Update on Neuroendocrine Carcinomas of the Larynx

Carolina Strosberg, MD; Alfio Ferlito, MD, DLO, DPath, FRCSEd ad hominem, FRCS (Eng, Glasg, Ir) ad eundem, FDSRCS ad eundem, FACS, FHKCORL, FRCPath, FASCP, IFCAP; Asterios Triantafyllou, PhD (Lond), FRCPath; Douglas R. Gnepp, MD; Justin A. Bishop, MD; Henrik Hellquist, MD, PhD, SAPath (Stockh), FRCPath; Primoz Strojan, MD, PhD; Stefan M. Willems, MD, PhD; Göran Stenman, DMD, PhD, FRCPath; Alessandra Rinaldo, MD, FRCSEd ad hominem, FRCS (Eng, Ir) ad eundem, FRCSGlasg, FACS; Juan C. Hernandez-Prera, MD


Am J Clin Pathol. 2019;152(6):686-700. 

In This Article

Well-differentiated Neuroendocrine Carcinoma of the Larynx

Well-differentiated neuroendocrine carcinomas are the least common type of neuroendocrine carcinoma of the larynx. Most commonly they occur in men in the sixth decade presenting with hoarseness. Smoking is generally a risk factor and, thus far, only one case has been reported in the literature with an associated carcinoid syndrome after developing liver metastases.[12] These neoplasms occur most often in the supraglottic area and grossly are characterized by a submucosal nodular or polypoid mass with a tan-white appearance varying in size from a few millimeters up to 3 cm in diameter. Notably, the terminology "tumorlet," used to describe a lung neuroendocrine tumor less than 5 mm, has not yet been applied in the larynx.[9]

Histologically, well-differentiated neuroendocrine laryngeal carcinomas have an organoid or trabecular growth pattern and a fibrovascular stroma Image 1A. The tumor cells are uniform with variably indistinct boundaries, increased nuclear:cytoplasmic ratio, eosinophilic cytoplasm, centrally located round nuclei, stippled "salt and pepper" chromatin, and inconspicuous nucleoli Image 1B. Some tumors may have focal or widespread spindle cell morphology. Marked pleomorphism and necrosis are absent by definition and the mitotic activity is low (fewer than two mitoses per 2 mm2 or 10 high-power fields [hpfs]).[5,9] Using classic histochemical techniques, black intracytoplasmic material is typically identified by argyrophilic or argentaffin stains. These tumors are consistently and strongly positive for AE1/AE3 and CAM5.2, and usually express epithelial membrane antigen (EMA) and carcinoembryonic antigen (CEA). In addition, CK7, CK20, and thyroid transcription factor 1 (TTF-1) may variably show some positivity.[9] Immunoreactivity for synaptophysin, chromogranin, CD56, and neuron-specific enolase is expected and consistent with the neuroendocrine origin of these tumors.[13,14] Expression of other neuroendocrine related peptides (ie, serotonin and somatostatin) has also been reported. Ultrastructural studies demonstrate abundant neurosecretory granules (90–230 nm), cellular junctional complexes, and inter- and intracellular lumina.[13]

Image 1.

Well-differentiated (A and B) and moderately differentiated (C and D) neuroendocrine carcinomas. A, Low magnification shows a submucosal tumor with organoid and trabecular growth (x40). B, The neoplastic cells are uniform with eosinophilic cytoplasm, round to oval centrally located nuclei, stippled chromatin in a "salt and pepper" configuration; note that no mitosis, pleomorphism, or necrosis are observed (x400). C, Low magnification shows a submucosal tumor growing in nests and solid sheets (x40). D, High magnification shows increased pleomorphism, nuclear hyperchromasia, and prominent nucleoli (x600).

Conservative but complete surgical resection, either partial laryngectomy or carbon dioxide laser resection, is the treatment of choice for well-differentiated laryngeal neuroendocrine carcinomas, and neck dissection is not indicated for a clinically negative neck.[15] Owing to the rarity of these tumors, data on survival and prognosis are scarce and based on case reports and metaanalyses. The majority of patients with well-differentiated neuroendocrine carcinomas seem to present with local disease with rare evidence of nodal metastases at the time of diagnosis (83.3% with stage I); these patients have a 5-year overall survival as high as 81.7%.[9,15] However, metastases to liver, bone, lymph nodes, and skin eventually develop in approximately 30% to 33% of cases, and at least two deaths have been reported.[13,15,16] Therefore, due to the well-documented metastatic potential of these tumors, they should not be regarded as indolent.[17]

Besides making the difference between well- and moderately differentiated neuroendocrine carcinoma based on mitotic rate and necrosis, the main differential diagnosis of well-differentiated neuroendocrine carcinoma is laryngeal paraganglioma. Similar to well-differentiated neuroendocrine carcinoma, the latter presents as a submucosal mass of the supraglottic larynx, presumably originating from the superior laryngeal paraganglia.[12] The histologic appearance is similar to paragangliomas arising in other sites. The absence of immunoreactivity for epithelial markers and identification of S100-protein–positive sustentacular cells are not features of well-differentiated neuroendocrine carcinomas but are typically seen in laryngeal paragangliomas.[14,18] Rare examples of cytokeratin-positive paragangliomas have been reported; however, the staining pattern is neither as diffuse nor strong as in well-differentiated neuroendocrine carcinomas.[19] More recently, GATA3, which is absent in neuroendocrine carcinomas, has emerged as a reliable marker for paragangliomas.[20]