Prevalence and association of hepatitis C virus infection with different types of lymphoma

To the Editor, Hepatitis C virus (HCV) is the most common blood-borne infection in the United States, affecting about 4.1 million people (1.6%) of the US population. Chronic HCV infection has been associated with extrahepatic hematological manifestations such as mixed cryoglobulinemia and lymphoma. Several reports support an association of HCV infection with the development of non-Hodgkin lymphomas (NHLs). Furthermore, eradication of the chronic HCV infection has been correlated with regression of certain NHLs. However, studies of patients with HCV infection and specific histological types of NHL and Hodgkin lymphoma (HL) are limited. We thus sought to determine the prevalence of HCV seropositivity in patients with different subtypes of NHL and HL and its association with these subtypes. We conducted a case–control study, abstracting data from the electronic medical records of cancer patients screened for HCV antibodies (anti-HCV) at The University of Texas MD Anderson Cancer Center from June 2004 to May 2014. HCV cases were defined as patients who tested positive for antiHCV. Among this group, patients with available information on detectable HCV-RNA or history of HCV infection treatment were considered to be chronically infected with HCV. NHL and HL cases were classified for subtype-specific analysis using the International Classification of Diseases, Ninth Revision, Clinical Modification codes and nested classification by the International Lymphoma Epidemiology Consortium Pathology Working Group. Controls were cancer patients without lymphoma and hepatocellular carcinoma who were screened for anti-HCV during the same period. The v test was used to calculate prevalence of HCV-seropositivity and the odds ratio (OR) as a measure of association with lymphoma. Bonferroni correction was performed to adjust p values, reducing false-positive rates owing to multiple testing. Hence, the p value for statistical significance was 0.0036. All hypothesis testing was two-sided. Statistical analyses were conducted using the Stata/IC software program (version 11.0; StataCorp, College Station, TX). The study was approved by the MD Anderson Institutional Review Board. Of 34,545 patients tested for anti-HCV during the study period, 8,310 (24.1%) had lymphoma (NHL, 7,030 [84.6%]; HL, 1,280 [15.4%]). Of these patients, 198 (2.4%) were positive for anti-HCV and considered cases, consisting of 173 with NHLs and 25 with HLs. We confirmed chronic HCV infection in 114 of the 173 (65.9%) NHL cases and 11 of the 25 (44.0%) HL cases. The overall prevalence of HCV-seropositivity was higher in the NHL patients (2.5%) than in the HL patients (1.9%) or controls (1.7%). HCV-seropositivity was significantly associated with NHL (OR, 1.5 [95% confidence interval (CI), 1.2–1.8]; p5 0.0030) but not HL (Table 1). Of the 173 patients with NHL, 153 (88.4%) had B-cell NHL, 16 (9.2%) had T-cell NHL and 4 (2.3%) had other lymphomas. When compared with that in the controls, HCV prevalence was higher in patients with B-cell NHLs (2.6%), with a significant association between HCV-seropositivity and B-cell NHL (OR, 1.6 [95% CI, 1.3–1.9]; p< 0.0001). The HCV prevalence in the T-cell NHL cases was similar to that in the controls (1.7%). In a subtype-specific analysis, the most common B-cell NHLs in the patients were diffuse large B-cell lymphoma (DLBCL; 43.9%), marginal zone (MZ) lymphoma (11.6%) and follicular lymphoma (10.6%). The prevalence of HCV-seropositivity was greater in the cases than in the controls for all B-cell NHL subtypes except follicular lymphoma, with the highest prevalence noted for MZ lymphoma (3.9%), Burkitt lymphoma (3.8%) and DLBCL (3.7%) (Table 1). Compared with controls, DLBCL had a 2.2-fold greater association with HCV-seropositivity (95% CI, 1.7–2.8; p< 0.0001), and MZ lymphoma had a 2.3-fold greater association with it (95% CI, 1.4–3.5; p5 0.0006). The most prevalent T-cell NHL was mycosis fungoides/S ezary syndrome, and patients with it had a slightly higher HCV infection prevalence (1.9%) than did the controls (1.7%). The predominant HL subtype was nodular sclerosis, and patients with it had an HCV infection prevalence of 2.2%. The association between HCV-seropositivity and either T-cell NHL or HL subtypes was not statistically significant. This is one of the largest studies to systematically evaluate the association of anti-HCV with different subtypes of NHL and HL. We found that HCV-seropositivity was associated with some but not all B-cell NHL subtypes. This finding enabled us to better define the subset of non-liver cancers linked with chronic HCV infection. The association of HCV-seropositivity with B-cell NHL but not T-cell NHL or HL can be supported by a proposed mechanism of chronic antigenic stimulation by HCV in specific B-cell clones, which induces malignant lymphoproliferation. In addition to generalized binding of HCV E2 protein to CD81, the HCV NS3/IgG antigen binds with a B-cell receptor, explaining selective proliferation of B-cell subtypes analogous to B-cell receptor segments, such as DLBCL and MZ lymphoma. Le tt er to th e E di to r