{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T07:44:16Z","timestamp":1791963856481,"version":"4.3.4"},"reference-count":66,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:00:00Z","timestamp":1791849600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:00:00Z","timestamp":1791849600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>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\u2010differentiated neuroendocrine tumours (NETs), poorly differentiated neuroendocrine carcinomas (NECs), and mixed neuroendocrine\u2013non\u2010neuroendocrine neoplasms (MiNENs), despite differences in biology, prognosis, and management. We systematically reviewed reported PHNENs using PRISMA\u2010based screening and expert pathology reappraisal within the WHO 6th edition morphology\u2010first 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\u2010level 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\u201067\/mitotic activity), as well as clinical\/imaging work\u2010up to exclude metastases from extrahepatic primaries. Of the 67 potentially eligible studies submitted to expert pathology\u2010based 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\u2010differentiated NETs (78.9%); NECs (8.8%), MiNENs (3.5%), and amphicrine carcinomas (1.8%) were less frequent. Some cases were high\u2010grade 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\u2010depth clinical\/imaging studies.<\/jats:p>","DOI":"10.1111\/liv.70921","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T06:44:17Z","timestamp":1791960257000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Primary Hepatic Neuroendocrine Neoplasms: Systematic Review and Expert Pathologist Reappraisal Using the\n                    <scp>WHO<\/scp>\n                    6th Edition Framework"],"prefix":"10.1111","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5693-9151","authenticated-orcid":false,"given":"Marcello","family":"Maestri","sequence":"first","affiliation":[{"name":"General Surgery Unit I\u2014Liver Service Fondazione IRCCS Policlinico San Matteo  Pavia Italy"},{"name":"Department of Clinical\u2010Surgical, Diagnostic and Pediatric Sciences University of Pavia  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9712-2553","authenticated-orcid":false,"given":"Ottavia","family":"Cicerone","sequence":"additional","affiliation":[{"name":"General Surgery Unit I\u2014Liver Service Fondazione IRCCS Policlinico San Matteo  Pavia Italy"},{"name":"Department of Clinical\u2010Surgical, Diagnostic and Pediatric Sciences University of Pavia  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7826-002X","authenticated-orcid":false,"given":"Alessandro","family":"Gambella","sequence":"additional","affiliation":[{"name":"Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DISC) University of Genoa  Genoa Italy"},{"name":"Azienda Ospedaliera Metropolitana (AOM) IRCCS Ospedale Policlinico San Martino  Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6477-3182","authenticated-orcid":false,"given":"Federica","family":"Grillo","sequence":"additional","affiliation":[{"name":"Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DISC) University of Genoa  Genoa Italy"},{"name":"Azienda Ospedaliera Metropolitana (AOM) IRCCS Ospedale Policlinico San Martino  Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1941-2403","authenticated-orcid":false,"given":"Stefano","family":"La Rosa","sequence":"additional","affiliation":[{"name":"Pathology Unit, Department of Medicine and Technological Innovation University of Insubria  Varese Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5714-7295","authenticated-orcid":false,"given":"Silvia","family":"Uccella","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences Humanitas University  Milan Italy"},{"name":"Department of Pathology IRCCS Humanitas Research Hospital  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2976-7032","authenticated-orcid":false,"given":"Alessandro","family":"Vanoli","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine\u2014Pathological Anatomy University of Pavia, Fondazione IRCCS Policlinico San Matteo  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,13]]},"reference":[{"key":"e_1_2_13_2_1","article-title":"Clinicopathological Characteristics and Survival Outcomes of Primary Hepatic Neuroendocrine Tumor: A Surveillance, Epidemiology, and End Results (SEER) Population\u2010Based Study","volume":"26","author":"Li Y. F.","year":"2020","journal-title":"Medical Science Monitor"},{"issue":"6","key":"e_1_2_13_3_1","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1016\/j.jceh.2019.08.002","article-title":"The Outcome of Primary Hepatic Neuroendocrine Tumors: A Single\u2010Center Experience","volume":"9","author":"Shah D.","year":"2019","journal-title":"Journal of Clinical and Experimental Hepatology"},{"issue":"9","key":"e_1_2_13_4_1","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.4251\/wjgo.v12.i9.1031","article-title":"Clinical Characteristics and Outcome of Primary Hepatic Neuroendocrine Tumors After Comprehensive Therapy","volume":"12","author":"Wang H. H.","year":"2020","journal-title":"World Journal of Gastrointestinal Oncology"},{"issue":"4","key":"e_1_2_13_5_1","doi-asserted-by":"crossref","first-page":"621","DOI":"10.5604\/01.3001.0010.0313","article-title":"Two Cases of Primary Hepatic Neuroendocrine Tumors and a Review of the Current Literature","volume":"16","author":"DeLuzio M. R.","year":"2017","journal-title":"Annals of Hepatology"},{"issue":"1","key":"e_1_2_13_6_1","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1002\/path.5977","article-title":"Molecular Deciphering of Primary Liver Neuroendocrine Neoplasms Confirms Their Distinct Existence With Foregut\u2010Like Profile","volume":"258","author":"Mestier L.","year":"2022","journal-title":"Journal of Pathology"},{"issue":"6","key":"e_1_2_13_7_1","doi-asserted-by":"crossref","first-page":"2759","DOI":"10.7314\/APJCP.2014.15.6.2759","article-title":"Computer Tomography and Magnetic Resonance Image Manifestations of Primary Hepatic Neuroendocrine Cell Carcinomas","volume":"15","author":"Huang J.","year":"2014","journal-title":"Asian Pacific Journal of Cancer Prevention"},{"key":"e_1_2_13_8_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.ijscr.2024.110647","article-title":"Role of Advanced Imaging in Primary Hepatic Neuroendocrine Tumor With Borderline Raised AFP and Negative Chromogranin Staining: A Case Report","volume":"125","author":"Fatima A.","year":"2024","journal-title":"International Journal of Surgery Case Reports"},{"issue":"4","key":"e_1_2_13_9_1","doi-asserted-by":"crossref","DOI":"10.1111\/jne.13495","article-title":"Primary Hepatic Neuroendocrine Neoplasms of Children, a Systematic Review","volume":"37","author":"Samady Khanghah A.","year":"2025","journal-title":"Journal of Neuroendocrinology"},{"issue":"2","key":"e_1_2_13_10_1","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1111\/his.13975","article-title":"The 2019 WHO Classification of Tumours of the Digestive System","volume":"76","author":"Nagtegaal I. 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