EDUCATION PRACTICE. Primary Sclerosing Cholangitis: Patients With a Rising Alkaline Phosphatase at Annual Follow-up.

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2007;5:32 36 EDUCATION PRACTICE Primary Sclerosing Cholangitis: Patients With a Rising Alkaline Phosphatase at Annual Follow-up PHUNCHAI CHARATCHAROENWITTHAYA and KEITH D. LINDOR Mayo Clinic College of Medicine, Rochester, Minnesota See Alvaro D, et al on page 415 for companion article in Gastroenterology. Clinical Scenario A 45-year-old man with chronic ulcerative colitis of 10 years duration and primary sclerosing cholangitis (PSC) is referred for elevated alkaline phosphatase level, detected in a routine blood test performed by the primary care physician. Review of a chemistry group from 2 years previously showed that the alkaline phosphatase level had doubled. The patient is concerned about the risk of cholangiocarcinoma in the setting of PSC with an increase in the level of alkaline phosphatase. The diagnosis of PSC was established about 3 years earlier when he had abnormal liver biochemical test results and cholangiographic findings consistent with disease. He had been on ursodeoxycholic acid at a daily dosage of 13 mg/kg. Regular follow-up surveillance colonoscopies showed no evidence of dysplasia. The patient is active at work and asymptomatic. He denies pruritus, fatigue, abdominal pain, fever, or bleeding. He has had substantial weight loss since starting an exercise and dietary modification program. Physical examination reveals a liver span of 8 cm. There are no spider angiomas, splenomegaly, ascites, or peripheral edema. Laboratory evaluation shows ALT of 72 U/L (normal, U/L), AST of 54 U/L (normal, U/L), alkaline phosphatase of 480 U/L (normal, U/L), albumin of 3.8 g/dl, and total bilirubin of 0.9 mg/dl. A complete blood count and coagulation parameters are normal. How should you counsel this patient with PSC and chronic ulcerative colitis regarding progression of PSC and the effect of ursodeoxycholic acid therapy on his liver? What should be the strategy to diagnose or exclude cholangiocarcinoma in this patient? Specifically, is there a role for serum markers for diagnosis of cholangiocarcinoma in PSC patients, and what is the accuracy of the various radiologic modalities and endoscopic methods available for the detection of cholangiocarcinoma complicating PSC? Do biliary brush cytology, advanced cytologic techniques, and endobiliary biopsy add significantly to the diagnosis of cholangiocarcinoma in patients with PSC? The Problem Primary sclerosing cholangitis (PSC) is characterized by diffuse inflammation and fibrosis of the biliary tree and usually leads to biliary cirrhosis, which can be complicated by portal hypertension and hepatic failure. The etiology of PSC remains unknown, although autoimmunity, effects of cytokines, infections, and abnormalities in bile acid transporter or ion channels might be underlying causes of PSC. PSC is closely associated with IBD, and approximately 75% of patients with PSC have coexisting IBD. In addition, 2.4% 7.5% of patients with IBD in Western countries have PSC. With the recognized association of PSC with IBD, screening biochemical tests to identify cholestasis, improvement in endoscopic techniques, and availability of noninvasive imaging of the biliary tree, there are an increasing number of patients with PSC who are being diagnosed during the asymptomatic stage of the disease. The overall incidence is cases per 100,000 person-years in the United States and in Northern Europe but less than 0.1 cases per 100,000 personyears in Southern Europe and Asia. The point prevalence of PSC in 2000 was 13.6 cases per 100,000 persons in the United States. Because of the progressive course of disease, frequent development of life-threatening complications, and the lack of effective therapy, PSC is an increasingly significant health care problem. Yet the optimal means of diagnosis, monitoring, and therapy for PSC and its complications are unclear. Clinical Course of Patients With Primary Sclerosing Cholangitis PSC usually is a progressive disease, eventually leading to cirrhosis, liver failure, and death at a median of years from time of diagnosis. Mortality is greater than for an agematched United States population. However, estimates of time to liver failure in any given patient can be difficult because of the unknown duration of subclinical disease. To provide more accurate individualized prognostic information and to assess the need of liver transplantation, various prognostic models based on actual data obtained from patients at a given point in time have been developed. The revised Mayo PSC risk score, which is based on the variables of age, bilirubin, albumin, AST, and variceal bleeding, has been independently cross-validated to predict median survival for individual patients (Web-based calculator available at Abbreviations used in this paper: CA, carbohydrate antigen; CEA, carcinoembryonic antigen; CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasound; MRI, magnetic resonance imaging; MRCP, magnetic resonance cholangiopancreatography; PET, positron emission tomography; PSC, primary sclerosing cholangitis by the AGA Institute /07/$32.00 doi: /j.cgh

2 January 2007 PSC: RISING ALKALINE PHOSPHATASE AT ANNUAL FOLLOW-UP 33 html). The majority of patients are initially asymptomatic, despite widespread cholangiographic involvement and advanced histology at the time of diagnosis. Seventeen percent of asymptomatic patients and 50% of symptomatic patients have cirrhosis on liver biopsy at the time of diagnosis. Symptomatic patients might have recurrent episodes of fever, jaundice, right upper quadrant pain, or itching. Episodes of fever might occur without an association with bacterial cholangitis and resolve spontaneously without antibiotics. Complications specific to PSC include bacterial cholangitis, biliary tract calculi, dominant biliary strictures, and cholangiocarcinoma. Approximately 5% 15% of patients have intermittent episodes of bacterial cholangitis especially after biliary interventions. If acute cholangitis occurs in a patient who has not had a recent biliary intervention, the presence of choledocholithiasis, dominant strictures, or bile duct cancer should be considered, prompting cholangiography. Dominant strictures occur in approximately 10% of patients with PSC during the natural course of disease. It is usually difficult to differentiate between a dominant benign stricture and malignant stricture caused by cholangiocarcinoma, especially in patients with long segment stenosis. Moreover, malignancies can arise from longstanding benign strictures. If a dominant stricture is found, brush cytologic specimens and biopsy of the biliary stricture should be obtained. Cholangiocarcinoma develops in 10% 15% of patients and can occur relatively early and before onset of cirrhosis. Nearly half of cholangiocarcinomas are diagnosed in individuals within 1 2 years of identifying PSC. Thereafter, the estimated annual risk is 0.5% 1.5%. Development of cholangiocarcinoma, however, appears to be independent of duration of PSC or IBD. The prognosis of patients with cholangiocarcinoma is dismal. Most of the patients are diagnosed in advanced stages, and median survival is 3 6 months if unresectable. Management Strategies and Supporting Evidence What Is the Diagnostic Strategy of Cholangiocarcinoma in Patient With Primary Sclerosing Cholangitis? Cholangiocarcinoma might be the initial presentation of PSC, and approximately 5% of all cholangiocarcinomas are multifocal. About two thirds of cholangiocarcinomas are localized to the perihilar region, one quarter arise from the distal extrahepatic duct, and the remainder are found in the intrahepatic ducts. Intrahepatic cholangiocarcinomas often present with advanced disease or might be diagnosed incidentally on abdominal imaging studies. Perihilar or extrahepatic cholangiocarcinoma commonly presents with cholestasis caused by biliary tract obstruction. However, differentiation of cholangiocarcinoma from preexisting PSC is difficult because the clinical presentation of cholangiocarcinoma can be similar to advanced stage PSC. Clinically, cholangiocarcinoma should be suspected when PSC patients exhibit rapid, progressive liver disease with worsening jaundice, weight loss, and abdominal pain. Occasionally paraneoplastic phenomena might occur, such as thrombotic events or hypercalcemia. Moreover, liver biochemical tests in PSC patients complicated with cholangiocarcinoma usually reveal cholestasis with marked elevations in alkaline phosphatase and/or bilirubin levels but are nonspecific and not helpful in establishing the diagnosis. Despite evaluation before liver transplantation, 9% 21% of PSC patients are incidentally found to have cholangiocarcinoma at the time of transplantation. The diagnosis of cholangiocarcinoma in patients with PSC requires a multidisciplinary approach with high clinical suspicion, tumor marker testing, appropriate imaging studies, and tissue sampling. Confirmatory histology and/or cytology should be obtained if at all possible. However, for patients with potentially curable surgery (radical tumor resection or liver transplantation), open or percutaneous biopsy is not recommended because of risk of tumor seeding. Once a biliary tract tumor is suspected, comprehensive staging must be carried out to screen for metastatic disease. Are Serum Markers Useful for Detection of Cholangiocarcinoma in Primary Sclerosing Cholangitis? Serum tumor markers are attractive, can be easily repeated over time, and have relatively low costs. Although several have been studied, there is no tumor marker considered specific for cholangiocarcinoma. Serum carbohydrate antigen (CA) 19-9 might be helpful for differentiation of cholangiocarcinoma complicating PSC from a benign dominant stricture in PSC. The majority of studies assessing the test properties of CA19-9 in PSC patients with relatively Table 1. Serum CA19-9 and CEA for Detecting Cholangiocarcinoma in Patients With PSC Author No. of PSC without CC No. of PSC with CC Serum marker Cutoff value of CA19-9 (U/mL), CEA (ng/ml) Sensitivity (%) Specificity (%) Positive predictive vaue Negative predictive value 200, 5; Nichols, CA19-9, CEA 100, 5 89, 38 86, 100,, Fisher, CA Ramage, CA19-9, CEA; 60, 53; 91, 86;, ;, ; Ramage score a Bjornsson, CA19-9, CEA; Ramage score 37, 5; , 33; 33 50, 85; 85 16, 29; 29 90, 88; 88 Chalasani, CA Siqueira, , , 25 CA19-9, CEA 180, , 68 98, 82,, Lindberg, CA19-9, CEA; Ramage score 100, 5; , 100; 71 90, 100; 90 88, 100; , 100; 82 Levy, CA , 129, or , 79, or 71 97, 99, or 99 44, 79, or 64 99, 99, or 99 CC, cholangiocarcinoma. a Ramage score: CA19-9 [CEA 40].

3 34 CHARATCHAROENWITTHAYA AND LINDOR CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 5, No. 1 advanced malignancy involved a relatively small sample; with a sensitivity ranging from 60% 100%; specificity was 50% 99% (Table 1). High CA19-9 levels have a high specificity but low sensitivity and detect only advanced disease. CA19-9 detects glycoproteins coated with sialylated blood group epitopes like sialyl Lewis. Thus, patients who are Lewis-negative have undetectable CA19-9 levels. Elevated CA19-9 levels can be detected in nonbiliary cancers (such as pancreatic and gastric cancer) or in nonmalignant conditions such as bacterial cholangitis. Because cholestasis itself might enhance expression of the marker, interpreting an elevated CA19-9 level in this setting is difficult. Carcinoembryonic antigen (CEA) has a lower diagnostic yield than CA19-9 in cholangiocarcinoma. Serum CEA levels greater than 5 ng/ml had sensitivity of 33% 68% and specificity of 82% 89% (Table 1). Combination of testing for CA19-9 and CEA or serial testing for tumor markers might increase sensitivity, but with an increase in false-positive results. In summary, there is no evidence that measurement of tumor markers is useful for monitoring tumor development or progression of cholangiocarcinoma in PSC. What Radiologic/Endoscopic Techniques Are Useful in Detecting Cholangiocarcinoma in Primary Sclerosing Cholangitis? In evaluating a PSC patient with suspected cholangiocarcinoma, radiologic methods are useful for localizing and characterizing the lesion, staging, and determining resectability. Cholangiocarcinoma should be suspected when a polypoid mass, progressive or marked dilatation of the bile duct, a thickened bile duct wall, or dominant ductal stricture is detected. Comparison with previous imaging is essential to detect progression of disease and the presence of complicating cholangiocarcinoma. Importantly, clinicians should be aware that abdominal lymphadenopathy is common in patients with PSC and is usually not a sign of malignancy or metastasis. Ultrasonography. Ultrasonography is commonly the initial imaging study. However, transabdominal ultrasonography is operator-dependent, and has low sensitivity. Intrahepatic cholangiocarcinoma appears as homogenously hyperechoic mass lesion. Hilar or extrahepatic cholangiocarcinoma might be present with intrahepatic bile duct dilatation. However, dilatation might not occur because of generalized periductal inflammation and fibrosis in PSC. Computed tomography. In suspected cholangiocarcinoma, computed tomography (CT) and/or magnetic resonance imaging (MRI) should be performed. The helical CT technique has improved visualization of anatomic details and allows multiphasic imaging after intravenous contrast injection. Intrahepatic tumors appear as hypoattenuating masses with irregular margins and various degrees of segmental intrahepatic bile duct dilatation. Delayed phase contrast enhancement within the lesion can be indicative of biliary tract tumor. Perihilar or distal extrahepatic cholangiocarcinoma typically causes dilated extrahepatic and intrahepatic bile ducts, but it might be difficult to visualize masses because of the infiltrative nature of the tumor. CT scans provide information about vascular involvement, extrahepatic invasion, and lymphadenopathy, information that is essential for determining the resectability of cholangiocarcinoma. Atrophy of the ipsilateral lobe with hypertrophy of the contralateral (atrophy-hypertrophy complex) suggests portal vein invasion. In a study evaluating the efficacy of CT for detecting cholangiocarcinoma complicating PSC, the average sensitivity and specificity of CT were 82% and 80%. Magnetic resonance imaging. Magnetic resonance imaging (MRI) including magnetic resonance cholangiopancreatography (MRCP) is theoretically attractive because it provides both cross-sectional imaging and noninvasive cholangiography. MRI is now recommended as the optimal initial investigation for suspected cholangiocarcinoma in many centers. On MRI, peripheral intrahepatic and perihilar cholangiocarcinoma appear hypodense on T1-weighted images and hyperdense on T2-weighted images. With dynamic MRI, cholangiocarcinoma shows moderate peripheral enhancement followed by progressive and concentric filling. Cholangiography. The diagnosis of cholangiocarcinoma often requires visualization of the biliary tract. However, it is often difficult to distinguish between benign and malignant strictures on the basis of cholangiographic findings. Cholangiographic findings suggestive of complicating bile duct carcinoma include a polypoid lesion, new onset or progressive stricture formation, and marked bile duct dilatation. Endoscopic retrograde cholangiopancreatography (ERCP) is accepted as the gold standard for delineation of the biliary tract. Unfortunately, complications occur in 3% 8% and include pancreatitis, biliary sepsis, bleeding, and intestinal or bile duct perforation. ERCP is frequently limited by the multiplicity of bile duct strictures and inadequate opacification of the ducts proximal to high-grade stenosis. Pros and cons of magnetic resonance cholangiopancreatography versus endoscopic retrograde cholangiopancreatography. A noninvasive examination that allows high-quality imaging of the biliary tract without the associated risks would be preferable in the diagnosis and surveillance of cholangiocarcinoma in PSC patients. MRCP can accurately assess the level of bile duct involvement and is as accurate as ERCP. MRCP has the advantage of showing ducts proximal to high-grade strictures and changes within the wall as well as allowing visualization in patients with biliary or gastrointestinal surgical procedures. Increased reliance on MRCP might allow less frequent use of ERCP. The shortcoming of MRCP is that it is purely diagnostic; not allowing any additional diagnostic or therapeutic interventions. In contrast, direct cholangiography (endoscopic or percutaneous) allows biliary tissue sampling and therapy such as dilatation or placement of stents. Of the 2 direct approaches to cholangiography, ERCP is preferred in patients with PSC because the presence of strictures increases the technical difficulty of percutaneous transhepatic cholangiography. Prophylaxis for bacterial cholangitis should be considered in the care of patients with PSC undergoing biliary manipulation. Endoscopic ultrasound. Endoscopic ultrasound (EUS) can be useful for the evaluation of distal bile duct lesions, vascular structures, and regional lymphadenopathy. EUS allows directed biopsies of mass lesions and lymph nodes for determining the presence of cholangiocarcinoma and lymph node metastasis, which have an influence on the clinical management. However, most studies have been performed in non-psc

4 January 2007 PSC: RISING ALKALINE PHOSPHATASE AT ANNUAL FOLLOW-UP 35 patients; therefore the role of EUS in identifying cholangiocarcinoma in PSC patients remains unclear. Direct endoscopic visualization of the biliary tract might be useful for tissue sampling from suspected lesions, but it is not widely available and requires further evaluation. Positron emission tomography. Positron emission tomography (PET) is based on accumulation of positron-emitting radiolabeled tracers in cholangiocarcinoma cells relative to hepatocytes, detected as hot spots by nuclear imaging. PET was proposed as a sensitive test for the detection of small cholangiocarcinomas and evaluates metastatic disease. Nonetheless, a recent study showed that PET was unreliable for the early diagnosis of cholangiocarcinoma, especially the infiltrative type in PSC patients. In addition, false-negative results are likely to occur because the tumor is less cellular, and false-positive results can also occur in patients with cholangitis or those with a stent in situ. In summary, patients with PSC and suspected cholangiocarcinoma should have an initial ultrasound followed by combined MRI and MRCP in cases with a heightened index of suspicion of biliary tract tumor. Where MRI/MRCP is not available, patients should have contrast enhanced spiral/helical CT. Invasive cholangiography should be reserved for tissue diagnosis or therapeutic interventions in which there is cholangitis, or stent insertion in unresectable cancer cases. All of these methods might be complementary, and in some patients all are necessary as part of the assessment of the feasibility of surgical intervention. What Is the Clinical Utility of Brush Cytology, Advanced Cytologic Techniques, and Endoscopic Biopsies? Tissue diagnosis of cholangiocarcinoma in patients with PSC is notoriously difficult because of the intense desmoplastic nature of the tumor. Biliary brushing cytology has become the method of choice for evaluating biliary tract strictures. Although specificity is high, sensitivity rates for malignancy are low, in the range of 30% 70% in PSC patients with the wide variations attributed to sampling, quality of the cytologic material, interpretation, and the expertise of the cytopathologist. Negative cytology from brushings does not exclude malignancy. The diagnostic yield of brush cytology might be increased with disruption of the stricture by dilatation, use of thin-preps, or new brush designs. Furthermore, combined biliary brush cytology and biopsy specimens increase the yield to 40% 70%. The addition of immunohistochemistry for p53 and K-ras mutation analysis has not increased the yield of cytology. Aneuploidy is a common feature of cholangiocarcinoma that might play a role in carcinogenesis in PSC and might appear before development of cholangiocarcinoma. It is hoped that advanced cytologic techniques such as digital image analysis techniques to evaluate for aneuploidy and the use of fluorescent in situ hybridization to identify cellular chromosomal aberrations might improve the diagnostic yield of brushings and aspirate specimens with limited cellularity obtained from biliary strictures. In the Mayo Clinic experience, the combination of digital image analysis and fluorescent in situ hybridization as a complementary approach for the diagnosis of cholangiocarcinoma in PSC patients with normal cytology has a sensitivity of 22% while retaining a specificity of 98%. Areas of Uncertainty Surveillance Programs of Cholangiocarcinoma in Patients With Primary Sclerosing Cholangitis The purpose of surveillance is to recognize cholangiocarcinoma at an early stage, when the tumor potentially is curable, and consequently to decrease tumor-related mortality. At present, cholangiocarcinoma does not satisfy the established criteria to recommend a surveillance program because (1) there is no clear risk factor associated with the development of cholangiocarcinoma in patients with PSC, (2) there is no noninvasive and accurate diagnostic strategy, (3) the established effective therapy is limited, and (4) there is no information about cost-effectiveness of the diagnostic strategy for the detection of cholangiocarcinoma in patients with PSC. Surveillance programs for early detection of cholangiocarcinoma should target a well-selected population at risk, because surveillance is extremely costly with huge economic implications. Risk factors for cholangiocarcinoma in PSC patients are not well-defined. Smoking and the presence of IBD might be predisposing risk factors, although these associations are controversial. Cohort studies in PSC patients to identify risk factors for this complication are warranted. The survival of PSC patients with cholangiocarcinoma is poor because early detection and treatment of cholangiocarcinoma are limited. Unfortunately, only a few patients diagnosed with tumor are potential candidates for cure by resection or liver transplantation. Moreover, data regarding the cost-effectiveness of surveillance for biliary tract tumors in patients with PSC are lacking. Large-scale long-term studies are required to assess the cost-effectiveness of various strategies. Published Guidelines The recent practice guidelines of the American College of Gastroenterology on the management of PSC address clinical features and management of chronic cholestasis and its complications including dominant biliary strictures and cholangiocarcinoma. These guidelines did not recommend a diagnostic strategy of screening cholangiocarcinoma in patients with PSC. However, these committees have addressed a controversial issue about surveillance guidelines for early detection of cholangiocarcinoma in patients with PSC. Currently, a consensus approach to the evaluation of cholangiocarcinoma has been proposed by the British Association for the Study of the Liver in These guidelines supporting the diagnosis of cholangiocarcinoma require multiple complementary studies. However, there is no specific consensus for the optimal diagnosis and treatment of cholangiocarcinoma in patients with PSC. Recommendations This patient should be counseled that PSC is a progressive disease, eventually leading to cirrhosis, liver failure, and death. On the basis of the revised Mayo PSC risk score, this patient is estimated to have a 1-year survival probability of 98% and 4-year survival probability of 92%. Ursodeoxycholic acid has not yet been proved to make a substantial change in the course of the disease. However, it might yet prove to be sufficiently effective in the prevention of colorectal neoplasia in PSC-IBD setting. Thus, this patient might be prescribed the drug for this reason alone. He should be counseled that PSC is a condition strongly predisposing for development of cholangiocarcinoma, which might

5 36 CHARATCHAROENWITTHAYA AND LINDOR CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 5, No. 1 Figure 1. Proposed diagnostic algorithm for cholangiocarcinoma in patients with PSC. Patients should be followed up annually and a CA19-9 level and an ultrasound evaluation obtained. If patient has changes in biochemical profile, persistently elevated CA19-9 levels, or presence of ultrasonographic evidence of biliary tract tumor, we recommend MRCP as the initial investigation and then proceed to ERCP if additional information or intervention such as tissue sampling is needed. If patients have deterioration in the clinical condition, patients should raise suspicion of cholangiocarcinoma and are candidates for ERCP with appropriate endoscopic intervention and cytologic testing. For patients with questionable cytohistologic findings, we recommend scheduled surveillance that combines the traditional tests with cholangiography and tissue sampling. develop with an estimated annual risk of 0.5% 1.5%. This patient is asymptomatic with elevation of alkaline phosphatase levels during annual follow-up. He has no clinical suspicion of cholangiocarcinoma or biliary tract obstruction. There is no specific guideline published to address this issue. Expert opinion, however, suggests following alkaline phosphatase levels at 3- to 6-month intervals. If the patient has persistent increase in alkaline phosphatase levels more than 50% above baseline, cholangiography should be performed to detect biliary abnormalities. In this patient, further serum CA19-9 testing and a crosssectional imaging of upper abdomen such as ultrasonography should be performed. In this initial evaluation, serum CA19-9 level was 20 U/mL, and abdominal ultrasound revealed no liver mass and bile duct dilatation. We therefore recommend monitoring liver biochemistries at 3-month intervals as well as annual followup, with serum CA19-9 level and ultrasound evaluation. If the patient has persistent changes in biochemical profiles, persistently elevated CA19-9 levels, or presence of ultrasonographic evidence of biliary tract tumor during follow-up, we favor MRCP as the initial investigation in an asymptomatic patient and then proceed to ERCP if additional information or intervention such as tissue sampling is needed as indicated in the proposed diagnostic algorithm in Figure 1. If the patient has deterioration in the clinical condition such as new onset of fever, sudden worsening of jaundice, unexplained weight loss, persistent upper abdominal pain, or intractable pruritus, suspicion of cholangiocarcinoma should be raised, and he should undergo ERCP with appropriate endoscopic intervention and cytologic testing. If the patient s biliary cytology shows atypia, we recommend scheduled surveillance that combines the traditional tests with cholangiography and biliary tissue sampling. The choice of modality also will depend on costs, availability, frequency of complication, and operator experience with the different methods. Suggested Reading 1. Levy C, Lindor KD. Primary sclerosing cholangitis: epidemiology, natural history, and prognosis. Semin Liver Dis 2006;26: Reddy SB, Patel T. Current approaches to the diagnosis and treatment of cholangiocarcinoma. Curr Gastroenterol Rep 2006; 8: Nehls O, Gregor M, Klump B. Serum and bile markers for cholangiocarcinoma. Semin Liver Dis 2004;24: Lee WJ, Lim HK, Jang KM, et al. Radiologic spectrum of cholangiocarcinoma: emphasis on unusual manifestations and differential diagnoses. Radiographics 2001;21: Kipp BR, Stadheim LM, Halling SA, et al. A comparison of routine cytology and fluorescence in situ hybridization for the detection of malignant bile duct strictures. Am J Gastroenterol 2004;99: Baron TH, Harewood GC, Rumalla A, et al. A prospective comparison of digital image analysis and routine cytology for the identification of malignancy in biliary tract strictures. Clin Gastroenterol Hepatol 2004;2: Lazaridis KN, Gores GJ. Primary sclerosing cholangitis and cholangiocarcinoma. Semin Liver Dis 2006;26: Lee YM, Kaplan MM, Practice Guideline Committee of the ACG American College of Gastroenterology. Management of primary sclerosing cholangitis. Am J Gastroenterol 2002;97: Larusso NF, Shneider BL, Black D, et al. Primary sclerosing cholangitis: summary of a workshop. Hepatology 2006;44: 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. Address requests for reprints to: Keith D. Lindor, MD, Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, Minnesota lindor.keith@mayo.edu; fax: (507) Supported by an overseas medical scholarship from the Faculty of Medicine, Siriraj Hospital, Mahidol University (P.C.).