Cellular senescence in biliary pathology. Special emphasis on expression of a polycomb group protein EZH2 and a senescent marker p16INK4a in bile ductular tumors and lesions.

A subgroup of intrahepatic cholangiocarcinoma and combined hepatocellular- cholangiocarcinoma contain a component of cholangiolocellular carcinoma, which is composed of small bile ductular cells. Ductular reaction, a reactive lesion at the portal tract interface comprising increased bile ductules, is frequently seen in chronic advanced liver diseases. Bile duct adenoma, a benign tumor/tumorous lesion is also composed of bile ductular cells. Differential diagnosis among these bile ductular tumors/lesions is sometimes difficult. Given overexpression of a polycomb group protein EZH2 in intrahepatic cholangiocarcinoma and high expression of senescence-associated p16INK4a in ductular reactions, we plan to apply immunostaining for EZH2 and p16INK4a for differential diagnosis of these bile ductular tumors/lesions. The expression of EZH2 was seen in all cases of cholangiolocellular carcinomas, while it was not observed in bile duct adenomas or ductular reactions. In contrast, the expression of p16INK4a was seen in most bile duct adenomas and all ductular reactions, whereas it was barely seen in cholangiolocellular carcinomas. A borderline between cholangiolocellular carcinoma and the surrounding ductular reaction was clearly highlighted by the reverse expression pattern of EZH2 and p16INK4a. In conclusion, immunostaining for EZH2 and p16INK4a may be useful for differential diagnosis for bile ductular tumors/lesions.