Post-transplant Lymphoproliferative Disease

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

Post-transplant malignancy 101

What are the most common type of cancers in kidney transplant recipients?

The three most common cancers are: non-melanoma skin cancers, Kaposi’s sarcoma and non-Hodgkin lymphomas. Compared to the general population, the risk of squamous cell carcinoma is 100x greater in transplant recipients. One interesting aspect about transplant recipients is that they have a much higher risk for a few specific malignancies but are not broadly predisposed to all cancers. As an example, the incidence of most common solid tumors in the general population (lung, prostate, breasts and colorectal) is only modestly increased or similar to the transplanted population. This suggests that other factors might play a role in the pathogenesis of malignancy post-transplantation.

What is the cause of increased risk of malignancies after transplantation?

There are several factors that seem to be associated with the development of malignancy after transplantation: impaired immune surveillance secondary to immunosuppression; carcinogenic factors like sun exposure; and host factors such as genetic predisposition to cancer, presence of oncogenic viral infection and prolonged dialysis.

How does a viral infection may increase the risk of malignancy?

Certain virus like EBV, HHV-8 and HPV carry viral oncogenes in their genome, which directly affect cell-cycle and apoptosis regulation. For example, HPV has the E6 oncogene that produces a protein that binds to p53, a major regulator of cell growth and tumor suppressor protein. Following E6 binding of p53, p53 is degraded, allowing unchecked cellular cycling and accumulation of chromosomal mutations without DNA repair.

Do different immunosuppressive drugs vary in their risk of post-transplant malignancy?

In general, the intensity and duration of immunosuppression therapy plays a major role in determining this risk of malignancy, since it severely disrupts the immune surveillance of cancers cells and dampen anti-viral immunity. Moreover, certain specific drugs like azathioprine and cyclosporine have been shown to directly lower the repair rate of DNA damage induced by solar UV radiation. In contrary, mTOR inhibitors have been shown to inhibit tumor growth mediated by both blockade of the PI3K-Akt-mTOR pathway, which is frequently activated in cancer, and by angiogenesis inhibition.

Compared to the general population, are there special screenings required for the kidney transplant recipient?

Since skin cancer is one of the most prevalent malignancies, recipients should be educated about their increased risk and recommended to reduce levels of sun exposure (especially between 10am and 4pm), wear protective clothing and apply sunscreen to sun-exposed areas, perform self-examinations and annual skin examinations by qualified health professional. For non-skin cancers, the KDIGO guidelines recommend solely reinforcement of the regular cancer screenings performed in the general population.

If a malignancy arise, what is the ideal approach?

The cancer should be managed with specific therapies for the particular tumor type associated with reduction and/or conversion to a mTOR inhibitor. The conversion to mTOR inhibitors have been successful in inducing complete regression of Kaposi’s sarcoma (figure) and decreasing the recurrence of skin cancers. General contraindications for conversion in kidney transplant recipients are proteinuria greater than 500mg/day and GFR less than 40 ml/min.

Gap in knowledge: we still need some prospective trials in order to determine if further cancer screening exams would be warranted in the transplant population that carries other competing risks like cardiovascular disease and infection.