Biliary carcinogenesis in pancreaticobiliary maljunction

The coexistence of bile duct carcinoma in choledochal cysts is well known. With large number of cases of congenital bile duct dilatation and pancreaticobiliary maljunction (PBM), it is now apparent that gallbladder carcinoma is more frequent in PBM without bile duct dilatation. The incidence of Gallbladder cancer in choledochal cyst and bile duct cancer in PBM, regardless of the presence of bile duct dilatation is significantly higher than that in control patients with biliary cancer but without PBM. A recent survey shows that the incidence of bile duct cancer in PBM without dilatation is equivalent to that of gallbladder cancer and bile duct cancer in patients with choledochal dilatation. Pathology in PBM is a result of reflux of pancreatic juice and stasis of the mixture in the biliary system. Carcinogenic factors thus present in the biliary contents induce epithelial changes in the biliary tract. In the biliary contents, activated pancreatic enzymes and secondary or deconjugated bile acids are markedly increased and they irritate the biliary mucosa. Mutagens are proven to form in the bile of PBM. In the epithelia of PBM, hyperplasia, metaplasia, and dysplasia are often found, and proliferative activity is increased; furthermore, K-ras gene mutation and overexpression of p53 protein are demonstrated. As for treatment of PBM, whether it is symptomatic or not, an operative procedure, is necessary, to prevent carcinogenic changes in the gallbladder and bile duct. Regardless of whether dilatation is present or not, total excision of the extrahepatic bile duct, along with gallbladder, is the treatment of choice, followed by hepaticojejunostomy or hepaticoduodenostomy.     

Precancerous conditions of biliary tract cancer in patients with pancreaticobiliary maljunction: reappraisal of nationwide survey in Japan

It is widely known that pancreaticobiliary maljunction (PBM), an anomalous arrangement of the pancreaticobiliary ductal system, is frequently associated with biliary tract cancer in patients with or without bile duct dilatation. In 1985, we surveyed patients with PBM who had been operated on at 133 Japanese institutions. A close relationship was shown between biliary tract carcinogenesis and PBM, according to the type of maljunction and age distribution: PBM patients with cystic dilatation had a high risk of bile duct cancer, even in those who were young (aged less than 20 years); the incidence of gallbladder cancer increased markedly in PBM patients over 40 years old with cystic dilatation, while it gradually increased with age in the PBM patients without cystic dilatation. Therefore, we recommend surgical treatment for patients with PBM even if they have no symptoms. Received: May 1, 2000 / Accepted: September 5, 2000     

Long-term results of treatment for pancreaticobiliary maljunction without bile duct dilatation

HYPOTHESIS: Resection of the gallbladder together with the dilated bile duct is the preferred treatment for pancreaticobiliary maljunction (PBM) with bile duct dilatation, whereas this treatment for PBM without bile duct dilatation is still controversial. DESIGN: Retrospective study of 196 patients from January 1979 to November 2004. SETTING: Two university hospitals. PATIENTS: One hundred ninety-six patients with PBM, 152 (78%) with and 44 (22%) without bile duct dilatation, formed the basis of this study. MAIN OUTCOME MEASURES: The effects of cholecystectomy on long-term results in the patients without bile duct dilatation. RESULTS: Significant differences were observed in patients without bile duct dilatation: patients were older, carcinoma of the gallbladder was more prevalent (19 patients [43.2%] without dilatation vs 9 patients [5.9%] with dilatation), and pancreatic cancer and pancreatitis were also more frequent. Most of their gallbladder carcinomas were found at stage IV (63%). The outcome was very poor in stage IV, whereas 5 patients in stage I and II lived for more than 5 years after surgery. Of the 44 patients without bile duct dilatation, 23 with carcinoma of the gallbladder or pancreas died and the other 2 were lost to follow-up. The remaining 19 patients were alive at the study's conclusion after cholecystectomy without bile duct resection. None of them had bile duct carcinoma at the time of surgery or during the mean follow-up period of 9 years after surgery. CONCLUSIONS: Prophylactic cholecystectomy without bile duct resection is the best treatment option for patients with PBM without bile duct dilatation. Possible association of gallbladder carcinoma should be kept in mind at the time of treatment of patients with PBM when the bile duct is not dilated.     

Pancreaticobiliary maljunction and carcinogenesis to biliary and pancreatic malignancy

Background  It is widely accepted that congenital choledochal cyst is associated with pancreaticobiliary maljunction (PBM). But, PBM is an independent disease entity from choledochal cyst. PBM is synonymous with “abnormal junction of the pancreaticobiliary ductal system”, “anomalous arrangement of pancreaticobiliary ducts”, “anomalous union of bilio-pancreatic ducts”, etc. Cases with PBM not associated with biliary duct dilatation are often found, and these cases are frequently complicated gallbladder cancer. The Japanese Study Group of Pancreaticobiliary Maljunction was started in 1983, and defined diagnostic criteria and nationwide registration system of PBM cases was started. PBM is defined as a union of the pancreatic and biliary ducts which is located outside the duodenal wall. Bile and pancreatic juice reflux and regurgitate mutually. Biliary carcinogenesis  The most bothersome problem is biliary carcinogenesis. Gallbladder cancers arise in 14.8% and bile duct cancers arise in 4.9%. The incidence of the gallbladder carcinoma of PBM without bile duct dilatation is 36.1%. Many investigators have tried to clarify the carcinogenic process, from various aspects. The biliary epithelia are injured by harmful substances, and in the course of repair, multiple alterations of oncogenes and tumor suppressor genes are followed, and they lead to carcinoma through multistage interaction. In the biliary epithelia of PBM, incidence and degree of hyperplasia are characteristic. K-ras gene mutations are observed in the cancerous as well as noncancerous lesions of biliary tract of PBM patients. Mutations of p53 gene and overexpression of p53 protein are also found in the cancerous and noncancerous lesions. These changes are called “hyperplasia–carcinoma sequence”. Treatment  Total excision of the extrahepatic bile duct with gallbladder followed by hepaticojejunostomy, Roux-en-Y, or end-to-side hepaticoduodenostomy are treatment of choice, even for cases with not dilated bile duct, because the incidence of cancer in the nondilated bile duct is not negligible, and genetic changes are seen in a nondilated bile duct.     

A case report of gallbladder cancer and pancreas cystic neoplasm associated with pancreaticobiliary maljunction

Introduction and importancePancreaticobiliary maljunction (PBM) is a rare congenital anomaly that is frequently associated with carcinoma of the biliary tract. However, there is still no clear evidence that PBM is associated with pancreatic tumors. Here we describe a case of gallbladder cancer and intraductal papillary mucinous neoplasm (IPMN) that is associated with PBM.Case presentationA 72-year-old man underwent a cholecystectomy with hepatectomy (S4a + S5) and regional lymph node dissection for gallbladder adenocarcinoma invading the front lobe branch of the hepatic artery. A pylorus-preserving pancreaticodudenectomy was also performed for pancreatic IPMN.Clinical discussionPresence of mucin type 6 (MUC6) -positive pyloric gland metaplasia in both the dilated pancreatic duct and the gallbladder background mucosa suggests that pancreatic IPMN and gallbladder cancer may have a common phenotypic origin. Additionally, analysis of 41 reported cases of pancreatic cancer associated with PBM revealed that in all metachronous multiple cancer cases, biliary tract cancer preceded the pancreatic cancer with congenital biliary dilatation accompanied by PBM. The analysis also revealed an increased proportion of pancreatic cancer cases with PBM in patients who had not undergone a flow diversion procedure located in pancreatic head.ConclusionWe show an interesting relationship between pancreatic/gallbladder cancer and PBM. More comprehensive evaluations of the whole pancreaticobiliary system in follow-up of patients with PBM is required to understand the full extent of this relationship.     

Pancreaticobiliary maljunction: pathophysiological and clinical aspects and the impact on biliary carcinogenesis

BACKGROUND: Pancreaticobiliary maljunction (PBM) is frequently associated with congenital choledochal cyst (CCBD), but differs in embryonic cause and clinical features. It is thought to develop as a misarrangement of the embryonic connections in the pancreaticobiliary ductal system, with the terminal bile duct joined to one of the ducts of the ventral pancreas. Clinical aspects are intermittent abdominal pain, relapsing acute pancreatitis, jaundice, cholangitis, and gallbladder cancer. In patients with PBM and CCBD, primary bile duct stones, acute cholangitis, and bile duct cancer are considered to result from cholestasis, regurgitation of pancreatic juice, and reciprocal reflux of bile and pancreatic juice. The mixture of bile and pancreatic juice due to recipocal reflex very likely plays an important role in biliary carcinogenesis. PATIENTS AND METHODS: We reviewed the pathophysiological and clinical aspects and biliary carcinogenesis in 250 PBM patients (169 with benign hepatobiliary and pancreatic disease, 81 with malignancy). RESULTS: PBM patients show elevated cellular proliferation activity in the gallbladder epithelia. A number of oncogenes and tumor suppressor genes have been identified and implicated in carcinogenesis, particularly the K- ras oncogene and the p53 suppressor gene. Some K- ras mutations do not appear essential for hyperplasia but may be an early event in carcinogenesis. The p53 mutations are involved in carcinogenesis in the biliary epithelium in PBM patients.     

Prophylactic excision of the gallbladder and bile duct for patients with pancreaticobiliary maljunction.

HYPOTHESIS: Pancreaticobiliary maljunction (PBM) is a high-risk factor for biliary tract carcinogenesis because of a continuous reflux of pancreatic juice into the biliary tract. It remains to be disclosed whether we should perform prophylactic excision of gallbladders and bile ducts. DESIGN: A person-year method. SETTING: A university hospital. PATIENTS: We studied 68 patients with PBM treated between August 1, 1974, and December 31, 1999. MAIN OUTCOME MEASURES: Relative risks (observed number-expected number ratios) of gallbladder and bile duct carcinomas according to type of bile duct dilation (ie, cystic dilation, diffuse dilation, and nondilation). RESULTS: Observed number-expected number ratios of gallbladder carcinomas were high: 291.3 in 43 patients with cystic dilation, 167.2 in 16 patients with diffuse dilation, and 419.6 in 7 patients with nondilation. Observed number-expected number ratios of bile duct carcinomas were 194.2 in 43 patients with cystic dilation before surgery and 142.8 in 39 patients with cystic dilation after long postsurgical follow-up. All these values were statistically significant (P<.01). CONCLUSIONS: The gallbladder carries a high risk for carcinogenesis in all types of dilation in patients with PBM. The bile duct carcinomas of PBM were exclusively identified by the type of cystic dilation. Prophylactic cholecystectomy should be recommended for all dilation types, and prophylactic excision of bile ducts including cholecystectomy should be performed in patients with PBM and cystic dilation. Complete excision of extrahepatic dilated bile ducts and careful follow-up for carcinogenesis in residual dilated bile ducts should be recommended for patients with PBM and cystic dilation.     

p53 gene mutation and p53 protein overexpression in a patient with simultaneous double cancer of the gallbladder and bile duct associated with pancreaticobiliary maljunction

Pancreaticobiliary maljunction (PBM) is associated with the occurrence of biliary cancer due to pancreatobiliary reflux. We present a case of simultaneous double cancer of the gallbladder and bile duct. A 77-year-old woman who had jaundice, intra- and extra-hepatic biliary ductal dilatation and a space-occupying lesion in the gallbladder and lower bile duct underwent pancreatoduodenectomy. The gallbladder cancer showed papillary carcinoma without mutation of the K-ras gene and with p53 non-sense mutation of CCA (Pro) to CA (Stop) on codon 301 in exon 8. The bile duct cancer revealed a well-differentiated adenocarcinoma without mutation of the K-ras gene and with p53 miss-sense mutation of GTG (Val) to GAG (Glu) on codon 272 in exon 8. There were no mutations of either the K-ras or p53 gene in non-cancerous epithelia. In contrast, only the mucosa of the common channel had p53 protein accumulation and high cell proliferation activity. Therefore, the genetic pathway might be the same in both the gallbladder and bile duct cancer, and a high potential for carcinogenesis might be present in the epithelium of the common channel in patients with PBM.     

Risk factors for biliary tract and ampullary carcinomas and prophylactic surgery for these factors

Curative resection is the only treatment for biliary tract cancer that achieves long-term survival. However, patients with advanced biliary tract cancer have only a limited prognosis even after radical surgical resection. Thus, to improve the longterm results, the early detection of biliary tract cancer and subsequent cure seem to be essential. The purpose of this study was to review the literature concerning the risk factors for cancerous and precancerous lesions of the biliary tract, and prophylactic surgery for these factors. It has been reported that pancreaticobiliary maljunction (PBM) with bile duct dilatation is a risk factor for gallbladder cancer and bile duct cancer, while PBM without bile duct dilatation is a risk factor for gallbladder cancer. Thus, in the former group, a prophylactic excision of the common bile duct and gallbladder should be recommended, while in the later group, a prophylactic cholecystectomy without bile duct resection may be the appropriate surgical procedure. It has also been reported that primary sclerosing cholangitis (PSC) is a risk factor for cholangiocarcinoma. Patients with PSC often develop advanced cholangiocarcinoma with a poor prognosis. In patients with PSC, therefore, strict follow-up should be recommended. Adenoma and dysplasia have been regarded as precancerous lesions of gallbladder cancer. A polypoid lesion of the gallbladder that is sessile, has a diameter greater than 10 mm, and /or grows rapidly, is highly likely to be cancerous and should be resected. Although gallstones seem to be closely associated with gallbladder cancer, there is no evidence of a direct causal relationship between gallstones and gallbladder cancer. Thus, a cholecystectomy is not advised for asymptomatic cholecystolithiasis. Controversy remains as to whether adenomyomatosis of the gallbladder and porcelain gallbladder are associated with gallbladder cancer. With respect to ampullary carcinoma, adenoma of the ampulla is considered to be a precancerous lesion. This article discusses the risk factors for cancerous and precancerous lesions of the biliary tract and prophylactic treatment for these factors.     

Metachronous cancer of gallbladder and pancreas with pancreatobiliary maljunction

Pancreaticobiliary maljunction is a congenital anomaly in which the junction between the pancreatic duct and the common bile duct is located outside the sphincter of Oddi. It is well known that pancreaticobiliary maljunction is frequently associated with carcinoma of thebiliary tract. We report a case of metachronous cancer of the gallbladder and pancreas associated with pancreaticobiliary maljunction and cystic dilatation of common bile duct in a 68-year-old Tunisian woman who underwent a cholecystectomy for acute cholecystitis. The pancreatic tumor was an adenosquamous carcinoma. Pancreaticobiliary maljunction allows for pancreatobiliary or biliopancreatic reflux which may induce biliary tract carcinoma. Few cases of multifocal cancer associated with this anomaly have been reported. The association with pancreatic carcinoma remains rare. Close attention should be given to both the biliary tract system and pancreas during the long-term follow-up of patients with pancreaticobiliary maljunction, especially after they have undergone a choledochojejunostomy.