Neuroendocrine tumors of the larynx are rare tumors in comparison to the much more common squamous cell carcinoma of the larynx. The current classification is similar to neuroendocrine tumors of the lungs.
Carcinoid tumor (Typical carcinoid)
Atypical carcinoid tumor
Small cell carcinoma (Small cell neuroendocrine carcinoma)
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
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EPIDEMIOLOGY CHARACTERIZATION SYNONYMS INCIDENCE 3% carcinoid tumors
54% atypical carcinoid tumors
34% small cell neuroendocrine carcinomas
AGE RANGE-MEDIAN Typical carcinoid (Well differentiated neuroendocrine carcinoma) 58 years (45-80 years) Atypical carcinoid (Moderately differentiated neuroendocrine carcinoma) Most frequent neuroendocrine laryngeal tumor
61 years (36-83 years)
Small cell neuroendocrine carcinoma (Poorly differentiated neuroendocrine carcinoma) 50-70 years (23-91 years)
3% <40 years
SEX (M:F) Typical carcinoid (Well differentiated neuroendocrine carcinoma) Males Atypical carcinoid (Moderately differentiated neuroendocrine carcinoma) Males 74% Small cell neuroendocrine carcinoma (Poorly differentiated neuroendocrine carcinoma)
DISEASE ASSOCIATIONS CHARACTERIZATION Typical carcinoid (Well differentiated neuroendocrine carcinoma) Atypical carcinoid (Moderately differentiated neuroendocrine carcinoma) Heavy smoking history Small cell neuroendocrine carcinoma (Poorly differentiated neuroendocrine carcinoma) Heavy smoking history
Schwartz-Bartter syndrome (Hypersecretion of the ADH)
CHARACTERIZATION RADIOLOGIC LABORATORY MARKERS Typical carcinoid (Well differentiated neuroendocrine carcinoma) Atypical carcinoid (Moderately differentiated neuroendocrine carcinoma) Most are aneuploid Small cell neuroendocrine carcinoma (Poorly differentiated neuroendocrine carcinoma)
CHARACTERIZATION GENERAL Typical carcinoid (Well differentiated neuroendocrine carcinoma) 83% occurred in the supraglottic larynx
Average 1.6 cm (0.5-3 cm)
Atypical carcinoid (Moderately differentiated neuroendocrine carcinoma) Supraglottic larynx
1.6 cm (0.2-4 cm)
Small cell neuroendocrine carcinoma (Poorly differentiated neuroendocrine carcinoma) Majority supraglottic larynx VARIANTS
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL Typical carcinoid (Well differentiated neuroendocrine carcinoma) Small uniform cells growing in nests, cords, sheets, or glands
Cells with clear to eosinophilic cytoplasm
Round to oval, spindled nuclei with finely stippled chromatin
No nucleoli, mitoses, necrosis, or pleomorphism
Highly vascular stroma
Atypical carcinoid (Moderately differentiated neuroendocrine carcinoma) Larger cells with occasional mitoses, prominence of nucleoli, and pleomorphism
May be cystic with intracystic projections of tumor cells
Small cell neuroendocrine carcinoma (Poorly differentiated neuroendocrine carcinoma) Sheets and ribbons of closely packed cells with scant, indistinct cytoplasm
Oval or spindled nuclei without nucleoli
May show rosettes or foci of squamous cell carcinoma or adenocarcinoma
- Primary combined squamous and small cell carcinoma of the larynx: a case report and review of the literature.
Jaiswal VR, Hoang MP.
Department of Pathology, The University of Texas Southwestern Medical Center, Dallas 75390-9073, USA.
Arch Pathol Lab Med. 2004 Nov;128(11):1279-82. Abstract quote
Primary laryngeal carcinomas comprise approximately 2% to 5% of all malignancies worldwide. Of these laryngeal carcinomas, approximately 99% are primary squamous 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 prognosis are different.
We report an additional case of combined small cell carcinoma of the larynx and discuss the histogenesis of this unusual neoplasm.
Neuroendocrine carcinomas of the larynx. A study of two types, one of which mimics thyroid medullary carcinoma.
Woodruff JM, Huvos AG, Erlandson RA, Shah JP, Gerold FP.
Am J Surg Pathol 1985 Nov;9(11):771-90 Abstract quote
We studied 13 neuroendocrine carcinomas of the larynx. They constituted 59% of the 22 nonepidermoid carcinomas of the larynx seen at Memorial Hospital during a 45-year period, and for which adequate material was available for review.
Four tumors were histologically identical to small cell carcinomas of the lung and were classified as small cell neuroendocrine carcinomas (SCNC). One case represents one of the original descriptions of the laryngeal SCNC. No SCNC was argyrophil, and of the three studied immunohistochemically, all contained neuron-specific enolase, one carcinoembryonic antigen (CEA) and one serotonin. Nine tumors were large cell carcinomas (LCNC). Eight LCNC were argyrophil, and all nine contained neuron-specific enolase, six calcitonin, four CEA, one HCG, two serotonin, and two somatostatin.
The laryngeal neuroendocrine carcinomas commonly presented in chronic cigarette smokers with mean ages of 63 (SCNC) and 60 (LCNC), were not associated with other endocrine tumors, and proved highly fatal in spite of radical surgery and radiation therapy. At last follow-up only one patient was alive (after 13 months). Patients dying with SCNC survived a mean of 11 months, and those with LCNC, 36 months. To determine whether the laryngeal LCNC most closely resembles pulmonary neuroendocrine tumors, head and neck paragangliomas, or thyroid medullary carcinoma (TMC), they were histologically, histochemically, and immunohistochemically compared with control cases of each group.
Overall, LCNC most closely resembles TMC, and given the frequency with which each presents as a neck mass, misinterpretation of one for the other is very possible. Evidence is provided suggesting that some LCNC have also been mistaken for the laryngeal paraganglioma.
CHARACTERIZATION Typical carcinoid (Well differentiated neuroendocrine carcinoma) Argyrophil positive (Grimelius stain)
Argentaffin negative (Fontana-Masson stain)
Atypical carcinoid (Moderately differentiated neuroendocrine carcinoma) Small cell neuroendocrine carcinoma (Poorly differentiated neuroendocrine carcinoma) TTF-1 Thyroid transcription factor-1, but not p53, is helpful in distinguishing moderately differentiated neuroendocrine carcinoma of the larynx from medullary carcinoma of the thyroid.
Hirsch MS, Faquin WC, Krane JF.
1Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Mod Pathol. 2004 Jun;17(6):631-6. Abstract quote
Moderately differentiated neuroendocrine carcinoma/atypical carcinoid tumor is the most common nonsquamous malignancy in the larynx; however, due to morphologic overlap and calcitonin immunoreactivity, it can be difficult to distinguish from thyroid medullary carcinoma. Currently, low serum calcitonin is the most reliable means for distinguishing primary laryngeal moderately differentiated neuroendocrine carcinoma from metastatic medullary carcinoma. Thyroid transcription factor-1 (TTF-1) is positive in at least 80% of medullary carcinomas, but has not been evaluated in laryngeal moderately differentiated neuroendocrine carcinomas. Additionally, it has been suggested that p53 is positive in laryngeal moderately differentiated neuroendocrine carcinomas and negative in other neuroendocrine tumors, but this has not been validated.
The purpose of this study was to determine if the immunohistochemical markers TTF-1 and p53 could be used to discriminate between laryngeal moderately differentiated neuroendocrine carcinomas and thyroid medullary carcinomas. Eight laryngeal moderately differentiated neuroendocrine carcinomas and 10 thyroid medullary carcinomas were identified from the archival files of the BWH and MGH Pathology Departments. Hematoxylin and eosin slides were reviewed, and immunohistochemistry was performed using antibodies to calcitonin, TTF-1, and p53. Calcitonin immunohistochemistry demonstrated immunoreactivity in 100% of laryngeal moderately differentiated neuroendocrine carcinomas (N=8) and 100% of thyroid medullary carcinomas (N=10). There was weak, focal immunoreactivity with TTF-1 in one of eight (13%) laryngeal moderately differentiated neuroendocrine carcinomas, whereas nine of ten (90%) medullary carcinomas were positive for TTF-1, with strong diffuse staining in seven of these cases (78%). p53 was positive in three of six (50%) laryngeal moderately differentiated neuroendocrine carcinomas, and three of ten (30%) medullary carcinomas.
Our data demonstrate that immunoreactivity for TTF-1, but not calcitonin or p53, may be helpful in distinguishing laryngeal moderately differentiated neuroendocrine carcinoma and thyroid medullary carcinoma. In particular, diffuse and/or strong TTF-1 immunoreactivity favors a diagnosis of primary thyroid medullary carcinoma over laryngeal moderately differentiated neuroendocrine carcinoma.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES Paraganglioma Positive for NSE, chromagranin, S-100 Carcinoid tumor Positive for NSE, chromagranin, keratin, CEA, calcitonin
Variable for S-100
Medullary carcinoma of the thryoid Positive for NSE, chromagranin, keratin, CEA, calcitonin, congo red for amyloid
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSTIC FACTORS Typical carcinoid (Well differentiated neuroendocrine carcinoma) 33% (4/12) developed distant mets to lymph nodes, liver, and bone
8% (1/12) DOD at 5 years
8% (1/12) with carcinoid syndrome
Atypical carcinoid (Moderately differentiated neuroendocrine carcinoma) 43% metastasized to cervical lymph nodes
44% mets to distant sites
5 YRS and 10YRS at 48% and 30%
Atypical carcinoid tumor of the larynx: an immunohistochemical, ultrastructural, and flow cytometric analysis.
McCluggage WG, Cameron CH, Arthur K, Toner PG.
Department of Pathology, Royal Group of Hospitals Trust, Belfast, Northern Ireland.
Ultrastruct Pathol 1997 Sep-Oct;21(5):431-8 Abstract quote
The clinicopathologic features, including a detailed immunohistochemical, ultrastructural, and flow cytometric analysis, are described in three cases of atypical carcinoid tumor of the larynx.
All patients had metastatic disease within cervical lymph nodes at presentation and eventually developed distant metastases. Special stains revealed focal intracytoplasmic mucin accumulation, and immunohistochemistry showed the tumors to be positive for CAM 5.2, CEA, chromogranin A, and calcitonin. In two cases, double-staining techniques revealed occasional cells that stained for both mucin and chromogranin A.
The histochemical and immunohistochemical findings in these two cases were confirmed at the ultrastructural level, with most tumor cells containing many neurosecretory granules. Smaller numbers of cells contained mucin vacuoles and, in occasional cells, both mucin and neuroendocrine granules were identified.
The three tumors exhibited positive staining with D07 (anti-p53), and flow cytometric analysis revealed DNA aneuploidy and polyploidy. The double-staining and ultrastructural features indicate that laryngeal atypical carcinoid qualifies for the designation of true amphicrine carcinoma. Further study is necessary to determine whether mutation of the p53 gene is important in the evolution of laryngeal neuroendocrine tumors and whether DNA aneuploidy or polyploidy identifies a subset of these tumors with a poor prognosis.
Small cell neuroendocrine carcinoma (Poorly differentiated neuroendocrine carcinoma) Aggressive and metastasis at initial diagnosis is the rule GENERAL
A review of neuroendocrine neoplasms of the larynx: update on diagnosis and treatment.
Ferlito A, Barnes L, Rinaldo A, Gnepp DR, Milroy CM.
Department of Otolaryngology-Head and Neck Surgery, University of Udine, Italy.
J Laryngol Otol 1998 Sep;112(9):827-34 Abstract quote
Neuroendocrine neoplasms of the larynx have been divided into those of epithelial or neural origin. The latter consist of paragangliomas while the epithelial origin group can be divided into the typical and atypical carcinoids and small cell neuroendocrine carcinomata, the latter consisting of the oat cell type, the intermediate cell type and the combined cell type. There are now over 500 cases of neuroendocrine neoplasms of the larynx in the literature.
The diagnosis is primarily based on light microscopy, and, in some instances, it may be supported by special histochemical studies. It should be confirmed by immunocytochemical and/or ultrastructural investigation. The different biological behaviour of neuroendocrine neoplasms of the larynx makes a specific diagnosis of paramount importance, since treatment depends on diagnostic accuracy.
Typical carcinoid is an extremely rare lesion. It is treated preferably by conservative surgery; elective neck dissection is not necessary because of the lack of lymph node metastases at diagnosis. Chemotherapy and/or radiotherapy have not been effective in the limited number of patients treated thus far. Prognosis is excellent with cure following surgery.
Atypical carcinoid is the most frequent non-squamous carcinoma of the larynx. The mainstay of treatment is surgery. Elective neck dissection should be performed because of the high likelihood of cervical lymph node metastases. Primary radiation therapy with adjuvant chemotherapy is not indicated. The survival rate is 48 per cent at five years and 30 per cent at 10 years.
Although the larynx is one of its most common extrapulmonary sites, small cell neuroendocrine carcinoma is still a rare tumour. Surgical results for this tumour have been disappointing and is reserved for cases of local relapse with no evidence of metastasis. Chemotherapy and radiotherapy currently appear to offer the least disabling and most effective forms of therapy. The two- and five-year survival rates are 16 per cent and five per cent, respectively. Paraneoplastic syndromes have occasionally been reported in association with carcinoid tumours (typical and atypical) and small cell neuroendocrine carcinoma. There have been also rare reports of an elevated neuropeptide serum level.
Paraganglioma is the only laryngeal neuroendocrine neoplasm with a female preponderance (3:1). Confusion with atypical carcinoid has led to incorrect diagnosis and inappropriate classification schemes, erroneously suggesting that laryngeal paraganglioma has the potential for aggressive behaviour. Conservative surgery represents the treatment of choice; elective neck dissection is not necessary, and the prognosis is excellent.
TREATMENT Typical carcinoid (Well differentiated neuroendocrine carcinoma) Conservative excision is treatment of choice
Larger tumors may require total laryngectomy
Neck dissection not warranted
Atypical carcinoid (Moderately differentiated neuroendocrine carcinoma) Partial or total laryngectomy with neck dissection
Small cell neuroendocrine carcinoma (Poorly differentiated neuroendocrine carcinoma) Therapeutic irradiation to larynx and neck with adjuvant chemotherapy
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