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Grade Progression and High-Grade Transformation in Neuroendocrine Neoplasms
Journal article   Peer reviewed

Grade Progression and High-Grade Transformation in Neuroendocrine Neoplasms

Udhayvir S Grewal, Matthew Gosse, Seth J Concors, Raul S Gonzalez, Po Hien Ear, Daniel M Halperin, Chandrikha Chandrasekharan, Simron Singh and Andrew M Bellizzi
Endocrine-related cancer, Vol.33(7), e260017
07/13/2026
DOI: 10.1530/ERC-26-0017
PMID: 42439380

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Abstract

Epithelial neuroendocrine neoplasms (NENs) comprise a biologically diverse group of malignancies that span a wide spectrum of differentiation, proliferative activity, and clinical behavior. Contemporary classifications distinguish well-differentiated neuroendocrine tumors (NETs) from poorly differentiated neuroendocrine carcinomas (NECs). However, growing longitudinal data indicate a subset of NETs may undergo temporal evolution characterized by rising Ki-67, increasing morphologic atypia, and acquisition of genomic alterations classically associated with NEC, particularly TP53 and, less commonly, RB1 inactivation. These phenomena, referred to as grade progression and high-grade transformation, can result in tumors with NEC-like behavior despite retention of a NET molecular backbone, creating diagnostic and therapeutic ambiguity. In this review, we synthesize recent evidence on the molecular, morphologic, and clinical features of gastroenteropancreatic NET grade progression and transformation, highlight the role of clonal evolution and treatment-associated selection pressure, and discuss implications for imaging, biopsy strategy, molecular profiling, and therapy selection.

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