Incidence of Extrahepatic Cancers Among Individuals With Chronic Hepatitis B or C Virus Infection

A Nationwide Cohort Study

Chai Yeong Hong; Dong Hyun Sinn; Danbee Kang; Seung Woon Paik; Eliseo Guallar; Juhee Cho; Geum-Youn Gwak


J Viral Hepat. 2020;27(9):896-903. 

In This Article


In this large population-based study, we found that chronic HBV or HCV infection was associated with increased risk of multiple extrahepatic cancers as well as liver cancer. Specifically, chronic HBV infection was associated with increased risk of haematologic malignancy, gallbladder cancer, pancreas cancer, stomach cancer, lung cancer, colorectal cancer and thyroid cancer. Chronic HCV infection was associated with increased risk of testis cancer, gallbladder cancer, prostate cancer and thyroid cancer. Our data imply that patients with viral hepatitis warrant careful attention due to their increased risk of extrahepatic cancer as well.

Several studies have examined the association between HBV infection and nonliver cancers. A Chinese study by Song et al reported that participants who were HBsAg seropositive (n = 15 355) had a higher risk of stomach cancer (HR: 1.41; 95% CI, 1.11–1.80), colorectal cancer (HR: 1.42; 95% CI, 1.12–1.81), oral cancer (HR: 1.58; 95% CI, 1.01–2.49), pancreatic cancer (HR: 1.65; 95% CI, 1.03–2.65) and lymphoma (HR: 2.10; 95% CI, 1.34–3.31) than participants who were HBsAg seronegative (n = 481 377).[3] In a study using the Taiwan National Health Insurance Research Database, patients with HBV infection exhibited an increased risk of colorectal cancer (HR: 1.36, 95% CI: 1.09–1.70), gallbladder and extrahepatic bile duct cancer (HR: 2.05, 95% CI: 1.07–3.91), pancreatic cancer (HR: 2.61, 95% CI: 1.47–4.61), kidney cancer (HR: 1.72, 95% CI: 1.10–2.68), ovarian cancer (HR: 2.31, 95% CI: 1.21–4.39) and non-Hodgkin's lymphoma (HR: 2.10, 95% CI: 1.25–3.52).[4] Other prospective studies have also reported that HBV is associated with pancreatic cancer (HR: 5.73)[5] and lymphoma (HR: 2.80; HR: 4.89).[6,7]

Several epidemiological studies have also explored the relationship of HCV with nonliver tumours. In a Taiwanese study, patients with HCV infection exhibited an increased risk of gallbladder and extrahepatic bile duct cancer (HR: 2.60, 95% CI: 1.42–4.73), ovarian cancer (HR: 5.15, 95% CI: 1.98–13.4) and non-Hodgkin's lymphoma (HR: 2.30, 95% CI: 1.34–3.96).[4] Rustagi et al have demonstrated that HCV is an independent risk factor for colorectal adenoma and reported that HCV is associated with a 2.04-fold higher risk of colorectal cancer.[22] Italian case-control studies by Antonelli et al and Montella et al have shown consistently increased prevalence and risk of thyroid cancer among patients diagnosed with HCV infection.[23,24] In a prospective study done by Su et al. the incidence of oral cancers was 2.28-fold higher (6.15 versus 2.69 per 10 000 person-years) among patients with HCV than in the nonviral hepatitis group (HR: 1.9, 95% CI: 1.2–3.0).[25]

A few plausible mechanisms can explain the causality of HBV or HCV infection on extrahepatic cancers. HBV is known as a hepatotropic virus, replicating in hepatocytes and causing HCC.[26,27] However, Song et al observed that, in most patients with stomach cancer and pancreatic cancer, HBX protein expression and anti-HBc protein expression were higher in cancer cells than in healthy parts of the specimens.[3] Thus, HBV might be harboured in nonliver cells and induce local inflammation. Chronic inflammation induced by HBV infection might play a role in the development of cancer. Viral oncogenic HBX protein may play a direct role in the development of cancer. Likewise, some studies have suggested that X protein from HBV can bind and interfere with components of the DNA repair machinery and p53 tumour suppressor in response to DNA damage, thereby increasing the risk of colorectal cancer.[28,29] In addition, the HBV X protein is highly expressed in the ovarian cancer cells of Chinese women, implying that it might be involved in the carcinogenesis of ovarian cancer.[30] HCV has been isolated from extrahepatic organs including kidney, oral mucosa and blood vessels.[31–33] It has been postulated that HCV plays a role in the development of extrahepatic tumours through various molecular, genetic and environmental mechanisms, including complement-mediated tissue injury, inhibition of lymphocyte-mediated apoptosis and mutation of somatic genes like proto-oncogenes or tumour suppressor genes.[33–36] We also observed a stronger association between chronic HBV or HCV infection and extrahepatic cancer development in certain subgroups (eg ever-smokers, ≥light alcohol drinkers and individuals without comorbidities), which requires further evaluation.

Our study has some limitations. The NHIS-NSC does not contain factors that may be related to the development of a specific type of cancer (eg Helicobacter pylori infection for stomach cancer), environmental exposure to chemicals, history of substance use or diet patterns. Therefore, we could not rule out the potential confounding effects of these factors. In addition, other viral infections such as Epstein-Barr virus, human papilloma virus and human immunodeficiency virus (HIV), which may coexist with HBV or HCV infection, may increase the risk of extrahepatic cancer.[37] Of these infections, our dataset had information only on coexisting HIV infections. In our study population, there were only four individuals infected with both hepatitis virus and HIV, and the potential impact of coexisting HIV infection on the study outcome is likely to be low. In this study, chronic HBV infection was defined as the presence of any ICD codes representing chronic HBV infection during the study period, presuming that they are vertical transmission, a major mode of HBV infection in Korea.[10] However, some patients may have acquired HBV infection in adulthood, which we did not have detailed information. Also, chronic viral hepatitis infection is a dynamic process that includes acute infection, transition to chronic persistent infection, spontaneous resolution and cure by antiviral treatment, and different phases of infection may affect the risk of extrahepatic cancer development differently. Additional studies with detailed information regarding the phase of chronic viral hepatitis infection are necessary to confirm our study findings. In addition, because we used claims data, it is possible that we miss unscreened or undiagnosed individuals with HBV or HCV infection and misclassified them as not infected.[38,39] The small number of events for specific rare cancers may reduce the statistical power of this study. However, this is a large population-based study using national representative data over several years of follow-up. The large sample size and the availability of data over an extended period of time are strengths of our study.

In summary, chronic HBV or HCV infection was not only associated with an increased risk of liver cancer, but also associated with an increased risk of multiple extrahepatic cancers, especially haematologic malignancy, oesophageal cancer, pancreas cancer, stomach cancer, lung cancer, colorectal cancer and thyroid cancer. Thus, physicians should pay attention to the development of extrahepatic cancers as well as liver cancer in these patients.