Bile-reflux into the pancreatic ducts is associated with the development of intraductal papillary carcinoma in hamsters

Background. Reflux of pancreatic juice into the biliary tract is a well-known risk factor for the development of biliary carcinoma. In this study, we investigated the significance of bile-reflux into the pancreatic ducts in pancreatic carcinogenesis, especially in the development of carcinoma in the main pancreatic duct in hamsters. Materials and methods. Syrian hamsters were subjected to three different surgical procedures: cholecystoduodenostomy with dissection of the extrahepatic bile duct on the distal end of the common duct (Model A); cholecystoduodenostomy along with a dissection of the common bile duct (Model B); or simple laparotomy (Model C). The animals then received weekly subcutaneous injections of N-nitrosobis(2-oxopropyl)amine (BOP), for 9 weeks, and were killed for pathological investigation at 16 weeks after the initial BOP administration. Results. Pancreas carcinomas developed in 95, 88, and 90% of the Model A hamsters (n = 22), B (n = 24), and C (n = 21), respectively. The induced pancreatic tumors were histologically classified into four types: papillary; tubular; cystic adenocarcinoma; or intraductal carcinoma of the main pancreatic duct consisting of intraductal papillary carcinoma (IPC) and intraductal tubular carcinoma (ITC). The number and the incidence of IPCs induced in Model A hamsters were 24 lesions and 77% and were statistically higher than those in Model B (7 lesions and 29%) and C hamsters (7 lesions and 33%) (P < 0.01). Bile-reflux into the pancreatic ducts was clearly demonstrated in only hamsters of Model A by means of Indocyanine green injection via the portal vein. Proliferative cell nuclear antigen labeling indices of the epithelial cells in the main pancreatic duct in hamsters, with no BOP treatment, were 3.8, 0.8, and 1.1% in Models A (n = 10), B (n = 10), and C (n = 10), respectively, and the difference was statistically significant (P < 0.01). Conclusions. Our findings suggest that bile-reflux into the pancreatic ducts is a significant factor predisposing to the development of IPC of the pancreas through an acceleration of epithelial cell kinetics of the main pancreatic duct. (c) 2006 Elsevier Inc. All rights reserved.