In this cohort study of 718,687 U.S. military veterans—the largest study ever conducted on the risk conferred by HCV infection for cholangiocarcinoma—we found in 146,394 veterans with HCV infection a significant 2.55-fold increase in the risk of ICC and a 15-fold increase in the risk of HCC but no evidence that HCV infection increases the risk of ECC. A small increase (HR = 1.23) detected in the risk of pancreatic cancer could have been due to confounding by alcohol use or other factors.
Cholangiocarcinoma is a highly fatal cancer of the biliary tree. In the U.S., approximately 5,000 new cases of cholangiocarcinoma are diagnosed annually, and these cases are equally distributed between ICC and ECC (17
). Data from the SEER program indicate that the incidence of ICC tripled between 1975 and 1999 before declining slightly afterward, whereas the rates of ECC have been steady (18
To our knowledge this is the first time a significant association has been detected between HCV and ICC in a large cohort study. This higher level of evidence supports and extends prior observations of an association from mostly hospital-based case-control studies. In a Japanese hospital-based study, investigators found that 36% of 50 patients with ICC but only 3% of 205 controls (other surgical patients who did not have primary liver cancer) were HCV seropositive (odds ratio [OR] = 16.87; 95% CI, 5.69, 50.00) (7
). Korean investigators performed a case-control study comparing 41 cases of ICC with 406 controls without cancer and found that 13.8% of cases (3.5% of controls) were anti-HCV and 12.5% of cases (2.3% of controls) were HBsAg positive (6
). An Italian case-control study (21 cases and 686 controls) found a positive association between ICC and HCV but not HBV (4
). In that study, the prevalence of anti-HCV was 23.1% in cases compared with 6.1% in controls. The adjusted OR for ICC was 9.7 (95% CI, 1.6, 58.9) for anti-HCV. The previous case-control studies provide consistent evidence for a statistical association between HCV and ICC; however, case-control studies risk bias by their nature. Selection bias is a problem when controls without cancer are not representative of the base population from which cases were identified, and ascertainment bias exists when cases are more likely than controls to be tested for HCV. These biases were likely present and could have skewed the results toward finding a significant association. Further, the temporal relationship, the incidence rate of ICC, and the risk of ICC could not have been adequately examined with a case-control design.
Despite the doubling in relative risk, the absolute risk of ICC as measured by the incidence rate is quiet low (4 per 100,000) as compared to HCC (382 per 100,000) in this study. The only other cohort study we found showed a relatively high incidence of ICC among patients with HCV-related cirrhosis (5
). The Japanese investigators reported that 2.3% of 600 patients with HCV-related cirrhosis developed ICC during an average follow-up of 7.2 years. That study, however, had the disadvantage of lacking internal controls free of HCV infection, and, thus, it was unable to derive relative risk estimates. Therefore, in aggregate, evidence points to an association between HCV and ICC, an association supported further by our cohort study findings.
HCV is a strong risk factor for HCC, and hepatocytes and cholangiocytes have the same progenitor cell; therefore, it could be postulated that HCV could induce carcinogenesis in both cell types by the same mechanism. In at least one study, HCV RNA has been detected in ICC tissue, which further supports the potential role of HCV infection in the pathogenesis of cholangiocarcinoma (3
). Preliminary evidence indicates that HCV core protein (HCV C protein) may promote the cellular proliferation of hilar cholangiocarcinoma cells and inhibit apoptosis (19
). It may be that effects are indirect as well, with HCV damaging the liver, causing cirrhosis, and thereby increasing ICC risk. Torbenson et al. reviewed 1058 cases of liver explants in patients with HCV as well as HCV uninfected control groups; cases of chronic biliary tract disease were excluded. Dysplasia of the intrahepatic bile ducts was seen in 19/1058 (1.8%) of cases and was associated with chronic HCV infection and alcohol use; 10 of 19 cases (52.6%) of dysplasia were in patients with chronic HCV, and 4 of 19 (21.1%) were in patients with HCV with a history of alcohol use (20
Our results do not support an association between HCV infection and ECC. This study and other case-control investigations previously conducted—one hospital based (22
) and another population based (8
)—suggested no significant change in the risk of ECC with HCV infection. Therefore, results from all three studies are consistent and describe risk factor profiles indicating ICC and ECC as two distinct malignancies.
This is the first study to formally examine the association between HCV and pancreatic cancer. The mixed findings in this study merit additional investigation. The hazard ratios for pancreatic cancer were consistently increased (HR: 1.23–1.32) after controlling for matching variables, previous VA use, race, and era of military service. The associations were attenuated, however, and no longer statistically significant when we controlled for variables related to alcohol use, pancreatitis, or choledocholithiasis, cholelithiasis, or primary sclerosing cholangitis. Alcohol use as well as chronic pancreatitis are known risk factors for pancreatic cancer as well as associated with HCV, and thus these factors could have been confounders of the association between HCV and pancreatic cancer. We were limited in our ability to adjust for tobacco smoking, a known risk factor for pancreatic cancer. Tobacco use is likely to be common among veterans, however there are no to data to support unequal tobacco use among veterans based on their HCV status; such a difference would have to be present for there to be confounding. Because the diagnostic code for smoking is vastly underutilized, we did not use it for this purpose. However, We have identified two conditions strongly linked to tobacco smoking: lung cancer and COPD. We calculated the incidence rates for each condition in a similar method to that employed for the main cancer outcomes, where we considered only cases diagnosed 6 months or longer than the index date for HCV. The incidence rates for these two conditions were very similar between the two groups with or without HCV infection and therefore adjustment for these conditions in the HCV-pancreatic cancer analyses was unnecessary.
The biological reason for an association between HCV and pancreatic cancer is unclear. A previous reported that patients diagnosed with acute hepatitis C also suffer from acute pancreatitis (10
). In addition, serum levels of pancreatic enzymes have been shown to increase with the progression of liver disease in patients diagnosed with viral hepatitis (11
Findings in this study also confirmed the high risk of HCC conferred by HCV infection (HR = 15.09). These are consistent with findings of a published meta-analysis, where the pooled odds ratio from 32 case-control studies was 17.3 (95% CI, 13.9–21.6) for anti-HCV/HCV RNA positivity in the setting of HBsAg negativity (23
), and confer internal validity to the study. We did not examine HBV in the current study because we have previously shown that HBV related ICD-9 codes are poorly predictive of the serological status in medical record (24
Strengths of the study include its large sample size and relatively long follow-up, which allowed the examination of otherwise rare malignancies. The study examined users of the VA health care system, which tends to be relatively stable and provides standardized access to veterans, independent of socioeconomic status. Use of a HCV infection—free veterans population as an internal control group, rather than the general population, was meant to ensure the comparability of the two groups with regard to features other than HCV. In addition, we conducted internal checks, including tests of the predictive value of codes used to denote HCV infection (13
), and the careful verification of outcomes of interest—ICC and ECC-- through a limited individual chart review. This review validated the use of logical algorithms to identify these conditions as well as adding assurance about the codes themselves. We previously conducted a similar chart validation study for HCC and reported a PPV of 94% (16
In the analyses, we obtained consistent results after considering a broad range of confounders, which encourages confidence in our findings. Efforts were made to clearly establish the existence of HCV infection before diagnosis of malignancy, and therefore we considered only cancers diagnosed 6 months following the HCV index date. Furthermore, in additional testing, the risks of several negative control cancers, including prostate cancer, colon cancer, and melanoma, which have no plausible relation to HCV infection, were not elevated, confirming the reliability of our database (13
Limitations to our study are in general those imposed by work with administrative datasets. Reliance on ICD-9 codes and large administrative databases for identifying HCV infection was necessary because laboratory data are not collected systematically nationwide. While our internal chart review study validated this approach, some misclassification was still present given that only a small proportion of cancer cases were diagnosed in the single center where the chart review was conducted. Other factors that may have affected our results include the reality that cancer rates are higher in veterans than in the general population (25
), the study group was overwhelmingly male, and exclusive reliance on VA records fails to capture all outcomes. Other limitation included the possibility of differential ascertainment of potential confounders in cancer cases vs. non-cases. However, when we conducted a sensitivity analysis that considered only confounders present at baseline, the results were similar to those in the primary analysis. Lastly, we did not capture cancer outcomes that were diagnosed outside the VA. The potential effect of missing information is difficult to predict
In conclusion, among 146,394 HCV-infected U.S. military veterans we found a 2.55-fold elevated risk of ICC. Our study is the largest epidemiologic study ever conducted to evaluate the relationship between HCV and ICC, ECC, and pancreas cancer. We adjusted our analyses for multiple confounding variables and found that the relationship between HCV and ICC remained significantly positive and that the association between HCV and ECC remained negative. Results also suggested a possible relationship to pancreatic cancer that requires further study.
These findings associating HCV and ICC but not ECC support those of prior smaller epidemiologic studies as well as previously described carcinogenic mechanisms related to HCV infection. From a clinical perspective, early intervention strategies, including screening HCV-positive individuals earlier or more rigorously, may improve the outcomes for both HCC and ICC. Additional epidemiological studies of ICC are needed, and new evaluations of the effects of early interventions, including HCV treatment, on the molecular carcinogenesis of ICC are warranted.