# Neuroendocrine Neoplasms of the Gastrointestinal Tract: Morphology, WHO 2022 Grading, and Prognostic Perspectives

## TL;DR

This review discusses the classification, diagnosis, and treatment of gastrointestinal neuroendocrine tumors, emphasizing recent advances in grading and prognosis.

## Contribution

The paper provides a comprehensive overview of diagnostic challenges and emerging biomarkers in GI NENs under the WHO 2022 grading system.

## Key findings

- Differentiating NET G3 from NEC remains a major diagnostic challenge due to overlapping features.
- Molecular profiling and AI are promising tools for improving prognostication and personalized treatment.
- Standardized diagnostic approaches are needed to reduce variability in Ki-67 interpretation and sampling.

## Abstract

Gastrointestinal neuroendocrine neoplasms (GI NENs) represent a heterogeneous group of tumors distinguished by variable morphology, proliferative behavior, and clinical outcomes. Their incidence continues to rise globally, driven by improved detection methods and increased understanding of neuroendocrine biology. This narrative review synthesizes current knowledge on the morphologic, immunohistochemical, and molecular features of GI NENs across anatomic sites, highlighting advances in diagnostic evaluation and the prognostic significance of the WHO 2022 grade. Key diagnostic challenges, including differentiating neuroendocrine tumor grade 3 (NET G3) from neuroendocrine carcinoma (NEC) and accurately assessing mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs), are examined alongside sources of variability such as Ki-67 interpretation and sampling limitations. Emerging prognostic biomarkers, digital pathology applications, and evolving therapeutic strategies, particularly somatostatin analogs, peptide receptor radionuclide therapy, and systemic chemotherapy, are reviewed in the context of precision oncology. Continued integration of molecular profiling, artificial intelligence, and standardized diagnostic approaches promises to refine prognostication and personalize management for patients with GI NENs.