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

Moderately Differentiated Neuroendocrine Carcinoma of the Larynx

Moderately differentiated neuroendocrine carcinomas are the most common type of laryngeal neuroendocrine carcinoma and, due to their relatively higher frequency, their clinicopathologic features are better understood. The majority of cases occur in male patients with a mean patient age of 61 years (range, 36–83 years) and a history of heavy tobacco smoking.[3] Historically, four cases associated with carcinoid syndrome have been reported; however, in retrospect at least one of these cases is currently better classified as a large cell neuroendocrine carcinoma.[21,22] The tumors present as supraglottic masses in the arytenoids, epiglottis, or aryepiglottic folds, commonly causing hoarseness or dysphagia. Similar to well-differentiated types, they may appear as polypoid or submucosal in association with surface ulceration. Their size varies from a few millimeters up to 4 cm in diameter; upon sectioning, they exhibit a tan-white surface.[3,23]

Moderately differentiated neuroendocrine carcinomas are also arranged in organoid, trabecular, cribriform, or solid growth patterns embedded in a prominent fibrovascular stroma Image 1C. They exhibit an infiltrative growth, including neurotropism and angioinvasion. The neoplastic cells show mild to marked cellular pleomorphism with round to oval nuclei, vesicular to hyperchromatic chromatin, and eosinophilic cytoplasm Image 1D. The nuclei can be centrally or eccentrically located, and nucleoli may be prominent. Oncocytic cytoplasmic changes, as well as focal glandular and squamous differentiation may be present.[3,14] According to the 2017 WHO Classification of Head and Neck Tumors, the identification of necrosis and/or a mitotic count of two to 10 mitoses per 2 mm2 or 10 hpfs are defining diagnostic features Image 2A.[9]

Image 2.

Moderately differentiated neuroendocrine carcinoma. A, High-power field showing cells with mild pleomorphism and one mitosis (x600). Immunoreactivity for (B) calcitonin (x100), (C) synaptophysin (x100), and (D) insulinoma-associated protein 1 (x200).

The majority of tumor cells diffusely express cytokeratins, synaptophysin, chromogranin, and CD56 Image 2C.[14] Moreover, the expression of insulinoma-associated protein 1 (INSM1) is a useful immunohistochemical marker to prove neuroendocrine differentiation in these tumors Image 2D.[24] Other positive markers include neuron-specific enolase, CD56, Leu 7 (CD57), neurofilament protein, EMA, and CEA.[23] In addition, S100 protein, somatostatin, serotonin, adrenocorticotropic hormone (ACTH), gastrin, and glucagon may also be positive.[3,14,23] Up to 80% of the cases have immunoreactivity for calcitonin, making the differentiation between moderately differentiated laryngeal neuroendocrine carcinoma and medullary thyroid carcinoma very difficult, especially when dealing with metastatic disease to cervical lymph nodes.[3] Both tumor types exhibit morphologic and immunophenotypic similarities, including similar growth patterns and reactivity for cytokeratins, synaptophysin, calcitonin, and CEA Image 2B. Clinical parameters can assist when this problem is encountered. The presence of a thyroid-based mass and increased serum calcitonin levels supports the diagnosis of medullary thyroid carcinoma. In addition, TTF-1 is strongly and diffusely positive in medullary thyroid carcinoma and usually negative in moderately differentiated neuroendocrine carcinoma, although some cases may be reactive.[1,3,9,14,23,25]

The identification of more than two mitoses per 2 mm2 or 10 hpfs and/or necrosis are the main criteria separating moderately from well-differentiated laryngeal neuroendocrine carcinoma.[9] Increased proliferation assessed by Ki67 (MIB1) is generally seen. Although several classification schemes based on Ki67 proliferation index have been proposed, no defined diagnostic cutoff have been validated and recognized to date, such as those for neuroendocrine tumors in the gastrointestinal tract.[9,26–28] Moreover, increased nuclear atypia, moderate pleomorphism, and prominent nucleoli should weigh in favor of moderately differentiated neuroendocrine carcinoma.

The majority of patients with moderately differentiated neuroendocrine carcinomas of the larynx present at early stage disease, while approximately 30% present with early distant metastases and advanced stage. Metastatic disease to the lung, bone, and liver has been reported in 38% to 44% of cases, while skin and subcutaneous metastasis are found in about 22% of patients.[15,23] In addition to the extent of disease at presentation, the size of the primary tumor has prognostic significance. Tumors measuring greater than 1 cm have been reported to have twice the mortality rate of lesions measuring less than 1 cm.[3,15,23]

Due to its clinical behavior, the recommended treatment for moderately differentiated neuroendocrine carcinomas is radical surgical resection. In a recent metaanalysis of 163 cases, van der Laan et al[15] reported a rate of regional recurrence of 28% in patients who did not receive neck dissection vs 0% for patients who underwent a radical neck surgical resection. Similar data were reported by Woodruff et al[23] in 1991, with nodal metastases observed in 43% of cases and a 30% rate of regional recurrences in patients who did not receive treatment of the neck. Therefore, neck dissection is warranted even with a clinically negative neck.[29] Surgery plus radiotherapy appears to be the second most frequent therapeutic modality, although a survival benefit has not been shown for this treatment and data suggest adjuvant radiotherapy might have no role in treating these tumors.[15] Regardless of adequate treatment, recurrences are common (62.5%) and can occur beyond 5 years of follow-up, as shown by a drop in 10-year disease-specific survival (DSS) compared to 5-year DSS (31.9% vs 52.8%, respectively). Therefore, a longer follow-up period, 10 years or more, is strongly advised.[15] Overall 5-year survival has been reported to be around 46% to 50%, and DSS has shown to be strongly correlated to tumor stage and treatment modality.[11,15,23] Patients with stage IV disease often do far worse when compared to patients with stages I to III (DSS of 8.5% vs 25.9% to 45.8%, respectively). Patients treated with surgery have a longer DSS (60.2%) in contrast to those who received radiotherapy only (53.8%); similar results were observed for patients who had received postoperative radiotherapy.[11,15,23]