Case Report: Diagnostic pitfall and biomarker-guided therapy in CD20-negative Epstein-Barr virus-positive diffuse large B-cell lymphoma.

De novo CD20-negative Epstein-Barr virus-positive diffuse large B-cell lymphoma, not otherwise specified (EBV+ DLBCL, NOS), is a rare subtype of DLBCL. CD20 loss complicates both diagnosis and treatment by limiting anti-CD20 antibody use and broadening differential diagnosis. We report a case where comprehensive immunophenotypic and molecular analyses enabled accurate diagnosis. A biomarker-driven strategy combining CD30-targeted therapy and PD-1 blockade achieved a complete metabolic response. This case underscores the importance of biology-based individualized treatment in EBV-associated lymphomas and the need for prospective studies of CD20-independent strategies in high-risk patients.