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Article: Clinicopathologic features, tumor immune microenvironment and genomic landscape of Epstein-Barr virus-associated intrahepatic cholangiocarcinoma

TitleClinicopathologic features, tumor immune microenvironment and genomic landscape of Epstein-Barr virus-associated intrahepatic cholangiocarcinoma
Authors
KeywordsClinicopathology
Epstein-Barr virus
Genomic landscape
Intrahepatic cholangiocarcinoma
Tumor immune microenvironment
Issue Date2021
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/jhep
Citation
Journal of Hepatology, 2021, v. 74 n. 4, p. 838-849 How to Cite?
AbstractBackground & aims: Little is known about Epstein-Barr virus (EBV)-associated intrahepatic cholangiocarcinoma (EBVaICC) because of its rarity. We aimed to comprehensively investigate the clinicopathology, tumor immune microenvironment (TIME) and genomic landscape of this entity in southern China. Methods: We evaluated 303 intrahepatic cholangiocarcinomas (ICCs) using in situ hybridization for EBV. We compared clinicopathological parameters between EBVaICC and nonEBVaICC, and we analyzed EBV infection status, tumor-infiltrating lymphocytes (TILs) and genomic features of EBVaICC by immunohistochemistry, double staining, nested PCR, multiplex immunofluorescence staining, fluorescence in situ hybridization and whole-exome sequencing. Results: EBVaICC accounted for 6.6% of ICCs and was associated with EBV latency type I infection and clonal EBV isolates. Patients with EBVaICC were more often female and younger, with solitary tumors, higher HBV infection rates and less frequent cirrhosis; the lymphoepithelioma-like (LEL) subtype was more common in EBVaICC. EBVaICC was associated with a significantly larger TIME component than nonEBVaICC. The LEL subtype of EBVaICC - associated with a significantly increased density and proportion of CD20+ B cells and CD8+ T cells - was associated with significantly higher 2-year survival rates than conventional EBVaICC and nonEBVaICC. Both PD-1 and PD-L1 in TILs, and PD-L1 in tumor cells, were overexpressed in EBVaICC. High PD-L1 expression in tumor cells and high CD8+ TIL densities were significantly more common in EBVaICC than in nonEBVaICC. Seven genes (MUC4, DNAH1, GLI2, LIPE, MYH7, RP11-766F14.2 and WDR36) were mutated in at least 3 patients. EBVaICC had a different mutational pattern to liver fluke-associated cholangiocarcinoma and HBV-associated ICC. Conclusions: EBVaICC, as a subset of ICC, has unique etiological, clinicopathological and genetic characteristics, with a significantly larger TIME component. Paradoxically, patients with EBVaICC could be candidates for immune checkpoint therapy. Lay summary: Epstein-Barr virus (EBV) is associated with a subtype of intrahepatic cholangiocarcinoma, with unique clinicopathological and genetic characteristics. The tumor immune microenvironment is also different in this tumor subtype and patients with EBV-associated intrahepatic cholangiocarcinoma may respond well to immune checkpoint inhibitors.
DescriptionHybrid open access
Persistent Identifierhttp://hdl.handle.net/10722/295838
ISSN
2023 Impact Factor: 26.8
2023 SCImago Journal Rankings: 9.857
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorHuang, YH-
dc.contributor.authorZhang, CZY-
dc.contributor.authorHuang, QS-
dc.contributor.authorYeong, J-
dc.contributor.authorWang, F-
dc.contributor.authorYang, X-
dc.contributor.authorHe, YF-
dc.contributor.authorZhang, XL-
dc.contributor.authorZhang, H-
dc.contributor.authorChen, SL-
dc.contributor.authorZhang, H-
dc.contributor.authorDeng, R-
dc.contributor.authorLi, CS-
dc.contributor.authorYang, MM-
dc.contributor.authorLi, Y-
dc.contributor.authorJiang, C-
dc.contributor.authorLee, TK-
dc.contributor.authorMa, SKY-
dc.contributor.authorZeng, MS-
dc.contributor.authorYun, JP-
dc.date.accessioned2021-02-08T08:14:44Z-
dc.date.available2021-02-08T08:14:44Z-
dc.date.issued2021-
dc.identifier.citationJournal of Hepatology, 2021, v. 74 n. 4, p. 838-849-
dc.identifier.issn0168-8278-
dc.identifier.urihttp://hdl.handle.net/10722/295838-
dc.descriptionHybrid open access-
dc.description.abstractBackground & aims: Little is known about Epstein-Barr virus (EBV)-associated intrahepatic cholangiocarcinoma (EBVaICC) because of its rarity. We aimed to comprehensively investigate the clinicopathology, tumor immune microenvironment (TIME) and genomic landscape of this entity in southern China. Methods: We evaluated 303 intrahepatic cholangiocarcinomas (ICCs) using in situ hybridization for EBV. We compared clinicopathological parameters between EBVaICC and nonEBVaICC, and we analyzed EBV infection status, tumor-infiltrating lymphocytes (TILs) and genomic features of EBVaICC by immunohistochemistry, double staining, nested PCR, multiplex immunofluorescence staining, fluorescence in situ hybridization and whole-exome sequencing. Results: EBVaICC accounted for 6.6% of ICCs and was associated with EBV latency type I infection and clonal EBV isolates. Patients with EBVaICC were more often female and younger, with solitary tumors, higher HBV infection rates and less frequent cirrhosis; the lymphoepithelioma-like (LEL) subtype was more common in EBVaICC. EBVaICC was associated with a significantly larger TIME component than nonEBVaICC. The LEL subtype of EBVaICC - associated with a significantly increased density and proportion of CD20+ B cells and CD8+ T cells - was associated with significantly higher 2-year survival rates than conventional EBVaICC and nonEBVaICC. Both PD-1 and PD-L1 in TILs, and PD-L1 in tumor cells, were overexpressed in EBVaICC. High PD-L1 expression in tumor cells and high CD8+ TIL densities were significantly more common in EBVaICC than in nonEBVaICC. Seven genes (MUC4, DNAH1, GLI2, LIPE, MYH7, RP11-766F14.2 and WDR36) were mutated in at least 3 patients. EBVaICC had a different mutational pattern to liver fluke-associated cholangiocarcinoma and HBV-associated ICC. Conclusions: EBVaICC, as a subset of ICC, has unique etiological, clinicopathological and genetic characteristics, with a significantly larger TIME component. Paradoxically, patients with EBVaICC could be candidates for immune checkpoint therapy. Lay summary: Epstein-Barr virus (EBV) is associated with a subtype of intrahepatic cholangiocarcinoma, with unique clinicopathological and genetic characteristics. The tumor immune microenvironment is also different in this tumor subtype and patients with EBV-associated intrahepatic cholangiocarcinoma may respond well to immune checkpoint inhibitors.-
dc.languageeng-
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/jhep-
dc.relation.ispartofJournal of Hepatology-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectClinicopathology-
dc.subjectEpstein-Barr virus-
dc.subjectGenomic landscape-
dc.subjectIntrahepatic cholangiocarcinoma-
dc.subjectTumor immune microenvironment-
dc.titleClinicopathologic features, tumor immune microenvironment and genomic landscape of Epstein-Barr virus-associated intrahepatic cholangiocarcinoma-
dc.typeArticle-
dc.identifier.emailMa, SKY: stefma@hku.hk-
dc.identifier.authorityMa, SKY=rp00506-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1016/j.jhep.2020.10.037-
dc.identifier.pmid33212090-
dc.identifier.scopuseid_2-s2.0-85102347749-
dc.identifier.hkuros321221-
dc.identifier.hkuros324085-
dc.identifier.volume74-
dc.identifier.issue4-
dc.identifier.spage838-
dc.identifier.epage849-
dc.identifier.isiWOS:000632039100009-
dc.publisher.placeNetherlands-

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