Epistein-Barr Virus Associated Primary Intrahepatic Lymphoepithelioma-Like Cholangiocarcinoma
Anthony WH Chan, Joanna HM Tong, Mandy YM Sung, Paul BS Lai, Ka-Fai To. The Chinese University of Hong Kong
Background: Lymphoepithelioma-like cholangiocarcinoma (LELCC) is a rare variant of intrahepatic cholangiocarcinoma (IHCC). Only 14 cases have been reported in the literature, and about 10 of them (70%) were associated with EBV. DNA hypermethylation is frequently observed in both EBV-associated carcinoma and IHCC, but has not been documented in LELCC yet.
Design: Seven cases of LELCC and 11 cases of IHCC in stage I were evaluated. Immunostaining for CK19, HepPar-1, EBV LMP-1, ER, PR, CD21 and p53, and in situ hybridization of EBER were performed. Methylation statuses of APC, ATM, DAP-kinase, E-cadherin, GSTP1, HIC1, HLTF, MGMT, MLH1, P14, P15, P16, RASSF1A, SOC-1, DLEC1, RARB, CRBPI, CRBPIV, ATF5 and DAB2 were analyzed by methylation-specific polymerase chain reaction.
Results: All 7 patients of LELCC were exclusively female and had stage I diseases. LELCC had a significantly better 2-year overall survival (100% vs 52.8%, p=0.011). All LELLC were composed of glandular component and 3 of them were mixed with undifferentiated compinent. Both glandular and undifferentiated components showed variable expression of CK19 but not HepPar-1, ER, PR and CD21. All were positive for EBER ISH but negative for EBV LMP-1. The methylation frequency of each locus in LELCC varied from 5.6% to 94.4%. The methylation index ranged from 0.30 to 0.55 and 0.15 to 0.50 in LELCC and IHCC, respectively. The mean methylation index of LELCC was statistically higher than that of IHCC (0.429 vs 0.291, p=0.016). Regardless of the EBV status, APC, E-cadherin, GSTP1, RASSF1A and RARB were methylated in more than 35% of all studied cases. Only CRBPI (85.7% vs 9.1%, p=0.002) and CRBPIV (85.7% vs 0%, p<0.001) showed statistically higher methylation frequencies in LELCC than IHCC. There was no statistical association among survival data, tumor size, histological grade, immunophenotype and methylation status in LELCC and IHCC.
Conclusions: A cohort of seven cases of EBV-associated LELCC was reported, which is the largest case series in the literature. EBV-associated LELCC is a distinctive variant of IHCC, characterized by marked female predominance, more favorable overall survival, and high frequent DNA hypermethylation. High incidence of CRBPI and CRBPIV methylation in LELCC suggested the disruption of the retinoic acid signaling pathway is important in its carcinogenesis.
Tuesday, March 20, 2012 1:00 PM
Poster Session IV # 238, Tuesday Afternoon