Historical Evolution of Terminology and Current Classification of Neuroendocrine Neoplasms of the Larynx and Mixed Neuroendocrine–Non-Neuroendocrine Neoplasms (MiNENs): A Narrative Review

Abstract

This is a narrative review that describes the evolution of terminology and classification schemes of neuroendocrine tumors (NETs), neuroendocrine carcinomas (NECs), mixed neuroendocrine–non-neuroendocrine neoplasms (MiNENs), and paragangliomas of the larynx, with the contribution of immunohistochemistry and treatment of neuroendocrine neoplasms of the larynx. Neuroendocrine neoplasms of the larynx comprise both epithelial (NET and NEC) and neural crest-derived (paraganglioma) neoplasms. Their terminology has evolved substantially over time, with current classifications emphasizing biologically and clinically meaningful categories aligned with contemporary WHO frameworks of other organs. These neoplasms may show overlapping clinical presentation and histomorphological features, which can complicate accurate subclassification. However, precise classification is essential, as these entities display markedly different biological behavior, ranging from indolent to highly aggressive with poor prognosis, and their treatment is essentially histology-tailored. Neuroendocrine neoplasms are classified into three categories comprising six tumor subtypes: well-differentiated neuroendocrine tumors (NETs; grades 1, 2, and 3), poorly differentiated neuroendocrine carcinomas (NECs; small-cell and large-cell types), and paragangliomas. An additional, not yet WHO-recognized category is MiNENs (mixed neuroendocrine–non-neuroendocrine neoplasms), defined by the coexistence of neuroendocrine and non-neuroendocrine components. These tumors exhibit distinct biological behavior and clinical significance.