Epstein-Barr virus-associated lymphoepithelioma-like cholangiocarcinoma: a rare variant of intrahepatic cholangiocarcinoma with favourable outcome

Aims: Lymphoepithelioma-like cholangiocarcinoma (LELCC) is a rare variant of intrahepatic cholangiocarcinoma (IHCC). Only 16 cases have reported previously in the literature, and about 62.5% of these cases were associated with Epstein-Barr virus (EBV). Methods and results: We present the largest series (seven cases) of LELCC with descriptions of clinical and pathological characteristics, investigations of aberrant DNA methylation and mutation analyses of EGFR and KRAS. The evaluation also included 11 cases of stage-matched conventional IHCC for comparison. Results: All seven patients of LELCC were female and had stage I disease. LELCC had significantly better 2-and 5-year overall survival than IHCC (100% versus 52.8%, and 100% versus 13.2%, respectively, P = 0.003). All seven LELCCs were EBV-associated and composed exclusively of adenocarcinoma with varied glandular differentiation, dense lymphoplasmacytic infiltrate, and variable expression of biliary-type cytokeratins (CK7 and CK19) and stemness markers (CD133 and EpCAM). Gene hypermethylation was more frequent in LELCC than IHCC. CRBPI (85.7% versus 9.1%, P < 0.003) and CRBPIV (85.7% versus 0%, P < 0.001) showed statistically higher methylation frequencies in LELCC than IHCC. No LELCC harboured any EGFR or KRAS mutation. Conclusion: Epstein-Barr virus-associated LELCC is a variant of IHCC, characterized by marked female predominance, favourable overall survival and distinctively frequent DNA hypermethylation.