Advanced endoscopy meets molecular diagnosis of cholangiocarcinoma.

Cholangiocarcinoma remains an aggressive and deadly malignancy that is often diagnosed late. Intrinsic tumour characteristics and the growth pattern of cancer cells contribute to the challenges of diagnosis and chemoresistance. However, establishing an early and accurate diagnosis, and in some instances identifying targetable changes, has the potential to impact survival. Primary sclerosing cholangitis, a chronic cholangiopathy prodromal to the development of a minority of cholangiocarcinomas, poses a particular diagnostic challenge. We present our diagnostic and theranostic approach to the initial evaluation of cholangiocarcinomas, focusing on extrahepatic cholangiocarcinoma. This involves a multipronged strategy incorporating advanced imaging, endoscopic methods, multiple approaches to tissue sampling, and molecular markers. We also provide an algorithm for the sequential use of these tools.

Primary Sclerosing Cholangitis Associated With Ulcerative Colitis Coexisting With Cholangiocarcinoma: A Case Report.

Primary sclerosing cholangitis (PSC) is a rare chronic inflammatory disease in which multifocal fibrosis of bile ducts causes eventually narrowing and even blocking, forming multifocal strictures alternated to dilatations. Here, we reported an extremely rare case of PSC associated with ulcerative colitis (UC) and coexisting with cholangiocarcinoma in a 33-year-old male presented with right upper quadrant pain and dark urine. Liver function tests were deranged, and ERCP found a beaded cholangiography appearance due to multifocal bile duct strictures alternating with normal and dilated segments of the common hepatic duct and the intrahepatic bile ducts. We aim to document this typical case of PSC associated with UC and coexisted with cholangiocarcinoma to add the existing data on these rare pathologies.

Performance of fluorescence in situ hybridization in biliary brushings with equivocal cytology: an institutional experience.

INTRODUCTION: Biliary brushing (BB) cytology has a sensitivity of 15%-65% and specificity approaching 100% for detecting malignancy. Fluorescence in-situ hybridization (FISH) using the UroVysion probe set has been advocated to enhance the detection of malignancies with reported sensitivity of 43%-84%. We sought to evaluate the performance of FISH in BB with equivocal cytology at our institution. MATERIALS AND METHODS: Patients with atypical and suspicious BB with concurrent diagnostic FISH performed at our institution from 2014 to 2021 were identified through a query of our pathology database. FISH (using UroVysion probe set containing centromere enumeration probes to chromosomes 3, 7, and 17) was positive if at least 5 cells demonstrated polysomy. Electronic medical records were reviewed for pathology results and outcomes. Patients were classified malignant if they had positive pathology or documented clinical impression of malignancy and benign if they had negative pathology and/or documented benign clinical course for at least 12 months. RESULTS: We identified 254 equivocal BB (238 atypical/16 suspicious) with concurrent FISH results from 191 patients (105 benign, 86 malignant). 12% (22/191) of patients were FISH positive. Twenty-four percent (21/86) of patients with malignancy had positive FISH but were nonspecific for pancreaticobiliary/ampullary adenocarcinomas. Almost all positive FISH were associated with malignancy (21/22; 95%). There was 1 positive FISH in a patient with primary sclerosing cholangitis who had a benign outcome. CONCLUSIONS: The small number of positive FISH results in BB with equivocal cytology raises the question of the optimal criteria for malignancy. Using only polysomy could result in lower sensitivity.

Difficult biliary cannulation in patients with distal malignant biliary obstruction: An underestimated problem?

BACKGROUND: Failed biliary cannulation still poses a major challenge in patients undergoing Endoscopic Retrograde Cholangiopancreatography (ERCP). To date, there is a lack of data on rates of Difficult Biliary Cannulation (DBC) in patients with distal malignant biliary obstruction (DMBO). MATERIALS: This was a retrospective study (09/2015 to 02/2019) of consecutive patients with DMBO that underwent ERCP in four Italian centers. The primary outcome was to evaluate the rate of DBC. Secondary outcomes were: cannulation failure, rate of adverse events (AEs), the predictive factors for DBC as well as for AEs. RESULTS: A total of 622 patients with DMBO, were included in the study, with 351(56,4%) matching the definition of DBC. One-hundred and two ERCP-related AEs occurred in 97 of 622 patients (15,6%). Subjects with DBC showed a higher risk for AEs (p = 0.02). The lack of pancreatitis prophylaxis (p = 0.03), diagnosis of cholangiocarcinoma (p = 0.02), the use of papillotomy (OR=1.98; 95%CI = 1.14-3.45) and the combination of two or more techniques for cannulation (OR = 2.88; 95%CI = 1.04-7.97) were associated with the occurrence of AEs. CONCLUSIONS: According to the results of this study, patients with DMBO carries a higher rate of DBC thus requiring alternative techniques for biliary drainage. Furthermore, DBC carries a high risk for AEs. Further prospective multicentric studies are needed to confirm these data in this specific subgroup of patients.

The Utility of Biliary Manometry in Assessing Early Catheter Removal After Percutaneous Balloon Dilatation of Hepaticojejunostomy Strictures.

Background and objective Percutaneous balloon dilatation followed by long-term internal-external biliary catheter (IEBC) placement is the standard radiological management for postoperative hepaticojejunostomy (HJ) strictures. The treatment is considered successful when cholangiography shows a free flow of contrast across the anastomosis and the patient passes a "clinical test". However, these tests may not be suitable predictors of long-term successful treatment outcomes. The purpose of this study was to assess the utility of biliary manometry in the evaluation of successful treatment outcomes after HJ stricture dilatation and IEBC placement and its efficacy as a tool for early catheter removal. Patients and methods A total of 14 patients underwent percutaneous balloon dilatation of HJ strictures with IEBC placement. A two-to-three-month interval was maintained between sessions of exchanging or upsizing IEBCs. Biliary manometry was performed after a mean duration of 6.3 months. Intra-biliary pressure of <15 mmHg was considered as the success threshold. Results Among the 14 patients, 11 patients passed initial manometry and had their IEBCs removed and were followed up for a mean duration of 47.8 months. Of these, one patient developed biliary obstruction after six months and underwent repeat HJ stricture dilatation and long-term IEBC placement. Three patients failed manometry and underwent re-dilatation of HJ strictures with IEBC placement. Using Kaplan-Meier survival analysis, the probability of patients remaining stricture-free after HJ stricture dilatation was found to be 100% at three months and 91% at six, 12, 18, 24, 36, and 47.8 months. Conclusion Biliary manometry prevents subjective variations in determining treatment endpoints and helps to assess early catheter removal after percutaneous balloon dilatation of HJ strictures.

[Complication management after bile duct surgery]. / Komplikationsmanagement nach Gallengangschirurgie.

Bile leakage and postoperative bile duct strictures or anastomotic stenosis after bilioenteric anastomosis are complex surgical complications, which are associated with increased morbidity and mortality. Detailed diagnostics and sophisticated decision-making is always requiered. Complex liver surgery (redo procedures, nonanatomic resections, etc.) and surgery involving the liver hilum or exposure of the intraparenchymal Glissonean sheath are risk factors for postoperative bile leakage. Bile leakage is defined as a bilirubin concentration at least three times greater than the serum bilirubin measured in an abdominal drainage on or after the third postoperative day or as the need for radiologic intervention because of biliary collection or relaparotomy for bile peritonitis. Therapeutic strategies for bile leakage comprise conservative watch and wait, interventional procedures (endoscopic or percutaneous biliary drainage) and relaparotomy and are selected based on the postoperative onset, output volume and anatomic localization of the bile leak. Conservative treatment and interventional procedures show a high success rate and should therefore be considered as the treatment of choice in most cases. In contrast to bile leakage, bile duct strictures and anastomotic stenosis are rarely observed after surgery and can usually be treated by interventional procedures. This review article discusses situation-dependent specific treatment of postoperative bile leakage as well as bile duct strictures and anastomotic stenosis in detail.

Predictors of success of treatment of distal two thirds common bile duct strictures: A retrospective Cohort study over two years.

BACKGROUND: Distal biliary stricture is a challenging clinical condition that requires a co-ordinated multidisciplinary approach. THE AIM OF THIS WORK: was to evaluate the predictors of success of different treatment modalities of distal two thirds CBD strictures. PATIENTS AND METHODS: Data were retrieved retrospectively from the medical records of the patients with distal biliary strictures treated in the Main Alexandria University Hospital from June 2013 to June 2015. Patients were classified into three groups according to the intervention performed: (endoscopic, open surgical, and percutaneous). In addition to the forth group that was followed up without intervention. RESULTS: The study included 282 patients. The mean age was 61.1 ± 10.8 years (25-78) years. The most frequent presenting symptom was jaundice. Pancreatic adenocarcinoma was the most common cause followed by fibrotic stricture secondary to stones. CONCLUSION: In univariate analysis, the success of treatment was significantly associated with the pathology of the stricture of the distal two thirds CBD. In the multivariate analysis, only two factors were affecting the success of the treatment; the stricture length and site.

Portal biliopathy.

Portal biliopathy refers to cholangiographic abnormalities which occur in patients with portal cavernoma. These changes occur as a result of pressure on bile ducts from bridging tortuous paracholedochal, epicholedochal and cholecystic veins. Bile duct ischemia may occur due prolonged venous pressure effect or result from insufficient blood supply. In addition, encasement of ducts may occur due fibrotic cavernoma. Majority of patients are asymptomatic. Portal biliopathy is a progressive disease and patients who have long standing disease and more severe bile duct abnormalities present with recurrent episodes of biliary pain, cholangitis and cholestasis. Serum chemistry, ultrasound with color Doppler imaging, magnetic resonance imaging with magnetic resonance cholangiopancreatography and magnetic resonance portovenography are modalities of choice for evaluation of portal biliopathy. Endoscopic retrograde cholangiography being an invasive procedure is indicated for endotherapy only. Management of portal biliopathy is done in a stepwise manner. First, endotherapy is done for dilation of biliary strictures, placement of biliary stents to facilitate drainage and removal of bile duct calculi. Next portal venous pressure is reduced by formation of surgical porto-systemic shunt or transjugular intrahepatic portosystemic shunt. This causes significant resolution of biliary changes. Patients who persist with biliary symptoms and bile duct changes may benefit from surgical biliary drainage procedures (hepaticojejunostomy or choledechoduodenostomy).

The role of intraductal ultrasonography in pancreatobiliary diseases.

Intraductal ultrasonography (IDUS) provides real-time, cross-sectional imaging of pancreatobiliary ducts and surrounding structures during endoscopic retrograde cholangiopancreatography using a high-frequency ultrasound (US) transducer. Hence, IDUS has been considered a sensitive tool in the evaluation of suspicious choledocholithiasis and neoplasms, to help distinguish between benign and malignant bile duct strictures or wall thickness, and to assess tumor extension and invasion depth. With the rapid development and enriched choices of sensitive diagnostic modalities include but are not limited to endoscopic US, peroral cholangioscopy, and confocal laser endomicroscopy, it is needed to systematically assess the role of IDUS in the investigation of pancreatobiliary diseases. Some new developments and innovative use of IDUS techniques will be discussed in this paper with the review of literature.

Multiple plastic stents for benign extrahepatic biliary strictures: report of a case.

The etiology of benign bile duct strictures is heterogeneous. Many of them may be secondary to intraoperative injury such as injuries occurring during laparoscopic cholecystectomy. The spectrum of symptoms at presentation varies from subclinical disease with elevation of liver function tests to complete biliary obstruction with jaundice and hyperbilirubinemia or external biliary fistula in the case of bile duct injury. Long-term consequences may lead to secondary biliary cirrhosis. This publication reports a case of a 49-year-old woman with symptomatic gallstone disease who underwent a laparoscopic cholecystectomy in November 2006. She underwent endoscopic retrograde cholangio-pancreatography due to jaundice, fever and abdominal pain. Then she underwent left hemi-hepatectomy in October 2008 and transplantation of the liver in January 2014. Traditionally, surgical repair has been the preferred approach in benign biliary strictures, but there is an increasing trend for use of minimally invasive endoscopic therapy in these patients.

Secondary sclerosing cholangitis in patients with drug-induced liver injury.

BACKGROUND: Secondary sclerosing cholangitis has clinical features similar to primary sclerosing cholangitis but originates from a known pathological entity. Secondary sclerosing cholangitis has not been investigated in patients with drug-induced liver injury. METHODS: Overall 102 patients diagnosed with drug-induced liver injury were identified and magnetic resonance cholangiopancreatography images of 25 patients were reviewed. RESULTS: Ten patients (all females) out of 102 had confirmed features of secondary sclerosing cholangitis on biliary imaging. Overall 70% of patients with sclerosing cholangitis had jaundice vs. 25% without sclerosing cholangitis (p<0.01). All sclerosing cholangitis patients had cholestatic/mixed type of liver injury and compared with patients with cholestatic/mixed liver injury without confirmed abnormal MRCP (n=52), they also had more frequently jaundice, 70% vs. 23% (p=0.0065), higher peak alkaline phosphatase 551 (352-716) vs. 329 (202-543) (p=0.055) and longer time to resolution of liver injury 152 days (123-353) vs. 62 days (36-91) than patients without confirmed sclerosing cholangitis (p<0.0009). CONCLUSIONS: Our results indicate that drugs can lead to bile duct injury visualized on imaging. This should be a part of the differential diagnoses of secondary sclerosing cholangitis. These patients were more likely to present with jaundice and longer recovery of liver injury than other patients with cholestatic/mixed type of drug-induced liver injury.

Comparative analysis of ERCP, IDUS, EUS and CT in predicting malignant bile duct strictures.

AIM: To compare endoscopic retrograde cholangio-pancreatography (ERCP), intraductal ultrasound (IDUS), endosonography (EUS), endoscopic transpapillary forceps biopsies (ETP) and computed tomography (CT) with respect to diagnosing malignant bile duct strictures. METHODS: A patient cohort with bile duct strictures of unknown etiology was examined by ERCP and IDUS, ETP, EUS, and CT. The sensitivity, specificity, and accuracy rates of the diagnostic procedures were calculated based on the definite diagnoses proved by histopathology or long-term follow-up in those patients who did not undergo surgery. For each of the diagnostic measures, the sensitivity, specificity, and accuracy rates were calculated. In all cases, the gold standard was the histopathologic staging of specimens or long-term follow-up of at least 12 mo. A comparison of the accuracy rates between the localization of strictures was performed by using the Mann-Whitney U-test and the χ(2) test as appropriate. A comparison of the accuracy rates between the diagnostic procedures was performed by using the McNemar's test. Differences were considered statistically significant if P < 0.05. RESULTS: A total of 234 patients (127 males, 107 females, median age 64, range 20-90 years) with indeterminate bile duct strictures were included. A total of 161 patients underwent operative exploration; thus, a surgical histopathological correlation was available for those patients. A total of 113 patients had malignant disease proven by surgery; in 48 patients, benign disease was surgically found. In these patients, the decision for surgical exploration was made due to the suspicion of malignant disease in multimodal diagnostics (ERCP, CT, or EUS). Fifty patients had a benign diagnosis and were followed by a surveillance protocol with a follow-up of at least 12 mo; the median follow-up was 34 mo. Twenty-three patients had extended malignant disease, and thus were considered palliative. A comparison of the different diagnostic tools for detecting bile duct malignancy resulted in accuracy rates of 91% (ERCP/IDUS), 59% (ETP), 92% (IDUS + ETP), 74% (EUS), and 73% (CT), respectively. In the subgroup analysis, the accuracy rates (%, ERCP + IDUS/ETP/IDUS + ETP; EUS; CT) for each tumor entity were as follows: cholangiocellular carcinoma: 92%/74%/92%/70%/79%; pancreatic carcinoma: 90%/68%/90%/81%/76%; and ampullary carcinoma: 88%/90%/90%/76%/76%. The detection rate of malignancy by ERCP/IDUS was superior to ETP (91% vs 59%, P < 0.0001), EUS (91% vs 74%, P < 0.0001) and CT (91% vs 73%, P < 0.0001); EUS was comparable to CT (74% vs 73%, P = 0.649). When analyzing accuracy rates with regard to localization of the bile duct stenosis, the accuracy rate of EUS for proximal vs distal stenosis was significantly higher for distal stenosis (79% vs 57%, P < 0.0001). CONCLUSION: ERCP/IDUS is superior to EUS and CT in providing accurate diagnoses of bile duct strictures of uncertain etiology. Multimodal diagnostics is recommended.

Intraductal ultrasound substantiates diagnostics of bile duct strictures of uncertain etiology.

AIM: To report the largest patient cohort study investigating the diagnostic yield of intraductal ultrasound (IDUS) in indeterminate strictures of the common bile duct. METHODS: A patient cohort with bile duct strictures of unknown etiology was examined by IDUS. Sensitivity, specificity and accuracy rates of IDUS were calculated relating to the definite diagnoses proved by histopathology or long-term follow-up in those patients who did not undergo surgery. Analysis of the endosonographic report allowed drawing conclusions with respect to the T and N staging in 147 patients. IDUS staging was compared to the postoperative histopathological staging data allowing calculation of sensitivity, specificity and accuracy rates for T and N stages. The endoscopic retrograde cholangio-pancreatography and IDUS procedures were performed under fluoroscopic guidance using a side-viewing duodenoscope (Olympus TJF 160, Olympus, Ltd., Tokyo, Japan). All procedures were performed under conscious sedation (propofol combined with pethidine) according to the German guidelines. For IDUS, a 6 F or 8 F ultrasound miniprobe was employed with a radial scanner of 15-20 MHz at the tip of the probe (Aloka Co., Tokyo, Japan). RESULTS: A total of 397 patients (210 males, 187 females, mean age 61.43 ± 13 years) with indeterminate bile duct strictures were included. Two hundred and sixty-four patients were referred to the department of surgery for operative exploration, thus surgical histopathological correlation was available for those patients. Out of 264 patients, 174 had malignant disease proven by surgery, in 90 patients benign disease was found. In these patients decision for surgical exploration was made due to suspicion for malignant disease in multimodal diagnostics (computed tomography scan, endoscopic ultrasound or magnetic resonance imaging). Twenty benign bile duct strictures were misclassified by IDUS as malignant while 14 patients with malignant strictures were initially misdiagnosed by IDUS as benign resulting in sensitivity, specificity and accuracy rates of 93.2%, 89.5% and 91.4%, respectively. In the subgroup analysis of malignancy prediction, IDUS showed best performance in cholangiocellular carcinoma as underlying disease (sensitivity rate, 97.6%) followed by pancreatic carcinoma (93.8%), gallbladder cancer (88.9%) and ampullary cancer (80.8%). A total of 133 patients were not surgically explored. 32 patients had palliative therapy due to extended tumor disease in IDUS and other imaging modalities. Ninety-five patients had benign diagnosis by IDUS, forceps biopsy and radiographic imaging and were followed by a surveillance protocol with a follow-up of at least 12 mo; the mean follow-up was 39.7 mo. Tumor localization within the common bile duct did not have a significant influence on prediction of malignancy by IDUS. The accuracy rate for discriminating early T stage tumors (T1) was 84% while for T2 and T3 malignancies the accuracy rates were 73% and 71%, respectively. Relating to N0 and N1 staging, IDUS procedure achieved accuracy rates of 69% for N0 and N1, respectively. LIMITATIONS: Pre-test likelihood of 52% may not rule out bias and over-interpretation due to the clinical scenario or other prior performed imaging tests. CONCLUSION: IDUS shows good results for accurate diagnostics of bile duct strictures of uncertain etiology thus allowing for adequate further clinical management.

Endoscopic and retrograde cholangiographic appearance of hepaticojejunostomy strictures: A practical classification.

AIM: To study the endoscopic and radiological characteristics of patients with hepaticojejunostomy (HJ) and propose a practical HJ stricture classification. METHODS: In a retrospective observational study, a balloon-assisted enteroscopy (BAE)-endoscopic retrograde cholangiography was performed 44 times in 32 patients with surgically-altered gastrointestinal (GI) anatomy. BAE-endoscopic retrograde cholangio pancreatography (ERCP) was performed 23 times in 18 patients with HJ. The HJ was carefully studied with the endoscope and using cholangiography. RESULTS: The authors observed that the hepaticojejunostomies have characteristics that may allow these to be classified based on endoscopic and cholangiographic appearances: the HJ orifice aspect may appear as small (type A) or large (type B) and the stricture may be short (type 1), long (type 2) and type 3, intrahepatic biliary strictures not associated with anastomotic stenosis. In total, 7 patients had type A1, 4 patients A2, one patient had B1, one patient had B (large orifice without stenosis) and one patient had type B3. CONCLUSION: This practical classification allows for an accurate initial assessment of the HJ, thus potentially allowing for adequate therapeutic planning, as the shape, length and complexity of the HJ and biliary tree choice may mandate the type of diagnostic and therapeutic accessories to be used. Of additional importance, a standardized classification may allow for better comparison of studies of patients undergoing BAE-ERCP in the setting of altered upper GI anatomy.