Shaib Y, El-Serag HB (2004) The epidemiology of cholangiocarcinoma. Semin Liver Dis, 24(2):115-125
Introduction
Because ICC originates in small biliary ducts or ductules, it usually presents as an intrahepatic mass and is therefore grouped in some studies with hepatocellular carcinoma (HCC) as a primary liver tumor. However, Klatskin tumors, which occur at the bifurcation of the right and left hepatic ducts, have traditionally been classified as extrahepatic.10,11
In many large cancer registry–based studies, however, Klatskin tumors were either not described or were classified as ICC. For example, in an analysis of CC in registries of the Surveillance Epidemiology and End Results (SEER) between 1975 and 1999, we found that Klatskin tumors composed up to 7% of all ICC and that 92% of Klatskin tumors were classified as ICC.
Incidence of ICC: According to the SEER registries, the age-adjusted incidence rates of ICC increased by 165% from 0.32 per 100,000 in 1975 to 1979 to 0.85 per 100,000 in 1995 to 1999. This increase in incidence was not associated with a significant change in the proportion of early-stage disease, microscopically confirmed tumors, tumors with smaller size, or staged tumors. For example, the proportion of cases with tumors less than 5 cm increased slightly from 23.4% in 1990 to 1994 to 25.4% in 1995 to 1999, but this increase was not statistically significant (p¼0.32). These findings suggest that the observed increase in incidence is a real increase and not a reflection of improved detection or reclassification of other cancers, such as HCC or ECC.8
In the United States, the age-adjusted mortality rates for ICC increased from 0.07 per 100,000 in 1973 to 0.69 per 100,000 in 1997.4 The increase in ICC-related mortality parallels, and is likely a result of, the increasing incidence of ICC, indicating poor survival with this malignancy.
Survival of Patients with ICC
Although the 1-year relative survival increased from 16.4% in 1975 to 1979 to 27.6% in 1995 to 1999, the 5-year survival did not show any significant change and has remained below 5% (Fig. 7). The improved short term but not long-term survival can be attributed to improved palliative treatments (stenting and drainage) or improved overall supportive medical care, or both. Alternatively the improved short-term survival could indicate lead- time bias related to early detection.
Risk Factors of Cholangiocarcinoma
Most cases develop in what is believed to be an otherwise normal liver.18 However, in approximately 10% of cases, CC is preceded by a chronic inflammatory disease process of the bile ducts that might induce progressive changes in the biliary epithelium that culminate in cancer.
PSC: In aggregate, these studies suggest that the risk of CC development is not related to the duration of PSC. Alternative explanations could be that the diagnosis of PSC is made at the time of clinical deterioration associated with the development of CC. Furthermore, cases of sclerosing cholangitis secondary to CC could be misdiagnosed as PSC.
The Rising of ICC in US
However, if the rising incidence rates of ICC were due to increased detection in the absence of a true increase, they should plateau once the dissemination of testing has been achieved. This has not happened yet; the increase in ICC seems to be progressive since the mid-1980s. Moreover, increased detection of cancer is usually associated with an increase in the proportion of patients with early-stage cancers, small-size tumors, and possibly improved short-term survival related to lead time bias. With the exception of the latter phenomenon, none of these changes has been observed. Last, the magnitude of decline in ECC has not been sufficient to fully explain the rising incidence in ICC.
The reasons for the increase in ICC are not known, because this question has not been addressed by published studies. It could reflect increasing prevalence of PSC, which has been anecdotally reported in the United States.46 However, if the noted increase in ICC were due to PSC, one would expect a change toward a younger age at diagnosis because PSC-related ICC is diagnosed at a relatively young age (47 years in one study20). The increasing incidence of ICC was not associated with a shift toward a younger age at diagnosis; most patients are diagnosed after 70 years of age, with most of the increase occurring among people over 65 years of age, thus making it unlikely that PSC is the main reason for this increase.
The risk of CC and especially ICC has been shown to be high among patients with liver cirrhosis, a condition with a high, and possibly rising, prevalence in the United States. Furthermore, some data suggest that hepatitis C infection with or without cirrhosis might be associated with a higher risk of ICC. Although CC remains an infrequent malignancy in the United States and other developed countries, there has been a progressive increase in the incidence of ICC. More studies are needed to evaluate the potential role of viral hepatitis in the pathogenesis of CC.
Introduction
Because ICC originates in small biliary ducts or ductules, it usually presents as an intrahepatic mass and is therefore grouped in some studies with hepatocellular carcinoma (HCC) as a primary liver tumor. However, Klatskin tumors, which occur at the bifurcation of the right and left hepatic ducts, have traditionally been classified as extrahepatic.10,11
In many large cancer registry–based studies, however, Klatskin tumors were either not described or were classified as ICC. For example, in an analysis of CC in registries of the Surveillance Epidemiology and End Results (SEER) between 1975 and 1999, we found that Klatskin tumors composed up to 7% of all ICC and that 92% of Klatskin tumors were classified as ICC.
Incidence of ICC: According to the SEER registries, the age-adjusted incidence rates of ICC increased by 165% from 0.32 per 100,000 in 1975 to 1979 to 0.85 per 100,000 in 1995 to 1999. This increase in incidence was not associated with a significant change in the proportion of early-stage disease, microscopically confirmed tumors, tumors with smaller size, or staged tumors. For example, the proportion of cases with tumors less than 5 cm increased slightly from 23.4% in 1990 to 1994 to 25.4% in 1995 to 1999, but this increase was not statistically significant (p¼0.32). These findings suggest that the observed increase in incidence is a real increase and not a reflection of improved detection or reclassification of other cancers, such as HCC or ECC.8
In the United States, the age-adjusted mortality rates for ICC increased from 0.07 per 100,000 in 1973 to 0.69 per 100,000 in 1997.4 The increase in ICC-related mortality parallels, and is likely a result of, the increasing incidence of ICC, indicating poor survival with this malignancy.
Survival of Patients with ICC
Although the 1-year relative survival increased from 16.4% in 1975 to 1979 to 27.6% in 1995 to 1999, the 5-year survival did not show any significant change and has remained below 5% (Fig. 7). The improved short term but not long-term survival can be attributed to improved palliative treatments (stenting and drainage) or improved overall supportive medical care, or both. Alternatively the improved short-term survival could indicate lead- time bias related to early detection.
Risk Factors of Cholangiocarcinoma
Most cases develop in what is believed to be an otherwise normal liver.18 However, in approximately 10% of cases, CC is preceded by a chronic inflammatory disease process of the bile ducts that might induce progressive changes in the biliary epithelium that culminate in cancer.
PSC: In aggregate, these studies suggest that the risk of CC development is not related to the duration of PSC. Alternative explanations could be that the diagnosis of PSC is made at the time of clinical deterioration associated with the development of CC. Furthermore, cases of sclerosing cholangitis secondary to CC could be misdiagnosed as PSC.
The Rising of ICC in US
However, if the rising incidence rates of ICC were due to increased detection in the absence of a true increase, they should plateau once the dissemination of testing has been achieved. This has not happened yet; the increase in ICC seems to be progressive since the mid-1980s. Moreover, increased detection of cancer is usually associated with an increase in the proportion of patients with early-stage cancers, small-size tumors, and possibly improved short-term survival related to lead time bias. With the exception of the latter phenomenon, none of these changes has been observed. Last, the magnitude of decline in ECC has not been sufficient to fully explain the rising incidence in ICC.
The reasons for the increase in ICC are not known, because this question has not been addressed by published studies. It could reflect increasing prevalence of PSC, which has been anecdotally reported in the United States.46 However, if the noted increase in ICC were due to PSC, one would expect a change toward a younger age at diagnosis because PSC-related ICC is diagnosed at a relatively young age (47 years in one study20). The increasing incidence of ICC was not associated with a shift toward a younger age at diagnosis; most patients are diagnosed after 70 years of age, with most of the increase occurring among people over 65 years of age, thus making it unlikely that PSC is the main reason for this increase.
The risk of CC and especially ICC has been shown to be high among patients with liver cirrhosis, a condition with a high, and possibly rising, prevalence in the United States. Furthermore, some data suggest that hepatitis C infection with or without cirrhosis might be associated with a higher risk of ICC. Although CC remains an infrequent malignancy in the United States and other developed countries, there has been a progressive increase in the incidence of ICC. More studies are needed to evaluate the potential role of viral hepatitis in the pathogenesis of CC.
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