Post-transplant Lymphoproliferative Disease

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Although the term Post-transplant Lymphoproliferative Disease (PTLD) encompasses all lymphoproliferative disorders post transplant, it generally refers to extra-nodal B-cell lymphomas due to Ebstein-Barr virus (EBV) infection. PTLD is a B-cell disease caused by iatrogenic T-cell dysfunction: in people with normally functioning immune systems, activated T-cells regulate B-cell proliferation, whereas in the transplant setting pharmacological T-cell inhibition permits proliferation of EBV-infected B-cells. PTLD is the commonest post-transplant malignancy in children, the second most common in adults and is the commonest cause of cancer-related post-transplant mortality

PTLD requires a high index of suspicion and must be on your radar. Early disease is often easily managed by lowering immunosuppression, but late detection is a disaster. Clinical presentations vary from a benign infectious mononucleosis syndrome to a severe malignant lymphoproliferative disorder; 3 distinct clinical syndromes are described:

1. Polyclonal B-cell proliferation with malignant transformation, widespread disease, and multiorgan involvement. This accounts for 30% of patients and presents within weeks of transplant. You’re less likely to miss this presentation, as patients are often closely monitored during this time.
2. The majority of cases (over 50%) present as an infectious mononucleosis within a year of transplant. This is due to a benign polyclonal proliferation of B cells. This is easily missed, which is a tragedy as this presentation is very responsive to lowering immunosuppression.
3. A minority present late with a monoclonal B-cell proliferation, extra-nodal disease, and visceral involvement late post-transplant.

    Diagnosis is by tissue biopsy (preferably excisional biopsy), and is based on histological, cytological and microbiological evidence: lymphoproliferation that disrupts tissue architecture, oligoclonal or monclonal cell lines and the presence of EBV in the tissue. One group that deserves particular attention is EBV –ve recipients who receive EBV +ve kidneys (EBV D+/R-). This small, single-center study of 34 such patients teaches us a lot about PTLD and makes the case for closely monitoring EBV D+/R- recipients:

    1. Of those EBV D+/R- recipients who were not monitored (n=6), 50% developed PTLD and lost their transplants
    2. Of the remainder, 60% developed EBV viremia and had their immunosuppression reduced; only 1 developed PTLD. This underscores how efficacious reducing immunosuppression can be.
    3. 6/20 with persistent viremia received rituximab; none got PTLD or lost their transplant. This needs to be replicated but is very encouraging.

    Here are some PTLD management pearls:

    1. The graft is a commonly affected site. Isolated allograft dysfunction can be a presentation PTLD, as is allograft dysfunction developing after an increase in immunosuppression.
    2. Check EBV in all flu-like illnesses; doubly so if lymphadenopathy is present; triply so if during the first post transplant year.
    3. Antivirals don’t work. EBV do not express thymidine kinase, the target of ganciclovir/acyclovir
    4. Reducing immunosuppression does work, if instituted early. A typical regimen would be to cut CNI by 50%, discontinue MMF/AZA, and continue the same or 50% less steroid
    5. Main risk factor is the EBV D+/R- recipient, and they need monitoring for EBV infection. Other risk factors include extremes of age, heavier immunosuppression especially anti-lymphocyte antibody use and CMV infection

    PTLD: Preventable with Timely Lowering of Drugs

    1 comment

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