{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:03:07Z","timestamp":1785456187041,"version":"3.56.0"},"reference-count":50,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2020,1,12]],"date-time":"2020-01-12T00:00:00Z","timestamp":1578787200000},"content-version":"am","delay-in-days":325,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#am"},{"start":{"date-parts":[[2019,2,21]],"date-time":"2019-02-21T00:00:00Z","timestamp":1550707200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002655","name":"Terry Fox Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002655","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["CA150272P3"],"award-info":[{"award-number":["CA150272P3"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Histopathology"],"published-print":{"date-parts":[[2019,4]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Access to tissue in patients with hepatocellular carcinoma (<jats:styled-content style=\"fixed-case\">HCC<\/jats:styled-content>) is limited compared to other malignancies, particularly at advanced stages. This has precluded a thorough characterisation of molecular drivers of <jats:styled-content style=\"fixed-case\">HCC<\/jats:styled-content> dissemination, particularly in relation to distant metastases. Biomarker assessment is restricted to early stages, and paired primary\u2013metastatic comparisons between samples from the same patient are difficult.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>We report the evaluation of 88 patients with <jats:styled-content style=\"fixed-case\">HCC<\/jats:styled-content> who underwent autopsy, including multiregional sampling of primary and metastatic sites totalling 230 nodules analysed. The study included morphological assessment, immunohistochemistry and mutation status of the <jats:italic><jats:styled-content style=\"fixed-case\">TERT<\/jats:styled-content><\/jats:italic> promoter, the most frequently mutated gene in <jats:styled-content style=\"fixed-case\">HCC<\/jats:styled-content>. We confirm a strong predilection of <jats:styled-content style=\"fixed-case\">HCC<\/jats:styled-content> for lung dissemination, including subclinical micrometastases (unrecognised during imaging and macroscopic examinations) in 30% of patients with disseminated disease. Size of dominant tumour nodule; multinodularity; macrovascular invasion; high histological, nuclear and architectural grades; and cellular crowding were associated with the presence of extrahepatic metastasis. Among the immunohistochemistry markers tested, metastatic nodules had significantly higher K19 and Ep<jats:styled-content style=\"fixed-case\">CAM<\/jats:styled-content> expression than primary liver tumours. Morphological and immunohistochemical features showed that metastatic <jats:styled-content style=\"fixed-case\">HCC<\/jats:styled-content> could be traced back to the primary tumour, sometimes to a specific hepatic nodule.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study suggests limited heterogeneity in metastatic sites compared to primary tumour sites.<\/jats:p><\/jats:sec>","DOI":"10.1111\/his.13809","type":"journal-article","created":{"date-parts":[[2019,1,12]],"date-time":"2019-01-12T13:28:15Z","timestamp":1547299695000},"page":"718-730","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A phenotypical map of disseminated hepatocellular carcinoma suggests clonal constraints in metastatic sites"],"prefix":"10.1111","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6123-2601","authenticated-orcid":false,"given":"Sebastiao N","family":"Martins\u2010Filho","sequence":"first","affiliation":[{"name":"Departamento de Patologia Faculdade de Medicina FMUSP Universidade de S\u00e3o Paulo S\u00e3o Paulo Brazil"},{"name":"Department of Pathology and Laboratory Medicine University Health Network University of Toronto Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venancio A F","family":"Alves","sequence":"additional","affiliation":[{"name":"Departamento de Patologia Faculdade de Medicina FMUSP Universidade de S\u00e3o Paulo S\u00e3o Paulo Brazil"},{"name":"Laboratorio de Patologia do F\u00edgado LIM 14 Hospital das Clinicas HCFMUSP Faculdade de Medicina Universidade de S\u00e3o Paulo S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alda","family":"Wakamatsu","sequence":"additional","affiliation":[{"name":"Laboratorio de Patologia do F\u00edgado LIM 14 Hospital das Clinicas HCFMUSP Faculdade de Medicina Universidade de S\u00e3o Paulo S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miho","family":"Maeda","sequence":"additional","affiliation":[{"name":"Liver Cancer Research Program Division of Liver Diseases Tisch Cancer Institute Department of Medicine Icahn School of Medicine at Mount Sinai New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda J","family":"Craig","sequence":"additional","affiliation":[{"name":"Liver Cancer Research Program Division of Liver Diseases Tisch Cancer Institute Department of Medicine Icahn School of Medicine at Mount Sinai New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aline K","family":"Assato","sequence":"additional","affiliation":[{"name":"Laboratorio de Patologia do F\u00edgado LIM 14 Hospital das Clinicas HCFMUSP Faculdade de Medicina Universidade de S\u00e3o Paulo S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Villacorta\u2010Martin","sequence":"additional","affiliation":[{"name":"Liver Cancer Research Program Division of Liver Diseases Tisch Cancer Institute Department of Medicine Icahn School of Medicine at Mount Sinai New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delia","family":"D'Avola","sequence":"additional","affiliation":[{"name":"Liver Unit Cl\u00ednica Universidad de Navarra Centro de Investigaci\u00f3n Biom\u00e9dica en Red en el \u00c1rea Tem\u00e1tica de Enfermedades Hep\u00e1ticas y Digestivas (Ciberehd) Pamplona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ismail","family":"Labgaa","sequence":"additional","affiliation":[{"name":"Liver Cancer Research Program Division of Liver Diseases Tisch Cancer Institute Department of Medicine Icahn School of Medicine at Mount Sinai New York NY USA"},{"name":"Department of Visceral Surgery Lausanne University Hospital CHUV Lausanne Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flair J","family":"Carrilho","sequence":"additional","affiliation":[{"name":"Departamento de Gastroenterologia Faculdade de Medicina FMUSP Universidade de S\u00e3o Paulo S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swan N","family":"Thung","sequence":"additional","affiliation":[{"name":"Department of Pathology Icahn School of Medicine at Mount Sinai New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Augusto","family":"Villanueva","sequence":"additional","affiliation":[{"name":"Liver Cancer Research Program Division of Liver Diseases Tisch Cancer Institute Department of Medicine Icahn School of Medicine at Mount Sinai New York NY USA"},{"name":"Division of Hematology and Medical Oncology Department of Medicine Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,2,21]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21262"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djx030"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-14-0155"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2011.12.021"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2016.05.035"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2015.05.061"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1113205"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1256930"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature22364"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2015.0020"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2017.05.014"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2017.06.007"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2009.06.003"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v22.i27.6246"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-16-1000"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09515"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14347"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2012-304351"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra061808"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0798-844"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.1385"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gtc.2017.01.009"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27545"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2013.114"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-14-0122"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0b013e3181e5dffa"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jss.2006.08.038"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0b013e31827332b0"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3465"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.12460"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1186\/1755-8794-7-23"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1229259"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7170"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27372"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature17038"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2017.00193"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1111\/jgh.12200"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00268-013-2374-1"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00268-014-2806-6"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28643"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1097\/SLA.0b013e31820508f1"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature20609"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1097\/MEG.0000000000000398"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24559"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1872-034X.2012.01010.x"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2015.10.014"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1377"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.03.043"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djx270"}],"container-title":["Histopathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fhis.13809","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/his.13809","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/his.13809","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/am-pdf\/10.1111\/his.13809","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/his.13809","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,11]],"date-time":"2023-09-11T06:53:37Z","timestamp":1694415217000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/his.13809"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2,21]]},"references-count":50,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2019,4]]}},"alternative-id":["10.1111\/his.13809"],"URL":"https:\/\/doi.org\/10.1111\/his.13809","archive":["Portico"],"relation":{},"ISSN":["0309-0167","1365-2559"],"issn-type":[{"value":"0309-0167","type":"print"},{"value":"1365-2559","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,2,21]]},"assertion":[{"value":"2018-07-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-12-18","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-02-21","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}