Neuroendocrine Carcinoma of the Larynx and Pharynx: A Clinical and Histopathological Study

SIMPLE SUMMARY: Neuroendocrine carcinomas (NECs) of the head and neck are rare. The presented series of 20 patients with laryngeal and pharyngeal NECs is population-based and one of the largest published to date. We analyzed the treatment results according to the type of therapy and the role of various standard (synaptophysin-chromogranin-CD56, Ki-67, p16, HPV, and EBV) and some novel (INSM1 and PD-L1) neuroendocrine markers or potential prognosticators. The results indicate the following: (1) laryngeal and pharyngeal NECs accounted for 0.43% and 0.17% of the cases in the corresponding tumor groups, respectively; (2) neuroendocrine differentiation can be reliably determined by INSM1 immunohistochemistry; (3) the prognosis was determined by the nodal stage and TNM stage but not by the histological grade (which refers to moderately and poorly differentiated NECs); (4) except in well-differentiated NECs and early-stage (T1-2N0-1) moderately/poorly differentiated NECs, aggressive multimodal therapy is needed; and (5) the p16, HPV, and EBV statuses failed to show any prognostic value. ABSTRACT: Neuroendocrine carcinomas (NECs) of the head and neck are rare and the experience scanty. The Cancer Registry of Slovenia database was used to identify cases of laryngeal and pharyngeal NECs diagnosed between 1995–2020. Biopsies were analyzed for the expression of standard neuroendocrine markers (synaptophysin, chromogranin, CD56), INSM1, Ki-67, p16, and PD-L1 (using the combined positive score, CPS). In situ hybridization for human papillomavirus (HPV) and Epstein–Barr virus (EBV) was performed. Twenty patients (larynx, 12; pharynx, 8) were identified. One tumor was well differentiated (WD), five were moderately differentiated (MD), and 14 were poorly differentiated (PD). Disease control was achieved solely by surgery in 4/4 MD/PD T1-2N0-1 tumors. Eight patients died of the disease, seven of which were due to distant metastases. All three traditional markers were positive in 11/17 NECs and the INSM1 marker in all 20 tumors. Two of fourteen p16-positive tumors were HPV-positive, but all three nasopharyngeal NECs were EBV-negative. Three tumors had CPSs ≥ 1. In conclusion, INSM1 was confirmed to be a reliable marker of neuroendocrine differentiation. Except in WD and early-stage MD/PD tumors, aggressive multimodal therapy is needed; the optimal systemic therapy remains to be determined. p16, HPV, and EBV seem to bear no prognostic information.