Differentiating well-differentiated neuroendocrine tumors grade 3 from poorly differentiated neuroendocrine carcinomas and adenocarcinoma with neuroendocrine differentiation: a comprehensive review

Abstract

Gastroenteropancreatic well-differentiated neuroendocrine tumors (NETs) exhibit markedly different behavior and responses to therapy compared to poorly-differentiated neuroendocrine carcinomas (NECs). However, in certain NETs-particularly grade 3 (Ki-67 > 20%) and the more recently recognized subgroup of G2b (Ki-67 of 10%- <= 20%)-often display ambiguous morphology or overlap with NECs and are associated with more aggressive clinical behavior, leading oncologists to consider whether these tumors may require management approaches similar to NECs. In some cases, a more aggressive clonal population evolves from a pre-existing NET. This may present as a distinct focus at diagnosis (suggesting intratumoral heterogeneity), or more commonly, a NET adopts NEC-like morphology and behavior over time (suggesting transformation). To distinguish these challenging cases, we recommend thorough pathological evaluation and a multidisciplinary approach. Particular attention should be given to necrosis, especially comedo-type patterns. Immunohistochemistry (IHC), including p53, Rb, and, if feasible, p16, ATRX, DAXX, and POU2F3 may provide insights Functional imaging-especially the DOTATATE to FDG uptake ratio-can further assist in assessing tumor behavior. These principles also apply to neuroendocrine neoplasms (NENs) associated with adenomas or adenocarcinomas. Occasionally, post-neoadjuvant resections reveal morphologically classic neuroendocrine component that were not identified in initial biopsies, raising questions about unsampled components, clonal selection, or therapy-induced change. In such cases, even when the Ki-67 index is low, NEC-like morphology should be documented in the report and the patient monitored closely due to the potential for progression. In conclusion, all gastroenteropancreatic neuroendocrine neoplasms should be extensively sampled for NEC-like features. A formal Ki-67 index must be determined using standardized methods. Cases with Ki-67 > 10% require careful evaluation. At minimum, patients should undergo close surveillance, with treatment plans reassessed if rapid progression or PET changes are observed.