EBV and post-transplant lymphoproliferative disorder: a complex relationship

Post-transplant lymphoproliferative disorders (PTLD) are a heterogeneous category of disease entities occurring in the context of iatrogenic immune suppression. Epstein-Barr virus (EBV)-driven B-cell lymphoproliferation represents the prototype of quintessential PTLD, which includes a range of histologies named nondestructive, polymorphic, and monomorphic EBV+ diffuse large B-cell lymphoma (DLBCL) PTLD. While EBV is associated with the majority of PTLD cases, other drivers of lymphoid neoplasia and lymphoma transformation can occur-with or without EBV as a codriver-thus underlining its vast heterogeneity. In this review, we discuss the evolution in contemporary PTLD nomenclature and its emphasis on more precise subcategorization, with a focus on solid organ transplants in children, adolescents, and young adults. We highlight the fact that patients with quintessential EBV-associated PTLD-including those with monomorphic DLBCL-can be cured with low-intensity therapeutic approaches such as reduction in immune suppression, surgical resection, rituximab monotherapy, or rituximab plus low-dose chemotherapy. There is, though, a subset of patients (approximately 30%-40%) with quintessential PTLD that remains refractory to lower-intensity approaches, for whom intensive, lymphoma-specific chemotherapy regimens are required. Other forms of monomorphic PTLD, which are as diverse as the spectrum of defined lymphoma entities that also occur in immunocompetent patients, are rarely cured with lower-intensity therapies and appear to be better categorized as posttransplant lymphomas. These distinct scenarios represent the variations in lymphoid pathology that make up a conceptual framework for PTLD consisting of lymphoid hyperplasia, neoplasia, and malignancy. This framework serves as the basis to inform risk stratification and determination of evidence-based treatment strategies.