In this study, we confirmed previously reported risk associations of pancreatic cancer with diabetes mellitus, cigarette smoking, and positive family history of cancer.23,24,28-30
Most important, we observed an association between past exposure to HBV and risk for pancreatic cancer development.
Our finding of a relationship between chronic HBV infection and pancreatic cancer perhaps should not be surprising for two reasons. First, findings from several previous studies indicate that HBV may replicate within the pancreas. Evidence for such replication includes the following: (1) detection of HBsAg in pancreatic juice among patients with acute and chronic HBV infection.18
This finding is analogous to detection of HBsAg in bile as a consequence of viral replication in the liver. (2) Detection of HBsAg and HBV core antigen in the cytoplasm of the acinar cells of the pancreas.19
(3) Confirmation of HBV-DNA integration in pancreatic tissue and pancreatic metastases to the liver in patients with HBV infection.11
(4) HBV reinfection and recurrence after liver transplantation, which may support the presence of extrahepatic reservoirs of the virus.31-33
(5) Demonstration in animal models that HBV infection can produce hepatic diseases similar to that produced by HBV in man (eg, woodchuck HBV in woodchucks and duck HBV in Pekin duck).34-36
Previous studies reported detection of replication-specific forms of viral nucleic acid, with evidence for duck HBsAg and duck HBV core antigen in pancreatic cells of congenitally infected Pekin ducks.37
The second reason why our finding of a relationship between chronic HBV infection and pancreatic cancer perhaps should not be surprising is that there have previously been clinical observations of impairment in pancreatic exocrine function in patients with chronic viral infection. Specifically, there have been reports of elevation of serum and urinary levels of pancreatic enzymes in patients with chronic HBV infection21,22
and evidence that acute pancreatitis may be an extrahepatic manifestation or a complication of fulminant, acute, or chronic vial hepatitis.38-41
A recent report showed that among 72 patients with acute viral hepatitis, seven patients (9.7%) developed acute pancreatitis.42
Interestingly, a follow-up study among Koreans43
reported that baseline abnormal levels of liver enzymes (AST and ALT) were significantly associated with pancreatic cancer development. However, the patients’ hepatitis virus infection status was not presented by the investigators.
Despite our findings and the evidence from previous studies outlined above, whether and to what extent chronic HBV infection increases the risk of pancreatic cancer is not clear. This study is the first to report an association between past exposure to HBV and pancreatic cancer. The risk was observed among patients with confirmed HBsAg-negative and anti-HBc–positive status, which suggests the possibility of occult HBV infection and long-lasting persistent viral infection. The clinical relevance of occult HBV infection is well documented.44,45
Occult HBV infection has been described in patients negative for HBsAg who have been previously exposed to HBV and recovered from acute or chronic infection46,47
as well as in patients with HCV infection,48-50
patients on hemodialysis,51
and among drug users.52
The underlying reason for lack of detectable HBsAg in patients with occult HBV infection is unclear. However, host immune response53,54
and HBV mutation that affect HBsAg antigenicity and synthesis55,56
have been hypothesized. Currently, it is generally accepted that occult HBV infection among patients without any serologic evidence for HBV infection is a risk factor for HCC development.57-59
The mechanisms whereby HBV might induce pancreatic cancer are unclear. However, in the case of HCC, HBV-DNA integration has been detected in hepatocytes before tumor development among patients positive and negative for HBsAg, which may enhance chromosomal instability and facilitate HCC development.60,61
In addition, the oncogenic role of the HBs and HBx proteins has been documented. HBx protein has been shown to transactivate both HBV and cellular genes, which may alter host gene expression and lead to HCC development.62
Meanwhile, the direct necrotic and inflammatory effect of viral hepatitis with cirrhosis cannot be excluded.63
On reviewing the medical records of patients with pancreatic cancer with anti-HBc–positive/anti-HBs–negative status (n = 12; ), we found that three patients (25%) had radiologic evidence of cirrhosis and two patients (16.7%) had pathologic evidence of chronic pancreatitis. However, our observation of the lack of association between HCV and pancreatic cancer suggests that direct inflammatory response plays a lesser role than HBV-DNA integration in pancreatic cancer development.
Another key finding of our study was the pancreatic cancer risk modification among diabetic patients with HBV infection. A high frequency of HBV and HCV infection was previously reported in diabetic patients.64
We previously demonstrated a synergism between diabetes and hepatitis virus in the development of HCC, a disease for which HCV, HBV, and diabetes are major risk factors.6
It is possible that the joint effect of these risk factors may increase susceptibility to chronic inflammation, DNA damage, and pancreatic cancer development.
Our study has some limitations. Because most patients with pancreatic cancer were diagnosed at a late stage, surgical tissues were not available to perform tumor HBV-DNA analysis. Moreover, we can not rule out the possibility of selection bias resulting from the use of healthy controls who were accompanying patients with cancer to the hospital; this may have overestimated or underestimated the prevalence of HBV infection among control participants. However, it is less likely that our finding of the positive relationship between HBV and pancreatic cancer is confounded by selection bias for the following reasons: (1) controls represent the study hospital from which patients with pancreatic cancer were selected23,24
; (2) all our points of estimate were adjusted for educational level as a surrogate marker for socioeconomic status and state of residency, as well as for significant demographic and risk factors of pancreatic cancer; (3) control recruitment was restricted to individuals not having accompanying GI cancers, including HCC, a primary liver cancer that is highly related to HBV and HCV infection; (4) the prevalence of anti-HBc among our controls was consistent with the United States population prevalence of 3% (95% CI, 2.4% to 3.7%)5
; (5) the prevalence of HBsAg among our controls was not significantly lower than the prevalence of the United States population of 0.3% (95% CI, 0.2% to 0.5%).65
Finally, the prevalence of diabetes mellitus and other environmental risk factors were comparable to other population-based studies.66
However, one may argue that HBV is a sexually transmitted disease, and the prevalence of HBV among our controls can be altered by sexual behavior and by the prevalence of the virus among their sexual partners. Nevertheless, the controls were not spouses of the patients with pancreatic cancer or of patients with other virus-related cancers. Moreover, the marital status of cases and controls are similar ().
In conclusion, our findings raise two crucial points. The first point is that our results indicate that past exposure and possibly chronic infection with HBV may be related to pancreatic cancer development. We found no significant association between HCV infection and pancreatic cancer. We believe that our sample size of the current matched case-control study provided more than 90% power to determine a significance relationship between past exposure to HBV infection and pancreatic cancer.67
However, further studies, including clinicopathologic investigations, are necessary for thorough evaluation of the HBV-pancreatic cancer relationship.
The second point raised by this study is that the observed high prevalence of anti-HBc–positive status in patients with pancreatic cancer with or without anti-HBs may be an indication of an occult HBV infection. Therefore, there is a potential for reactivation of HBV among these patients when they receive chemotherapy treatment. Hepatic failure is a significant problem related to HBV reactivation in chemotherapy-treated patients with cancer.15-17
The mechanism of HBV reactivation during chemotherapy is not clear. It has been suggested that chemotherapy may enhance the replication of HBV.68-70
Liver failure may then develop after treatment cessation as a consequence of rebound recovery of the immune function to attack the infected liver.71-73
Given that pancreatic cancer is often surgically unresectable, chemotherapy is the most common intervention in managing patients with pancreatic cancer. Reactivation of occult HBV infection was previously reported in a single immunosuppressed patient with pancreatic cancer.14
However, in this study, 10 (83%) of the 12 patients with confirmed HBsAg–negative, anti-HBc–positive, anti-HBs–negative disease did not receive chemotherapy before blood was drawn and thus would not have been at risk for viral reactivation and hepatitis. Therefore, if an HBV-pancreatic cancer association is confirmed, oncologists may want to consider checking HBV status of patients before beginning chemotherapy. In addition, plasma or serum HBV-DNA may be necessary to perform among those with evidence for past exposure to HBV (anti-HBc–positive) during the course of treatment. Evidence for HBV infection among these patients should be closely monitored by hepatologists during their chemotherapy treatment. A recent report revealed a preventive role of lamivudine in persons with HBV infection who are undergoing chemotherapy.74
Future collaboration between hepatologists and oncologists may assist in developing guidelines for management of HBV infection among patients with cancer.
Should the association between HBV infection and pancreatic cancer be confirmed by other studies, such findings would offer an important additional insight into the etiology of pancreatic cancer and may identify a readily modifiable risk factor that can decrease the risk of pancreatic cancer.