Neuroendocrine Tumors (NETs) of the Larynx

Abstract

To review the current state of knowledge regarding neuroendocrine tumors (NETs) of the larynx, with a particular focus on their epidemiology, etiopathogenesis, clinico-pathological features, immunohistochemical profile, and differential diagnostics. Narrative review. Diagnostic criteria for laryngeal NETs were recently defined in the 5th edition of the WHO Classification of Head and Neck Tumors, which newly introduces the entity of NET, grade 3 (G3 NET). However, some of these criteria are still considered provisional. The most common NET of the larynx is the G2 NET. These tumors typically affect older men, with the supraglottic region being the most frequent localization. For a definitive diagnosis, it is essential to demonstrate the epithelial origin and neuroendocrine differentiation of these tumors using cytokeratins and neuroendocrine markers (e.g., chromogranin, INSM1, synaptophysin). The differentiation between individual NET types is based on mitotic activity and/or Ki-67 proliferation index, as well as the presence or absence of necrosis. Laryngeal NETs typically exhibit wild-type p53 expression and retained Rb1 and somatostatin receptor 2 expression. This can be utilized in the differential diagnosis from neuroendocrine carcinomas (NECs). Given that laryngeal NETs frequently express calcitonin, they must be differentiated from medullary thyroid carcinoma (MTC), particularly in lymph node metastases. A high frequency of HRAS gene mutations has been recently demonstrated in laryngeal NETs, underlining their distinctness from their gastroenteropancreatic and thoracopulmonary counterparts. By utilizing the proposed diagnostic criteria for individual types of laryngeal NETs, it is anticipated that more precise knowledge regarding the clinico-pathological characteristics of these exceedingly rare tumors will be obtained, particularly with respect to their biological behavior and prognosis.