Prognosis depends on:
– Extent and location of the primary lesion

– Presence of cervical lymph node metastasis:
■ Appears to represent most important deter-
minant of survival
■ Influenced by location of primary tumor (see
above)
■ Occurs in 30% to 40% of cases
■ Most commonly involves upper and midjug-
ular lymph nodes

■ Uncontrolled neck metastasis is a source of
therapeutic failure.
– Nature of the primary therapy
Glottic Squamous Cell Carcinoma

(Fig. 16-32)
Definition: Squamous cell carcinoma that involves
structures of glottis, including the true vocal cords, and
anterior and posterior commissures.
Clinical
• Represents from 60% to 65% of all laryngeal squa- Fig. 16-32.
mous cell carcinomas
• Majority arise from anterior portion of true vocal Laryngectomy specimen showing a glottic-based
cord: (squamous cell) carcinoma.
m Involvement of anterior commissure alone is
uncommon (less than 10% of cases) Histology

m Secondary involvement is more common, seen in • Most often are well-differentiated to moderately dif-
up to 46% of cases. ferentiated squamous cell carcinomas
m Posterior portion of true vocal cord is uncommon • High-grade intraepithelial dysplasia/CIS seen adja-
site for carcinoma to develop. cent to invasive carcinoma
m Equally distributed between right and left true cord • Invasive pattern is predominantly infiltrative but can
• Most common presenting symptom is hoarseness. be pushing.
• As a result of interference with vocal cord mobility
symptoms develop early in the course of disease. Spread
• Many glottic carcinomas are small, limited in size, • Spread of glottic carcinomas include:
tend to be localized and are amenable to conserva- m Across the anterior commissure to involve the
tive therapy. opposite vocal cord

m Anteriorly through the Broyle’s ligament (ante-
Pathology rior commissure tendon) with deep invasion and
Gross penetration of the thyroid cartilage in the midline
• Early lesions: with invasion of the soft tissues of the neck
m Irregular area of mucosal thickening of varying m Posteriorly to involve arytenoids
size m Extension to supraglottis with involvement of the
• Advanced lesions: ventricle, false vocal cords, and epiglottis:

m Exophytic, fungating, endophytic, or ulcerated – Occurs in approximately 20% to 25% of
mass, which can attain a large size cases
m Extension to subglottis: Incidence of nodal metastasis in T1 lesions ranges

m
– Occurs in approximately 20% to 25% of cases from 0 to 6%.

– Greater access to lymphatic channels with m Incidence of nodal metastasis in T2 lesions ranges
potential for spread to paratracheal and medi- from 4% to 11%.

astinal lymph nodes m Majority of cervical lymph node metastasis occur-
– Potential to invade cricothyroid membrane ring in glottic carcinomas is seen in T3 and T4

growing into soft tissues of the neck lesions:
– Do not invade thyroid cartilage until more than – Incidence of nodal metastasis in T3 lesions
1 cm into subglottis ranges from 14% to 22%.
m Extension into Reinke space along the vocal cord – Incidence of nodal metastasis in T4 lesions
ligament with infiltration into the vocalis muscle: ranges from 25% to 41%.
– This pattern of invasion defines vocal cord • Overall 5-year survival rates include:
fixation. m T1: 82% to 96%
■ In presence of fixed cord incidence of nodal m T2: 51% to 85%
metastasis is approximately 25%. m T3: 48% to 59%
– If cord is not fixed, then invasion is superficial m T4: 0 to 30%
to conus elasticus. • Risk factors associated with incidence of locore-

■ Absent cord fixation incidence of nodal gional failure include:
metastasis is less than 2%. m Prior tracheotomy
m Poor histologic differentiation
Treatment and Prognosis m Subglottic extension >1 cm
• Treatment depends on staging: m Histologically positive lymph nodes
m For early glottic cancers (T1 and T2) excellent • Risk of distant metastases increased in association
control can be achieved by radiation or partial with presence of metastatic carcinoma to a lymph
laryngectomy or even endoscopic resection in node with extranodal invasion into perinodal soft
some lesions. tissue (extranodal extension)
– Advantages of radiation include:
■ Better voice control than that achieved by
hemilaryngectomy Subglottic Squamous Cell

■ Hemilaryngectomy (i.e., vertical hemilaryn-
gectomy) can be used successfully for salvage

in those patients in whom radiation has Definition: Squamous cell carcinoma that involves
failed. subglottis, which begins 1 cm below apex of ventricle
m For advanced glottic cancers (T3 and T4) total to its inferior border represented by rim of cricoid
laryngectomy with or without radiation therapy: cartilage.
– Not all advanced glottic cancers require total
laryngectomy. Clinical
– Certain T3 glottic cancers, including those with • Considered uncommon, accounting for less than 5%
mobile arytenoids and less than 7 mm of sub- of all laryngeal carcinomas
glottic extension, are potential candidates for • Tend to remain clinically quiescent, presenting with
subtotal laryngectomy. advanced disease
• Neck dissection (radical neck dissection or modified • Most common presenting symptoms relate to airway
radical neck dissection): obstruction (dyspnea, stridor) and to vocal cord fixa-
m Performed in patients with clinically N+ neck tion (voice changes):
disease m May necessitate emergency tracheotomy to main-
m For advanced glottic carcinomas rates of occult tain airway

metastasis in clinically N0 neck approach 20%
and are higher for those carcinomas that cross the Pathology
midline, so these patients may be considered for Gross
elective neck dissection for staging purposes when • Large exophytic, fungating, ulcerating, or endo-
surgery is performed for primary disease. phytic mass
m Glottic lymphatic drainage is to upper and lower
jugular chains. Histology

• Glottic region has sparse lymphatic drainage; as such • Tend to be moderately to poorly differentiated squa-
the overall incidence of lymph node metastasis is mous cell carcinoma
low: • Invasive pattern is predominantly infiltrative.
m Posterolateral to the paratracheal lymph nodes,

which are continuous with lymph nodes in the
superior mediastinum

• Treatment is dependent on staging:
m For early-stage subglottic cancers (T1 and T2):
– Radiotherapy alone or conservative surgery

m For advanced-stage subglottic cancers (T3
and T4):
– Radical surgical extirpation through wide field
laryngectomy
m In general, subglottic tumors present with
advanced disease and because of proximity to
cricothyroid space and the cricoid cartilage; sur-
gical treatment usually necessitates a total
laryngectomy.
m Due to involvement of the thyroid gland in
approximately 10% to 20% of cases, recom-

mended that one or both thyroid lobes be removed
• Radical neck dissection is advocated in advanced
subglottic carcinoma:
m Approximately 15% to 25% of patients have
cervical lymph node metastases but paratracheal

lymph nodes that are clinically negative (N0)
harbor metastatic tumor from subglottic primary
carcinoma in up to 50% of cases, leading to rec-
ommendation of clearing the paratracheal as well
as superior mediastinal lymph nodes.
• Overall 5-year survival rate is approximately
Fig. 16-33.
40%:
m Death due to subglottic carcinoma often due to
Laryngectomy specimen showing a subglottic-based local or stomal recurrence:
(squamous cell) carcinoma. – Refers to diffuse infiltration of carcinoma at
junction of amputated trachea and skin
Spread – Dreaded complication of total laryngectomy
• Tendency to spread circumferentially and anteriorly – Occurs in approximately 2% to 15% of
through the cricothyroid membrane with involve- patients who have had total laryngectomies
ment of thyroid gland and paratracheal and prelar- – Most often occurs within 1 to 2 years after
yngeal (Delphian) lymph nodes total laryngectomy
• May spread: – 70% of patients with stomal recurrence die
m Posteriorly below the thyroid cartilage with within the first year after laryngectomy and
involvement of the cervical esophagus 98% within 2 years.
m Inferiorly with involvement of the trachea – Inadequate tumor resection at the inferior
m Medially into the cricoarytenoid joint with margin contributes to early stomal recurrence.
involvement of the hypopharynx • Distant metastases occur in 15% to 20%:
m Into the thyroarytenoid muscle to produce vocal m Most often to lungs and bones
cord fixation
m Superiorly to involve the glottic and supraglottic
Transglottic Squamous Cell
regions
• Subglottic region of larynx has lymphatic drainage
to: Definition: Transglottic carcinoma represents a carci-
m Upper and lower jugular lymph node chains noma that crosses ventricles in a vertical direction to
m Anteriorly to prelaryngeal (Delphian) lymph involve supraglottis and glottis (and often subglottis):
node, which in turn drains to the pretracheal and m Most likely are glottic cancer with supraglottic
supraclavicular lymph nodes extension
A C
Fig. 16-34. Transglottic carcinoma.

A, Transglottic carcinoma characterized by carcinoma that crossed the ventricles in a vertical direction with involvement of
the glottic and supraglottic larynx. B, Bilateral vocal cord paralysis in a patient with a transglottic carcinoma. C, Patients
with transglottic carcinoma have a high incidence of nodal metastasis as seen in this patient with a right lateral neck mass
histologically composed of a keratinizing squamous cell carcinoma.
Clinicopathologic Features m Should be suspected in patients with referred

• Usually but not always represent advanced-stage otalgia
tumors m 26% with nodal metastasis at presentation and
• Majority are moderately differentiated with infiltrat- additional 19% subsequently develop positive
ing margins. lymph nodes during course of disease
• High incidence of nodal metastases and extralaryn- • High incidence of vocal cord paralysis
geal spread: • May be understaged as a result of undetectable car-
m Extralaryngeal spread present in approximately tilaginous invasion
one third of patients • Treatment generally requires radical surgery and
m Spread to paraglottic space radiotherapy.
m Submucosal spread to piriform sinus • In limited patients conservation techniques may be
m Extralaryngeal escape by growing through the used.
cricothyroid or thyrohyoid membranes • Overall 5-year survival is approximately 50%.
Tracheal Squamous Cell Carcinoma BOX 16-4 Variants of Squamous Cell Carcinoma
Clinical • Papillary squamous cell carcinoma
• Most common malignant neoplasm of the trachea • Verrucous carcinoma
• More common in men than in women; most common • Spindle cell squamous carcinoma
• Basaloid squamous cell carcinoma
in the fifth to seventh decades of life • Adenosquamous carcinoma
• Clinical presentation includes stridor, cough, hemop- • Lymphoepithelial-like carcinoma
tysis, hoarseness, weight loss; superior vena cava • Giant cell carcinoma
syndrome may occur in minority of cases: • Others
m Delay in diagnosis is common as symptoms may
be attributed to asthma.
• Tracheal carcinoma at the level of the thyroid can be • There is no current TNM classification for tracheal
misinterpreted as invasive thyroid cancer. carcinomas.
• In order of frequency tracheal carcinomas occur:
m Lower third (45%) > upper third (32%) > middle
third (15%) > multiple sites (8%)

VARIANTS OF SQUAMOUS
• Cause: CELL CARCINOMA (Box 16-4
m Most patients reported to be heavy tobacco and Table 16-3)
smokers
Papillary (Exophytic) Squamous
Pathology
Cell Carcinoma (PSCC)
Gross
• Polypoid mass protruding into the tracheal lumen:
m Most tend to be large, measuring 4 cm in greatest Definition: Invasive squamous cell carcinoma with a
dimension. predominant papillary and/or exophytic component.
• Uncommonly grows circumferentially or with an
annular appearance Clinical
• Uncommon but distinct subtype of head and neck
Histology SCC
• Variable architectural features including exophytic • Demographics are similar to those of conventional
and papillary SCC with the tendency to affect men more than
• Variable morphologic findings ranging from well to women and occurring in adults with a mean age in
poorly differentiated the seventh decade of life.
• Predilect to the larynx, oral cavity, oropharynx,
Spread hypopharynx, and sinonasal tract:
• Invasion through tracheal wall is common. m Larynx is most common site of occurrence.
• Lymph node metastasis is common and includes m Within the larynx most of these carcinomas are
spread to paratracheal, deep cervical, mediastinal, located in the supraglottis followed by the glottis
and peribronchial lymph nodes. and rarely in the subglottis.
m Less commonly, may occur in other mucosal sites
Treatment and Prognosis of the upper aerodigestive tract including (but not
• Surgical resection and primary reconstruction is best limited to):
curative treatment modality available at present: – Oropharynx (tonsil and base of tongue), oral
m Many tracheal carcinomas are too large or exten- cavity, sinonasal tract, nasopharynx
sive at presentation for surgical cure. • Symptoms vary according to the site of involvement:
• In patients with advanced disease (i.e., inoperable m Laryngeal involvement includes hoarseness and
tumors), radiotherapy can represent a management airway obstruction; less often, dysphagia and
option: hemoptysis may occur.
m Variable success in controlling disease • Development:
• Approximately 35% have nodal metastasis at m Majority arise de novo unassociated with pre- or
presentation. coexisting papilloma

• Distant metastases commonly occur: m Minority develop in association
m Primarily to lungs, liver, and bones • Cause:

• Clinical course is rapid and prognosis is poor: m Etiologically associated with human papillomavi-
m 5-year survival rates 5% to 15% rus (HPV) but histology and subsite localization
m 10-year survival rates 6% to 7% may corroborate whether HPV may be involved:
TABLE 16-3 Clinicopathologic Features of Select Squamous Cell Carcinoma Variants

PSCC VC SCSC BSCC
Age/Gender 7th decade; 6th-7th decades; 6th-8th decades; 6th-7th decades;
M>F M>F M>F M>F
Site* Larynx > oropharynx, Oral cavity > larynx Larynx: true vocal cord > Hypopharynx (piriform
oral cavity, sinonasal (glottis) false vocal cord, sinus), larynx
tract nasopharynx supraglottis (supraglottis),
oropharynx (tonsil,
base of tongue)
Symptoms Hoarseness and airway Oral: mass with or Hoarseness, airway Hoarseness, dysphagia,
obstruction without pain obstruction, dysphagia pain, neck mass
Larynx: hoarseness
RF Tobacco and alcohol Tobacco (chewing, No known risk factors Tobacco and alcohol
smoking)
HPV-associated Transcriptionally active Not implicated Transcriptionally active Transcriptionally active
(transcriptionally high-risk HPV may be high-risk HPV may be high-risk HPV may be
active) identified identified; often site identified; often site
specific† specific†
Histology Filiform to papillary to Epithelial proliferation Malignant Invasive neoplasm
broad-based bulbous with uniform undifferentiated spindle composed
to exophytic growth squamous cells cell and pleomorphic predominantly of
with fibrovascular without dysplastic cellular proliferation pleomorphic basaloid
cores; squamous features or mitoses; and the presence of a cells with associated
epithelium is marked surface conventional squamous minor squamous cell
cytologically keratinization cell component component (epithelial
malignant; surface (“church-spire” (carcinoma in situ and/ dysplasia, abrupt
keratinization is keratosis); broad or or invasive SCC); may keratinization,
generally limited bulbous rete pegs be entirely composed carcinoma in situ,
and often absent; with a pushing, not of malignant invasive carcinoma);
considered as being infiltrative, margin undifferentiated spindle variety of growth
invasive even in the cells (cellular or patterns, including
absence of definitive hypocellular solid, lobular,
stromal invasion; collagenized) without cribriform; cords,
usually arise de differentiated epithelial trabeculae and
novo but may be component gland-like or cystic
associated with growth; increased
precursor papilloma mitotic activity,
or occurrence at site comedonecrosis in
of prior papilloma center of neoplastic
lobules; peripheral
nuclear palisading and
basement membrane–
like material may be
seen
IHC Positive for Positive for cytokeratins Positive for cytokeratins Consistently positive for
cytokeratins (IHC (IHC typically not in majority of cases cytokeratins;
typically not required required for (approximately 60%), neuroendocrine
for diagnosis); p16 diagnosis); p16 but may be negative in markers are usually
typically negative typically negative approximately 40% of negative but occasional
cases; variable cases may be positive;
reactivity for p63; may variable expression for
be positive for vimentin, NSE, S100
vimentin, desmin, protein, and actins; site
actins; p16 typically specific tumors may be
negative but may be p16+†
positive†
Treatment Surgery Surgery Surgery with or without Surgery, ND, radiation,
adjunctive radiotherapy and chemotherapy
Spread Regional lymph nodes; Locally invasive; not Metastasizes to regional Early dissemination to
distant metastasis is metastatic lymph nodes and lung regional and distant
rare (lung) lymph nodes, lung,
bone, skin, brain
Continued
TABLE 16-3 Clinicopathologic Features of Select Squamous Cell Carcinoma Variants—cont’d

PSCC VC SCSC BSCC
Prognosis Similar to conventional Excellent Dependent on stage but For non–HPV-associated:

SCC of similar stage overall prognosis is poor, often resulting in
although may have poor death within a year
an overall more Although number of from diagnosis
favorable prognosis HPV-positive cases are For HPV-associated BSCC:
than comparable too small for any share better outcomes
conventional SCC; definitive conclusions, similar to
HPV-related PSCCs positive viral status oropharyngeal
not associated with does not appear to nonkeratinizing
statistically confer any prognostic (HPV-associated)
significant improved benefit carcinomas
patient outcomes,
although the
HPV-positive tumors
tend to have better
survival compared
with the HPV-
negative tumors
BSCC, Basaloid squamous cell carcinoma; HPV, human papillomavirus; IHC, immunohistochemistry; ND, neck dissection; PSCC, papillary
squamous cell carcinoma; RF, potential risk factors; SCSC, spindle cell squamous carcinoma; VC, verrucous carcinoma.
*Most common sites in the head and neck.
†
Oropharyngeal BSCCs and SCSCs may harbor transcriptionally active HPV.
– Oropharyngeal PSCCs tend to be nonkeratiniz- – Tend to lack transcriptionally active virus:

ing and associated with high-risk HPV. ■ May be shown to harbor transcriptionally
– Laryngeal and oral PSCCs tend to be keratin- active virus

izing and not associated with HPV. □ Oral cavity and to a lesser extent larynx
m Smoking and alcohol linked to the development more likely to be associated with transcrip-
of PSCC tionally active HPV than conventional
SCC.
Pathology m Nonkeratinizing type:
Gross – Papillae completely covered by immature basa-

• Most often seen as a solitary lesion with a polypoid, loid cells
exophytic, or papillary growth – Tend to predilect to oropharynx
• Tumor size may range from 2 mm up to 4 cm. – Tend to be p16 positive and p53 negative
– Tend to harbor transcriptionally active
Histology virus
• Filiform growth with finger-like projections and • May be entirely in situ (irrespective of size) or show
identifiable fibrovascular cores or a broad-based only superficial invasion:
bulbous to exophytic growth with rounded projec- m Definitive invasion may be difficult to demon-
tions resembling a cauliflower-like growth pattern in strate in biopsy specimens.

which fibrovascular cores can be seen but tend to be m Multiple biopsies may be required to establish the
limited to absent. diagnosis.

• Squamous epithelium is cytologically malignant: m Some authorities believe that, despite the pres-
m Malignant epithelium identifies these tumors as ence of carcinomatous epithelium suggesting an

carcinomas as opposed to papillomas. in situ process rather than invasive carcinoma,
• Surface keratinization is generally limited and often the extent of growth with the formation of a
absent. clinically appreciable exophytic mass goes beyond
• Two morphologic types may be identified: the general concept of an in situ carcinoma and
m Keratinizing type: that these tumors should be considered as being
– Epithelial cells show maturation with minimal at least superficially invasive even in the absence
surface parakeratin. of definitive stromal invasion.
– Tend to predilect to larynx, oral cavity • Usually arise de novo without identification of coex-
– Tend to be p16 negative and p53 positive: isting benign lesion such as a papilloma although
■ May be p16 positive association with precursor papilloma or occurrence
See Table 16-3.
• Papilloma/papillomatosis:
m Papillomas are distinguished by their bland epi-
thelial proliferation.
m Cytologic abnormalities may be seen in papillo-
mas, but they tend to be focal when present but

do not approach the level of dysplasia seen in
papillary SCC.
• Conventional squamous cell carcinoma
• Verrucous carcinoma:
m Characterized by a verrucous growth pattern
with marked keratosis in layers or tiers, absent

nuclear atypia, absent mitotic activity beyond the
basal layer, and a pushing rather than infiltrative
pattern of invasion:
– Such features contrast with those seen in
PSCC.

• Surgery is preferred treatment.
• Adjunctive therapy (i.e., radiation) may be used.
• Majority of papillary SCCs are low clinical stage
(T2)
• Overall behavior similar to conventional SCC of
similar stage, although a better overall prognosis
reported for PSCC than for conventional SCC when
matched for T stage.
m 2- and 5-year disease-free survival rates reported
Fig. 16-35. Resected PSCC. to be 68% and 46%, respectively

m Overall survival rate reported to be 90% and
Laryngectomy specimen showing papillary squamous cell 72% at 2 and 5 years, respectively
carcinoma appearing as a solitary papillary/exophytic lesion • Recurrence and metastasis (locoregional and distant)
in the supraglottic larynx.
may occur:
m Distant metastases are rare and may include the
lung.
in patients with previous history of a papilloma at • HPV-related PSCCs:
the site of the papillary SCC has been reported m Not associated with statistically significant
• Immunohistochemistry and molecular genetics: improved patient outcomes, although the HPV-
m Transcriptionally active high-risk HPV may be positive tumors tend to have better survival com-
identified: pared with the HPV-negative tumors
– Indirectly by p16 overexpression m Even though PSCCs in larynx and oral cavity
– Directly by mRNA in situ hybridization (ISH) harbor transcriptionally active HPV, it has been
for E6/E7 proteins not shown that they are biologically different
■ Tend to be located in oropharynx with non- from HPV-negative ones or that they should be
keratinizing morphology treated differently
■ Oral cavity and less often laryngeal PSCC m Based on current state of knowledge, HPV
may be shown to harbor transcriptionally testing in routine practice advocated only for
active HPV by p16 staining and E6/E7 oropharyngeal PSCC with no known utility
mRNA ISH for HPV testing in PSCCs of larynx and oral
m p53 immunoreactivity reported: cavity
– Tend to occur in keratinizing type • p53 staining reported to be associated with poor
– Tend to be absent in nonkeratinizing type survival
C D
Fig. 16-36. Papillary squamous cell carcinoma.

Papillary/exophytic squamous cell carcinoma showing (A and B) papillary or filiform growth, (C and D) broad-based bulbous
to rounded exophytic growth. Note the absence of surface keratosis.
Verrucous Carcinoma (VC) Clinical

• Affects men more than women; generally occurs in
the sixth and seventh decades of life
Definition: Highly differentiated variant of squamous • Can occur anywhere in the upper aerodigestive tract,
cell carcinoma with locally destructive but not meta- but most common sites of occurrence include:
static capabilities characterized by exophytic and/or m Oral cavity:
warty appearance, absence of epithelial dysplasia, and – Represents the most common site of occur-
presence of pushing margins. rence in the head and neck, accounting for
Synonym: Ackerman tumor approximately 75% of all cases
Fig. 16-37. PSCC.

The epithelium in papillary squamous cell carcinoma is
cytologically malignant, which differentiates it from a
papilloma; surface keratosis is absent. Fig. 16-38. Verrucous carcinoma.
– Most commonly arise on the buccal mucosa Laryngeal verrucous carcinoma appearing as a large,
and gingiva tan-white, and warty to fungating mass.
m Larynx:
– Represents the second most frequent site of • Cause of VC remains speculative and includes:
occurrence m Tobacco smoking or chewing
■ Accounts for 15% to 35% of all VCs m Most recent data from the literature do not sup
■ Represents from 1% to 4% of all laryngeal port etiologic link to HPV (high risk or low risk).
carcinomas – Active role of HPV is more likely as a promoter
– Most common site of occurrence in the larynx in the multistep process of carcinogenesis in
is the glottic area (anterior true vocal cord); squamous cells of the upper aerodigestive tract.
less common sites of occurrence include the – Two viral oncoproteins of high-risk HPVs, E6
supraglottis, hypopharynx and subglottis, and and E7, promote tumor progression by inacti-
trachea. vating the p53 and retinoblastoma tumor sup-
m Nasal fossa pressor gene products, respectively, thereby
m Sinonasal tract and nasopharynx disrupting cell-cycle regulatory pathways in the
m Middle ear (rare) genetic progression to head and neck SCC.
• Symptoms vary according to site:
m Larynx: hoarseness is most common complaint,
Pathology
less frequent symptoms include airway obstruc- Gross
tion, hemoptysis, dysphagia • Tan or white, warty, fungating or exophytic, firm to
m Oral cavity: mass with or without pain hard mass of varying size measuring up to 9 to
m Sinonasal tract: airway obstruction 10 cm in diameter
m Nasopharynx: dysphagia • In general, the tumors are attached by a broad base.
Advancing front of tumor characterized by broad

m
Histology or bulbous rete ridges with a pushing but not
• Histologic appearance is that of a benign-appearing infiltrative margin with smooth stromal interface
squamous cell proliferation, requiring the following – Extends below level of identifiable intact sub-
characteristics for diagnosis: jacent normal epithelium
m Marked surface keratinization (“church-spire” • Chronic inflammatory cell infiltrate composed of
keratosis): lymphocytes, plasma cells, and histiocytes may be
– Filiform projections prominent along the advancing from of the tumor.
– Commonly in form of parakeratin • Immunohistochemistry and molecular genetics:
– Orthokeratin with sparse keratohyaline gran- m May be p16 (false) positive showing patchy stain-
ules may be present. ing lacking diffuse (greater than 75%) nuclear
m Uniform cells without dysplastic features or and cytoplasmic staining associated with true
mitoses: positive reactivity
– Cells arranged in orderly maturation pattern m Lack evidence of transcriptionally active high-
toward (markedly keratotic) surface risk HPV by DNA polymerase chain reaction
– Mitotic figures can be seen along basal zone (PCR) and E6/E7 mRNA reverse transcription
but should not be present in more superficial PCR
aspects of the epithelium. m p53 overexpression may be found.
A B
Fig. 16-39. Histology of verrucous carcinoma.

The histologic features of verrucous carcinoma include (A, B) marked surface keratinization (“church-spire” keratosis),
bulbous rete pegs “pushing” into the underlying stroma;
C D
Fig. 16-39, cont’d

(C) rounded rete pegs with absence of cytologic atypia; (D) mitotic figures can be seen but are limited to the basal
zone area. Note the rounded nests with smooth stromal interface.
A B
Fig. 16-40. Squamous cell carcinoma with verrucoid features.

A, The histologic features of laryngeal squamous cell carcinoma with verrucoid features at low magnification may suggest
a possible diagnosis of verrucous carcinoma. B, At higher magnification despite cytologically bland-appearing elongated/
angulated rete ridges (left) areas of marked dysplasia are present, conferring a diagnosis of a conventional squamous cell
carcinoma differentiating it from verrucous carcinoma. The overall changes were not those of a hybrid carcinoma (i.e.,
admixture of verrucous carcinoma and conventional squamous cell carcinoma). Hybrid carcinomas may occur in the larynx
but more often occur in oral cavity lesions.
propensity to progress to either VC or conven-

Hybrid Carcinoma tional types of squamous cell carcinomas:
• Tumor showing mixed histology, including foci of – Considered premalignant lesion
VC and foci of conventional squamous cell m Rare aggressive form of oral leukoplakia with a
carcinoma: tendency to recur, often with multifocal oral
m Biologic risk is that of conventional SCC includ- involvement, and to undergo malignant
ing potential for metastatic tumor. transformation
m May occur in larynx but more commonly seen in m Most common in women (4 : 1), mean age in
oral cavity lesions eighth decade of life, and long history (decades)
m Careful sampling and evaluation of the depth of of oral leukoplakia
the lesion are important to exclude a possible m Most commonly begins on the buccal mucosa
diagnosis of hybrid carcinoma. followed by the hard and soft palate, alveolar
m Some authorities suggest that the SCC compo- mucosa, tongue, floor of mouth, gingiva, and lip
nent be invasive >2 mm beyond verrucous m Cause:
component. – No specific risk factors associated with devel-
opment of PVL
Biopsy Diagnosis of Verrucous Carcinoma – History of tobacco use present in a high per-
• Pathologic diagnosis of VC may be extremely diffi- centage of patients (greater than 50%) but a
cult, requiring multiple biopsies over several years significant minority of patients have no history
prior to identification of diagnostic features support- of tobacco use
ing appropriate interpretation: – No relationship to HPV or EBV
m Clinician and pathologists should be aware of m Clinical and pathologic appearance in the early
this fact. stages of PVL no different from any other type of
m Adequate biopsy material is critical to interpreta- leukoplakic lesion, making diagnosis of PVL in
tion and should include adequate epithelial- its early stages virtually impossible
stromal interface. m Clinically, lesion is flat, thickened keratosis with
m Pathologist should not overinterpret a verrucoid the histologic appearance of a nondysplastic ker-
lesion as a carcinoma without adequate tissue atosis; with progression of disease, the lesions
sampling including the presence of ample subja- become multiple, multifocal, and confluent with
cent stroma. an exophytic and/or warty (verrucoid) appear-
m Diagnosis of VC at initial presentation and biopsy ance; it is in the latter clinical form that squamous
is extremely challenging given overall bland cyto- cancer (verrucous carcinoma or conventional
morphology and shared features with reactive squamous cell carcinoma) is seen.
verrucoid hyperplastic lesions m Any given lesion may show a combination of
m Recurrence of tumor at a future time may be the verrucous hyperplasia, verrucous carcinoma, and
diagnostic clue to diagnosis of VC. conventional well-differentiated squamous cell
carcinoma.
Differential Diagnosis m Given the fact that PVL is associated with VC in
See Table 16-3. a high percentage of cases, some authors believe
• “Conventional” squamous cell carcinoma: that PVL should be considered as a premalignant
m Differentiation of VC from a “conventional” type condition or an early biologic form of VC:
of carcinoma is based on the presence or absence – This consideration would then obviate the con-
of cytologic abnormalities (i.e., dysplasia). fusion, clinically and pathologically, that sur-
m Any dysplastic epithelial changes should raise rounds the use of the term verrucous hyperplasia
serious concern for the possible diagnosis of con- in describing these oral cavity lesions.
ventional SCC and exclude a diagnosis of VC m Histology of PVL (see Section 2 for images)
although recent classification suggested a cate- includes:
gory of VC with epithelial dysplasia or invasion – Composed of hyperplastic squamous epithe-
≤2 mm in depth from nearest VC area (referred lium with regularly spaced, verrucous epithelial
to as VC with dysplasia or minimal invasion). projections and associated hyperkeratosis
m Hybrid neoplasms composed of VC and coexist- – Sharply defined lesion and in contrast to the
ing conventional SCC occur (see above). downward growth into the underlying submu-
• Proliferative verrucoid leukoplakia (PVL): cosal compartment by the bulbous rete pegs in
m PVL and verrucous hyperplasia represent inter- VC, hyperplastic epithelium in PVL remains
related and irreversible mucosal lesions of the superficial (without submucosal invasion) and
oral cavity and upper aerodigestive tract with a does not extend deeper than that of the
adjacent epithelium; this raises the issue of ade Spindle Cell (Squamous)
quate sampling and the difficulties in differen- Carcinoma (SCSC)
tial diagnosis on incisional biopsy material.
– To exclude the presence of submucosal inva-
sion, complete excision of the lesion allowing Definition: Biphasic variant of squamous cell carcinoma
for histologic examination of the entire lesion composed of conventional squamous cell carcinoma
is most appropriate. (in situ or invasive carcinoma) associated with a
– Treatment of PVL is by surgical excision. malignant spindle-shaped and pleomorphic (epithelioid)
– Disease-free survival rates after surgery are low component.
due to recurrence and multifocal involvement. Synonyms: “Sarcomatoid” carcinoma, carcinosar-
– Radiotherapy has not been shown to be effec- coma, pleomorphic carcinoma, metaplastic carcinoma,
tive in controlling disease. collision tumor, pseudosarcoma, Lane tumor
• Keratotic squamous papilloma
• Reactive keratosis and epithelial hyperplasia Clinical
• Pseudoepitheliomatous hyperplasia • Considered uncommon
• Verruca vulgaris • Overwhelming majority occur in men (85%);
• Keratoacanthoma (when verrucous carcinoma affects most frequent in sixth through eighth decades
cutaneous sites) of life
• Can occur anywhere in upper aerodigestive tract, but
Treatment and Prognosis most common sites of occurrence include larynx and
• Surgery is the preferred therapeutic modality for VC oral cavity:
of all sites: m Larynx:
m In larynx extent of surgery depends on clinical – True vocal cords > false vocal cords and
stage: supraglottis
– T1: laser excision m Oral cavity:
– T2: hemilaryngectomy – Lips, tongue, gingiva, floor of mouth, buccal

– T3, T4: total laryngectomy mucosa
• Radiotherapy can be used in selected cases: m Other sites include:
m May be used in patients with advanced disease – Oropharynx (tonsil, base of tongue), hypo-
and/or in patients who are not good surgical pharynx, sinonasal tract, nasopharynx
candidates • Symptoms vary according to site:
m Previous reason cited for not irradiating VC is m Larynx: hoarseness, voice changes, airway
purported induction of anaplastic transformation obstruction, dysphagia
of VC after radiotherapy. m Oral cavity: mass or nonhealing sore with or
– Reported VC treated by radiation that under- without pain

went anaplastic transformation more likely did m Oropharynx, hypopharynx, sinonasal tract. and
not represent VC but represented hybrid carci- nasopharynx: airway obstruction, pain, epistaxis,
nomas or pure conventional SCC misdiagnosed discharge, facial deformity, unilateral otitis media,
as VC. orbital symptoms
• Prognosis is excellent after complete surgical removal. • Cause:
• Local recurrence may occur if incompletely excised. m Associated with tobacco use (cigarette smoking)
• Therapy and prognosis for VC with epithelial dys- m May occur in areas of prior irradiation:
plasia or minimal invasion appears to be similar to – Radiation-induced carcinoma

(pure) VC than to hybrid carcinoma. – Prior radiation used in treatment of other
• Cervical adenopathy may be associated with VC, mucosal-based carcinomas
representing reactive changes and not metastatic m Not associated with transcriptionally active
disease: HPV:
m Neck dissection generally not warranted in – Limited numbers of oropharyngeal cases shown
treatment to harbor transcriptionally active, high-risk
m Hybrid carcinomas have potential to metastasize. HPV; HPV may be identified in both conven-
m Hybrid carcinomas should be staged and managed tional and spindle cell components.
as conventional squamous cell carcinomas. • Histogenesis of the spindle cells is controversial as
• Distant metastases do not occur evidenced by the array of names given to this tumor:
• Death due to disease occurs in approximately 4% of m Epithelial derivation is supported by:
cases: – Intimate association with conventional squa-

m Due to local uncontrollable disease mous cell carcinoma
Fig. 16-42. Histology of SCSC.

A, B, The diagnostic histologic features of spindle cell
squamous carcinoma include the presence of
differentiated squamous cell carcinoma in the form of
intraepithelial dysplasia/carcinoma in situ and/or invasive
squamous cell carcinoma and associated undifferentiated
malignant spindle-shaped and pleomorphic cell
proliferation. Note the intimate association of the
differentiated squamous cell carcinoma and the
malignant spindle cell component.
– Presence of cytokeratin immunoreactivity in

the majority of cases and absence of immuno-
reactivity with other antibodies
– Ultrastructural evidence of epithelial
differentiation
– Tendency to metastasize to lymph nodes rather
than viscera by hematogenous routes supports
carcinomatous nature
B – Epithelial tropism of HPV infection confirms
the epithelial nature of the spindle cell
component.
Fig. 16-41.
A, Laryngeal spindle cell squamous carcinoma
Pathology
endoscopically appearing as a polypoid mass protruding Gross
into and partially obstructing the laryngeal lumen. • Polypoid or fungating mass commonly found in the
B, Autopsy specimen of a large, solid laryngeal spindle larynx, hypopharynx, oral cavity, and sinonasal tract
cell carcinoma completing obstruction of the airway. • Variations in the gross appearance may correlate
with the primary site of occurrence:
Fig. 16-43. Histology of SCSC.

In spindle cell squamous carcinoma the undifferentiated
malignant cell component may include (left) spindle-shaped
cells and/or (right) pleomorphic (epithelioid) cells. Mitotic
figures including atypical mitoses can be identified.
Larynx: polypoid or exophytic

m
Other sites: fungating and/or ulcerative

m
• Firm, tan-white, gray, or pink mass varying in size

from 1 to 6 cm B
Histology
• Histologic features that define SCSC include the Fig. 16-44. Histology of SCSC.
identification of a malignant undifferentiated spindle Some examples of spindle cell squamous carcinoma lack a
cell and pleomorphic cellular proliferation and differentiated epithelial component and are entirely
the presence of a conventional squamous cell composed of an undifferentiated spindle-shaped cellular
component. proliferation with a storiform and/or fascicular growth.
These histologic findings coupled with absence of
Differentiated Squamous Cell Component immunoreactivity for epithelial markers and possible
• Includes either intraepithelial dysplasia and/or presence of immunoreactivity for mesenchymal markers
frankly invasive squamous carcinoma (typically may suggest a diagnosis of a sarcoma. In spite of these
keratinizing and of varying differentiation) findings, the presence of a polypoid (superficial) mucosal-
based mass is a feature of carcinomas, including spindle
• Squamous cell component may be limited, requiring
cell squamous carcinoma and not typically one associated
multiple sectioning for identification or it may be with a mucosal-related sarcoma.
absent in a given lesion:
m Surface ulceration with associated fibrinoid
necrosis, granulation tissue, and mixed acute and
chronic inflammation may be present. many mitoses, including typical and atypical
m Reactive (nonneoplastic) myofibroblastic cell forms:
component as part of the inflammatory cell m Multinucleated giant cells may be present.
response may be present. m Necrosis is not uncommon.
• Hypocellular collagenized variant:

Spindle Cell Component m Spindle cell proliferation may be sparsely
• Spindle-shaped and/or pleomorphic (epithelioid) cel- cellular (hypocellular) with marked stromal
lular components generally represent dominant cell collagenization.
type. m Even in presence of limited cellularity there is still
• Growth pattern varies including fascicular, stori- nuclear pleomorphism and mitotic figures, includ-
form, or palisading and may include an associated ing atypical mitoses.
collagenized to myxoid-appearing stroma. • Heterologous elements can be seen including bone
• Generally is hypercellular and pleomorphic with and cartilage and may include:
large, hyperchromatic nuclei, prominent nucleoli, m Benign bone (osteoid) and/or cartilage
A B
C D
Fig. 16-45. Collagenized or hypocellular SCSC.

Collagenized and hypocellular variant of spindle cell squamous carcinoma shows a prominent collagenized stroma with
varying but less cellularity as compared with more usual type of spindle cell squamous carcinoma. Despite the relative
hypocellularity, the cells are markedly pleomorphic and atypical mitotic figures are identified.
m May include malignant bone (osteosarcomatous) – Absence of cytokeratin staining does not pre-
and/or malignant cartilage (chondrosarcoma- clude a diagnosis of spindle cell squamous
tous) foci carcinoma.
m Rhabdomyosarcomatous elements may rarely be m p63 (nuclear) immunoreactivity often mirrors
present: cytokeratin reactivity but may be positive in cases

– Rhabdomyoblasts identified lacking cytokeratin staining:
– Myogenic markers including desmin, myo- – Transcription factor consistently expressed in
genin, and myoglobin are positive. normal squamous epithelium and in squamous
• Histochemical stains: cell carcinoma
m Essentially noncontributory to the diagnosis – Recognizes DNp63 and TAp63 isoforms of the
• Immunohistochemistry: p63 molecule
m Spindle cells are cytokeratin immunoreactive in – May be positive in soft tissue tumors and reac-
the majority of cases but may be absent in up to tive stromal proliferations
40% of cases. m p40 (nuclear) immunoreactivity may be present:
– Broad spectrum of cytokeratin staining should – Recognizes only squamous-specific isoform

be used, including: DNp63
■ Pancytokeratin (AE1/AE3), CAM5.2, CK5/6, – Less consistently positive than p63
OSCAR, CK18, CK903 – Less likely to be positive in soft tissue tumors
– May vary from focal to diffuse and reactive stromal proliferations
A B
C D
Fig. 16-46. SCSC with features suggesting inflammatory myofibroblastic tumor (IMT).
SCSCs may coexist with a reactive myofibroblastic proliferation or may have features suggesting a myofibroblastic
dominant lesion (e.g., IMT), including (A) polypoid mass with a granulation tissue-like appearance; (B through D) cells
with basophilic to eosinophilic fibrillar-appearing cytoplasm, some with axonal extensions, with or without an associated
inflammatory cell infiltrate. Although myofibroblastic dominant lesions may have increased mitotic activity, the presence of
atypical mitoses (not shown) would be a feature associated with malignancy.
m Vimentin reactivity consistently identified in all – Positive cases tend to be located in

cases: oropharynx.
– Diffuse and strongly reactive – Rare in nonoropharyngeal locations
m Various myogenic markers, including desmin and • Electron microscopy:
actins, may be present: m Majority of cases show evidence of epithelial
– Coexpression of mesenchymal markers and derivation, including desmosomes, tonofilaments,

epithelial markers (i.e., cytokeratin) may occur. macula adherens.
– Expression of myogenic markers could corre- m Considered less sensitive in comparison to
late to presence of myofibroblastic cells as a immunohistochemistry in identifying epithelial
reactive proliferation as part of wound healing differentiation
secondary to ulceration. • Cytogenetics and molecular genetics:
– In the absence of rhabdomyoblastic differentia- m Identical (immunohistochemical) p53 expression
tion, other myogenic markers including myo- patterns in the epithelial and spindle cell com
genin and myoglobin typically are not present. ponents support concept that these phenotypi-
m S100 protein and melanoma-related markers cally divergent cell populations share similar
(HMB-45, melan-A, tyrosinase, MITF1, Sox10) developmental pathways and divest concept that
are negative. SCSC represents a reactive process or a collision
m p16 positivity may be present in a minority of tumor between epithelial and mesenchymal
cases: components
A B
C D
E F
Fig. 16-47. Heterologous elements in SCSC.

Heterologous elements that may be found in spindle cell squamous carcinoma include (A) osteoid and
(B) osteosarcomatous foci. Additional heterologous components that can be found in spindle cell squamous carcinoma
include chondroid and chondrosarcomatous foci (not shown). C and D, Rhabdomyosarcomatous differentiation can on rare
occasions be seen in association with SCSC manifested in the form of spindle-shaped strap cells lying just below the
surface squamous epithelium confirmed by (E) desmin and (F) myogenin (nuclear) immunoreactivity.
A B
C D
E F
Fig. 16-48. IHC in SCSC.

The immunohistochemical (IHC) antigenic profile
of spindle cell squamous carcinoma may include
(A) cytokeratin (AE1/AE3); (B) CAM 5.2 (low molecular
weight keratin); (C) CK 5/6; (D) p63 (nuclear stain);
G (E) vimentin; (F) smooth muscle actin; (G) desmin
(right panel).
A B
Fig. 16-49. Metastatic SCSC.

Nodal metastasis in spindle cell squamous carcinoma may include the differentiated epithelial component only, the spindle
cell component only, or both. (A and B) This cervical neck nodal metastasis that occurred in a patient with a laryngeal
spindle cell squamous carcinoma was entirely composed of a malignant spindle cell component. C, The neoplastic cells
were focally cytokeratin (AE1/AE3) positive.
m Varying findings reported on the presence of high- – Altered expression of cadherin-catenin complex
risk HPV in SCSC: associated with morphologic transition from
– Majority of SCSC of head and neck, including epithelial to spindle cell phenotype:
those arising in the oropharynx, are not related ■ Reminiscent of epithelial-mesenchymal tran-
to transcriptionally active HPV sition (EMT)

– A few p16-positive oropharyngeal SCSCs ■ Supports role of EMT in pathogenesis of
shown to harbor HPV16 by DNA in situ SCSC, which is further supported by pres-
hybridization but HPV not detected in p16- ence of Snail-1 expression, a potent inducer
positive nonoropharyngeal lesions: of EMT, in cases of SCSC
■ In HPV-positive tumors, HPV identified – Studies on mouse model developed in SCSC
in both conventional and spindle cell showed:
components ■ Marked downregulation of epithelial differ-
m Significant downregulation of miR-200 family entiation markers and cell adhesion genes
and miR-205, loss of desmosomal cadherins, and ■ Inhibition in expression of growth factors
altered expression of classic cadherins in SCSC and receptors important for epithelial prolif-
reported in comparison with conventional squa- eration with increase in expression of growth
mous cell carcinoma: factors and receptors that regulate fibroblast
– Downregulation of miR-200 family and miR- and mesenchymal cell proliferation
205 strongly supports the postulated role of ■ Largest class of upregulated genes in SCSC
epithelial-mesenchymal transition in spindle was chemokine receptors and ligands in

cell squamous carcinoma. volved in tumor cell invasion and metastasis.
A B
Fig. 16-50. Laser resection of polypoid SCSC.

A, Polypoid spindle cell squamous carcinoma; such a tumor with polypoid growth and limited invasive component could
potentially be treated by conservative surgery to include polypectomy with tumor free margins. B, Example of a patient
with a vocal cord polypoid spindle cell squamous carcinoma treated by laser excision (polypectomy); intraoperative
consultation (frozen section) identified the absence of carcinoma at the deep surgical margins (not shown). C, Postlaser
removal. On long-term follow-up (>5 years), this patient has been free of tumor (recurrence or progression).
■ Above changes in gene expression show m These lesions are moderately cellular with a
loss of epithelial characteristics, acquisition proliferation of spindle-shaped cells but do
of mesenchymal phenotypes, and increased not display a striking degree of nuclear
propensity for invasion and metastasis pleomorphism.
by SCSC. m Mitotic figures may be encountered but atypical
mitoses are not seen; the findings of atypical

mitoses should prompt consideration of a true
Differential Diagnosis malignancy.
See Table 16-3. m Although these lesions are not encapsulated, they
• Reactive lesions (e.g., contact ulcers), reactive do not exhibit the insidious pattern of infiltration
myofibroblastic lesions (e.g., nodular fasciitis), and of adjacent tissues, which is characteristic of
inflammatory myofibroblastic tumor (IMT): more aggressive lesions, such as SCSC.
m May fill the submucosal region, abutting the • Radiotherapy may be used as an adjunct to surgery
basement membrane on which the mucosal epi- but neither radiotherapy nor chemotherapy has
thelial cells are resting; however, the spindle cell merit as sole therapeutic modality:
proliferation does not infiltrate into the mucosal m Reports of patients with early-stage SCSC of the
epithelial cells; nevertheless, the overlying mucosa glottis (i.e., T1 and T2 lesions) treated with radia-
may appear atrophic in areas. tion in a similar manner as early-stage conven-
m Typically are cytokeratin, p63, and p40 tional squamous cell carcinoma:
negative: – Histologic diagnosis of SCSC by itself
– Cytokeratin or p63 reported in IMT and gran- should not influence the decision to treat a
ulation tissue patient with early-stage glottic disease with
m Myofibroblastic cells may be muscle-specific actin irradiation.
(HHF35), smooth muscle actin, and vimentin – Results show that patients with early-stage
positive. glottic SCSC treated by radiation alone had
m Cells of IMT may be ALK1 positive, a feature not similar control rates to irradiated patients with
identified in SCSC. similar volume disease with the more typical
• Postradiation changes: squamous cell carcinoma
m Radiation (myo)fibroblasts may raise concern for • Overall 5-year survival of patients with laryngeal
presence of malignant spindle cells. SCSC reported to be 59%
m Radiation (myofibroblasts) may be cytokeratin • Prognosis dependent on the clinical stage but, in
and p63 positive. general, is considered poor:
m Tend to occur in association with other radiation- m Depth of invasion important prognostic
associated histologic changes parameter:
• Subglottic stenosis – Minimally invasive tumors better prognosis
• Sarcomas: than tumors with any significant degree of
m Sarcomas of the mucosal surfaces of the head and invasion
neck in general and the larynx in specific (except – Polypoid lesions with limited presence of
for chondrosarcoma), including undifferentiated limited invasion behave less aggressively than
pleomorphic sarcoma, fibrosarcoma, malignant flat, ulcerative, and more deeply invasive
peripheral nerve sheath neoplasm, synovial tumors:
sarcoma, and others, are rare. ■ 90% overall 3-year survival reported for
m In general, mucosal-based sarcomas of the upper patients with glottic polypoid SCSC
aerodigestive tract are deeply seated in any given ■ 44% overall 3-year survival reported for
location and do not usually result in a polypoid patients with sessile glottic SCSC
mass protruding from a mucosal surface. – Polypoid configuration alone does not confer
m As a rule, in the absence of any other confirma- better prognosis but depends on extent of inva-
tory studies, a malignant spindle cell neoplasm of sion within the polypoid lesion.
a mucosal surface of the upper aerodigestive tract m Size of tumor does not correlate with survival.
presenting as a polypoid lesion or identified in • Prognosis also linked to location of lesion:

more superficial locations of the submucosa m Vocal cord lesions, in particular glottic SCSC,
should be considered as an SCSC; the latter is true tend to manifest symptoms early in the disease
even in the absence of a squamous carcinomatous course and have better prognosis than SCSC
component, the presence of heterologous matrix- arising in other sites (supraglottis, hypo-, oro-,
producing elements, absence of cytokeratin and nasopharynx, oral cavity, and sinonasal tract)
immunoreactivity and presence of mesenchymal in which symptoms tend to occur only after
type markers. the tumor has become large and extensively
• Mucosal malignant melanoma infiltrative.
• Although number of HPV-positive cases are too
small for any definitive conclusions, positive viral
Treatment and Prognosis status does not appear to confer any prognostic
• Surgery is the preferred mode of therapy: benefit.
m Often necessitates radical extirpation • Metastatic disease primarily occurs to cervical lymph
m Conservative (limited) surgery such as polypec- nodes and lung and may include:
tomy can be performed in limited settings such as m Conventional squamous cell carcinoma alone
the occurrence in an at-risk or poor surgical can- m Spindle cell carcinoma alone
didate who has a polypoid lesion and tumor-free m Both conventional and spindle cell squamous
margins can be achieved. carcinoma
Basaloid Squamous Cell Carcinoma Hypopharynx (piriform sinus)

m
Larynx (supraglottis)
(BSCC) (Figs. 16-51 through 16-56) m
m Oropharynx (palatine tonsil, base of tongue)
Definition: High-grade variant of squamous cell carci- • Symptoms depend on the site of occurrence and rela-
noma histologically characterized by an invasive neo- tive to laryngeal tumors include:
plasm predominantly composed of basaloid-appearing m Hoarseness, dysphagia, pain, or a neck mass
cells intimately associated with dysplastic squamous • Cause:

epithelium, in situ squamous cell carcinoma, and/or m Strong association with tobacco and alcohol
invasive squamous cell carcinoma. use:

Synonyms: Basaloid carcinoma; adenoid-cystic–like – Generally linked to hypopharyngeal and laryn-
carcinoma geal lesions
m Association with human papillomavirus (HPV):
Clinical – Linked with oropharyngeal lesions

• Occurs more commonly in men than in women; ■ Referred to as HPV-associated basaloid squa
predominantly occurs in the sixth to seventh decades mous cell carcinoma of the oropharynx—
of life see Section 3
• May occur in any mucosal site of upper aerodigestive – Many but not all of oropharyngeal BSCCs
tract but tends to predilect to: associated with HPV 16
A B
C D
Fig. 16-51. Basaloid squamous cell carcinoma.

Histologic features of basaloid squamous cell carcinoma include (A) infiltrating cellular neoplasm with varied growth
patterns including lobular, trabecular, and solid; comedonecrosis can be seen in the center of neoplastic lobules;
(B) “jigsaw” puzzle-like configuration of the neoplastic lobules; (C) higher magnification showing juxtaposition of a lobule
with comedotype necrosis (left) and adjacent area in which reduplicated basement membrane-like material (right)
reminiscent of salivary gland tumors is present; (D) a predominant basaloid cell proliferation characterized by nuclear
hyperchromasia, marked nuclear pleomorphism, increased mitotic activity, and individual cell necrosis; peripheral nuclear
palisading is present, usually focally, but without retraction artifact of adjacent stroma as occurs in cutaneous basal cell
carcinomas.
A B
Fig. 16-52. BSCC.

The squamous differentiated component of basaloid
squamous cell carcinoma is frequently the minor
component and may appear as (A) focal areas of
keratinization, (B) larger confluent foci of keratinization,
or (C) bona fide foci of invasive keratinizing squamous C
cell carcinoma.
– HPV-associated basaloid squamous cell carci- variety of growth patterns, including solid, lobular,
noma of the oropharynx: cribriform, cords, trabeculae, and gland-like or
■ Predilect to base of tongue > tonsil cystic growth.
■ More common in men than women
■ p16 positive and presence of transcription-
ally active HPV Basaloid Cell Component

■ Confers a better prognosis than non–HPV- • Predominant cell type consists of cells with pleomor-
associated BSCC phic, hyperchromatic nuclei, scanty cytoplasm, and
• Increasing evidence identifying the presence of HPV increased mitotic activity:
in association with BSCC of the head and neck (see m Peripheral nuclear palisading may be present.
later under Genetics and Cytogenetics) • Comedonecrosis may be seen in the center of neo-
• Cell of origin has not definitively been identified but plastic lobules.
in all probability is a single totipotential cell capable • Direct continuity with surface epithelium may be
of divergent differentiation and located either in the present:
basal cell layer of the surface epithelium or within m Surface epithelium in direct continuity with inva-
seromucous glands. sive basaloid component may or may not show

intraepithelial dysplasia.
Pathology • Intercellular deposition of a hyalin or mucohyalin
Gross material can be seen:
• Firm to hard, tan-white mass often with associated m Similar appearance to reduplicated basement
central necrosis measuring up to 6.0 cm in greatest membrane material seen in some salivary gland
dimension tumors
• Infrequently, may be exophytic in appearance. m May impart cribriform-type growth pattern
• Gland-like spaces may be present:

Histology m May contain mucinous or hyalinized material
• Invasive neoplasm composed of basaloid cells with • Cells with clear-appearing cytoplasm may be seen
an associated squamous component demonstrating either focally or more extensively.
A B
Fig. 16-53. BSCC with high-grade intraepithelial dysplasia/CIS.

A, B, High-grade intraepithelial dysplasia/CIS is a frequent feature seen in association with basaloid squamous cell
carcinoma.
A B
C D
Fig. 16-54. Other findings in BSCC.

Morphologic variations that can be seen in association with basaloid squamous cell carcinoma include (A) spindle-shaped
cells with storiform growth; (B) rosettes; (C) clear cells; (D) clear cells contain glycogen as evidenced by the presence of
(left) periodic acid Schiff–positive intracytoplasmic material that is cleared by (right) diastase digestion.
A B
Fig. 16-55. Infiltrative growth in BSCC.

Basaloid squamous cell carcinomas often are extensively infiltrative, including the presence of (A) neurotropism and
(B) endothelial-lined (arrows) lymph-vascular space invasion and (C) deep invasion into skeletal muscle.
• Additional findings may include: • Squamous cell component may variably include:
m Spindle cell component may be identified: m Dysplastic squamous epithelium and/or carci-
– Usually very limited in extent and does not noma in situ (CIS)
predominate m Invasive differentiated squamous cell carcinoma
– Rare examples in which the spindle cell com- characterized by presence of intercellular bridges,
ponent may predominate keratin pearl formation, and/or individual cell
– Features diagnostic for BSCC still present keratinization (cells with abundant eosinophilic
m Infrequently, true neural-type rosettes may be cytoplasm)
present. m Foci of abrupt keratinization
m Extracellular calcifications may be present. • Histologic features (growth patterns and cell types)
are same whether associated with or not associated
with HPV:
Squamous Cell Component m Presence or absence of HPV represents key feature
• Typically, represents minor component and may be in distinguishing these tumor types.
focally present: • Histochemistry:
m In biopsies squamous cell component may be m Diastase-sensitive, periodic acid Schiff–positive
absent. intracytoplasmic material indicative of glycogen
A B
C D
Fig. 16-56. BSCC: differential diagnosis.

The differential diagnosis of basaloid squamous cell carcinoma, especially in biopsy material, includes adenoid cystic
carcinoma and small cell neuroendocrine carcinoma. The presence of a basaloid cell proliferation with (A) pseudocystic
spaces and (B) reduplicated basement membrane material in these examples of basaloid squamous cell carcinoma can
suggest a diagnosis of adenoid cystic carcinoma. C, However, the presence of (left panel) marked nuclear pleomorphism
with increased mitotic activity seen in basaloid squamous cell carcinoma contrasts with the (right panel) isomorphic, small
angulated basaloid cells lacking pleomorphism and mitotic activity as seen in usual types of adenoid cystic carcinomas.
D, Further, the presence of (left panel) squamous differentiation in basaloid squamous cell carcinoma is a finding not
identified in (right panel) adenoid cystic carcinoma. In addition, adenoid cystic carcinomas show the presence of true
glandular differentiation, a feature not seen in basaloid squamous cell carcinoma (not shown). The absence of staining for
neuroendocrine markers assists in differentiating basaloid squamous cell carcinoma from small cell neuroendocrine
carcinoma.
may be present, especially in cells with clear m CD56 reactive:

cytoplasm. – Not sensitive or specific marker for neuroendo-
m Alcian blue–positive material may be present crine differentiation
within the cystic spaces. m Neuroendocrine markers (i.e., chromogranin and
• Immunohistochemistry: synaptophysin) usually negative but occasional

m Consistently reactive for cytokeratins (AE1/AE3, cases may be (focally) synaptophysin positive
CAM5.2, CK5/6, CK903, OSCAR): m Variable expression for vimentin, NSE, S100
– Do not show punctate paranuclear reactivity protein, and smooth muscle actin:
seen in small cell neuroendocrine carcinoma – Numerous S100 protein dendritic cells can
m p63 diffusely and strongly reactive be seen.
m EMA positive in majority of cases m CD117 negative
m CEA may be positive and tend to be limited to m Melanoma markers (e.g., HMB-45, melan-A,
squamous component. tyrosinase, MITF1, Sox10) negative
m May be p16 positive: • More recent data suggest stage for stage, prognosis
– Typically seen in association with oropharyn- similar to that for conventional SCC:
geal tumors m Compared with SCC, BSCC not shown to be an
• Electron microscopy: independent adverse prognostic factor for patients

m Features of squamous cell carcinoma are present, with head and neck cancer
including cell groups with numerous and m BSCC histology does not have independent
prominent tonofilament bundles, increased des- adverse prognostic effect on overall survival.
mosomes, and epithelial pearls and loose stellate • HPV-positive BSCCs as compared with HPV-negative
granules or replicated basal lamina within the BSCCs:
cystic spaces and absence of glandular m Have improved overall survival
differentiation. m May be due to increased radiosensitivity of HPV-
• Cytogenetics and molecular genetics: positive tumors

m Increasing evidence identifying HPV in associa- m Explains lower hazard ratio for death in patients
tion with oropharyngeal BSCC: with oropharynx BSCC

– High-risk HPV identified by in situ hybridiza-
tion or PCR Adenosquamous Carcinoma (ASC)
m MYB-NFIB gene fusion:
– Absent in BSCC
– Present in adenoid cystic carcinoma Definition: Malignant high-grade surface epithelial-
derived neoplasm with histologic features of a squa-
Differential Diagnosis mous cell carcinoma and adenocarcinoma.
(Tables 16-3 and 16-4)
• Shallow biopsies may belie the depth and extent Clinical
of invasion and may not be representative of the • Rare neoplasm
lesion, leading to erroneous classification. • More common in men than in women; occur over a
• Adenoid cystic carcinoma wide age range but are most frequently seen in the
• Adenosquamous carcinoma sixth to seventh decades of life
• Small cell undifferentiated neuroendocrine • May occur in virtually all upper aerodigestive tract
carcinoma sites but is identified most frequently in the larynx,
• Olfactory neuroblastoma (for sinonasal tract BSCC) hypopharynx, and less often in the oral cavity
(tongue, floor of mouth, palate), oropharynx (tonsil,
Treatment and Prognosis base of tongue) and sinonasal cavity
• Preferred treatment includes radical surgical exci- • Symptoms vary according to the site of occurrence:
sion, neck dissection, and combined radiation and m Larynx: dysphagia, hoarseness, a mass with or
chemotherapy: without pain

m As result of early regional lymph node and distant
visceral metastases, radical neck dissection and

supplemental radio- and chemotherapy may be
included in the initial management protocol.
• Aggressive, high-grade tumor with increased ten-
dency to be multifocal, deeply invasive, and
metastatic:
m Metastases occur via lymphatics and blood vessels
with sites of predilection including regional and

distant lymph nodes, lung, bone, skin, and brain.
m Metastases include basaloid and squamous cell
components.
• Associated with increased incidence of second
primary malignancy in upper aerodigestive tract
• Initially considered to be rapidly fatal neoplasm
associated with high mortality rates within the first
year after diagnosis and believed to be more aggres-
sive than conventional SCC when matched stage
for stage Fig. 16-57. Adenosquamous carcinoma.
m Likely correlated to tendency to present with Supraglottic exophytic and ulcerated neoplasm that proved
advanced clinical stage disease to be an adenosquamous carcinoma.
TABLE 16-4 Basaloid Squamous Cell Carcinoma: Differential Diagnosis

BSCC AdCC SCUNC
Age/Gender 6th-7th decades; 5th-7th decades; no gender 6th-7th decades;
M>F predilection except for M>F
submandibular tumors,
which predilect to women
Location Predilects to hypopharynx Major salivary glands and Uncommon in H&N: larynx
(piriform sinus), larynx minor (intraoral) minor (supraglottis) is the most
(supraglottis), and salivary glands; may occur in common site; other H&N
oropharynx (tonsils, base of other mucosal sites including sites rare and may include
tongue) sinonasal tract; rare in the sinonasal tract and parotid
larynx and hypopharynx gland
Histology: 1. Invasive lobules with 1. Invasive with cribriform 1. Submucosal invasive tumor
1. Growth comedotype necrosis, solid, growth (representing the with solid nests, sheets or
2. Cytomorphology cords, trabeculae gland-like; most frequent pattern), ribbons and absence of a
cribriform pattern may be tubular/glandular, solid; fibrovascular stroma
seen but tends to be limited; pseudocysts present 2. Hypercellular tumor with
intercellular basement- 2. Composed predominantly of hyperchromatic,
membrane–type material abluminal (myoepithelial) pleomorphic, oval to
may be present cells composed of spindle-shaped nuclei,
2. Composed predominantly of isomorphic cells with increased nuclear-to-
pleomorphic, hyperchromatic (basaloid) cytoplasmic ratio,
hyperchromatic basaloid angular to oval nuclei, nondescript cytoplasm, and
cells with numerous absent to small nucleoli, indistinct cell borders;
mitoses; squamous cell eosinophilic to clear- nuclear chromatin described
component (dysplasia, CIS, appearing cytoplasm lacking as “salt and pepper” in
invasive SCC) is the minor nuclear pleomorphism and appearance with absence of
component; neural-type mitotic activity; in addition, nucleoli; “crush” artifact is
rosettes rarely may be luminal (duct) epithelial cells frequently present; confluent
present present lining true glandular foci of necrosis and
spaces characterized by the individual cell necrosis seen;
cells with round nuclei and abundant mitoses, including
eosinophilic-appearing atypical forms; nuclear
cytoplasm molding may be identified;
neural-type rosettes may be
present
Surface involvement Present in the form of Absent Absent but surface may be
dysplasia or CIS ulcerated
Squamous Present but is the minor Absent Present but when found is
differentiation component and may only typically limited in extent
focally be found
Neurotropism Yes Yes Yes
IHC Diffuse and strong reactivity Abluminal cells: positive for Positive for cytokeratins often
for cytokeratins and p63; cytokeratins, p63, S100 with punctate paranuclear
neuroendocrine markers protein, calponin, SMA, pattern; CK5/6 usually
(e.g., synaptophysin, others) SMMS, vimentin negative; p63 may be
usually negative but Duct cells: positive for positive but usually not as
occasionally may be positive; cytokeratins, EMA, CEA, consistently positive as seen
p16 typically negative in CD117 in BSCC and AdCC;
nonoropharyngeal sites All cell types negative for neuroendocrine markers
and may be positive in neuroendocrine markers (e.g., synaptophysin, others)
oropharyngeal tumors (chromogranin and positive; calcitonin rarely
synaptophysin) positive
HPV association Possible* No Possible*
(transcriptionally
active)
Gene fusion Absent MYB-NFIB present Absent
Treatment Surgery, radiotherapy, Surgery and radiotherapy Systemic chemotherapy and
chemotherapy therapeutic irradiation
Continued
TABLE 16-4 Basaloid Squamous Cell Carcinoma: Differential Diagnosis—cont’d

BSCC AdCC SCUNC
Spread Metastasis frequent often at Metastasis (local or distant) Metastasis frequent (even at
presentation to cervical uncommon: distant presentation) to regional
lymph nodes and lung metastasis occurs late in lymph nodes and to liver,
disease course to lungs, lung, bone, and brain
bone, brain, and liver
Prognosis Dependent on clinical stage Short-term prognosis is good Poor:
but overall considered to be but long-term prognosis is 16% 2-year survival;
poor; HPV-associated share poor; survival rates include: 5% 5-year survival
better outcomes similar to 5-year 71% to 89% Presence of transcriptionally
oropharyngeal 10-year 29% to 71% active HPV does not alter
nonkeratinizing (HPV- 15-year 29% to 55% poor prognosis
associated) carcinomas
AdCC, Adenoid cystic carcinoma; BSCC, basaloid squamous cell carcinoma; CIS, carcinoma in situ; HPV, human papillomavirus; IHC,
immunohistochemistry; SCUNC, small cell undifferentiated neuroendocrine carcinoma.
*BSCC and SCUNC may harbor transcriptionally active HPV especially when of oropharyngeal origin.
A B
Fig. 16-58. Adenosquamous carcinoma.

A, Invasive carcinoma originating from the surface epithelium (left) consisting of an admixture of glandular and squamous
differentiation. B, The glands and squamous foci may be intimately admixed or (C) lie adjacent to one another (left panel
squamous differentiation and right panel glandular differentiation). These tumors are high-grade malignancies composed of
pleomorphic cells with prominent eosinophilic nucleoli and increased mitotic activity.
Squamous Cell Component

• Includes invasive SCC and/or high-grade intraepithe-
lial dysplasia/CIS:
m Squamous cell differentiation evident by the
presence of individual cell keratinization, inter-

cellular bridges, keratin pearl formation, and/or
dyskeratosis
m Varies from well to poorly differentiated
m Often high-grade intraepithelial dysplasia/CIS of
surface epithelium is present

– May extend to seromucous glands
A – Often identified in direct continuity to surface
epithelium
• May be admixed with or distinct from adenocarci-
nomatous component
Adenocarcinoma Component
• Characterized by gland formation with or without
complex (gland in gland) growth
• Characterized by presence of moderate to marked
nuclear pleomorphism and increased mitotic
activity
• Necrosis may be present.
B • Typically identified in the submucosa:
m Usually seen in deeper aspects of the tumor
m Mucous cell differentiation usually not seen and

Fig. 16-59. Adenoid squamous cell carcinoma. not a prerequisite for diagnosis
Adenoid squamous cell carcinoma is characterized by • May be admixed with or distinct from squamous cell
pseudolumen formation due to acantholysis, creating the carcinomatous component
appearance of gland formation that may suggest a • Histochemistry:
diagnosis of adenosquamous carcinoma. m Intracellular and intraluminal mucicarmine and
diastase-resistant, PAS-positive material is seen

associated with the glandular component.
• Cause: m Intracytoplasmic mucin-positive material not
m No clearly defined cause typically present
m May be related to alcohol and/or tobacco use • Immunohistochemistry (both components):
• Cell of origin not definitively identified but in all m Cytokeratin positive, including AE1/AE3,
probability is a single totipotential cell capable of CAM5.2, 34βE12 (CK903) in squamous and
divergent differentiation and located either in the glandular components
basal cell layer of the surface epithelium or within m p63 positive in squamous cell component
mucoserous glands; in the latter, the cell arises from m CEA, CK7 positive in glandular component
excretory or interlobular salivary gland ducts – CK20 absent in glandular component

m High proliferation rates as seen by Ki67 (MIB1)
Pathology staining
Gross m Overexpression of p53
• Exophytic or submucosal, friable, edematous, or • Electron microscopy:

granular mass with or without surface ulceration m Squamous cell carcinoma component:
measuring from 0.6 to 5.0 cm. – Bundles of tonofilaments, increased desmo-

somes, and epithelial pearls
Histology m Adenocarcinoma component:
• Infiltrating cytologically high-grade neoplasm com- – Acini and luminal microvilli

posed of solid nests and glandular growth • Cytogenetics and molecular genetics:
• Necrosis and perineural invasion commonly m Absence of MECT1-MAML2 gene translocation
identified m High prevalence of aneuploidy
• Rare examples of ASC with intestinal phenotype m Prognosis similar to that of squamous cell
reported: carcinoma
m Located in hypopharynx
m Composed of superficial squamous cell carci- Treatment and Prognosis

noma and adenocarcinoma with intestinal pheno- • Radical surgical excision is preferred treatment. As
type, the latter showing tubuloglandular and a result of the propensity for this neoplasm to dem-
cribriform architecture and immunoreactivity for onstrate early regional lymph node metastasis,
CK7, CK20, CDX2, CEA, and villin radical neck dissection may be necessary as part of
• HPV-associated ASC: the initial management; radiotherapy is of question-
m Small minority may be associated with HPV. able benefit.
m Locations include oropharynx and sinonasal • Prognosis is poor as this neoplasm is aggressive and
tract. high grade with increased tendency to be multifocal,
m Histology similar to non–HPV-associated ASCs deeply invasive, and metastatic:
m Overexpression of p16 m These neoplasms behave very aggressively regard-
m Show active viral transcription with detectable less of the size of the neoplasm.
high-risk HPV E6 and E7 • Metastases occur via lymphatics and blood vessels
m Appear to be associated with better clinical with sites of predilection, including regional lymph
outcome than non–HPV-associated ASCs nodes, lung, and liver:
m Metastatic disease histologically is similar to the
primary neoplasm and includes both malignant

Differential Diagnosis (Table 16-5) histologic components.
• Mucoepidermoid carcinoma (MEC): m Nodal metastases reported in up to 75% of cases
m Rarely if ever a surface epithelial-derived m Distant metastases reported in up to 25% of cases
neoplasm • 5-year survival rates are approximately 15% to

m Lacks squamous carcinoma in situ that is typi- 25%.
cally present in adenosquamous carcinoma • 3-year and median overall survival, disease-free sur-
m Typically lacks evidence of intercellular bridges vival (DFS), and locoregional control reported to be
or keratinization 52%, 32%, and 47%, respectively.
m In low-grade and intermediate-grade tumors m DFS negatively influenced by presence of extra-
shows combination of three cell types including capsular extension and advanced stage
mucocytes, epidermoid cells, and intermediate m Overall prognosis of locoregionally advanced
cells ASC remains poor.

m Presence of MECT1-MAML2 gene translocation: m Early-stage ASC patients managed with com-
– Consistently present in low- and intermediate- bined modality treatment may have prolonged
grade MECs DFS.
– High-grade tumors considered to be MEC but • HPV-associated (oropharyngeal) ASC may have
lacking MECT1-MAML2 gene translocation more favorable outcome as compared with non–
likely not MECs and may be ASCs HPV-associated ASC with longer survival rates:
• Adenoid squamous cell carcinoma (see Fig. 16-57): m Too few reported cases to clearly determine if
m Also referred to as acantholytic squamous cell these are distinct variant that can be classified
carcinoma according to HPV status.
m Not a distinct clinical subtype but is a histomor-
phologic subtype of squamous cell carcinoma

m Most common in sun-exposed areas of the head OTHER UNCOMMON
and neck; rare tumor of mucosal sites CARCINOMA VARIANTS
m Surface-derived squamous cell carcinoma that is
histologically characterized by the presence of Lymphoepithelial-Like Carcinoma

pseudolumen formation due to acantholysis, cre-
(Fig. 16-60)
ating the appearance of gland formation; there is
no evidence of glandular differentiation either in Definition: Undifferentiated carcinoma with prominent
the form of mucocytes or glands associated benign lymphocytic cell infiltrate that is his-
m Histochemical stains for epithelial mucin are tologically identical to the more common nasopharyn-
negative. geal undifferentiated carcinoma.
m Cytokeratin, EMA, and p63 strongly positive • See Section 3, Pharynx, for a more complete
m Absence of endothelial cell–related markers (e.g., discussion.
CD31, CD34, factor VIII–related antigen, others) • Rare tumor type of the larynx and trachea
TABLE 16-5 Adenosquamous Carcinoma: Differential Diagnosis

MEC, Low- and SCC, Adenoid, or
ASC Intermediate Grade NS Acantholytic
Architecture/growth Haphazard, infiltrative Haphazard, infiltrative Retention of lobular Haphazard, infiltrative
growth growth architecture growth
Cellular components Invasive squamous Admixture of mucous, Smooth round to oval Nests and cords of
cell carcinoma and epidermoid, and nests of metaplastic squamous cells with
adenocarcinoma: 2 intermediate; bland squamous epithelium irregular outlines and
components may be cytology; irregular cell with bland cytology; variable amount of
intermixed or more nests may show residual cytologic atypia; may
often are distinct ductal lumina with entrap residual glands
and separate; mucous cells but the tumor itself
adenocarcinoma is contains no mucocytes
gland-forming but
without mucocytes
Cyst formation Absent Present: prominent Absent Absent
component in
low-grade and
frequent component
in intermediate-grade
Keratinization and Present Absent May be present Present
intercellular bridges
Surface epithelium HGSIL/CIS usually Submucal in location May show PEH; Often dysplastic and/or
present; direct continuity when occurs in usually not connected in direct continuity
with the carcinoma; mucosal sites without with NS with the carcinoma;
surface may be involvement (direct may be ulcerated
ulcerated continuity) to surface
epithelium; ulceration
may be present
Mucin production Intraluminal; Intracytoplasmic and Retained in residual Absent
intracytoplasmic intraluminal mucocytes of
uncommon but may be seromucous glands
present
Extravasated mucin Absent Present May be present Absent
Necrosis May show tumor Absent Lobular infarction of May show tumor
necrosis salivary gland acini necrosis
TALP inflammation Typically absent Often present Nonspecific chronic Typically absent
although nonspecific inflammation may be although nonspecific
chronic inflammation present chronic inflammation
may be present in may be present in
association with association with
desmoplasia desmoplasia
Gene fusion Absent MECT1-MAML2 Absent Absent
present
ASC, Adenosquamous carcinoma; CIS, carcinoma in situ; HGSIL, high-grade squamous intraepithelial lesion; MEC, mucoepidermoid
carcinoma; NS, necrotizing sialometaplasia; PEH, pseudoepitheliomatous hyperplasia; SCC, squamous cell carcinoma; TALP, tumor-
associated lymphoid proliferation.
• More common in men than in women; most frequent Aggregates or syncytia of neoplastic cells charac-
m
in the seventh decade of life terized by enlarged vesicular nuclei and promi-
• More common in Caucasian populations than in nent nucleoli
Asian populations m Foci of squamous cell differentiation including
• Tendency to occur in the supraglottic larynx abrupt keratinization of conventional foci of

• Most common symptoms include hoarseness and a squamous cell carcinoma can be seen.
neck mass: • Prominent benign lymphocytic cell infiltrate is
m Less often, sore throat, dysphagia, hemoptysis, present; a variable amount of plasma cell may be
and otalgia present.
• Histology identical to its more common nasopharyn- • Carcinoma in situ of the overlying surface epithelium
geal counterpart, including: may be present.
Fig. 16-60. Lymphoepithelial-like carcinoma.

B
Rare example of laryngeal lymphoepithelial-like carcinoma
showing histomorphologic features similar to those of its
more common nasopharyngeal counterpart, including
neoplastic cells characterized by enlarged vesicular
nuclei and prominent nucleoli with variable amount of
associated benign lymphoplasmacytic cell infiltrate. In situ
hybridization for Epstein-Barr–encoded RNA was negative
(not shown).
• Neoplastic cells are immunoreactive for

cytokeratins.
• Rarely associated with Epstein-Barr virus
• Risk factors for the development of this carcinoma
may include excessive use of tobacco and alcohol.
• Treatment varies and has included limited to radical
surgery with adjuvant therapy (radiation and C
chemotherapy).
• Cervical nodal metastases occurs in a nearly 75% of
patients; distant metastases including to the lung, Fig. 16-61. Giant cell carcinoma.
liver, bone, skin occur in approximately 25% of A, B, Upper tracheal malignant neoplasm showing a
patients. submucosal proliferation composed of numerous
• Nearly one third of patients reported dead of disease noncohesive multinucleated (osteoclast-like) giant cells
at a 21-month median follow-up. with abundant eosinophilic cytoplasm. C, Associated
smaller malignant cells with increased mitotic activity
including atypical mitoses are present. Immunoreactivity
Giant Cell Carcinoma (Fig. 16-61) for cytokeratins was positive (not shown). Whether this
Definition: Undifferentiated carcinoma with many neoplasm represents a distinct entity (i.e., giant cell
bizarre multinucleated giant cells with or without light carcinoma) or a part of another malignant neoplasm
remains uncertain.
microscopic evidence of squamous or glandular differ-

entiation, and with intracytoplasmic polymorphonu- Differential Diagnosis
clear leukocytes or cellular debris. • Spindle cell squamous carcinoma
Synonyms: Large cell carcinoma; pleomorphic carci- • Sarcomas
noma; anaplastic carcinoma
• By some criteria presence of squamous or glandular Treatment and Prognosis
differentiation excludes a diagnosis of giant cell • Surgery (i.e., partial or total laryngectomy) plus
carcinoma. adjuvant therapy (radiation and chemotherapy) is
• Diagnosis may be predicated on the quantity of giant the recommended treatment.
cells in a given carcinoma, although various reports • Increased incidence of cervical nodal metastasis
cite various percentages of giant cells as qualifying necessitates neck dissection
as a giant cell carcinoma. • Very few reported cases but overall prognosis is poor
• Given the fact that when giant cells are seen in squa-
mous cell carcinoma or adenocarcinoma they repre-
sent a minor component focally present and are not LARYNGEAL SALIVARY GLAND
diffusely present, a carcinoma with a diffuse giant MALIGNANT NEOPLASMS
cell population and/or a giant cell component seen
in significant quantities should allow classification as • Malignant salivary gland tumors of the larynx and
a giant cell carcinoma. trachea are rare.
• Presence of intracytoplasmic polymorphonuclear • Although any type of malignant salivary gland tumor
leukocytes or cellular debris would further buttress may occur in these locations, the most common
this diagnosis. tumor types are adenoid cystic carcinoma and muco-
epidermoid carcinoma.
Clinical Adenoid Cystic Carcinoma of the

• Extremely rare
• More common in men than in women; most frequent
Larynx and Trachea
in the sixth to seventh decades of life • Equal gender predilection; occurs over a wide age
• Occurs in any site of the larynx without predilection range but most common in the sixth to eighth
to any one location decades
• Most common symptoms include dyspnea and • Majority are subglottic followed by the
dysphagia. supraglottis
• May be linked to cigarette smoking and alcohol use • Symptoms include airway obstruction, dysphagia,
hoarseness, sore throat, and pain.
• Histology is similar to adenoid cystic carcinoma of
Pathology more common locations.
Histology • Differential diagnosis includes basaloid squamous
• Histologically similar to giant cell carcinoma of the cell carcinoma and small cell undifferentiated neuro-
lung endocrine carcinoma (see Table 16-4)
• Light microscopy is characterized by: • Surgery is the preferred treatment with postoperative
m Presence of numerous, noncohesive bizarre- radiotherapy:
appearing multinucleated giant cells with abun- m Given the propensity to occur in the subglottic
dant eosinophilic cytoplasm that may be larynx, a total laryngectomy is often required.
vacuolated m Supraglottic tumors may be treated by partial
m Often contain polymorphonuclear leukocytes or laryngectomy.

cellular debris • Unless there is clinical evidence of neck disease, a
• A background cellular infiltrate that includes smaller neck dissection would not appear to be warranted.
anaplastic cells is present. • Prognosis is similar to adenoid cystic carcinomas of
• Increased mitotic activity including atypical mitoses more usual sites.
is present.
• Immunoreactivity for cytokeratin is present. Mucoepidermoid Carcinoma of the
• May occur in a mixed form in association with squa-
mous cell carcinoma, adenocarcinoma, or spindle
Larynx and Trachea
cell squamous carcinoma: • More common in men than in women; occurs over
m May be referred to as pleomorphic carcinoma a wide age range but most common in the sixth
m Raises question whether giant cell carcinoma is a decade:
specific entity m Tracheal tumors may occur in pediatric ages.
• Majority are supraglottic.

BOX 16-5 Classification of Laryngeal
• Symptoms include hoarseness, dyspnea, dysphagia, Neuroendocrine Tumors
foreign body sensation, and a neck mass.
• Histology is similar to mucoepidermoid carcinomas Benign
of more common locations. • Laryngeal paraganglioma
• Differential diagnosis includes adenosquamous car- Malignant
cinoma and necrotizing sialometaplasia (Table 16-5): • Carcinoid tumor (well-differentiated neuroendocrine
m Likely many tumors reported as laryngeal high-
carcinoma)
• Atypical carcinoid (moderately differentiated
grade mucoepidermoid carcinoma with poor neuroendocrine carcinoma)
prognosis represent adenosquamous carcinoma. • Small cell undifferentiated neuroendocrine carcinoma
• Surgery is the preferred treatment: (poorly differentiated neuroendocrine carcinoma)
m Supraglottic tumors may be treated by partial • Large cell undifferentiated neuroendocrine carcinoma
laryngectomy. (poorly differentiated neuroendocrine carcinoma)
• Unless there is clinical evidence of neck disease, a
neck dissection for low- and intermediate-grade
mucoepidermoid carcinoma is not warranted. cell undifferentiated neuroendocrine carcinoma
m Neck dissection is warranted for a diagnosis of (SCUNC)
high-grade mucoepidermoid carcinoma. m Large cell neuroendocrine carcinoma (LCNEC)
• Prognosis is similar to mucoepidermoid carcinomas subsumed within the broader category of

of more usual sites: PDNEC
m Overall survival rates for all grades of laryngeal • Order of frequency of occurrence of laryngeal neu-
MEC are 75% to 80%. roendocrine carcinomas is:
m For low-grade MEC the 5-year survival rate is m Atypical carcinoid (MDNEC) > small cell carci-
90% to 100%. noma (PDNEC) > carcinoid tumor (WDNEC)

m For high-grade MEC the overall 5-year survival
rate is 50% to 55%: Clinical (as a Group)

– As previously noted it is likely that tumors • There is much overlap in demographics and clinical
reported as laryngeal high-grade mucoepider- features for all subtypes of laryngeal neuroendocrine
moid carcinoma with poor prognosis represent carcinomas:
adenosquamous carcinoma. m Histology and prognosis vary per subtype
m See Tables 16-6 and 16-7 for clinical and patho-
logic features of laryngeal neuroendocrine

LARYNGEAL carcinomas.
NEUROENDOCRINE • More common in men than in women;
CARCINOMAS generally occurs in the sixth to seventh decades
of life
Definition: Heterogeneous group of malignant neo- • Supraglottic larynx is overwhelmingly the most
plasms characterized by the presence of neuroendocrine common site of occurrence:
differentiation with prognosis dependent on tumor type. – May occur less often in the glottis and
• In general, an uncommon class of neoplasms in the subglottis
head and neck. • Hoarseness is most common complaint; other symp-
• May be identified in virtually all sites of the head and toms may include dysphagia.
neck: • History of cigarette smoking linked with atypical
m Most common: larynx ≫ sinonasal tract carcinoid, small cell carcinoma, and large cell neu-
m Less common: salivary glands, pharynx (naso- roendocrine carcinoma but does not appear to be
pharynx and oropharynx), oral cavity linked with development of carcinoid tumor
• Histologic and immunohistochemical findings similar
irrespective of site of origin
• Classification of laryngeal neuroendocrine carcino-
Carcinoid Tumor (Fig. 16-62)
mas includes (Box 16-5): Synonyms: Well-differentiated neuroendocrine carci-
m Carcinoid tumor or well-differentiated neuroen- noma (WDNEC); typical carcinoid
docrine carcinoma (WDNEC)
m Atypical carcinoid or moderately differentiated Clinical
neuroendocrine carcinoma (MDNEC) • Least common of the laryngeal neuroendocrine
m Small cell carcinoma or poorly differentiated carcinomas
neuroendocrine carcinoma (PDNEC) or small • Generally not associated with smoking history
TABLE 16-6 Clinical Features of Laryngeal Neuroendocrine Tumors

Feature LP CT ACT SCUNC LCNEC
Frequency Rare Least common Most common 2nd most Uncommon
common
Age/gender 5th decade; 7th decade (on 7th decade (on 6th-7th decades; Occurs over a wide
F>M avg.); avg.); M>F age range;
M>F M>F average age of
59 years
M>F
RF None known None known Smoking Smoking Smoking
HPV-associated None known None known None known Possible* None known
Site Supraglottis: AE Supraglottis: Supraglottis: AE Supraglottis, but Supraglottis
fold and FVC AE fold, fold, arytenoids, may occur
arytenoid, FVC elsewhere in
FVC the larynx
Symptoms Hoarseness; Hoarseness Hoarseness Hoarseness Hoarseness,
dysphagia, dysphagia,
dyspnea, stridor otalgia, weight
loss; heartburn,
cervical
adenopathy
Paraneoplastic Exceptional; may May occur but Rare Occasional Unknown
syndrome be multicentric rare
with other H&N
paragangliomas
Treatment Surgery is Surgery Surgery; adjuvant Systemic Chemoradiotherapy
curative radiotherapy and chemotherapy
chemotherapy and therapeutic
irradiation
Spread None Approximately Metastasis common Metastasis Commonly present
33% have to cervical lymph frequent (even with advanced
distant nodes, lung, at presentation) stage (stages III
metastases bone, liver, skin to regional and IV)
(liver and lymph nodes
bone) and to liver,
lung, bone, and
brain
Prognosis Excellent Indolent Fully malignant Poor: 5-year disease-
biology with neoplasm; 16% 2-year specific survival
excellent tumor confined to survival; (DSS) of 15% to
behavior larynx: 5% 5-year 21%
62% median 3.9-yr survival;
survival; 5-year disease-
48% 5-yr survival; specific survival
30% 10-year (DSS) of 19%;
survival presence of
transcriptionally
active HPV does
not alter poor
prognosis
ACT, Atypical carcinoid tumor; AE fold, aryepiglottic fold; CT, carcinoid tumor; FVC, false vocal cord; LCNEC, large cell neuroendocrine
carcinoma; LP, laryngeal paraganglioma; RF, risk factor(s); SCUNC, small cell undifferentiated neuroendocrine carcinoma.
*May harbor transcriptionally active HPV especially when of oropharyngeal origin.
772
TABLE 16-7 Pathologic Features of Laryngeal Neuroendocrine Tumors

Feature LP CT ACT SCUNC LCNEC
Histology Cell nest or “Zellballen” Submucosal tumor with Submucosal tumor with Submucosal tumor with Presence of tumor cells
pattern characteristic of organoid or trabecular organoid, trabecular, solid nests, sheets, or with moderate to abundant
paragangliomas of all growth pattern and cribriform, or solid ribbons and absence of a cytoplasm, presence of
sites; cell nests separated fibrovascular stroma; growth and fibrovascular fibrovascular stroma; features of neuroendocrine
by prominent neoplastic cells are stroma; neoplastic cells hypercellular tumor with differentiation including
fibrovascular tissue; chief uniform with centrally show mild to marked hyperchromatic, organoid nesting,
cells (predominant cell) located round nuclei, cellular pleomorphism pleomorphic, oval to trabecular growth, rosettes,
are round or oval with vesicular chromatin, and with round to oval spindle-shaped nuclei, and peripheral palisading;
uniform nuclei, dispersed eosinophilic cytoplasm; nuclei, vesicular to increased nuclear-to- increase mitotic activity
chromatin pattern, and low nuclear-to- hyperchromatic cytoplasmic ratio, (greater than 10 mitoses
abundant eosinophilic, cytoplasmic ratio; chromatin, and nondescript cytoplasm and per 10 high-power fields
granular, or vacuolated nuclear chromatin eosinophilic cytoplasm; indistinct cell borders: [2 mm2]
cytoplasm; sustentacular described as “salt and nuclei can be centrally nuclear chromatin described
cells lie at the periphery pepper” in appearance or eccentrically located; as “salt and pepper” in
of the cell nests as with absence of nucleoli may be appearance with absence of
SECTION 5 Larynx and Trachea
spindle-shaped, nucleoli; absence of prominent; nuclear nucleoli; “crush” artifact is

basophilic-appearing cells pleomorphism, mitoses, chromatin described as frequently present; confluent
but are difficult, if not necrosis “salt and pepper” in foci of necrosis and
impossible, to identify by appearance with individual cell necrosis seen;
light microscopy absence of nucleoli; abundant mitoses, including
mitotic activity present atypical forms; nuclear
but uncommon; necrosis molding may be identified;
uncommon neural-type rosettes rarely
may be present
Infiltration Absent Absent Present including Present including Present including
neurotropism neurotropism neurotropism; may invade
pre-epiglottic space
Angioinvasion Absent Absent Present Common Common
IHC Chief cells positive for Positive for cytokeratins Positive for cytokeratin Positive for cytokeratins Neuroendocrine
neuroendocrine and neuroendocrine (96%); chromogranin (AE1/AE3) but CK5/6 and markers positive (e.g.,
markers (synaptophysin, markers (e.g., (94%), synaptophysin 34βE12 typically negative; synaptophysin, others);
others) and GATA3; synaptophysin, others); (100%), calcitonin (80%); CK7 and CK20 may be positive for cytokeratin
sustentacular cells: S100 may be positive for also positive for NSE, positive neuroendocrine (AE1/AE3) but CK5/6 and
protein positive; p63 calcitonin, serotonin, Leu-7, NFP, EMA, CEA; markers (e.g., synaptophysin, 34βE12 typically negative;
negative somatostatin, and p63 variably positive others) NSE, Leu-7, NFP, calcitonin and TTF1
bombesin; p63 negative; and when present tends EMA, CEA, TTF-1; calcitonin negative
GATA3 negative to be weak; GATA3 rarely positive; GATA3
negative negative
HPV association No known association No known association No known association Possible* Not known
(transcriptionally but identified in a single
active) reported case
ACT, Atypical carcinoid tumor; CEA, carcinoembryonic antigen; CT, carcinoid tumor; EMA, epithelial membrane antigen; LCNEC, large cell neuroendocrine carcinoma; LP, laryngeal
paraganglioma; NFP, neurofilament protein; NSE, neuron specific enolase; SCUNC, small cell undifferentiated neuroendocrine carcinoma; TTF-1, thyroid transcription factor 1.
*May harbor transcriptionally active HPV, especially when of oropharyngeal origin with one reported positive case originating in the larynx.
A B
C D
Fig. 16-62. Laryngeal carcinoid tumor.

A, Submucosal cellular tumor. B and C, Organoid and solid areas composed of uniform cells with centrally located round
nuclei, dispersed nuclear chromatin-lacking pleomorphism, mitoses, or necrosis. Immunoreactivity is present for
(D) cytokeratin (CAM5.2) with paranuclear dot-like staining and (E) synaptophysin.
• Carcinoid syndrome may rarely occur in association described as “salt and pepper” in appearance with
with carcinoid tumor: absence of nucleoli
m Occurs when carcinoid tumor secretes certain • Absence of pleomorphism, mitoses, necrosis
chemicals into bloodstream, causing a variety of • Glands and/or squamous differentiation can be seen.
signs and symptoms • Surface ulceration uncommon
m Most common in association with carcinoid • Vascular, lymphatic, and perineural invasion absent
tumors of the gastrointestinal tract or lungs • Histochemistry:
m Typically occurs in patients who have advanced m Argyrophilic staining (e.g., Churukian-Schenk)
disease positive characterized by presence of intracyto-

m Most common signs and symptoms of carcinoid plasmic granular material typically appearing
syndrome include: black
– Skin flushing – Extent and degree of staining inversely paral-
– Diarrhea: lels tumor grade with decreasing staining with
■ Frequent watery stools sometimes accompa- less differentiation
nied by abdominal cramps m Argentaffin staining (e.g., Fontana-Masson) may
– Rapid heartbeat be positive characterized by presence of intracy-

– Difficulty breathing: toplasmic black material.
■ Asthma-like signs and symptoms (e.g., m In presence of glandular differentiation, intralu-
wheezing and shortness of breath) may occur minal mucicarmine and diastase-resistant, PAS-
at same time of skin flushing positive material can be seen.
– Facial skin lesions: • Immunohistochemistry:
■ Purplish spider-like veins may appear on m Cytokeratins positive:
nose and upper lip. – AE1/AE3, CAM5.2 consistently strongly

m Treatment usually involves treating the cancer, positive
but as most carcinoid tumors do not cause carci- – CK7, CK20 may be positive
noid syndrome until an advanced stage of disease m EMA, CEA positive
a cure may not be possible: m Synaptophysin, chromogranin, neuron-specific

– In such cases, medications may relieve enolase, CD56, Leu-7 (CD57) positive
symptoms. m Serotonin and somatostatin may be positive.
– Medications used are able to block cancer cells m Calcitonin, TTF1, S100 protein negative
from secreting chemicals: m p63 usually negative
– Injections of medications octreotide (San • Electron microscopy:

dostatin) and lanreotide (Somatuline Depot) m Abundant neurosecretory granules (90 to
may reduce the signs and symptoms of carci- 230 nm); cellular junctional complexes, intercel-
noid syndrome, including skin flushing and lular, and intracellular lumina are present.
diarrhea.
– Octreotide may also slow growth of carcinoid Differential Diagnosis
tumors. • Laryngeal paraganglioma:
– Side effects of octreotide and lanreotide include m Absent staining with epithelial markers:
diarrhea, abdominal pain, and bloating, which – Rare examples may be cytokeratin positive.
may subside over time. m Presence of S100 protein (and GFAP) in periph-
eral situated sustentacular cells:

– Feature not identified in neuroendocrine
Pathology carcinomas
Gross m GATA3 immunoreactivity seen in paraganglio-
• Submucosal nodular or polypoid mass with a tan- mas but absent in (laryngeal) neuroendocrine
white appearance varying in size from a few milli- carcinomas
meters up to 3 cm in diameter • Atypical carcinoid (see below)
• Surface ulceration is generally absent.
Histology • Conservative but complete surgical excision is pre-
• Submucosal tumor arranged in organoid or trabecu- ferred treatment.
lar growth pattern with fibrovascular stroma • Neck dissection not indicated
• Uniform cells with centrally located round nuclei, • Indolent biologic behavior:
vesicular chromatin and eosinophilic cytoplasm; low m Generally carries an excellent prognosis after
nuclear-to-cytoplasmic ratio; nuclear chromatin excision
5-year disease-specific survival (DSS) of 100%

m
reported
• May metastasize in approximately one third of
patients:
m Metastasis occurs to liver, bone, lymph nodes,
and skin.
m Metastases may occur late in the disease course.
Atypical Carcinoid
Synonym: Moderately differentiated neuroendocrine
carcinoma (MDNEC)
Clinical
• Most common laryngeal neuroendocrine carcinoma
• Most patients have a history of heavy tobacco
smoking use.
Fig. 16-64. Atypical carcinoid.

A, B, Laryngeal atypical carcinoid characterized by the
presence of a submucosal neoplastic proliferation with
organoid growth and fibrovascular stroma.

Laryngeal atypical carcinoid appearing as a large
supraglottic-based mass with extension outside the larynx
proper.
A B
C D

A through D, Laryngeal atypical carcinoid with organoid or cell nest, trabecular and solid growth patterns composed of
cells with round to oval nuclei, dispersed to hyperchromatic nuclear chromatin, inconspicuous to small nucleoli and
eosinophilic cytoplasm; variable but definite nuclear pleomorphism is present, and there is increased mitotic activity. The
presence of nuclear pleomorphism and mitotic activity is greater than that seen in carcinoid tumor but not as prominent as
in small cell and large cell neuroendocrine carcinomas. E, Perineural invasion (arrow) can be seen in atypical carcinoid
representing another feature that would contrast to (typical) carcinoid tumor.
A B
C D
Fig. 16-66. Immunohistochemical staining of atypical carcinoid.

Immunoreactivity in laryngeal atypical carcinoid includes (A) cytokeratin (CAM5.2), (B) synaptophysin, (C) calcitonin, and
(D) thyroid transcription factor 1. E, Ultrastructural findings include the presence of neurosecretory granules (lower right of
illustration).
• Carcinoid syndrome rarely occurs in association

with atypical carcinoid tumor.
Pathology
Gross
• Submucosal nodular or polypoid mass with a tan-
white appearance varying in size from a few milli-
meters up to 4 cm in diameter.
• Surface ulceration may be present.
Histology
A • Submucosal tumor arranged in organoid, trabecular,
cribriform, or solid growth with a prominent fibro-
vascular stroma; infiltrative growth is present,
including neurotropism and angioinvasion.
• Neoplastic cells show mild to marked cellular pleo-
morphism with round to oval nuclei, vesicular
to hyperchromatic chromatin, and eosinophilic
cytoplasm:
m Nuclei can be centrally or eccentrically located.
m Nucleoli may be prominent.
m Nuclear chromatin described as “salt and pepper”
in appearance with absence of nucleoli

m Oncocytic cytoplasmic changes may be present.
• Mitoses, although uncommon, can be seen:

m Never reach a level associated with large cell neu-
roendocrine carcinoma of 10 mitoses per 10 high-

power fields (see below)
• Necrosis may be focally identified.
• Glands and squamous differentiation can be identi-
fied; neural-type rosettes rarely may be present:
m May rarely occur in association with squamous
B
cell carcinoma
m In presence of squamous differentiation, a diag-
Fig. 16-67. Metastatic atypical carcinoid. nosis of basaloid squamous cell carcinoma should
Metastasis from laryngeal atypical carcinoid tumor may be excluded.
include (A) subcutaneous metastasis and (B) cervical neck • Surface ulceration may be prominent.
lymph node with almost complete replacement of the • Lymph-vascular and/or and perineural invasion may
lymph node by metastatic tumor. In the presence be present.
of an unknown primary tumor, the histology and • Histochemistry:
immunohistochemical staining of metastatic laryngeal m Presence of epithelial mucin (diastase-resistant,
atypical carcinoid will be similar to those of a metastatic PAS-positive, and occasionally mucicarmine posi-
medullary thyroid carcinoma, including immunoreactivity tive), argyrophilia; rarely, argentaffin positive
for cytokeratins, neuroendocrine markers, calcitonin, and • Immunohistochemistry:
thyroid transcription factor 1. In contrast to medullary
m Cytokeratins (96%), chromogranin (94%), syn-
thyroid carcinoma, serum calcitonin levels would not be
aptophysin (100%)
expected to be elevated in patients with laryngeal atypical
m Other positive markers may include neuron-
carcinoid tumor.
specific enolase, CD56, Leu-7 (CD57), neurofila-
ment protein, epithelial membrane antigen, and
carcinoembryonic antigen positive
m Calcitonin is frequently positive (up to 80% of
cases).
m S100 protein, somatostatin, serotonin, adreno-
corticotropic hormone, gastrin, and glucagon

may be positive.
p63 variably positive and when present tends to

m • Radiotherapy and chemotherapy not considered
be focal and weak beneficial as this tumor type is resistant to these
m TTF1 and melanoma-related markers are therapies.
negative. • Overall survival rates include:
m Increased proliferation rates seen by Ki67 (MIB1) m 5-year survival rate of 48%
staining m 10-year survival rate of 30%
m p53 overexpression • 5-year disease-specific survival (DSS) of 53%:

m p16 and HPV16 by PCR reported positive in a m Patients treated with surgery had better DSS than
single case: those treated with radiotherapy.

– Whether there is any link and/or role of high- m Postoperative radiotherapy did not result in better
risk HPV in pathogenesis remains uncertain. DSS.

– Whether there is any ameliorating effect • Fully malignant tumor that often metastasizes to:
of HPV on prognosis of LNEC remains m Cervical lymph nodes (43% of patients)
uncertain. m Lungs, bone, liver (44% of patients)
• Electron microscopy: m Skin and subcutaneous tissue (22% of patients)
m Neurosecretory granules are commonly seen (70 • Prognosis is dependent on extent of disease at
to 420 nm); cellular junctional complexes, inter- presentation:
and intracellular lumina are present. m When the tumor is confined to the larynx,
62% tumor-free over median of 3 years 9

Differential Diagnosis months
• Carcinoid tumor m Presence of metastatic disease (either at presenta-
• Medullary thyroid carcinoma: tion or developing subsequently) is an ominous

m Differentiation of atypical carcinoid from a sign, with death at intervals ranging from 1 to 6
medullary thyroid carcinoma can be problematic years.
in presence of cervical lymph node metastasis • Size of primary tumor is prognostically important
of unknown primary origin given overlapping as tumors measuring greater than 1 cm have twice
histologic and immunohistochemical features the mortality rate as tumors measuring less than
including: 1 cm.
– Organoid growth with cells showing features • Death results from metastatic disease.
of neuroendocrine differentiation
– Immunohistochemical reactivity for cytokera-
tins, synaptophysin, and calcitonin
m Presence of a thyroid-based mass would support
Small Cell Undifferentiated
a diagnosis of medullary thyroid carcinoma, but Neuroendocrine Carcinoma
in the absence of a thyroid mass, differentiation (SCUNC) (Figs. 16-68
can be made on basis of increased serum calcito-
through 16-70)
nin levels, which are almost invariably elevated
in medullary thyroid carcinoma and almost Synonyms: Poorly differentiated neuroendocrine carci-
always within normal limits in atypical carcinoid noma (PDNEC); small cell carcinomas; “oat” cell
• Basaloid squamous cell carcinoma carcinoma
• Laryngeal malignant melanoma
Clinical
Treatment and Prognosis • Second most common laryngeal neuroendocrine car-
• Complete surgical excision is the preferred cinoma but represents less than 1% of all laryngeal
treatment: malignant tumors
m Depending on site surgery may include partial or • Most patients have a history of heavy tobacco
total laryngectomy smoking use.
m High incidence of cervical lymph node metastasis • A paraneoplastic syndrome occasionally may occur
warrants neck dissection even in clinically N0 in association with SCUNC and may include:
necks: m Cushing syndrome
– Nodal metastasis may be present at time of m Eaton-Lambert syndrome
presentation or subsequently develop nodal m Schwartz-Bartter syndrome
metastasis.
– Patients not undergoing surgical treatment of Pathology
the neck reported to develop isolated regional Gross
recurrence in 30% of cases • Submucosal mass usually with surface ulceration
A B
C D
Fig. 16-68. Small cell undifferentiated neuroendocrine carcinoma of the larynx.

A, Submucosal hypercellular tumor with solid, trabecular, and lobular growth. B, Small round cell malignant infiltrate
composed of hyperchromatic, round to oval to spindle-appearing nuclei with nuclear molding, inconspicuous to small
nucleoli, and increased mitotic activity. C and D, Small round cell (undifferentiated) malignant cellular infiltrate with
confluent foci of necrosis as well as individual cell necrosis with numerous mitotic figures present.
Histology • May occur in association with squamous cell carci-

• Submucosal tumor may be arranged in solid nests, noma and less often with an adenocarcinoma:
sheets, or ribbons with absence of a fibrovascular m These tumors are referred to as combined or com-
stromal component. posite tumors.

• Hypercellular with hyperchromatic, pleomorphic, • Surface ulceration often present
oval to spindle-shaped nuclei, increased nuclear-to- • Lymph-vascular and/or and perineural invasion may
cytoplasmic ratio, nondescript cytoplasm, and indis- be present.
tinct cell borders: • In combined or composite carcinoma there is
m Nuclear chromatin may vary from dispersed an admixture of small cell neuroendocrine carci-
coarse-appearing described as “salt and pepper” noma and either a squamous cell carcinoma or
to hyperchromatic. adenocarcinoma:
m Absence of nucleoli m Squamous carcinoma component includes carci-
m “Crush” artifact is frequently present. noma in situ and/or invasive squamous cell
m Confluent foci of necrosis and individual cell carcinoma.
necrosis seen m In presence of squamous differentiation a diagno-
m Abundant mitoses, including atypical forms sis of basaloid squamous cell carcinoma should
m Nuclear molding may be identified. be excluded.
• Glands and squamous differentiation rarely • Histochemistry:
present m Argyrophilia rarely present
• Neural-type rosettes rarely may be present. m Argentaffin stains usually negative
Fig. 16-69. SCUNC.

In addition to the usual morphology, other findings that
may be seen in (laryngeal) small cell undifferentiated
neuroendocrine carcinoma may include (A) prominent
Fig. 16-70. IHC in SCUNC.
spindle-shaped nuclei and (B) presence of true (neural-
type) rosettes. Immunoreactivity that can be seen in small cell
undifferentiated neuroendocrine carcinoma may include
Staining for epithelial mucin (e.g., mucicarmine,
m
(A) cytokeratin (CAM5.2) with paranuclear dot-like staining;
PAS with diastase) may be present. (B) synaptophysin.
• Immunohistochemistry:
m Cytokeratins (AE1/AE3, CAM5.2, others)
positive: Calcitonin rarely is positive.
m
– Often characterized by paranuclear (punctate) Melanocytic, hematolymphoid, and mesenchy-

m
staining pattern mal (e.g., myogenic) markers negative

– CK7 and CK20 may be positive. m In association with laryngeal SCUNC, p16, and
m High molecular weight cytokeratins, including HPV16 by PCR reported positive in a single case:
CK 5/6 and CK903 (34βE12), typically negative – Whether there is any link and/or role of high-
but may be positive and when positive is focal risk HPV in pathogenesis remains uncertain.
m Neuroendocrine markers, including synaptophy- – Whether there is any ameliorating effect
sin, CD56, neuron-specific enolase positive: of HPV on prognosis of LNEC remains
– Chromogranin may be positive but only focally uncertain.
and may be negative. m In association with oropharyngeal SCUNC, p16,
– CD57, neurofilament protein may be positive. and HPV DNA identified in majority of cases (see
– TTF1 may be positive. Section 3, Pharynx)
m Variability of p63 staining that may include focal • Electron microscopy:
to diffuse reactivity m Scanty neurosecretory granules (50 to 200 nm);
m Epithelial membrane antigen and carcinoembry- cellular junctional complexes, inter- and intracel-
onic antigen positive lular lumina are usually absent.
Differential Diagnosis Large Cell Neuroendocrine

• Poorly differentiated squamous cell carcinoma: Carcinoma (LCNEC) (Figs. 16-71
m Cytokeratin staining present but lacks punctate
and 16-72)
paranuclear staining seen in SCUNC
m High molecular weight keratins including CK5/6 Definition: Neoplasm fulfilling proposed diagnostic cri-
and CK903 (34βE12) diffusely and strongly teria for pulmonary large cell neuroendocrine carci-
positive noma, albeit in the larynx.
m p63 diffuse and strong reactivity • Relatively recently defined subtype of NEC likely
• Basaloid squamous cell carcinoma (see Table 16-4) previously subsumed within the spectrum of atypical
m In larynx also predilects to supraglottis carcinoids but distinct from atypical carcinoid histo-
m Cytokeratin staining present but lacks punctate logically and associated with poorer outcome
paranuclear staining seen in SCUNC • Within the classification of neuroendocrine carcino-
m High molecular weight keratins including CK5/6 mas, LCNEC belongs with small cell neuroendocrine
and CK903 (34βE12) diffusely and strongly carcinoma within the spectrum of poorly differenti-
positive: ated neuroendocrine carcinomas.
– SCUNC lacks such diffuse and strong staining.
m p63 diffuse and strong reactivity: Clinical
– SCUNC lacks such diffuse and strong • To date, fewer than 50 cases reported in the
staining. literature
m Absence of TTF1 contrasts with the positive • Laryngeal LCNEC:
immunohistochemical staining pattern for this m More common in men than women
marker in SCUNC. m Occur over a wide age range; average age of
• Adenoid cystic carcinoma (see Table 16-4) 59 years

• Adenosquamous carcinoma • Symptoms may include hoarseness, dysphagia, ody-
• Paraganglioma nophagia, otalgia, weight loss, heartburn (pyrosis),
• Extramedullary plasmacytoma and/or cervical adenopathy
• Metastatic small cell carcinoma of lung origin • Sites of origin include larynx > oropharynx, sinona-
• Primary laryngeal malignant melanoma and meta- sal, hypopharynx, nasopharynx:
static melanoma to the larynx m In larynx predilect to supraglottic region
m With defined criteria (see below) likely will be
Treatment and Prognosis recognized in other head and neck sites

• Preferred treatment is nonsurgical and includes • Most patients have history of heavy tobacco
chemoradiotherapy: smoking.
m Many patients have disseminated disease at pre- • No known association with HPV
sentation, obviating the option of laryngectomy
and neck dissection. Pathology
• Highly lethal tumors with aggressive malignant Histology (Table 16-8)
behavior: • Criteria for diagnosis include:
m Metastases are commonly seen to: m Presence of features of neuroendocrine differen-
– Regional lymph nodes in a majority of patients tiation including organoid nesting, trabecular
(60% to 90%) growth, rosettes, and peripheral palisading
– Liver, lung, bone, and brain m Presence of enlarged tumor cells with vesicular
• Prognosis is poor: chromatin, small to prominent nucleoli, and

m 2-year survival of 16% moderate to abundant cytoplasm
m 5-year survival of 5% m Increased mitotic activity (greater than 10 mitoses
• 5-year disease-specific survival (DSS) of 19% per 10 high-power fields [2 mm2])

• Treatment for combined or composite carcinoma is m Confirmation of neuroendocrine differentiation
same as for small cell undifferentiated neuroendo- using immunohistochemical staining for chromo-
crine carcinoma without combined squamous cell granin, synaptophysin, neuron-specific enolase,
carcinoma or adenocarcinoma. and/or neural cell adhesion molecule (CD56)
• In contrast to the relatively favorable prognosis asso- m All four of requisite criteria must be present to
ciated with HPV-associated squamous cell carcino- make a diagnosis of LCNEC.

mas of head and neck, findings of HPV-associated • Immunohistochemistry
neuroendocrine carcinomas suggest aggressive m Reactivity for cytokeratin (AE1/AE3):
behavior despite association with HPV. – CK5/6 and 34βE12 typically negative
A B
C D
Fig. 16-71. Laryngeal large cell neuroendocrine carcinoma.

The histologic findings seen in large cell neuroendocrine carcinoma of the larynx include (A and B) presence of features of
neuroendocrine differentiation including organoid, cell nest, and/or trabecular growth. C and D, Presence of large lesional
cells vesicular chromatin, identifiable nucleoli, and moderate to abundant cytoplasm as well as increased mitotic activity
(overall greater than 10 mitoses per 10 high-power fields [2 mm2]. (Unstained slides provided by James Lewis Jr., MD.)
m Neuroendocrine markers (chromogranin, synap- – Absence of p53 overexpression

tophysin, and CD56) positive – 83% 5-year survival as compared with <21%
m Calcitonin and thyroid transcription factor 1 5-year survival in LCNEC
typically negative
m Increased proliferation rates by Ki67 (MIB1) Treatment and Prognosis
staining typically >20% • Preferred treatment is nonsurgical and includes
m p53 overexpression chemoradiotherapy:
m Many patients have disseminated disease at pre-
Differential Diagnosis sentation, obviating the option of laryngectomy

• Atypical carcinoid (AC): and neck dissection.
m Lacks increased mitotic rate, Ki67 labeling • Commonly present with advanced stage (stages III
indices, p53 immunoreactivity, and low 5-year and IV):
survival rates associated with LCNEC: m May be metastatic to cervical lymph nodes at
– Mitotic activity in AC less than 10 mitoses per presentation

10 high-power fields m May be metastatic to distant sites at presentation
– Ki67 indices in AC less than 20% (more on (e.g., liver)

order of less than 10%) • 5-year disease-specific survival (DSS) of 15% to 21%
A B
C D
Fig. 16-72. IHC reactivity in laryngeal large cell neuroendocrine carcinoma.

Confirmation of neuroendocrine differentiation by immunohistochemical staining includes reactivity for (A) synaptophysin,
(B) chromogranin (focal positive cells), and (C) CD56. D, In addition, cytokeratin (CAM5.2) with paranuclear dot-like staining
is also present. (Unstained slides provided by James Lewis Jr., MD.)
LARYNGEAL MUCOSAL m In the upper aerodigestive tract, the most common

MALIGNANT MELANOMA site of occurrence is the sinonasal tract.
m Primary laryngeal mucosal malignant melanomas
See illustrations under mucosal malignant melanoma of (PLMMM) are rare with fewer than 60 cases
the sinonasal tract. reported in the world literature.
Definition: Neural crest-derived neoplasms originat- m Metastasis to mucosal site must be excluded
ing from melanocytes and demonstrating melanocytic prior to diagnosing primary mucosal malignant
differentiation. melanoma.
Clinical Primary Laryngeal Mucosal Malignant

• Approximately 15% to 20% of all malignant mela- Melanoma (PLMMM)
nomas arise in head and neck sites, and of these more • Much more common in men than in women, with
than 80% are of cutaneous origin; of the approxi- more than 80% of cases occurring in men; occur
mate remaining 20%, the majority are of ocular over a wide age range from 35 to 86 years of age,
origin. with an average age of 58 years, and are most fre-
• Mucosal malignant melanomas (MMM) of the upper quent in the sixth and seventh decades of life
aerodigestive tract represent from 0.5% to 3% of • Most cases occur in Caucasians but blacks are also
melanomas of all sites: affected.
including black, brown, red-pink, tan-gray, and

TABLE 16-8 Pathologic Criteria for Large Cell
Neuroendocrine Carcinoma of the Larynx white
• Range in size from 3 to 4 mm up to 8.0 cm in great-
Requisite Criteria* Other Typical Features
est dimension
Tumor cells with moderate to Nuclei with prominent
abundant cytoplasm nucleoli Histology
Features of neuroendocrine Cellular pleomorphism • Infiltrative tumors composed of epithelioid cells,
differentiation (organoid nesting,
spindle-shaped cells, or an admixture of cell types
trabecular growth, rosettes, and
peripheral palisading) • Epithelioid MMM:
m Growth patterns vary and include solid, organ-
Mitotic activity > 10/10 hpf Large areas of necrosis
(2 mm2) oid, nested, trabecular, alveolar, or any combina-
tion of these patterns.
Confirmation of neuroendocrine
m Cells are round to oval, tend to be markedly
differentiation using
immunohistochemical staining pleomorphic with increased nuclear-cytoplasmic
for chromogranin-A, ratio, vesicular to hyperchromatic nuclei, promi-
synaptophysin, neuron-specific nent eosinophilic nucleoli, and eosinophilic to
enolase, and/or neural cell
adhesion molecule (CD56) clear-appearing cytoplasm.
m Nuclear pseudoinclusions and nuclear molding
*All four requisite criteria must be present. are present.
From Lewis J, Spence DC, Chiosea S, et al: Large cell
m Epithelioid cells may have plasmacytoid features
neuroendocrine carcinoma of the larynx: definition of an entity,
Head Neck Pathol 4:198-207, 2010. with eccentric located nuclei and an eosinophilic
cytoplasm; a paranuclear clear zone is not
seen.
• Majority (more than 60% of case in which the site • Spindle MMM
is documented) occur in the supraglottic larynx, m Growth patterns include storiform or fascicular.
including the epiglottis, arytenoids, aryepiglottic m Cells are oblong to cigar-shaped, markedly pleo-
folds, ventricle, false vocal cord, and piriform fossa morphic, with large vesicular to hyperchromatic
m Other less common sites of occurrence include nuclei, absent to prominent nucleoli, and scant
the glottic region along the true vocal cord and eosinophilic cytoplasm.
the posterior commissure. m Spindle cells may have an associated myxoid
m To date, no documented reports involve the sub- stroma.

glottic region. m Tumors with mixed epithelioid and spindle cells
• Clinical presentation includes hoarseness, dysphagia, can be seen.

sore throat, intermittent hemoptysis, neck or jaw • For epithelioid and spindle cell MMM, necrosis and
pain, and a cervical neck mass: increased mitoses with atypical mitotic figures are
m Symptoms generally occur over short periods of common findings; uncommon features include neo-
time, ranging from 3 to 6 months. plastic giant cells and glandular and squamous
• Multicentric (synchronous, metachronous) MMM differentiation.
of other upper aerodigestive tract sites are not typi- • Intracytoplasmic melanin may be present but often
cally present. melanin pigment is not readily identifiable:
• No known etiologic factors: m May demonstrate presence of heavy melanin
m Occur in patients who smoke tobacco and/or deposition but approximately one third of
drink alcohol but no definitive link to these risk cases have focal, weak pigmentation or are
factors nonpigmented.
m Melanosis, intralaryngeal nevi, and lentigo of the m When present, intracytoplasmic melanin is
larynx have been reported; given the development usually found in scattered cells.
of cutaneous malignant melanomas from con- • In the presence of an intact surface epithelium, con-
genital melanocytic nevi and intradermal nevi, it tinuity of the tumor with the surface epithelium (i.e.,
is possible to suggest that PLMMM may arise junctional or pagetoid changes) can be identified;
from malignant transformation of intralaryngeal however, even in the presence of intact surface epi-
melanocytes or melanocytic lesions. thelium, junctional changes may not be seen:
m Given the fact that normal melanocytes may
Pathology localize to the submucosal compartment within
Gross minor salivary glands or within the stroma, junc-
• Nodular, mulberry-like, sessile, polypoid, exophytic, tional change is not required to render a diagnosis
or pedunculated lesions with equally variable color, of MMM.
• Histochemistry: lymph-vascular space invasion, and metastatic

m Argentaffin (Fontana stain) and argyrophilic disease (regional and distant).
(Churukian-Schenk stain) positive
m Intracytoplasmic diastase-sensitive, periodic acid
Schiff material indicative of glycogen can be NONEPITHELIAL MALIGNANT

seen. NEOPLASMS OF THE LARYNX
m Mucin is absent.
• Immunohistochemistry: • Nonepithelial malignant tumors of the larynx and

m S100 protein positive trachea are rare and include sarcomas and hemato-
m Melanocytic markers including HMB-45, melan- lymphoid malignancies.
A, tyrosinase, MiTF, Sox10 positive • In the larynx, most common sarcoma is chondrosar-
m Vimentin positive coma (see below).
m Epithelial, neuroendocrine, and hematolymphoid • Other sarcomas that may arise in the larynx and
markers are negative. trachea include:
m Desmin, actins, myogenin, and myoglobin are m Synovial sarcoma
negative. m Liposarcoma (see below)
• Electron microscopy: m Rhabdomyosarcoma
m The ultrastructural findings of malignant mela- m Leiomyosarcoma
noma include the presence of organelles charac- m Angiosarcoma
teristic of melanocytic differentiation; the latter m Malignant peripheral nerve sheath tumor
include melanosomes and premelanosomes, both m Undifferentiated pleomorphic sarcoma
of which are membrane-limited vesicles with dis- m Fibrosarcoma
tinctive internal structure varying from parallel m Osteosarcoma
lamellae to helical to zigzag structures with a m Others
periodicity of 8 to 10 nm. • Malignant lymphomas of the larynx and trachea are

rare and include:
Differential Diagnosis m Non-Hodgkin lymphomas:
• Squamous cell carcinoma – Most are B-cell lymphomas including diffuse

• Spindle cell squamous carcinoma large B-cell lymphoma and extranodal mar-
• Neuroendocrine carcinoma ginal B-cell lymphoma of the MALT type
• Inflammatory myofibroblastic tumor – Rarely peripheral T-cell lymphomas and NK/T-
cell lymphoma of nasal-type
Treatment and Prognosis m Plasmacytoma
• Radical surgical excision is the preferred treatment. m Hodgkin lymphoma
• Adjuvant radiotherapy and chemotherapy of ques-

tionable value Chondrosarcoma
• Poor prognosis:
m 5-year survival rate of less than 20%
• Approximately 80% of patients with PLMMM Definition: Malignant tumor of cartilage.

have metastatic disease to the regional lymph
nodes as well as to distant viscera (e.g., brain, Clinical
lungs, bone). • In general, rare neoplasm in all head and neck
• Pathologic criteria that are used to predict the bio- sites
logic behavior in association with cutaneous mela- • Represents most common nonepithelial malignancy
nomas, including the depth of invasion, age and of the larynx, accounting for 75% of all sarcomas
gender of the patient, and cytomorphology, generally of this region, but only represents approximately 1%
do not apply for PLMMM; in addition: of all laryngeal tumors:
m In some studies prognostic significance has not m Other sites of involvement include mandible,
been found for tumor thickness, level of invasion, maxilla, maxillofacial skeleton (nose and parana-
ulceration, mitotic index, or nerve/nerve sheath sal sinuses), nasopharynx.
involvement for MMM. m See Section 2, Oral Cavity, for discussion of
m Other studies have shown significant adverse gnathic chondrosarcomas including mesenchy-
prognostic factors for disease-specific survival for mal chondrosarcoma.
MMM of the head and neck linked to advanced • More common in men than women; may occur over
clinical stage at presentation, tumor thickness a wide age range but most often occur in the sixth
of greater than 5 mm, histologically proven through ninth decades of life
A B
C D
E F
Fig. 16-73. Chondrosarcoma of the larynx.

A, Endoscopic view shows a large bulge in the region of the cricoid (C). Note that the mucosa is intact and is not
ulcerated. B, T1-weighted image shows the large submucosal mass (arrowhead). Note its position in the posterior larynx.
There is no abnormality in the paraglottic fat (arrow). C, Slightly lower than B. Axial image through the cricoid cartilage
shows a well-defined defect (arrowhead). The sharp margin would be unusual in invasion by squamous carcinoma. This
indicates the origin within the cricoid cartilage. D, T2-weighted axial image shows the tumor (T) to have the high signal
characteristic of chondrosarcoma. E, Axial CT shows a large mass with small punctate calcifications (arrowheads). This
suggests the chondroid nature of the lesion. F, Axial scan through the cricoid shows the sharp margin of the lesion
(arrowheads) as it abuts the normal cartilage. (From Som PM, Curtin HD: Head and neck imaging, ed 5, Philadelphia, 2011, Elsevier,
Figure 31-87, p 1978.)
MRI: delineates the extent of invasiveness and/or

m
tumor boundaries
• No definitive cause and no link to pre-existing
chondroma.
Pathology
Gross
• Bulky tumors that distort site of origin
• On cut section these tumors are solid with a smooth
and lobulated appearance, are firm to hard consis-
tency, are gray to white, and often measure greater
than 2 cm in diameter.
• Degenerative changes may result in cyst forma-
tion, soft areas, and myxoid or gelatinous appear-
ance.
• Fleshy appearance may indicate foci of dedifferen-
tiation.
Histology
• Graded as low-grade or high-grade lesions based on
the degree of cellularity, pleomorphism, multinucle-
ated cells, and mitoses:
m Most laryngeal chondrosarcomas are histologi-
cally low grade.

• At low magnification appear lobulated with irregular
borders:
m Invasive growth into adjacent structures can be
seen.
• Majority are histologically low-grade that in com-
parison with chondromas show:
m Increased cellularity
Fig. 16-74. Laryngeal chondrosarcoma.
m Nuclear hyperchromasia
Laryngeal chondrosarcoma appearing as smooth, lobulated, m Nuclear pleomorphism
glistening mass arising from the cricoid cartilage. m Binucleate or multinucleate cells
m Mitoses are uncommon and necrosis is typically
• Most common site in the larynx is anterior surface absent.

of the posterior lamina of the cricoid cartilage: • High-grade chondrosarcomas are less common:
m Less often arises in the thyroid cartilage and m Retaining overall lobular configuration although
arytenoids: may only be focally identified

– Predominantly occur in ossified hyaline m Histologically readily apparent as malignant
cartilages based on the presence of hypercellularity, marked
– Nearly all cases arise from hyaline rather than nuclear pleomorphism with bizarre cells, pres-
elastic cartilage. ence of prominent nucleoli, increased mitotic
• Clinical presentation includes hoarseness, airway activity, and necrosis.
obstruction, and dyspnea. • In all histologic grades, ossification and/or calcifica-
m Vocal cord paralysis may be present. tion of hyaline cartilage may be present.
m Involvement of the thyroid lamina may result in • Can be diagnosed on biopsy but must adhere to strict
the presence of a neck mass. histologic criteria and clinical/radiologic correlation
m Typically are submucosal appearing endoscopi- recommended
cally as a subglottic swelling with overlying intact • Other histologic subtypes may include clear cell
mucosa chondrosarcoma and dedifferentiated chondrosar-
• Radiology: coma:
m CT scan: circumscribed, hypodense mass with m Clear cell chondrosarcoma:
stippled to coarse calcifications resulting in – Characterized by chondrocytes with clear cyto-

expansion of the affected cartilage plasm and distinct cell membranes
A C
D E
Fig. 16-75. Low-grade laryngeal chondrosarcoma.

Laryngeal chondrosarcoma, low-grade (A) lobulated cartilaginous lesion showing increased cellularity; (B) occurrence of
chondrosarcoma in hyaline cartilage with associated ossification and calcification (arrows) is a frequent finding; note the
increased cellularity; (C and D) varying degree of increased cellularity may be present but the presence of binucleate
chondrocytes (arrows) and nuclear pleomorphism and hyperchromasia (arrowheads) is a feature of low-grade
chondrosarcoma. These overall findings contrast with those of chondroma, which generally lacks increased cellularity and
atypical chondrocytes, but in any given case differentiating low-grade chondrosarcoma from chondroma can be extremely
difficult. Lesional cells are immunoreactive for (E) S100 protein and
Continued
Typically, chondromas are small, measuring less

m
than 1 to 2 cm
m Histologically are characterized by the presence
of scattered chondrocytes without nuclear atypia,

hyperchromasia, binucleate, or multinucleate
cells or mitoses.
m S100 protein and podoplanin (D2-40) positive
m Any purportedly recurrent chondroma likely rep-
resents a chondrosarcoma.
• Chondromatous metaplasia/hamartoma (chondro-
metaplasia):
m May present as a nodular mass of the larynx
associated with progressive dysphonia, dyspnea,

and dysphagia
F m History of laryngeal trauma
m CT scan shows a rounded and circumscribed mass
Fig. 16-75, cont’d without infiltration of the surrounding tissues.

m Histologically characterized by the nodular fibro-
(F) podoplanin (D2-40). elastic cartilaginous tissue surrounded by a thin
rim of fibrous tissue; rare hypercellular areas and
occasional binucleated cells with slight hyper-
chromasia and irregular nuclear profiles may be
seen but mitotic activity was absent
m History of laryngeal trauma with the subsequent
progressive onset of clinical symptoms helps to

distinguish the chondrometaplastic nodule from
true laryngeal cartilaginous tumor (e.g., chon-
droma and chondrosarcoma).
• Chordoma

• For laryngeal chondrosarcoma treatment includes
wide local (conservation) excision:
m Conservative (organ sparing) surgery if feasible is
recommended:
Fig. 16-76. Laryngeal chondrosarcoma, high grade.
– Endoscopic resection can be used for managing
Left, Markedly cellular chondroid neoplasm. Right, selected newly diagnosed cases of cricoid
the tumor is composed of pleomorphic cells with chondrosarcoma.
hyperchromatic, pleomorphic nuclei, prominent nucleoli, – Organ preservation surgery represents a treat-
multinucleated cells, and mitoses. ment option.
m Total laryngectomy recommended in presence of
high-grade histology, in presence of extensive

Dedifferentiated chondrosarcoma:
m cricoid involvement, and/or when conservative
– Characterized by the presence of an admixture surgery is not possible
of differentiated chondrosarcoma with high- • Radiotherapy and chemotherapy not demonstrated
grade, noncartilaginous sarcoma to be effective therapeutic modalities
• Immunohistochemistry (all types): • In general, cure is achieved following complete exci-
m Vimentin and S100 protein positive sion of the tumor
m Podoplanin (D2-40) positive m Local recurrence occurs in approximately 25% of
cases and can be managed by additional (defini-

Differential Diagnosis tive) surgery.
• Chondroma: m Recurrence is associated with incomplete excision
m May be extremely difficult to differentiate from and may occur years after initial diagnosis:
low-grade chondrosarcoma – Long-term follow-up advised
Distant metastases are uncommon but can occur

m m Myxoid/round cell liposarcoma
(lungs). m Pleomorphic liposarcoma (PL)
– Presence of higher-grade morphology and/or
dedifferentiation more likely to be associated Atypical Lipomatous Tumor/Well-Differentiated
with metastasis Liposarcoma (ALT/WDS)
• 1-year, 5-year, and 10-year disease-specific survival • Most common morphologic type (30% to 40%) in
reported as 96.5%, 88.6%, and 84.8%, respectively late adult life
m Most common morphologic type in relationship
to upper aerodigestive tract liposarcomas

Liposarcoma (Figs. 16-77 through 16-82) • Often diagnosed as lipoma due to its bland histology
Definition: Malignant tumor of adipocytes. and only following one or more recurrences is a
• Arise from primitive mesenchymal cells rather than diagnosis of liposarcoma rendered.
mature adipose tissue, accounting for its presence in • Histologically resembles a lipoma except for:
areas relatively devoid of fat (e.g., head and neck) m Greater variation in the size and shape of the
adipocytes
Clinical m Presence of scattered lipoblasts:
• Represent 15% to 25% of all sarcomas – Absence of lipoblasts does not preclude a diag-
• Approximately 3% to 6% occur in head and neck: nosis of well-differentiated liposarcoma.
m In head and neck the most common sites of m Absence of encapsulation
occurrence include the larynx and hypopharynx • Term atypical lipoma or atypical lipomatous tumor
followed by the neck. has been used for superficial (cutaneous or subcuta-
• For laryngeal and hypopharyngeal liposarcoma: neous) lipogenic tumors with histologic appearance
m Tends to affect men more than women; occur of well-differentiated liposarcomas that have a ten-
over a wide age range but are most common in dency to recur.
the sixth and seventh decades of life m Use of this terminology should be viewed with
• For neck liposarcomas: caution in those well-differentiated liposarcomas

m No gender predilection; occur over a wide age occurring in more vital areas (deep neck, naso-
range but usually occur in younger ages (approxi- pharynx, sinonasal cavity, larynx, and hypophar-
mately a decade younger) than non–head and ynx) where inadequate excision and subsequent
neck liposarcomas recurrence may result in increased morbidity and
• Symptoms vary per site of involvement and size of mortality.
the tumor: m Use of well-differentiated liposarcoma rather
m Larynx: hoarseness, dysphonia, dysphagia, than atypical lipoma should convey to the surgeon
airway obstruction that the neoplasm requires complete resection in
m Pharynx: dysphagia and airway obstruction as conservative a manner as to ensure tumor-free
m Neck: slowly growing painless mass margins and not just simple excision.
• Arise de novo; rarely originate from a pre-existing
lipoma Dedifferentiated Liposarcoma (DL)
• No known associated etiologic factors • Histologic progression of ALT/WDL to a higher-
grade, less well-differentiated neoplasm in:
Pathology m Primary (de novo) neoplasm (90%)
Gross m Recurrent neoplasm (10%)
• Circumscribed and/or encapsulated, lobulated mass • High-grade component usually is nonlipogenic and
varying in appearance from yellow to tan-white and only rarely is lipogenic.
with a myxoid or gelatinous appearance • Accounts for 18% of all liposarcomas
• Although liposarcomas can attain very large sizes, • Most common site of occurrence is retroperitoneum
those identified in the head and neck rarely exceed ≫> extremities
10 cm and are generally under 5 cm in greatest • Less than 20% occur in H&N (and other) sites
dimension. • Histology:
m In approximately 90% dedifferentiated compo-
Histology nent has appearance of high-grade fibrosarcoma

• WHO classification includes: or undifferentiated pleomorphic sarcoma
m Atypical lipomatous tumor/well-differentiated – Display range of subtypes including:
liposarcoma (ALT/WDL) ■ Most common: storiform-pleomorphic and
m Dedifferentiated liposarcoma (DL) myxoid forms
A C
Fig. 16-77. Laryngeal liposarcoma.

A, Laryngeal liposarcoma appearing as a circumscribed polypoid, pedunculated mass. B, Resected hypopharyngeal
liposarcoma with characteristic yellow appearance. C and D, This patient had a large hypopharyngeal-based mass that he
was capable of “bringing up” at will; the tumor was excised via a lateral pharyngotomy approach.
C D
E F
Fig. 16-78. Laryngeal well-differentiated liposarcoma.

Laryngeal atypical lipomatous neoplasm/well-differentiated (lipoma-like) liposarcoma. A, Submucosal (surface squamous
epithelium in lower left) adipose tissue proliferation composed of nests of fat cells separated by fibrous septa.
B, Adipocytes show variation in size and shape. C and D, Multivacuolated lipoblasts. Immunohistochemical staining
assists in the diagnosis with reactivity for (E) MDM2 and (F) CDK4. These markers are absent in lipomas.
A B
C D
E F
Fig. 16-79. Dedifferentiated liposarcoma.

A, Cervical neck dedifferentiated liposarcoma showing transition or interface between atypical lipomatous tumor/well-
differentiated liposarcoma (bottom half) and dedifferentiated zone (top half). B, Area showing appearance of fibrosarcoma.
C and D, Areas resembling undifferentiated pleomorphic sarcoma. The presence of immunoreactivity for (E) MDM2 and
(F) CDK4 supports a diagnosis of dedifferentiated liposarcoma and allows for differentiation from other sarcomas (e.g.,
fibrosarcoma, undifferentiated pleomorphic sarcoma).
C D
Fig. 16-80. Laryngeal myxoid and round cell liposarcoma.

Cellular myxoid lesion with plexiform capillary pattern plexiform vascularity with a delicate arborizing (capillary-like) pattern
and lipoblasts in varying stages of development including signet-ring appearance. Myxoid liposarcoma is typically negative
for MDM2 and CDK4.
■ Less common: giant cell and inflammatory • Most common in lower extremity (75% of cases):
forms m Medial thigh > popliteal area
m In approximately 10% may resemble low-grade m Less commonly occurs in retroperitoneum
fibrosarcoma or fibromatosis m Rare in head and neck
• Myxoid liposarcoma characterized by:

Myxoid Liposarcoma m Lobular or nodular growth
• Continuum of lesions that include differentiated m Uniform round to oval mesenchymal

myxoid tumors with lipoblastic differentiation to (nonlipogenic-appearing) cells
poorly differentiated round cell tumors with incon- m Variable numbers of signet ring lipoblasts are
spicuous lipoblastic differentiation; included in this present:

category are lesions previously referred to as round – Usually readily identifiable
cell liposarcoma. – May be most prominent at periphery of
• Represents one third to one half of all liposarcomas nodules
• Occurs in younger age group than ALT/WDL m Prominent myxoid stroma rich in glycosamino-
and DL: glycans or hyaluronidase-sensitive acid

m Peak incidence in fifth decade of life m Mucopolysaccharides
A B
C D
Fig. 16-81. Laryngeal myxoid and round cell liposarcoma.

Laryngeal myxoid/round cell liposarcoma. A and B, Transition from myxoid area (left) to cellular area composed of round
cells. C and D, Densely cellular proliferation solid sheets of primitive round cells with hyperchromatic nuclei, enlarged
nucleoli, increased nuclear-to-cytoplasmic ratio, vacuolated-appearing cytoplasm, and increased mitotic activity (arrows).
Myxoid/round cell liposarcomas are typically negative for MDM2 and CDK4.
m Delicate plexiform capillary vascular pattern – Cellular component typically lacks nuclear
present: pleomorphism, significant mitotic activity, or
– Represents an important diagnostic clue tumor giant cells.
– Assists in differentiating from benign tumors – Extracellular mucin pools or lakes creating a
(e.g., myxoma, others) lymphangioma-like appearance can be identified.
A B
Fig. 16-82. Cervical neck pleomorphic liposarcoma.

A, Cellular tumor composed of spindle and multinucleated giant cells. B, Left, markedly pleomorphic cells with
cytoplasmic vacuolization; right, extra- and intracellular eosinophilic hyaline globules. C, Multivacuolated lipoblast (arrow).
Pleomorphic liposarcomas are typically negative for MDM2 and CDK4.
– Cartilaginous, osseous, leiomyomatous differ- – Further support of this consideration is the

entiation may occur; rarely, rhabdomyosarco- presence of shared chromosomal aberrations
matous differentiation may be present. (see below).
• Round cell liposarcoma:
m Represents poorly differentiated form of myxoid
liposarcoma characterized by the presence of: Pleomorphic Liposarcoma

– Densely cellular proliferation solid sheets of • High-grade sarcoma composed of:
back-to-back primitive round cells with hyper- m Variable numbers of pleomorphic lipoblasts char-
chromatic nuclei, prominent nucleoli, increased acterized by spindle and giant cells with one or
nuclear-to-cytoplasmic ratio, and granular to more enlarged hyperchromatic nuclei scalloped
vacuolated-appearing cytoplasm by cytoplasmic vacuoles
– Increased mitotic activity as well as necrosis m Cytoplasmic vacuoles contain lipid droplets.
and hemorrhage are present. m Majority of tumors have fascicles of spindle-
– Sparse to absent intervening myxoid, fibrillar, shaped cells and smaller, round cells admixed
or myxomucinous stroma with multinucleated giant cells resembling such
– Plexiform capillary vascular pattern present tumors as undifferentiated pleomorphic sarcoma,
but generally compressed by the cellular as well as the pleomorphic lipoblasts
proliferation m Limited lipoblastic features may be present.
m Presence of transitional areas from myxoid to m Prominent cytoplasmic eosinophilia may be

hypercellular round cell supports contention that present and in the presence of limited lipoblastic
myxoid and round cell liposarcomas represent a findings may suggest a diagnosis of rhabdomyo-
histological continuum of myxoid liposarcomas: sarcoma.
m Extra- and intracellular eosinophilic hyaline glob-

ules may be identified and likely represent lyso- General Histologic Considerations
somal structures. • Lipoblasts:
m Absence of areas of ALT/WDL or other line of m Neoplastic cell recapitulates differentiation
differentiation cascade of normal fat:
m Epithelioid variant: – Hyperchromatic indented or scalloped nucleus
– Predominantly composed of solid, cohesive – Lipid-rich droplets in cytoplasm
sheets and clusters of epithelioid cells with – Appropriate histologic background
round to oval nuclei, prominent nucleoli, m Importance overemphasized
eosinophilic cytoplasm, and distinct cell m Few present in ALT/WDL:
borders – Pattern and cellular components more

– Focally, lipogenic differentiation in the form of important
pleomorphic lipoblasts is present. m Simulators of lipoblasts:
– Often associated with a higher mitotic rate – Reactive changes (fat necrosis; atrophy; foreign
than is seen in association with pleomorphic body reaction)
(nonepithelioid) liposarcoma. – Fixation artifact
• Tumor necrosis is present in all morphologic types – Signet ring cells in other neoplasms
of pleomorphic liposarcoma. • Mitoses, necrosis, and hemorrhage can be identified
in all histologic variants and generally correlate to
Mixed Type Liposarcoma the amount of cellular pleomorphism (mitoses are
• Extremely rare, representing approximately 5% (or particularly prominent in the pleomorphic variant).
less) of all liposarcomas • Histochemistry:
• Primarily occur in retroperitoneum m Special stains are of little if any assistance in
• Histologically defined by the presence of combined: diagnosis.

m Classic WDL associated with classic pleomorphic • Immunohistochemistry:
liposarcoma m Adipocytes and lipoblasts variable S100 protein
m ALT/WDL with myxoid/round cell and well- immunoreactive

differentiated/dedifferentiated liposarcoma m Vimentin positive
m Myxoid/round cell and pleomorphic liposar- • Cytogenetics and immunohistochemistry:

coma m ALT/WDL:
• Molecular testing has allowed for classification of – Characterized by giant marker and ring
some of these mixed-type liposarcomas within one chromosomes:
of neoplasm within current WHO classification. ■ Contain amplified sequences 12q13-15, site
of several genes (MDM2, CDK4, others)

Spindle Cell Liposarcoma ■ MDM2 (and HMGA2) consistently
• Considered to represent rare atypical/low-grade amplified
malignant lipogenic neoplasm regarded as a variant ■ CDK4 co-amplified in approximately 90%
of atypical lipomatous tumor – MDM2 and CDK4

• Tends to occur in subcutaneous tissue of the extremi- ■ IHC:
ties, trunk, and head and neck region □ MDM2 and CDK4 detected in majority of
• Histologically, variably cellular neoplasms composed ALT/WDL: (nuclear staining) is a reason-

of atypical lipogenic cells showing variations in size able first tool in diagnosis
and shape, and spindled tumor cells with slightly ■ FISH:
enlarged, often hyperchromatic nuclei: □ Highly sensitive and specific
m Multivacuolated lipoblasts may be present. □ Superior to immunohistochemistry
m Focal myxoid stromal changes may be present. □ Small false-positive rate
• Immunohistochemically: ■ Absent in lipomas
m CD34 at least focally positive ■ Small percentage of spindle cell/pleomorphic
m Only scattered cells in limited cases may show lipoma express MDM2 and CDK4
nuclear expression of MDM2. ■ Recommendation for use:
m FISH analysis negative for MDM2/CDK4 □ Lipomatous tumors with equivocal cyto-
amplification logic atypia

• Based on clinicopathologic and molecular findings □ Recurrent lipomas
may represent atypical/low-grade counterpart of □ Deep lipomas with atypia >15 cm
spindle cell lipoma rather than morphologic variant □ Retroperitoneal and intra-abdominal
of ALT/WDL tumors without atypia
m Dedifferentiated liposarcoma: • Recurrence is common:

– Share similar findings as ALT/WDL although m Generally occurs within 3 years after the initial
display more extensive chromosomal treatment

abnormalities m Usually same histology as the primary tumor but
■ 12q13-15 amplifications more complex than may “dedifferentiate” with a histologic appear-
in ALT/WDL ance less differentiated and with a more aggres-
– IHC: sive biology than the primary tumor.
■ MDM2 and CDK4 reactivity • Nodal metastasis rare and neck dissection generally
m Myxoid and round cell liposarcoma: not indicated
– Characterized by reciprocal t(12;16)(q13;p11) • Distant metastasis may occur and are more common
translocation: with the higher-grade histologic variants:
■ Present in more than 90% of cases m Metastases occur to the lungs, bone, and
■ Results in fusion of the DDIT3 gene on liver.
chromosome 12 with FUS gene on chromo- • 5-year survival rate for all liposarcomas of the head
some 16: and neck approximately 67%
□ Presence of FUS/DDIT3 fusion sensitive • 5-year survival rates influenced by histologic
and specific for myxoid liposarcoma type:
■ Chimeric FUS-DDIT3 gene results in 3 m Well-differentiated:
fusion transcripts: – 85% to 100% 5-year survival

□ Type II identified in most myxoid/round m Myxoid:
cell liposarcomas – 71% to 95% 5-year survival

– Staining for MDM2 and CDK4 typically m Round cell:
negative – 12.5% to 55% 5-year survival

m Pleomorphic liposarcoma: m Pleomorphic:
– Various chromosomal gains and losses – 0 to 45% 5-year survival

– Dysregulation of several tumor suppressor • In addition to histologic type, other factors impor-
pathways common tant in prognosis include:
– No amplification of 12q14-15 region m Size of the tumor
– Staining for MDM2 and CDK4 typically m Location of the tumor:
negative – Laryngeal/hypopharyngeal and facial tumors

have the best prognosis.
– Mouth and pharynx have the worst
Differential Diagnosis prognosis.
• Lipoma • Controversy exists as to the issue of multicentric
• Myxoma (intramuscular; nerve sheath) occurring liposarcomas vs. metastatic liposarcoma:
• Other sarcomas: m Presence of clonality in multifocal myxoid lipo-
m Rhabdomyosarcoma sarcoma supportive of metastasis rather than

m Undifferentiated pleomorphic sarcoma multifocal tumor
m Myxoid chondrosarcoma
m PNET/Ewing sarcoma
• Chordoma
• Signet ring cell carcinoma or lymphoma SECONDARY TUMORS
• Malignant melanoma
• Metastatic tumors to the larynx and trachea are
rare.
Treatment and Prognosis • Most common tumor types to metastasize to this
• Wide local surgical excision is the preferred treat- region include malignant melanoma and various car-
ment to include tumor-free margins. cinomas including those originating from the kidney,
m More aggressive surgical procedures may be indi- breast, lung, prostate, gastrointestinal tract (e.g.,
cated for the other histologic variants. colon, stomach); less frequently, metastasis may orig-
• Utility of radiotherapy remains controversial, but inate from the female genital tract, kidney, thyroid
evidence supports the use of postoperative radio- gland, and other sites.
therapy as an adjunct to surgery: • In the larynx, most common site of metastasis is
m In cases in which the tumor cannot be completely supraglottis followed by the subglottis:
resected m Supraglottis and less so the subglottis are
m In cases in which surgical margins are close richly vascularized as compared with the glottic
region, accounting for the greater incidence of • Metastasis to the larynx and trachea often occurs in
metastasis to the supraglottic and subglottic the setting of disseminated disease in terminal or
larynx. near-terminal patients.
• Symptoms vary per site of involvement:
m Larynx: hoarseness, dysphagia, and/or pain
FURTHER READING
m Trachea: cough, dyspnea, stridor, and hemoptysis
• Metastasis usually localizes to the submucosa or to References may be accessed online at ExpertConsult
cartilage that has undergone ossification. .com.
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Chapter

Neoplasms of the Larynx

BOX 16-1 Classification of Laryngeal and Tracheal Neoplasms

Benign • Verrucous carcinoma

epithelial origin: tumors:

m Most common malignant neoplasm is squamous hemangioma, granular cell tumor

BENIGN NEOPLASMS OF THE LARYNX AND HYPOPHARYNX

m Number of lesions: solitary versus multiple

m Histology: nonkeratinizing and keratinizing

Fig. 16-2. Recurrent respiratory (laryngeal)

– Although not universally accepted, 20 years

(e.g., hoarseness). where ciliated respiratory epithelium meets

B Fig. 16-5. Malignant transformation.

• Cause: – Rarely, HPV 16, 18, 31, 33, and 35

(1) first-born child, (2) vaginal delivery, and

has been advocated in this clinical setting but

delivery with the virus remaining dormant

TABLE 16-1 Laryngeal Papillomas: Clinical-Pathologic Features

JO-RRP AO-RRP Keratinizing Papilloma

mRNAs by underlying vascular endothelial cells,

m Infrequently occurs in mucosal sites, including

epithelium containing fibrovascular cores – HPV 2 and 4 typically associated with VV of

plastic lesion or carcinoma is low. skin and includes:

papillomatosis or may in fact represent an exo- m Recurrence may rarely occur.

phytic squamous cell carcinoma. • Verrucous carcinoma

m In situ hybridization for angiogenic growth factor m Voice preservation

thelium of squamous papillomas in RRP, as well disease eradication

– Tracheotomy may be required to maintain a respiratory tract parenchyma is associated with

imately one third of patients. posed infection, and malignant transformation.

• Complications of surgery may include: nonirradiated patients is 2%.

m Scarring irradiated patients is 14%.

m Arytenoid fixation squamous cell carcinoma.

ciated complications, including: noma may:

term and repeated management: result in loss of HPV expression.

m HPV can be identified in nonpapillomatosis larynx or in the lung.

75% of patients: (i.e., in nonirradiated patients) tend to:

dictable nature of recurrent tumor: patients tend to:

multiple operative procedures. and nonsmoking patients tend to:

■ Malignant transformation not reported to be

parameters and an anatomic assessment of A

tion with the functional score to measure

Keratinizing Papilloma (Papillary

Pathology Dysplasia can be seen ranging from mild to mod-

Gross erate to severe and should be reported as such

to diagnose dysplasia because laryngeal papillo-

Treatment and Prognosis

m Various designated oncocytic cyst, oncocytic pap-

that may occur in mucosa of upper aerodigestive

Fig. 16-9. Laryngeal IMT.

4 months traumatic intubation), human herpesvirus-8

Fig. 16-10. Myofibroblasts in IMT.

Fig. 16-11. Immunohistochemistry of IMT.

myxoid to fibromyxoid stroma, prominent vascular- epithelioid or histiocytoid, including round to

inapparent nucleoli, and long cytoplasmic exten- • Histochemistry:

(tadpole-like) appearance. • Immunohistochemistry:

a low nuclear-to-cytoplasmic ratio. vimentin

eosinophilic inclusions: typically present but may vary from focal to

tologic findings associated with IMT m CD68 may be focal in histiocytic-appearing

present typically absent but staining for cytokeratins may

Inflammatory Cells ■ Imperfect correlation to ALK mutations