Primary Hepatic Neuroendocrine Neoplasms: Systematic Review and Expert Pathologist Reappraisal Using the WHO 6th Edition Framework
TL;DR
PHNEN literature is constrained by rarity, uncertainty of hepatic origin, and historical misclassification, so future studies and registries should report a minimum diagnostic dataset with standardised terminology according to the WHO 6th edition framework and in‐depth clinical/imaging studies.
Abstract
Primary hepatic neuroendocrine neoplasms (PHNENs) are exceedingly rare. Published evidence often lacks adequate clinicopathological support for a primary hepatic origin and uses inconsistent historical terminology. Previous reviews have pooled well‐differentiated neuroendocrine tumours (NETs), poorly differentiated neuroendocrine carcinomas (NECs), and mixed neuroendocrine–non‐neuroendocrine neoplasms (MiNENs), despite differences in biology, prognosis, and management. We systematically reviewed reported PHNENs using PRISMA‐based screening and expert pathology reappraisal within the WHO 6th edition morphology‐first framework. A systematic literature search was conducted in PubMed/MEDLINE, Scopus, and Web of Science. Titles, abstracts, and full texts were screened according to predefined eligibility criteria; eligible articles underwent second‐level expert assessment of pathology, including morphology (including NET G3 vs. NEC and MiNEN vs. amphicrine carcinoma), immunohistochemistry (expression of at least two NE markers), proliferation (Ki‐67/mitotic activity), as well as clinical/imaging work‐up to exclude metastases from extrahepatic primaries. Of the 67 potentially eligible studies submitted to expert pathology‐based reappraisal, 28 studies (49.1%) were retained in the final dataset with 57 likely NEN cases (mainly case reports/small case series). Among the 57 cases, most were well‐differentiated NETs (78.9%); NECs (8.8%), MiNENs (3.5%), and amphicrine carcinomas (1.8%) were less frequent. Some cases were high‐grade NENs that could not be distinguished as well or poorly differentiated (7%). PHNEN literature is constrained by rarity, uncertainty of hepatic origin, and historical misclassification. Future studies and registries should report a minimum diagnostic dataset with standardised terminology according to the WHO 6th edition framework and in‐depth clinical/imaging studies.