Biliary carcinogenesis in pancreaticobiliary maljunction

Abstract

Pancreaticobiliary maljunction (PBM) is a congenital malformation in which the pancreatic and bile ducts join anatomically outside the duodenal wall. Because of the excessive length of the common channel in PBM, sphincter action does not directly affect the pancreaticobiliary junction, which allows pancreatic juice to reflux into the biliary tract. According to the results of a nationwide survey, bile duct and gallbladder cancers were found in 6.9 and 13.4 % of adult patients with congenital biliary dilatation, respectively, and in 3.1 and 37.4 % of those with PBM without biliary dilatation, respectively. Biliary tract cancers develop about 15-20 years earlier in patients with PBM than in individuals without PBM; they sometimes develop as double cancers. Carcinogenesis is strongly associated with stasis of bile intermingled with refluxed pancreatic juice. Epithelial cells in the biliary tract of PBM patients are under constant attack from activated pancreatic enzymes, increased secondary bile acids, or other mutagens. This can result in hyperplastic change with increased cell proliferation activity, and in turn, oncogene and/or tumor suppressor gene mutations in the epithelia, leading to the biliary tract carcinogenesis. The carcinogenesis of biliary tract cancer accompanying PBM is considered to involve a hyperplasia-dysplasia-carcinoma sequence induced by chronic inflammation caused by the reflux of pancreatic juice into the biliary tract, which differs from the adenoma-carcinoma sequence or the de novo carcinogenesis associated with biliary tract cancers in the population without PBM. Patients with a relatively long common channel have a similar, albeit slightly lower, risk for gallbladder cancer compared with PBM patients.

Management of anomalous pancreaticobiliary junction

“…APBJ is a congenital malformation in which the pancreatic and bile ducts join anatomically outside the duodenal wall and beyond the influence of the sphincter of Oddi. [2][3][4][5][6][7] The persistent reflux of pancreatic juice into the biliary duct injures the biliary epithelium, resulting in a high incidence of biliary cancer. [2][3][4][5][6][7][8] Among APBJ patients, some have biliary dilatation (dilatated type; choledochal cyst), whereas others have no dilatation (undilatated type).…”

Gallbladder carcinoma associated with unique distribution of intraductal papillary neoplasm of bile duct accompanied by pancreaticobiliary maljunction

“…We herein report a widely spreading IPNB with a unique distribution: the majority of the tumor was localized in the CBD with a small portion of tumor extending to the GB, whereas invasive carcinoma lesion was not observed in the CBD but in the GB only. IPNB and PBM are regarded as a precancerous lesion and as a risk factor for biliary tract cancer, respectively. Excessive reflux of pancreatic juice into the biliary tract is thought to cause critical changes in the epithelium of the biliary tract, leading to the carcinogenesis through a hyperplasia‐dysplasia‐carcinoma sequence .…”

“…IPNB and PBM are regarded as a precancerous lesion and as a risk factor for biliary tract cancer, respectively. Excessive reflux of pancreatic juice into the biliary tract is thought to cause critical changes in the epithelium of the biliary tract, leading to the carcinogenesis through a hyperplasia‐dysplasia‐carcinoma sequence . Considering an absence of hyperplasia which is essential for GB carcinoma formation caused by PBM, GB carcinoma in this case is thought to have originated from IPNB without PBM involvement.…”

Pancreaticobiliary Maljunction: Markedly High Risk for Biliary Cancer

“…As a result of these changes in the mucosal epithelia, in association with DNA mutations, cancer development and progression are ultimately promoted. The predominant mechanism responsible for the development of biliary tract cancer in patients with PBM appears to be the hyperplasia-dysplasia-carcinoma sequence, which is thought to differ from the predominant mechanisms seen in patients without PBM, which are the adenoma-carcinoma sequence and the de-novo carcinogenesis [4,[6][7][8].…”

“…The characteristic pathological change seen in PBM patients is epithelial hyperplasia of the gallbladder due to longstanding continuous stasis of the bile intermixed with refluxed pancreatic juice [4]. In order to identify PBM without biliary dilatation at an early stage, it is important to perform magnetic resonance cholangiopancreatography for patients with gallbladder wall thickening on screening ultrasonography under suspicion of PBM [8,10].…”