Hepatitis C virus and extrahepatic malignancies: where we stand and how we can advance the field

Chronic hepatitis C virus (HCV) infection is increasingly recognized as a cause of not only cirrhosis and hepatocellular carcinoma but also a wide range of systemic disorders, including extrahepatic malignancies (1,2). Notably, its association with cancers—especially non-Hodgkin lymphoma (NHL)—has drawn growing interest (2). Epidemiological and clinical studies showed that HCV infection was more common in patients with NHL than in the general population, with a relative risk of 1.7–3.0 (2). Follicular center lymphoma, marginal zone lymphoma (MZL), and diffuse large B cell lymphoma (DLBCL) occurred more frequently in HCV-infected individuals (3), whereas a French cohort—reflecting low national HCV prevalence—found low-grade MZL and high-grade DLBCL to be most common (4).

Beyond lymphoma, several studies have evaluated HCV-related extrahepatic malignancies. A U.S. registry-based case-control study of older adults reported positive associations between HCV and cancers of the bile ducts, pancreas, anus, and certain non-melanoma skin cancers, as well as myelodysplastic syndrome, while inverse associations were seen for uterine and prostate cancers (5). These associations persisted after sensitivity analyses and socioeconomic adjustment (5). A systematic review (6) found limited evidence—beyond B-cell NHL—supporting increased risks of extrahepatic malignancies in HCV-infected individuals, noting only intrahepatic cholangiocarcinoma and a possible link with pancreatic cancer. Similarly, the Japan Public Health Center (JPHC) cohort of 20,360 individuals followed for ~16 years reported no significant association between HCV or HBV infection and pancreatic cancer (7). Beyond NHL and cholangiocarcinoma, recent meta-analyses suggested associations between HCV infection and pancreatic adenocarcinoma (8), colorectal neoplasia (9), lung cancer (10), and renal cell carcinoma (11). A French cohort reported higher oral cavity cancer incidence and lower prostate cancer incidence in HCV-infected individuals (12). Nationwide data from Korea showed increased risks of testicular, gallbladder, prostate, and thyroid cancers (13). In Taiwan, HCV was linked to gastric (14) and esophageal cancers (15), and viral eradication reduced gastric cancer risk, especially in younger patients (16). Even high-quality studies reported inconsistent findings, likely reflecting regional or genetic factors that influence HCV-related carcinogenesis. This highlights the importance of separating universal risks, such as NHL, from region-specific risks when assessing HCV’s oncogenic potential.

Tao et al. (17) investigated the impact of antiviral therapy on the incidence of extrahepatic malignancies other than hepatocellular carcinoma among patients with chronic HCV infection. They conducted long-term follow-up—up to 15 years—of more than 17,000 HCV-infected individuals across four U.S. healthcare systems, focusing on four cancers: lung cancer, NHL, breast cancer (in women), and prostate cancer (in men) (17). Their analyses employed multivariable models incorporating timevarying covariates, as well as generalized estimating equation (GEE) models treating death as a competing risk or secondary endpoint. Treatment-selection bias was addressed using time-varying propensity scores (17).

A key finding was that patients who received interferon-based therapy or direct-acting antivirals (DAAs) had significantly lower lung cancer risk compared with untreated individuals, regardless of treatment success (17). The adjusted hazard ratio (aHR) for patients who achieved sustained virologic response (SVR) was 0.35 [95% confidence interval (CI): 0.24–0.52], while even nonSVR patients demonstrated a similarly reduced risk (aHR 0.34; 95% CI: 0.21–0.55) (17). In contrast, for NHL, a reduced risk was observed only among patients who achieved SVR (aHR 0.42; 95% CI: 0.21–0.84), whereas no significant risk reduction was noted in those without SVR (17). No associations were identified between antiviral therapy and the risks of breast cancer or prostate cancer (17). A retrospective cohort study using a large U.S. nationwide database (18) did not evaluate individual cancer types; however, Tao et al.’s findings regarding lung cancer and NHL were consistent with the observation that DAA-treated patients had significantly lower risks of extrahepatic malignancies compared with untreated individuals (18). In contrast, the results for breast and prostate cancer did not align with those reported in the study using the U.S. nationwide database (18).

The authors highlighted key strengths, including a large and diverse cohort, long follow-up, time-varying analyses, and methods addressing competing risks (17). They also acknowledged limitations such as variable screening practices, potential baseline underdiagnosis, small case numbers for certain cancers, limited lifestyle data, and the lack of comparisons with uninfected populations (17). Despite these limitations, the study’s real-world design enhances its generalizability. As the causal link between HCV and extrahepatic malignancies remains debated, understanding how antiviral therapy and viral eradication modify cancer risk is particularly important.

The authors proposed potential mechanisms underlying the reduced lung cancer risk, citing three key studies (17). Viral eradication following HCV treatment was associated with decreased plasma levels of immune checkpoint molecules such as programmed cell death-1 and its ligand programmed death-ligand 1 (PD-L1), inflammatory chemokines including C-X-C motif ligand 8 (CXCL8) and CXCL10, and the anti‑inflammatory cytokine interleukin-10, along with reductions in multiple interferonstimulated genes (19). Treatment with pegylated interferon-α plus ribavirin led to down-modulation of serum levels of major Th1 and Th17 proinflammatory mediators and profibrotic growth factors within 12 weeks of therapy initiation (20). Following DAA therapy, expression of the immune checkpoint molecule T cell immunoglobulin and mucin domain 3 and PD-L1 decreased in both adaptive and innate immune cells, suggesting a potential restoration of exhausted adaptive immune responses (21). Collectively, these findings indicate that attenuation of chronic inflammation and systemic immune activation may contribute to a more favorable antitumor immune environment.

However, while these biological mechanisms adequately explain the reduced risk among patients achieving SVR, the finding that lung cancer risk was similarly reduced in non-SVR patients—where viremia persists—presents a major methodological red flag. It is biologically implausible to attribute a comparable risk reduction in treatment failures to the same antiviral pathways. Instead, this paradoxical observation strongly suggests the presence of residual confounding, selection bias, or a “healthy-user effect” (healthcare engagement bias). Individuals who actively undergo complex antiviral therapies, regardless of treatment outcome, often exhibit unmeasured health-seeking behaviors—such as higher smoking cessation rates, better adherence to screening, or general lifestyle modifications—compared to the untreated population. This critical limitation highlights the inherent difficulty of fully controlling for confounding by indication in retrospective database studies. Therefore, rather than reflecting a direct oncogenic influence of HCV or a true therapeutic effect of the antivirals on lung tissue, these findings underscore how healthcare engagement can distort epidemiological associations in large-scale cohorts.

The finding that reduced NHL risk was limited to patients who achieved SVR aligns well with the mechanisms described in the aforementioned studies (19-21), including attenuation of chronic inflammation, down-regulation of immune checkpoint molecules, and normalization of immune parameters. It is also consistent with the hypothesis—discussed later—that HCV infects B cells and promotes lymphomagenesis through chronic antigenic stimulation (22). Furthermore, these observations support results from a prospective study in which DAA therapy for HCVassociated indolent lymphomas yielded an overall lymphoma response rate of 45%, including complete responses in 8 patients (20%) and partial responses in 10 patients (25%) (23). Similarly, a retrospective cohort study of 20 HCV-infected patients with DLBCL demonstrated that DAA therapy was independently associated with improved disease-free survival when combined with chemotherapy (24). Collectively, the findings from Tao et al. (17) provided further evidence supporting the association between chronic HCV infection and NHL.

In contrast, Tao et al. found no significant association between antiviral therapy and the risks of breast or prostate cancer (17). This lack of association does not strongly support a causal link between HCV infection and these malignancies. Regarding breast cancer, previous studies—including the U.S. registry-based case-control study mentioned earlier (5)—have also reported no significant association with HCV infection. Thus, further investigation using more refined study designs, such as prospective cohorts with more comprehensive adjustment for carcinogenic risk factors or analyses stratified by geographic and population differences, may be warranted. The potential relationship between HCV infection and prostate cancer risk will be discussed later.

From a statistical perspective, the use of time-varying propensity scores is appropriate in clinical settings where treatment initiation varies across individuals and covariates change over time. Multinomial GEE models are well suited for outcomes with more than three categories and for repeated‑measures data, enabling estimation of population‑averaged effects. In this study, the four cancer types constituted the outcome categories, and accounting for within‑individual correlation was essential, making this approach methodologically sound. The use of cause-specific discrete hazard ratios was also appropriate, as it accommodates competing risks within discrete time intervals and allows for estimation of cancer-specific risks, thereby facilitating clearer interpretation of biological mechanisms and treatment effects.

Tao et al. examined four cancers (17). NHL is an obvious choice, and lung and breast cancers are supported by prior meta-analytic evidence (8,25). In contrast, the justification for including prostate cancer is weak: a French cohort showed lower incidence in HCV-infected individuals (12), a meta-analysis found a nonsignificant trend toward reduced risk (11), and a U.S. survey reported no association (26). The null findings in the present study (17) therefore align with these literatures (11,26). Given the heterogeneity surrounding prostate cancer and HCV infection, further prospective, well-adjusted, or region-stratified analyses are needed. Applying the same analytic approach to cancers more plausibly linked to HCV—particularly intrahepatic cholangiocarcinoma—would be especially informative.

In addition to the limitations acknowledged by the authors, potential unmeasured confounders warrant consideration. First, the duration of HCV infection prior to treatment was not evaluated. Because chronic antigenic stimulation is a key driver of HCV-related extrahepatic oncogenesis, particularly lymphomagenesis (22), the cumulative exposure time—or the interval between HCV acquisition and antiviral therapy—could significantly influence cancer risk. Similarly, the age at infection and route of transmission, both of which accelerate hepatic fibrosis progression (27), might also affect extrahepatic malignant transformation. Future prospective studies with well-defined infection dates are needed to clarify these duration-dependent risks.

Second, geographic and genetic diversity may limit the generalizability of Tao et al.’s findings (17). While they noted racial differences in lung cancer risk, global literature underscores substantial regional heterogeneity in HCV-associated malignancies. For instance, the prevalence of HCV in B-cell NHL varies dramatically by country (28), and certain urologic cancer risks demonstrate opposing geographical patterns between North America and Europe (11). Furthermore, host genetic factors, such as polymorphisms in B-cell activating factor or the human leukocyte antigen-G, are increasingly implicated in HCV-related carcinogenesis (29,30). Therefore, expanding these analyses globally is essential to distinguish universal HCV-related cancer risks from those dictated by regional or ethnic variations.

Third, although Tao et al. appropriately adjusted for key time-varying covariates like type 2 diabetes, body mass index (BMI), and smoking (17), future studies should expand this panel. Confounding comorbidities, such as chronic kidney disease—which is independently linked to several extrahepatic cancers (31)—and detailed alcohol consumption history (32), should be rigorously controlled to isolate the direct oncogenic effects of HCV.

Understanding HCV-related extrahepatic malignancies requires consideration of both direct viral effects and genetic or environmental modifiers. When HCV’s direct oncogenic influence is weak, environmental risk reduction is critical; when strong, early antiviral therapy—even in childhood—may be warranted. Determining whether these associations are direct or indirect remains a central research question. This will require not only epidemiological studies but also mechanistic studies, including basic research and genetic analyses such as single nucleotide polymorphism and genome-wide association studies.

In conclusion, a comprehensive, multi-pronged research approach is required. Global analyses combined with region-specific comparisons will help distinguish universal HCV-related cancer risks from those influenced by regional or ethnic factors. Cohorts with clearly defined infection dates are especially important, and studies should adjust broadly for background cancer risks while prospectively assessing extrahepatic malignancies in infected versus control populations. Given the scarcity of prospective data—aside from the JPHC cohort (7)—firm conclusions remain limited for cancers other than NHL and cholangiocarcinoma. Broad, well-designed prospective studies across diverse populations are essential.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0742/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0742/coif). The author has no conflicts of interest to declare.

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