Clinicopathologic features, tumor immune microenvironment and genomic landscape of Epstein-Barr virus-associated intrahepatic cholangiocarcinoma
Authors: Yu-Hua Huang, Chris Zhi-yi Zhang, Qun-Sheng Huang, Joe Yeong, Fang Wang, Xia Yang, Yang-Fan He, Xiao-Long Zhang, Hua Zhang, Shi-Lu Chen, Yin-Li Zheng, Ru Deng, Cen-Shan Lin, Ming-Ming Yang, Yan Li, Chen Jiang, Terence Kin-Wah Lee, Stephanie Ma, Mu-Sheng Zeng, Jing-Ping Yun
Journal: Journal of Hepatology (2020)

Highlights•EBVaICC accounted for 6.6% of ICCs and was associated with EBV latency type I infection and clonal EBV isolates.•EBVaICChas unique characteristics related to etiology, clinicopathology and molecular genetics.•Both PD-1 and PD-L1 in tumor-infiltrating lymphocytes and PD-L1 in tumor cells are overexpressed in EBVaICC.•Patients with EBVaICC may respond well to immune checkpoint inhibitors.•The lymphoepithelioma-like subtype of EBVaICC is related to favorable survival.AbstractBackground & AimsLittle 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.MethodsWe 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.ResultsEBVaICC 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.ConclusionsEBVaICC, 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 summaryEpstein-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.Graphical abstract