Cancer of the gallbladder associated with pancreaticobiliary maljunction without bile duct dilatation in a European patient

A rare case of pancreaticobiliary maljunction (PBM) without dilatation of the biliary tract (DBT) associated with gallbladder carcinoma is described herein. A 62‐year‐old European woman with a long history of right upper abdominal pain was diagnosed as having PBM without DBT by endoscopic retrograde cholangiopancreatography and other examinations. Excision of the gallbladder and biliary duct with a Roux‐en‐Y hepaticojejunostomy was performed, and subsequent pathological examination of the surgical specimen showed a well differentiated adenocarcinoma of the gallbladder. She had no clinical symptoms for 58 months postoperatively. PBM allows reflux of pancreatic juice into the biliary tract. Recent findings support the idea that epithelial hyperplasia plays an important role in gallbladder carcinogenesis with PBM, and also support the concept that gene mutations are involved in the carcinogenesis of biliary epithelium in patients with PBM. For these reasons, we advocate that resection of the extrahepatic biliary tract in PBM patients without bile duct dilatation, rather than cholecystectomy alone, is the treatment of choice for preventing bile duct carcinoma.     

Spontaneous necrosis of gallbladder carcinoma in patient with pancreaticobiliary maljunction

While gallbladder carcinoma is occasionally associated with pancreaticobiliary maljunction, spontaneous necrosis of carcinoma is extremely rare. We herein present a case of spontaneous necrosis of gallbladder carcinoma associated with direct invasion of viable cancer cell nests to the muscularis propria and subserosal layer located beneath the primary nodules. A 65-year-old Japanese man was admitted to a local hospital, complaining of repeated discomfort in the right hypochondrium. Ultrasonography and computed tomography scanning revealed cholecystitis associated with gallstones. Cholecystectomy was performed, and operative cholangiography demonstrated pancreaticobiliary maljunction. The resected gallbladder showed multiple mixed stones filled with necrotic debris and bile sludge. Scrutiny of the mucosal surface revealed multiple small necrotic nodules in the fundus, which were histologically confirmed to be necrotic remnants of a cancerous glandular structure. Small nests of papillary adenocarcinoma were found beneath the nodules in the muscularis propria and in the venous structure located in the connective tissues next to the divided margin of the gallbladder bed. Resection of S4a and S5 of the liver and resection of the extrahepatic bile duct was then performed to remove the remaining cancerous tissues and/or micrometastasis in the liver and bile duct. The biliary tree was reconstructed with a hepaticoduodenostomy. No cancer nests or any precancerous lesions were found in the additionally resected specimens. This case indicates a unique morphological feature of gallbladder carcinoma associated with pancreaticobiliary maljunction, which provides some insight into the pathogenesis of spontaneous necrosis of gallbladder carcinoma.     

Synchronous gallbladder and pancreatic cancer associated with pancreaticobiliary maljunction

We report the case of a 46-year-old woman who presented with chronic intermittent abdominal pain without jaundice; abdominal ultrasonography showed thickening of the gallbladder wall and dilatation of the bile duct. Endoscopic retrograde cholangiopancreaticography showed pancreatobiliary maljunction with proximal common bile duct dilatation. Pancreatobiliary maljunction was diagnosed. A computed tomography scan of the abdomen showed suspected gallbladder cancer and distal common bile duct obstruction. A pancreatic head mass was incidentally found intraoperative. Radical cholecystectomy with pancreatoduodenectomy was performed. The pathological report showed gallbladder cancer that was synchronous with pancreatic head cancer. In the pancreatobiliary maljunction with pancreatobiliary reflux condition, double primary cancer of the pancreatobiliary system should be awared.     

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.     

Relationship between pancreaticobiliary maljunction and gallbladder carcinoma: a meta-analysis

BACKGROUND: Reports on the relationship between pancreaticobiliary maljunction (PBM) and gallbladder carcinoma (GBC) are conflicting. The frequency of PBM in GBC patients and the clinical features of GBC patients with PBM vary in different studies. DATA SOURCES: English-language articles describing the association between PBM and GBC were searched in the PubMed and Web of Science databases. Nine case-control studies fulfilled the inclusion criteria and addressed the relevant clinical questions of this analy...     

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.     

Recent advances in pancreaticobiliary maljunction

The purpose of this review is to evaluate our current knowledge of the embryologic etiology of pancreaticobiliary maljunction (PBM), its diagnosis, clinical aspects, and treatment, and to clarify the mechanisms of PBM involvement in carcinogenesis. Although the embryologic etiology of PBM still awaits clarification, an arrest of the migration of the common duct of the biliary and pancreatic ducts inwards in the duodenal wall has hitherto been speculated to result in a long common channel in PBM. However, we propose the hypothesis that the etiology of PBM is caused by a disturbance in the embryonic connections (misarrangement) of the choledochopancreatic duct system in the extremely early embryo. That is, PBM is an anomaly caused by a misarrangement whereby the terminal bile duct joins with a branch of the ventral pancreatic duct system, including the main pancreatic duct. PBM is frequently associated with congenital bile duct cyst (CCBD). However, these two anomalies are thought to have different embryonic etiologies. The diagnostic criteria for PBM are the radiological and anatomical detection of the extramural location of the junction of the pancreatic and biliary ducts in the duodenal wall. However, in PBM patients with a short common duct (less than 1 cm in length), detection of the extramural location is difficult. The clinical features of PBM are intermittent abdominal pain, with or without elevation of pancreatic enzyme levels; and obstructive jaundice, with or without acute pancreatitis, while the clinical features of PBM patients with CCBD are primary bile duct stone and acute cholangitis. The optimum approach for the treatment of PBM is the prevention of the reciprocal reflux of bile and pancreatic juice in the pancreas and the bile duct system. To achieve these aims, the surgical approach is most effective, and complete biliary diversion procedures with bile duct resection (for example, choledochoduodenostomy or choledochojejunostomy of the Roux‐en‐Y type) are most useful. Recently, it has been recognized that the development of biliary ductal carcinoma is associated with PBM. That is, the development of gallbladder cancer occurs frequently in PBM patients without CCBD, and bile duct cancer originating from the cyst wall also occurs in PBM patients with CCBD. It is speculated that the pathogenesis of the bile duct or gallbladder cancer in PBM patients involves the reciprocal reflux of bile and pancreatic juice. Investigations of epithelial cell proliferation in the gallbladder of PBM patients, and of K‐ras mutations andp53 suppressor gene mutations, loss of heterozygosity ofp53, and overexpression of thep53 gene product in gallbladder cancer and noncancerous lesions in PBM patients have been carried out in various laboratories around the world. The results support the conclusion that PBM is a high risk factor for the development of bile duct carcinoma.     

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.     

Carcinoma of the cystic duct associated with pancreaticobiliary maljunction

Received: February 4, 2000 / Accepted: May 26, 2000     

Mixed neuroendocrine non-neuroendocrine neoplasm of the gallbladder complicated by a pancreaticobiliary maljunction of a non-dilated biliary duct: A case report

Rationale:Mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN) is a rare tumor. MiNEN of the gallbladder (GB) with pancreaticobiliary maljunction (PMJ) is extremely rare. The origin of MiNEN of the GB remains unknown; the biliary tract normally lacks neuroendocrine cells. MiNEN of the GB has a poor prognosis; because of its rarity, no treatment or management guidelines have been established yet.Patient concerns:A 47-year-old male presenting with right hypochondrial pain and malaise for 3 months was referred to our hospital for further management.Diagnosis:The neuron-specific enolase level was increased. Contrast-enhanced computed tomography revealed a mass of 70 mm in size with unclear boundaries in the liver. The GB was surrounded by this mass, narrowing the lumen of the GB. Many swollen lymph nodes were observed in the hepatoduodenal ligament. Endoscopic retrograde cholangiopancreatography revealed a PMJ with a non-dilated biliary duct. A percutaneous biopsy was performed on the liver mass, and the pathological findings were neuroendocrine carcinoma (NEC) (small cell type). We diagnosed a NEC of the GB, T3N1M0, stage IIIB (Union for International Cancer Control, 7th edition).Interventions:Because of advanced lymph node metastasis, we considered this tumor difficult to cure solely by surgical intervention. After initial chemotherapy consisting of cisplatin and irinotecan, a marked reduction in both tumor and lymph node sizes enabled conversion surgery. The pathological diagnosis of the resected tumor was MiNEN consisting of NEC and adenocarcinoma. The primary lesion was the adenocarcinoma occupying the luminal side of the GB. As a postsurgical treatment, the patient received additional irradiation therapy to the common hepatic duct and liver stump because of positive surgical margins.Outcomes:At 13 months postoperatively, computed tomography findings revealed the appearance of a hypervascular liver tumor, and laboratory data showed increased serum neuron-specific enolase levels. Chemotherapy was unsuccessful, leading to the death of the patient 36 months from the date of diagnosis.Lessons:There are several reports on the development of MiNEN of the GB. In our case, a PMJ-related adenocarcinoma of the GB transdifferentiated into NEC. Further accumulation of cases is necessary to establish a treatment strategy for MiNEN of the GB.     

Cell kinetic study of the gallbladder epithelium,with special reference to the pancreaticobiliary maljunction

The bromodeoxyuridine labelling index (BrdU-LI), ornithine decarboxylase (ODC) activity, and bile elements in the gallbladder were examined in 23 patients to investigate cell kinetics and oncogenesis in gallbladder epithelium with pancreaticobiliary maljunction (PBMJ). The patients were classified into five groups: group I (4 patients without biliary disorder), group II (8 patients with cholecystolithiasis), group III (4 patients with PBMJ), group IV (3 patients with gallbladder cancer and PBMJ), and group V (4 patients with gallbladder cancer). In non-cancerous epithelium, the BrdU-LI in groups III (2.88±3.07%), IV (4.92±2.73), and V (5.93±2.08) was significantly higher than in group I (0.06±0.12), and the ODC activity in groups III (7.83±6.82 pmole CO₂/h per mg protein), IV (17.21±9.44), and V (11.27±12.33) was also significantly higher than that in group I (1.39±1.78). Both BrdU-LI and ODC activity were high in epithelium showing metaplasia in 3 patients from groups III and IV. In groups I and II, the lithocholic acid (LCA) fraction showed a positive correlation with BrdU-LI (correlation coefficient, 0.90) and ODC activity (correlation coefficient, 0.91). From these results, it can be concluded that the gallbladder epithelium in patients with PBMJ, and its metaplastic changes, show an increase in cell proliferation, which is important in the progression of cancer.     

Triple carcinomas of the biliary tract associated with congenital choledochal dilatation and pancreaticobiliary maljunction

We report a rare case of triple carcinomas of the biliary tract associated with congenital choledochal dilatation (CCD) and pancreaticobiliary maljunction (PBM). The patient was a 58-year-old Japanese man who complained of epigastralgia. Ultrasonography and computed tomography revealed an elevated lesion inside the markedly dilated extrahepatic bile duct, thickening of the gallbladder wall, and small polypoid lesions in the gallbladder. Magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography showed CCD and PBM. With a diagnosis of carcinoma of the bile duct and cholesterol polyps in the gallbladder, pylorus-preserving pancreaticoduodenectomy was performed. The resected specimen showed two elevated lesions in the dilated bile duct, cholesterol polyps, and an area of irregular mucosa in the gallbladder. Histopathological examination showed two carcinomas in the bile duct, an adenosquamous cell carcinoma, and a moderately differentiated tubular adenocarcinoma, and a well differentiated tubular adenocarcinoma of the gallbladder. Two years and 6 months after the operation, a solitary metastatic liver tumor was detected. Left hepatic lobectomy was performed. At present, 7 months after the second operation, the patient is doing well with no signs of recurrence. Multiple carcinomas in the biliary tract associated with CCD and PBM, including the details in the present patient, were reviewed. Received: March 31, 1999 / Accepted: October 22, 1999     

Gallbladder carcinoma associated with occult pancreatobiliary reflux in the absence of pancreaticobiliary maljunction

We herein report a case of gallbladder carcinoma associated with occult pancreatobiliary reflux (PR) in the absence of pancreatobiliary maljunction. A 67‐year‐old woman was referred to our hospital for the evaluation and treatment of a gallbladder tumor. Ultrasonography and computed tomography showed a nodular lesion in the fundus of the gallbladder, indicating the possibility of a gallbladder carcinoma. Endoscopic ultrasonography showed the nodular tumor and thickness of the surrounding epithelium. Endoscopic retrograde cholangiopancreatography revealed a normal pancreaticobiliary junction without the common channel and a slight dilatation of the common bile duct (15 mm in diameter). An open cholecystectomy and partial resection of the liver bed of the gallbladder with regional lymphadenectomy was performed. A C‐tube was inserted from the cut end of the cystic duct into the common bile duct to prevent bile stasis. Biliary amylase and lipase levels sampled in the gallbladder were 2604 IU/l and 775 IU/l, respectively. Biliary amylase level in the bile collected from the C‐tube in the common bile duct was 119 550 IU/l on postoperative day (POD) 6 and 22 265 IU/l on POD 12. These observations suggested that PR was present in this patient. The histopathological findings of the resected specimen showed a well‐differentiated adenocarcinoma of the gallbladder with invasion to the muscle layer and no metastasis of the resected lymph nodes. A high index of nuclear staining for MIB‐I in the cancer cells (about 10%) was exhibited, and a few cells in the normal epithelium also stained positive.     

Endoscopic findings of the duodenal papilla in patients with pancreaticobiliary maljunction

Background: To our knowledge this is the first report describing the relation between the form of the duodenal papilla and the pancreaticobiliary maljunction (PBM). Methods: The duodenal papilla was studied endoscopically in 46 patients with PBM and in 80 patients without PBM. Results: The duodenal papilla was classified into three types by three independent endoscopists. Conclusion: The oral protrusion of the duodenal papilla in patients with PBM was shorter or absent compared with the duodenal papilla in patients without PBM.     

Metachronous double cancer of the gallbladder and common bile duct

We report a rare case of metachronous double cancer of the biliary tract. At age 59 years, a man had undergone a cholecystectomy and resection of the liver bed for gallbladder cancer pathologically diagnosed as papillary adenocarcinoma, in 1997. Four years later, he was admitted to our hospital with jaundice. At first, we suspected lymph node metastasis of the gallbladder cancer along the common bile duct. But abdominal computed tomography demonstrated circular wall thickness of the common bile duct, so primary bile duct cancer was strongly suspected. Thus, extended right hepatectomy and pancreaticoduodenectomy were performed after right portal vein embolization. The pathological diagnosis of the resected specimen was well-differentiated tubular adenocarcinoma, and this case was clarified to be metachronous double cancer. A review of the literature regarding double cancer of the biliary tract is presented following this case report. We showed that half of 30 cases of double cancer of the biliary tract were not associated with pancreaticobiliary maljunction, including all 6 metachronous cases.     

Severe dysplasia of the gallbladder associated with occult pancreatobiliary reflux

Pancreatobiliary reflux usually occurs in patients with pancreaticobiliary maljunction and can be associated with the occurrence of gallbladder carcinoma. We present the case of a patient with pancreatobiliary reflux despite having a normal pancreatobiliary junction (occult pancreatobiliary reflux; OPBR), in whom the resected gallbladder presented severe dysplasia. The patient, a 61-year-old woman, showed thickness of the gallbladder wall, detected by ultrasonography and computed temography (CT). Her biliary amylase level in the common bile duct was 103 000 IU/l, and in the gallbladder it was 153 500 IU/l, although endoscopic retrograde cholangiopancreatography revealed a normal pancreaticobiliary junction. Immunohistochemical staining showed many p53-positive nuclei in the dysplastic lesion, and about 50% of the dysplastic cells exhibited diffuse nuclear staining for Ki-67. In the present patient, early diagnosis of occult pancreatobiliary reflux led to early detection of a precancerous lesion of the gallbladder mucosa.     

Epithelial cell proliferation and gene mutation in the mucosa of gallbladder with pancreaticobiliary malunion and cancer

The significant association between pancreaticobiliary malunion (PBM), especially undilated-type PBM, and a high risk of gallbladder cancer is known. Reflux and stasis of pancreatic juice induce various epithelial changes in the gallbladder. Recently, epithelial hyperplasia of the gallbladder was shown to be significantly and frequently associated with undilated-type PBM, and it is suggested that the majority of epithelial hyperplasia may exist at birth or be acquired in early childhood, and thereafter present throughout the lives of PBM patients. Cell kinetic studies demonstrated a significant stepwise increase in cellular proliferative activity from normal gallbladder mucosa, through epithelial hyperplasia to cancer. Epithelial hyperplasia with increased proliferative activity may predispose the mucosa to mutational events, thereby increasing cancer risk in PBM patients. K-ras mutations were frequently detected in gallbladder cancer in PBM patients and in epithelial hyperplasia as well. Epithelial hyperplasia is demonstrated to be an important premalignant lesion of gallbladder cancer. A multistep process of carcinogenesis as a consequence of multiple genetic alterations of oncogenes and tumor suppressor genes has been demonstrated in various organs; however, there is limited information on the molecular mechanism in gallbladder carcinogenesis with PBM. Recent findings support the idea that epithelial hyperplasia plays an important role in gallbladder carcinogenesis with PBM and also support the concept that neoplastic development in gallbladder with PBM also evolves through a multistep process associated with hyperproliferation and genetic alterations.