I.

PATHOLOGY

About 95% of laryngeal carcinomas are typical squamous cell lesions.

Rarely, adenocarcinomas are seen, presumably arising from mucous glands. The
tumor usually develops directly on the vocal cords, but it may arise above or
below the cords, on the epiglottis or aryepiglottic folds, or in the pyriform
sinuses. Those confined within the larynx proper are termed intrinsic, whereas
those that arise or extend outside the larynx are called extrinsic.
1. Sequence of Hyperplasia, Metaplasia, Dysplasia, Carcinoma.

A spectrum of epithelial alterations is seen in the larynx. These are termed,

from one end to the other, hyperplasia, atypical hyperplasia, dysplasia, carcinoma
in situ, and invasive carcinoma. Macroscopically, the epithelial changes range
from smooth, white or reddened focal thickenings, sometimes roughened by
keratosis, to irregular verrucous or ulcerated, white-pink lesions looking like
cancer.
When first seen, the orderly thickenings have almost no potential for
malignant transformation, but the risk rises to 1% to 2% during the span of 5 to
10 years with mild dysplasia and 5% to 10% with severe dysplasia. In essence,
there are all gradations of epithelial hyperplasia of the true vocal cords, and the
likelihood of the development of an overt carcinoma is directly proportional to
the level of atypia when the lesion is first seen. Only histologic evaluation can
determine the gravity of the changes.
a. Metaplasia

Squamous metaplasia may result from numerous stimuli, among which

are chronic irritation and inflammation. The mechanism of metaplasia of
respiratory epithelial cells is most commonly the result of stem cell metaplasia.

However, studies by McDowell et al. (1979) suggested that metaplasia may arise
from fully mature cells, such as mucus-secreting cells, which are still capable of
cell division. But more recent findings have indicated that an indirect mechanism
of metaplasia may play a role in this process (Leube and Rustad, 1991).
In the respiratory epithelium, the stem cell normally gives rise to
pseudostratified columnar epithelium, but in the presence of certain stimuli it may
differentiate into squamous epithelium. The lack of vitamin A may be associated
with such squamous metaplasia, since animals deficient in this vitamin show
extensive squamous metaplasia of mucous columnar epithelium; treatment with
vitamin A may reverse the squamous metaplasia.
The mechanism of this metaplasia also appears to result from
redifferentiation of certain stem cells (shown as small black nuclei along the
basement membrane) of each of the epithelia. Because these epithelial cells are
constantly being replaced by progeny of the stem cells, in the absence of vitamin
A or in the presence of some chronic stimulus as yet undefined, the differentiation
of the stem cell may be redirected to the more primitive squamous epithelium.
b. Dysplasia

Dysplasia refers to the abnormalities in cellular morphology indicative of

premalignant changes. Dysplasia has classically been graded as mild, moderate,
or severe carcinoma in situ (CIS). This schema is based on relative thickness of
the atypical cells, defined as those immature cells with nuclear pleomorphism,
atypical mitotic figures, and disturbed polarity.
Many authors and pathologists will group severe dysplasia and CIS
together because they both appear to have equal biological potential to progress to
invasive cancer. Other authors have suggested further simplication, grouping
dysplasias together as either low grade or high grade. This approach would allow
for better classification of histological.

Squamous Cell Carcinoma

The vast majority of malignancies of the supraglottis and glottis are SCCs.

Squamous cell carcinomas of the larynx follow the growth pattern of all
squamous cell carcinomas. They begin as in situ lesions that later appear as pearly
gray, wrinkled plaques on the mucosal surface, ultimately ulcerating and
fungating (Fig. 17-9). The degree of anaplasia of the laryngeal tumors is highly
variable. Sometimes massive tumor giant cells and multiple bizarre mitotic
figures are seen.

Figure x.1. Macroscopic and Microscopic Image of Laryngeal SCC

As expected with lesions arising from recurrent exposure to environmental
carcinogens, adjacent mucosa may demonstrate squamous cell hyperplasia with
foci of dysplasia, or even carcinoma in situ.
From the anatomical fact, it is proven that each part of larynx is separated
by a membrane. Dye injected in the supraglottic space remains confined and does
not travel to the ventricular or glottic tissues. Likewise, glottic dye injections do
not pass superiorly to the ventricle or inferiorly to the mucosa overlying the
cricoid. This anatomical structure may limit the spread of the cancerous cells to
the adjacent parts of the larynx.

The attachment of the vocal ligaments also limits the spread of carcinoma
from one lateral side to the other. The vocal folds have a relative paucity of
lymphatics, as compared with the supraglottis and the pre-epiglottic space. This
paucity of lymphatic vessels is most marked in the anterior vocal folds and
accounts for the rarity of cervical metastases of T1 glottic carcinomas. The
lymphatic channels of the vocal fold become denser posteriorly in the region of
the arytenoids. Glottic carcinomas may spread by undermining the tissue around
the ventricles (paraglottic region), escaping the endolarynx and spreading
laterally by invading the cricothyroid ligament and the inferior aspect of the
thyroid lamina. Ossified thyroid lamina is more prone to tumor invasion as
compared with the relatively avascular nonossified cartilage. Carcinoma may also
spread superiorly into the vestibular fold by undermining paraglottic ventricular
tissue.
The epiglottis is composed of fenestrated cartilage, which allows for early
tumor spread from the laryngeal surface to the lingual surface and into the preepiglottic space. The latter contains abundant lymphatics; tumor spread into this
space increases the risk for cervical metastasis and worsens prognosis. The preepiglottic space is bound anteriorly by the thyrohyoid membrane. Tumor that
breaches this space invades into the base of tongue. The superior boundary of the
pre-epiglottic space is the hyoepiglottic ligament, which connects the hyoid bone
to the epiglottis. Epiglottic carcinomas, which are inferior to the hyoepiglottic
ligament (infrahyoid tumors), are more commonly encountered than those
superior to the hyoepiglottic ligament (suprahyoid tumors). The hyoepiglottic
ligament provides a barrier blocking the inferior passage of the infrequent
suprahyoid carcinomas into the pre-epiglottic space.
Histologically, SCCs may be recognized by their ability to produce keratin
(Fig. 48-8). Intercellular bridges may be seen as fine hairlike structures between
cells. Well- and moderately differentiated SCCs are usually associated with a
surface mucosal component (in situ carcinoma), which clinically appears as an
erythroleukoplakic irregularities.

Figure 48.8. Irregular infiltrating islands of squamous carcinoma

producing keratin pearls.

Poorly differentiated SCCs may appear clinically ulcerated or entirely

submucosal, with little perceptible mucosal involvement. Two variants of SCC
deserve mention: verrucous carcinoma and spindle carcinoma.
Verrucous carcinoma (VC) is a clinicopathologically distinct, welldifferentiated variant of squamous carcinoma, which is cytologically benign yet
clinically aggressive. VC presents as a slow-growing, gray-white, firm, warty
tumor with a cauliflower like surface and sharply demarcated margins (Fig. 489). Clinically, lymph nodes are usually palpable in patients with VCs that are
benign but reactive. A male predominance is seen with VC, which relates to
cigarette-smoking and tobacco-chewing habits. The oral cavity is the most
common site for VC, usually on the buccal mucosa or gingival; the larynx is a
less common site of occurrence.

Figure 48-9 Buccal verrucous carcinoma, with typical cauliflowerlike

gray-white papillary surface.
Spindle squamous cell carcinomas (SpCCs) may be associated with a
prominent malignant spindle cell component with a wide spectrum of
appearances; the general term spindle cell carcinomas has been advocated for
these tumors, which may cause diagnostic problems on preoperative biopsies.
SpCCs are uncommon. Sixty five percent of these cases occurred in the
larynx/epiglottis/vocal cords/pyriformis sinus and hypopharynx. There is a
pronounced male predisposition, and most patients are between the fifth and ninth
decades. The tumors may be polypoid and exophytic, or ulcerating and
infiltrating, but the tendency for laryngeal tumors is to retain an exophytic
polypoid growth pattern. Histologically, SpCCs contain either in situ SCC or
invasive SCC, with an additional, obviously malignant spindle cell component.

Neuroendocrine Tumors
Neuroendocrine tumors of the larynx are divided into two broad

categories based on their tissue of origin: epithelial and paraganglionic. The

epithelial-derived tumors, known as neuroendocrine carcinomas (NECs), are

uncommon neoplasms constituting 0.06% of laryngeal malignancies. Due to

differences in biological behavior and histologic growth patterns, this group of
neoplasms is further subclassified into three distinct subtypes: carcinoid tumor
[well-differentiated neuroendocrine carcinoma (WDNEC)], atypical carcinoid
tumor [moderately differentiated neuroendocrine carcinoma (MDNEC)], and
small cell carcinoma, including both the intermediate and oat cell variants [poorly
differentiated neuroendocrine carcinoma (PDNEC)].
MDNECs are the most frequently encountered type of NEC, followed by
PDNEC. There is a strong association of MDNEC and PDNEC with a history of
smoking. Tumors most commonly arise in supraglottic sites with only very
occasional tumors arising in other areas of the larynx (Fig. 48-12).

Figure 48-12 Supraglottic ulcerated laryngeal neuroendocrine

carcinoma.

Histologically,

glandular

component

is

common.

Cellular

pleomorphism, mitotic activity, or necrosis is usually absent in WDNEC.

MDNECs are characterized by infiltrative growth and a varied histologic pattern,
which may include glandular, organoid, acinar, trabecular, solid, and nesting
architectures (Fig. 48-13).

The Figure 48-13 MDNEC has a paraganglioma-like organoid pattern and

stippled nuclear chromatin.

Adenoid Cystic Carcinoma

Salivary glandtype neoplasms are rare tumors in the larynx, accounting

for less than 0.7% of laryngeal carcinomas. The four most common malignant
salivary tumors are adenosquamous carcinoma, followed with equal incidences
of adenoid cystic and mucoepidermoid carcinoma, and lastly malignant mixed
tumors. Other salivary tumors that arise, albeit rarely, in the larynx include
myoepithelioma (benign and malignant), acinic cell carcinoma, epithelial
myoepithelial carcinoma, clear cell carcinoma, and salivary duct carcinoma.

Adenoid cystic carcinoma (ACC) of the larynx represents from 0.07 to

0.25% of laryngeal carcinomas. Approximately 60% involve the subglottis, 33%
the supraglottis, and 6% the vocal fold. Extralaryngeal invasion may result in
initial presentation as a thyroid mass.
The majority of tumors diffusely invade the submucosa and adjacent soft
tissues without protruding into the laryngeal lumen (Fig. 48-14).ACC may form
three patterns: tubular, cribriform, and solid. The cribriform is the most frequent
and the solid pattern the least frequent pattern observed. Adenoid cystic
carcinomas are composed of cells of two types: ductal cells and abluminal
myoepithelial cells.

Figure 48-14 Infiltrating adenoid cystic carcinoma

REFERENCES

Cotran, R.S., Kumar, V.K., Collins, T. 1999 . Head And Neck. In : Robbins :
Pathologic Basis of Diseases. 6th edition. Philadelphia : W.B. Saunders Company.
P. 765 766.
Van De Water, Staecker, H. 2006. Laryngeal Pathology. In : Otolaryngology :
Basic Science and Clinical Review. 1st edition. New York : Thieme Medical
Publisher Inc. p. 579 586.