Cholangiocarcinoma in primary sclerosing cholangitis: Who is at risk and how do we screen?

Primary sclerosing cholangitis (PSC) is a chronic liver disease, characterized by inflammation, destruction and fibrosis of the intrahepatic as well as extrahepatic bile ducts, which eventually results in biliary cirrhosis.1,2 The diagnosis is based on a combination of cholestatic liver tests, a characteristic cholangiogram—stenotic areas alternating with areas of dilation—and a liver biopsy specimen showing periportal inflammation, bile duct destruction, cholestasis, and fibrosis. The disease is usually progressive and the only known treatment for advanced, decompensated disease is orthotopic liver transplantation. Cholangiocarcinoma is a relatively uncommon cancer of the biliary tract.3 Originally, cholangiocarcinoma was defined as cancer of the intrahepatic bile ducts, but lately the term also has been used to describe perihilar and distal extrahepatic disease. As in PSC, the diagnosis is based on a combination of cholestatic liver tests and a cholangiogram, which typically shows a high grade or complete bile duct obstruction, in the majority of cases in the perihilar region. Bile samples and ductal brush cytology as well as intraductal biopsies may confirm the diagnosis, but not infrequently do not yield a pathological diagnosis because of the desmoplastic nature of the tumor. It is not hard to imagine that identification of a possible malignant stricture among multiple benign strictures throughout the entire biliary tree is very difficult. First, there are no simple criteria that determine whether a stricture is benign or malignant in patients with PSC. Second, only a minority of patients eventually develop cholangiocarcinoma. Although lifetime risks in excess of 30% have been reported, the risk in most studies is around 10%. 4-6 Third, in a substantial number of cases, cholangiocarcinoma is either the first sign of PSC or is found within 2 years after PSC is diagnosed.5,7 Lastly, in some cases of cholangiocarcinoma ductal changes are so extensive, that the cholangiogram resembles a picture as seen in PSC. It has been my personal experience that a high degree of clinical suspicion and repeated diagnostic procedures (e.g., on a monthly or bimonthly basis) are sometimes needed to make the diagnosis in these patients. Therefore, it would be of great diagnostic help if we could identify early indicators of malignant transformation or—even better—risk factors that predispose patients with PSC to the development of cholangiocarcinoma. Currently, the most frequently used indicator is the serum Cancer Antigen 19-9 (CA 19-9) level. Definite risk factors associated with the development of cholangiocarcinoma are not established for patients with PSC, although age, tobacco use, and intraductal gallstone disease have been reported as risk factors in patients without PSC. In this issue of HEPATOLOGY, Chalasani et al. report the results of a multicenter, case control study aimed at identifying risk factors and indicators of cholangiocarcinoma in patients with PSC. Unlike other studies, they do not find a correlation with a history of smoking8 or evidence of a ‘‘rapid clinical and biochemical deterioration,’’7 but instead report a significant correlation between the development of cholangiocarcinoma and the presence of alcohol consumption. How should we interpret this finding? On the one hand, the findings make sense. Alcohol has been found to be a risk factor for numerous cancers, including cancers of the larynx, esophagus, lung, and breast.9 Alcohol abuse results in cirrhosis and hepatocellular cancer, and alcohol consumption also is known to accelerate the development of cirrhosis and probably hepatocellular cancer in other liver diseases, most notably hepatitis C. Finally, prolonged high alcohol consumption was present in nearly half of 112 patients with cholangiocarcinoma reported by Altaee et al.10 However, one needs to be careful not to over-interpret the findings. First, this is a retrospective study with all its associated flaws, as acknowledged by the authors. It is uncommon to find a group of mostly men of whom 78% never used alcohol. In addition, patients tend to give lower estimates of the amount of alcohol they consume than their family members. In fact, in a prospective study of patients with pancreatic and distal biliary tree cancers, patient and family members disagreed most on the history regarding the consumption of alcoholic drinks.11 Second, the actual numbers in this study were small: 11 of 26 patients with cholangiocarcinoma were using alcohol, where as 17 of 78 used alcohol in the noncancer group. Misclassification of 1 or 2 patients in either group could have made the observed difference nonsignificant. Third, analysis of a dose-response relationship was not possible because of insufficient data. In general, a cause-effect relationship is strengthened by a dose-effect relationship, as has been described for alcohol in other cancers, such as breast cancer.12,13 Furthermore, recent extensive alcohol consumption—that is, within the years immediately leading up to the diagnosis of cancer—may be more important than having ever used alcohol.13,14 Fourth, other investigators have been unable to find a correlation between alcohol consumption and the development of cholangiocarcinoma in patients with PSC.8 Alcohol use is not universally associated with an increased risk for cancer. On Abbreviations: PSC, primary sclerosing cholangitis; CA 19-9, Cancer Antigen 19-9. From the Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN. Received November 1, 1999; accepted November 3, 1999. Address reprint requests to: Piet C. de Groen, M.D., Division of Gastroenterology and Hepatology, Mayo Clinic and foundation, 200 First Street, Rochester, MN 55905. Fax: 507-284-5486. Copyright r 2000 by the American Association for the Study of Liver Diseases. 0270-9139/00/3101-0039$3.00/0