Results/Discussion
Of the 152 cardiac transplant recipients reviewed at our institution between 1985-2017, three were identified to have EBV SMT. All tumors were confirmed by EBER CISH; a chromogenic in situ hybridization stain against viral RNA. Liver was the most common site of EBV SMT consistent with current pediatric reports1,3,12. In our series, the average time to diagnosis was appx 32 months (range 25-38 months) following transplant. Lui et al describes the interval between transplantation and tumor to be a mean of 42 months in pediatric patients compared with the adult population mean of 73–114 months6.
Outcomes in pediatric populations differ from current adult literature which describe EBV SMT as having excellent prognosis2,3,8. Pediatric data has shown EBV SMTs occurring in children are linked to higher mortality rates7,9. One explanation may be that children are at increased risk of primary infection with associated higher EBV viral loads post-transplant3,8. Our cohort demonstrated one case with EBV donor/recipient mismatch although she had a favorable course and remains alive today. All three patients in our series had EBV DNAemia/viremia at time of diagnosis with levels that ranged from 7,365 to 161,475 copies/mL. Stubbins demonstrated EBV SMT occurring exclusively in the pediatric cardiac transplant population despite similar numbers of EBV seronegative patients in their study who underwent liver transplant. This suggests there are risk factors other than EBV seronegatively that contribute to the development of EBV SMT. Stubbins postulated that the aggressive immunosuppression used in cardiac transplant recipients may increase the risk of developing EBV SMT. Another unique aspect of pediatric heart transplant is the surgical removal of the thymus which may result in skewed profiles of peripheral T cells leading to premature immunosenescence8.
In our series, two patients were diagnosed with EBV SMT after a known PTLD diagnosis, while the other patient presented with a primary EBV SMT. A meta-analysis by Jonigk et al shows 12/68 patients were diagnosed with PTLD prior to the development of EBV SMT. Of the 12 patients, 11 were pediatric (92%)3. Comparably, Stubbins et al showed EBV SMT occurring after primary diagnosis of PTLD in 14 of 36 cases (39%). This was observed less frequently in adults 2/51 cases (4%)8. The high association between EBV SMT and PTLD that was also seen in our cohort strongly suggests that immunosuppression plays a key role. It is well understood that EBV PTLD lymphomas are driven by latent EBV infected B-cells via latent membrane proteins (LMP), and generally occur in the initial one to two years following transplant13. Known risk factors include type of organ transplant, age, and EBV seronegativity14. Given the similar timeline of pediatric EBV SMT and PTLD occurring post-transplant in association with high immunosuppressive states, we may be able to apply those same risk factors when trying to stratify patients at highest risk for developing EBV SMT.
Current therapies for the treatment of EBV SMT include resection when possible, although this can be limited due to the multi-focal nature of disease at diagnosis. Other therapies include reduction of immunosuppression alone or in conjunction with surgery, chemotherapy, immunotherapy, and the use of MTOR inhibitors such as sirolimus. In our cohort, one patient received CAR-T therapy. While not curative, it resulted in stabilization of her disease, and she remains alive today. The remaining cases, for which reduction in immunosuppression, surgery and imatinib were used, resulted in death from progressive disease. Treatment for EBV SMT is still poorly understood because the mechanism for EBV cell entry and tumorigenesis has yet to be identified. Although the study by Tan et al did not reach statistical significance, their work demonstrated improved mortality in patients who were switched from cyclosporine-based immunosuppression to mTOR inhibition after SMT diagnosis7. Similarly, in our cohort, case one demonstrated a positive response to Sirolimus, although to what degree is difficult to conclude given she had multiple therapeutic interventions.