EDUCATION PRACTICE. Biliary Stricture and Negative Cytology: What Next? AClinical Scenario. The Dilemma

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2011;9: EDUCATION PRACTICE Biliary Stricture and Negative Cytology: What Next? GREGORY A. COTÉ and STUART SHERMAN Division of Gastroenterology, Indiana University School of Medicine, Indianapolis, Indiana This article has an accompanying continuing medical education activity on page e97. Learning Objectives At the end of this activity, the learner will know the advantages and limitations of different diagnostic modalities used in the work-up of patients with biliary strictures. AClinical Scenario 40-year-old woman with a history of ulcerative colitis since age 10 and a 3-year history of primary sclerosing cholangitis (PSC) presents to her local hepatologist with abrupt onset of jaundice (alkaline phosphatase 1167 U/L [normal range, U/L], total bilirubin 7.0 mg/dl [normal range, mg/dl]) and pruritis. She was initially diagnosed with PSC 3 years ago after undergoing an endoscopic retrograde cholangiopancreatography (ERCP) for an asymptomatic elevation in her alkaline phosphatase. At that time, ERCP demonstrated changes consistent with PSC; specifically, cholangiography revealed diffuse beading and strictures of her intrahepatic biliary tree, hepatic confluence, and proximal common hepatic duct. At that time, there were no dominant strictures that required endoscopic treatment. She had been lost to follow-up until her current presentation. A serum carbohydrate antigen (CA)19-9 is 20 U/mL (normal range 0 37 U/mL) and dual phase computerized tomography (CT) of the liver reveals no focal mass. Given her recent development of jaundice, she undergoes a repeat ERCP which identifies a high grade stricture of the hepatic confluence that is brushed for cytology and treated with balloon dilation (Figure 1). Her cholestatic laboratory values and pruritis improve following balloon dilation. Cytologic brushings demonstrate benign epithelial cells with atypia but no malignancy. What next? The Dilemma Usually, a cytopathological assessment that reveals no evidence of malignancy should be very encouraging to a patient and their treating physician. Unfortunately, a negative cytologic brushing obtained during ERCP from an extrahepatic biliary stricture often leaves the endoscopist wondering, Is the stricture really benign or did I miss something? The lack of confidence in a negative brushing stems from its poor sensitivity (37% 56%) and suboptimal negative predictive value. 1 3 As a result, the physician is left to decide whether or not to pursue additional diagnostic testing, refer to a surgeon, or assume that the stricture is truly benign. There is a broad differential diagnosis for extrahepatic biliary strictures (Table 1), and the pretest probability for each patient should be a principal consideration in determining: (1) the need for tissue sampling during the first ERCP; and (2) the need for pursuing a malignant work-up after the first sample returns benign tissue or inadequate cellularity. Patients with biliary strictures typically present with abnormal liver chemistries (primarily elevation in alkaline phosphatase, total bilirubin) with or without clinical manifestations of biliary obstruction: jaundice, abdominal pain, pruritis, tea-colored urine, acholic stools, or some combination. Cross-sectional imaging (CT or magnetic resonance imaging) is often used to differentiate extrahepatic biliary obstruction from other causes of cholestasis; the presence of a biliary stricture is suggested by an abrupt cut-off of Figure 1. Cholangiography demonstrates irregularity of the upper common hepatic duct and focal stricture at the hilum (arrow). Abbreviations used in this paper: CA19-9, carbohydrate antigen; CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasound; EUS-FNA, endoscopic ultrasound-guided fine needle aspiration; FISH, fluorescence in situ hybridization; PSC, primary sclerosing cholangitis by the AGA Institute /$36.00 doi: /j.cgh

2 740 COTÉ AND SHERMAN CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 9 Table 1. Focused Differential Diagnosis of Extrahepatic Biliary Strictures in Adults Benign, intrinsic Benign, extrinsic Malignant, intrinsic Malignant, extrinsic PSC Chronic pancreatitis Cholangiocarcinoma Pancreatic adenocarcinoma Gallstones Organized pancreatic fluid collection/pseudocyst Ampullary adenocarcinoma Portal lymphadenopathy (metastatic adenocarcinoma, lymphoma, melanoma) Postoperative (OLT, CCY, biliary Acute pancreatitis Hepatocellular carcinoma Gallbladder carcinoma reconstruction [eg, hepaticojejunostomy]) Stent-associated Hepatocellular carcinoma Ischemic Gallbladder (eg, Mirizzi syndrome) Gallbladder carcinoma Lymphoplasmacytic sclerosing pancreatitis/cholangitis Vascular (portal vein thrombosis, periductal varices) Infectious (HIV, parasites) CCY, cholecystectomy; HIV, human immunodeficiency virus; OLT, orthotopic liver transplant. the bile duct or change in duct caliber with or without the presence of a focal mass lesion, coupled with the presence of biliary dilation proximal to the site of obstruction. Unfortunately, serum CA19-9 is only modestly sensitive and specific as a screening tool because it may be elevated in the setting of biliary obstruction from benign causes. 4,5 A CA U/mL is thought to have a sensitivity of 75% and specificity of 80% in the setting of PSC, and persistent elevation after biliary decompression is suggestive of malignancy. 6 Because serum tumor markers and cross-sectional imaging cannot provide a definitive diagnosis in most cases, ERCP remains an important tool to further characterize the stricture (ie, define its location relative to the hepatic confluence and possible involvement of intrahepatic ducts), obtain tissue, and treat the jaundice via balloon dilation, transpapillary stent placement, or both (for symptomatic patients). While ERCP is highly effective in palliating obstructive jaundice, confirming a definitive diagnosis through ERCP remains a challenge. Intraductal brushings continue to be the preferred first-line approach for tissue sampling because it has a low-risk profile and is technically undemanding in most cases. However, most studies report a sensitivity of 27% to 56%. 1 3 The reasons for such a low sensitivity are likely multifactorial: first, tumors that are extrinsic to the bile duct or laterally spread along the submucosa (ie, periductal) are less likely to exfoliate malignant cells when agitated with an intraductal brush. Second, limitations in brush design and insufficient to-and-fro manipulation across the biliary stricture (or other technical aspects to brushing) by the endoscopist or their assistant may also play a role. Studies comparing brush designs or the use of an intraductal basket to obtain tissue have yielded conflicting results. 3,7 Dilation of the stricture before tissue sampling does not appear to impact the diagnostic yield. 8 Finally, the importance of slide preparation techniques and cytopathologist expertise remain unclear. 9,10 The limitations of cholangiography and brushings have prompted investigators to explore alternative methods to confidently differentiate the indeterminate bile duct stricture. Management Strategies Alternate Tissue Sampling Techniques During ERCP Endobiliary forceps biopsies and fluoroscopicallyguided fine needle aspiration (FNA) offer alternative techniques to obtain tissue from biliary strictures during ERCP. 11 In a prospective study of 133 patients with a biliary stricture (104 subsequently proven to have cancer), the sensitivity of brushing alone (30%), FNA alone (30%), and biopsy alone (43%) were similar. However, the combination of 2 (eg, brushing and biopsy, 55%; FNA and biopsy, 53%) and 3 (62%) techniques yielded higher results. Consequently, some endoscopists perform multimodality tissue sampling during the initial ERCP when cancer is highly suspected. With 2 modalities, intraductal biopsies are typically favored over FNA as the second modality for tissue acquisition as FNA does not improve the sensitivity of brushing alone. Specimens obtained using forceps biopsies can be smashed between 2 glass slides and fixed with rapid Papanicolaou to allow for an on-site evaluation (Smash protocol). Early experience with this approach shows a dramatic improvement in overall sensitivity (76%); however, these results have not been confirmed in other studies. 12 Unfortunately, intraductal forceps biopsies are often technically more difficult to obtain than brushings, time-consuming (because several passes are often required to obtain a visible specimen) and intermittently unsuccessful because of inflexible devices that cannot be passed to the level of the stricture. This is especially problematic in proximal strictures and PSC, where the duct diameter is often 6 mm. There are limited data suggesting repeat brushings during the same procedure improve the diagnostic yield: among 139 patients with biliary strictures (116 with subsequent confirmation of malignancy), the sensitivity of 2 intraductal brushings was 44% as compared with a single intraductal brushing of 31% to 34.5% (P.001). 8 The yield of 3 or more brushings performed during the first ERCP is unknown, but there seems to be modest benefit of repeating ERCP with brushings after 2 previous ERCPs having negative samples. 13 Repeat samples can be facilitated by the use of a catheter left in the biliary tree to permit passage of multiple brushes or forceps. Endoscopic Ultrasound-Guided Fine Needle Aspiration (EUS-FNA) EUS-FNA is highly ( 80%) sensitive for distal bile duct strictures secondary to pancreatic adenocarcinoma or cholangiocarcinoma Because endoscopic ultrasonography (EUS) provides complementary information on tumor staging and offers superior diagnostic yield to ERCP, EUS-FNA has largely replaced ERCP-based tissue sampling techniques as the firstline modality for confirming a diagnosis in the setting of a

3 September 2011 BILIARY STRICTURE AND NEGATIVE CYTOLOGY 741 distal bile duct stricture with a high preclinical suspicion of malignancy. However, EUS cannot offer biliary drainage except in rare cases; for symptomatic patients who require biliary drainage, concomitant stenting via ERCP can be performed in the same setting or at a different time depending on the availability of staff and access to fluoroscopy. The performance characteristics of EUS-FNA for proximal (defined as 2 cm from the hepatic confluence) strictures is significantly lower, having a sensitivity of 59% and negative predictive value of 29%. 16,17 Therefore, ERCP remains the preferred first-line approach to confirming a tissue diagnosis in most cases, particularly those who are symptomatic and may require dilation and/or stenting. EUS-FNA can be performed as a second-tier test if initial tissue samples obtained via ERCP are inconclusive. Tumor seeding of the FNA tract should be considered in patients who may undergo surgical resection, particularly in proximal strictures where FNA is often performed through the gastric wall or duodenal bulb. Intraductal ultrasound (IDUS) can be performed during ERCP and improves the sensitivity/specificity of cholangiography 18 but is limited by poor interobserver variability, fragile devices, and the inability to acquire a specimen through the ultrasound probe. FISH Fluorescence in situ hybridization (FISH) is a newer molecular technique that uses fluorescently-labeled DNA probes to identify aneusomy (abnormal loss or gain of chromosomes or chromosomal loci) of individual cells. In theory, this technique permits the differentiation of malignant from benign fibroinflammatory strictures of the bile duct using fewer cells than routine cytology or flow cytometry analysis. 18 Importantly, because approximately 80% of pancreatobiliary malignancies express these cellular alterations, the sensitivity of FISH is consequently limited. In addition, some patients with benign, fibroinflammatory bile duct strictures (particularly in the setting of PSC) have chromosomal abnormalities; as a result, the specificity of FISH is lower than routine cytology, ranging from 67% to 88%. 19 Therefore, FISH has not been accepted as a routine screening tool for malignancy but improves sensitivity 14% to 24% when routine cytology is negative. 18 In PSC patients with a high clinical suspicion of cholangiocarcinoma, we routinely perform FISH during the initial ERCP to optimize sensitivity and minimize the need for repeat procedures; in non- PSC cases, FISH is typically reserved for indeterminate strictures where initial testing is inconclusive. Cholangioscopy Direct visualization of biliary strictures via cholangioscopy either percutaneous or endoscopic may improve the performance characteristics of routine cholangiography and cytology in diagnosing malignancy. 20 Spyglass Direct Visualization System (Boston Scientific Corp, Natick, Massachusetts) allows for single operator, fiberoptic cholangioscopy with intraductal biopsies under direct visualization. This technology has largely replaced older and more cumbersome motherdaughter endoscope systems for cholangioscopy in the United States. While its incremental benefit over routine cytology and fluoroscopically-directed biopsies appears promising, its utility is still unproven in the setting of a randomized clinical trial. 21 Newer advances such as narrow-band imaging, autofluorescence imaging, and endomicroscopy may improve the sensitivity/specificity of cholangioscopy and expand the role for intraductal therapeutics such as photodynamic therapy and radiofrequency ablation. These technologies remain in their nascence and require further study before widespread application can be recommended. Surgery Among non-psc patients with a high clinical suspicion for extrahepatic cholangiocarcinoma that appears resectable on cross-sectional imaging (CT, magnetic resonance cholangiopancreatography) or during initial ERCP, surgical exploration by an expert hepatobiliary-pancreatic surgeon is a reasonable option even in the setting of negative cytology. Staging laparoscopy followed by removal (if malignancy is confirmed) may expedite an inevitable visit to the operating room suite for those patients that are good operative candidates and have a high pretest probability of resectable cancer (eg, early cholangiocarcinoma or small pancreatic adenocarcinoma missed on cross-sectional imaging). The benefits of preoperative biliary drainage via ERCP or percutaneous transhepatic cholangiography are debatable, particularly in the absence of deep jaundice (typically defined as a bilirubin 12 mg/dl). 22 If surgical consultation and laparoscopy can be performed expeditiously, then this may be preferred over further diagnostic testing. Areas of Uncertainty Further studies are needed to clarify the role for new technologies such as cholangioscopy, cholangioscopy-directed biopsies, FISH, and advanced imaging techniques (eg, endomicroscopy, narrow band imaging). Because the diagnostic yield of a single intraductal brushing is so poor, should FISH, cholangioscopy, repeat (how many?) brushings, or some combination be routinely performed during the initial ERCP? In the current US health care system, the added costs of these technologies may be offset by improvements in the diagnostic yield of the first ERCP, thereby reducing the need for downstream tests. Similar to EUS-FNA where multiple passes improve the diagnostic yield, prospective studies evaluating the incremental benefit of 2 or more intraductal brushings during the initial ERCP are needed. Enhanced cross-sectional imaging and EUS may further limit the role for diagnostic ERCP but is unlikely to replace its therapeutic impact for effecting biliary drainage. The improved safety profile of laparoscopy should encourage gastroenterologists to obtain an expert surgical opinion early in the management of these patients; while sometimes we feel an obligation to confirm a tissue diagnosis before consultation, surgery may be the inevitable outcome. Published Guidelines There are no formal society recommendations that offer an algorithm to evaluate patients with indeterminate biliary strictures. However, guidelines from the British Association for the Study of the Liver (BASL) and American Association for the Study of Liver Diseases (AASLD) discuss the role of ERCP in the diagnosis and management of cholangiocarcinoma and PSC, respectively. 6,23 In both of these documents, the use of crosssectional imaging (CT, magnetic resonance imaging/magnetic resonance cholangiopancreatography) and EUS are favored over purely diagnostic ERCP, unless concomitant tissue acquisition or biliary drainage is needed. While ERCP provides access to the

4 742 COTÉ AND SHERMAN CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 9 biliary tree for different diagnostic modalities (cholangioscopy, site-directed biopsy, brushing, intraductal biopsy, intraductal FNA, FISH, intraductal ultrasound), none of these have proven to be the panacea for providing a definitive diagnosis of malignancy. Recommendations The diagnostic and therapeutic strategy for each patient with a biliary stricture and negative cytology should be individualized. In our estimation, there are 3 pertinent questions to guide diagnostic and therapeutic decision-making. 1. What Is the Likelihood of Malignancy? Perhaps the greatest challenge in patients with biliary obstruction is determining their risk of underlying malignancy. For PSC patients, new onset jaundice, interval development of a dominant stricture, or an increased/elevated CA19-9 should raise the clinical suspicion for cancer. Among non-psc patients, the absence of a clear benign etiology (eg, recent cholecystectomy), older age, jaundice at presentation, underlying chronic liver disease, and an elevated CA19-9 portend a greater cancer risk. If ERCP is performed, careful attention to the characteristics of the stricture may affect the level of suspicion: cholangiography alone is reasonably sensitive (66%) for predicting malignancy when a classic shelf-like obstruction is identified. 20 If an ominous-appearing stricture is identified during the initial ERCP and the clinical history is concerning (eg, unexplained weight loss, painless jaundice, older age, concomitant liver disease), then a negative brushing should not reassure the treating physician given the high pretest probability; further testing or direct surgical referral may be appropriate. 2. Is the Patient a Reasonable Surgical Candidate? If the answer to this question is yes, then we recommend early referral to a liver transplant surgeon (PSC patients) or hepatobiliary-pancreatic surgeon (non-psc patients). Among patients with a very high pretest probability of malignancy and reasonable operative risk, exploratory laparoscopy may be preferred over additional diagnostic testing. The threshold for surgery is likely to change with advances in nonsurgical treatment modalities for cholangiocarcinoma. 3. Does the Patient Have Clinical Manifestations of Biliary Obstruction? Preoperative biliary drainage of common bile duct strictures appears unlikely to have an impact on postoperative complications in patients with mild jaundice. 24 In the absence of deeper jaundice (typically defined as a serum total bilirubin of 12.0 mg/dl), the therapeutic role of ERCP with stent placement may be limited. The use of unilateral, bilateral, or no preoperative drainage of hilar strictures requires further study. Therefore, before committing the patient to the risks of ERCP, the need for preoperative tissue confirmation and alternative diagnostic tests (eg, EUS) should be considered. Therefore, ERCP may be deferred in favor of EUS-FNA or direct surgical exploration (particularly in the setting of a discrete mass on cross-sectional imaging) in these cases, depending on the suspicion for malignancy and potential for surgical resection. Among non-psc patients with highly suspicious biliary strictures, early surgery is a reasonable approach. Case Summary Given a high pretest suspicion for malignancy (new dominant stricture, abrupt onset of jaundice), the patient had a Figure 2. Suggested diagnostic algorithm for patients with an indeterminate stricture and absence of a discrete mass on cross sectional imaging. In patients with a high clinical suspicion of malignancy, consider early surgical consultation. Defined as 2 cm from the hepatic confluence.

5 September 2011 BILIARY STRICTURE AND NEGATIVE CYTOLOGY 743 repeat ERCP at our institution with brushings for cytology and FISH. While routine cytology only demonstrated mildly atypical cells, FISH identified polysomy in chromosomes 3, 7, and 17. FISH findings were confirmed during a third ERCP, at which time intraductal biopsies revealed no confirmation of malignancy. Nevertheless, the patient underwent a staging laparoscopy to confirm the absence of adenocarcinoma in her portal lymph nodes; she subsequently completed neoadjuvant chemoradiation following by orthotopic liver transplant based on the Mayo protocol. 25 Her liver explant demonstrated adenocarcinoma in situ in her extrahepatic biliary tree. Conclusions There are a multitude of nonoperative tools to evaluate indeterminate biliary strictures: tumor markers, cross sectional imaging, EUS-FNA, and a variety of ERCP-based techniques. Unfortunately, each has their advantages and limitations. As a result, a rational approach to their utilization is needed. In our practice, we typically follow a diagnostic algorithm based on: (1) the presence of PSC, and (2) the location of non-psc strictures (Figure 2). Our proposed algorithm may change dramatically with further advances in direct cholangioscopy, molecular imaging, and tissue acquisition methods. Until that time, each patient with an indeterminate bile duct stricture requires a multidisciplinary approach with the goals of maximizing sensitivity for detecting malignancy in the most cost-effective manner. Suggested Reading 1. Lee JG, Leung JW, Baillie J, et al. Benign, dysplastic, or malignant making sense of endoscopic bile duct brush cytology: results in 149 consecutive patients. Am J Gastroenterol 1995; 90: Glasbrenner B, Ardan M, Boeck W, et al. Prospective evaluation of brush cytology of biliary strictures during endoscopic retrograde cholangiopancreatography. Endoscopy 1999;31: Fogel EL, debellis M, McHenry L, et al. Effectiveness of a new long cytology brush in the evaluation of malignant biliary obstruction: a prospective study. Gastrointest Endosc 2006;63: Goonetilleke KS, Siriwardena AK. Systematic review of carbohydrate antigen (CA 19 9) as a biochemical marker in the diagnosis of pancreatic cancer. Eur J Surg Oncol 2007;33: Levy C, Lymp J, Angulo P, et al. The value of serum CA 19 9 in predicting cholangiocarcinomas in patients with primary sclerosing cholangitis. Dig Dis Sci 2005;50: Khan SA, Davidson BR, Goldin R, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut 2002;51;Suppl 6:VI1 VI9. 7. Dumonceau JM, Macias Gomez C, Casco C, et al. Grasp or brush for biliary sampling at endoscopic retrograde cholangiography? A blinded randomized controlled trial. Am J Gastroenterol 2008; 103: de Bellis M, Fogel EL, Sherman S, et al. Influence of stricture dilation and repeat brushing on the cancer detection rate of brush cytology in the evaluation of malignant biliary obstruction. Gastrointest Endosc 2003;58: Logrono R, Kurtycz DF, Molina CP, et al. Analysis of false-negative diagnoses on endoscopic brush cytology of biliary and pancreatic duct strictures: the experience at 2 university hospitals. Arch Pathol Lab Med 2000;124: Harewood GC, Baron TH, Stadheim LM, et al. Prospective, blinded assessment of factors influencing the accuracy of biliary cytology interpretation. Am J Gastroenterol 2004;99: Jailwala J, Fogel EL, Sherman S, et al. Triple-tissue sampling at ERCP in malignant biliary obstruction. Gastrointest Endosc 2000; 51: Wright ER, Bakis G, Srinivasan R, et al. Intraprocedural tissue diagnosis during ERCP employing a new cytology preparation of forceps biopsy (Smash protocol). Am J Gastroenterol 2011;106: Rabinovitz M, Zajko AB, Hassanein T, et al. Diagnostic value of brush cytology in the diagnosis of bile duct carcinoma: a study in 65 patients with bile duct strictures. Hepatology 1990;12: DeWitt J, Devereaux B, Chriswell M, et al. Comparison of endoscopic ultrasonography and multidetector computed tomography for detecting and staging pancreatic cancer. Ann Intern Med 2004;141: LeBlanc JK, Ciaccia D, Al-Assi MT, et al. Optimal number of EUS-guided fine needle passes needed to obtain a correct diagnosis. Gastrointest Endosc 2004;59: Mohamadnejad M, DeWitt JM, Sherman S, et al. Role of EUS for preoperative evaluation of cholangiocarcinoma: a large singlecenter experience. Gastrointest Endosc 2011;73: DeWitt J, Misra VL, Leblanc JK, et al. EUS-guided FNA of proximal biliary strictures after negative ERCP brush cytology results. Gastrointest Endosc 2006;64: Levy MJ, Baron TH, Clayton AC, et al. Prospective evaluation of advanced molecular markers and imaging techniques in patients with indeterminate bile duct strictures. Am J Gastroenterol 2008; 103: Bangarulingam SY, Bjornsson E, Enders F, et al. Long-term outcomes of positive fluorescence in situ hybridization tests in primary sclerosing cholangitis. Hepatology 2010;51: Tischendorf JJ, Krüger M, Trautwein C, et al. Cholangioscopic characterization of dominant bile duct stenoses in patients with primary sclerosing cholangitis. Endoscopy 2006;38: Chen YK, Pleskow DK. SpyGlass single-operator peroral cholangiopancreatoscopy system for the diagnosis and therapy of bileduct disorders: a clinical feasibility study (with video). Gastrointest Endosc 2007;65: National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Hepatobiliary cancers. Version Available at: pdf/hepatobiliary.pdf. Accessed March 14, Chapman R, Fevery J, Kalloo A, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology 2010;51: van der Gaag NA, Rauws EA, van Eijck CH, et al. Preoperative biliary drainage for cancer of the head of the pancreas. N Engl J Med 2010;362: Rea DJ, Heimbach JK, Rosen CB, et al. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg 2005;242: ; Discussion:8 61. Reprint requests Address requests for reprints to: Gregory Coté MD, MS, Indiana University School of Medicine, 550 N. University Boulevard, UH 4100, Indianapolis, Indiana gcote@iupui.edu; fax: (317) Conflicts of Interest The authors disclose the following: Dr Coté is a consultant for Boston Scientific Corp and has recieved honoraria from Olympus, America. Dr Sherman has received honoraria from Boston Scientific Corp, Olympus America, Repligen, and Cook.