Head and Neck Large Cell Neuroendocrine Carcinoma Should Be Separated From Atypical Carcinoid On the Basis of Different Clinical Features, Overall Survival, and Pathogenesis

Abstract

According to the 2005 World Health Organization classification of head and neck tumors, neuroendocrine tumors can be subdivided into typical carcinoid, atypical carcinoid, and small cell carcinoma. Similar tumors diagnosed as large cell neuroendocrine carcinomas (LCNECs) in the lung are diagnosed as atypical carcinoids in the head and neck region. We studied neuroendocrine tumors and analyzed whether LCNEC should be separated from atypical carcinoid in the head and neck region. Twenty-three cases of primary head and neck neuroendocrine tumors were included and subdivided into typical carcinoid, atypical carcinoid, and small cell carcinoma according to the 2005 World Health Organization guidelines, and then LCNECs were separated from atypical carcinoids according to modified criteria using the Ki-67-labeling index and mitotic count. Clinical information and survival data were obtained, and immunohistochemical studies for p53 were conducted. The 5-year survival rates for the 2 typical carcinoids, 7 atypical carcinoids, 7 LCNECs, and 7 small cell carcinomas were 100.0%, 83.3%, 21.4%, and 20.8%, respectively (P=0.032). The LCNEC patients were older (mean age, 61 vs. 41 y; P=0.038), more commonly in advanced stage (stages III and IV 100% vs. 28.6%, P=0.01), with a poorer prognosis (5-year survival 21.4% vs. 83.3%, P=0.03), and more commonly had tumors overexpressing p53 (85.7% vs. 0%, P=0.005) as compared with atypical carcinoid patients. LCNECs should be separated from atypical carcinoids as a new entity of neuroendocrine carcinoma in the head and neck region. The new classification may provide better risk stratification and useful information for proper treatment.

ISL1 expression is not restricted to pancreatic well-differentiated neuroendocrine neoplasms, but is also commonly found in well and poorly differentiated neuroendocrine neoplasms of extrapancreatic origin

“…In addition to ISL1, we stained a substantial fraction of the cases with TP53, which is known to be overexpressed in poorly differentiated neuroendocrine neoplasms of the pancreas 16 and neuroendocrine carcinomas from extrapancreatic sites. 17 We demonstrate in particular that ISL1 expression is mostly lost in pancreatic poorly differentiated neuroendocrine neoplasms, while it is almost ubiquitously observed in their extrapancreatic neuroendocrine counterparts. TP53 expression was inversely related to ISL1 positivity in poorly differentiated neuroendocrine neoplasms of the pancreas, but paralleled that of ISL1 in poorly differentiated extrapancreatic neuroendocrine neoplasms.…”

“…These features have also been observed in large cell neuroendocrine carcinomas and atypical carcinoids of the head and neck, and have been used as a distinguishing criterion. 17,21 In extrapancreatic neuroendocrine neoplasms, including neuroendocrine neoplasms of neuroblastic origin, ISL1 expression lacks the relationship to histological differentiation seen in pancreatic neuroendocrine neoplasms. Almost all extrapancreatic neuroendocrine carcinomas that were studied including Merkel cell carcinomas and neuroendocrine carcinomas of the lung and head and neck region strongly expressed ISL1.…”

Update from the 4th Edition of the World Health Organization Classification of Head and Neck Tumours: What is New in the 2017 WHO Blue Book for Tumours of the Hypopharynx, Larynx, Trachea and Parapharyngeal Space

“…The terminology and classification of laryngeal neuroendocrine carcinomas have been changed and adjusted with recognition of the different biological behaviour and histological features of a particular entity in comparison with the classification used in previous edition [11][12][13]. Large cell neuroendocrine carcinoma, the main target of disagreement, which was previously grouped with atypical carcinoid/moderately differentiated NEC, grade II, is now transferred into a subtype of poorly differentiated NEC, grade III.…”

“…Thus, in the WHO Blue Book 2017, the classification of neuroendocrine tumours is now categorized as follows: well-differentiated, moderately-differentiated (Fig. 4a) and poorly-differentiated neuroendocrine carcinoma, which is additionally divided into two subtypes: small cell NEC (SmCNEC) and large cell NEC (LCNEC) [12,13,52,53].…”

“…Particular attention is devoted to two histological subtypes of poorly differentiated NEC: small cell NEC (SmCNEC) and large cell NEC (LCNEC). LCNEC, which was grouped in the previous edition, WHO 2005, with atypical carcinoid/ moderately-differentiated neuroendocrine carcinoma, grade II, is now transferred to a subtype of poorly differentiated NEC, grade III, since these tumours show a specific morphology and are associated with a poorer outcome [11][12][13].…”