Clinicopathologic features, tumor immune microenvironment and genomic landscape of Epstein-Barr virus-associated intrahepatic cholangiocarcinoma
Clinicopathologic features, tumor immune microenvironment and genomic landscape of Epstein-Barr virus-associated intrahepatic cholangiocarcinoma
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EB病毒相关肝内胆管癌的临床病理特征、肿瘤免疫微环境和基因组景观
DOI：
10.1016/j.jhep.2020.10.037
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发表时间：
2021-03-15
影响因子：
25.7
通讯作者：
Yun, Jing-Ping
中科院分区：
文献类型：
--
作者：
Huang, Yu-Hua;Zhang, Chris Zhi-Yi;Yun, Jing-Ping
背景与目的：由于EB病毒相关性肝内胆管癌（EBVaICC）的罕见性，目前对其知之甚少。我们的目的是全面调查的临床病理学，肿瘤免疫微环境（TIME）和基因组景观，这一实体在中国南方。方法：我们评估了303例肝内胆管癌（ICC）采用原位杂交EB病毒。比较EBVaICC与non-EBVaICC的临床病理特征，并通过免疫组化、双重染色、巢式PCR、多重免疫荧光染色、荧光原位杂交和全外显子组测序等方法分析EBVaICC的EBV感染状况、肿瘤浸润淋巴细胞（TIL）和基因组特征。EBVaICC占ICC的6.6%，与EBV潜伏I型感染和克隆性EBV分离株相关。EBVaICC患者更常见于女性和年轻人，孤立性肿瘤，HBV感染率较高，肝硬化发生率较低;淋巴上皮瘤样（LEL）亚型在EBVaICC中更常见。EBVaICC与一个显着较大的时间比nonEBVaICC组件。EBVaICC的LEL亚型-与CD 20 + B细胞和CD 8 + T细胞的密度和比例显著增加相关-与传统EBVaICC和nonEBVaICC相比，与显著更高的2年生存率相关。TIL中的PD-1和PD-L1以及肿瘤细胞中的PD-L1在EBVaICC中过表达。肿瘤细胞中PD-L1的高表达和CD 8 + TIL的高密度在EBVaICC中比在nonEBVaICC中更常见。在至少3名患者中有7个基因（MUC 4、DNAH 1、GLI 2、LIPE、MYH 7、RP 11 -766F14.2和WDR 36）突变。结论：EBVaICC作为ICC的一个亚类，具有独特的病因学、临床病理学和遗传学特征，其TIME成分明显大于ICC。Epstein-Barr病毒（EBV）是肝内胆管癌的一种亚型，具有独特的临床病理学和遗传学特征。这种肿瘤亚型的肿瘤免疫微环境也不同，EBV相关肝内胆管癌患者可能对免疫检查点抑制剂反应良好。(C)2020年欧洲肝脏研究协会。由爱思唯尔公司出版
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 clinico-pathological parameters between EBVaICC and nonEBVaICC, and we analyzed EBV infection status, tumor-infiltrating lympho-cytes (TILs) and genomic features of EBVaICC by immunohisto-chemistry, 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 chol-angiocarcinoma 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 clini-copathological 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. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V.