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Fluorescent in situ hybridization testing in primary sclerosing cholangitis: Useful testing or a random chance result?

Primary sclerosing cholangitis (PSC) has long been recognized as a predisposing factor for the development of cholangiocarcinoma, although the causative risk factors remain largely unknown. By definition, patients with PSC have fibrosing inflammatory strictures of the biliary tract, usually multiple and diffuse, that may affect the intrahepatic and/or extrahepatic biliary tree. This process leads to progressive cholestatic liver disease, which may cause unremitting pruritus, cholangitis, and ultimately liver failure. Liver transplantation is the only known curative therapy, and is usually very effective. Approximately 5%-10% of patients undergoing liver transplantation at most centers have PSC as the indication, with reported 10-year survival rates approaching 80% in many reports.1 The risk of developing cholangiocarcinoma in the setting of PSC has been well recognized for many years, and is now a dreaded complication feared by patients with PSC, their families, and their physicians. Although the lifetime risk of developing cholangiocarcinoma in patients with PSC is estimated to be more than 1500 times greater than in the non-PSC population,2 it is also equally clear that “early” liver transplantation should not be undertaken, because the risks of this complex procedure and life-long immunosuppression outweigh any potential risk of cancer reduction. The estimated risk of development of cholangiocarcinoma in patients with PCS is approximately 1% per year over 10 years and a cumulative lifetime risk of 9%-31%,3 but the mortality risk after liver transplantation is approximately 10% in the first year alone. The challenge therefore, is how best to perform adequate surveillance testing for the detection of earlystage cholangiocarcinoma in patients with PSC but who do not otherwise need liver replacement therapy. Unlike for non-PSC patients with biliary tract strictures, the development of strictures in the setting of PSC is usually part of the natural history and not unexpected. In addition, confirmation of this malignancy may be one of the most difficult challenges in all solid organ malignancies, because access is highly restricted, direct biopsies are difficult to obtain, and cytologic assessment with brush analysis is frequently falsely negative, probably related to the desmoplastic reaction so frequently associated with such tumors. Based on the significant diagnostic challenges of standard biopsy techniques and low sensitivity of cytology for hilar cholangiocarcinoma, investigators at the Mayo Clinic have spearheaded efforts to develop additional techniques to improve diagnostic accuracy in this malignancy. In particular, the use of digital image analysis and fluorescent in situ hybridization (FISH) have been investigated for a variety of malignancies of the liver, biliary tract, and pancreas,4-8 and multivariate modeling using these advanced techniques has been proposed for use in indeterminate biliary strictures.9 Of note, the testing and validation of FISH in cholangiocarcinoma including the specific probes and assessment techniques has largely taken place in patients who were selected for investigation based on a high likelihood of cholangiocarcinoma. In this issue of HEPATOLOGY, Bangarulingam et al. report their experience in a large cohort of patients with PSC, all of whom were undergoing endoscopic retrograde cholangiopancreatography (ERCP) for management of PSC, but many apparently without dominant strictures or mass lesions on cross-sectional imaging to support a diagnosis of cholangiocarcinoma.10 A total of 235 patients with PSC underwent one or more FISH analyses over an almost 5-year time period, among whom 56 (24%) patients had biopsy or cytologic evidence of cholangiocarcinoma during the period of study. Although 120/235 (51%) of patients had a positive FISH test at some point during the period of study, only one-third (40/120, 33%) of these were ultimately diagnosed with cholangiocarcinoma by tissue analysis. Put another way, two-thirds (80/120, 66%) of the patients with a positive FISH did not have cholangiocarcinoma. The authors note the very low sensitivity and specificity of tetrasomy or trisomy FISH results: only 14/73 (19%) FISH-positive Abbreviations: ERCP, endoscopic retrograde cholangiopancreatography; FISH, fluorescent in situ hybridization; PSC, primary sclerosing cholangitis. Address reprint requests to: William C. Chapman, M.D., Professor and Chief, Division of General Surgery, Chief, Section of Transplantation, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8109, St. Louis, MO 63110. E-mail: chapmanw@wustl.edu; fax: 314-361-4197. Copyright © 2009 by the American Association for the Study of Liver Diseases. Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hep.23457 Potential conflict of interest: Nothing to report.