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.     

Relation between K-ras codon 12 mutation and p53 protein overexpression in gallbladder cancer and biliary ductal epithelia in patients with pancreaticobiliary maljunction

It is well known that the incidence of biliary cancer is higher in patients with pancreaticobiliary maljunction (PBM) than in individuals without PBM. However, the relationship between PBM and the carcinogenesis remains unclear. The purpose of the present study was to examine histopathologic changes in the mucosa of the gallbladder and bile duct in patients with PBM, and to investigate K‐ras oncogene mutation and overexpression of p53 protein in the mucosa. We examined 47 surgical specimens of gallbladder and 36 surgical specimens of bile duct obtained from 48 patients with PBM. The 48 patients were divided into three age groups: group A (0—3 years), group B (4—39 years), and group C (40 years or more). Investigation of K‐ras mutation and overexpression of p53 protein was performed using an enriched polymerase chain reaction (PCR) and enzyme‐linked mini‐sequence assay (ELMA), and by the streptavidin‐biotin (SAB) method, using DO‐7 antibodies, respectively. Hyperplastic changes in the gallbladder mucosa were observed in patients in the three groups. However, metaplastic or dysplastic changes were observed in the mucosa of only groups B and C. K‐ras gene mutation in the gallbladder mucosa was found in 18.8% of the hyperplastic mucosae in group B and in 20% in group C. The mutation was found in 33.3% of lesions with metaplastic change associated with hyperplastic changes and in 25% of lesions with dysplastic changes in group C. No mutation was observed in the non‐cancerous mucosae of gallbladders and bile ducts without congenital dilatation of the bile duct. Overexpression of p53 protein was observed only in carcinoma of the gallbladder; in seven of nine advanced carcinomas and in two of three carcinomas in situ. We concluded that the mucosal epithelia of the biliary system in patients with PBM showed a high frequency of gene mutations and the carcinogenesis appeared in involve a multistage process of mutation in the K‐ras gene and the p53 supressor gene.     

Metachronous double cancer of the gallbladder and pancreas associated with pancreaticobiliary maljunction

A 50-year-old Japanese woman complained of abdominal and back pain. Ten years previously she had undergone cholecystectomy, choledochectomy, and Roux-en-Y choledochojejunostomy for gallbladder cancer associated with pancreaticobiliary maljunction without bile duct dilatation. On the present admission, ultrasonography (US) and computed tomography (CT) demonstrated a large mass, 60 mm in size, in the pancreatic tail. Endoscopic retrograde cholangiopancreatography (ERCP) showed obstruction of the main pancreatic duct in the tail of the pancreas and revealed that the pancreatic duct was joined to the bile duct 25 mm above the papilla of Vater. The patient underwent distal pancreatectomy, splenectomy, left adrenalectomy, and partial gastrectomy. Histological examination revealed moderately differentiated ductal adenocarcinoma that had invaded to the proper muscle of the stomach. Double cancer of the gallbladder and pancreas in a patient with pancreaticobiliary maljunction is rare. Although the etiology of cancer of the pancreas associated with pancreaticobiliary maljunction is unclear, we should pay close attention to the pancreas as well as the biliary tract during the long-term follow-up of patients with pancreaticobiliary maljunction after they have undergone a choledochojejunostomy.     

p53 Gene mutations and overexpression of p53 product in cancerous and noncancerous biliary epithelium in patients with pancreaticobiliary maljunction

To investigate the molecular mechanisms of the high incidence of carcinogenesis in the biliary epithelium of patients with pancreaticobiliary maljunction, we examined p53 gene mutations, loss of heterozygosity of p53, and overexpression of p53 gene product in the cancerous and noncancerous biliary epithelium of 27 patients with pancreaticobiliary maljunction. Mutations of the p53 gene were examined by polymerase chain reaction-single strand conformation polymorphism and a direct sequencing method. Loss of heterozygosity of the p53 gene was determined using a double-targeted fluorescence in situ hybridization method. Expression of p53 gene product was examined using immunohistochemical staining. Mutations of the p53 gene were found in 4 of 5 biliary carcinomas (80%) and in 10 of 26 noncancerous biliary lesions (38.5%). Point mutations of the p53 gene were detected at codons 207, 212, and 217 on exons 5 through 8. The incidence of p53 gene mutations on exons 5, 6, 7, and 8 was 12.9%, 36.4%, 0.0%, and 13.8%, respectively. Loss of heterozygosity of p53 was shown in 72% of the cells obtained from the cancerous lesion, and in an average of 14% obtained from the noncancerous lesions. Overexpression of p53 protein was found in 57.1% of carcinoma, and in 31.3% of the noncancerous lesions. These results suggest that p53 gene mutations are involved in the carcinogenesis of biliary epithelium in patients with pancreaticobiliary maljunction.     

Carcinoma of the cystic duct associated with pancreaticobiliary maljunction

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

Advanced bile duct carcinoma in a 15-year-old patient with pancreaticobiliary maljunction and congenital biliary cystic disease

We report a case of advanced bile duct carcinoma arising in a 15-year-old female with pancreaticobiliary maljunction and congenital biliary cystic disease. Pancreaticoduodenectomy and partial resection of the liver was performed. Surgical and histopathological findings indicated advanced tubular adenocarcinoma, classified as final stage IVb according to the General rules for surgical and pathological studies on cancer of the biliary tract proposed by the Japanese Society of Biliary Surgery, 5th edition, and stage IV according to the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC), 6th edition. She underwent chemotherapy with gemcitabine HCl after discharge. She died of cachexia 14 months after the surgery. Although it is well known that biliary malignancies arise frequently in patients with pancreaticobiliary maljunction, it is uncommon for advanced bile duct carcinoma to occur in a 15-year-old female. We should pay attention to the possibility of biliary malignancy in patients with pancreaticobiliary maljunction and congenital biliary cystic disease, even when the patients are juveniles.     

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.     

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.     

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...     

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     

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.     

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.     

Clinical problems in the surgical treatment of pancreaticobiliary maljunction

The results of surgical treatment of pancreaticobiliary maljunction at our department are described. The 67 patients who underwent surgery for this disease were divided by age into an adult group (45 patients, aged 16 years and over) and a pediatric group (22 patients, aged less than 16 years). The incidence of concomitant carcinoma before surgery and the incidence and severity of postoperative cholangitis were compared between these two groups. In addition, the cell proliferating activity of the biliary tract epithelium in cancer-free patients was compared between the two groups, using the proliferating cell nuclear antigen labeling index (PCNA LI). Ten patients (all adults) were diagnosed with cancer (gallbladder carcinoma in 7 and bile duct carcinoma in 3) before surgery. The surgical techniques used for reconstruction in the cancer-free patients were: in the adult group, hepaticoduodenostomy in 9 patients, Roux-en-Y hepaticojejunostomy in 17, jejunal interposition in 8, and another technique in 1. In the pediatric group, hepatico-duodenostomy was performed in 17 patients. Roux-en-Y hepaticojejunostomy in 3, and jejunal interposition in 2. Postoperative cholangitis occurred in 6 adults (including 2 with severe form) and 1 child (mild case). The PCNA LI of the biliary tract epithelium was high compared to control findings in the biliary tract epithelium of 10 adult patients without pancreaticobiliary maljunction. In the adult group with dilated extrahepatic bile ducts (n=10 examined) this index was 11.4% for the bile duct epithelium (control, 1.5%) and 12.7% for the gallbladder epithelium (control, 1.4%). In the adult group with non-dilated extrahepatic bile ducts (n=5 examined) it was 5.9% for the bile duct epithelium and 13.1% for the gallbladder epithelium. In the pediatric group (n=10 with extrahepatic bile duct dilatation) it was 7.5% for the bile duct and 9.7% for the gallbladder epithelium. (Differences from control values were all significant.) These results suggest that surgery for this disease should be performed as early as possible and that extrahepatic bile duct excision and biliary reconstruction should be performed whether or not extrahepatic bile ducts are dilated.     

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.     

联合检测粪便中k-ras与p53基因诊断大肠癌

目的探讨粪便中k-ras与p53基因突变的检测用于大肠癌诊断及筛查的可行性。方法应用聚合酶链反应-单链构象多态性分析-银染法检测大肠癌组织及粪便中k-ras与p53基因突变,并与粪便潜血实验比较。结果31例大肠癌患者组织中k-ras基因突变9例,粪便中检测出7例;p53突变12例,粪便中检测到p53突变10例,二者符合率分别为77%（7/9）和83%（10/12）,而在正常组织及正常人粪便中均未检测到突变,特异性100%。粪便中k-ras与p53基因突变与肿瘤分化程度,Dukes分期,肿瘤部位,粪便潜血,癌胚抗原无关。结论粪便中突变基因检测有望成为一种新的大肠癌无创性筛查方法。     

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.     

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.     

Anomalous junction of the pancreaticobiliary duct accompanied by gallbladder cancer and obstructive jaundice in a patient with high serum and bile cytokine levels

We report a case of anomalous junction of the pan creaticobiliary duct (AJPBD) associated with gallbladder cancer and obstructive jaundice in a patient with high serum and bile cytokine levels. The patient was a 63-year-old woman who complained of right hypochondralgia. Ultrasound, computed tomography, percutaneous transhepatic cholangiography, and endoscopic retrograde cholangio-pancreatatography revealed dilation of the bile ducts, an elevated lesion of the gallbladder, and AJPBD. She underwent percutaneous transhepatic cholangio-drainage (PTCD) for obstructive jaundice. However, the total bilirubin concentration remained high 7 days after PTCD. Her serum interleukin 6 level was 57 359 pg/ml before PTCD, and gradually decreased to 10 pg/ml after PTCD. Bile interleukin 6 level was 10 pg/ml before PTCD, 8997 pg/ml 3 h after PTCD and gradually decreased there after. Serum and bile levels of tumor necrosis factor α and hepatocyte growth factor were high before and after PTCD. The patient underwent an extended cholecystectomy and resection of the extrahepatic bile duct. The resected specimen showed two elevated lesions of the gallbladder which, microscopically, revealed moderately differentiated tubular adenocarcinoma. These findings suggest that pre-existing inconspicuous inflammation of the biliary tract due to reflux of pancreatic juice is involved in elevation of serum and bile cytokines, and that cytokines may participate in gallbladder carcinogenesis associated with AJPBD. (Received July 24, 1997; accepted Jan. 23, 1998)