Primary Hepatic Neuroendocrine Neoplasms: Systematic Review and Expert Pathologist Reappraisal Using the WHO 6th Edition Framework

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.