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.     

Periampullary diverticula cause pancreatobiliary reflux

BACKGROUND: Periampullary diverticula are associated with dysfunction of the sphincter of Oddi. Papillary dysfunction may allow reflux of pancreatic juice as well as intestinal contents into the common bile duct. We prospectively investigated pancreatobiliary reflux in patients with and without periampullary diverticula. METHODS: The ductal bile was sampled for amylase concentration during endoscopic retrograde cholangiopancreatography in 47 patients with choledocholithiasis (n = 29; with (n = 14) or without (n = 15) periampullary diverticula) or gallbladder cholesterol polyps (n = 18; with (n = 6) or without (n = 12) diverticula). RESULTS: The amylase concentration within the ductal bile was significantly higher in choledocholithiasis patients with periampullary diverticula (1621 +/- 587 IU/l) than in those without diverticula (1155 +/- 418 IU/l). The amylase concentration tended to be higher in gallbladder polyp patients with diverticula (1087 +/- 275 IU/l) than in those without diverticula (833 +/- 272 IU/l). Irrespective of the presence or absence of diverticula, patients with bile duct stones had significantly higher amylase concentrations than those with gallbladder polyps. CONCLUSIONS: Periampullary diverticula cause pancreatobiliary reflux. Further investigation is required to determine the clinical implication of pancreatobiliary reflux.     

Gallbladder carcinoma associated with pancreatobiliary reflux

INTRODUCTIONIt is well known that pancreatobiliary reflux is an important risk factor for the carcinogenesis of the biliary system in patients with pancreaticobiliary maljunction(PBM)[1,2],which is a congenital anomaly defined as an abnormal union of the …     

Gallbladder carcinoma associated with pancreatobiliary reflux

AIM: To detect the patients with and without pancreaticobiliary maljunction who had pancreatobiliary reflux with extremely high biliary amylase levels.METHODS: Ninety-six patients, who had diffuse thickness (＞3 mm) of the gallbladder wall and were suspected of having a pancreaticobiliary maljunction on ultrasonography, were prospectively subjected to endoscopic retrograde cholangiopancreatography, and bile in the common bile duct was sampled. Among them,patients, who had extremely high biliary amylase levels (＞10000 IU/L), underwent cholecystectomy, and the clinicopathological findings of those patients with and without pancreaticobiliary maljunction were examined.RESULTS: Seventeen patients had biliary amylase levels in the common bile duct above 10000 IU/L, including 11 with pancreaticobiliary maljunction and 6 without pancreaticobiliary maljunction. The occurrence of gallbladder carcinoma was 45.5% (5/11) in patients with pancreaticobiliary maljunction, and 50% (3/6) in those without pancreaticobiliary maljunction.CONCLUSION: Pancreatobiliary reflux with extremely high biliary amylase levels and associated gallbladder carcinoma could be identified in patients with and without pancreaticobiliary maljunction, and those patients might be detected by ultrasonography and bile sampling.     

A case of gallbladder carcinoma associated with pancreatobiliary reflux in the absence of a pancreaticobiliary maljunction： A hint for early diagnosis of gallbladder carcinoma

A 62-year-old man with progressive thickening of the gallbladder wall visited our outpatient clinic. The biliary amylase level in the common bile duct was 19900 IU/L and that of the gallbladder was 127000 IU/L, although endoscopic retrograde cholangiopancreatography revealed no pancreaticobiliary maljunction. Histology demonstrated a moderately differentiated adenocarcinoma of the gallbladder. Pancreatobiliary reflux and associated gallbladder carcinoma were confirmed in the present case, in the absence of a pancreaticobiliary maljunction. Earlier detection of the pancreatobiliary reflux and progressive thickening of the gallbladder wall might have led to an earlier resection of the gallbladder and improved this patient's poor prognosis.     

Choledochal cyst,pancreatobiliary malunion,and cancer

A review of the clinical features of biliary cancer with choledochal cyst and pancreatobiliary malunion is presented, together with a recent case report. Biliary cancer develops in about 25% of patients with choledochal cyst and pancreatobiliary malunion, and usually occurs in younger patients (usually those in their 40s) than does biliary carcinoma in the general population. The risk of malignancy in the retained cyst with internal drainage is higher than that in the primary cyst. Early excision of the retained cyst should be performed as quickly as possible, even if the patient is symptomless. Some bile acid fractions and refluxed pancreatic enzymes in bile are possibly responsible for carcinogenesis. Carcinoma generally develops in the extrahepatic bile duct and gallbladder, and rarely in the intrahepatic bile duct. In cystic dilatation, cancer usually occurs in the common bile duct, while in diffuse or non-dilated type, it develops in the gallbladder. Multicentric carcinomas develop in the bile duct either synchronously or metachronously. The prognosis of biliary cancer is usually dismal. However, aggressive procedures are now gaining better results than conventional approaches. The procedure of choice for choledochal cyst or malunion is to prevent the development of cancer by performing an early excision. Removal of the entire extrahepatic bile duct is necessary, even in patients with malunion and no biliary dilatation. Carcinoma rarely arises in the intrahepatic bile duct after excisional surgery, probably due to the long-standing stricture of the bile duct. Capacious anastomosis and/or ductoplasty is essential. Carcinoma may also develop in the remnant bile duct. Excision of the distal duct extending into the pancreas is also necessary.     

Clinical study of choledochocele: is it a risk factor for biliary malignancies?

Background We aimed to clarify the clinical characteristics of choledochocele and to evaluate the possibility of choledochocele as a risk factor for biliary malignancies.Methods The clinical feature, the configuration of the pancreatobiliary ductal system, coexistent pancreatobiliary lesions, and amylase level in bile in 21 patients with choledochocele were reviewed. The correlation between the configuration, comorbid diseases, and amylase level in the bile was investigated.Results There was a female predominance, and 57% of the patients showed abdominal pain. Quite a few patients showed elevation of the levels of hepatobiliary enzymes. The configuration of the pancreatobiliary ductal system and choledochocele was classified into two categories: type I, where the choledochocele and pancreatic duct were visualized independently or simultaneously (90.5%); and type II, where the pancreatic duct was visualized after filling of the choledochocele (9.5%). Among coexistent bilio-pancreatic diseases, biliary stone diseases were the most frequent. Biliary malignancy was seen in 3 patients (14.3%). The amylase level in the bile was high in 50% (4/8) of the patients examined. The rate of abnormal elevation of amylase level in the bile in the two types of pancreatobiliary ductal system and choledochocele was 3/7 and 1/1, respectively.Conclusions The prevalence of organic abnormal arrangement of the pancreatobiliary ductal system in which the choledochocele serves as a common channel is low. However, there are patients with suspected functional abnormal arrangement of the pancreatobiliary ductal system, who may possibly be a high-risk group for biliary malignancy.     

Assessment of occult pancreatobiliary reflux in patients with pancreaticobiliary disease by ERCP

Background The aim of this study was to evaluate the degree of occult pancreatobiliary reflux by measuring the biliary amylase levels in the common bile duct (CBDA) and gallbladder (GBA) at endoscopic retrograde cholangiopancreatography (ERCP).Methods Eligible patients included 86 consecutive cases of pancreaticobiliary disease with prospective implementation of bile collection during an ERCP procedure. Patients with pancreatobiliary maljunction (PBM) were excluded. Nineteen cases of eligible patients had simultaneous collection of gallbladder bile. Bile was further collected by cholecystectomy in 8 cases.Results Twenty-two cases (26%) revealed a CBDA level higher than serum amylase (high bile amylase level, HBA group) and 64 cases exhibited a CBDA level lower than serum (LBA group). The mean values of CBDA in the HBA and LBA groups were 5502IU/l and 29IU/l, respectively. The rate of HBA was significantly higher in patients who were elderly, had a dilated common bile duct, and those with choledocholithiasis (P < 0.05). Three cases (16%) showed a CBDA greater than twice the GBA. Eleven cases (58%) exhibited a GBA higher than the CBDA. The values of GBA obtained during ERCP and cholecystectomy were consistent.Conclusions These findings suggest that even non-PBM cases can exhibit occult pancreatobiliary reflux, which can thereby cause biliary disease.     

Pancreatobiliary reflux and the length of a common channel

Background/purpose

Gallbladder cancer occurs frequently in patients with pancreaticobiliary maljunction due to pancreatobiliary reflux. Pancreatobiliary reflux is also detected in some patients with a relatively long common channel. This study aimed to clarify the correlation between pancreatobiliary reflux and the length of a common channel.

Methods

Two hundred and three patients, in whom both the length of a common channel and amylase level in the bile were measured, were enrolled from nine centers.

Results

Bile amylase level was correlated with the length of a common channel (P < 0.01). The minimum length of a common channel that could induce a markedly elevated amylase level in the bile (>1,000 mg/dl) was determined as 5 mm. We redefined high confluence of pancreatobiliary ducts (HCPBD) as cases with a common channel ≥5 mm, in which the communication between the pancreatic and bile ducts was occluded with the sphincter contraction. Gallbladder cancer was found in 20% of 56 redefined HCPBD patients. Bile amylase level >1,000 mg/dl and biliopancreatic reflux were detected in 79 and 95% of the patients, respectively.

Conclusions

Patients with a common channel ≥5 mm (redefined HCPBD) should be monitored for the development of gallbladder cancer, as they frequently showed significant pancreatobiliary reflux.     

Occult pancreatobiliary reflux in patients with a normal pancreaticobiliary junction

BACKGROUND: The aim of this study was to investigate pancreatobiliary reflux in individuals with a normal pancreaticobiliary junction. METHODS: Seventy-four patients with a normal pancreaticobiliary junction, as determined by ERCP, underwent secretin injection MRCP before cholecystectomy. Based on changes in the diameter of the biliary system after secretin injection, patients were categorized into enhanced or nonenhanced groups. RESULTS: Biliary amylase was measured in the 4 patients allocated to the enhanced group and 60 in the nonenhanced group. The mean (SD) biliary amylase level in the gallbladder was 123,723 (115,125) IU/L in the enhanced group and 238 (507) IU/L in the nonenhanced group (p < 0.0001). The mean (SD) biliary amylase level in gallbladders with carcinoma (n = 7) was 68,281 (106,500) IU/L, which was significantly higher than that in gallbladders without carcinoma (p < 0.01). CONCLUSION: Pancreatobiliary reflux similar to that seen in patients with pancreaticobiliary maljunction can occur in individuals with a normal pancreaticobiliary junction and may be associated with carcinoma of the gallbladder. Secretin injection MRCP is useful for identifying these individuals.     

Papillary adenocarcinoma of the subvesical duct

This is, to our knowledge, the first report of papillary adenocarcinoma originating in the subvesical bile duct. A 77‐year‐old man was referred to our hospital for further evaluation of liver dysfunction. Serum liver function test results on admission included: aspartate aminotransferase, 99 IU/l; alanine aminotransferase, 149 IU/l; lactate dehydrogenase, 438 IU/l; alkaline phosphatase, 992 IU/l; leucine aminopeptidase, 320 IU/l; and gamma‐glutamyl transpeptidase, 593 IU/l. Serum carbohydrate antigen (CA) 19‐9 value was high (80 U/ml). Abdominal ultrasonogram, computed tomographic scan, and percutaneous transhepatic cholangiogram demonstrated a mass in the common hepatic duct, and dilatation of the intrahepatic bile ducts. A laparotomy was performed on May 14, 1997. The tumor originated in the dilated subvesical duct that joined the common hepatic duct, and projected into the common hepatic duct. The patient underwent cholecystectomy, resection of the subvesical duct and the common hepatic duct, dissection of regional pericholedochal lymph nodes, and Roux‐en‐Y hepaticojejunostomy. The resected tumor presented macroscopically as a papillary mass measuring 4.0 × 2.0 cm. The pathological diagnosis was papillary adenocarcinoma. The immunostaining positivity rates for MIB‐1 and p53 protein were 49.6% and 33.8%, respectively.     

Occult pancreatobiliary reflux and gallbladder carcinoma]

A total of 108 patients with a normal pancreaticobiliary junction who had gallbladder wall thickness as shown by ultrasonography or computed tomography underwent secretin injection magnetic resonance cholangiopancreatography. Based on the changes in the diameter of the biliary system after secretin injection, patients were categorized into the intensified group (n = 19) or the non-intensified group (n = 89). The mean (+/- SD) biliary amylase level in the bile duct was 41674 (+/- 59779) IU/L in the intensified group, which was significantly higher than that in the non-intensified group (210 (+/- 418)) IU/L (p < 0.0001). There were four patients with carcinoma of the gallbladder in the intensified group and their biliary amylase level in the bile duct was 90783 (+/- 82528) IU/L. Pancreatobiliary reflux similar to that seen in patients with pancreaticobiliary maljunction can occur in persons with a normal pancreaticobiliary junction and this may be associated with carcinoma of the gallbladder. Secretin injection magnetic resonance cholangiopancreatography proved useful to identify such persons.     

Histological features of precancerous and early cancerous lesions of biliary tract carcinoma

Biliary tract carcinoma develops within the intrahepatic or extrahepatic biliary tree and gallbladder. Primary sclerosing cholangitis, hepatolithiasis, congenital choledochal cyst, liver fluke infection, pancreatobiliary maljunction, toxic exposures and hepatitis virus infection are risk factors for the development of human biliary carcinoma. The precise molecular abnormalities of biliary carcinogenesis are still unknown, but chronic inflammatory conditions induce the production of reactive oxygen or nitrogen species leading to DNA damage. Recent studies indicate that cholangiocarcinoma of the large bile duct may arise in premalignant lesions such as biliary intraepithelial neoplasm (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB). BilIN and IPNB are generally confined to the large and septal‐sized bile duct. BilINs are occasionally observed in non‐biliary liver cirrhosis as well as chronic biliary disease. In contrast, the precursor lesion of intrahepatic cholangiocarcinoma of the small bile duct type remains unclear. We herein demonstrated the histological characteristics of different tumor development pathways from premalignant lesion to carcinoma in different sites of the biliary tree.     

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.     

Does endoscopic sphincterotomy cause prolonged pancreatobiliary reflux?

OBJECTIVE: Endoscopic sphincterotomy (ES) reduces sphincter function, which may allow reflux of pancreatic juice and intestinal contents into the common bile duct. The reflux, if present, may cause development of biliary tract carcinomas, as may anomalous pancreaticobiliary junction. We prospectively investigated pancreatobiliary and duodenobiliary reflux after ES. METHODS: In 15 patients with choledocholithiasis, ductal bile was sampled for amylase concentration and bacterial culture during endoscopic retrograde cholangiopancreatography, before and at 7 days to 5 yr after ES. To provide comparative data, ductal bile was sampled in 11 patients with gallbladder cholesterol polyps or anomalous pancreaticobiliary junction who did not undergo ES. RESULTS: Amylase concentration of ductal bile in patients with choledocholithiasis before ES was not different from that in patients with gallbladder polyps. Its concentration was increased 7 days after ES compared with that before ES, reaching the level of that in patients with anomalous pancreaticobiliary junction. Thereafter, amylase concentration gradually decreased, returning to that before ES by 1 yr. After ES, bactobilia occurred in 60-80% of patients, although none developed acute cholangitis. CONCLUSIONS: Although ES causes transient pancreatobiliary reflux, the reflux is abolished by 1 yr after ES. ES is unlikely to increase the risk for development of biliary tract carcinoma as long as cholangitis or bile duct stones do not recur.     

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.     

Smallest Todani’s type II choledochal cyst

A choledochal cyst is defined as an isolated or combined congenital dilation of the extra hepatic or intrahepatic biliary tree. Todani and colleagues proposed the five types of congenital choledochal cysts which have gained widespread acceptance. Type II choledochal cyst, a diverticulum of common bile duct, is rarest, and most reported cases of Type II were as large as several centimeters in size. We herein report the case of a small Type II choledochal cyst which was resected at pancreatoduodenectomy for carcinoma of the papilla of Vater. A 58-year-old Japanese male was referred to our hospital for the evaluation of jaundice. Preoperative cholangiogram via the percutaneous transhepatic biliary drainage tube revealed a complete obstruction at the narrow terminal segment. Furthermore, a small diverticular protrusion was demonstrated on the lower part of the common bile duct. The resected specimen showed a 2.2 x 1.7 x 1.2 cm carcinoma of the major papilla, and a deep, 2 mm in diameter and 5 mm in depth, depression on the posterior wall of the common bile duct. The anomalous pancreatobiliary duct was not seen. The deep depression was confirmed microscopically to penetrate the fibromuscular layer of the common bile duct and diagnosed as a Todani's Type II choledochal cyst. To our knowledge, the current case is the smallest Type II choledochal cyst which was completely resected.     

Amylase levels in bile in patients with a morphologically normal pancreaticobiliary ductal arrangement

Background We investigated the presence of occult pancreaticobiliary reflux in patients with a morphologically normal pancreaticobiliary ductal arrangement by measuring biliary amylase levels and compared histopathological findings of the gallbladder between groups with high and low biliary amylase levels. Methods In 178 patients with a normal pancreaticobiliary ductal arrangement who had undergone endoscopic retrograde cholangiopancreatography (ERCP), we sampled bile from the bile duct and measured amylase levels. Then we compared clinical features and histological findings of the gallbladder between high (HALG) and low amylase level groups (LALG). Results A high biliary amylase level was observed in 25.8% (46/178) of the patients. The prevalence of a high biliary amylase level was high in patients with gallbladder carcinoma (40%) and in those with choledocholithiasis (28.4%). The level of amylase in bile was high in patients with gallbladder carcinoma, adenomyomatosis of the gallbladder, and chronic cholecystitis. A strong correlation between the levels of amylase and lipase in bile and the dominance of amylase of pancreatic origin in bile were confirmed by isozyme analysis. Thickening of the gallbladder mucosa was a significant manifestation in HALG. Histological examination of the gallbladder mucosa showed that incidences of metaplastic change and atypical epithelium and Ki67-LI in were higher in HALG than in LALG. Conclusions Occult pancreaticobiliary reflux is observed in a considerable number of ERCP candidates. Those who show an extremely high biliary amylase level, at least, may be at high risk for biliary malignancies.     

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.     

Precancerous mucosal changes in the gallbladder of patients with occult pancreatobiliary reflux

BACKGROUND: Pancreatobiliary reflux can occur even if the pancreaticobiliary junction is normal (occult pancreatobiliary reflux), and it may be associated with gallbladder carcinoma. The aim of the present study was to examine precancerous mucosal changes in the gallbladder from patients with occult pancreatobiliary reflux. METHODS: The mucosa of the gallbladder from 13 patients who underwent cholecystectomy was examined histopathologically. These patients had an anatomically normal pancreatobiliary junction and a biliary amylase concentration greater than 10,000 IU/L. The gallbladder of patients without carcinoma was further examined by using immunohistochemical techniques to detect Ki-67, and the results were compared with those from control patients. RESULTS: Of the 13 patients, 5 (38%) had gallbladder carcinoma and 8 (62%) did not. Of the 8 patients without carcinoma, 4 (50%) had dysplasia accompanied by hyperplasia, and 2 (25%) had hyperplasia alone of the gallbladder mucosa. The Ki-67 labeling index was significantly higher in hyperplastic and dysplastic mucosa than in control gallbladder mucosa (p < 0.0004). CONCLUSIONS: Occult pancreatobiliary reflux could be associated with precancerous mucosal changes in the gallbladder, such as hyperplasia and dysplasia with increased cellular proliferation, and could be a possible risk factor for gallbladder carcinoma.