Gastroenteropancreatic Neuroendocrine Neoplasms: Clinical and Translational Perspectives

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a heterogeneous group of malignancies characterized by the expression of neuroendocrine markers. In recent years, GEP-NENs have gained increasing clinical attention because of their rising prevalence and the need for more effective therapeutic strategies for them. GEP-NENs are classified into gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs), based on the Ki-67 proliferation index and histological differentiation. GEP-NETs are generally characterized by relatively indolent clinical behavior, typically limited genomic alterations, and responsiveness to molecularly targeted therapies, whereas GEP-NECs are highly aggressive neoplasms frequently harboring TP53 and RB1 alterations, and are typically treated with cytotoxic chemotherapy. Though these definitions provide a useful framework for tumor classification, real-world GEP-NENs frequently exhibit substantial intra- and intertumoral heterogeneity, making clinical interpretation considerably more complex. Recently, a subset of well-differentiated neoplasms with high Ki-67 indices has been recognized as gastroenteropancreatic neuroendocrine tumors G3 (GEP-NETG3), representing tumors that do not fit neatly into the conventional classification system. Treatment strategy for GEP-NETG3 highlights the difficulties faced for filling the gap between pathological classification and biomarkers currently used to guide clinical management. Addressing this challenge requires a multifaceted approach, integrating clinical and translational research to better capture the biological complexity of these tumors. In this review, we summarize the current understanding of GEP-NENs, focusing on their biological features, therapeutic implications, and emerging insights from both clinical and translational research perspectives.