An increasing incidence of cholangiocarcinoma: Why?

Abstract

Shaib YH, Davila JA, McGlynn K, El-Serag HB (Sections of Health Services Research and Gastroenterology, The Houston Veterans Medical Center, Baylor College of Medicine, Houston, Texas; and The National Cancer Institute, National Institutes of Health, Bethesda, Maryland). Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase? J Hepatol 2004;40:472–477.These investigators examined the validity of the reported rising rates of intrahepatic cholangiocarcinoma (ICC) in the United States using data from the Surveillance Epidemiology and End Results (SEER) program and calculating the incidence rates from 1975 to 1999, together with each tumor stage, microscopically confirmed cases, and survival rates. A total of 2864 cases of ICC were identified. There was a major increase in incidence after 1985, and the incidence increased by 165% over the entire period. There were no significant changes in the staging, size of tumor at diagnosis, or the percent of microscopically confirmed cases. However, over the entire period, there was a significant improvement in the 1-year survival rates, from 15.8% to 26.3%, but not in the 5-year survival rates, 2.6% from 1995 to 1999 compared to 3.5% in 1995 to 1999. The fact that the staging and percentage of tumors confirmed microscopically were unchanged over the entire period suggests that the results indicate a true increase in ICC.CommentRecently, the incidence of hepatocellular carcinoma has been shown to be significantly increasing in the U.S. (Ann Intern Med 2003;139:817–823). Data from SEER indicate that approximately 10% of these cases are ICC, and the age-adjusted incidence of ICC in the U.S. has been reported to have increased from 0.13 per 100,000 to 0.67 per 100,000 (Hepatology 2001;33:1353–1357). The question remained as to whether this was a true increase, or whether this apparent increase was simply the result of the availability of improved diagnostic tests. Unless stated otherwise, we have abbreviated all cholangiocarcinomas as ICC. Up until the 1980s, the “gold standards” for the diagnosis of ICC were percutaneous intrahepatic cholangiography or endoscopic cholangiography (ERC). Both techniques were invasive and suffered from significant complications (Gastroenterology 1976;70:314–320). In the noninvasive investigation of patients with intrahepatic obstructive jaundice, abdominal ultrasonography is of limited value for the diagnosis of ICC. Until the mid-1990s, conventional abdominal computerized tomography (CT) suffered from the need for considerable breath holding by the patient because of the relatively lengthy examination time of up to 5 minutes. As a result, the most likely radiological abnormality seen on CT would be an abrupt dilatation of the intrahepatic bile ducts (N Engl J Med 1997;336:1889–1894), which then required an invasive procedure to confirm the diagnosis of ICC. With the introduction of helical spiral CT scanning (Am J Roentgenol 1993;160:719–725), CT examination of the liver was shortened to 30 seconds. This enabled the examination to be performed while the breath was held for 1 or 2 breaths, and scan during hepatic enhancement with intravenous contrast material (Radiol Clin North Am 1995;33:863–886). With the advent of magnetic resonance imaging, the technique of magnetic resonance cholangiography (MRC) was introduced (Radiology 1991;181:805–808). This was accomplished by acquiring heavily T2-weighted magnetic resonance sequences, resulting in a high signal intensity of stationary or slow moving fluids, such as bile, in contrast to the low intensity of solid organs or rapidly moving fluids, such as veins and arteries (Radiology 1994;192:19–21). Unlike ERC, MRC virtually always results in the production of a cholangiogram and is devoid of radiation (J Hepatol 1999;30:334–338). For the diagnosis of ICC, MRC can achieve a sensitivity of about 90%, and a specificity ranging from 70% to 100% (Radiology 1995;197:109–115, Endoscopy 1997;29:182–187, Gastroenterology 1996;110:589–597). In patients with bile duct obstruction, bile-filled dilated ducts are particularly well seen on MRC (Gastroenterology 2003;124:1686–1699). However, MRC lacks the possibility of analyzing the bile for biliary tumor markers (Am J Surg 1996;171:147–153) to perform brush cytology (Hepatology1993;18:1399–1403) or a biopsy.Yet all these advances have not led to an improvement in the detection of ICC because all the tumor characteristics of ICC found in this survey did not differ significantly from previous studies, including the percentage of early or operable tumors. Therefore, this seems to be a true increase in ICC and agrees with similar findings in the other 4 continents of the world (J Hepatol 2002;37:806–813). So the question remains as to the reason(s) for this increase. There are a number of congenital conditions of the biliary tree that are associated with ICC, such as Caroli’s Disease (Am J Surg 1983;145:41–48), congenital hepatic fibrosis (J Hepatol 1998;28:717–722), and choledochal cyst (Gastroenterology 1978;74:1286–1294). But there is no evidence that these rare conditions have increased in frequency. Similarly, although ICC has been described in association with thorotrast hepatoxicity (Br J Hosp Med 1979;21:478–481), most of the thorotrast tumors were angiosarcomas (Environ Res 1979;18:74–87), and this radiographic agent has been banned for 50 years. A much more common association is with recurrent infective cholangitis associated with chronic infection with clonorchis sinensis (J Pathol Bacteriol 1956;72:239–246) and opisthorchis viverrini (Gastroenterology 1985;89:151–156). However, these fluke infections are found predominantly in Southeast Asians. These infestations could not account for the increase in the white population of the U.S. unless they occurred, but were undiagnosed in veterans of the Korean and Vietnam wars? Although the patients’ ages are compatible with this, we are given no information as to the percentage of veterans that developed ICC.ICC is a well known complication of primary sclerosing cholangitis (PSC), usually secondary to chronic ulcerative colitis. In a 3-year follow-up study, 2 of 75 patients with PSC (3%) developed cholangiocarcinoma (J Hepatol 1999,30:669–673). Most large-scale studies, mainly from Scandinavia, with median follow-up times of 5 years, reported a lifetime risk for cholangiocarcinoma of about 8%–10% (Gut 1996;38:610–615, Scand J Gastroenterol 1997;32:1042–1045). However, a more recent nationally based study from the same Swedish group of 604 patients with PSC, with a median follow-up period of 5.7 years, found that the risk of hepatobiliary tumors was increased 161 times over the population at-large, with a frequency of 13% (J Hepatol 2002;36:321–327). Thirty-seven percent of the tumors were diagnosed within 1 year of the diagnosis of PSC, agreeing with previous findings for ICC (Ann Surg 1991;213:21–25). Seventy percent of the patients had concomitant inflammatory bowel disease. Patients with chronic ulcerative colitis, but no evidence of PSC, also have an increased risk of ICC (Am J Surg 1971;121:39–45). However, 23% of PSC patients undergoing liver transplantation were found to have ICC (Gastroenterology 1991;100:1710–1717). The incidence of PSC has been reported to be increasing in the U.S. (Gastroenterology 1980;79:200–206). It is 3 times as common in men than in women and has an estimated prevalence of 21 per 100,000 men (Gastroenterology 2003;125:1364–1369). It is also becoming more common in children (Hepatology 2003;38:210–217) and may be part of the clinical manifestations of cystic fibrosis (J Hepatol 2002;37:192–197). The mechanism of ICC in PSC is thought to be caused by dysregulation of cholangiocyte proliferation, secondary to chronic inflammation (J Hepatol 2000;33:333–340). Excessive production of nitric oxide by cholangiocytes might induce DNA damage and impair DNA repair mechanisms (Cancer Res 2000;60:184–190), whereas interleukin (IL)-6 sustains the proliferation of cholangiocarcinoma cell lines (Hepatology 1999;30:1128–1133). In at least 2 studies, excessive alcohol intake has been shown to be a risk factor for cholangiocarcinoma in PSC patients (Cancer 1991;68:2051–2055, Hepatology 2000;31:7–11). Unfortunately, the authors did not present any data for underlying or associated diseases. Therefore, we do not know the impact of PSC on the rising incidence of ICC.The diagnosis of ICC in patients with PSC remains problematic. There are hopeful signs that diagnosis via serum markers may be improving. For example, in a recent study in patients with PSC, and in agreement with previous studies (Mayo Clin Proc 1993;68:874–879, Gastroenterology 1995;108:865–869), serum carcinoma antigen (CA) 19-9 levels were significantly higher in patients with ICC compared with those without (Hepatology 2000;31:7–11). A serum CA19-9 level >100 U/mL had 75% sensitivity and 80% specificity in identifying PSC patients with ICC. In another study in PSC patients, in which all the imaging modalities, both noninvasive and invasive, had once again been shown to be poor predictors of malignancy, the combination of CA19-9 and carcinoembryonic antigen (CEA) gave an accuracy of 86% (Gastroenterology 1995;108:865–869). This was not significantly different from that recently reported using CA19-9 alone. In another recent study, the accuracy of serum CA19-9 and CEA were 82.7% and 78%, respectively (World J Gastroenterol 2004;10:427–432). However, this remains controversial because other studies found that these and other markers had low specificity (J Hepatol 1999;30:669–673). Another tumor marker recently investigated was the cytokine IL-6. The sensitivity and specificity of serum IL-6 levels for distinguishing benign from malignant biliary strictures were 71% and 90%, respectively (Hepatogastroenterology 2004;51:15–19). Finally, the measurement of the biliary isoenzyme of alkaline phosphatase (BALP) in patients with elevated serum alkaline phosphatase in nonjaundiced malignancy was investigated. BALP differentiated ICC from other malignancies with 85% sensitivity and 79% specificity (J Cancer Res Clin Oncol 2004;130:87–92).If PSC still only accounts for the minority of patients with ICC, what other possible etiologic factors are there? One suggestion has been that the hepatitis viruses HBV and HCV might be associated (Hepatology 1998;28:921–928). Thus far, 3 studies from Korea, Japan, and Italy have shown an increased incidence of ICC among patients with chronic HCV infection, with or without cirrhosis (J Hepatol 2004;40:472–477). No such study has yet been performed in the U.S. The association between hepatocellular carcinoma (HCC) and HCV is well established. It has recently been suggested that both HCC and ICC may originate from the same hepatic progenitor cells (J Hepatol 2004;40:298–304).Despite recent advances in the use of Digital Image Analysis of endoscopic brushings (Clin Gastroenterol Hepatol 2004;2:214–219), and endoscopic ultrasound–guided fine needle aspiration biopsy (Clin Gastroenterol Hepatol 2004;2:209–213), the continued search for improved serological tumor markers for the diagnosis of cholangiocarcinoma will hopefully lead to an improvement in the overall diagnosis so that these markers could begin to be used in the screening of populations at risk. Shaib YH, Davila JA, McGlynn K, El-Serag HB (Sections of Health Services Research and Gastroenterology, The Houston Veterans Medical Center, Baylor College of Medicine, Houston, Texas; and The National Cancer Institute, National Institutes of Health, Bethesda, Maryland). Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase? J Hepatol 2004;40:472–477. These investigators examined the validity of the reported rising rates of intrahepatic cholangiocarcinoma (ICC) in the United States using data from the Surveillance Epidemiology and End Results (SEER) program and calculating the incidence rates from 1975 to 1999, together with each tumor stage, microscopically confirmed cases, and survival rates. A total of 2864 cases of ICC were identified. There was a major increase in incidence after 1985, and the incidence increased by 165% over the entire period. There were no significant changes in the staging, size of tumor at diagnosis, or the percent of microscopically confirmed cases. However, over the entire period, there was a significant improvement in the 1-year survival rates, from 15.8% to 26.3%, but not in the 5-year survival rates, 2.6% from 1995 to 1999 compared to 3.5% in 1995 to 1999. The fact that the staging and percentage of tumors confirmed microscopically were unchanged over the entire period suggests that the results indicate a true increase in ICC. CommentRecently, the incidence of hepatocellular carcinoma has been shown to be significantly increasing in the U.S. (Ann Intern Med 2003;139:817–823). Data from SEER indicate that approximately 10% of these cases are ICC, and the age-adjusted incidence of ICC in the U.S. has been reported to have increased from 0.13 per 100,000 to 0.67 per 100,000 (Hepatology 2001;33:1353–1357). The question remained as to whether this was a true increase, or whether this apparent increase was simply the result of the availability of improved diagnostic tests. Unless stated otherwise, we have abbreviated all cholangiocarcinomas as ICC. Up until the 1980s, the “gold standards” for the diagnosis of ICC were percutaneous intrahepatic cholangiography or endoscopic cholangiography (ERC). Both techniques were invasive and suffered from significant complications (Gastroenterology 1976;70:314–320). In the noninvasive investigation of patients with intrahepatic obstructive jaundice, abdominal ultrasonography is of limited value for the diagnosis of ICC. Until the mid-1990s, conventional abdominal computerized tomography (CT) suffered from the need for considerable breath holding by the patient because of the relatively lengthy examination time of up to 5 minutes. As a result, the most likely radiological abnormality seen on CT would be an abrupt dilatation of the intrahepatic bile ducts (N Engl J Med 1997;336:1889–1894), which then required an invasive procedure to confirm the diagnosis of ICC. With the introduction of helical spiral CT scanning (Am J Roentgenol 1993;160:719–725), CT examination of the liver was shortened to 30 seconds. This enabled the examination to be performed while the breath was held for 1 or 2 breaths, and scan during hepatic enhancement with intravenous contrast material (Radiol Clin North Am 1995;33:863–886). With the advent of magnetic resonance imaging, the technique of magnetic resonance cholangiography (MRC) was introduced (Radiology 1991;181:805–808). This was accomplished by acquiring heavily T2-weighted magnetic resonance sequences, resulting in a high signal intensity of stationary or slow moving fluids, such as bile, in contrast to the low intensity of solid organs or rapidly moving fluids, such as veins and arteries (Radiology 1994;192:19–21). Unlike ERC, MRC virtually always results in the production of a cholangiogram and is devoid of radiation (J Hepatol 1999;30:334–338). For the diagnosis of ICC, MRC can achieve a sensitivity of about 90%, and a specificity ranging from 70% to 100% (Radiology 1995;197:109–115, Endoscopy 1997;29:182–187, Gastroenterology 1996;110:589–597). In patients with bile duct obstruction, bile-filled dilated ducts are particularly well seen on MRC (Gastroenterology 2003;124:1686–1699). However, MRC lacks the possibility of analyzing the bile for biliary tumor markers (Am J Surg 1996;171:147–153) to perform brush cytology (Hepatology1993;18:1399–1403) or a biopsy.Yet all these advances have not led to an improvement in the detection of ICC because all the tumor characteristics of ICC found in this survey did not differ significantly from previous studies, including the percentage of early or operable tumors. Therefore, this seems to be a true increase in ICC and agrees with similar findings in the other 4 continents of the world (J Hepatol 2002;37:806–813). So the question remains as to the reason(s) for this increase. There are a number of congenital conditions of the biliary tree that are associated with ICC, such as Caroli’s Disease (Am J Surg 1983;145:41–48), congenital hepatic fibrosis (J Hepatol 1998;28:717–722), and choledochal cyst (Gastroenterology 1978;74:1286–1294). But there is no evidence that these rare conditions have increased in frequency. Similarly, although ICC has been described in association with thorotrast hepatoxicity (Br J Hosp Med 1979;21:478–481), most of the thorotrast tumors were angiosarcomas (Environ Res 1979;18:74–87), and this radiographic agent has been banned for 50 years. A much more common association is with recurrent infective cholangitis associated with chronic infection with clonorchis sinensis (J Pathol Bacteriol 1956;72:239–246) and opisthorchis viverrini (Gastroenterology 1985;89:151–156). However, these fluke infections are found predominantly in Southeast Asians. These infestations could not account for the increase in the white population of the U.S. unless they occurred, but were undiagnosed in veterans of the Korean and Vietnam wars? Although the patients’ ages are compatible with this, we are given no information as to the percentage of veterans that developed ICC.ICC is a well known complication of primary sclerosing cholangitis (PSC), usually secondary to chronic ulcerative colitis. In a 3-year follow-up study, 2 of 75 patients with PSC (3%) developed cholangiocarcinoma (J Hepatol 1999,30:669–673). Most large-scale studies, mainly from Scandinavia, with median follow-up times of 5 years, reported a lifetime risk for cholangiocarcinoma of about 8%–10% (Gut 1996;38:610–615, Scand J Gastroenterol 1997;32:1042–1045). However, a more recent nationally based study from the same Swedish group of 604 patients with PSC, with a median follow-up period of 5.7 years, found that the risk of hepatobiliary tumors was increased 161 times over the population at-large, with a frequency of 13% (J Hepatol 2002;36:321–327). Thirty-seven percent of the tumors were diagnosed within 1 year of the diagnosis of PSC, agreeing with previous findings for ICC (Ann Surg 1991;213:21–25). Seventy percent of the patients had concomitant inflammatory bowel disease. Patients with chronic ulcerative colitis, but no evidence of PSC, also have an increased risk of ICC (Am J Surg 1971;121:39–45). However, 23% of PSC patients undergoing liver transplantation were found to have ICC (Gastroenterology 1991;100:1710–1717). The incidence of PSC has been reported to be increasing in the U.S. (Gastroenterology 1980;79:200–206). It is 3 times as common in men than in women and has an estimated prevalence of 21 per 100,000 men (Gastroenterology 2003;125:1364–1369). It is also becoming more common in children (Hepatology 2003;38:210–217) and may be part of the clinical manifestations of cystic fibrosis (J Hepatol 2002;37:192–197). The mechanism of ICC in PSC is thought to be caused by dysregulation of cholangiocyte proliferation, secondary to chronic inflammation (J Hepatol 2000;33:333–340). Excessive production of nitric oxide by cholangiocytes might induce DNA damage and impair DNA repair mechanisms (Cancer Res 2000;60:184–190), whereas interleukin (IL)-6 sustains the proliferation of cholangiocarcinoma cell lines (Hepatology 1999;30:1128–1133). In at least 2 studies, excessive alcohol intake has been shown to be a risk factor for cholangiocarcinoma in PSC patients (Cancer 1991;68:2051–2055, Hepatology 2000;31:7–11). Unfortunately, the authors did not present any data for underlying or associated diseases. Therefore, we do not know the impact of PSC on the rising incidence of ICC.The diagnosis of ICC in patients with PSC remains problematic. There are hopeful signs that diagnosis via serum markers may be improving. For example, in a recent study in patients with PSC, and in agreement with previous studies (Mayo Clin Proc 1993;68:874–879, Gastroenterology 1995;108:865–869), serum carcinoma antigen (CA) 19-9 levels were significantly higher in patients with ICC compared with those without (Hepatology 2000;31:7–11). A serum CA19-9 level >100 U/mL had 75% sensitivity and 80% specificity in identifying PSC patients with ICC. In another study in PSC patients, in which all the imaging modalities, both noninvasive and invasive, had once again been shown to be poor predictors of malignancy, the combination of CA19-9 and carcinoembryonic antigen (CEA) gave an accuracy of 86% (Gastroenterology 1995;108:865–869). This was not significantly different from that recently reported using CA19-9 alone. In another recent study, the accuracy of serum CA19-9 and CEA were 82.7% and 78%, respectively (World J Gastroenterol 2004;10:427–432). However, this remains controversial because other studies found that these and other markers had low specificity (J Hepatol 1999;30:669–673). Another tumor marker recently investigated was the cytokine IL-6. The sensitivity and specificity of serum IL-6 levels for distinguishing benign from malignant biliary strictures were 71% and 90%, respectively (Hepatogastroenterology 2004;51:15–19). Finally, the measurement of the biliary isoenzyme of alkaline phosphatase (BALP) in patients with elevated serum alkaline phosphatase in nonjaundiced malignancy was investigated. BALP differentiated ICC from other malignancies with 85% sensitivity and 79% specificity (J Cancer Res Clin Oncol 2004;130:87–92).If PSC still only accounts for the minority of patients with ICC, what other possible etiologic factors are there? One suggestion has been that the hepatitis viruses HBV and HCV might be associated (Hepatology 1998;28:921–928). Thus far, 3 studies from Korea, Japan, and Italy have shown an increased incidence of ICC among patients with chronic HCV infection, with or without cirrhosis (J Hepatol 2004;40:472–477). No such study has yet been performed in the U.S. The association between hepatocellular carcinoma (HCC) and HCV is well established. It has recently been suggested that both HCC and ICC may originate from the same hepatic progenitor cells (J Hepatol 2004;40:298–304).Despite recent advances in the use of Digital Image Analysis of endoscopic brushings (Clin Gastroenterol Hepatol 2004;2:214–219), and endoscopic ultrasound–guided fine needle aspiration biopsy (Clin Gastroenterol Hepatol 2004;2:209–213), the continued search for improved serological tumor markers for the diagnosis of cholangiocarcinoma will hopefully lead to an improvement in the overall diagnosis so that these markers could begin to be used in the screening of populations at risk. Recently, the incidence of hepatocellular carcinoma has been shown to be significantly increasing in the U.S. (Ann Intern Med 2003;139:817–823). Data from SEER indicate that approximately 10% of these cases are ICC, and the age-adjusted incidence of ICC in the U.S. has been reported to have increased from 0.13 per 100,000 to 0.67 per 100,000 (Hepatology 2001;33:1353–1357). The question remained as to whether this was a true increase, or whether this apparent increase was simply the result of the availability of improved diagnostic tests. Unless stated otherwise, we have abbreviated all cholangiocarcinomas as ICC. Up until the 1980s, the “gold standards” for the diagnosis of ICC were percutaneous intrahepatic cholangiography or endoscopic cholangiography (ERC). Both techniques were invasive and suffered from significant complications (Gastroenterology 1976;70:314–320). In the noninvasive investigation of patients with intrahepatic obstructive jaundice, abdominal ultrasonography is of limited value for the diagnosis of ICC. Until the mid-1990s, conventional abdominal computerized tomography (CT) suffered from the need for considerable breath holding by the patient because of the relatively lengthy examination time of up to 5 minutes. As a result, the most likely radiological abnormality seen on CT would be an abrupt dilatation of the intrahepatic bile ducts (N Engl J Med 1997;336:1889–1894), which then required an invasive procedure to confirm the diagnosis of ICC. With the introduction of helical spiral CT scanning (Am J Roentgenol 1993;160:719–725), CT examination of the liver was shortened to 30 seconds. This enabled the examination to be performed while the breath was held for 1 or 2 breaths, and scan during hepatic enhancement with intravenous contrast material (Radiol Clin North Am 1995;33:863–886). With the advent of magnetic resonance imaging, the technique of magnetic resonance cholangiography (MRC) was introduced (Radiology 1991;181:805–808). This was accomplished by acquiring heavily T2-weighted magnetic resonance sequences, resulting in a high signal intensity of stationary or slow moving fluids, such as bile, in contrast to the low intensity of solid organs or rapidly moving fluids, such as veins and arteries (Radiology 1994;192:19–21). Unlike ERC, MRC virtually always results in the production of a cholangiogram and is devoid of radiation (J Hepatol 1999;30:334–338). For the diagnosis of ICC, MRC can achieve a sensitivity of about 90%, and a specificity ranging from 70% to 100% (Radiology 1995;197:109–115, Endoscopy 1997;29:182–187, Gastroenterology 1996;110:589–597). In patients with bile duct obstruction, bile-filled dilated ducts are particularly well seen on MRC (Gastroenterology 2003;124:1686–1699). However, MRC lacks the possibility of analyzing the bile for biliary tumor markers (Am J Surg 1996;171:147–153) to perform brush cytology (Hepatology1993;18:1399–1403) or a biopsy. Yet all these advances have not led to an improvement in the detection of ICC because all the tumor characteristics of ICC found in this survey did not differ significantly from previous studies, including the percentage of early or operable tumors. Therefore, this seems to be a true increase in ICC and agrees with similar findings in the other 4 continents of the world (J Hepatol 2002;37:806–813). So the question remains as to the reason(s) for this increase. There are a number of congenital conditions of the biliary tree that are associated with ICC, such as Caroli’s Disease (Am J Surg 1983;145:41–48), congenital hepatic fibrosis (J Hepatol 1998;28:717–722), and choledochal cyst (Gastroenterology 1978;74:1286–1294). But there is no evidence that these rare conditions have increased in frequency. Similarly, although ICC has been described in association with thorotrast hepatoxicity (Br J Hosp Med 1979;21:478–481), most of the thorotrast tumors were angiosarcomas (Environ Res 1979;18:74–87), and this radiographic agent has been banned for 50 years. A much more common association is with recurrent infective cholangitis associated with chronic infection with clonorchis sinensis (J Pathol Bacteriol 1956;72:239–246) and opisthorchis viverrini (Gastroenterology 1985;89:151–156). However, these fluke infections are found predominantly in Southeast Asians. These infestations could not account for the increase in the white population of the U.S. unless they occurred, but were undiagnosed in veterans of the Korean and Vietnam wars? Although the patients’ ages are compatible with this, we are given no information as to the percentage of veterans that developed ICC. ICC is a well known complication of primary sclerosing cholangitis (PSC), usually secondary to chronic ulcerative colitis. In a 3-year follow-up study, 2 of 75 patients with PSC (3%) developed cholangiocarcinoma (J Hepatol 1999,30:669–673). Most large-scale studies, mainly from Scandinavia, with median follow-up times of 5 years, reported a lifetime risk for cholangiocarcinoma of about 8%–10% (Gut 1996;38:610–615, Scand J Gastroenterol 1997;32:1042–1045). However, a more recent nationally based study from the same Swedish group of 604 patients with PSC, with a median follow-up period of 5.7 years, found that the risk of hepatobiliary tumors was increased 161 times over the population at-large, with a frequency of 13% (J Hepatol 2002;36:321–327). Thirty-seven percent of the tumors were diagnosed within 1 year of the diagnosis of PSC, agreeing with previous findings for ICC (Ann Surg 1991;213:21–25). Seventy percent of the patients had concomitant inflammatory bowel disease. Patients with chronic ulcerative colitis, but no evidence of PSC, also have an increased risk of ICC (Am J Surg 1971;121:39–45). However, 23% of PSC patients undergoing liver transplantation were found to have ICC (Gastroenterology 1991;100:1710–1717). The incidence of PSC has been reported to be increasing in the U.S. (Gastroenterology 1980;79:200–206). It is 3 times as common in men than in women and has an estimated prevalence of 21 per 100,000 men (Gastroenterology 2003;125:1364–1369). It is also becoming more common in children (Hepatology 2003;38:210–217) and may be part of the clinical manifestations of cystic fibrosis (J Hepatol 2002;37:192–197). The mechanism of ICC in PSC is thought to be caused by dysregulation of cholangiocyte proliferation, secondary to chronic inflammation (J Hepatol 2000;33:333–340). Excessive production of nitric oxide by cholangiocytes might induce DNA damage and impair DNA repair mechanisms (Cancer Res 2000;60:184–190), whereas interleukin (IL)-6 sustains the proliferation of cholangiocarcinoma cell lines (Hepatology 1999;30:1128–1133). In at least 2 studies, excessive alcohol intake has been shown to be a risk factor for cholangiocarcinoma in PSC patients (Cancer 1991;68:2051–2055, Hepatology 2000;31:7–11). Unfortunately, the authors did not present any data for underlying or associated diseases. Therefore, we do not know the impact of PSC on the rising incidence of ICC. The diagnosis of ICC in patients with PSC remains problematic. There are hopeful signs that diagnosis via serum markers may be improving. For example, in a recent study in patients with PSC, and in agreement with previous studies (Mayo Clin Proc 1993;68:874–879, Gastroenterology 1995;108:865–869), serum carcinoma antigen (CA) 19-9 levels were significantly higher in patients with ICC compared with those without (Hepatology 2000;31:7–11). A serum CA19-9 level >100 U/mL had 75% sensitivity and 80% specificity in identifying PSC patients with ICC. In another study in PSC patients, in which all the imaging modalities, both noninvasive and invasive, had once again been shown to be poor predictors of malignancy, the combination of CA19-9 and carcinoembryonic antigen (CEA) gave an accuracy of 86% (Gastroenterology 1995;108:865–869). This was not significantly different from that recently reported using CA19-9 alone. In another recent study, the accuracy of serum CA19-9 and CEA were 82.7% and 78%, respectively (World J Gastroenterol 2004;10:427–432). However, this remains controversial because other studies found that these and other markers had low specificity (J Hepatol 1999;30:669–673). Another tumor marker recently investigated was the cytokine IL-6. The sensitivity and specificity of serum IL-6 levels for distinguishing benign from malignant biliary strictures were 71% and 90%, respectively (Hepatogastroenterology 2004;51:15–19). Finally, the measurement of the biliary isoenzyme of alkaline phosphatase (BALP) in patients with elevated serum alkaline phosphatase in nonjaundiced malignancy was investigated. BALP differentiated ICC from other malignancies with 85% sensitivity and 79% specificity (J Cancer Res Clin Oncol 2004;130:87–92). If PSC still only accounts for the minority of patients with ICC, what other possible etiologic factors are there? One suggestion has been that the hepatitis viruses HBV and HCV might be associated (Hepatology 1998;28:921–928). Thus far, 3 studies from Korea, Japan, and Italy have shown an increased incidence of ICC among patients with chronic HCV infection, with or without cirrhosis (J Hepatol 2004;40:472–477). No such study has yet been performed in the U.S. The association between hepatocellular carcinoma (HCC) and HCV is well established. It has recently been suggested that both HCC and ICC may originate from the same hepatic progenitor cells (J Hepatol 2004;40:298–304). Despite recent advances in the use of Digital Image Analysis of endoscopic brushings (Clin Gastroenterol Hepatol 2004;2:214–219), and endoscopic ultrasound–guided fine needle aspiration biopsy (Clin Gastroenterol Hepatol 2004;2:209–213), the continued search for improved serological tumor markers for the diagnosis of cholangiocarcinoma will hopefully lead to an improvement in the overall diagnosis so that these markers could begin to be used in the screening of populations at risk.