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

作者：Huang, Yu-Hua; Zhang, Chris Zhi-Yi; Huang, Qun-Sheng; Yeong, Joe; Wang, Fang; Yang, Xia; He, Yang-Fan; Zhang, Xiao-Long; Zhang, Hua; Chen, Shi-Lu; Zheng, Yin-Li; Deng, Ru; Lin, Cen-Shan; Yang, Ming-Ming; Li, Yan; Jiang, Chen; Kin-Wah Lee, Terence; Ma, Stephanie; Zeng, Mu-Sheng; Yun, Jing-Ping^*

来源：Journal of Hepatology, 2021, 74(4): 838-849.

DOI：10.1016/j.jhep.2020.10.037

• Clinicopathology
• Epstein-Barr virus
• Genomic landscape
• Intrahepatic cholangiocarcinoma
• Tumor immune microenvironment

BACKGROUND & 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.

• 单位
  The Hong Kong Polytechnic University; the University of Hong Kong; The University of Hong Kong; The University of Hongkong; the Hong Kong Polytechnic University