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

Abstract

Background and Aims

Little is known about EBV-associated intrahepatic cholangiocarcinoma (EBVaICC) due to 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 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, with EBV latency type I infection and clonal EBV isolates form. Distinctive clinicopathological characteristics of EBVaICC included female predominance, younger patient predominance, solitary tumor, higher HBV infection rate, lower cirrhotic background and increased lymphoepithelioma-like (LEL) subtype proportion. EBVaICC had a significantly larger TIME component than nonEBVaICC. The LEL subtype of EBVaICC, which had a significantly increased density and proportion of CD20+ B cells and CD8+ T cells, was significantly related to longer 2-year OS and RFS than EBVaICC conventional type and nonEBVaICC. Both PD-1 and PD-L1 in TILs and PD-L1 in tumor cells were overexpressed in EBVaICC. Tumor microenvironment immune type (TMIT) I (PDL1-Tumor+/CD8-High) was significantly more common in EBVaICC than in nonEBVaICC. Mutated genes in at least three cases, including MUC4, DNAH1, GLI2, LIPE, MYH7, RP11-766F14.2 and WDR36, were uncovered. EBVaICC had different mutational pattern compared with reported liver fluke-associated cholangiocarcinoma and HBV-associated ICC.

Conclusions

EBVaICC, as a subset of ICC, has unique etiological characteristics, clinicopathology and molecular genetics with a significantly larger TIME component. Most cases belong to TMIT I. Paradoxically, patients with EBVaICC could be candidates for immune checkpoint therapy.

Introduction

Intrahepatic cholangiocarcinoma (ICC) is the second most common malignancy of the liver, with a much higher incidence in parts of the Eastern world compared to the West [

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Epidemiology and risk factors: intrahepatic cholangiocarcinoma.