<aside> 💡 PTLD may present with a wide spectrum of clinical manifestations, ranging from isolated hepatitis, lymphoid interstitial pneumonitis, and meningoencephalitis to an IM-like syndrome with peripheral adenopathy, fever, and/or hepatitis.

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From the life cycle of EBV infection to PTLD development.

Epstein–Barr virus (EBV) enters the body through the laryngopharynx and penetrates the mucosal epithelium. EBV infects submucosal B cells, forcing viral gene transcript expression as the infected cell passes through the lymph node germinal centre and matures. Some latently infected memory B cells leave the germinal centre and persist, whereas occasionally some infected memory cells evolve to plasma cells that shed newly assembled free virions into saliva. The B cell blasts are kept from proliferating by EBV-specific CD8‑expressing cytotoxic T cells (CTLs). However, extrinsic and nonspecific immunosuppression, as received by transplant recipients, can impair the CTL-mediated suppression, thereby allowing B cell proliferation and eventual post-transplant lymphoproliferative disease (PTLD) development. The different viral latency stages and associated characteristic protein expression patterns are shown.

Development of PTLD after Solid-Organ Transplantation

• Recipients of solid organ transplants receive immunosuppressive therapy to prevent allograft rejection. Immunosuppressive therapy can be divided into induction therapy, administered in the peritransplantation period, and maintenance therapy, started at the time of transplantation and typically continued during the lifetime of the allograft.
• The induction regimen mainly consists of high dose glucocorticoids and monoclonal or polyclonal T cell–depleting and T cell–nondepleting antibodies.
• Maintenance therapy often includes low dose glucocorticoids, calcineurin inhibitors (cyclosporine and tacrolimus), antimetabolic agents (azathioprine and mycophenolate mofetil), and mammalian target of rapamycin (mTOR) inhibitors (everolimus and sirolimus).
• During the posttransplantation period, immunosuppressive therapy may be increased to manage episodes of allograft rejection (red bars). During this course of ongoing immunosuppression, EBV infection (both primary infection and reactivation) may lead to uncontrolled lymphocyte proliferation. In addition, genomic aberrations may occur, promoting lymphomagenesis.
• Early detection of an increased viral load in EBV driven lymphomas offers an opportunity to try to preempt the development of PTLD by reducing immunosuppression, with or without other interventions. If this strategy fails or is not performed (preemptive strategies cannot be used in EBV negative disease), PTLD can develop.
• If PTLD is suspected, a biopsy should be performed, with pathological confirmation according to the World Health Organization (WHO) 2017 classification. In addition, accurate staging is necessary. If immunosuppressive therapy has not been reduced, this should be done promptly, in most cases followed by antilymphoma treatment.
• After completion of treatment, reduction of immunosuppression (RIS) should be continued, if possible. If rejection occurs during followup, immunosuppressive therapy should be increased.
• Eventually, most patients have progression to end stage graft failure (because of chronic allograft rejection or for other reasons). Limited experience has shown that retransplantation is feasible in patients with a history of PTLD.

• The incidence of PTLD ranges from 1% to 5% in patients undergoing renal, heart, liver, and non-T-cell–depleted HSCT to >10% in those undergoing lung, small bowel, and T cell–depleted HSCT.
  • Recipients of a non-T-cell–depleted HSCT have the lowest risk, with HSCT-PTLD occurring in <2% of patients.
• A lower chance occurs in older as opposed to younger age, sibling over cadaver donor, and single over multiple transplants.
• PTLDs commonly arise in the lymph nodes, gastrointestinal tract, liver, central nervous system and lungs.

Subtypes