Prevalence and Clinical Implications of Epstein–Barr Virus Infection in De Novo Diffuse Large B-Cell Lymphoma in Western Countries

Abstract

Purpose Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) of the elderly is a variant of DLBCL with worse outcome that occurs most often in East Asian countries and is uncommon in the Western hemisphere. We studied the largest cohort of EBV+ DLBCL, independent of age, treated with R-CHOP in developed Western countries. Experimental design A large cohort (n=732) of patients with DLBCL treated with R-CHOP chemotherapy are included from the multicenter Consortium. This study group has been studied for expression of different biomarkers by immunohistochemistry, genetic abnormalities by fluorescent in situ hybridization and mutation analysis, genomic information by gene expression profiling (GEP) and gene set enrichment analysis (GSEA). Results Twenty-eight patients (4.0%) were positive for EBV with a median age of 60.5 years. No clinical characteristics distinguished patients with EBV+ DLBCL from patients with EBV-negative DLBCL. Genetic aberrations were rarely seen. NF-κB p50, phosphorylated STAT-3 and CD30 were more commonly expressed in EBV+ DLBCLs (P<.05). Significant differences in survival were not observed in patients with EBV-positive DLBCL versus EBV-negative DLBCL. CD30 co-expression appeared to confer inferior outcome although statistical significance was not achieved. GEP showed a unique expression signature in EBV-positive DLBCL. GSEA revealed enhanced activity of the NF-κB and JAK/STAT pathways. Conclusions The clinical characteristics of patients with EBV+ versus EBV-negative DLBCL are similar and EBV infection does not predict a worse outcome. EBV+ DLBCL, however, has a unique genetic signature. CD30 expression is more common in EBV+ DLBCL and, when present, is associated with an adverse outcome.

EBV‐positive diffuse large B‐cell lymphoma of the elderly: 2016 update on diagnosis, risk‐stratification, and management

“…In this study, a notable adverse prognostic factor was lymphopenia defined as an absolute lymphocyte count of <1.0 3 10 9 /L. Of potentially clinical implication is the finding that expression of CD30 is not only increased but also associated with a worse OS in patients with EBV-positive DLBCL [16]. In this study, EBER1/CD301 DLBCL patients had worse outcome than EBER1/CD30-or EBER-/CD301 DLBCL patients.…”

“…In a multicenter consortium study on DLBCL patients treated uniformly with R-CHOP, the response and survival rates of 28 patients with EBV-positive DLBCL was compared with 695 EBVnegative patients, and showed no statistical differences [16]. Interestingly, there were no differences in clinical presentation between the two groups.…”

“…Gene expression profiling shows that EBV-positive DLBCL is molecularly distinct from EBVnegative DLBCL. The gene set enrichment assay (GSEA) demonstrated an enhanced Toll-like receptor signaling pathway (which has many similarities to the NF-jB pathway) and the JAK-STAT pathway [16]. Clonal rearrangement of the immunoglobulin gene is seen in approximately 60% of cases, and a subset of cases shows rearrangements of the T-cell receptor [14].…”

Evaluation of NF-κB subunit expression and signaling pathway activation demonstrates that p52 expression confers better outcome in germinal center B-cell-like diffuse large B-cell lymphoma in association with CD30 and BCL2 functions

“…8 Although several groups have shown NF-κB expression in DLBCL, many of these studies have lacked cutoff values for respective NF-κB proteins or did not study all five subunits. More importantly, they did not specifically exclude cases with infection by Epstein-Barr virus, which is known to activate the NF-κB pathway 26 or had relatively small cohort of patients. 16 In this study, expression of p50, p52, p65, RELB, and c-Rel was observed in 34%, 12%, 20%, 14% and 23% of patients, respectively, and expression of p50/p65, p50/c-Rel and p52/RELB dimers was seen in 11%, 11% and 3% of patients, respectively.…”

“…Such observation has been found in several former and current publications. 18,21,22,24,[26][27][28] Expression of NF-κB Subunits in DLBCL Nuclear expression with or without cytoplasmic expression of each marker in lymphoma cells was considered positive (Figure 1a). Excluding 36 cases with tissue exhaustion, a total of 278 (56%) cases expressed at least one of NF-κB subunits (Table 1).…”