K-ras and p53 gene mutations in noncancerous biliary lesions of patients with pancreaticobiliary maljunction

Background/Purpose: We investigated the molecular mechanisms of carcinogenesis in the biliary epithelium in patients with pancreaticobiliary maljunction. Methods: Point mutations of the K-ras gene and the p53 gene, and the overexpression of p53 gene products were examined in the cancerous and noncancerous biliary epithelium of 37 patients with pancreaticobiliary maljunction, with or without biliary dilatation. Results: In the gallbladder epithelium of 5 patients with pancreaticobiliary maljunction associated with biliary carcinoma, K-ras gene mutations were detected in 3 (60%), p53 gene mutations in 3 (60%), and the overexpression of p53 gene products in 4 (80%), while in the bile duct epithelium of these patients, these features were found in 2 of 3 (66.7%), in all of 3 (100%), and none of 3 (0%) specimens, respectively. In the gallbladder epithelium of patients with pancreaticobiliary maljunction without biliary carcinoma, K-ras gene mutations were detected in 8 of 24 (33.3%) specimens, p53 gene mutations were detected in 16 of 27 specimens (59.3%), and the overexpression of p53 protein was detected in 5 of 27 (18.5%) specimens, while in the bile duct epithelium of these patients, these features were found in 10 of 25 (40%) specimens, 14 of 25 (56%) specimens, and 6 of 24 (25%) specimens, respectively. Conclusions: These results suggest that noncancerous lesions of the biliary epithelium in patients with pancreaticobiliary maljunction have mutations of the K-ras gene and/or the p53 gene, which provides genetic evidence that biliary epithelium has high carcinogenic potential. Received: June 7, 2001 / Accepted: August 21, 2001     

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.     

Pancreaticobiliary maljunction: retrospective and nationwide survey in Japan

Pancreaticobiliary maljunction (PBM) is a congenital anomaly defined as a union of the pancreatic and biliary duct that is located outside the duodenal wall. The Japanese Study Group on Pancreaticobiliary Maljunction and the Committee for Registration enrolled and analyzed 1627 patients with PBM who had been diagnosed and treated from January 1, 1990 to December 31, 1999 at 141 hospitals throughout the country. There were 1239 patients with dilatation of the bile duct (group A) and 388 patients without dilatation (group B). The average age was 24 years in group A and 47 years in group B; the age was significantly higher in group B. The type of confluence between the terminal choledochus and the pancreatic duct has been classified into three types (type a, right-angle type; type b, acute-angle type; and type c, complex type). In group A, type a accounted for 57.9% and was significantly more frequent compared with the other types (type b, 32.4%; type c, 5.6%). In group B, type b accounted for 60.8%, being significantly more frequent compared with the other types (type a, 29.4%; type c, 7.2%). Subjective symptoms, preoperative complications (e.g., liver dysfunction and acute pancreatitis), pancreatic stone, and pancreatic duct morphological abnormality were significantly more frequent in group A. However, the amylase levels in the bile and gallbladder were significantly higher in group B, and the presence of gallstone and morphological abnormality of the gallbladder was significantly more frequent in group B. The occurrence rate of cancer in the biliary tract was 10.6% in group A and 37.9% in group B, being significantly higher in group B. In group A, cancer of the extrahepatic bile duct was seen in 33.6% and cancer of the gallbladder was seen in 64.9%, but gallbladder cancer was present significantly more frequently in the patients with diffuse or cylindrical dilatation, and bile duct cancer was present significantly more frequently in the patients with cystic dilatation. In group B, 93.2% of the patients had gallbladder cancer, and bile duct cancer was found in as few as 6.8%. Against this background Japanese surgeons regard cholecystectomy, resection of the extrahepatic bile duct, and hepaticojejunostomy as standard operations for PBM with dilatation of the bile duct. However, opinion on whether or not the bile duct should be removed in the treatment of PBM without dilatation of the bile duct has been divided among Japanese surgeons. A randomized controlled trial is necessary.     

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.     

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.     

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.     

胰胆管合流异常合并胆囊床迷走胆管致术后胆汁漏

LG是治疗胆囊结石和慢性胆囊炎的有效方法。回顾性分析2012年8月解放军第八十八医院收治的1例因胰胆管合流异常以及胆囊床迷走胆管致LC术后胆汁漏、腹腔感染患者的临床资料,旨在探讨比类疾病的正确诊断和治疗方法。     

合并胰胆管合流异常的急性胆源性胰腺炎32例分析

目的 通过磁共振胰胆管成像检查评价成人胰胆管合流异常并探讨其和急性胆源性胰腺炎发生的关系.方法 对照观察伴有胰胆管合流异常与不伴胰胆管合流异常之成人急性胆源性胰腺炎患者153例,比较其保守治疗前后的各项肝功能指标的差别.结果 通过磁共振胰胆管成像检出的32例急性胆源性胰腺炎患者合并胰胆管合流异常,与其余121例不伴胰胆管合流异常的成人急性胆源性胰腺炎患者比较.保守治疗后胰胆管合流异常(PBM)组和不伴胰胆管合流异常(NPBM)组的TB、ALT、AST、ALP、GGT都明显降低,其中ALT、AST、GGT的变化差异有统计学意义(P＜0.05).PBM组的ALT、AST和GGT都高于NPBM组,差异有统计学意义(P＜0.05).结论 胰胆管合流异常是导致急性胆源性胰腺炎的重要原因之一,MRCP作为一种无创的胆胰管道系统成像技术对于胰胆管合流异常的研究是一种安全、可靠的检查方法.     

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     

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. Received for publication on Feb. 5, 1999; accepted on March 29, 1999     

胰胆管汇合异常病理解剖与胰胆系疾病关系研究

多层螺旋CT及图像后处理技术、MRI等的广泛应用,为胰胆管汇合部解剖学研究提供了重要手段.通过胰胆管汇合异常与胆道系统病变关系研究,可以提高对胆道系统病的发病机理、病理过程的认识,为预防性治疗提供依据.本文对胰胆管汇合异常的定义、分型、病理解剖及其与胆系疾病的关系、临床治疗进行综述.     

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.     

Anomalous biliary drainage associated with pancreaticobiliary maljunction and nondilatation of the common bile duct

A case report is presented of an infant with jejunal atresia and hyperbilirubinemia with diagnosed pancreaticobiliary maljunction without choledochal dilatation. Common channel insertion was into the third portion of the duodenum.     

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 and p53 suppressor gene mutations, loss of heterozygosity of p53, and overexpression of the p53 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. Received: March 12, 2001 / Accepted: April 16, 2001     

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. Received for publication on Feb. 3, 1999; accepted on Oct. 18, 1999     

Potential diagnostic value of pancreatic isoamylases for pancreaticobiliary maljunction with mild biliary dilatation in patients and a porcine model

Purpose

The aim of this study was to evaluate the diagnostic value of serum pancreatic isoamylases for pancreaticobiliary maljunction (PBM) with mild biliary dilatation.

Methods

Serum and bile from 8 children with PBM and mild biliary dilatation (6 to 11 mm in diameter) and 4 young pigs with an anastomosis constructed between an isolated pancreas-duodenal segment and the gallbladder were studied for pancreatic isoamylases. Using an electrophoretic technique, the assay of pancreatic isoamylases was expressed by peak appearance rate (PAR). Serum from 20 healthy children served as normal controls.

Results

In the serum of the patients, preoperatively there were 5 pancreatic peaks with PAR as follows: P1, 100%; P2, 100%; P3, 100%; P4, 100%; and P5, 66.7%. These abnormal pancreatic isoamylases disappeared 2 weeks after operative treatment. In normal controls, there were only P1 (PAR, 40%) and P2 (PAR, 100%). Mild cylindrical dilatation (6 to 8 mm in diameter) of the common bile duct developed in the porcine PBM model. There were P1 (PAR, 100%) and P2 (PAR, 100%) in the porcine serum preoperatively. Thirty days and 60 days after establishing the model, there appeared in the serum 6 pancreatic peaks with PAR as follows: P1, 100%; P2, 100%; P3, 75%; P4, 100%; P5, 100%, and P6; 75%. The bile patterns of pancreatic isoenzymes in the patients and pigs were similar to those in serum.

Conclusions

Abnormal pancreatic isoamylases are characteristically present in the serum from both children and a porcine model of PBM and mild biliary dilatation. Assay for these abnormalities is promising to recognize this subset of patients in whom diagnosis remains a challenge.     

儿童胆道扩张症与胰胆管合流异常的相关性

目的 通过回顾性分析先天性胆道扩张症(CBD)临床病例资料,比较合并胰胆管合流异常(PBM)与无合流异常病例的临床特征之间的差异,探讨PBM以及共同管长度与CBD的发病、临床症状、相关实验室检查结果的相关性,为CBD的发病机理和诊断治疗提供新的理论依据.方法 回顾性总结2017年1月至2019年12月首都医科大学附属北...     

Congenital dilatation of the common bile duct and pancreaticobiliary maljunction—clinical implications

Clinical conditions and diagnosis  Congenital dilatation of the common bile duct is a disease in which the extrahepatic bile duct, or both the extra and intrahepatic bile ducts, is dilated in various ways. Pancreaticobiliary maljunction is a disease in which the pancreatic duct meets the bile duct outside of the duodenal wall beyond the sphincter Oddi. Recently, these diseases have been thought to be closely related to each other but to be different malformations. Biliary tract carcinoma, especially bile duct carcinoma, is found in about 30% of patients with congenital dilatation of the bile duct. The concomitance of bile and pancreatic juice and their stasis in the biliary tract induce cellular proliferation and reproduction and stimulate genetic alterations in biliary epithelium, which may play an important role in carcinogenesis of the bile duct. Therapeutic strategies  Endoscopic retrograde cholangiopancreatography is useful for examining pancreaticobiliary maljunction. The operation is dilated bile duct resection and hepaticojejunostomy, which ensure that pancreatic juice and bile do not mix in the bile duct. Gallbladder carcinoma develops in more than 90% of pancreaticobiliary maljunction without bile duct dilatation.     

p53 overexpression and K-ras gene mutations in primary sclerosing cholangitis-associated biliary tract cancer

Cholangiocarcinoma occurs frequently in patients with primary sclerosing cholangitis (PSC). We evaluated the incidence and prognostic significance of p53 protein overexpression and K-ras gene mutations in patients with biliary tract cancer and PSC. p53 protein expression was determined in specimens from 12 patients with biliary tract cancer, using the antibody, D07. K-ras mutations were detected using DNA sequencing and a mutation ligation assay. Accumulation of p53 protein was detected in 6 of 12 tumors (50%). K-ras mutations were detected in 4 of 12 tumors (33%). Overall survival in patients with p53-negative tumors was significantly longer (P < 0.05) than that in patients with p53-positive (mutant) tumors. Similarly, overall survival was significantly longer (P < 0.05) in the absence of a K-ras mutation than in patients with a tumor containing a K-ras mutation. Mean interval from the time of diagnosis of PSC until the diagnosis of biliary tract cancer was significantly shorter (P < 0.05) in patients with p53 overexpression than in those patients without p53 overexpression (2 versus 47 months). p53 overexpression and K-ras mutations occur commonly in patients with PSC and biliary tract cancer and are associated with a shortened survival. Patients with longstanding PSC are less likely to have these genetic alterations and may have a better prognosis. Received: September 24, 1999 / Accepted: June 6, 2000     

Clinicopathology of pancreaticobiliary maljunction: relationship between alterations in background biliary epithelium and neoplastic development

Background/Purpose Between 1988 and 2003, 38 patients underwent biliary resection for pancreaticobiliary maljunction (PBM). We reviewed the histopathologic findings for the surgically resected specimens to compare the clinical and pathologic features and assess the relationship between changes in the background biliary epithelium and the development of neoplasms.Methods Papillary hyperplasia (PHP) seen in the biliary epithelium of patients with PBM, was classified into grades 0–III in the gallbladder and grades 0–II in the extrahepatic bile duct, according to the extent, and was assessed for links with tumors in the same specimens.Results The incidence of gallbladder carcinoma was 13/21 in grades I–II, versus 0/16 in grade III, while the incidence of bile duct carcinoma was 4/20 in grade I versus 0/5 in grade II. Furthermore, these incidences for patients below age 50 years and age 50 or older were 1/18 versus 12/20, and 0/14 versus 6/17, respectively.Conclusions PHP of the biliary epithelium in PBM patients is an important precursor lesion, especially for gallbladder cancer, and the risk becomes greater with age, regardless of the type of pancreatobiliary junction (PBJ) and its location in the biliary tract.