In this large cohort study of healthy workers and their families in South Korea, we documented an excess risk of NHL among people infected with HBV (adjusted HR 1.74, 95%CI 1.45–2.09). A strength of our study is that HBV infection was documented prospectively, and we demonstrated that the increased risk of NHL persisted during follow-up throughout a 14-year period. Furthermore, NHL risk remained elevated after we adjusted for potential confounding factors including demographic characteristics, alcohol use, and liver function test abnormalities. We did not see associations between HBsAg status and risk of Hodgkin lymphoma, multiple myeloma, or leukemia, suggesting that HBV does not contribute to the development of these hematologic malignancies and lending specificity to the association with NHL.
Prior studies of the relationship between HBV and NHL risk have been conducted in both HBV endemic countries (e.g., South Korea, China) and non-endemic countries (e.g., U.S., Australia) (3
). As discussed in a recent systematic review (22
), previous retrospective case-control studies have generally supported an association (odds ratios 1.5–3.6) (3
). However, these studies have typically been somewhat small (N=200–600 cases) and have used unrepresentative convenience samples of controls (e.g., hospitalized patients with cancer, blood donors). In comparison, larger registry-based studies have provided mixed results. A population-based case-control study of elderly adults in the U.S. (N=33,940 NHL cases) failed to document associations between HBV infection and various specified NHL subtypes (10
), but HBV prevalence was very low (0.2%) and may have been under-ascertained. Two prior cohort studies of HBV infected persons, similar in design to our study but smaller, have also been published. Ulcickas Yood et al. observed an elevated risk of NHL in a cohort of 3888 HBV infected patients in a U.S. health maintenance organization (hazard ratio 2.30 based on 8 NHL cases) (11
). In contrast, Amin and coworkers found no elevation in NHL risk among 39,109 Australians reported to an HBV infection registry (23
The collected evidence from these studies, along with data from our study demonstrating the presence of HBV infection more than a decade before NHL diagnosis, suggest that HBV may play a causal role in the development of NHL. If HBV infection causes NHL, the mechanism is unknown. One plausible mechanism could be that HBV-related hepatitis might cause chronic activation of B-cells, predisposing to DNA damage and transformation into lymphoma. Similar pathways are proposed for HCV-mediated lymphomagenesis (12
). HBV DNA has been detected within peripheral blood B-cells (24
), but it is uncertain whether HBV could directly transform lymphocytes, because based on limited data (4
), HBV is not present in NHL tumor cells. In our study, NHL risk was increased among subjects with elevated ALT or AST, but the associations with HBsAg were not explained by these elevations, since we observed an independent effect of HBsAg positivity in multivariate models. Furthermore, we did not observe an additive risk for NHL among HBsAg positive people with elevated liver function tests. Likewise, Wang et al. did not find an elevated prevalence of serum HBeAg (a marker of high-level HBV replication and liver damage) among NHL cases (6
Because various NHL subtypes likely have differing etiology (25
), a strength of our study was the availability of subtype data for a large fraction of NHL cases. We found that HBsAg positive individuals had an elevated risk of DLBCL, the most common NHL subtype, which mirrors an association demonstrated for HCV (10
). We also saw suggestive, although non-significant, associations with follicular and T-cell NHLs. Nonetheless, the associations that we observed with specific NHL subtypes should be interpreted cautiously, because over half of NHLs were coded as “other/unknown” subtype, and some people had more than one NHL subtype indicated (although in most instances, this occurred when there was both a specified subtype and “other/unknown” subtype). We found HBsAg positivity to be associated with a significantly elevated risk for other/unknown NHLs, and it is possible that this association is due to a large fraction of undiagnosed DLBCLs in this group. The group of other/unknown NHLs may also include cases of marginal zone and lymphoplasmacytic NHLs, low-grade NHL subtypes that have been associated with HCV (10
). Of interest, a recent case report described an HBV-infected patient with splenic marginal zone NHL who developed a complete hematologic remission following a flare of her infection (27
), suggesting that the tumor was linked immunologically with the infection.
Based on a small number of cases, we observed a borderline increased risk for malignant immunoproliferation in association with HBsAg positivity. This finding is notable because this poorly specified category of neoplasms includes Waldenström macroglobulinemia, which is essentially synonymous with lymphoplasmacytic lymphoma. Waldenström macroglobulinemia and lymphoplasmacytic lymphoma have also been linked with HCV infection (26
). We are not aware of prior reports describing an elevated risk of immunoproliferative conditions among HBV infected people, although HBV is associated with the occurrence of other immune-related conditions including polyarteritis nodosa, glomerulonephritis, and potentially essential mixed cryoglobulinemia (28
Strengths and limitations of our study should be considered. Strengths include the large size of the KCPS cohort, its representativeness of a healthy segment of the South Korean population, and the prospective documentation of HBsAg results. Although HBsAg was measured at only a single timepoint for most subjects, South Korea exhibits an endemic pattern of HBV infection, and most HBsAg positive individuals likely had chronic infection that had been present since childhood and that persisted throughout our follow-up (17
). Indeed, for a sizeable subset of subjects, we were able to confirm that HBsAg positivity was chronic, and we showed that this group had similarly elevated risk (or perhaps even higher risk) for NHL and malignant immunoproliferation. Unfortunately, we could not include additional serum markers (e.g., HBeAg, HBV DNA) that would reflect severity of HBV infection. Our results are unlikely to be due to confounding by infection with HCV or HIV, because these infections are rare in South Korea, and we excluded people with evidence for these infections from our study sample. We used several systems of records to ascertain the occurrence of hematologic malignancy, and we had sufficient data on subtypes of NHL to examine them separately. However, we could not retrieve medical records to obtain additional information or confirm the NHL subtype diagnoses.
In a country such as South Korea where HBV prevalence is high, a substantial number of cancer patients are at risk of developing severe HBV-related liver disease with initiation of chemotherapy, and this risk may be reduced with use of appropriate chemoprophylaxis with lamivudine (29
). In addition to the 12.8% of South Korean NHL cases who were HBsAg positive, a large fraction of NHL patients would be expected to have serologic evidence for resolved HBV infection (i.e., absence of HBsAg with antibody to HBV core antigen), although we did not have data on this group. Recent evidence points to a high risk of HBV reactivation among such patients in association with use of rituximab-containing chemotherapy regimens (30
). Finally, even though we did not see an increased prevalence of HBsAg in association with other hematologic malignancies, HBsAg prevalence was nonetheless as high as in the Korean general population (~9%). HBsAg positive patients with these other malignancies would also be at high risk for HBV-related liver disease induced by cytotoxic chemotherapy. These considerations support systematic screening for HBV infection among patients with hematologic malignancy who live in endemic regions or have emigrated from these regions, and appropriate monitoring and prophylaxis of HBV infected patients to mitigate HBV-induced liver disease arising during chemotherapy (32
Additional research is required to clarify whether the association between HBV infection and NHL is causal. Even if the association proves causal, given the modest magnitude of the association between HBsAg positivity and NHL risk, HBV infection would account for only a small minority of NHL cases in endemic regions (e.g., population attributable risk = 6% in our Korean cohort) (33
). Thus, while universal HBV vaccination is effective in preventing HBV infection and dramatically reduces the occurrence of liver cancer in endemic regions (34
), vaccination programs would be expected to have a limited effect on NHL incidence. Nonetheless, among HBV infected people who develop NHL, it is possible that HBV explains a sizeable fraction of cases (e.g., attributable risk = 43% in our cohort) (33
). For HCV-infected patients with low-grade NHL (especially marginal zone lymphomas), HCV treatment appears effective in leading to hematologic remission (35
). Thus, we speculate that therapy directed at HBV in similar low-grade NHLs might similarly lead to a clinical response and obviate the need for chemotherapy. It will be important to evaluate this possibility in appropriate clinical series.