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.