Pancreaticobiliary Maljunction Patients Research Articles

Development of a CT-based radiomics-clinical model to diagnose acute pancreatitis on nonobvious findings on CT in children with pancreaticobiliary maljunction.

Since neither abdominal pain nor pancreatic enzyme elevation is specific for acute pancreatitis (AP), the diagnosis of AP in patients with pancreaticobiliary maljunction (PBM) may be challenging when the pancreas appears normal or nonobvious on CT. This study aimed to develop a quantitative radiomics-based nomogram of pancreatic CT for identifying AP in children with PBM who have nonobvious findings on CT. PBM patients with a diagnosis of AP evaluated at the Children's Hospital of Soochow University from June 2015 to October 2022 were retrospectively reviewed. The radiological features and clinical factors associated with AP were evaluated. Based on the selected variables, multivariate logistic regression was used to construct clinical, radiomics, and combined models. Two clinical parameters and 6 radiomics characteristics were chosen based on their significant association with AP, as demonstrated in the training (area under curve [AUC]: 0.767, 0.892) and validation (AUC: 0.757, 0.836) datasets. The radiomics-clinical nomogram demonstrated superior performance in both the training (AUC, 0.938) and validation (AUC, 0.864) datasets, exhibiting satisfactory calibration (P > .05). Our radiomics-based nomogram is an accurate, noninvasive diagnostic technique that can identify AP in children with PBM even when CT presentation is not obvious. This study extracted imaging features of nonobvious pancreatitis. Then it developed and evaluated a combined model with these features.

Using machine learning models to predict acute pancreatitis in children with pancreaticobiliary maljunction.

To develop a model to identify risk factors and predictors of acute pancreatitis in children with pancreaticobiliary maljunction (PBM). We screened consecutive PBM patients treated at two centers between January, 2015 and July, 2021. For machine learning, the cohort was divided randomly at a 6:4 ratio to a training dataset and a validation dataset. Three parallel models were developed using logistic regression (LR), a support vector machine (SVM), and extreme gradient boosting (XGBoost), respectively. Model performance was judged primarily based on the area under the receiver operating curves (AUC). A total of 99 patients were included in the analysis, 17 of whom suffered acute pancreatitis and 82 did not. The XGBoost (AUC = 0.814) and SVM (AUC = 0.813) models produced similar performance in the validation dataset; both outperformed the LR model (AUC = 0.805). Based on the SHapley Additive exPlanation values, the most important variable in both the XGBoost and SVM models were age, protein plugs, and white blood cell count. Machine learning models, especially XGBoost and SVM, could be used to predict acute pancreatitis in children with PBM. The most important contributing factor to the models were age, protein plugs, and white blood cell count.

Combination of UNet++ and ResNeSt to classify chronic inflammation of the choledochal cystic wall in patients with pancreaticobiliary maljunction.

The aim of this study was to establish an automatic classification model for chronic inflammation of the choledoch wall using deep learning with CT images in patients with pancreaticobiliary maljunction (PBM). CT images were obtained from 76 PBM patients, including 61 cases assigned to the training set and 15 cases assigned to the testing set. The region of interest (ROI) containing the choledochal lesion was extracted and segmented using the UNet++ network. The degree of severity of inflammation in the choledochal wall was initially classified using the ResNeSt network. The final classification result was determined per decision rules. Grad-CAM was used to explain the association between the classification basis of the network and clinical diagnosis. Segmentation of the lesion on the common bile duct wall was roughly obtained with the UNet++ segmentation model and the average value of Dice coefficient of the segmentation model in the testing set was 0.839 ± 0.150, which was verified through fivefold cross-validation. Inflammation was initially classified with ResNeSt18, which resulted in accuracy = 0.756, sensitivity = 0.611, specificity = 0.852, precision = 0.733, and area under curve (AUC) = 0.711. The final classification sensitivity was 0.8. Grad-CAM revealed similar distribution of inflammation of the choledochal wall and verified the inflammation classification. By combining the UNet++ network and the ResNeSt network, we achieved automatic classification of chronic inflammation of the choledoch in PBM patients and verified the robustness through cross-validation performed five times. This study provided an important basis for classification of inflammation severity of the choledoch in PBM patients. We combined the UNet++ network and the ResNeSt network to achieve automatic classification of chronic inflammation of the choledoch in PBM. These results provided an important basis for classification of choledochal inflammation in PBM and for surgical therapy.

Stepwise correlation of TP53 mutations from pancreaticobiliary maljunction to gallbladder carcinoma: a retrospective study

BackgroundThe genetic changes underlying carcinogenesis in patients with risk factors of gallbladder carcinoma (GBC) remains controversial, especially in patients with pancreaticobiliary maljunction (PBM). This study aimed to clarify the association between risk factors of GBC and genetic changes using next-generation sequencing (NGS).MethodsWe retrospectively analyzed resected tissues of 64 patients who were diagnosed with GBC (n = 26), PBM [with GBC (n = 8), without GBC (n = 20)], and chronic cholecystitis, used as a control group (n = 10). DNA was extracted from tumors and their surrounding tissues, which were precisely separated by laser-capture microdissection. Gene alterations of 50 cancer-related genes were detected by NGS and compared with clinical information, including PBM status.ResultsThe most frequent gene alterations in GBC tissues occurred in TP53 (50%), followed by EGFR (20.6%), RB1 (17.6%), and ERBB2 (17.6%). Gene alterations that were targetable by molecular targeted drugs were detected in 20 cases (58.8%). Statistical analysis of gene alterations and risk factors revealed that TP53 alteration rate was higher in GBC patients with PBM than those without PBM (p = 0.038), and the TP53 mutation rates in the epithelium of control patients, epithelium of PBM patients without GBC, peritumoral mucosa of GBC patients with PBM, and tumor tissue of GBC patients with PBM were 10, 10, 38, and 75%, respectively (p < 0.01).ConclusionsTP53 alteration more than KRAS mutation was revealed to underlie carcinogenesis in patients with PBM.

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

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

Pancreaticobiliary maljunction in Turkish patients: a multicenter case series.

Pancreaticobiliary maljunction (PBM) is a malformation in which the pancreatic and bile ducts join outside the duodenal wall. It is associated with various biliary and pancreatic diseases. In addition, patients with PBM carry a substantial lifetime risk of developing biliary or gallbladder carcinoma. We aimed to present a multicenter case series of PBM from Turkey. This study was conducted in adult and pediatric PBM patients who were referred to three tertiary reference centers of Turkey for endoscopic retrograde cholangiopancreatography (ERCP) between July 2007 and May 2020. The clinical presentations, types of PBM, ERCP findings, surgical histories, and the postoperative courses, including the development of biliary malignancies, were retrospectively reviewed. The study group included 47 (31 adult and 16 children) patients. Type D PBM was more frequent (13/41: 27.7%) than that reported in Eastern studies. Type A PBM was more common in the adults (51.6% vs. 12.5%, p < 0.05), whereas type C was more common in pediatric patients (31.3% vs. 13.2%, p < 0.05). Although fusiform anatomy was predominant in both of the groups, cystic dilatation was more common (25.8% vs. 12.5%) in adults and the common bile duct diameter was greater [22mm (range 11-58) vs. 12mm (range 5-33)] in adult patients compared to pediatric patients. Resective surgeries were more frequently done in pediatric patients (73.3% vs. 53.6%), whereas cholecystectomy was more frequently performed in adult patients (21.4% vs. 6.7%). Although our findings were compatible with Eastern studies, type D PBM (associated with pancreas divisum) was more frequent in our study population.

Imaging of Pancreaticobiliary Maljunction.

Pancreaticobiliary maljunction (PBM) is a congenital malformation in which the pancreatic and bile ducts join outside the duodenal wall, usually forming a long common channel. A major issue in patients with PBM is the risk of biliary cancer. Because the sphincter of Oddi does not regulate the pancreaticobiliary junction in PBM, pancreatic juice frequently refluxes into the biliary tract and can cause various complications, including biliary cancer. Most cancers arise in the gallbladder or dilated common bile duct, suggesting that bile stasis is related to carcinogenesis. Early diagnosis and prophylactic surgery to reduce the risk of cancer are beneficial. The diagnosis of PBM is made mainly on the basis of imaging findings. The development of diagnostic imaging modalities such as multidetector CT and MR cholangiopancreatography has provided radiologists with an important role in diagnosis of PBM and its complications. Radiologists should be aware of PBM despite the fact that it is rare in non-Asian populations. In this review, the authors present an overview of PBM with emphasis on diagnosis and management of PBM and its complications. For early diagnosis, the presence of extrahepatic bile duct dilatation or gallbladder wall thickening may provide a clue to PBM with or without biliary dilatation, respectively. The pancreaticobiliary anatomy should be closely examined if imaging reveals these findings. Radiologists should also carefully evaluate follow-up images in PBM patients even years after prophylactic surgery because residual bile ducts remain at risk for cancer.©RSNA, 2020.

Classification of pancreaticobiliary maljunction and its clinical features in adults.

In pancreaticobiliary maljunction (PBM), reflux of pancreatic juice and bile produces various pathological conditions in the biliary tract and pancreas. Clinical features according to the classification of PBM by confluence between the distal bile duct and the main pancreatic duct proposed in 2015 were evaluated in children. Clinical features and complicating diseases according to the PBM classification were evaluated in 168 adult PBM patients. Patency of Santorini duct and associated biliary carcinomas were evaluated in 123 patients. Similar to children, there were significant differences in age (P<0.01) and type of common bile duct (P<0.01) between the groups of the classification. Unlike in children, there was no significant difference in the incidence of abdominal pain and hyperamylasemia. There were 87 associated biliary carcinomas (79 gallbladder carcinomas and eight cholangiocarcinomas). PBM patients with a cudgel-type Santorini duct, which is greater than 2mm in diameter, did not develop biliary carcinomas, compared to 61.1% of those with other types of Santorini duct (P<0.01). Clinical features according to the PBM classification in adults were different from those in children. Although biliary carcinomas were frequently seen in adult PBM patients, none of those with a cudgel-type Santorini duct developed biliary carcinoma.

Increased prevalence of pancreaticobiliary maljunction in biliary malignancies.

The incidence of pancreaticobiliary maljunction is thought to approximate 1:100,000 within Western populations. We aimed to study the significance of pancreaticobiliary maljunction in biliary tract malignancies. Medical records and magnetic resonance cholangiopancreatography images of 252 consecutive patients treated for biliary malignancies during 2005-2016 were reviewed. Patients with other known risk factors for biliary cancers (n = 27) were excluded. A common pancreaticobiliary channel measuring ⩾10 mm outside the duodenal wall was defined as pancreaticobiliary maljunction. Of the 225 patients, a reliably interpretable preoperative magnetic resonance cholangiopancreatography was available for 73 (32%). Sex (47% vs 57% females) and age at diagnosis (67 vs 66 years) were similar among patients with or without an magnetic resonance cholangiopancreatography (p = ns for both). In magnetic resonance cholangiopancreatography, a pancreaticobiliary maljunction with a median length of 20 mm (range 10-23 mm) was identified in four patients (5.5%, 95% confidence interval 1.6-14), while none had evident accompanying biliary tree dilatation. Pancreaticobiliary maljunction patients were significantly more often females (100% vs 43%, p = 0.043), less likely to have intrahepatic bile duct cancer (0% vs 65%, p = 0.019) while more likely to have gallbladder cancer (75% vs 22%, p = 0.044) compared to the others. Age at diagnosis (66 vs 67 years, p = 0.898), extrahepatic bile duct cancer incidence (25% vs 13%, p = 0.453), and survival status at last follow-up (50% vs 42% alive, p = 1.000) were comparable between the subgroups. The prevalence of pancreaticobiliary maljunction is substantially higher in adults with biliary malignancies than one would expect based on its incidence, reinforcing the etiologic role of pancreaticobiliary maljunction especially in females with gallbladder cancer.

Endoscopic therapy for patients with pancreaticobiliary maljunction: a follow-up study.

BackgroundData on the experience of endoscopic retrograde cholangiopancreatography (ERCP) in the management of pancreaticobiliary maljunction (PBM) is limited.MethodsA retrospective review of patients with PBM who underwent therapeutic ERCP at our endoscopy center between January 2008 and January 2016 was performed. Demographic, clinical, radiological and endoscopic data was documented. Patients who underwent sphincterotomy were divided into dilated group and undilated group based on their common channel diameter.ResultsSixty-three PBM patients underwent 74 ERCP procedures. The technical success rate was 97.3%. ERCP therapy significantly decreased the levels of elevated liver enzymes and bilirubin. After an average of 27 months follow-up, 7 patients (11.1%) were lost. The overall effective rate of ERCP therapy was 60.7% (34/56). Decline in severity and frequency of abdominal pain was significant. Procedure-related complications were observed in 5 (6.8%) cases. Between the dilated group and undilated group, no significant difference was observed in effective rate, adverse events and follow-up results.ConclusionsERCP can serve as a transitional step to stabilize PBM patients before definitive surgery. PBM patients with undilated common channel could benefit from sphincterotomy as well as those with dilated common channel.

Biliary carcinogenesis in pancreaticobiliary maljunction.

Pancreaticobiliary maljunction (PBM) is a congenital malformation in which the pancreatic and bile ducts join anatomically outside the duodenal wall. Because of the excessive length of the common channel in PBM, sphincter action does not directly affect the pancreaticobiliary junction, which allows pancreatic juice to reflux into the biliary tract. According to the results of a nationwide survey, bile duct and gallbladder cancers were found in 6.9 and 13.4% of adult patients with congenital biliary dilatation, respectively, and in 3.1 and 37.4% of those with PBM without biliary dilatation, respectively. Biliary tract cancers develop about 15-20years earlier in patients with PBM than in individuals without PBM; they sometimes develop as double cancers. Carcinogenesis is strongly associated with stasis of bile intermingled with refluxed pancreatic juice. Epithelial cells in the biliary tract of PBM patients are under constant attack from activated pancreatic enzymes, increased secondary bile acids, or other mutagens. This can result in hyperplastic change with increased cell proliferation activity, and in turn, oncogene and/or tumor suppressor gene mutations in the epithelia, leading to the biliary tract carcinogenesis. The carcinogenesis of biliary tract cancer accompanying PBM is considered to involve a hyperplasia-dysplasia-carcinoma sequence induced by chronic inflammation caused by the reflux of pancreatic juice into the biliary tract, which differs from the adenoma-carcinoma sequence or the de novo carcinogenesis associated with biliary tract cancers in the population without PBM. Patients with a relatively long common channel have a similar, albeit slightly lower, risk for gallbladder cancer compared with PBM patients.

Altered expression levels of occludin, claudin-1 and myosin light chain kinase in the common bile duct of pediatric patients with pancreaticobiliary maljunction.

BackgroundIn pancreaticobiliary maljunction (PBM), the sphincter of Oddi can not control bile and pancreatic juice flow, which may lead to two-way reflux of bile and pancreatic juice, thus causing chronic inflammation, thickening, fibrosis and metaplasia of the common bile duct wall. These pathophysiological changes have been linked to disruption of the epithelium barrier in the common bile duct. We hypothesized that the expression of tight junction-associated proteins may be dysregulated in the common bile duct in PBM. In the current study, we sought to analyze the expression of tight junction-associated proteins in the common bile duct epithelium of pediatric patients with PBM.MethodsSpecimens of the common bile duct were collected from 12 pediatric patients with PBM and 10 non-PBM controls. The expression of the tight junction-associated proteins occludin and claudin-1 in the epithelium was examined by immunohistochemistry. The Image-Pro Plus v. 6.0 image analysis software was used to calculate the mean qualifying score (MQS) of imunostained sections of common bile duct epithelium. Total protein extracts of common bile duct were analyzed by Western blotting assays to examine expression of occludin, claudin-1 and myosin light chain kinase (MLCK). Spearman correlation analysis was used to analyze the relation between MLCK and occludin, MLCK and claudin-1.ResultsImmunostained sections of the common bile duct epithelium showed significantly higher MQS in pediatric patients than controls for occludin (44.11 ± 13.82 vs. 11.30 ± 9.58, P = 0.0034) and claudin-1 (63.44 ± 23.59 vs. 46.10 ± 7.84, P = 0.0384). Western blotting also showed significantly higher expression of occludin, claudin-1 and MLCK in the common bile duct of patients than of controls (P = 0.0023, 0.0015, 0.0488). Spearman correlation analysis showed that MLCK expression correlated positively with the expression of occludin (rs = 0.61538, P = 0.0032) and claudin-1 (rs = 0.7972, P = 0.0019).ConclusionsOccludin and claudin-1 are up-regulated in the common bile duct epithelium of pediatric PBM patients. MLCK may be involved in the process of up-regulation of the tight junction-associated proteins in PBM.

The process of diagnosing pancreaticobiliary maljunction

Background: Pancreaticobiliary maljunction (PBM) patients have a high rate of biliary cancers. This study aimed to show strategy for early detection of PBM before the development of biliary cancer. Methods: We investigated pancreatobiliary complications, age at diagnosis and process of diagnosis in 111 PBM patients (with biliary dilatation (BD) (n=55) and without BD (n=56)). Results: Eighteen patients of 55 PBM patients with BD(33%: bile duct cancer, n=9; gallbladder cancer, n=10) and 33 of 56 PBM patients without BD (68%: gallbladder cancer only) developed biliary cancer. PBM patients with BD in association with gallbladder cancer were older than those without gallbladder cancer (p<0.01). The number of PBM patients with associated biliary cancer increased with age (p<0.01). Thirteen PBM patients with BD and 33 PBM patients without BD were diagnosed by symptoms due to advanced biliary cancers. PBM without BD was suspected in 9 patients based on findings of gallbladder wall thickening on ultrasonography (US), and the diagnosis was made with magnetic resonance cholangiopancreatography (MRCP) and/or endoscopic retrograde cholangiopancreatography before the development of biliary cancer.

Pancreaticobiliary maljunction and biliary cancer.

Pancreaticobiliary maljunction (PBM) is a congenital malformation in which the pancreatic and bile ducts join anatomically outside the duodenal wall. Japanese clinical practice guidelines on how to deal with PBM were made in 2012, representing a world first. According to the 2013 revision to the diagnostic criteria for PBM, in addition to direct cholangiography, diagnosis can be made by magnetic resonance cholangiopancreatography (MRCP), 3-dimensional drip infusion cholangiography computed tomography, endoscopic ultrasonography (US), or multiplanar reconstruction images by multidetector row computed tomography. In PBM, the common channel is so long that sphincter action does not affect the pancreaticobiliary junction, and pancreatic juice frequently refluxes into the biliary tract. Persistence of refluxed pancreatic juice injures epithelium of the biliary tract and promotes cancer development, resulting in higher rates of carcinogenesis in the biliary tract. In a nationwide survey, biliary cancer was detected in 21.6% of adult patients with congenital biliary dilatation (bile duct cancer, 32.1% vs. gallbladder cancer, 62.3%) and in 42.4% of PBM patients without biliary dilatation (bile duct cancer, 7.3% vs. gallbladder cancer, 88.1%). Pathophysiological conditions due to pancreatobiliary reflux occur in patients with high confluence of pancreaticobiliary ducts, a common channel ≥6 mm long, and occlusion of communication during contraction of the sphincter. Once the diagnosis of PBM is established, immediate prophylactic surgery is recommended. However, the surgical strategy for PBM without biliary dilatation remains controversial. To detect PBM without biliary dilatation early, MRCP is recommended for patients showing gallbladder wall thickening on screening US under suspicion of PBM.

Exploring the length of the common channel of pancreaticobiliary maljunction on magnetic resonance cholangiopancreatography.

In the revised diagnostic criteria for pancreaticobiliary maljunction (PBM), PBM can be diagnosed from a long common channel by magnetic resonance cholangiopancreatography (MRCP). However, it is necessary to differentiate from high confluence of pancreaticobiliary ducts (HCPBD) with a relatively long common channel (≥6 mm) and effect of the sphincter in the pancreaticobiliary junction. This multicenter study aimed to explore definite value of the length of an abnormally long common channel, which enables to distinguish PBM from HCPBD on MRCP. In 184 PBM patients and 22 HCPBD patients who were diagnosed by direct cholangiography and underwent MRCP, the length of the common channel was measured. The length of the common channel was 16.2 ± 6.9 mm on direct cholangiography and 13.9 ± 6.2 mm on MRCP in PBM patients, and 7.7 ± 1.5 mm and 6.6 ± 1.4 mm in HCPBD patients. The optimal cut off value of the length of the common channel to distinguish PBM from HCPBD was identified to be 9 mm. Pancreaticobiliary maljunction can be diagnosed from an abnormally long common channel on MRCP, but in cases of the common channel ≤9 mm on MRCP, direct cholangiography is needed to confirm PBM.

Importance of early diagnosis of pancreaticobiliary maljunction without biliary dilatation

To clarify the strategy for early diagnosis of pancreaticobiliary maljunction (PBM) without biliary dilatation and to pathologically examine gallbladder before cancer develops. The anatomy of the union of the pancreatic and bile ducts was assessed by using endoscopic retrograde cholangiopancreatography (ERCP). Patients with a long common channel in which communication between the pancreatic and bile ducts was maintained even during sphincter contraction were diagnosed as having PBM. Of these, patients in which the maximal diameter of the bile duct was less than 10 mm were diagnosed with PBM without biliary dilatation. The process of diagnosing 54 patients with PBM without biliary dilatation was retrospectively investigated. Histopathological analysis of resected gallbladder specimens from 8 patients with PBM without biliary dilatation or cancer was conducted. Thirty-six PBM patients without biliary dilatation were diagnosed with gallbladder cancer after showing clinical symptoms such as abdominal or back pain (n = 16) or jaundice (n = 12). Radical surgery for gallbladder cancer was only possible in 11 patients (31%) and only 4 patients (11%) survived for 5 years. Eight patients were suspected as having PBM without biliary dilatation from the finding of gallbladder wall thickening on ultrasound and the diagnosis was confirmed by ERCP and/or magnetic resonance cholangiopancreatography (MRCP). The median age of these 8 patients was younger by a decade than PBM patients with gallbladder cancer. All 8 patients underwent prophylactic cholecystectomy and bile duct cancer has not occurred. Wall thickness and mucosal height of the 8 resected gallbladders were significantly greater than controls, and hyperplastic changes, hypertrophic muscular layer, subserosal fibrosis, and adenomyomatosis were detected in 7 (88%), 5 (63%), 7 (88%) and 5 (63%) patients, respectively. Ki-67 labeling index was high and K-ras mutation was detected in 3 of 6 patients. To detect PBM without biliary dilatation before onset of gallbladder cancer, we should perform MRCP for individuals showing increased gallbladder wall thickness on ultrasound.

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

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. 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 analysis. Data were extracted independently by two reviewers using a predefined spreadsheet. The incidence of PBM was higher in GBC patients than in controls (10.60% vs 1.76%, OR: 7.41, 95% CI: 5.03 to 10.87, P<0.00001). The proportion of female patients with PBM was 1.96-fold higher than in GBC patients without PBM (80.5% vs 62.9%, OR: 1.96, 95% CI: 1.09 to 3.52, P=0.12). GBC patients with PBM were 10 years younger than those without PBM (SMD: -9.90, 95% CI: -11.70 to -8.10, P<0.00001). And a difference in the incidence of associated gallstone was found between GBC patients with and without PBM (10.8% vs 54.3%, OR: 0.09, 95% CI: 0.05 to 0.17, P<0.00001). Among the GBC patients with PBM, associated congenital dilatation of the common bile duct was present with a higher incidence ranging from 52.2% to 85.7%, and 70.0%-85.7% of them belonged to the P-C type of PBM (the main pancreatic duct enters the common bile duct). No substantial heterogeneity was found and no evidence of publication bias was observed. PBM is a high-risk factor for developing GBC, especially the P-C type of PBM without congenital dilatation of the common bile duct. To prevent GBC, laparoscopic cholecystectomy is highly recommended for PBM patients without congenital dilatation of the common bile duct, especially relatively young female patients without gallstones.

Gene Expression Profiling Reveals Upregulated UCA1 and BMF in Gallbladder Epithelia of Children With Pancreaticobiliary Maljunction

Pancreaticobiliary maljunction is usually associated with choledochal cysts and often causes biliary carcinoma; however, the mechanism of carcinogenesis remains unknown. No study has analyzed overall changes in genetic expression beginning during childhood in gallbladder epithelia with pancreaticobiliary maljunction. The genomewide expression of gallbladder epithelia was analyzed in 6 children with pancreaticobiliary maljunction and in 4 pediatric controls. Selected genes that were expressed differentially were further analyzed by the real-time reverse transcription-polymerase chain reaction (RT-PCR). The products of upregulated genes confirmed by real-time RT-PCR were immunohistochemically analyzed using gallbladders from 19 children with pancreaticobiliary maljunction, 5 pediatric controls, and 5 children with gallstones. Microarray analysis identified 188 upregulated and 160 downregulated genes. RT-PCR confirmed upregulation in 5 of 6 genes and downregulation in 1 of 5 genes, including UCA1, DUOX2, DUOXA2, ID1, BMF, and GP2. Immunohistochemistry showed a significantly higher expression of BMF in the pancreaticobiliary maljunction patients than in the controls and gallstone patients. This study identified several deregulated genes in the gallbladder of children with pancreaticobiliary maljunction, which may contribute to the pathophysiology. UCA1, a noncoding RNA, is an oncofetal gene, and its upregulation may be important for biliary carcinogenesis. The elevated expression of BMF may function as an apoptotic activator in proliferative gallbladder epithelia.

Endoscopic diagnosis of pancreaticobiliary maljunction

Pancreaticobiliary maljunction (PBM) is a congenital anomaly defined as a junction of the pancreatic and bile ducts located outside the duodenal wall, usually forming a markedly long common channel. As the action of the sphincter of Oddi does not functionally affect the junction in PBM patients, continuous pancreatobiliary reflux occurs, resulting in a high incidence of biliary cancer. PBM can be divided into PBM with biliary dilatation (congenital choledochal cyst) and PBM without biliary dilatation (maximal diameter of the bile duct ≤ 10 mm). The treatment of choice for PBM is prophylactic surgery before malignant changes can take place. Endoscopic retrograde cholangiopancreatography (ERCP) is the most effective examination method for close observation of the pattern of the junction site. When the communication between the pancreatic and bile ducts is maintained, despite contraction of the sphincter on ERCP, PBM is diagnosed. In these patients, levels of pancreatic enzymes in the bile are generally elevated, due to continuous pancreatobiliary reflux via a long common channel. Magnetic resonance cholangiopancreatography and 3D-computed tomography can diagnose PBM, based on findings of an anomalous union between the common bile duct and the pancreatic duct, in addition to a long common channel. Endoscopic ultrasonography and intraductal ultrasonography can demonstrate the junction outside the duodenal wall, and are useful for the diagnosis of associated biliary cancer. Gallbladder wall thickness on ultrasonography can be a screening test for PBM.

Pancreatobiliary Disorders Associated with Pancreaticobiliary Maljunction

Aim: To clarify the features of biliary carcinomas and pancreatic disorders associated with pancreaticobiliary maljunction (PBM). Method: A total of 107 PBM patients with biliary dilatation were reviewed (52 with and 55 without PBM). Clinicopathological findings of biliary carcinomas, and acute or chronic pancreatitis were examined in association with PBM. We also investigated pancreatographic findings in PBM patients and the relationship to their clinical findings in view of pancreatic juice flow. Results:Gallbladder and bile duct carcinomas were seen in 11 (21%) and 8 (15%) of the 52 patients with PBM and biliary dilatation, respectively. In patients with PBM without biliary dilatation (n = 55), only gallbladder carcinoma was detected in 36 (65%) patients. At diagnosis, patients with gallbladder or bile duct carcinoma associated with PBM were younger than those without PBM (p < 0.01). Gallstones were detected only in 6% of the patients with PBM-associated gallbladder carcinoma. Multiple biliary carcinomas were detected in 3 patients (38%) with PBM-associated bile duct carcinoma. While 48 patients (60%) with biliary carcinoma and PBM had a normal pancreatic duct system, only 2 gallbladder carcinomas occurred in 11 dorsal pancreatic duct (DPD)-dominant patients (p < 0.05). Amylase concentration in the bile of DPD-dominant patients was significantly lower than that of patients with a normal pancreatic duct system (p < 0.05). Ten PBM patients had pancreatic disorders: acute pancreatitis (n = 3), chronic pancreatitis (n = 5), and pancreatic carcinoma (n = 2). Conclusions: In PBM patients, pancreatobiliary reflux frequently leads to biliary cancer, and biliopancreatic reflux often leads to acute or chronic pancreatitis. The biliary tract of PBM patients can be considered premalignant.