1. Primary Combined Squamous and Small Cell Carcinoma
of the Larynx
A Case Report and Review of the Literature
Vilkesh R. Jaiswal, MD; Mai P. Hoang, MD
c Primary laryngeal carcinomas comprise approximately
2% to 5% of all malignancies worldwide. Of these laryn-geal
carcinomas, approximately 99% are primary squa-mous
cell carcinomas. During the past 30 years, about 160
cases of primary small cell carcinoma of the larynx have
been reported. Combined primary squamous and small cell
carcinoma of the larynx, the so-called composite tumor of
the larynx, is even more rare, with only 13 published cases
to date. Although the major risk factors for developing
these composite tumors of the larynx are thought to be
similar to other more common neoplasms of the larynx,
such as squamous cell carcinoma, the treatment and prog-nosis
are different. We report an additional case of com-bined
small cell carcinoma of the larynx and discuss the
histogenesis of this unusual neoplasm.
(Arch Pathol Lab Med. 2004;128:1279–1282)
Primary laryngeal carcinoma is estimated to comprise
2% to 5% of all malignancies worldwide. In the Unit-ed
States, this translates to about 12 500 new cases of pri-mary
laryngeal carcinomas annually. Of these laryngeal
carcinomas, approximately 99% or more are primary
squamous cell carcinomas.1 The remaining types of pri-mary
laryngeal carcinomas, especially small cell carcino-ma,
are rare. During the past 30 years, slightly more than
500 cases of primary neuroendocrine carcinomas of the
larynx have been reported in the literature worldwide. Of
these, only about 160 cases have been classified as small
cell carcinomas.2 Combined primary squamous and small
cell carcinoma of the larynx, the so-called composite tumor
of the larynx, is even more rare. Our review of the literature
revealed only 13 published cases of primary squamous and
small cell carcinoma of the larynx to date.3–10 Although the
major risk factors for developing these composite tumors
of the larynx are thought to be similar to other more com-mon
neoplasms of the larynx, such as squamous cell car-cinoma,
the treatment and prognosis are different.1–10 We
Accepted for publication June 30, 2004.
From the Department of Pathology, The University of Texas South-western
Medical Center, Dallas.
The authors have no relevant financial interest in the products or
companies described in this article.
Corresponding author: Mai P. Hoang, MD, Department of Pathology,
The University of Texas Southwestern Medical Center, 5323 Harry Hines
Blvd, Dallas, TX 75390-9073 (e-mail: mai.hoang@utsouthwestern.edu).
report an additional case of primary squamous and small
cell carcinoma of the larynx.
REPORT OF A CASE
A 41-year-old man with a 20-pack-year smoking history and
no other significant medical history presented with hoarseness
of 6 months’ duration. An endoscopic examination revealed a
lesion in the left posterior ventricle that extended up to the left
false vocal cord. At the same time, a bulky right laryngeal lesion
was seen involving both the laryngeal ventricle and false vocal
cord. The lesions were biopsied, and the diagnosis of combined
squamous and small cell carcinoma of the larynx was rendered.
Both chest radiography and computed tomography demonstrated
no evidence of pulmonary disease. The patient underwent 2 cy-cles
of chemotherapy, including cisplatin and etoposide, and is
currently undergoing radiotherapy. He is alive 8 months status
post diagnosis.
MATERIALS AND METHODS
Four-micrometer-thick sections were cut from the paraffin
blocks and stained with hematoxylin-eosin. Additional paraffin
sections were obtained for immunohistochemical studies, which
were performed by avidin-biotin peroxidase complex technique,
the heat-induced epitope retrieval buffer, and primary antibodies
against cytokeratins (AE1/AE3, 1:50, Zymed Laboratories, South
San Francisco, Calif), CD56 (1:10, Monosan, San Francisco, Calif),
chromogranin (1:700, Dako Corporation, Carpinteria, Calif),
CD20 (L26, 1:40, Signet Laboratory, Dedham, Mass), CD3 (1:200,
Dako), and leukocyte common antigen (1:40, Dako). Appropriate
positive and negative controls were included.
PATHOLOGIC FINDINGS
Biopsies from the left true vocal cord and left laryngeal
ventricle revealed full-thickness squamous dysplasia con-sistent
with squamous cell carcinoma in situ (Figure, A).
No invasive tumor was identified on these small biopsy
specimens. In contrast, biopsies of the right hemilarynx
revealed a submucosal and dense infiltrate of neoplastic
cells arranged in solid nests and sheets with minimal in-tervening
stroma (Figure, B). The neoplastic cells were
pleomorphic with hyperchromatic nuclei, high nuclear-cy-toplasmic
ratio, and marked crushed artifact (Figure, C).
There was no glandular or squamous differentiation pres-ent
in this component of the tumor. These neoplastic cells
strongly expressed cytokeratins (AE1/AE3) (Figure, D)
and CD56 (Figure, E), and focally expressed chromogran-in
(Figure, F). They were negative for CD20, CD3, and
leukocyte common antigen. Based on these findings, the
diagnosis of combined squamous and small cell carcino-ma
of the larynx was rendered.
Arch Pathol Lab Med—Vol 128, November 2004 Combined Small Cell Carcinoma of Larynx—Jaiswal & Hoang 1279

2. A, Full-thickness squamous dysplasia consistent with squamous cell carcinoma in situ (hematoxylin-eosin, original magnification 3100). B and C,
A dense submucosal proliferation (B) of hyperchromatic neoplastic cells with minimal cytoplasm and nuclear molding (C) (hematoxylin-eosin,
original magnifications 3100 [B] and 3200 [C]). D, Strong cytokeratin (AE1/AE3) immunoreactivity in the small cell carcinoma component (original
magnification 3200). E, Strong CD56 immunoreactivity (original magnification 3400). F, Focal chromogranin immunoreactivity (original magni-fication
3400).
COMMENT
Combined small cell carcinoma, as defined by the In-ternational
Association for the Study of Lung Cancer, con-sists
of small cell carcinoma with a component of squa-mous
cell carcinoma or adenocarcinoma.11 Combined pri-mary
squamous and small cell carcinoma of the larynx is
rare, and only 13 cases have been reported in the literature
to date.3–10 The clinical features of these cases of combined
small cell carcinoma of the larynx, together with those of
the current case, are summarized in the Table. They have
clinical features similar to those of small cell carcinoma.
All patients were men within an age range of 41 to 83
years (median, 55 years), and all had a significant history
of smoking (Table). The presenting symptoms included
1280 Arch Pathol Lab Med—Vol 128, November 2004 Combined Small Cell Carcinoma of Larynx—Jaiswal & Hoang

3. Clinical and Pathologic Data of 14 Cases of Combined Squamous and Small Cell Carcinoma of the Larynx
Case
No. Source, y
Age,
y/Sex Site
Positive
Lymph
Nodes
Distant
Metastasis Therapy Follow-up
1 Yucel et al,3 2000 32/M Supraglottic 1 2 SL, MND, chemotherapy AWD, 1 y
2 Gianoli et al,4 1992 83/M Right supraglottic 2 2 TL, MND NED, 8 mo
3 Cosby and Babin,5 1988 56/M Left supraglottic 1 2 TL, RND, chemotherapy Lost to follow-up
4 Chen et al,6 1986 55/M Right hemilarynx, left
supraglottic
1 2 TL, RND, chemotherapy,
XRT
DOD, 9 mo
5 Chen et al,6 1986 55/M Right supraglottic 2 2 SL, RND, chemotherapy AWD, 13 mo
6 Ferlito et al,7 1985
Gnepp et al,8 1983
57/M Right pyriform sinus 1 1 TL, RND, XRT DOD, 3.5 mo
7 Ferlito et al,7 1985 56/M Epiglottis 2 2 Chemotherapy, XRT NED, 5 y
8 Ferlito et al,7 1985 45/M Right aryepiglottic fold
and pyriform sinus
1 2 Chemotherapy, XRT DOD, 21 mo
9 Ferlito et al,7 1985 47/M Right aryepiglottic fold
and pyriform sinus
1 2 Chemotherapy, XRT AWD, 39 mo
10 Ferlito et al,7 1985 54/M Anterior commisure, vo-cal
cords, subglottic
2 2 TL, RND NED, 2 y
11 Ferlito et al,7 1985 50/M Left hemilarynx 1 NA TL, RND, XRT DOD, 14 mo
12 Mills et al9, 1983 49/M Right pyriform sinus 1 2 TL, RND, XRT NED, 6 mo
13 Eubesi et al,10 1978 63/M Right hemilarynx 1 2 HL, RND AWD, 10 mo
14 Current case 41/M Left vocal cord, right
hemilarynx
NA 2 Chemotherapy, XRT NED, 8 mo
* Plus sign indicates metastasis present; minus sign, metastasis absent; NA, information not available; SL, supraglottic laryngectomy; MND,
modified neck dissection; TL, total laryngectomy; RND, radical neck dissection; XRT, radiation therapy; HL, hemilaryngectomy; AWD, alive with
disease; NED, no evidence of disease; and DOD, died of disease.
hoarseness, dysphagia, and in some cases, a neck mass.
Although this composite tumor has been reported at var-ious
locations in the larynx, the supraglottic region is the
most frequently involved site—similar to primary laryn-geal
small cell carcinoma.8 Paraneoplastic processes, such
as Eaton-Lambert syndrome and syndrome of inappro-priate
secretion of antidiuretic hormone, may occur in as-sociation
with laryngeal small cell carcinoma, but these
syndromes have not been reported with combined small
cell carcinoma of the larynx.12
The clinical course of combined small cell carcinoma is
similar to that of small cell carcinoma of the larynx; it
displays aggressive biologic behavior with early distant
metastasis as a rule.3–10 Most patients were given multi-modality
therapy, which included a combination of sur-gery,
radiation therapy, and chemotherapy (Table). Al-though
survival for more than 3 years has been reported,
most patients die within 2 years of the diagnosis, even
with adjuvant radiation and chemotherapy (Table).
In combined carcinoma of the larynx, small cell carci-noma
was commonly associated with a synchronous and
invasive squamous cell carcinoma. An in situ squamous
cell carcinoma was seen in one case reported by Ferlito et
al7 and in the current case. However, only small biopsies
and no resections were performed on these patients, there-fore
an invasive squamous cell carcinoma cannot be ex-cluded.
Before rendering a diagnosis of a combined squa-mous
and small cell carcinoma of the larynx, it is impor-tant
to ascertain through clinical workup that the small
cell carcinoma component is not a metastasis from either
a gastrointestinal or bronchogenic origin. Other neuroen-docrine
neoplasms, such as carcinoid tumor, atypical car-cinoid
tumor, pure small cell carcinoma, and large cell
neuroendocrine carcinoma, should be considered in the
differential diagnosis. Nonkeratinizing squamous cell car-cinoma
must be excluded. Basaloid squamous cell carci-noma
is also a consideration; however, this tumor would
show large epithelial lobules with comedo-like central ne-crosis,
abundant stroma with hyalinization along the tu-mor
nests, and lack of CD56 expression.13 In these settings,
a panel of appropriate immunohistochemical stains would
be helpful.
It is believed that the neuroendocrine Kulchitsky cell (or
argyrophilic cell) found in the mucosa of the larynx and
other endodermally derived tissue is the histogenetic pre-cursor
of small cell carcinoma of the larynx. Combined
small cell carcinoma has been described in the lung, tra-chea,
and esophagus.14–16 It has been speculated that these
biphasic neoplasms are derived from a common neoplastic
stem cell that can differentiate into the Kulchitsky cells
(neuroendocrine cells) as well as squamous or glandular
cells in the appropriate microenvironment.3 This hypoth-esis
is not unlikely, since the neural crest cells have been
shown to have broad differentiating capability.17 These
findings lend support to the hypothesis that neoplastic
cells of tumors such as ours, which display both squamous
and neuroendocrine differentiation, are derived from
common pluripotential stem cells.
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