by John G. Batsakis, MD
No more than 1% of the epithelial malignancies of the
larynx are nonsquamous in phenotype. (1) This small group
of glandular neoplasms can be divided, as has been done in the sinonasal
tract, into those taking origin from the surface mucosa and those arising
in seromucous glands (so-called subsurface origin). (1,2) As
a group, laryngeal nonsquamous epithelial malignancies have a far lower
incidence than counterparts in the sinonasal tract.
In the larynx, the subsurface carcinomas outnumber the surface-origin
nonsquamous carcinomas by a very considerable margin, with adenoid cystic
carcinoma the most frequent and most readily recognized. The histologic
equivalent of the papillary low-grade surface adenocarcinoma of the paranasal
sinuses is very rare.
The site of origin of the nonsquamous carcinomas of the larynx follows
the anatomic distribution of the larynx's subepithelial glands and the
intraepithelial mucous glands. Approximately two thirds of the adenoid
cystic carcinomas are in the subglottic. The other nonsquamous carcinomas,
in contrast, are rarely subglottic, with supraglottic and transglottic
involvement being nearly equal. (1)
The number, distribution, and density of the glands in macroscopically
normal adult laryngeal mucosae have been described by
Bak-Pedersen and Nielsen. (3)
The overall density of glands in the intrinsic larynx has been estimated
to be between 23 and 47 glands per square centimeter. The lower part of
the glottic region shows the greatest differences in density: 13 glands
per square centimeter on the vocal cords to 128 per square centimeter on
the false vocal cords and medial wall of Morgagni's sinus. The greatest
concentration of glands is in the saccule (139 glands per square centimeter),
and the region is also the one with the greatest median density (82 glands
per square centimeter). There is a very low density of glands in the extrinsic
laryngeal regions (epiglottic vallecula, pyriform recess).
Except for adenoid cystic carcinomas, salivary-type carcinomas are rare
in the larynx. Even pleomorphic adenomas are almost
curiosities in the larynx. (1,4) 4 Immunocytochemical
methods have now appropriately classified as neuroendocrine neoplasms
many types formerly included under the generic heading of adenocarcinoma. (5,6) These
in turn are subtyped as typical or atypical carcinoids
and small cell neuroendocrine carcinomas. (6,7)
Damiani et al (3) have suggested there is a continuum
of laryngeal surface carcinomas: 1) non-mucin-producing squamous cell carcinoma,
2) squamous cell carcinoma with unicellular mucin production, 3) mucoepidermoid-adenosquamous
carcinoma, 4) adenocarcinoma with variable degrees of squamous metaplasia,
and 5) pure adenocarcinoma. All except the first are rare in the larynx.
The combining of mucoepidermoid carcinoma with adenosquamous carcinoma
reflects the difficulty surgical pathologists have in distinguishing between
these two carcinomas in mucosae. Even considering the two carcinomas as
a diagnostic unit, it is evident that they are uncommon neoplasms in the
larynx. In their report of 21 mucoepidermoid-adenosquamous carcinomas from
the Armed Forces Institute of Pathology (AFIP) files of 1945 to 1979, Damiani
et al (3) indicated there had been only 32 previously
reported cases in the world's literature.
If the histologic appearances permit, it is important to separate the
mucoepidermoid-adenosquamous carcinoma group into high and low grades because
of the marked differences in prognosis. Eight of the 21 AFIP neoplasms
were called low-grade mucoepidermoid carcinomas. (The descriptions and
photomicrographs are appropriate.) Nine, according to the authors, were
more appropriately considered adenosquamous carcinomas than mucoepidermoid
carcinomas. By an actuarial method, the 3-, 5-, and 10-year survival for
all of the low-grade mucoepidermoid carcinomas was 100%, regardless of
clinical stage (6 of the 8 were stage 1 or 2). For the adenosquamoushigh-grade
mucoepidermoid carcinomas, the survival followed clinical stage and grade,
and was 53% at 3 years post-therapy. On the basis of our own experience
and that of the AFIP, it is safe to presume that except for low-grade mucoepidermoid
carcinomas, other supposed grades of that carcinoma in the larynx are much
more likely to be adenosquamous carcinomas.
It has been earlier mentioned that prior to immunohistochemical techniques,
neuroendocrine neoplasms were misclassified as forms of subsurface adenocarcinomas
in the larynx. With their recognition, neuroendocrine carcinomas rank second
in frequency to subsurface salivary carcinomas, most often adenoid cystic
carcinomas. (1)
The Table presents the two categories of neuroendocrine neoplasms of
the larynx based on their proposed generative tissues, epithelial and paraganglionic,
and the recommended histopathologic classification. Numerous markers justify
the encompassing rubric of neuroendocrine for these neoplasms. These include
an argyrophilia of cytoplasmic granules; immunoreactivity with antibodies
against chromogranin; neuron- spec ific enolase , neurofilament protein
, Leu7, calcitonin, and synaptophysin; electron optic findings of membrane-bound
dense-core granules; occasional association with paraneoplastic syndromes;
and the rarely seen extracellular elevations of peptides, amines, and hormones.
Carcinoids of Larynx. Carcinoids are the most numerous of the
neuroendocrins tumors of the larynx. They exist in two types, typical and
atypical, with the typical carcinoid being the least common of any laryngeal
neuroendocrine tumor. They derive from uncommitted stem cells that are
apparently most plentiful in the supraglottic, since that is the region
of predilection. (6,7,9)
A histopathologic diagnosis of a typical laryngeal carcinoid is based
on an organoid or ribbon architecture in which the cells are uniform and
small. The cells are typically devoid of cellular pleomorphism, mitoses,
or necrosis. An atypical carcinoid differs by manifesting cellular pleomorphism,
nuclear atypia, hyperchromatism, more than a rare division figure, and
necrosis. A variant of atypical carcinoid is medullary thyroid carcinoma-like,
even to displaying amyloid and immunocytochemically demonstrable calcitonin.
Both typical and atypical forms, however, are usually nonfunctional.
There are considerable biologic differences between the types of carcinoids.
To date, none of the typical carcinoids of the larynx have had regional
Iymph node metastases at the time of clinical diagnosis, and overall, metastasis
to Iymph nodes is unusual. (6) Four of the 13 reported
tumors have manifested distant metastases, but only 1 patient has died
of disease. Indeed, most patients with a typical carcinoid are alive and
free of neoplasm after complete surgical removal of their neoplasms.
This rather benign course is in contrast to that of an atypical carcinoid.
Woodruff and Senie, (10) in their survey of 127 cases,
found metastases to the neck nodes in 43%, to skin and subcutaneous locations
in 22%, and to distant sites in 44%. Nearly half of a follow-up population
of 119 patients died because of their neoplasms. The cumulative proportion
surviving was 48% at 5 years and 30% at 10 years. Surgical resection was
the principal therapeutic modality and survival rates were not changed
by adjuvant irradiation.
Both carcinoids display intracellular, neuroendocrine, immunocytochemical
markers in a varying reactivity. Keratins are also reactive. It should
be noted that the immunodetection of calcitonin is so common that it has
come to be regarded as a very specific marker for an
atypical carcinoid of the larynx, either in the primary or in its metastases. (9) In
addition to the intracellular calcitonin, the resemblance of medullary
carcinoma of the thyroid is further accentuated by the presence of amyloid
and, at times, systemic manifestations of the calcitonin. (9)
Small Cell Neuroendocrine Carcinoma. This carcinoma is estimated
to account for about 0.5% of all primary laryngeal carcinomas and, like
its neuroendocrine companions, has a predilection for men. (6) The
supraglottic has the highest incidence of involvement, but no part of the
endolarynx is spared.
Neuroendocrine carcinomas of the larynx share histologic features and
descriptive subcategories with counterparts in the lungs, ie, oat cell,
intermediate cell, and combined types. While I do not subscribe to these
sometimes illusory subtypes, they are entrenched in the literature and
hence require acknowledgment. The oatcell neuroendocrine carcinoma displays
itself in sheets, cords, and ribbons of small, hyperchromatic, undifferentiated
cells with very scant cytoplasm. Necrosis, mitoses, and endovascular or
Iymphatic invasion are frequent. Substantiating a neuroendocrine differentiation,
rosettes may occasionally be seen. The intermediate cell type has a slightly
larger cell and more cytoplasm, and is more often variably shaped. As the
designation indicates, combined forms show either an oat or intermediate
cell type in company with squamous carcinoma, adenocarcinoma, or other
classes of malignancy.
Small cell neuroendocrine carcinoma of the larynx is an aggressive and
lethal malignancy. Metastases to cervical Iymph nodes coincident with discovery
of the primary occur in nearly 50% of the patients. The prognosis is as
poor as that for small cell carcinomas of the lung and it is unrelated
to the size of the tumor. Gnepp et al" indicate that three quarters of
their study population died because of the carcinoma, usually with disseminated
metastases and with an average survival of 9.8 months. There is a dismal
5% 5-year survival. These data reflect the treatmentresistant nature of
the carcinoma. Ablative surgery is usually not an option because of the
high metastatic rate. Combination therapy, chemotherapy, and radiotherapy,
or other newer modalities, applicable as well to pulmonary cell carcinomas,
are the treatments of choice.
Paraganglioma. Laryngeal paragangliomas take origin from paraganglionic
tissues normally found in the larynx. The paraganglia of the larynx are
part of the branchiomeric paraganglionic system and are distributed in
a paired, bilateral fashion in relation to laryngeal
arteries and nerves.(l2) A superior pair is found in
the anterior third of the false vocal cords in relation to the superior
laryngeal artery and nerve and next to the superior margin of the thyroid
cartilage. The inferior pair of paraganglia are typically found near the
cricoid cartilage, either between it and the thyroid cartilage or between
the cricoid and the first tracheal ring. The associated neurovascular structures
are the inferior laryngeal artery and nerve. Neurovascular relationships
with paraganglia are further underscored by the occasional findings of
paraganglionic tissues within recurrent laryngeal nerves.
Smaller, aberrant or accessory paraganglionic tissues
within the larynx have also been described. Barnes, (13) after
a critical review of the world s literture through April 1990, rejected
44 of the 78 reported laryngeal paMgangliomas. This indicates surgical
pathologists are either unfamiliar with the lesion when it occurs in the
larynx or they have been presented with biopsy specimens that lack the
features found in extralaryngeal paragangliomas. Endoscopic biopsy forceps
compression of the tissues may play a role by obscuring expected histologic
findings. The misdiagnoses have taken two directions: a misinterpretation
of an atypical carcinoid as a paraganglioma or, conversely, mistaking a
paraganglioma for a higher-grade neoplasm. As a consequence, the comparatively
benign paraganglioma has acquired an unjustified poor prognosis.
The paraganglioma is the only laryngeal neuroendocrine neoplasm with
a female preference (3:1 over males). (13) The supraglottic
(principally the right aryepiglottic fold-false vocal cord region) has
accounted for 82% of the tumors. Fifteen percent have been subglottic,
and 3%, glottic tumors. There are no documented examples of clinically
functional or multiple (extralaryngeal) forms.
Surgical removal by some form (local, cryosurgery, supraglottic, or total
laryngectomy) has been the mainstay of treatment. Local recurrence, usually
attributed to incomplete removal, has been recorded in 17% of the cases
accepted by Barnes. (13) Only 1 of 34 paragangliomas
has metastasized. This low metastatic rate ranks these paMgangliomas with
jugulotympanic tumors and behind tumors of the vagal and carotid bodies.
1. Batsakis JG, Luna MA, El-Nagger AK. Nonsquamous
carcinomas of the larynx. Ann Otol Rhinol Laryngol 1992; 101: 1024-6. Return
2. Manning JT, Batsakis IG. Salivary-type
neoplasms of the sinonasal tract. Ann Otol Rhinol Laryngol 1991;100:691-4.
3. Bak-Pedersen K, Nielsen KO. Subepithelial
mucous glands in the adult human larynx. Studies on number, distribution
and density. Acta Otolaryngol (Stockh) 1986;102:341-52. Return
4. Spiro RH, Lewis JS, Hajdu Sl, Strong
EW. Mucus gland tumors of the larynx and laryngopharynx. Ann Otol
Rhinol Laryngol 1976;85:498-503. Return
5. Milroy CM, Ferlito A. Immunchistochemical
markers in the diagnosis of neuroendocrine neoplasms of the head
and neck. Ann Otol Rhinol Laryngol 1995;104:413-8. Return
6. Batsakis JG, El-Naggar AK, Luna MA. Neuroendocrine
tumors of larynx. Ann Otol Rhinol Laryngol 1992;101:710-4. Return
7. Ferlito A, Milroy CM, Wenig BM, Barnes
L, Silver CE. Laryogeal paraganglioma versus atypical carcinoid
tumor. Ann Otol Rhinol Laryngol 1995;104:78-83. Return
8. Damiani JM, Damiani KK, Hauck K, Hyams VJ. Mucoepidermoid-adenosquamous
carcinoma of the larynx and hypopharynx: a report of 21 cases and
a review of the literature. Otolaryngol Head Neck Surg 1981;89:235-43.
9. WoodruffJM, Huvos AG, Erlandson RA, Shah
JP, Gerold FP. Neuroendocrine carcinomas of the larynx. A study
of two types, one of which mimics thyroid medullary carcinoma.
Am J Surg Pathol 1985;9:771-90. Return
10. WoodruffJM, Senie RT. Atypical carcinoid
tumor of the larynx. A critical review of the literature. ORL J
Otorhinolaryngol Relat Spec 1991;53:194-209. Return
11. Gnepp DR, Ferlito A, Hyams V. Primary anaplastic small
cell (oat cell) carcinoma of the larynx. Review of the literature
and report of 18 cases. Cancer 1983;51:1731-45.
12. FerlitoA, Barnes L, Wenig BM. Identification,
classification, treatment, and prognosis of laryngeal paraganglioma.
Review of the literature and eight new cases. Ann Otol Rhinol Laryngol
1994;103:525-36. Return
13. Barnes L. Paraganglioma of the larynx.
A critical review ofthe literature. ORL J Otorhinolaryagol Relat
Spec 1991 ;53:220. Return
top |
