Research ArticleAre common factors involved in the pathogenesis of primary liver cancers? A meta-analysis of risk factors for intrahepatic cholangiocarcinoma
Introduction
Cholangiocarcinomas are aggressive malignancies arising from the biliary tract and are challenging to diagnose, prevent or treat [1]. The two major clinical phenotypes of cholangiocarcinoma are intrahepatic and ductal/peri-hilar cancers. These phenotypes differ in their anatomical locations, presentation, natural history, and management. Intrahepatic cholangiocarcinomas (IH-CCA) are similar to hepatocellular cancer (HCC) in their presentation as mass lesions within the liver. Both HCC and IH-CCA are primary epithelial malignancies of the liver and are often classified together as primary liver cancers in epidemiological reports. The incidence of HCC is increasing in the United States and other countries [2], [3]. In contrast to HCC, the true incidence and risk factors for IH-CCA are less well recognized possibly because of the much lower prevalence of these cancers relative to HCC. Recent reports suggest that the incidence of IH-CCA is also increasing [4], [5], [6], [7], [8], [9]. Data from the Surveillance, Epidemiology, and End Results program, for example, indicated an increase in the age-adjusted annual incidence of IH-CCA in the United States from 0.13 to 0.58 per 100,000 over a twenty-five-year period with similar trends observed from many other countries worldwide [7], [8]. However, more recent analyses indicate that these changes may have reflected differences in coding and diagnosis [10], [11], [12]. Hilar cholangiocarcinomas, for example, are inconsistently classified and their designation as intra-hepatic cholangiocarcinoma has made accurate determinations of true incidence rates for intrahepatic cancers impossible.
Most patients with IH-CCA do not have any apparent risk factors. Both infectious and non-infectious etiologies have been implicated as risk factors for IH-CCA [13]. Indeed, parasitic liver-flukes, primary sclerosing cholangitis, biliary cysts, hepatolithiasis, and toxins are well recognized risk factors [1], [14], [15], [16]. Some of the variations in the incidence of IH-CCA worldwide can be accounted for by differences in the geographic prevalence of causative liver fluke infectious. Other than in regions where liver flukes are endemic such as South East Asia, the majority of patients with IH-CCA do not have any of these risk factors. Salmonella and Helicobacter infections have been implicated in gallbladder cancer but their contribution to IH-CCA is unknown. Recent studies have identified several other conditions that can contribute to an increased risk of IH-CCA such as chronic viral hepatitis B and C, obesity, diabetes, alcohol, and smoking [9], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27]. The evaluation of these risk factors has led to conflicting results in some cases. It is unclear to what extent these differences reflect geographic differences, the study design or the population studied. Thus, our objectives were to evaluate these emerging risk factors for IH-CCA by systematically examining the results of reported case–control series from geographically diverse regions. The results of these meta-analyses identify that IH-CCA has many risk factors in common with HCC, and quantitate the overall odds ratios for selected risk factors. These studies support the presence of common mechanisms for the pathogenesis of primary epithelial neoplasia within the liver and lead to exciting hypotheses regarding the etiology and pathogenesis of these cancers. By defining populations at risk for IH-CCA, these observations can form the basis for future efforts at screening or surveillance for these cancers with the goal of decreasing the incidence and mortality from these cancers.
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Literature search
Studies were identified by searching both the National Library of Medicine’s MEDLINE database using PubMed and by using Google Scholar search. Studies were not limited by language or to any geographic region. The most recent search was performed on August 12, 2011. The search strategy was based on combinations of the key words, “risk”, “smoking”, “diabetes”, “obesity”, “hepatitis” with “cholangiocarcinoma” or “biliary tract cancers”, and restricted to studies performed after 1990 to avoid any
Study characteristics
A search of PubMed and Google Scholar identified a total of 334 citations, of which 323 were excluded as they did not fulfill the selection criteria, were published prior to 1990, or were duplicates (Fig. 1). Eleven studies qualified for inclusion. The characteristics of the populations studied in these reports are summarized in Table 1. Studies were performed in both regions of high prevalence of hepatobiliary cancers such as Japan (1 study), Korea (1 study), and China (3 studies), as well as
Discussion
While the predisposition of biliary tract inflammation to carcinogenesis is recognized in the biliary tract, many patients with IH-CCA do not have readily recognizable biliary tract inflammation or infection. Traditional infectious risk factors for IH-CCA include the liver flukes Clonorchis sinensis and Opisthorchis viverrini, both of which are now recognized as group 1 carcinogens and causes of cholangiocarcinoma by the International Agency for Research in Cancer of the World Health
Financial support
Supported in part by NIH grant DK 069370 (TP).
Conflict of interest
The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
The underlying research reported in this study was funded by the NIH Institutes of Health.
References (38)
- et al.
Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase?
J Hepatol
(2004) Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States
Hepatology
(2001)- et al.
Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based case–control study
Clin Gastroenterol Hepatol
(2007) - et al.
Primary sclerosing cholangitis and ulcerative colitis: evidence for increased neoplastic potential
Hepatology
(1995) - et al.
Risk factors of intrahepatic cholangiocarcinoma in the United States: a case–control study
Gastroenterology
(2005) - et al.
Hepatitis B virus-associated intrahepatic cholangiocarcinoma and hepatocellular carcinoma may hold common disease process for carcinogenesis
Eur J Cancer
(2010) - et al.
Viral hepatitis is associated with intrahepatic cholangiocarcinoma with cholangiolar differentiation and N-cadherin expression
Mod Pathol
(2011) - et al.
The risk of liver and bile duct cancer in patients with chronic viral hepatitis, alcoholism, or cirrhosis
Hepatology
(2001) Cholangiocarcinoma – controversies and challenges
Nat Rev Gastroenterol Hepatol
(2011)- et al.
The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update
Ann Intern Med
(2003)