Post-transplant lymphoproliferative disorder after solid organ transplantation: a comprehensive review

Post-transplant lymphoproliferative disorder (PTLD) is a serious and heterogeneous neoplastic complication of solid organ transplantation (SOT), arising in the setting of sustained pharmacological immunosuppression. This review is specifically focused on PTLD in the SOT setting; PTLD after hematopoietic stem cell transplantation (HSCT) differs substantially in risk factors, pathogenesis, and management, and is beyond the scope of this work. PTLD incidence ranges from 1% to 20%, depending on the grafted organ, with the highest per-procedure rates in intestinal and multiorgan transplants, and the highest absolute case burden in kidney recipients, given transplant volume. PTLD demonstrates a bimodal temporal distribution: an early, predominantly EBV-driven peak at 12-24 months post-transplant, and a late peak at 5-10 years, with a higher proportion of EBV-negative cases. Contemporary evidence suggests a possible decline in early EBV-positive PTLD with improved surveillance, while late-onset EBV-negative PTLD is stable or increasing. EBV establishes latency type III in PTLD-associated B cells, driving proliferation through viral oncoproteins LMP1 and EBNA2. The latency program correlates with histological category and clinical behavior: latency III predominates in early lesions and polymorphic PTLD with strong EBER expression, whereas EBV-negative monomorphic PTLD displays greater genomic complexity, resembling de novodiffuse large B-cell lymphoma (DLBCL), with frequent TP53 mutations and chromosomal gains. The WHO 2022 and ICC 2022 frameworks define four histopathological categories-non-destructive lesions, polymorphic PTLD, monomorphic PTLD, and classic Hodgkin lymphoma (CHL)-type PTLD-each with distinct morphological, immunophenotypic, EBER, and clonality profiles that directly determine treatment intensity. Management follows a sequential strategy: immunosuppression reduction (ISR) as the mainstay first step, followed by rituximab, then chemoimmunotherapy (R-CHOP) for refractory or high-risk disease, with PET/CT-based response assessment using Lugano criteria at each decision point. Tabelecleucel, an allogeneic EBV-specific cytotoxic T-lymphocyte (CTL) product, represents the first approved cellular therapy for refractory EBV-positive PTLD. Immune checkpoint inhibitors carry unacceptably high organ rejection rates and are not recommended for standard PTLD management. Key unmet needs include standardizing EBV surveillance thresholds for preemptive intervention, biomarker-driven risk stratification (PD-L1, LMP1, tumor EBV viral load), and prospective multicenter data on novel immunotherapy combinations in immunosuppressed transplant recipients.