Retrospective Study of the Incidence and Risk Factors for Hematological Malignancies in Patients with Hepatitis B Virus Infection

Background: Hepatitis B infection may be associated with an increased risk of non hodgkins lymphoma, especially diffuse large B cell lymphoma. Whether an intact immune system is required hepatitis B mediated lymphomagenesis and if factors such as other viral co infections and paraproteins may further compound this risk remains unclear. We retrospectively studied our large database of HBsAg positive patients for diagnoses of hematological malignancies or premalignant disorders (HM) and the risk factors for their development.

Methods: Patients over the age of 18 with at least one positive HBsAg test between Jan 1^st 2001 and Dec 31^st 2011 were identified using the medical center database, clinical looking glass. Data were collected regarding demographics, HIV and hepatitis C status. Serum protein electrophoresis tests done after the HBsAg test were reviewed. Results of all biopsies performed for each patient, ICD9 and cancer registry diagnoses were reviewed for biopsy confirmed diagnoses of a HM. Liver biopsy results were reviewed for evidence of chronic hepatitis changes.

Results: 3177 of 216,522 patients (1.5%) tested were HBsAg positive. Mean age of the HBsAg positive group was 43 years, 56% were male. 44% were black, 8% white and 7.4% were Asian. 33.6% of these patients had two positive HBsAg tests 6 months apart. 10.3% of patients underwent a liver biopsy and 9.4% of patients had biopsy changes consistent with chronic hepatitis.

Of the 3177 patients, 4.9% (155 patients) had a biopsy of any lymphatic tissue or bone marrow performed. 2.2 % (71 patients) had a hematological malignancy or premalignant disorder diagnosed. 0.4% (12 patients) had an insufficient specimen for diagnosis and were excluded from further analysis. Of the 71 patients with a HM, 30 (42.3%) had a high grade B or T cell lymphoma; 12 (16.9%) had myeloma or smoldering myeloma; 11 (15.5%) had a low grade lymphoma; 6 (8.4%) had myelodysplasia, myeloproliferative disorder or acute leukemia and 11 (15.5%) had a premalignant disorder including multicentric castleman, MGUS or NK cell lymphocytosis. 47% of high grade lymphomas occurred in an extranodal location.

Within the HBsAg positive population, HM positive patients (n=71) compared to HM negative controls (n=3094) were significantly older (52.5 vs 43 yrs, p<0.001) and more likely to be male (73.2% vs 55.5% p:0.003) HM positive patients were tested for other viral coinfections more often and were more likely to be seropositive for HIV (62.7% vs 31.4%, p<0.001) and Hepatitis C (20% vs 10.7%, p:0.014) . HM positive patients were also tested for paraprotein more frequently and had a significantly higher prevalence of paraproteinemia than their HM negative counterparts. (58.1% vs. 15.4%, p<0.0001) On multivariate analysis, male gender (OR: 2.4, 95% CI:1.1-4.9), paraprotein positivity (OR:16.3, 8.0-33.7) and HIV positivity (OR:2.6, 1.4-4.9) but not Hepatitis C positivity emerged as independent risk factors for development of HM. (Table 1)

Of those patients with HBsAg positivity diagnosed with hematological malignancies, patients co-infected with HIV and hepatitis B had a significantly higher proportion of DLBCL cases as compared to those with hepatitis B alone (46.9% vs 10.5%, p:0.013).

Conclusions: Concurrent HIV infection and paraproteinemia were associated with increased risk of HM in our HBsAg positive patients. Of those who develop HM, HIV and Hepatitis B co-infected patients have a higher proportion of DLBCL. These data suggest synergistic mechanisms of Hepatitis B and HIV in abnormal B cell proliferation. Being a retrospective study, inherent biases exist in terms of which patients get certain tests. Further work is required to confirm these findings and to elucidate the mechanisms of lymphomagenesis in this population.