Posttransplant Lymphoproliferative Disease in Pediatric Liver Transplantation

Abstract

The incidence, risk factors, and outcome of posttransplant lymphoproliferative disease (PTLD) were examined for 298 children undergoing liver transplantation. The overall incidence of PTLD was 8.4% (25 of 298). Intensity of immunosuppression was found to be a major risk factor for the development of PTLD. Cyclosporine and tacrolimus when used as primary immunosuppression were associated with the development of PTLD in 4.3% and 6.6% of cases (P=NS). OKT3 and tacrolimus, when used as rescue therapy for steroid-resistant rejection, were associated with a comparable increase in the risk of developing PTLD (10.9% and 11.1%, P=NS). Patients requiring both OKT3 and tacrolimus to treat refractory rejection were at significantly increased risk for PTLD (28.1% vs. 4.3% or 6.6%, P<0.0001). PTLD was more common in patients who received transplants for Langerhans cell histiocytosis relative to other indications for transplantation (66% vs. 8.4%, P=0.0005). The data also support an association between primary Epstein-Barr virus (EBV) infections following transplantation and the development of PTLD. While only three patients were EBV seropositive before transplantation (14%), 19 patients were EBV seropositive at the time of diagnosis of PTLD (90%), confirming a high incidence of primary EBV infections in patients with PTLD (21 patients had both pre- and posttransplant EBV serologies). In this series, PTLD was associated with a mortality rate of 60%, and 12 of the 15 patients who died had persistent tumor at the time of death. Five of the 13 patients rendered disease-free developed ductopenic rejection. Of the four with severe liver dysfunction, two have undergone successful retransplantation and are alive without evidence of PTLD. In conclusion, intense immunosuppression using OKT3 and tacrolimus as rescue agents was associated with a significant increase in the incidence of PTLD. Primary EBV infection after transplantation further accentuated this risk. Independent of these risk factors, patients with Langerhans cell histiocytosis were at significantly increased risk for PTLD. The identification of high-risk patients should allow the development of protocols to screen patients for primary EBV infections and early indications of PTLD, as well as the institution of preemptive antiviral and antitumor therapies.

Successful Renal Retransplantation after Post-Transplant Lymphoproliferative Disease

“…Our results, together with nine previously reported cases (Table 2), seem to indicate that renal retransplantation can safely be proposed for patients who have previously experienced monoclonal B-cell PTLD, especially if the lymphoma was located in the kidney allograft. Interestingly, organ retransplantation has been successfully achieved in PTLD following liver and intestinal transplantation (12)(13)(14)(15).…”

Management of the pediatric liver transplant patient

“…Polymorphic PTLD has a better prognosis than monomorphic disease. 96 True monoclonal disease proven by gene rearrangement studies appears to have a worse outcome, 97 although even some of these children may respond to withdrawal of immunosuppression.…”

Atypical Lymphoproliferative Diseases

“…65,85,112,113 Over 90% of early (fewer than 6 months post transplantation) PTLDs are EBV positive, whereas late (more than 2 years) PTLDs tend to be EBV negative. The incidence of PTLD is highest in the first year after transplantation when EBV CTL immunity is lowest.…”

“…And finally, the ex vivo generation of EBV-specific CTL used clinically has generally utilized only EBV-seropositive donors, which represents expansion of memory EBV-specific CTL. 19 The highest risk individuals are EBV-seronegative individuals, 61,62,104,112,113 and generation of EBV-specific CTL from an EBV-naïve individual, though possible, is technically challenging. There is one report of infusion of ex vivo generated EBV-specific T cells in a lung recipient with PTLD, which was well tolerated and effective.…”