What role does Epstein–Barr virus (EBV) play in the pathogenesis of post-transplantation lymphoproliferative disorders?
Post-transplantation lymphoproliferative disorders (PTLDs) are defined as lymphomas that occur after transplantation. Although lymphoproliferative disorders were initially reported to be a rare complication of transplantation, observations during the past decade have shown that they are not uncommon and are associated with poor outcomes. Read the latest NEJM Review Article here.
Q: What types of solid-organ transplants are associated with the highest incidence of PTLD?
A: In the adult population, recipients of kidney transplants have the lowest incidence of PTLD (0.8 to 2.5%), followed by recipients of pancreatic transplants (0.5 to 5.0%), liver transplants (1.0 to 5.5%), heart transplants (2.0 to 8.0%), lung transplants (3.0 to 10.0%), and multiorgan and intestinal transplants (≤20%).
Q: What histologic lesions comprise the PTLDs?
A: The standard for the diagnosis of PTLD is histopathological examination and categorization according to the World Health Organization (WHO) 2017 classification, which distinguishes six subclasses of PTLD: three types of nondestructive PTLD (plasmacytic hyperplasia, infectious mononucleosis–like PTLD, and florid follicular hyperplasia), polymorphic PTLD, monomorphic PTLD (B-cell, T-cell, or natural killer–cell types), and classic Hodgkin’s lymphoma–like PTLD. An association with Epstein-Barr virus (EBV) infection is observed in almost all cases of nondestructive PTLD, more than 90% of cases of polymorphic and Hodgkin’s lymphoma–like PTLD, and approximately half of monomorphic cases.
Morning Report Questions
Q: What role does EBV play in the pathogenesis of PTLD?
A: Cases of PTLD were originally considered to be uniformly EBV-driven, but according to reports published in the past decade, up to 50% of PTLD cases that develop after solid-organ transplantation are not associated with EBV. The pathogenesis of EBV-positive cases is clear, with an iatrogenic, immunosuppression-related decrease in T-cell immune surveillance as the major contributing factor. By expressing different latent antigens during B-cell development, EBV incorporates the normal B-cell program promoting proliferation and transformation of these cells. In normal circumstances, these antigens elicit a T-cell response that destroys the majority of EBV-infected B cells. This immunologic response is diminished in transplant recipients, resulting in B-cell transformation and development of lymphomas. The pathogenesis of EBV-negative cases of PTLD is less clear. Proposed hypotheses include hit-and-run EBV infection (i.e., EBV infection that initiates the pathogenesis of PTLD and then disappears), infection with cytomegalovirus or another, unknown virus, persistent antigen stimulation by the graft, and long-term immunosuppression.
Q: Are there genetic differences between EBV-positive and EBV-negative PTLD?
A: Molecular-genomic studies of the diffuse large B-cell lymphoma subtype have revealed clear differences between EBV-positive and EBV-negative PTLD. Whereas EBV-negative cases share many genomic and transcriptomic features with diffuse large B-cell lymphoma in immunocompetent patients, EBV-positive cases have fewer genomic abnormalities, an observation that is consistent with the development of many EBV-positive cases very soon after transplantation. The more complex copy-number aberrations observed in EBV-negative cases reflect the typical accumulation of genomic alterations seen in diffuse large B-cell lymphoma in immunocompetent patients. From a genomic point of view, EBV-negative PTLD may therefore be considered a lymphoma occurring coincidentally in a transplant recipient. Although the molecular genetic separation between EBV-positive and EBV-negative cases of PTLD is clear, the clinical consequences of EBV status are less clear. Tumor EBV status is not prognostic or predictive with respect to treatment response in adults with PTLD. An additional clinical observation arguing against two distinct subtypes is the finding that a proportion of both EBV-positive and EBV-negative cases of PTLD respond to a reduction in immunosuppressive therapy as the sole intervention.
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