Pancreatobiliary Maljunction-associated Gallbladder Cancer Is as Common in the West, Shows Distinct Clinicopathologic Characteristics and Offers an Invaluable Model for Anatomy-induced Reflux-associated Physio-chemical Carcinogenesis

Abstract

Objective:To determine the associations of pancreatobiliary maljunction (PBM) in the West.Background:PBM (anomalous union of common bile duct and pancreatic duct) is mostly regarded as an Asian-only disorder, with 200X risk of gallbladder cancer (GBc), attributed to reflux of pancreatic enzymes. Methods: Radiologic images of 840 patients in the US who underwent pancreatobiliary resections were reviewed for PBM and contrasted with 171 GBC cases from Japan.Results:Eight % of the US GBCs (24/300) had PBM (similar to Japan; 15/ 171, 8.8%), in addition to 1/42 bile duct carcinomas and 5/33 choledochal cysts. None of the 30 PBM cases from the US had been diagnosed as PBM in the original work-up. PBM was not found in other pancreatobiliary disorders. Clinicopathologic features of the 39 PBM-associated GBCs (US:24, Japan:15) were similar; however, comparison with non-PBM GBCs revealed that they occurred predominantly in females (F/M = 3); at younger (<50-year-old) age (21% vs 6.5% in non-PBM GBCs; P = 0.01); were uncommonly associated with gallstones (14% vs 58%; P < 0.001); had higher rate of tumor-infiltrating lymphocytes (69% vs 44%; P = 0.04); arose more often through adenoma-carcinoma sequence (31% vs 12%; P = 0.02); and had a higher proportion of nonconventional carcinomas (21% vs 7%; P = 0.03). Conclusions: PBM accounts for 8% of GBCs also in the West but is typically undiagnosed. PBM-GBCs tend to manifest in younger age and often through adenoma-carcinoma sequence, leading to unusual carcinoma types. If PBM is encountered, cholecystectomy and surveillance of bile ducts is warranted. PBM-associated GBCs offer an invaluable model for variant anatomy-induced chemical (reflux-related) carcinogenesis.

Variant anatomy of the biliary system as a cause of pancreatic and peri-ampullary cancers

“…All of these together point to the milieu of this relatively small region, where 3 physiologically distinct environments converge, as the culprit for the development of these cancers. Other external observations that lend further credence to this include the established etiopathogenetic association of other anatomic variations such as pancreatobiliary maljunction (supra-Oddi union of common bile duct with main pancreatic duct), leading to reflux and causing cancers of the gallbladder, bile ducts and pancreas 18,19,28,34 as well as the well-known anatomic association of gastro-esophageal junction cancers developing through reflux and Barrett metaplasia. This is also supported by the fact that "transitional" zones where different epithelial types and milieus converge (as in the peri-ampullary region) are particularly vulnerable to chemical alterations as is well known for endoectocervical transition zone in the uterus and hilar lung cancers where transformation of respiratory to squamous epithelium takes place.…”

Dysplasia and carcinoma of the gallbladder: pathological evaluation, sampling, differential diagnosis and clinical implications

“…An important risk factor that pathologists ought to be aware of is the pancreaticobiliary maljunction, which is the supra‐oddi union of the common bile duct and the main pancreatic duct, allowing reflux of pancreatic enzymes to the gallbladder. Pancreaticobiliary maljunction accounts for 5–10% of GBCs both in the East and West, 14,15 and offers an invaluable model of anatomy‐induced carcinogenesis. It also bears a risk for bile duct cancers.…”

“…It also bears a risk for bile duct cancers. The risk of carcinoma in such patients is so high that in a patient with this anomaly the gallbladder should be removed and examined entirely to rule out carcinoma 14,15 …”

“…Of note, ICNs are responsible for approximately 6–8% of all invasive carcinomas 18 . This association seems to be more prominent in patients with chemical carcinogenesis, as exemplified in pancreaticobiliary maljunction cases where the reflux of the pancreatic acinar enzymes leads to reflux cholecystopathy and ultimately to invasive carcinoma 14,15 . A quarter of the pancreaticobiliary maljunction‐associated GBCs prove to be through the ICN pathway 15 …”

Risk factors for the onset of gallbladder cancer: a review

“…Muraki et al found that 8% of patients with GBC in the US had PBM (24/300), in Japan the situation is similar (15/171, 8.8%), but PBM is usually not diagnosed initially. 31 Hyvarinen et al reported that the estimated prevalence of PBM among patients with GBC was 17%. 32 Fujimoto et al observed that the incidence of GBC among PBM patients was 58% (7/12), and elevated bile amylase levels in PBM patients with serum amylase levels close to the upper limit of normal range seems may be related with GBC.…”