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

Classification of Neuroendocrine Carcinomas of the Larynx: Historical Evolution

An early proposal by Woodruff et al[1] in 1985 divided laryngeal neuroendocrine carcinomas into two major histologic types, small cell and large cell. The former subtype referred to tumors with morphologic resemblance to pulmonary small cell carcinoma, while the latter corresponded to tumors composed of cells with moderate to abundant cytoplasm, predominately arranged in nests, cords, or ribbons. According to this system, large cell neuroendocrine carcinoma was further divided into two subgroups based on differentiation. The first subgroup resembled atypical pulmonary carcinoids, while the second subgroup consisted of less differentiated neoplasms with intermediate cell morphology exhibiting a mixture of large and small cells.[1] It is important to note that the nomenclature "large cell neuroendocrine carcinoma" from the Woodruff's system did not derive from the diagnostic term "pulmonary large cell neuroendocrine carcinoma," a tumor that was not completely defined until 1991.[2]

In 1988, Wenig et al[3] adapted the classification of Gould et al[4] of neuroendocrine carcinomas of the lung and separated laryngeal neuroendocrine carcinomas into three categories: well-differentiated neuroendocrine carcinoma, moderately differentiated neuroendocrine carcinoma, and poorly differentiated neuroendocrine carcinoma. This reflected an attempt to standardize terminology, allowing for a more uniform correlation between histology and biologic behavior. The second edition of the WHO histologic typing published in 1991 adopted this concept, but endorsed instead the terms typical carcinoid, atypical carcinoid, and small cell carcinoma, respectively; small cell carcinoma was further subdivided into oat cell, intermediate cell, and combined cell types.[5]

The revised 2005 WHO classification of head and neck tumors continued this trend and partially mirrored the 2004 WHO classification of tumors of the lung.[6,7] Accordingly, laryngeal neuroendocrine carcinomas were divided into four categories: typical carcinoid, atypical carcinoid, small cell carcinoma, and combined small cell carcinoma with non-small cell carcinoma. In addition, the cardinal distinguishing features of the lung classification, that is, mitotic activity and necrosis, were applied to laryngeal neuroendocrine carcinomas. At that time, the term "large cell neuroendocrine carcinoma" did not feature in the laryngeal system as a distinct category, and tumors that fulfilled diagnostic criteria for large cell neuroendocrine carcinoma in the lung were designated as atypical carcinoid.[6]

Since 2005, the strict and widespread use of diagnostic criteria of pulmonary large cell neuroendocrine carcinoma prompted reconsideration and eventually led to increased recognition of this type in the larynx. Different groups have provided evidence that large cell neuroendocrine carcinoma should be separated from atypical carcinoid and regarded as a distinct subtype based on its singular clinical, morphologic, and immunohistochemical features.[8] Consequently, the classification evolved and now includes large cell neuroendocrine carcinoma as a distinct subtype of high-grade neuroendocrine carcinoma in the larynx. The recent 2017 WHO Classification of Head and Neck Tumors has endorsed these changes and lists large cell neuroendocrine carcinoma and small cell neuroendocrine carcinoma under the rubric of poorly differentiated neuroendocrine carcinoma.[9] The updated classification follows the nomenclature proposed by Wenig et al[3] in the late 1980s and later supported by Mills[10] in 2002, which aims to combine histology and clinical behavior in one terminology: well-differentiated neuroendocrine carcinoma, moderately differentiated neuroendocrine carcinoma, and poorly differentiated neuroendocrine carcinoma.[11]