Abstract
OBJECTIVE: High-grade neuroendocrine neoplasms (NENs) with a Ki-67 index >20% are currently classified as either grade 3 neuroendocrine tumors (NET G3) or neuroendocrine carcinomas (NEC). This study evaluates whether this subclassification is of diagnostic and prognostic significance. DESIGN: We analyzed 98 high-grade NENs from 87 patients, categorized into NET G3 (n = 19), NEC (n = 76), and equivocal cases (n = 3). METHODS: Histopathologic features, Ki-67 index, p53 and RB1 immunohistochemistry, growth patterns, necrosis, and somatostatin receptor type 2 (SSTR2) expression were assessed. Survival analyses were performed using Kaplan-Meier methods. RESULTS: NEC patients were older, had higher Ki-67 indices, and more often displayed solid growth, while NET G3 showed organoid architecture. Aberrant p53 and RB1 expression were significantly more common in NECs (P = 0.001 and P < 0.001). NET G3 patients had significantly longer overall survival than NEC patients (P = 0.03). Within NECs, tumor origin influenced prognosis: colorectal NECs had better outcomes (HR = 0.494, P = 0.027), while cancer of unknown primary (CUP) was associated with worse survival (HR = 2.033, P = 0.022). Notably, 81% of NECs expressed SSTR2, suggesting potential diagnostic and therapeutic relevance. CONCLUSIONS: NET G3 and NEC show distinct clinicopathologic and prognostic profiles. Tumor origin offers additional stratification within NECs, while SSTR2 expression may inform targeted approaches. These findings underscore the need for nuanced classification and personalized management of high-grade NENs.