Abstract: Purpose: Epstein?Barr virus?positive (EBVþ) 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 EBVþ DLBCL, independent of age, treated with rituximab combined with CHOP (R-CHOP) in developed Western countries. Experimental design: A large cohort (n ¼ 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 EBVþ DLBCL from patients with EBV-negative (EBV) DLBCL. Genetic aberrations were rarely seen. NF-kB p50, phosphorylated STAT-3, and CD30 were more commonly expressed in EBVþ DLBCLs (P < 0.05). Significant differences in survival were not observed in patients with EBVþ DLBCL versus EBV DLBCL. However, CD30 expression combined with EBV conferred an inferior outcome. GEP showed a unique expression signature in EBVþ DLBCL. GSEA revealed enhanced activity of the NF-kB and JAK/STAT pathways independent of molecular subtype. Conclusions: The clinical characteristics of patients with EBVþ versus EBV DLBCL are similar and EBV infection does not predict a worse outcome. EBVþ DLBCL, however, has a unique genetic signature. CD30 expression is more common in EBVþ DLBCL and, consistent CD30 and EBV is associated with an adverse outcome. Clin Cancer Res; 20(9); 2338?49. 2014 AACR.

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