Identification of Cholangiocarcinoma by Using the Spyglass Spyscope System for Peroral Cholangioscopy and Biopsy Collection

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012;10:466 471 ENDOSCOPY CORNER Identification of Cholangiocarcinoma by Using the Spyglass Spyscope System for Peroral Cholangioscopy and Biopsy Collection ALI A. SIDDIQUI,* VAIBHAV MEHENDIRATTA,* WHITNEY JACKSON,* DAVID E. LOREN,* THOMAS E. KOWALSKI,* and MOHAMAD A. ELOUBEIDI *Division of Gastroenterology and Hepatology, Department of Internal Medicine, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania; and Division of Gastroenterology, American University of Beirut, Beirut, Lebanon This article has an accompanying continuing medical education activity on page e48. Learning Objectives At the end of this activity, the learner should know about the utility of cholangioscopy in evaluation of biliary strictures and characterization of pathology. BACKGROUND & AIMS: It is a challenge to collect samples from bile duct strictures to diagnose patients with cholangiocarcinoma. We investigated the utility of the Spyglass Spyscope, a single-operator endoscope that is used to perform cholangiopancreatoscopy, to identify extrahepatic cholangiocarcinoma in patients who were not diagnosed with this disorder by endoscopic retrograde cholangiopancreatography (ERCP) cytology or endoscopic ultrasound guided fine-needle aspiration (EUS-FNA) analyses. METHODS: We conducted a retrospective analysis of data from 30 patients (median age, 67 years; 67% male) with indeterminate extrahepatic biliary strictures who were ultimately diagnosed with cholangiocarcinoma but had inconclusive results from initial biliary ductal brush cytology and EUS-FNA analyses. Patients then underwent cholangioscopy by using the Spyglass Spyscope and intraductal biopsy analysis. None of the patients had a definitive mass in abdominal imaging or EUS analyses. RESULTS: The biliary stricture was located in the common bile duct in 13 patients and in the common hepatic duct in 17 patients. The Spyglass Spyscope system had 77% accuracy (23 of 30) in the diagnosis of malignancies that were inconclusive on the basis of ERCPguided brush or EUS-FNA analyses. CONCLUSIONS: The Spyglass Spyscope for cholangioscopy and biopsy collection identified malignancies with 77% accuracy in patients with suspected cholangiocarcinoma. Keywords: Bile Duct Cancer; Diagnostic; Endoscopy; Inflammation. Cholangiocarcinomas (CCAs) are rare but very fatal tumors. The incidence and mortality of this cancer appear to be increasing worldwide. 1 3 In patients with suspected CCA, several noninvasive tests like computed tomography (CT) cholangiography 4 and magnetic resonance cholangiopancreatography 5 can be used for the diagnosis of biliary tumors. Endoscopic retrograde cholangiopancreatography (ERCP) continues to remain the modality of choice for initial characterization of bile duct strictures. However, the sensitivity of ERCP with brush cytology alone for the diagnosis of malignant biliary strictures ranges from 33% 58%. 6 9 Without a diagnosis of malignancy, beneficial therapy might potentially be withheld in these patients. The current clinical protocol in many institutions is to perform an endoscopic ultrasound guided fine-needle aspiration (EUS-FNA) in patients with suspected extrahepatic CCA if the ERCP brush cytology is negative or equivocal. Results from several clinical trials confirmed that EUS-FNA is a sensitive method for the diagnosis of malignant biliary strictures after negative results or unsuccessful ERCP brush cytology. 10 13 EUS-FNA has been reported to have a sensitivity as high as 86% for the diagnosis of CCA. 11,14 However, the majority of patients in these trials had a definite mass lesion seen in the bile duct that was then targeted by EUS-FNA. A significant number of patients with CCA have bile wall thickening at the site of the stricture without any distinct mass lesion seen on endosonography. There is limited literature on the accuracy of EUS-FNA for the diagnosis of CCA in patients with a biliary stricture in whom no distinctive mass lesion is seen on EUS and other imaging studies. In this subset of patients, peroral cholangioscopy might have an advantage of directly visualizing a stricture seen on fluoroscopy and obtaining directed tissue biopsies of the stricture by using miniature cholangioscopy biopsy forceps. 15,16 The Spyglass Spyscope (Microvasive Endoscopy, Boston Scientific Corp, Natick, MA) is a new single-operator endoscope that has been introduced to perform cholangiopancreatoscopy. 16 The purpose of this study was to report the utility of the SpyGlass cholangioscopy system for the preoperative diagnosis of extrahepatic CCA and its ability to make a tissue diagnosis in patients with negative or nondiagnostic tissue sampling by ERCP brush cytology and EUS-FNA. Abbreviations used in this paper: CCA, cholangiocarcinoma; CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; EUS-FNA, endoscopic ultrasound guided fine-needle aspiration; IDUS, intraductal ultrasound; MRI, magnetic resonance imaging; SD, standard deviation. 2012 by the AGA Institute 1542-3565/$36.00 doi:10.1016/j.cgh.2011.12.021

May 2012 SPYGLASS FOR DIAGNOSIS OF CHOLANGIOCARCINOMA 467 Methods Patients This study was approved by the Institutional Review Board at Thomas Jefferson University. We evaluated our endoscopy and pathology database to evaluate all patients with extrahepatic bile duct strictures who underwent SpyGlass cholangioscopy during a 38-month period (April 2008 June 2011) for suspected CCA. Extrahepatic bile strictures were defined as those located in the common bile duct or common hepatic duct. Our inclusion criteria included all patients who had CCA diagnosed on the basis of surgical pathology and/or clinical and imaging findings. All patients included were those who had undergone an initial ERCP with a biliary sphincterotomy, brush cytology, and stent placement, followed by EUS-FNA of an extrahepatic bile duct stricture without an associated mass that was pathologically interpreted as nondiagnostic or negative for malignancy. Patients with benign strictures, pancreatic adenocarcinoma, perihilar CCA, and intrahepatic CCA were excluded from the trial. In patients who underwent surgical resection, surgical pathology was used to distinguish extrahepatic CCA from pancreatic adenocarcinoma. In patients who were not operated on, diagnoses of extrahepatic CCA were based on imaging studies and clinical follow-up. Medical records on all patients included were evaluated for clinical presentations, prior radiographic data, clinical follow-up, and overall patient outcomes. SpyGlass Cholangioscopy Technique Before SpyGlass cholangioscopy, the endoscopist reviewed the previous cholangiography to determine whether the stricture was located in the common bile duct or common hepatic duct. 17 All patients received antibiotic prophylaxis by using ciprofloxacin 400 mg intravenously. Initial cannulation of the bile duct was achieved, and a cholangiogram was performed to identify the site of biliary stenosis. The SpyGlass apparatus was introduced through the working channel of the duodenoscope and then advanced into the biliary tract. The site of the biliary stricture was then examined by repeat advancement and withdrawal of the SpyGlass. 16 The visual characteristics that the endoscopist evaluated to identify the site of malignancy were (1) exophytic lesions, (2) ulcerations, (3) papillary mucosal projections, (4) dilated tortuous vessels, and (5) raised lesions. 15,16 When a distinct mass lesion was identified on cholangioscopy, biopsies were acquired from several different areas under direct visualization by using the SpyBite forceps. 15,16 When no obvious mass lesion was seen, random biopsies were performed from within the stenosis. The biopsy specimens were then examined by 1 of 2 pathologists who were experienced in the interpretation of gastrointestinal pathology. End Points The primary end point for the current study was the procedural success of SpyGlass cholangioscopy in adequately visualizing the extrahepatic biliary stricture and the success of obtaining a positive biopsy for malignancy in CCA patients in whom the initial ERCP with brush cytology followed by EUS-FNA was nondiagnostic or negative. Complications in the study were defined as any divergence from the routine course after SpyGlass cholangioscopy as reported by the endoscopists, recovery room nurses, or in the medical records. Complications during the procedure such as perforation, bleeding, hypotension, or respiratory distress were carefully documented. The electronic medical records were also evaluated for any patient admissions required after the procedure. Statistical Analysis The results of the SpyGlass cholangioscopy-directed forceps biopsy results were compared with the following reference methods of tissue diagnosis: (1) intraoperative biopsy or surgical specimen results; (2) biopsy specimens obtained by other methods (eg, percutaneous aspiration of the primary tumor or a metastasis, either initially or during follow-up); (3) clinical course based on a 6-month follow-up in which that patient developed radiographic evidence of local or distant metastasis, or death attributed to a malignant bile duct lesion on the basis of clinical records. All biopsy specimens acquired by SpyGlass were categorized as positive or negative for malignancy. Any specimen interpreted as highly suspicious or suspicious for malignancy was considered positive for malignancy. Any specimen interpreted as atypical was considered negative for malignancy. To determine the operating characteristics of SpyGlass cholangioscopydirected biopsies in detecting cancer, the diagnostic accuracy was calculated. 13 Analyses were performed by using SAS V9.1 (SAS Institute, Cary, NC). Results Baseline Patient Characteristics Thirty patients were included in the study. All of the patients had a proven diagnosis of extrahepatic CCA on the basis of criteria mentioned in the Methods section. The median age of the patients was 67 years (standard deviation [SD], 11.9); 20 (67%) were male (67% white, 18% black, 12% Hispanic, 3% other). The clinical presentation in these patients was painless jaundice (89%), weight loss (14%), poor appetite (10%), malaise (21%), and abdominal pain (29%). No mass lesion was identified in either a CT scan or magnetic resonance imaging Table 1. Patient and Clinical Data Parameter Descriptive statistics Median age, y (range) 67 (45 87) Gender, n (%) Male 20 (67) Female 10 (33) Race, n (%) White 20 (67) Black 5 (18) Hispanic 4 (12) Other 1 (3) Clinical presentation, n (%) Jaundice 27 (89) Abdominal pain 9 (29) Weight loss 4 (14) Poor appetite 3 (10) Malaise 6 (21) Mean bile duct stricture length (mm), (range) 12.8 (8 20) Stricture location, n (%) Common bile duct 13 (43) Common hepatic duct 17 (57)

468 SIDDIQUI ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 5 (MRI) scans. Patient demographics at baseline and clinical data are summarized in Table 1. Endoscopic Retrograde Cholangiopancreatography With Brush Cytology and Endoscopic Ultrasound Guided Fine-Needle Aspiration All patients underwent an initial ERCP with plastic stent placement. The biliary stricture was located in the common bile duct in 13 patients (43%) and in the common hepatic duct in 17 patients (57%). During ERCP, tissue samples were obtained from the biliary stricture by using a conventional, over-the-guidewire cytology brush. The initial cytology brushings were all negative for malignancy; 26 were reported as having atypical epithelial cells, and 4 were interpreted as being benign. Because of the high clinical probability that these patients had a primary biliary malignancy, these patients then underwent an EUS to detect any distinct biliary lesion. EUS detected a biliary wall thickening at the site of stricture in 26 of the patients evaluated (87%). No discrete mass lesion was identified by EUS in any of the patients. EUS-FNA was then attempted in the suspected region of biliary stricture by using visualization of biliary wall thickening and/or stent as a guide. A median of 5 passes (range, 4 9 passes) with the FNA needle was performed via a transduodenal approach without complications to obtain adequate samples. Cytologic diagnoses were atypical cytology (n 23) or benign ductal epithelial cells (n 7). EUS-FNA cytology results did not demonstrate malignancy in any of the patients. SpyGlass Cholangioscopic Findings Patients in the trial underwent cholangioscopy with the SpyGlass apparatus after an equivocal ERCP with brushings and EUS-FNA cytology. SpyGlass demonstrated papillary polypoid lesions in 1 patient, ulcerated mass lesion in 7 patients, friable stricture with dilated tortuous vessels in 2 patients, and a circumferential fibrostenotic ulcerated lesion in 20 patients. SpyBite biopsies were obtained under direct visualization from these sites. Operating Characteristics of SpyGlass-Guided Biopsies The median number of biopsy bites performed was 5 (range, 3 7). The specimens obtained from all patients were adequate for histologic evaluation as per the pathologist s evaluation. Of the 30 patients in the study with a final diagnosis of malignancy, 23 (77%) had a biopsy by SpyGlass read as carcinoma (true positives), and 7 (23%) had a biopsy interpreted as benign (false negatives). Of the 23 of 30 patients with SpyGlass biopsies read as positive for cancer, 16 were interpreted as being clearly positive for malignancy and 17 as being highly suspicious for malignancy. In patients with false-negative biopsy results, 4 had strictures located in the common bile duct, and 3 had strictures in the common hepatic duct. Of these 7 patients with false-negative biopsy results, 1 had a friable stricture with dilated tortuous vessels, 2 had ulcerated mass lesions, and 4 had fibrostenotic ulcerated lesions visualized on SpyGlass. The mean number of SpyGlass-directed biopsies read as carcinoma was not statistically different when compared with biopsies interpreted as benign (4.7 vs 4.5, respectively; P.75). The overall diagnostic accuracy of SpyGlass-directed biopsies for diagnosing malignant biliary ductal lesions that were inconclusive on previous ERCP-guided brushing and EUS-FNA was 77% (23 of 30). Location of the bile duct stricture did not influence the overall accuracy of SpyBite. Patient Follow-up Patients were followed for a median duration of 7 months (range, 3 12). Of the 23 patients diagnosed with CCA by SpyGlass-guided biopsies, 4 of 23 patients were found to have distant metastasis on repeat imaging studies, and 19 of 23 patients were referred for surgical resection. Of the 19 patients referred for surgery, 1 was found to have an unresectable tumor during laparotomy because of major vessel involvement, and 2 were found to have radiographically occult peritoneal or liver metastasis on laparotomy. Of the 7 patients with CCA in whom the SpyGlass-guided biopsies were interpreted as benign (falsenegative patients), 2 were found to have liver metastasis on follow-up CT scans, 1 was diagnosed with CCA on a repeat ERCP with brush cytology, and 4 at surgery. Eighteen of 30 patients (60%) had died as a result of complications of tumor progression on follow-up. Complications One patient (3.3%) presented with postprocedure pancreatitis after SpyGlass cholangioscopy. She was admitted to the hospital for 3 days and subsequently discharged without any complications. One patient presented to the emergency department with self-limiting abdominal pain and was subsequently discharged home. Discussion In the current study of 30 patients with malignant extrahepatic CCA, all of whom had no diagnosis established by conventional endoscopic modalities, SpyGlass-directed biopsies had the ability to make a tissue diagnosis in 77% of cases. Our results suggest that single-operator SpyGlass cholangioscopy with biopsies might be the appropriate strategy for patients in whom cholangiocarcinoma is suspected, but in whom the initial ERCP with brush cytology followed by EUS-FNA was nondiagnostic or negative. Our study is also unique in that it only evaluated patients with biliary stenosis in whom no associated biliary mass lesion was seen on imaging studies and EUS. These are the lesions that are potentially the most difficult to obtain the definitive tissue diagnosis. By establishing a final diagnosis of CCA, these patients then benefited from directed therapy for their disease. Recent advances have made available multiple options for treatment of biliary neoplasms; this underscores the importance of a timely diagnosis for CCA. 18,19 The detection rate for brush cytology for the diagnosis of cholangiocarcinoma varies from 44% 80%. 5,7,9,17,20,21 Detection of CCA by using forceps biopsy under fluoroscopic guidance is also quite variable, ranging between 37% 86%. 7,21,22 EUS-FNA has now been demonstrated as a sensitive method for the diagnosis of malignant extrahepatic biliary strictures after negative results by ERCP brush cytology (sensitivity, 27% 86%). 10,11,13,20 It should be noted that EUS demonstrated a mass involving the bile ducts in the majority of these patients, and hence EUS-FNA was used to perform targeted biopsies of these lesions. This might have accounted for the relatively high sensitivity of EUS-FNA to detect a cancer. This is unlike our

May 2012 SPYGLASS FOR DIAGNOSIS OF CHOLANGIOCARCINOMA 469 Figure 1. Proposed algorithm for the diagnosis of extrahepatic bile duct strictures. study in which we specifically evaluated patients in whom no mass lesion was seen on EUS, and EUS-FNA was attempted in the suspected region of biliary stricture. A disadvantage of EUS-FNA is that it has a low negative predictive value, varying from 28% 57%. 10,11,13 This has been attributed to the tumor being associated with significant fibrosis or ulceration because CCAs are usually desmoplastic tumors with low cellularity. 11 Cholangioscopy has a particular advantage over other tests because it allows for direct visualization of a bile duct, allowing for directed biopsies of the suspicious lesion. The traditional method of peroral cholangioscopy entails using the mother-baby cholangioscopy. The disadvantages to this apparatus are that it requires 2 operators and is fragile and easily damaged. SpyGlass cholangioscopy with the SpyBite biopsy forceps is a single-operator system that allows for cholangioscopic-guided biopsies of suspicious strictures. 16 Chen et al 16 have also demonstrated that the success rate for simulated biopsy with the SpyGlass system was 3 times that with the conventional choledochoscope. There are several studies that have validated SpyGlass cholangioscopy in the diagnosis of malignancy in patients with indeterminate bile duct strictures. Chen et al 16 evaluated 22 patients with indeterminate strictures who underwent SpyGlass-directed biopsies and demonstrated 71% sensitivity and 100% specificity in diagnosing malignant strictures. A recent prospective study by Ramchandani et al 23 evaluating 33 patients showed similar results. It should be noted that direct peroral and Spyglass cholangioscopy might lead to several complications. 24 Although antibiotic prophylaxis is recommended for patients undergoing cholangioscopy, recent studies have failed to show that they reduce the risk of cholangitis rates. 24,25 Peroral cholangioscopy has been demonstrated to have cholangitis rates of 0% 14%. 15,24,26 Other complications attributed to cholangioscopy include bile duct leak (1%) and hemobilia (0% 3%). 24,27,28 Figure 1 summarizes our recommended protocol for the diagnosis of extrahepatic bile duct strictures on the basis of anecdotal experience. Patients with suspected extrahepatic bile duct strictures on initial imaging studies (CT scan or MRI) should undergo ERCP with brush cytology. If the cytology results are interpreted as nondiagnostic or negative for malignancy and there is still a suspicion that this stricture is malignant, the patient should undergo EUS-FNA at the site of stenosis. If no biliary mass lesion is identified by EUS, then the patient should undergo Spyglass cholangioscopy. If EUS identifies a biliary mass lesion, FNA should be

470 SIDDIQUI ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 5 performed to confirm that the mass is malignant. If the cytology results of EUS-FNA are still inconclusive for malignancy, SpyGlass cholangioscopy with directed biopsies should be performed. If the SpyGlass-directed biopsies are negative or nondiagnostic for malignancy, then a careful discussion should take place with the patient to consider surgical resection of the site or close clinical follow-up with repeat imaging studies. We recommend a multidisciplinary approach involving the patient, gastroenterologist, and a surgeon to agree on a consensus management protocol. Several limitations of the present study should be acknowledged. First, it was retrospective, and we analyzed the results in only 30 patients. Surgical pathology was not available in all our cases because a significant number of patients (n 18) with cholangiocarcinoma were unresectable at the time of diagnosis. However, we had good clinical follow-up and therefore were able to follow the natural history of the patient during at least 6 months. Second, we evaluated only the operating characteristics for SpyGlass cholangioscopy in patients with documented CCA and did not evaluate a control group with benign biliary strictures. However, previous trials cited in the article have demonstrated that SpyGlass-directed biopsies have a high specificity and negative predictive value for the evaluation of malignant biliary strictures. 16,23 Our study did not evaluate the role of biliary intraductal ultrasound (IDUS) as an adjunct diagnostic tool to biliary brushing and cholangioscopy for the evaluation of biliary strictures. 29 31 Although IDUS might yet provide an additional tool to diagnose indeterminate biliary strictures, its use is still currently limited. 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May 2012 SPYGLASS FOR DIAGNOSIS OF CHOLANGIOCARCINOMA 471 tional methods, including mechanical lithotripsy. Endoscopy 2005;37:542 547. 29. Farrell RJ, Agarwal B, Brandwein SL, et al. Intraductal US is a useful adjunct to ERCP for distinguishing malignant from benign biliary strictures. Gastrointest Endosc 2002;56:681 687. 30. Vazquez-Sequeiros E, Baron TH, Clain JE, et al. Evaluation of indeterminate bile duct strictures by intraductal US. Gastrointest Endosc 2002;56:372 379. 31. Domagk D, Poremba C, Dietl KH, et al. Endoscopic transpapillary biopsies and intraductal ultrasonography in the diagnostics of bile duct strictures: a prospective study. Gut 2002;51: 240 244. Reprint requests Address requests for reprints to: Ali A. Siddiqui, MD, Associate Professor of Medicine, Thomas Jefferson University Hospital, 132 South 10th Street, Philadelphia, Pennsylvania 19107. e-mail: ali.siddiqui@jefferson.edu; fax: (215) 955-6678. Conflicts of interest The authors disclose no conflicts. Funding This study was funded entirely through existing intramural funds and salary support.