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Background
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)
ParagangliomaOUTLINE
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS INCIDENCE 3% carcinoid tumors
54% atypical carcinoid tumors
34% small cell neuroendocrine carcinomas
9% paragangliomaAGE RANGE-MEDIAN 58 years (45-80 years) Most frequent neuroendocrine laryngeal tumor
61 years (36-83 years)50-70 years (23-91 years)
3% <40 yearsMales Males 74%
DISEASE ASSOCIATIONS CHARACTERIZATION Heavy smoking history Heavy smoking history
Schwartz-Bartter syndrome (Hypersecretion of the ADH)
Eaton-Lamber syndrome
Cushing's syndrome
LABORATORY/
RADIOLOGIC/
OTHER TESTSCHARACTERIZATION RADIOLOGIC LABORATORY MARKERS Most are aneuploid
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION GENERAL 83% occurred in the supraglottic larynx
Average 1.6 cm (0.5-3 cm)Supraglottic larynx
1.6 cm (0.2-4 cm)Majority supraglottic larynx VARIANTS
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL Small uniform cells growing in nests, cords, sheets, or glands
Pseudorosettes occasionally
Cells with clear to eosinophilic cytoplasm
Round to oval, spindled nuclei with finely stippled chromatin
No nucleoli, mitoses, necrosis, or pleomorphism
Highly vascular stromaLarger cells with occasional mitoses, prominence of nucleoli, and pleomorphism
May be cystic with intracystic projections of tumor cellsSheets 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 adenocarcinomaVARIANTS COMBINED
- 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.MEDULLARY CARCINOMA-LIKE 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.
SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHERCHARACTERIZATION Argyrophil positive (Grimelius stain)
Argentaffin negative (Fontana-Masson stain)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-100Medullary carcinoma of the thryoid Positive for NSE, chromagranin, keratin, CEA, calcitonin, congo red for amyloid
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Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
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Last Updated November 11, 2004
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