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-positive (EBV(+)) 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 rituximab combined with CHOP (R-CHOP) in developed Western countries.

Experimental design: A large cohort (n = 732) of patients with DLBCL treated with R-CHOP chemotherapy is included from the multicenter consortium. This study group has been studied for expression of different biomarkers by immunohistochemistry, genetic abnormalities by FISH 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 (EBV(-)) DLBCL. Genetic aberrations were rarely seen. NF-κB p50, phosphorylated STAT-3, and CD30 were more commonly expressed in EBV(+) DLBCLs (P < 0.05). Significant differences in survival were not observed in patients with EBV(+) DLBCL versus EBV(-) DLBCL. However, CD30 expression combined with EBV conferred an inferior outcome. GEP showed a unique expression signature in EBV(+) DLBCL. GSEA revealed enhanced activity of the NF-κB and JAK/STAT pathways independent of molecular subtype.

Conclusions: The clinical characteristics of patients with EBV(+) versus EBV(-) 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, consistent CD30 and EBV is associated with an adverse outcome. Clin Cancer Res; 20(9); 2338-49. ©2014 AACR.

Figure 1. Impact of Epstein-Barr virus (EBV) infection on overall and progression-free survival of patients with diffuse large B-cell lymphoma (DLBCL)

A and B. In the training set (n=500), overall survival (OS) and progression free survival (PFS) were not significantly different between EBV+ DLBCL and EBV− DLBCL (P=.189 and P=.687, respectively). C. Lack of difference in OS between EBV+ DLBCL and EBV− DLBCL was reproduced (P=.849) in the validation set (n=232). D. Combining the training set and validation set, OS was not significantly different between EBV+ DLBCL and EBV− DLBCL (P=.192). E and F. EBV positivity in DLBCL also failed to show any significant difference in cases of germinal center B-cell (GCB) versus activated B-cell (ABC) phenotype, OS (P=.650 and P=.290, respectively).

Figure 2. Impact of CD30 expression and Epstein-Barr virus (EBV) infection on overall survival and progression-free survival of diffuse large B-cell lymphoma (DLBCL) patients

A and B. Compared to patients with EBER− CD30− DLBCL, patients with EBER⁺ CD30⁻ patients did not have significantly different OS (P=.560) and PFS (P=.343). C and D. Co-expression of EBER and CD30 in DLBCL showed worse OS (P=.014) compared to patients with EBER− CD30− DLBCL. However, PFS was not significantly different (P=.257) between the two groups. E and F. Worse outcome was observed in patients with EBER⁺ CD30⁺ DLBCL compared with EBER⁺ CD30⁻ DLBCL in OS (P=0.042), but not in PFS (P=.145). G and H. Patients with EBER⁺ CD30⁺ DLBCL have significantly worse OS and PFS compared to patients with EBER− CD30⁺ DLBCL (P<.001 and P=.001, respectively).

Figure 3. Gene expression profiling and gene set enrichment assay (GSEA) in EBV+ diffuse large B-cell lymphoma (DLBCL)

A. A unique gene expression signature was found in EBV+ DLBCL compared with EBV-negative DLBCL. B. DLBCLs with co-expression of EBER and CD30 showed a gene expression signature distinct from cases with EBER⁺ CD30⁻. C and D. GSEA validated enhanced activity of NF-κB pathway and JAK/STAT pathway in EBV+ DLBCL.