{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:55:39Z","timestamp":1792000539627,"version":"4.4.0"},"reference-count":47,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,7,11]],"date-time":"2022-07-11T00:00:00Z","timestamp":1657497600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Isolated hepatic localizations of neuroendocrine tumors (NETs) are generally considered as metastatic NETs of unknown primary but could correspond to primary hepatic NETs (PHNETs), a poorly explored entity. We aimed to describe the clinicopathological and molecular features of PHNETs and compare them with other primary NETs. We assembled a retrospective cohort of patients managed for hepatic localization of NET without extra\u2010hepatic primary tumor after exhaustive clinical, imaging, and immunohistochemical characterization. We performed whole\u2010exome sequencing with mutational and copy number analysis. Transcriptomic profiles were compared with pancreatic (<jats:italic>n<\/jats:italic>\u2009=\u200931), small\u2010bowel (<jats:italic>n<\/jats:italic>\u2009=\u200922), and lung (<jats:italic>n<\/jats:italic>\u2009=\u200915) NETs using principal component analysis, unsupervised clustering, and gene set enrichment analysis. Among 27 screened patients, 16 had PHNET (solitary tumor in 63%, median size 11\u2009cm, G2 NETs in 81%) following clinical and pathological review. DNA analyses showed \u2018foregut\u2010like\u2019 genomic profiles with frequent alterations in pathways of Fanconi DNA repair (75%), histone modifiers (58%), adherens junctions (58%), and cell cycle control (50%). The most frequently involved genes were <jats:italic>KMT2A<\/jats:italic> (58%), <jats:italic>ATM<\/jats:italic> (42%), <jats:italic>CDH1<\/jats:italic>, <jats:italic>CDKN2C<\/jats:italic>, <jats:italic>FANCF<\/jats:italic>, and <jats:italic>MEN1<\/jats:italic> (33% each). Transcriptomic analyses showed that PHNETs clustered closer to foregut (pancreatic, lung) NETs than to midgut (small\u2010bowel) NETs, while remaining a distinct entity with a specific profile. Assessment of potentially predictive biomarkers suggested efficacy of treatments usually active in foregut NETs. In conclusion, PHNETs display a foregut\u2010like molecular profile distinct from other types of NETs, with recurrent molecular alterations. Upon exhaustive work\u2010up to exclude an unrecognized primary tumor, PHNETs should not be considered metastatic NETs from an unknown primary. \u00a9 2022 The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.5977","type":"journal-article","created":{"date-parts":[[2022,6,10]],"date-time":"2022-06-10T00:59:38Z","timestamp":1654822778000},"page":"58-68","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Molecular deciphering of primary liver neuroendocrine neoplasms confirms their distinct existence with foregut\u2010like profile"],"prefix":"10.1002","volume":"258","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9715-9189","authenticated-orcid":false,"given":"Louis","family":"de Mestier","sequence":"first","affiliation":[{"name":"Universit\u00e9 de Paris, Centre of Research on Inflammation, INSERM U1149  Paris France"},{"name":"Universit\u00e9 de Paris, Department of Pancreatology and Digestive Oncology, ENETS Centre of Excellence, Beaujon Hospital (APHP)  Clichy France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00e9my","family":"Nicolle","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, Centre of Research on Inflammation, INSERM U1149  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7695-7317","authenticated-orcid":false,"given":"Nicolas","family":"Pot\u00e9","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, Centre of Research on Inflammation, INSERM U1149  Paris France"},{"name":"Universit\u00e9 de Paris, Department of PathologyENETS Centre of Excellence, Beaujon\/Bichat Hospitals (APHP)  Clichy\/Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinciane","family":"Rebours","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, Centre of Research on Inflammation, INSERM U1149  Paris France"},{"name":"Universit\u00e9 de Paris, Department of Pancreatology and Digestive Oncology, ENETS Centre of Excellence, Beaujon Hospital (APHP)  Clichy France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Cauchy","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, Centre of Research on Inflammation, INSERM U1149  Paris France"},{"name":"Universit\u00e9 de Paris, Department of Hepato\u2010Bilio\u2010Pancreatic Surgery, ENETS Centre of Excellence, Beaujon Hospital (APHP)  Clichy France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Hentic","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, Department of Pancreatology and Digestive Oncology, ENETS Centre of Excellence, Beaujon Hospital (APHP)  Clichy France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9rique","family":"Maire","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, Department of Pancreatology and Digestive Oncology, ENETS Centre of Excellence, Beaujon Hospital (APHP)  Clichy France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxime","family":"Ronot","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, Centre of Research on Inflammation, INSERM U1149  Paris France"},{"name":"Universit\u00e9 de Paris, Department of Radiology, ENETS Centre of Excellence, Beaujon Hospital (APHP)  Clichy France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachida","family":"Lebtahi","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, Centre of Research on Inflammation, INSERM U1149  Paris France"},{"name":"Universit\u00e9 de Paris, Department of Nuclear Medicine, ENETS Centre of Excellence, Beaujon Hospital (APHP)  Clichy France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain","family":"Sauvanet","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, Department of Hepato\u2010Bilio\u2010Pancreatic Surgery, ENETS Centre of Excellence, Beaujon Hospital (APHP)  Clichy France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val\u00e9rie","family":"Paradis","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, Department of Pancreatology and Digestive Oncology, ENETS Centre of Excellence, Beaujon Hospital (APHP)  Clichy France"},{"name":"Universit\u00e9 de Paris, Department of PathologyENETS Centre of Excellence, Beaujon\/Bichat Hospitals (APHP)  Clichy\/Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Ruszniewski","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, Centre of Research on Inflammation, INSERM U1149  Paris France"},{"name":"Universit\u00e9 de Paris, Department of Pancreatology and Digestive Oncology, ENETS Centre of Excellence, Beaujon Hospital (APHP)  Clichy France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Couvelard","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, Department of Pancreatology and Digestive Oncology, ENETS Centre of Excellence, Beaujon Hospital (APHP)  Clichy France"},{"name":"Universit\u00e9 de Paris, Department of PathologyENETS Centre of Excellence, Beaujon\/Bichat Hospitals (APHP)  Clichy\/Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4935-3865","authenticated-orcid":false,"given":"J\u00e9r\u00f4me","family":"Cros","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, Department of Pancreatology and Digestive Oncology, ENETS Centre of Excellence, Beaujon Hospital (APHP)  Clichy France"},{"name":"Universit\u00e9 de Paris, Department of PathologyENETS Centre of Excellence, Beaujon\/Bichat Hospitals (APHP)  Clichy\/Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,7,11]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2017.0589"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(63)90951-6"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-11-0013"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.12659\/MSM.923375"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dld.2020.02.011"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1159\/000471879"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11154-017-9437-9"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2007.15.4377"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature21063"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4518"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2821"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-24812-3"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.32334"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature15393"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature19057"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2892"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3703"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmoldx.2016.10.002"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdu479"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv468"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-7"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-20-0227"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13040643"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1607427"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)00817-X"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1009290"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.27716"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(07)70410-2"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2018-00160"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijscr.2021.105940"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v18.i22.2881"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12957-021-02187-5"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/bjs.5073"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.surg.2016.05.055"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-019-01934-9"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.113.126896"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1001\/archsurg.2010.10"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00268-015-2963-2"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0000000000000876"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10585-014-9672-3"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2013.105"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-3281"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.4174\/astr.2019.97.4.176"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00261-018-1653-6"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000011764"},{"key":"e_1_2_8_48_1","unstructured":"deMestierL CrosJ.Molecular deciphering of primary liver neuroendocrine neoplasms confirms its distinct existence with foregut\u2010like profile. Zenodo v1.0. [Accessed 4 June 2022]. Available from:https:\/\/zenodo.org\/record\/6606256#.YpsyExPMK8V"}],"container-title":["The Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.5977","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/path.5977","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.5977","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T11:52:38Z","timestamp":1761047558000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/path.5977"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,11]]},"references-count":47,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,9]]}},"alternative-id":["10.1002\/path.5977"],"URL":"https:\/\/doi.org\/10.1002\/path.5977","archive":["Portico"],"relation":{},"ISSN":["0022-3417","1096-9896"],"issn-type":[{"value":"0022-3417","type":"print"},{"value":"1096-9896","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,11]]},"assertion":[{"value":"2022-03-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-06-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-07-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}