Post-Transplant Lymphoproliferative Disorder

Loss of T-cell surveillance over EBV

• EBV infects B cells and persists lifelong in memory B cells expressing a restricted, immunologically quiet latency programme. Control depends entirely on EBV-specific cytotoxic T cells
• Transplant immunosuppression — particularly T-cell-depleting therapy — removes that control. Infected B cells then switch to latency III, expressing the full complement of latent proteins (EBNA-1 to 6, LMP-1, LMP-2), which are powerfully growth-promoting
• LMP-1 mimics constitutively active CD40, driving NF-κB; LMP-2A mimics tonic B-cell receptor signalling. Together they provide continuous proliferation and survival signals
• Latency III is highly immunogenic — precisely why it is normally suppressed and why restoring T-cell function can eradicate it
• Over time, somatic mutations accumulate (including MYC rearrangement and TP53 loss), the proliferation becomes clonal and immunologically autonomous, and it will no longer regress with reduced immunosuppression. This progression from reversible to irreversible is the reason early recognition matters
• EBV-negative PTLD (roughly 20-40%, and disproportionately late-onset) has a different, less well-defined pathogenesis, resembles sporadic lymphoma more closely, and responds less well to reduction of immunosuppression

• EBV serostatus mismatch — a seronegative recipient receiving an organ from a seropositive donor (D+/R−) — is the single strongest risk factor, raising risk many-fold. This is why children are at highest risk: most are EBV-naive at transplantation
• Intensity and duration of immunosuppression, more than any specific agent. T-cell-depleting agents — antithymocyte globulin, alemtuzumab, muromonab (OKT3) — carry the highest risk. Calcineurin inhibitors and azathioprine contribute
• Organ transplanted, tracking the amount of lymphoid tissue transferred and the immunosuppression required:
• Highest: intestinal and multivisceral, then lung and heart-lung
• Intermediate: heart, pancreas
• Lowest: kidney and liver
• Time since transplantation: incidence peaks in the first year (predominantly EBV-positive), with a second, lower, sustained late risk (more often EBV-negative)
• Recipient age — bimodal, with children and older adults at higher risk
• CMV mismatch or CMV disease
• Haematopoietic stem cell transplantation: T-cell-depleted grafts, unrelated or mismatched donors, and treatment of graft-versus-host disease. In HSCT the proliferating cells are usually of donor origin, whereas in solid organ transplantation they are usually of recipient origin

• Fever, night sweats, weight loss and malaise — nonspecific, and easily attributed to infection in a patient who is expected to get infections
• Infectious mononucleosis-like syndrome with fever, pharyngitis, tonsillar enlargement and lymphadenopathy, particularly in children with early EBV-positive disease
• Lymphadenopathy, which may be localized or generalized
• Extranodal disease is the rule rather than the exception — a key difference from ordinary lymphoma:
• Gastrointestinal tract: abdominal pain, obstruction, bleeding, perforation
• Central nervous system: focal deficits, seizures, altered cognition — more frequent than in immunocompetent lymphoma
• Lung, liver, kidney, skin and bone marrow
• Involvement of the allograft itself, presenting as graft dysfunction that mimics rejection — a rising creatinine in a kidney transplant, worsening gas exchange in a lung transplant, abnormal liver enzymes in a liver transplant
• Tonsillar and adenoidal enlargement in children, sometimes with airway obstruction
• Cytopenias from marrow involvement or haemophagocytosis
• Elevated LDH and, frequently but not invariably, a rising blood EBV DNA load

• Tissue biopsy is essential and cannot be skipped. It is the only way to distinguish PTLD from rejection and from infection, and the three have incompatible treatments. Where the allograft is the affected organ, biopsy it
• Histology and classification under the WHO scheme:
• Non-destructive PTLD — plasmacytic hyperplasia, infectious mononucleosis-like, florid follicular hyperplasia. Polyclonal, architecture preserved
• Polymorphic PTLD — architecture effaced, a full range of B-cell maturation present, often oligoclonal
• Monomorphic PTLD — meets criteria for a defined lymphoma, most commonly diffuse large B-cell lymphoma; also Burkitt, plasma cell neoplasms and, less often, T- or NK-cell types
• Classic Hodgkin lymphoma-type PTLD — the least common
• EBER in situ hybridization on tissue is the standard method for demonstrating EBV within the lesion; immunohistochemistry for LMP-1 supports it
• Immunophenotyping and clonality studies (immunoglobulin gene rearrangement) to establish lineage and clonality
• Blood EBV DNA load by PCR — used for serial surveillance in high-risk recipients (particularly D+/R− and paediatric patients), where a rising load prompts pre-emptive reduction of immunosuppression. It is a screening and monitoring tool, not diagnostic on its own: a raised load may occur without PTLD, and EBV-negative PTLD occurs with a normal load
• Staging: PET-CT (highly useful in PTLD), CNS imaging and lumbar puncture given the frequency of CNS involvement, bone marrow biopsy, and LDH
• Exclude infection — CMV, other opportunistic pathogens — which can coexist and mimic

Reduction of immunosuppression comes first

• Reduction of immunosuppression (RIS) is first-line for essentially all PTLD and can produce complete remission on its own, particularly in early, polymorphic, EBV-positive disease
• Typical approach: reduce or withdraw the antimetabolite, reduce calcineurin inhibitor dose substantially, and maintain corticosteroids at a low dose. The degree of reduction is balanced against the consequences of losing the graft — a life-threatening lymphoma justifies accepting rejection risk, and this is an explicit conversation with the transplant team
• The critical caveat: RIS alone is unlikely to control monomorphic, monoclonal or EBV-negative disease, and waiting on it in an aggressive lymphoma wastes time
• Response is assessed at 2-4 weeks; failure to respond triggers escalation

Escalation

• Rituximab for CD20-positive disease is the next step, and is highly effective. A risk-stratified sequential approach — rituximab first, with chemotherapy added only for those failing to achieve complete response — was validated in the PTLD-1 trial and reduces toxicity for responders
• Chemotherapy, usually R-CHOP, for monomorphic disease not responding to RIS and rituximab, or for aggressive disease at presentation. Toxicity and infection risk are higher than in immunocompetent patients, and growth factor and antimicrobial support are needed
• EBV-specific cytotoxic T lymphocytes — adoptive cellular therapy restoring the missing immune surveillance directly — are effective in EBV-positive disease, with tabelecleucel an allogeneic, off-the-shelf product available in some jurisdictions. This is the most mechanistically elegant treatment available, and is particularly relevant after HSCT
• Surgery or radiotherapy for localized disease, for CNS disease, or for complications such as perforation or obstruction
• CNS PTLD is treated as primary CNS lymphoma, with high-dose methotrexate-based therapy

A persistent misconception worth stating plainly

• Antiviral drugs (aciclovir, ganciclovir) do not treat established PTLD. They inhibit the viral DNA polymerase during lytic replication, whereas PTLD is driven by latent EBV in proliferating B cells, which does not express the viral thymidine kinase or replicate its genome by that pathway. Their role, if any, is in prophylaxis, and even that is contested

Prevention

• EBV viral load surveillance in high-risk recipients, with pre-emptive reduction of immunosuppression on a rising load
• Minimizing overall immunosuppression and avoiding unnecessary T-cell-depleting induction
• Consideration of EBV serostatus in donor-recipient matching where feasible

• Allograft rejection and graft loss as a direct consequence of reducing immunosuppression — the central, unavoidable trade-off of treatment. In kidney transplantation the fallback is dialysis; in heart, lung or liver transplantation there may be no fallback, which makes the calculus far harder
• Graft failure from PTLD infiltration of the transplanted organ itself
• Gastrointestinal perforation, obstruction and haemorrhage, sometimes precipitated by rapid tumour response
• CNS disease, which carries a poor prognosis and requires blood-brain-barrier-penetrant therapy
• Overwhelming infection — patients are immunosuppressed by transplantation, by the disease, and by its treatment simultaneously
• Progression from reversible polymorphic disease to irreversible monomorphic lymphoma where diagnosis or escalation is delayed
• Chemotherapy toxicity amplified by transplant comorbidity: renal impairment from calcineurin inhibitors compounding methotrexate clearance, cardiac limitations for anthracyclines, and profound cytopenias
• Hepatitis B reactivation after rituximab, and prolonged hypogammaglobulinaemia
• Haemophagocytic lymphohistiocytosis in EBV-driven disease
• Relapse, and the risk of a second PTLD after subsequent re-transplantation
• Mortality remains substantial, particularly in monomorphic, CNS, late-onset and EBV-negative disease

• PTLD is a spectrum, from polyclonal infectious-mononucleosis-like hyperplasia to monoclonal aggressive lymphoma — usually diffuse large B-cell lymphoma. Where the patient sits determines the treatment
• Reduction of immunosuppression is first-line therapy and may cure early, polymorphic, EBV-positive disease outright. No other lymphoma is treated by stopping a drug
• The mechanism is loss of EBV-specific cytotoxic T-cell surveillance, allowing EBV-infected B cells to enter latency III with LMP-1 mimicking constitutive CD40 signalling
• The EBV-seronegative recipient of a seropositive donor organ (D+/R−) is at highest risk — which is why children are the highest-risk group, being mostly EBV-naive
• Risk tracks with immunosuppression intensity and lymphoid tissue transplanted: intestinal and lung transplants highest, kidney and liver lowest. T-cell-depleting induction (ATG, alemtuzumab) is a major risk factor
• Antivirals do not treat established PTLD — aciclovir and ganciclovir act on lytic replication, and PTLD is driven by latent EBV
• PTLD in the allograft mimics rejection, and the two require opposite changes in immunosuppression. Biopsy before acting
• Extranodal and CNS involvement are far more common than in immunocompetent lymphoma — image the brain
• EBV viral load is for surveillance and pre-emptive intervention, not for diagnosis. A raised load can occur without PTLD, and EBV-negative PTLD occurs with a normal load. EBER on tissue is the standard
• Early-onset disease (first year) is usually EBV-positive; late-onset is more often EBV-negative, behaves like sporadic lymphoma, and responds less well to reduction of immunosuppression
• Rituximab first, chemotherapy for non-responders — the risk-stratified sequential approach spares toxicity in patients who respond
• EBV-specific cytotoxic T lymphocytes restore the missing surveillance directly and are the most mechanistically targeted option available
• In solid organ transplantation the proliferating cells are usually of recipient origin; after stem cell transplantation they are usually donor-derived