Carcinogenetic process in gallbladder mucosa with pancreaticobiliary maljunction (Review).

Pancreaticobiliary maljunction (PBM) is a congenital anomaly with a high incidence of biliary tract carcinoma. Pathological findings strongly suggest that there is a hyperplasia-dysplasia-carcinoma sequence in carcinogenesis of PBM. A molecular biological analysis revealed high incidence of cellular proliferation activating factors such as TGF-alpha, COX-2 from the hyperplasia stage. In addition, cellular proliferative activity including BrdU, AgNOR, PCNA, and Ki-67 was significantly higher in regular gallbladder mucosa without PBM. Furthermore, a high incidence of K-ras gene mutation could be seen in hyperplasia (13-63%) and microsatellite instability could be observed in 60% of all cases in dysplasia. In cancerous lesions, a high rate of overexpression of cyclin D1, beta-catenin, p53, as well as p53 gene mutation has been recognized. These results suggest that a multistep carcinogenetic process contributes to the carcinogenesis of PBM, similar to that of other cancers. In addition, after preventive operation with resection of the extrahepatic bile duct is performed, carcinogenesis in the remnant biliary tract or pancreatic duct is rarely found. Whether the carcinogenesis is a result of the accumulation of genetic alteration from shortly after birth, or a result of regurgitation of gastrointestinal juice due to hepaticoenterostomy, remains unknown. Since a high frequency of COX-2 is positive in PBM, COX-2 inhibitors such as NSAIDs may play an important role in preventing carcinogenesis.