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.


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.
Adachi
Tomohiko
T
Department of Transplantation and Digestive Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan. adatomo@nifty.com
Tajima
Yoshitsugu
Y
Kuroki
Tamotsu
T
Mishima
Takehiro
T
Kitasato
Amane
A
Fukuda
Kenzo
K
Tsutsumi
Ryuji
R
Kanematsu
Takashi
T
D000230:Adenocarcinoma / Q000139:chemically induced / Q000209:etiology* / Q000473:pathology; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001655:Bile Reflux / Q000150:complications* / Q000473:pathology; D002273:Carcinogens; D021441:Carcinoma, Pancreatic Ductal / Q000139:chemically induced / Q000209:etiology* / Q000473:pathology; D002291:Carcinoma, Papillary / Q000139:chemically induced / Q000209:etiology* / Q000473:pathology; D002455:Cell Division; D002767:Cholecystostomy; D003135:Common Bile Duct / Q000601:surgery; D006224:Cricetinae; D004195:Disease Models, Animal; D004385:Duodenostomy; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D008647:Mesocricetus; D009602:Nitrosamines; D010183:Pancreatic Ducts / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000139:chemically induced / Q000209:etiology* / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D046628:Sphincter of Oddi Dysfunction / Q000150:complications / Q000378:metabolism
D001647:Bile Acids and Salts; D002273:Carcinogens; D009602:Nitrosamines; D018809:Proliferating Cell Nuclear Antigen; C013622:nitrosobis(2-oxopropyl)amine