Lymphopenia Is an Adverse Prognostic Factor in EBV-Positive Diffuse Large B-Cell Lymphoma

Background: EBV-positive diffuse large B-cell lymphoma (EBV+ DLBCL) of the elderly is a provisional entity included in the 2008 WHO Classification of Lymphomas. Diagnostic criteria include age >50 years, DLBCL morphology and EBV expression in lymphomatous cells. However, these criteria are evolving as several patients younger than 50 years of age without immunodeficiency have been diagnosed. Also, a specific cut-off for the percentage of EBV expression has not been defined. Lymphopenia, monocytosis, neutrophil-to-lymphocyte ratio (NLR) and the lymphocyte-to-monocyte ratio (LMR) have been reported prognostic in patients with DLBCL and other lymphomas. The goal of this retrospective study is to evaluate these novel prognostic factors in a cohort of EBV+ DLBCL patients.

Methods: Between January 2002 and January 2014, all patients meeting criteria for EBV+ DLBCL were included in the analysis. Patients with evidence of immunosuppression were excluded. All cases were positive for the presence of EBV-encoded RNA (EBER) by in situ hybridization, and CD20 and/or PAX-5 expression by immunohistochemistry. Clinical and pathological data were reviewed retrospectively. Lymphopenia was defined as an absolute lymphocyte count <1000/uL, and monocytosis as an absolute monocyte count >600/uL. NLR was defined as the division of the absolute neutrophil count over the absolute lymphocyte count. LMR was defined as the division of the absolute lymphocyte count over the absolute monocyte count. Patient's biopsies were analyzed for the expression of BCL6, CD10, CD30 and MUM-1/IRF4. Overall survival (OS) curves were calculated using the Kaplan-Meier method, and compared using the log-rank test.

Results: A total of 45 EBV+ DLBCL patients are included in this study. The median age was 68.9 years (range 25-95 years). Four patients (9%) were younger than 50 years. The male:female ratio was 2.2:1. B symptoms occurred in 60%, ECOG >1 in 55%, advanced stage (III/IV) in 58%, and elevated LDH levels in 44%. The International Prognostic Index (IPI) score was 0-2 in 39% and 3-5 in 61% of the patients. Lymphopenia was seen in 35%, and monocytosis in 69% of patients. Extranodal disease occurred in 23 patients (51%): stomach (n=3), tonsil (n=3), pleura (n=2), palate (n=2), cecum (n=2), bone marrow (n=2), ileum (n=1), bone (n=1), skin (n=1), lung (n=1), meninges (n=1), soft tisue (n=1) and peritoneum (n=1). Based on the Hans classification, 76% had non-germinal center origin. Ki67 expression was >80% in 53% of the patients. Chemotherapy was not received in 25% of the cases due to poor performance status. The Oyama score was: 0 factors (13%), 1 factor (47%), and 2 factors (40%) with 2-year OS of 86%, 49% and 27%, respectively (p=0.016). Lymphopenia was an adverse prognostic factor for OS (HR 3.23, 95% CI 1.24-8.43; p=0.017) in the univariate analysis. The 2-year OS for EBV+ DLBCL patients with lymphopenia was 24%, and 55% for patients without lymphopenia. Monocytosis, NLR and LMR were not significantly associated with OS in our cohort of EBV+ DLBCL patients.

Conclusions: Lymphopenia, defined as an absolute lymphocyte count <1000/uL, appears as a prognostic factor for OS in EBV+ DLBCL.