Refining Classification and Prognosis of Gastric Neuroendocrine Neoplasms: Virchows Archiv | November 2025

Introduction

Gastric neuroendocrine neoplasms (gNENs) represent a heterogeneous group of tumors with rising incidence, encompassing well-differentiated neuroendocrine tumors (NETs), poorly differentiated neuroendocrine carcinomas (NECs), and mixed neuroendocrine–non-neuroendocrine neoplasms (MiNENs). Accurate classification is critical, as clinical behavior ranges from indolent lesions amenable to endoscopic surveillance to aggressive malignancies requiring multimodal therapy. Recent advances emphasize the integration of histopathology with clinical and biochemical parameters, particularly in gastric NETs.

Problem Statement

Traditional classification based solely on proliferative indices (mitotic count and Ki-67) is insufficient in gastric NETs, where tumor biology is strongly influenced by the underlying clinicopathologic context. There is a need for a more practical and prognostically relevant framework that incorporates factors such as gastrin levels, gastric acid secretion, and background mucosal pathology to guide diagnosis and management.

Summary

This comprehensive review highlights that gNENs are classified into NETs, NECs, and MiNENs, with distinct biological and clinical profiles. Among these, enterochromaffin-like (ECL) cell NETs are most common and uniquely stratified into five subtypes based on pathogenetic mechanisms, including hypergastrinemia and acid secretion status. Type 1 NETs, associated with autoimmune atrophic gastritis, are typically indolent with excellent prognosis, whereas type 3 NETs arise sporadically and demonstrate aggressive behavior with higher metastatic potential. Intermediate forms, such as type 2 NETs linked to MEN1-associated gastrinoma, require targeted evaluation and management.

Importantly, the review proposes a simplified, clinically applicable classification based on gastrin levels and gastric acid status, enabling rapid risk stratification and treatment decisions. NECs and MiNENs remain highly aggressive entities with poor prognosis, necessitating early recognition and intensive therapy. Overall, integrating morphologic, immunophenotypic, and clinical data is essential for accurate diagnosis, prognostication, and personalized management of gastric neuroendocrine neoplasms.