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To determine whether genetic alterations in intrahepatic cholangiocarcinoma (ICC) differ by the association of chronic inflammation induced by hepatolithiasis, we analyzed p53 protein overexpression, aberrant β-catenin nuclear expression, microsatellite instability (MSI) status, and K-ras codon 12 mutation in 20 cases with ICC (13 with hepatolithiasis and seven without hepatolithiasis). Positive frequencies of each variable for ICC with and without hepatolithiasis were: p53 overexpression, 38% vs 14%; aberrant β-catenin nuclear expression, 23% vs 0%; MSI-high, 0% vs 0%; MSI-low, 13% vs 17%; and K-ras mutation, 31% vs 14%. Aberrant β-catenin nuclear expression showed a sporadic pattern in all cases. There were no significant differences in any of the frequencies between ICCs with and without hepatolithiasis. These results suggest that genetic alterations in ICC do not differ according to the presence of chronic inflammation by hepatolithiasis. However, these results may be partly attributable to the small sample number of ICC cases with hepatolithiasis in the present study. Additional studies of ICC with hepatolithiasis and further investigations are required to obtain definitive conclusions. With regard to ICC without hepatolithiasis, the present results imply that alterations of p53 and K-ras may play crucial roles in the carcinogenesis of a subset (30 to 40%) of ICC, and adenomatous polyposis coli (APC) alterations represented by aberrant β-catenin nuclear expression and defects in the DNA mismatch repair system represented by MSI-high may not contribute to ICC carcinogenesis.